UEG President, Matthias Löhr, and Vice-President, Joost Drenth, discuss the latest in gastroenterology
The Microbiota in Gastric Cancer: What Do We Know? Infographic:
Editorial Board 07 Welcome
Foreword
Congress Review
10 Review of the 32nd United European Gastroenterology (UEG) Week 2024, 12th–15th October 2024
Congress Features
19 New Frontiers in Inflammatory Bowel Disease Monitoring
Katrina Thornber
23 Controversies in the Management of Colorectal Neoplasia
Aleksandra Zurowska
Abstract Reviews
28 Hot- Versus Cold-Snare Endoscopic Mucosal Resection for NonAmpullary Duodenal Lesions: Consolidating the Cold Revolution into Clinical Practice
Beany et al.
30 Improving Colorectal Polyp Optical Diagnosis with Computer Aided Characterisation: A Real-Time Comparison with Endoscopists and Its Impact as a Training Tool
Hossain et al.
33 Patients with Endoscopy-Negative Heartburn or Epigastric Pain Syndrome Are Not Different and Benefit from Poliprotect after PPI Deprescription
Corazziari et al.
35 Abstract Highlights
Congress Interviews
44 Matthias Löhr
51 Joost Drenth
Interviews
55 Jean-Frederic Colombel
61 Michael Camilleri Infographics
68 Optimise Eosinophilic Oesophagitis (EoE) Care
70 The Microbiota in Gastric Cancer: What Do We Know? Articles
72 Gut Bacterial Microbiome Profiles Associated with Colorectal Cancer Risk: A Narrative Review and Meta-Analysis
Russ et al.
84 Cytomegalovirus/Herpes Simplex Virus Co-infection with Associated Oesophageal Stricture in a Young Immunocompetent Woman: A Case Report and Literature Review
Godfrey and Patwardhan
90 Infective Endocarditis Following Selective Angioembolisation for Lower Gastrointestinal Tract Bleeding: A Case Report
Bai et al.
"Beyond education, a key pillar of UEG is research and clinical excellence"
Editorial Board
Editor-in-Chief
Prof Sorin Barbu
“Iuliu Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
President of the Romanian Pancreatic Club since 2007, Councillor in the Executive Committee of the European Federation –International Society for Digestive Surgery (EFISDS), and member of the UEG Public Affairs Committee and of the European Pancreatic Club since 2002.
Prof Dan Dumitrascu
"Iuliu Hațieganu" University of Medicine and Pharmacy, Romania
Dr Oliver Grundmann
University of Florida, USA
Prof Christoph Gubler
Stadtspital Zürich, Switzerland
Dr Hasan Haboubi
Swansea University, UK
Prof Najib Haboubi
Spire Hospital, UK
Dr Waseem Hamoudi
Royal Hospital, Jordan
Dr Devika Kapuria
Washington University, USA
Dr Panagiotis Kasapidis
Central Clinic of Athens, Greece
Prof Milan Lukáš
Charles University, Czech Republic
Dr Venkata Pawan Kumar Lekharaju
Wirral University Teaching Hospital NHS Trust, UK
Aims and Scope
EMJ Gastroenterology is an open access, peer-reviewed eJournal committed to publishing the highest quality medical research concerning all aspects of digestive system function and disease to help advance development of this field.
The journal is published annually, six weeks after the United European Gastroenterology (EUG) Week, providing the latest developments in the field, and features highlights from this congress, alongside interviews with experts in the field, reviews of abstracts presented at the congress, as well as indepth features on congress sessions. The journal also covers advances within the clinical and pharmaceutical arenas by publishing sponsored content from congress symposia, which is of high educational value for healthcare professionals. This undergoes rigorous quality control checks by independent experts and the in-house editorial team.
EMJ Gastroenterology also publishes peer-reviewed research papers, review articles, and case reports in the field. In addition, the journal welcomes the submission of features and opinion pieces intended to create a discussion around key topics in the field and broaden readers’ professional interests. The journal is managed by a dedicated editorial team that adheres to a rigorous double-blind peer-review process, maintains high standards of copy editing, and ensures timely publication.
EMJ Gastroenterology endeavours to increase knowledge, stimulate discussion, and contribute to a better understanding of digestive system disorders. Our focus is on research that is relevant to all healthcare professionals. We do not publish veterinary science papers or laboratory studies not linked to patient outcomes. We have a particular interest in topical studies that advance knowledge and inform of coming trends affecting clinical practice in gastroenterology.
Further details on coverage can be found here: www.emjreviews.com
Editorial Expertise
EMJ is supported by various levels of expertise:
• Guidance from an Editorial Board consisting of leading authorities from a wide variety of disciplines.
• Invited contributors who are recognised authorities in their respective fields.
• Peer review, which is conducted by expert reviewers who are invited by the Editorial team and appointed based on their knowledge of a specific topic.
• An experienced team of editors and technical editors.
Peer Review
On submission, all articles are assessed by the editorial team to determine their suitability for the journal and appropriateness for peer review.
Editorial staff, following consultation with either a member of the Editorial Board or the author(s) if necessary, identify three appropriate reviewers, who are selected based on their specialist knowledge in the relevant area.
All peer review is double blind. Following review, papers are either accepted without modification, returned to the author(s) to incorporate required changes, or rejected.
Editorial staff have final discretion over any proposed amendments.
Submissions
We welcome contributions from professionals, consultants, academics, and industry leaders on relevant and topical subjects. We seek papers with the most current, interesting, and relevant information in each therapeutic area and accept original research, review articles, case reports, and features.
We are always keen to hear from healthcare professionals wishing to discuss potential submissions, please email: editorial.assistant@emjreviews.com
To submit a paper, use our online submission site: www.editorialmanager.com/e-m-j
Submission details can be found through our website: www.emjreviews.com/contributors/authors
Reprints
All articles included in EMJ are available as reprints (minimum order 1,000). Please contact hello@emjreviews.com if you would like to order reprints.
Distribution and Readership
EMJ is distributed through controlled circulation to healthcare professionals in the relevant fields across Europe.
Indexing and Availability
EMJ is indexed on DOAJ, the Royal Society of Medicine, and Google Scholar®; selected articles are indexed in PubMed Central® .
EMJ is available through the websites of our leading partners and collaborating societies. EMJ journals are all available via our website: www.emjreviews.com
Open Access
This is an open-access journal in accordance with the Creative Commons Attribution-Non Commercial 4.0 (CC BY-NC 4.0) license.
Congress Notice
Staff members attend medical congresses as reporters when required.
All information obtained by EMJ and each of the contributions from various sources is as current and accurate as possible. However, due to human or mechanical errors, EMJ and the contributors cannot guarantee the accuracy, adequacy, or completeness of any information, and cannot be held responsible for any errors or omissions. EMJ is completely independent of the review event (UEG Week 2024) and the use of the organisations does not constitute endorsement or media partnership in any form whatsoever. The cover photo is of Vienna, Austria, the location of UEG Week 2024.
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Welcome
Dear Readers,
It is a great pleasure to welcome you to the 2024 issue of EMJ Gastroenterology, bringing you all the latest advancements in the field and essential highlights from this year’s United European Gastroenterology (UEG) Week, held in Vienna, Austria.
One of the key topics in gastroenterology this year has been the worrying increase in mortality rates and rising incidence of earlyonset colorectal cancer across Europe, which necessitate the implementation of prevention strategies and enhanced screening initiatives to ensure early detection. It is thus encouraging seeing initiatives such as that of The Austrian Society for Gastroenterology and Hepatology, the Austrian Cancer Aid Society, and other stakeholders calling for a standardised, nationwide screening programme for colorectal cancer, covering a significant gap in preventative healthcare policies. It would be great to see more countries that might lack screening strategies follow suit, in order to help improve patient outcomes for this potentially fatal disease.
Against this backdrop, we are excited to share this issue, where you can find extensive coverage of many such pertinent topics and emerging trends in the field.
I would like to close by thanking our Editorial Board, contributors, and peer reviewers for their invaluable expertise in bringing together this high-quality array of content. We eagerly anticipate your continued engagement through article submissions and feedback, as we collectively strive to elevate the quality of gastroenterology care.
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Evgenia Koutsouki Editor
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Foreword
I am delighted to introduce to you the latest edition of EMJ Gastroenterology, which encloses a variety of peer-reviewed articles, abstracts, interviews with specialty leaders, and a comprehensive review of United European Gastroenterology (UEG) Week 2024, held in Vienna, Austria between the 12th–15th October. Experts from over the globe gathered at this leading international congress to share the latest advances in the field, bringing innovation, education, and clinical excellence to the forefront of gastroenterology.
EMJ had the pleasure of interviewing UEG President Matthias Löhr, expert in pancreatology, and Vice President Joost Drenth, specialist in autoimmune liver diseases, who both share the latest advances in their field and provide key insights into the mission and future of UEG. Coverage from UEG Week 2024 also includes two important features discussing new frontiers in inflammatory bowel disease monitoring, and addressing controversies in the management of colorectal neoplasia.
The peer-reviewed articles selected for this issue cover a range of hot topics in gastroenterology, including a review and meta-analysis of gut bacterial microbiome profiles associated with colorectal cancer risk from Russ et al.
In an insightful case report, Bai et al. present a rare complication of selective angioembolisation for lower gastrointestinal tract bleeding. Additionally, Godfrey and Patwardhan raise awareness to herpes virus and cytomegalovirus co-infection as a potential cause of oesophageal stricture.
This issue also brings you an insightful infographic reviewing the current landscape of the microbiota in gastric cancer. Finally, don’t miss our exclusive interviews with renowned gastroenterology experts JeanFrederic Colombel and Michael Camilleri.
Experts from over the globe gathered at this leading international congress to share the latest advances in the field
I would like to take this opportunity to thank all of the contributors in this issue, including peer-reviewers and the Editorial Board, for their support. I hope you enjoy reading the journal.
Professor Sorin Barbu
"Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
UEG WEEK 2024
Beyond education, a key pillar of UEG is research and clinical excellence
Review of United European Gastroenterology (UEG) Week 2024 Congress Review
THE sixth time, United European Gastroenterology (UEG) Week returned to the dazzling city of Vienna, Austria, gathering over 11,000 participants from 114 countries across the globe.
Inaugurating the opening plenary of the 32nd UEG Week, UEG President Matthias Löhr and UEG Scientific Committee Chair Julia Mayerle extended warm words of welcome to a packed hall. With research visibility as a key priority for UEG, Mayerle proudly announced that 700 moderated poster sessions were presented this year, among a staggering 3,800 abstracts, a record for UEG.
Marlies Schijven, Amsterdam UMC, the Netherlands, delighted the audience with her ingenious talk ‘Serious Gaming in GI Disease: Playfully Preparing Generation Z’, which provided a fresh perspective on how to educate the next generation of gastroenterologists. Nowadays, the average young person in the USA spends 10,000 hours gaming by the age of 21 years, only 24 hours less than time spent in a classroom in middle and high school, explained Schijven. Quoting Albert Einstein, she stated that “play is the highest form of research,” and medical video games are a clever and innovative way to educate gastroenterologists. Serious gaming and gamification are emerging as the latest training technologies, and they are already proving their teaching effectiveness, stated Schijven, especially when combined with virtual reality. She urged the audience
to foster understanding and collaboration between generations, explaining that only this concerted effort can truly transform the field of research.
Beyond education, a key pillar of UEG is research and clinical excellence, and prizes are awarded each year to the best five submitted abstracts to celebrate the people behind the research. This year, the award-winning abstracts spanned a variety of topics, from oesophageal disease to inflammatory bowel disease and immunology, showcasing the multidisciplinarity of UEG. Awardees Wentao Shao, Elaine Kilgour, Anne M. van der Waaij, Pim Stougie, and Arno R. Bourgonje were invited to the stage, followed by a talk from Bourgonje, who presented his abstract on pre-diagnostic antibody signatures for Crohn’s disease and ulcerative colitis.
The ceremony continued with the prestigious UEG Research Prize, which was awarded this year to Enrique de-Madaria, Balmis General University Hospital, Alicante, Spain
Serious gaming and gamification are emerging as the latest training technologies
for the WATERLAND trial, which evaluates normal saline versus lactated Ringer’s solution for acute pancreatitis resuscitation. With patients recruited from 47 centres, 18 countries, and five continents, this is now the randomised controlled trial on acute pancreatitis with the most patients, and across the most countries.
Matthias H. Tschöp, Helmholtz Munich, Germany, then delivered an insightful talk on the immense potential of gut hormone co-agonists, which are revolutionising the field of obesity and metabolic syndrome. According to the WHO, 2.8 million people die each year as a result of being overweight or obese. GLP-1 receptor agonists are now responding to this unmet clinical need, explained Tschöp, and while obesity is not close to being ‘cured’ yet, these drugs are bringing us one step closer to overcoming the obesity pandemic. This could have significant implications for other diseases, potentially reducing the incidence of Type 2 diabetes, cardiovascular disease, kidney disease, dementia, and more.
Finally, the ceremony came to a close with the UEG 2024 Lifetime Achievement Award, which went to Paul Fockens, Amsterdam UMC, the Netherlands, a world-renowned pioneer in endoscopy and endosonography. Fockens has been heavily involved in postgraduate training worldwide, has served as past President of UEG from 2016–2019, and was elected an Honorary Fellow for the American, Japanese, and European Society of Gastroenterology. As a leading figure in education, innovation, and clinical excellence, Fockens set the stage for a week of high-quality, cutting-edge research in gastroenterology.
Read on for more in-depth coverage from UEG Week 2024, and stay tuned for UEG Week 2025, which will take place in Berlin, Germany, from 4th–7th October 2025!
Fockens set the stage for a week of high-quality, cutting-edge research in gastroenterology
Pre-diagnostic Antibody Signatures Identified in Inflammatory Bowel Disease
AN AWARD-winning abstract presented at UEG Week 2024 has identified distinct antibody responses in Crohn's disease (CD) and ulcerative colitis (UC) that occur years before the disease is diagnosed. This finding could mark a crucial step towards developing preventive strategies for inflammatory bowel disease (IBD), a chronic, debilitating condition that currently requires lifelong medical treatment or surgery.
IBD is characterised by complex immunological changes, yet the specific antibody patterns involved in the early stages of disease development have remained elusive. While over 300 IBDspecific antibodies have been identified, this study aimed to provide an in-depth profile of systemic antibody responses before and after IBD onset.
By focusing on preclinical biomarkers, Arno Bourgonje, Icahn School of Medicine at Mount Sinai, New York, USA, and colleagues, hoped to shift the treatment paradigm from managing established disease to preventing its onset, an approach that has shown success in other autoimmune conditions like rheumatoid arthritis and Type 1 diabetes.
The research, part of the Lifelines Cohort Study in the Netherlands, involved 167,000 participants. The study identified 178 individuals who developed IBD during a median follow-up time until diagnosis of 3.9 years. Most individuals newly developed UC (n=123; 69.1%), followed by CD (n=44; 24.7%), and undetermined IBD (IBD-U; n=11; 6.2%). Using a cuttingedge technique known as phage-display immunoprecipitation sequencing (PhIP-Seq), the researchers profiled antibody responses against 344,000 antigens, including microbial, food, and immune antigens.
A total of 5,174 antibody responses were observed in 5–95% of participants. Notably, 59 antibodies were found to differ significantly between pre- and post-diagnosis stages, with 14 antibody signatures previously reported in established IBD. Following diagnosis,
patients with IBD showed reduced antibody responses against Epstein-Barr virusassociated peptides, such as Epstein-Barr nuclear antigen-1 and capsid protein V26, as well as reduced antibodies against varicella-zoster virus, herpes simplex virus type 1, and noroviruses.
In contrast, individuals who developed CD exhibited increased pre-diagnosis responses to bacterial flagellins (notably from Lachnospiraceae and pathogenic Legionella bacteria).
Individuals who developed CD exhibited increased pre-diagnosis responses to bacterial flagellins
Patients with UC showed elevated antibody responses to viral (human adenovirus C, enteroviruses B/C) and bacterial (pneumococcal histidine triad proteins) pathogens post-diagnosis compared to pre-diagnosis.
This research represents the first comprehensive, high-resolution analysis of antibody changes during the transition from preclinical to established IBD, offering a potential avenue for early detection and prevention of CD and UC.
59 antibodies were found to differ significantly between preand post-diagnosis stages, with 14 antibody signatures previously reported in established IBD
Austrian Experts Call for Nationwide Colorectal Cancer Screening
LEADING Austrian health experts gathered at UEG Week 2024 to push forward the implementation of a nationwide, quality-assured colorectal cancer (CRC) screening programme starting at age 45 years. This call comes in response to alarmingly high mortality rates and a rising incidence of CRC across Austria and Europe.
CRC mortality rose by Between 2000–2019,
CRC cases in Europe increased by 33% 19%
CRC remains one of the deadliest forms of digestive cancer, and statistics from the UEG White Book 2 reveal a worrying trend. Between 2000–2019, CRC cases in Europe increased by 33%, and CRC mortality rose by 19%. In Austria, over 5,000 new cases were diagnosed in 2019, resulting in more than 2,500 deaths. In 2019, more than 20,000 women and over 23,000 men were living with CRC. Primary causes include lifestyle factors, including poor diet, smoking, alcohol consumption, and lack of physical activity.
Unlike other European countries such as Germany, which has offered widespread CRC screening for over two decades, Austria currently lacks a national screening initiative. Despite consensus on the benefits of early detection, the introduction of such a programme has been delayed due to differing interests within the Austrian healthcare system and varying approaches of federal states.
The Austrian Society for Gastroenterology and Hepatology (ÖGGH), the Austrian Cancer Aid Society, and other stakeholders are united in their call for a standardised, nationwide screening programme for CRC. Experts emphasise that early detection through routine screening, particularly colonoscopy, is the most effective way to prevent CRC or detect it in its early, more treatable stages.
“If polyps, which are potential precursors to CRC, are detected and removed during a colonoscopy, CRC can be prevented. This is a major advantage compared to other cancers. As a medical society, we urgently call for the nationwide implementation of a screening programme for everyone aged 45 to 75, as this could save many lives,” stated Harald Hofer, President of ÖGGH.
New Imaging Technique Shows Promise for Personalised Oesophageal Cancer Treatment
A TOP abstract presented at UEG Week 2024 explored a breakthrough imaging technique aimed at improving treatment outcomes for patients with locally advanced oesophageal cancer (EC).
Currently, patients with EC are treated with a combination of neoadjuvant chemo(radio) therapy (nCRT) followed by surgery, but only 16–43% achieve a complete pathological response. To improve these odds, researchers are investigating the use of immune checkpoint inhibitors (ICI) that target PD-1 and PD-L1 proteins, but effective patient selection for ICI therapy remains challenging.
This new study tests a novel imaging method, ultrasound-guided quantitative fluorescence molecular endoscopy, designed to visualise PD-L1 protein levels in tumours. By using the fluorescently labelled ICI drug durvalumab-680LT, the technique allows for the visualisation of PD-L1 expression, offering a way to better select patients for ICI therapy. The aim is to assess both the safety and effectiveness of the technique in monitoring drug distribution across cancerous tissues before and after nCRT.
By using the fluorescently labelled ICI drug durvalumab-680LT, the technique allows for the visualisation of PD-L1 expression
Fifteen EC patients scheduled for nCRT have been enrolled in the study so far, divided into different dose groups receiving 4.5 mg or 15 mg of durvalumab-680LT, or no dose as a control. A final group of patients will receive 25 mg of the drug.
Results so far are promising: fluorescence signal intensities were higher in tumour biopsies compared to healthy oesophageal tissue in both the 4.5 mg and 15 mg dose cohorts, indicating that durvalumab-680LT successfully targeted tumour tissue. Mucosal and ultrasound-guided spectroscopy gave similar results, with higher signals in tumour tissue both in vivo and ex vivo compared to healthy tissue. Furthermore, a broad range of fluorescence signals were observed within tumours, suggesting variability in PD-L1 expression among patients.
So far, the procedure has been welltolerated, with no serious adverse effects reported. Further analysis will determine how well this technique correlates with traditional PD-L1 staining methods, and its potential to improve patient selection for ICI treatment. If successful, this innovative approach could guide more effective, personalised treatments for patients with EC in the future.
New Study Links Stress to Accelerated Colorectal Cancer Growth
NEW research, presented by Qing Li, Sichuan University of China, at UEG Week 2024, has revealed that chronic stress can accelerate the progression of colorectal cancer (CRC) by disrupting the balance of gut microbiota, specifically targeting bacteria vital to the body's immune response.
The study sheds light on how stress-induced changes in the gut can promote tumour growth, suggesting new preventive and therapeutic strategies against CRC. The researchers found that stress impacts gut bacteria, particularly reducing beneficial types within the Lactobacillus genus. Lactobacillus plays a key role in supporting the immune system, specifically by helping CD8+ T cells, which are crucial in fighting tumour growth.
In the study, when the researchers eliminated gut bacteria in mice using antibiotics, tumour progression was exacerbated, especially under chronic stress. However, supplementing with Lactobacillus in stressed subjects showed a reduction in tumour formation, underscoring its potential as a therapeutic target in CRC management.
The team conducted faecal microbiota transplantation to assess the effects of gut microbiota on tumour growth, finding that Lactobacillus plantarum, a strain of Lactobacillus, influences bile acid metabolism in a way that enhances CD8+ T cell function. This discovery suggests that restoring Lactobacillus could
strengthen immune defences against CRC. Surprisingly, tests showed that Lactobacillus requires specific substances within the gut to activate CD8+ T cells, suggesting the need for a natural gut environment for optimal effectiveness.
The study’s implications point to the positive impact Lactobacillus-based therapies could offer as a novel approach, especially when combined with traditional cancer treatments, for individuals dealing with chronic stress. This approach could have particular significance, given CRC’s status as one of the most common cancers and leading causes of cancer-related death in Europe. The next phase of research will involve analysing faecal and tumour samples from CRC patients, aiming to establish whether reductions in Lactobacillus levels correspond with higher stress levels and weakened immune response.
The study sheds light on how stress-induced changes in the gut can promote tumour growth
Novel Procedure May Eliminate Insulin Dependency in Type 2 Diabetes
PIONEERING research presented at UEG Week 2024 has revealed a new treatment approach for Type 2 diabetes (T2D) that could dramatically reduce, or even eliminate, the need for insulin therapy.
The first-inhuman study involved 14 participants aged 28–75 years, with BMIs ranging from 24–40 kg/m²
Over 422 million people globally live with T2D, with most patients relying on insulin therapy to manage their blood sugar levels. However, insulin therapy often leads to side effects like weight gain, making diabetes management more challenging. The new treatment aims to offer a viable alternative.
The first-in-human study involved 14 participants aged 28–75 years, with BMIs ranging from 24–40 kg/m². Each patient underwent a novel procedure called ReCellularisation via Electroporation Therapy (ReCET), an endoscopic treatment that uses electroporation to ablate the duodenal mucosa and improve the body’s sensitivity to endogenous insulin. After the procedure, patients followed a 2-week liquid diet before being started on semaglutide, which was gradually increased to a weekly dose of 1 mg.
At the 6- and 12-month follow-ups, 12 out of 14 participants (86%) had stopped using insulin, and they maintained good blood sugar control. At the 24-month mark, HbA1c levels remained below 7.5% for these
patients. The treatment was well-tolerated, with 93% of participants reaching the maximum dose of semaglutide, although one experienced nausea.
“Unlike drug therapy, which requires daily medication adherence, ReCET is compliance-free, addressing the critical issue of ongoing patient adherence in the management of T2D. In addition, the treatment is disease-modifying: it improves the patient’s sensitivity to their own (endogenous) insulin, tackling the root cause of the disease, as opposed to currently available drug therapies, that are at best disease-controlling,” stated lead author Celine Busch, Amsterdam UMC, the Netherlands.
Encouraged by these results, the researchers are planning to launch larger randomised controlled trials to further validate the findings. The EMINENT-2 trial is now ongoing, with the addition of a sham procedure and mechanistic assessments to better understand how ReCET works.
An Innovative Obesity Treatment: Nanoparticles to Target Fat Absorption
A NOVEL approach to tackle obesity has been developed by researchers, in which an innovative nanoparticle system inhibits an enzyme called Sterol Oacyltransferase 2 (SOAT2) in the small intestine, subsequently reducing the body’s capacity to absorb fat.
This groundbreaking research was presented at UEG Week 2024, showcasing a breakthrough in obesity treatment, and offers a potential avenue for preventing diet-induced obesity.
Despite extensive research in the field of fat metabolism, effective methods to inhibit intestinal fatty acid absorption have not yet been defined. Therefore, researchers have developed a revolutionary nanoparticle system designed to deliver small interfering RNAs (siRNA) directly to the small intestine. These siRNAs reduce SOAT2 expression, thereby inhibiting fat absorption without affecting other metabolic processes. In pre-clinical trials, mice who received the nanoparticle therapy absorbed significantly less fat and were prevented from developing obesity, compared to untreated mice, even when on a high-fat diet. Alongside these promising results, this strategy offers the added benefits of being non-invasive and low in toxicity.
The study elucidated the mechanism by which SOAT2 regulates fat absorption, whereby inhibiting SOAT2 in the intestine promotes the degradation of CD36, a fattransport protein, via cellular stress and recruitment of E3 ligase RNF5. Unlike livertargeted SOAT2 inhibition, which has been associated with hepatic fat accumulation, this intestine-specific approach avoids such risks affecting the liver, thus enhancing treatment safety.
Mice who received the nanoparticle therapy absorbed significantly less fat and were prevented from developing obesity
The study’s findings indicate that this targeted therapy may be a promising alternative to clinical obesity treatment. Future research will focus on validating these results in larger animal models to confirm the nanoparticle system's safety and efficacy, with the long-term goal of clinical application in humans. By directly addressing fat metabolism and diet-related weight gain, this new therapy could reshape the landscape of obesity treatment.
New Frontiers in Inflammatory Bowel Disease Monitoring
THE GLOBAL health burden of inflammatory bowel disease (IBD) is increasingly prevalent in today’s world, partly due to unhealthy lifestyle choices and growing obesity rates. The remitting and relapsing nature of IBD means treatment is complicated and non-linear. Coupled with the complex interactions between genetic and lifestyle factors, a streamlined approach to treatment is yet to be defined. Nevertheless, there have been huge advancements in the field, with several key publications paving the way in IBD research. Experts at United European Gastroenterology (UEG) Week 2024 highlighted several of the latest key advancements, and hinted at what’s to come for IBD management in the coming years.
MODERN INFLAMMATORY BOWEL DISEASE MONITORING
Robert Hirten, Icahn School of Medicine at Mount Sinai, New York, USA, began with a forward-thinking approach to IBD management. In a world driven by technology, non-invasive and wearablebased monitoring is an exciting new frontier in medicine.
The current state of disease monitoring in IBD has two key features. First, care is primarily received in clinical settings, with patients required to make frequent visits to their clinician and attend further appointments for blood tests, stool tests, endoscopies, and imaging. Second, current monitoring in IBD is cross-sectional. At an appointment, the clinician assesses the patient at a single point in time, despite IBD being a complex, chronic, and progressive disease. Thus, Hirten argued, the clinician is forced to build a complicated picture of the patient’s health with only snippets of information from each visit. This leads to delays in receiving and interpreting results, and therefore delays in changes to therapy; a challenge given the dynamic remitting and relapsing nature of IBD.
Therefore, Hirten emphasised the need to work towards a dynamic, granular, and longitudinal assessment of IBD. This would include long-term, at-home monitoring of physiological signals, blood markers, activity levels, symptoms, the exposome, and the microbiome. Hirten acknowledged that this is not a novel concept, and has already been applied to other diseases, such as the use of wearable patches for at-home glucose monitoring in patients with diabetes. Currently, the landscape of health wearables is dominated by optical sensors, such as the Apple Watch (Apple, Cupertino, California, USA) or the Fitbit (Fitbit Inc, San Francisco, California, USA), and sweat sensors, a more recent innovation on the rise.
Hirten provided examples to validate his proposal that at-home monitoring with wearable devices is the way forward. By combining machine learning algorithms with heart rate variability data, measured using optical sensors, research has shown that a wearable device can differentiate between inflammatory and non-inflammatory states in patients with IBD.1 This approach illustrates the feasibility of using wearables to identify, and potentially predict IBD flares, offering an appealing alternative to current monitoring methods that depend on invasive and inconvenient assessments.
A
wearable device can differentiate between inflammatory and noninflammatory states in patients with IBD
On the other hand, sweat sensors detect changes in electrolytes, metabolites, small molecules, proteins, and vitamins using non-invasive sweat patches. In IBD, recent research has demonstrated that sweat sensors can detect elevated expression of calprotectin in patients with active IBD, compared to those in remission, highlighting a strategy for monitoring disease activity and guiding timely interventions in IBD.2
Overall, Hirten proposed a remote monitoring paradigm in which select individuals, such as those in remission or starting a new medication, are provided with a wearable device, and the data collected are analysed to assess the likelihood of a flare-up or remission. When a specific threshold, such as the risk of a flare, is reached, both the patient and clinician would be notified, ensuring timely intervention and personalised care.
NEW DRUGS ON THE HORIZON
Sreedhar Subramanian, Cambridge University Hospital NHS Foundation Trust, UK, provided a comprehensive summary of new and upcoming developments in drug research for IBD.
Following a period of relative stagnation between 2017–2020, there has been a sudden explosion of new therapeutic agents
for IBD, particularly for ulcerative colitis, with even more in the pipeline. Notable emerging therapies include new drugs based on existing mechanisms of action, innovative strategies like combination treatments and bi-specific antibodies, as well as entirely new approaches, including cell-based therapies and microbiota modulation.
One therapeutic with a novel mechanism of action involves antibodies that target tumour necrosis factor-like cytokine 1A (TL1A), a cytokine encoded by the TNFSF15 gene, which is associated with disease susceptibility and progression. Research behind targeting TL1A has been building for almost two decades, with an emerging body of evidence implicating TL1A in the pathogenesis of IBD. Tulisokibart, a TL1A monoclonal antibody, has been shown to significantly increase the percentage of patients who achieve clinical remission.3 Similarly, the anti-TL1A antibody PRA023 has demonstrated efficacy in Crohn’s disease, where patients receiving PRA023 achieved significantly greater rates of endoscopic response and clinical remission.4
Another promising therapeutic strategy involves upregulating anti-inflammatory microRNAs (miRNAs). Interest in miRNAs has surged, especially following the recent awarding of the 2024 Nobel Prize in Physiology or Medicine to Victor Ambros and Gary Ruvkun for their discovery of miRNAs and their groundbreaking work on posttranscriptional gene regulation. Currently, the medical use of microRNAs is limited to diagnostic strategies, but emerging research is expanding the landscape of possibility for miRNA-based therapeutics, although none have yet been approved.
A diet high in ultraprocessed foods has been associated with an increased risk of Crohn’s disease, but not ulcerative colitis
Hirten also touched on the recent excitement surrounding JAK inhibitors, and explained that there are more gut-selective JAK inhibitors on the horizon. However, he claimed that a “more interesting” therapeutic agent are TYK2 inhibitors. By selectively inhibiting TYK2 signalling pathways, they interfere with fewer molecular mechanisms, and therefore have a better safety profile.
Hirten concluded his talk with “a note of caution”, warning that not all therapies will come to fruition, despite the excitement they may have surrounding them. The downfall of cobitolimod, a TL9 agonist, known for its notable Phase II success, but early termination during Phase III due to lack of efficacy,5 highlights the need to be “cautiously optimistic about what the pipeline holds”. Looking ahead, Hirten identified three key research priorities: discovering new therapeutic targets, deepening our understanding of the mechanisms behind both new and existing drugs, and better understanding individual differences in treatment responses. These steps will help clinicians to select the most effective, personalised strategy for each patient.
LIFESTYLE INTERVENTIONS
Iris Dotan, Rabin Medical Center, Petah Tikva, Israel, wrapped up the meeting with “the most important lecture of this entire session”. Whilst showing appreciation for the previous talks, Dotan noted that not all patients will undergo continuous monitoring with wearables, or receive one of the many
novel drugs in the pipeline, but all patients with IBD need to address lifestyle factors. In particular, diet, smoking, psychosocial factors, and physical activity levels are considered modifiable factors with the potential to transform patient outcomes.
Doten highlighted research involving approximately 500,000 patients over 12 years that revealed how genetic and lifestyle factors are independently associated with susceptibility to Crohn’s disease and ulcerative colitis. The study also demonstrated that adherence to a favourable lifestyle, such as one that doesn’t include smoking, but has a diet rich in fruit, vegetables, and fibre, is associated with a nearly 50% reduction in risk of Crohn’s disease and ulcerative colitis, even among those high genetic risk.6
Adherence to a favourable lifestyle, such as one that doesn’t include smoking, but has a diet rich in fruit, vegetables, and fibre, is associated with a nearly 50% reduction in risk of Crohn’s disease and ulcerative colitis
Additionally, a diet high in ultra-processed foods has been associated with an increased risk of Crohn’s disease, but not ulcerative colitis, she noted.7 In another study, researchers explored the
profiles of beneficial versus pathogenic microbiome clusters in first-degree relatives of patients with Crohn’s disease. Following a Mediterranean-like diet, there were notable alterations in their microbiome, with decreased levels of Ruminococcin and Dorea, and increased levels of Faecalibacterium. 8 Additionally, the Mediterranean-like diet was linked to reduced subclinical gut inflammation, as indicated by lower faecal calprotectin levels.
Doten acknowledged the growing awareness around food avoidance and explained that despite what patients may have been told 10 years ago, being overly restrictive can harm social interactions, lead to nutrient deficiencies, altered microbial composition, fatigue, and impaired quality of life. Instead, clinicians should promote
References
1. Hirten R et al. Physiological metrics collected from wearable devices identify inflammatory and clinical inflammatory bowel disease flares. Gastroenterology. 2024;164(4):S28.
2. Shahub S et al. Continuous monitoring of CRP, IL-6, and calprotectin in inflammatory bowel disease using a perspiration-based wearable device. Inflamm Bowel Dis. 2024;DOI:10.1093/ ibd/izae054.
3. Sands BE et al. Phase 2 trial of antiTL1A monoclonal antibody tulisokibart for ulcerative colitis. N Engl J Med. 2024;391(12):1119-29.
a healthy and diverse Mediterranean diet; one that is evidence-based and avoids unnecessary restrictions.
CONCLUSION
To conclude the session, Doten offered some practical recommendations: adhering to a Mediterranean diet, minimising processed foods, screening for food restrictions and nutritional deficiencies, quitting smoking, increasing physical activity to at least 150 minutes per week, and addressing psychological comorbidities. Stating that many clinicians often overlook these modifiable factors, she advocated for the development of an effective, scalable, long-term lifestyle intervention strategy to potentially alter disease risk and progression.
4. Feagan BG et al. The anti-TL1A antibody PRA023 demonstrated proofof-concept in crohn’s disease: phase 2a APOLLO-CD study results. Journal of Crohn's and Colitis. 2023;17(Suppl 1):i162-4.
5. Clinical Trials Arena. InDex Pharmaceuticals terminates phase III cobitolimod trial. 2023. Available at: https://www.clinicaltrialsarena. com/news/index-terminates-trialcobitolimod/?cf-view. Last accessed: 1 October 2024.
6. Sun Y et al. The contribution of genetic risk and lifestyle factors in the development of adult-onset
inflammatory bowel disease: a prospective cohort study. Am J Gastroenterol. 2023;118(3):511-22.
7. Narula N et al. Food processing and risk of inflammatory bowel disease: a systematic review and metaanalysis. Clin Gastroenterol Hepatol. 2023;21(10):2483-2495.e1.
8. Turpin W et al. Mediterraneanlike dietary pattern associations with gut microbiome composition and subclinical gastrointestinal inflammation. Gastroenterology. 2022;163(3):685-98.
Controversies in the Management of Colorectal Neoplasia
AN INSIGHTFUL session presented at United European Gastroenterology (UEG) Week 2024 delved into advancements in staging, immunotherapy, and surgical techniques for colon and rectal cancers. In this, a series of experts emphasised evolving practices designed to improve colorectal cancer outcomes while preserving patient quality of life.
HOW TO PROPERLY STAGE RECTAL CANCER
Gina Brown, Imperial College London, UK, delivered a compelling talk dissecting the numerous ways of properly staging rectal cancer. Brown begun by explaining that, although we have reached a new point in the assessment of early rectal cancers, we are also in a situation where patients with early-stage rectal cancers are increasingly being offered a lot of treatment in order to preserve the rectum, with many beginning treatments with radiotherapy and total neoadjuvant therapy. This raises the question of how we can do better than that, as unnecessary treatment can lead to functional impairments, especially when applied to tumours that could be safely removed with less invasive procedures.
Brown also emphasised to radiologists that lymph node size alone does not always indicate malignancy, as most enlarged lymph nodes are not in fact malignant. However, some early features in rectal cancer that physicians should look out for, such as macroscopic discontinuous extramural vascular invasion, can result in recurrence despite a successful local excision. Another recommendation for radiologists is to assess the muscular preservation around the tumour on MRI scans rather than focusing solely
on traditional T-staging (T1, T2). If the muscularis propria is intact, the lesion may be suitable for local excision, eliminating the need for additional surgery or therapy.
She continued by highlighting that, in many cases, patients with early T1 and even some T2 tumours could avoid extensive surgery if preoperative staging accurately identified the depth of invasion and condition of the muscular layer. Current staging methods, primarily focused on assigning T1 or T2 classifications, can lead to overtreatment.
Current staging methods, primarily focused on assigning T1 or T2 classifications, can lead to overtreatment
Brown stressed that improved preoperative staging could avoid aggressive treatments such as radiotherapy, which may cause side effects like bowel dysfunction and impaired sphincter function, affecting the patient’s long-term well-being. Additionally, unnecessary preoperative treatments often prevent reversing stomas due to the effects of radiotherapy on the sphincter function and on the anastomosis. Brown then advocated that this new approach,
which relies on staging, should be based on MRI-assessed muscular preservation rather than solely on T-staging.
Brown then described ‘Proforma’, the protocol she developed, which is the recommended reporting structure for staging early rectal cancer using MRI. This entails starting by firstly stating the morphology, whether the tumour is flat, polypoidal, and mucin-containing. The second step is to measure the diameter and thickness of the lesion, and then determine if the muscular layer is intact, which would indicate potential suitability for local excision. Additionally, it is recommended to assess the degree of preservation of the mucosa, submucosa, and the muscularis propria layers at the stalk. Visible submucosa suggests an early T1 stage, which is often suitable for less invasive treatment. The lymph nodes should also be assessed for malignant characteristics, but malignancy should only be suspected if there are clear signs such as capsular breach or extra-nodal deposits. The final step includes checking for signs of tumour invasion beyond the muscular wall, as this can indicate higher risk of recurrence.
The results from the PRESERVE trial were presented, which was just launched in the UK. The trial aimed to standardise the MRIstaging technique and to determine the diagnostic accuracy of identifying rectal tumours suitable for local excision using MRI.1
So far, the results demonstrated a significant improvement in accurately identifying early rectal cancers suitable for local excision, with trained radiologists increasing their staging accuracy from 29% to over 80%. After just two focused training sessions, radiologists demonstrated improved accuracy in identifying muscular preservation.
After just two focused training sessions, radiologists demonstrated improved accuracy in identifying muscular preservation
Brown emphasised that these results will train radiologists to start looking at the MRI scans in a different way, looking at the degree of preservation rather than guessing the T stage. The trial aims to further validate this MRI-based staging approach across multiple centres in the UK.
Brown concluded her talk by sharing a compelling example of a patient who initially faced overtreatment due to staging inaccuracies: a small polyp was over-staged, leading to unnecessary surgery and a permanent change in their quality of life. With the structured MRI protocol and improved staging, this patient could have avoided major surgery and retained rectal function.
Brown reinforced the potential of MRIbased staging by describing a successful case where MRI-staging protocol was used effectively in a patient with a small, early-stage tumour who underwent local excision, avoiding unnecessary heavy treatments. This patient experienced full recovery with normal quality of life, requiring only periodic follow-ups.
TREATING ADVANCED COLORECTAL CANCERS
The session continued with a talk delivered by Eric Van Cutsem, Digestive Oncology, University of Leuven, Belgium. Van Cutsem began by providing a brief overview of treatment strategies for colon and rectal cancer. In treating metastatic colorectal cancer (mCRC), he described the use of PD antibodies and CTLA-4 antibodies as checkpoint inhibitors, particularly for patients with mismatch repair (MMR)deficient tumours, which improve survival and reduce tumour growth compared to chemotherapy alone. Van Cutsem explained that immunotherapy is increasingly becoming a standard in rectal cancer to avoid extensive surgery, particularly in cases with high operative risks.
For locally advanced, operable colon cancer (Stage II and III), Van Cutsem discussed the growing interest in immunotherapy as a preoperative strategy. He described several studies by Chalabi et al.,2 Hu et al.,3 and Ludford et al.,4 which suggest that administering immunotherapy before surgery can achieve substantial tumour regression, and even complete responses in a significant number of patients. While these findings are promising, more evidence is needed to make immunotherapy a standard replacement for surgery. Currently, minimally invasive laparoscopic surgery remains the standard for fit patients, but immunotherapy offers a potential alternative in cases with high surgical risks or older patients with right-sided tumours and large lymph node involvement.
Turning to mismatch repair-deficient rectal cancers, Van Cutsem explained that immunotherapy is also being explored
as a non-surgical alternative. Patients in advanced stages of the disease and with high operative risks may achieve tumour control without surgery using checkpoint inhibitors such as pembrolizumab and CTLA-4 antibodies.
In his concluding remarks, Van Cutsem stressed that immunotherapy offers great potential for organ preservation, especially for patients where surgery may be difficult and have a large impact on their quality of life.
TREATING EARLY RECTAL CANCER
The session was continued with a talk by Willem Bemelman, Amsterdam University Medical Center, the Netherlands, who elaborated on the topic of rectal cancer treatment from a surgeon’s point of view.
Bemelman began by acknowledging that the field is currently experiencing a growing complexity of decision-making in rectal cancer, particularly around balancing oncologic control with efforts to minimise morbidity. Bemelman explained that, historically, total mesorectal excision has been the standard approach, as it offers good cancer control.
The field is currently experiencing a growing complexity of decisionmaking in rectal cancer, particularly around balancing oncologic control with efforts to minimise morbidity
However, this leads to significant functional loss and quality of life issues. He explained that local excision offers an organpreserving option with fewer long-term effects, although it can bring challenges such as potential local recurrence and lymphatic spread.
To navigate these complex challenges, Bemelman introduced the role of multidisciplinary planning and preoperative staging with MRI to determine the best
treatment path. In this approach, significant rectal lesions would be reviewed by a multidisciplinary team to create a personalised strategy, and the decision between different resection planes such as endoscopic mucosal dissection, intramuscular dissection, or full-thickness excision would be tailored based on the lesion depth and location. Bemelman then cautioned that full thickness excision near the pelvic floor could complicate potential salvage surgery if recurrence occurs, which makes this approach more appropriate if the tumour is surrounded by a layer of mesorectum.
Bemelman then introduced a relatively novel approach to local excision, the intramuscular dissection plane. This method, previously described by Spinelli et al.,5 involves dissecting between the circular and longitudinal muscle layers, potentially enabling en bloc tumour resection while preserving the rectal structure. Bemelman then presented a patient case detailing how intramuscular dissection using a combination of gel and adrenaline injection can lift and separate the lesion, which allowed for precise excision with clear margins.
Finally, Bemelman explained the role of pathology in guiding further treatment following resection, particularly in evaluating risk factors such as deep submucosal invasion, vascular involvement, tumour differentiation, and tumour budding.
In his concluding remarks, Bemelman outlined preliminary results of the
References
1. Balyasnikova S et al. Diagnostic accuracy of high-resolution MRI as a method to predict potentially safe endoscopic and surgical planes in patients with early rectal cancer. BMJ Open Gast. 2017;4:e000151.
2. Chalabi et al. Neoadjuvant immune checkpoint inhibition in locally advanced MMR-deficient colon cancer: The NICHE-2 study. Ann Oncol. 2022;33(Suppl 7):S1389.
TESAR trial for the treatment of highrisk T1 and T2 tumours, which aimed to explore whether completion of TME surgery, adjuvant chemoradiotherapy, or surveillance can effectively manage residual risk for tumours. Early results suggest that completion surgery and adjuvant therapy reduce local recurrence; however, they are linked to higher morbidity than surveillance.6 Bemelman explained that non-surgical follow-up may be a viable option in these cases.
CONCLUSION
Across their presentations, the experts highlighted a shared commitment to refining colorectal cancer treatment by adopting more personalised, risk-based approaches. Brown’s focus on MRI staging protocols aims to reduce unnecessary treatments, preserving function and quality of life. Van Cutsem illustrated the role of immunotherapy in treating mismatch repair-deficient tumours, offering a non-surgical option for organ preservation. Bemelman emphasised precise surgical techniques and the role of pathology in guiding follow-up care to avoid overtreatment while maintaining cancer control. Together, these insights reflect a significant shift toward patient-centred, minimally invasive options that balance oncologic control with quality-of-life preservation, shaping the future of colorectal cancer management.
3. Hu H et al. Neoadjuvant PD-1 blockade with toripalimab, with or without celecoxib, in mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancer (PICC): a single-centre, parallel-group, noncomparative, randomised, phase 2 trial. Lancet Gastroenterol Hepatol. 2022;7(1):38-48.
4. Ludford K et al. Neoadjuvant pembrolizumab in localized microsatellite instability high/deficient
5. Spinelli A et al. Intermuscular dissection: the new frontier to resect early neoplastic rectal lesions? Dis Colon Rectum. 2021;64(1):17-8.
6. Borstlap WA et al. A multi-centred randomised trial of radical surgery versus adjuvant chemoradiotherapy after local excision for early rectal cancer. BMC Cancer. 2016;16:513.
Abstract Reviews
Sharing insights from United European Gastroenterology (UEG) Week 2024, the following abstract reviews spotlight exciting new developments in the field of gastroenterology.
Hot- Versus Cold-Snare Endoscopic Mucosal Resection for Non-Ampullary Duodenal Lesions: Consolidating the Cold Revolution into Clinical Practice
Authors: *Andrawus Beany,1,2,3 Enrik John Torres Aguila,1,4 Anna Agnieszka Wawer,1,5 Dauda Bawa,1 Jin Tan,1,5 Rajvinder Singh,1,5
1. Department of Gastroenterology, Lyell McEwin Hospital, Elizabeth Vale, Australia
2. Gastroenterology Institute, Rambam Health Care Campus, Haifa, Israel
3. The Ruth and Bruce Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel
4. St. Luke's Medical Center Global City, Institute of Digestive and Liver Diseases, Taguig City, Philippines
5. University of Adelaide School of Medical Sciences, Adelaide, Australia
* Correspondence to andrew@rmc.gov.il
Disclosure: The authors have declared no conflicts of interest.
Endoscopic mucosal resection (EMR) has increasingly gained acceptance as a minimally invasive intervention for the treatment of duodenal lesions.1 Despite the overall good results, there can be significant morbidity associated with performing EMR in the duodenum. Data comparing hot- and cold-snare approaches in the duodenum are currently scarce.2,3,4 The authors’ aim was to assess the efficacy and safety of hot-
snare EMR (H-EMR) versus cold-snare EMR (C-EMR) for the resection of non-ampullary duodenal lesions.
METHODS
A prospectively collected database of duodenal lesions treated using EMR at a single tertiary medical centre between 2010–2023 was performed. Patient demographics, lesion and procedure characteristics, outcomes, and adverse events were analysed using R statistical software. The lesion size and procedural time were analysed using the Mann-Whitney U test, while clinical outcomes were analysed using the Fisher’s exact test. Cost savings were calculated from the averted use of clips.
RESULTS
Seventy-one cases of non-ampullary duodenal lesions resected using the EMR technique were included (46 H-EMR; 25 C-EMR). Fifty-one lesions were resected en-bloc (31 H-EMR versus 20 C-EMR), while 20 lesions were resected in a piecemeal fashion (15 H-EMR versus 5 C-EMR). Similar demographics, lesion, and procedure characteristics were observed in both cohorts (Table 1). Technical success was 100%, and no delayed perforations occurred in either cohort. Lesions resected via H-EMR had higher rates of immediate perforation (2.2% versus 0%; p=1.0) and delayed bleeding (9.1% versus 0%; p=0.28)
compared to C-EMR. Interestingly, recurrence rates were higher in the H-EMR arm (15.2% versus 8%; p=0.70). C-EMR technique achieved a crude cost saving from clips alone of 135 USD per patient compared to the H-EMR technique.
CONCLUSION
While both cohorts demonstrated excellent technical success, there was a trend towards lower adverse events and recurrence rates, as well as cost savings, when C-EMR technique was used for non-ampullary duodenal lesions. The authors’ data consolidates previous findings and suggests an acceptable role of the cold resection
approach in the duodenum. However, larger prospective comparative trials are warranted to bolster the present evidence and shape the state of the art.
References
1. Klein A et al. Endoscopic resection of large duodenal and papillary lateral spreading lesions is clinically and economically advantageous compared with surgery. Endoscopy. 2017;49:659-67.
2. Trivedi M et al. Comparison of cold snare and hot snare polypectomy for the resection of sporadic nonampullary duodenal adenomas. Gastrointest Endosc. 2022;96:657-64.e2.
3. Repici A et al. Cold versus hot EMR for large duodenal adenomas. Gut. 2022;71:1763-5.
4. Wang H et al. Cold snare EMR for the removal of large duodenal adenomas. Gastrointest Endosc. 2023;97:1100-8.
Table 1: Patient, lesion and procedure characteristics, and clinical outcomes.
Table 1: Continued.
Haemostatic agent (e.g., Purastat [3-D Matrix Medical Technology; Tokyo, Japan] or Hemospray [Cook Medical; Bloomington, Indiana, USA])
Clinical outcomes, n (%)
APC: argon plasma coagulation; ASA: American Society of Anesthesiologists; CAST: cold-forceps avulsion with adjuvant snare-tip soft coagulation; EMR: endoscopic mucosal resection; STSC: snare-tip soft coagulation.
Improving Colorectal Polyp Optical Diagnosis with Computer Aided Characterisation: A Real-Time Comparison with Endoscopists and Its Impact as a Training Tool
Authors: *E. Hossain,1,2 M. Stefanovic,3
B. Hayee,4 E.J. Schoon,5 P.R. Aepli,6
S. Subramaniam,7 Q.E.W. van der Zander,8 P. Bhandari9
1. Queen Elizabeth Hospital, Gastroenterology, London, UK
2. Portsmouth University Hospitals NHS Trust, Gastroenterology, UK
3. Diagnostični center Bled, Gastroenterološki Oddelek, Bled, Slovenia
4. King’s College Hospital, Gastroenterology, London, UK
5. Catharina Hospital, Department of Gastroenterology and Hepatology, Eindhoven, the Netherlands
Several studies have shown that image enhancement technologies like narrowband imaging (NBI) and blue-light imaging (BLI) in expert hands can meet the Preservation and Incorporation of Valuable endoscopic Innovations
(PIVI) criteria. However, attempts at more widespread generalisation of optical diagnosis have failed due to the inability of general endoscopists to meet the established standards.1,2
CAD-EYE (Fujifilm, Tokyo, Japan) is a novel AI-driven optical diagnosis system (CADx) that has shown encouraging preliminary results in expert hands or in single centre studies.
METHODS
This is a multicentre prospective observational study comparing the performance of CAD-EYE with that of endoscopists. A total of four centres from Europe (Portsmouth, UK; London, UK; Eindhoven, the Netherlands; and Llubjana, Slovenia) were involved in the recruitment of both patients and endoscopists for this study. A total of 10 endoscopists were involved in the study from four European centres. The participating endoscopists were categorised into two groups: five experts and five non-experts.
The CAD-EYE system is a real-time convolutional neural network-based image analysis system that can detect and characterise polyps in real time.
RESULTS
The overall sensitivity, negative predictive value (NPV), and accuracy by all endoscopists were 84.4%, 74.1%, and 86.2% respectively. CAD-EYE diagnosis was recorded in 85.9% of polyps. The overall sensitivity, NPV, and accuracy of CAD-EYE were 83.0%, 72.8%, and 85.9%, respectively (p>0.05; Table 1).
Optical diagnosis was performed with high confidence by the endoscopists in 84.9% of diminutive polyps (≤5 mm), with an overall sensitivity, NPV, and accuracy of 84.6%, 74.5%, and 84.9%, respectively. CAD-EYE diagnosis was recorded in 84.2% of diminutive polyps, with an overall sensitivity, NPV, and accuracy of 83.4%, 73.2%, and 84.2%, respectively (p>0.05).
Performance of expert endoscopists versus non-experts
Table 1: Performance of CAD-EYE compared with expert endoscopists and non-experts.
The endoscopists’ optical diagnosisbased post-polypectomy surveillance interval was calculated in all patients and compared with histology-based surveillance, and it achieved a 90.7% (95% CI: 84.6–93.8%) and 92.9% (95% CI: 89.4–95.0%) concordance with British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE) guidelines, respectively. The postpolypectomy surveillance interval based on CAD-EYE diagnosis was calculated and compared with histology-based surveillance, and it achieved 91.9% (95% CI: 88.7–93.2%) and 93.4% (95% CI: 90.2–96.8%) concordance with BSG and ESGE guidelines, respectively.
An improvement in the performance of nonexperts during the study was noted, with an improvement in accuracy from 63% for the first 50 polyps to 85% for the last 50 polyps, with an associated increase in sensitivity (65% and 82%), specificity (50% and 91%), NPV (55% and 79%), and also degree of confidence (65% and 90%; p<0.05).
CONCLUSION
CAD-EYE-based diagnosis can meet PIVI criteria and help introduce a ‘resect and discard’ approach, and leave in situ strategies even in the hands of non-experts. The authors have also demonstrated an improvement in performance of non-expert endoscopists over the course of the study.
References
1. ASGE Technology Committee; Abu Dayyeh BK et al. ASGE Technology Committee systematic review and meta-analysis assessing the ASGE PIVI thresholds for adopting real-time endoscopic assessment of the histology of diminutive colorectal polyps. Gastrointest Endosc. 2015;81(3):502.e1-16.
2. Rondonotti E et al. Blue-light imaging compared with high-definition white light for real-time histology prediction of colorectal polyps less than 1 centimeter: a prospective randomized study. Gastrointest Endosc. 2019;89(3):554-564.e1.
Patients with Endoscopy-Negative Heartburn or Epigastric Pain Syndrome Are Not Different and Benefit from Poliprotect after PPI Deprescription
Authors: *Enrico Stefano Corazziari,1 Antonio Gasbarrini,2 Lucia D'Alba,3 Valeria D'Ovidio,4
Oliviero Riggio,5 Sandro Passaretti,6 Bruno Annibale,7 Michele Cicala,8 Alessandro Repici,9 Gabrio Bassotti,10 Carolina Ciacci,11 Antonio Di Sabatino,12 Matteo Neri,13 Maria Consiglia Bragazzi,5 Emanuela Ribichini,6 Giulia Radocchia,5 Paola Lovino,11 Massimiliano Marazzato,5 Serena Schippa,5 Danilo Badiali5
1. IRCCS Humanitas Research Hospital, Rozzano, Italy
Heartburn often co-exists with functional dyspepsia (FD) and pathological gastroesophageal reflux has been reported in up to 50% of FD patients without reflux symptoms.1,2 Proton pump inhibitors (PPI) are the first-line treatment for both FD and heartburn. Patients with epigastric pain syndrome (EPS), but not postprandial distress syndrome (PDS), benefit from PPI treatment.3,4 PPIs should be considered
for de-prescribing, namely in nonerosive reflux disease and FD.5 However, discontinuation of prolonged PPI therapy is followed by rebound acid hypersecretion and often by symptom recurrence.
AIMS AND METHODS
Aims are to assess whether endoscopynegative patients reporting heartburn (ENH) or EPS: 1) belong to the same clinical category, 2) benefit from the same treatment, and 3) benefit from the mucosal protective agent Poliprotect (Aboca, Sansepolcro, Italy) in the PPI deprescription phase of a randomised controlled trial.
Methods were reported in a published randomised controlled trial.6 Briefly, patients with ENH (n=81; 63% female) or EPS (n=45; 67% female) started omeprazole (20 mg once daily) for 4 weeks. At PPI withdrawal, they started Poliprotect (made from Aloe vera, Malva sylvestris, Althaea officinalis, limestone, nahcolite, Glycyrrhiza glabra, Matricaria recutita) 1.55 g tablet on demand for 4 weeks. Visual Analogue Scale (VAS) assessed daily symptom severity. A 50% VAS decrease from basal values defined a responder. Antacid was used as the rescue medicine. Post hoc analysis of data. Statistics with Wilcoxon rank sum test, and 2-sample test for equality of proportions, with continuity corrections.
RESULTS
Demography, Gastrointestinal Symptom Rating Scale (GSRS), and Gastrointestinal Quality of Life Index (GIQLY) scores did not differ between ENH and EPS. During deprescription, Poliprotect on-demand intake (mean [M] ± standard deviation [SD]) was 2.36 (2.14) tablets/day. VAS score (M [95% CI]) was 25.6 (21.0–30.2) and 25.2 (18.5–31.9) at the end of PPI treatment and 25.7 (20.8–30.5) and 21.4 (15.1–27.7) at the
end of the deprescription in ENH and EPS, respectively. Rescue medicine consumption (M±SD; not significant) was 9.1±12.1 sachets and 8.7±10.8 during the 4-week PPI treatment and 11.1±12.2 and 20.2±23.4 during the 4 weeks of deprescribing in patients with ENH and EPS, respectively. Responders’ rate was 48% and 51.3% at the end of PPI treatment and 51.3% and 55% at the end of the deprescription in ENH and EPS, respectively. Of the entire sample, 43% were non-responders at the end of PPI treatment, and 33.3% of them became responders at the end of the deprescribing phase. GSRS symptoms and GIQLY quality of life items were superimposable at the end of PPI treatment and the end of deprescription, in ENH and EPS. Treatment satisfaction was reported on the Overall Treatment Effect questionnaire by 82.8% and 85.7% at the end of PPI treatment and 81.3% and 95% at the end of the deprescription phase in ENH and EPS, respectively.
CONCLUSION
Patients that are upper endoscopynegative with heartburn and EPS cannot be distinguished by demography; accompanying gastrointestinal symptoms; gastrointestinal, physical, mental, and social items of quality of life; symptom severity; and response to treatment. The clinical use of the symptoms of heartburn, epigastric pain, or burning to differentiate patients with
typical reflux-like symptoms from EPS is not supported by the present data. It would therefore appear that patients with EPS and endoscopy-negative heartburn belong to the same clinical therapeutic category. At PPI deprescription, Poliprotect, at the mean daily intake of 2.3 tablets appears equally effective in patients with ENH and EPS in: 1) counteracting the rebound acid hypersecretion effect, 2) maintaining the beneficial effect obtained with the previous PPI treatment, and 3) reverting one-third of PPI non-responders to responders without any additional request for antacids.
References
1. Tack J et al. Prevalence of acid reflux in functional dyspepsia and its association with symptom profile. Gut. 2005;54:1370-6.
2. Xiao YL et al. Prevalence and symptom pattern of pathologic esophageal acid reflux in patients with functional dyspepsia based on the Rome III criteria. Am J Gastroenterol. 2010;105:2626-31.
3. Moayyedi P et al. Pharmacological interventions for non-ulcer dyspepsia. Cochrane Database Syst Rev. 2006;(4):CD001960.
4. Ford AC et al. Systematic review and network metaanalysis: efficacy of drugs for functional dyspepsia. Aliment Pharmacol Ther. 2021;53(1):8-21.
5. Targownik LE et al. AGA clinical practice update on de-prescribing of proton pump inhibitors: expert review. Gastroenterology. 2022;162(4):1334-42.
6. Corazziari ES et al. Poliprotect vs omeprazole in the relief of heartburn, epigastric pain, and burning in patients without erosive esophagitis and gastroduodenal lesions: a randomized, controlled trial. Am J Gastroenterol. 2023;118(11):2014-24.
The following highlights showcase late-breaking research presented at United European Gastroenterology (UEG) Week 2024, bringing you the most recent developments in the field. Topics covered include the role of statins in the management of inflammatory bowel disease, novel therapeutic targets and predictive biomarkers for Crohn’s disease, and updates on the management of constipation.
Statin Use May Reduce Severity of Inflammatory Bowel Disease
NEW research presented at UEG Week 2024 suggests that statins, commonly used to lower cholesterol, may also help ease the severity of inflammatory bowel disease (IBD).
Conducted between 2006–2020, the nationwide cohort study followed nearly 32,000 adults diagnosed with IBD, assessing whether statins, when taken after diagnosis, could reduce disease progression in ulcerative colitis (UC; n=19,788) and Crohn's disease (CD; n=12,582).
Among all participants, 1,733 patients with UC and 962 patients with CD became regular statin users after their diagnosis. Researchers excluded individuals who had been prescribed statins in the 12 months before, or 6 months after, their IBD diagnosis to ensure clear comparisons. After 1:1 propensity score matching, the authors compared statin users with non-users by applying Cox proportional hazards modelling to estimate the risk of IBD-related surgery, hospitalisations, and disease flares.
At start of follow-up, the median age for statin users with UC was 61 years, and 59 years for those with CD. After a median 3.4 years of follow-up, the team found that, in patients with UC, statin use was linked to a significant reduction in the risk of IBD-related surgeries, hospitalisations, and disease flares (marked by the need for additional treatments like corticosteroids, immunomodulators, or anti-TNF treatment). Specifically, statin users with UC had a 45% lower risk of surgery, a 32% lower risk of hospitalisations, and a 14% lower risk of flares.
For patients with CD, the benefits were less broad but still notable. Statin use was associated with a 46% reduced risk of surgery, but did not significantly impact hospitalisations or disease flares. The number of patients needed to treat to prevent one IBD-related surgery was 345 in UC, compared to 161 in CD.
Statin users with UC had a 45% lower risk of surgery, a 32% lower risk of hospitalisations, and a 14% lower risk of flares
Overall, this study highlights the potential for statins to play a role in managing IBD, especially in patients with UC. These findings open new avenues for IBD management, particularly for reducing the need for surgery.
Promising Results from Targeted Faecal Microbiota Transplantation Trial for Patients with Kidney Cancer
A GROUNDBREAKING study from Italy has revealed that targeted faecal microbiota transplantation (FMT) may enhance the effectiveness of combined immune checkpoint inhibitors (ICI) and tyrosine-kinase inhibitors (TKI) in patients with advanced renal cell carcinoma.
The preliminary findings from the TACITO trial, led by Gianluca Ianiro and presented at UEG Week 2024, indicate that using faecal matter from donors who respond positively to ICIs could significantly improve patient outcomes.
The randomised, double-blind, placebo-controlled trial involved 50 patients receiving first-line therapy with the ICI, pembrolizumab, and the TKI, axitinib. Participants were divided equally to receive either donor FMT (d-FMT) from a responder or placebo FMT (p-FMT). The study aimed to assess whether d-FMT could improve progression-free survival (PFS) at 12 months, with secondary outcomes including overall survival and objective response rate.
As of August 2024, 44 patients completed the follow-up. Results showed a 12-month PFS rate of 66.7% in the d-FMT group compared to 35.0% in the p-FMT group, a statistically significant difference (p=0.036).
The median PFS was 14.2 months for the d-FMT arm versus 9.2 months for the p-FMT arm. Notably, the objective response rate was also higher in the d-FMT group at 54%, compared to 28% in the p-FMT group.
Safety data revealed minimal adverse events, with only one patient in the p-FMT arm experiencing Grade 3 oral mucositis
Safety data revealed minimal adverse events, with only one patient in the p-FMT arm experiencing Grade 3 oral mucositis.
These promising preliminary results suggest that FMT derived from successful ICI responders may enhance treatment efficacy for advanced renal cell carcinoma, potentially transforming therapeutic strategies for patients facing this challenging cancer. Further investigation and follow-up are needed to confirm these findings and fully understand the implications of this innovative approach.
Results showed a 12-month PFS rate of
Compared to in the d-FMT group 66.7 % in the p-FMT group 35.0 %
Novel Therapeutic Targets in Perianal Fistulising Crohn's Disease
PERIANAL fistulas affect approximately 30–40% of patients with Crohn’s disease (CD), significantly impacting their quality of life and presenting substantial management challenges.
These complex lesions are often resistant to standard treatments, underscoring the need for a deeper understanding of their underlying mechanisms. A recent study presented at UEG Week 2024 involved a comprehensive analysis of three patient groups: patients with perianal fistulising CD (PCD; n=25), non-perianal Crohn's disease (NPCD; n=10), and idiopathic perianal fistulas (IPF; n=28). To gain insights into the immune response associated with PCD, biopsies were collected from various sites, including fistula tracts, openings, and rectal mucosa, during examinations under anaesthesia or colonoscopy.
Using mass cytometry and single-cell RNA sequencing, the researchers conducted an in-depth analysis of the mucosal immune cells present in these biopsies. Their findings revealed a notably skewed immune landscape in patients with PCD compared to those with NPCD and IPF. Notably, there was a significant expansion of Th17 cells within the fistula tracts, alongside IL-17producing CD8 T cells in the rectum of patients with PCD. These observations suggest a potential pathogenic role for these immune cell types in the development and persistence of perianal fistulas.
These findings highlight the pathogenic role of hyperactivated IL-17 signalling, suggesting it as a potential therapeutic target for PCD
Perianal fistulas affect approximately 30–40% of patients with Crohn’s disease
30-40 %
The study also identified altered exhaustion markers, such as CD39 and CD127, in both CD4 and CD8 T cells from patients with PCD, indicating a dysfunctional immune response that may contribute to the chronicity of the condition. Furthermore, regulatory B cells, which are crucial for maintaining immune balance and modulating gut health, were found to be dramatically diminished in PCD compared to IPF. Additionally, the results showed an increased presence of CD172+TREM1+ macrophages in PCD, cells known to be associated with resistance to anti-TNF therapies in luminal CD, suggesting that they may contribute to the treatment challenges faced by patients with PCD.
These findings highlight the pathogenic role of hyperactivated IL-17 signalling, suggesting it as a potential therapeutic target for PCD. By identifying these novel targets, this study paves the way for future research aimed at developing more effective treatment strategies for patients with perianal fistulising Crohn's disease.
Tasty & Healthy: A New Diet for Children and Young Adults with Crohn's Disease
NEW data from the Tasty & Healthy (T&H) trial presented at UEG Week 2024 has demonstrated that a flexible exclusion diet is highly effective for inducing remission in children and young adults with mild-to-moderate Crohn's disease (CD).
This showed similar clinical outcomes to exclusive enteral nutrition (EEN) while achieving higher tolerability. EEN is traditionally effective in inducing remission in CD, but due to its structured and restrictive nature, it can be difficult for patients to maintain. The T&H diet, which excludes processed food, gluten, red meat, and dairy (except plain yogurt), offers a more flexible alternative without mandatory ingredients or the need for partial enteral nutrition.
Researchers compared the tolerability and effectiveness of the T&H diet to EEN in children and young adults aged 6–25 years with mild-to-moderate CD. A total of 97 participants were randomised to T&H or EEN for 8 weeks. Both groups received weekly dietary support, and clinical data were collected at baseline and every 2 weeks. The primary outcomes included clinical remission, mucosal inflammation (mucosal healing is defined by mucosal inflammation non-invasive (MINI) index of <8 points), and inflammatory markers such as C-reactive protein, erythrocyte sedimentation rate, and calprotectin. Tolerability was assessed through adherence monitoring, judged by weekly interviews and 24-hour intake diary. Of the 83 patients who completed the trial, 41 were in the T&H group and 42 in the EEN group (mean age 14.5±3.7 years).
%
The T&H diet had significantly higher tolerability, with 88% of patients adhering to the diet compared to 52% in the EEN group.
The T&H diet offers a more flexible alternative without mandatory ingredients or the need for partial enteral nutrition
The results showed that the T&H diet had significantly higher tolerability, with 88% of patients adhering to the diet compared to 52% in the EEN group (odds ratio: 6.3; 95% CI: 2.2–22.0; p<0.001). Clinical remission rates at Week 8 were comparable between groups. With intent-to-treat analysis, remission was 56% in the T&H group versus 38% with EEN (p=0.1), and mucosal healing (a MINI index >8 ) was observed in 54% of patients in the T&H group compared to 41% in the EEN group (odds ratio: 2.6; 95% CI: 1.1–6.3; p=0.026). Both diets significantly improved inflammatory markers, with no major differences in C-reactive protein, erythrocyte sedimentation rate, or calprotectin levels between groups. Three mild adverse events were reported, two in the EEN group (nausea and dizziness), and one in the T&H group (constipation).
The results of the study demonstrate that the T&H diet is a well-tolerated, flexible dietary approach that offers similar clinical benefits to EEN for managing mild-tomoderate CD in paediatric populations, with a higher tolerability. Further research is needed to assess its long-term outcomes and broader applications.
L-carnitine Supplementation Effective for Non-Alcoholic Fatty Liver Disease
NOVEL research presented at UEG Week 2024 has revealed that L-carnitine supplementation significantly improves liver function and reduces fat accumulation in patients with non-alcoholic fatty liver disease (NAFLD), with reductions in liver enzyme levels and improvements in ultrasonographic liver grades.
NAFLD, the hepatic manifestation of metabolic syndrome, is a leading cause of liver failure and transplants worldwide. Currently, the primary treatment for NAFLD involves lifestyle modifications and weight reduction. This study aimed to evaluate the impact of L-carnitine, an amino acid essential for lipid metabolism and the beta-oxidation of long-chain fatty acids, on NAFLD. The multicentre, randomised, clinical trial sought to determine whether L-carnitine could offer an additional therapeutic benefit beyond lifestyle modifications in improving liver health.
The study involved 393 patients with NAFLD (55.2% male; average age: 44.8 years; 76.7% of Middle Eastern/North African ethnicity) from five referral centres across three countries. Participants were randomly assigned to either the L-carnitine supplementation group (Group A) or the control group (Group B).
Group A received 1,000 mg of L-carnitine twice daily for 12 weeks, while Group B was advised on lifestyle modifications only. The baseline metabolic profile, including liver enzyme levels, was recorded for all participants. After 12 weeks, hepatic fat
status was reassessed using ultrasound, and the biophysical parameters were compared between the groups.
The analysis revealed that alanine aminotransferase levels in Group A decreased significantly from 65.6 to 40.9, but only reduced from 62.8 to 50.7 in Group B (p=0.0029). Similarly, there was a significant difference in the reductions of aspartate aminotransferase levels between groups, with a decrease from 50.9 to 35.7 in Group A, compared to a decrease from 54.7 to 44.85 in Group B (p=0.046). Additionally, ultrasonographic evaluation revealed that the proportion of patients with Grade 3 NAFLD in Group A decreased from 37.9% to 12.6%, whereas in Group B it declined from 36.6% to 22.7% (p<0.05).
In conclusion, L-carnitine supplementation appears to be an effective adjunct therapy for managing NAFLD, with significant improvements in liver function markers and reduction of fat accumulation in the liver. Given these results, L-carnitine could be considered for inclusion in clinical practice to enhance NAFLD management, though further long-term studies are needed to assess its sustained efficacy and safety.
NAFLD, the hepatic manifestation of metabolic syndrome, is a leading cause of liver failure and transplants worldwide
Partially Hydrolysed Guar Gum: New Treatment for Constipation?
PARTIALLY hydrolysed guar gum (PHGG), a water-soluble fibre, can significantly improve bowel movement frequency in adults with chronic constipation, according to new research presented at UEG Week 2024.
Constipation is commonly treated with non-absorbable fibre supplements, but evidence supporting their effectiveness is inconsistent. Previous studies have indicated that PHGG, a water-soluble fibre derived from the endosperm of Cyamopsis tetragonolobus L. seeds, may help relieve constipation, with benefits observed as early as 1 week into treatment.
The study aimed to provide more robust data by extending the treatment duration to 6 weeks and using a larger sample size, including 160 adults with chronic functional constipation or constipation related to irritable bowel syndrome. PHGG was compared to a placebo to assess its effectiveness and safety.
In this double-blind, randomised, placebocontrolled trial, participants were divided into two groups, with 80 receiving 10 g of PHGG and 80 receiving a placebo. Outcomes were measured through daily diaries,
By the end of the study, 50% of participants in the PHGG group had three or more SBMs per week, compared to 32.5% in the placebo group
tracking bowel movement frequency, stool characteristics (using the Bristol Stool Scale), and symptom severity (using the PAC-SYM questionnaire). The primary goal was to see how PHGG affected the frequency of spontaneous bowel movements (SBM).
Results showed that PHGG significantly increased SBM frequency compared to the placebo group. By the end of the study, 50% of participants in the PHGG group had three or more SBMs per week, compared to 32.5% in the placebo group. Additionally, 34.2% of PHGG users met the pre-defined responder criteria of ≥3 SBM/week and an increase of ≥1 SBM from baseline for at least 4 of the 6 weeks of treatment, achieving a significant improvement in their bowel movement frequency. This was compared to only 17.7% of placebo users.
PHGG was generally well tolerated, with no serious adverse events reported and no treatment discontinuations due to side effects. The study concluded that PHGG effectively increased bowel movement frequency without increasing gastrointestinal symptoms, making it a promising option for individuals with chronic constipation or irritable bowel syndrome-related constipation.
Limited Value of Colonoscopy for Evaluating Constipation in Young Women
A LARGE-SCALE, multi-centre study presented at UEG Week 2024 has shed new light on the effectiveness of colonoscopy as a diagnostic tool for young women with constipation.
The study, conducted across seven endoscopy departments between 2016–2021, analysed colonoscopy findings in a cohort of women aged 40 years and younger to assess the procedure’s diagnostic value in cases of isolated constipation.
Constipation is one of the most common gastrointestinal disorders affecting women, with a variety of potential causes. The research team aimed to determine whether colonoscopy, a common procedure used to diagnose gastrointestinal conditions, is necessary or beneficial for younger women presenting with constipation.
The study included a total of 377,795 patients, of which 198,629 (52.6%) were female. Of these women, 7,872 underwent colonoscopies for constipation and other symptoms (Cohort 1), while 6,852 underwent colonoscopy specifically for constipation (Cohort 2). The findings in younger women under 40 years of age were compared to those in older women.
Results revealed that colonoscopies performed on women under 40 years old had a limited diagnostic yield. In both cohorts, approximately 75% of colonoscopies in this age group returned normal results.
Cohort 1: UC was found in 1.2 % Crohn's disease in 0.7 % of women under 40 years of age
However, the study did highlight a higher prevalence of inflammatory bowel diseases, such as ulcerative colitis (UC) and Crohn's disease, amongst younger women compared to older women. In Cohort 1, UC was found in 1.2% and Crohn’s disease in 0.7% of women under 40 years of age. In Cohort 2, UC was present in 0.7% and Crohn’s disease in 0.2%.
In contrast, the prevalence of conditions like diverticulosis and polyps increased significantly with age, with a notable rise in women over 40 years old. Among women younger than 40, the rate of diverticulosis was only 0.5%, and the rate of polyps was 7.4%. Only one case of colorectal cancer was identified in women under 40 years.
The study also compared findings between genders and found no significant difference in the prevalence of inflammatory bowel diseases, diverticulosis, polyps, or colorectal cancer between men and women under 40 years.
Ultimately, the study concluded that colonoscopy has limited diagnostic value for isolated constipation in young women, suggesting that clinicians should consider other, less invasive diagnostic tools before recommending colonoscopy in such cases.
In Cohort 2: UC was found in 0.7 %
Crohn's disease in 0.2 % of women under 40 years of age
In
New Study Identifies Predictive Biomarkers for Inflammatory Bowel Disease Treatments
A
NEW study from Spain has advanced the search for predictive biomarkers that could enhance personalised medicine for patients with inflammatory bowel disease (IBD).
The research, presented at UEG Week 2024, highlights the importance of understanding the diverse biological factors that influence treatment responses in conditions like Crohn’s disease (CD) and ulcerative colitis (UC).
Inflammatory bowel diseases are characterised by significant heterogeneity, making it challenging to predict which patients will respond to therapies, particularly biologics and JAK inhibitors. The study involved a multiomic analysis of 53 patients with active CD and 50 with active UC, assessing their responses to treatments over 14 weeks. By employing techniques such as RNA sequencing, liquid chromatography-mass spectrometry, and 16S rRNA gene sequencing, researchers aimed to identify specific biomarkers associated with treatment responses.
Results revealed several promising indicators. Differential gene expression analyses in intestinal tissues highlighted key differences between responders and nonresponders among patients with UC treated with anti-TNF, vedolizumab, and tofacitinib.
Proteomic analyses identified various proteins that could differentiate responders from non-responders, particularly for anti-TNF treatment, with predictive values indicated by area under the curve scores of 0.81 and 0.96 for CD and UC, respectively.
Metabolomic findings showed an upregulation of 21 lipoproteins in serum from CD responders to ustekinumab, while metabolic pathways linked to ketone and butyrate metabolism were enriched. Additionally, significant differences in miczrobial composition were noted in patients with UC, depending on their treatment response.
The findings from this study represent a significant step toward personalised treatment strategies for patients with IBD, suggesting that biomarkers in gene expression, protein levels, metabolites, and gut microbiota composition could guide therapy selection. Further research is essential to validate these biomarkers and their potential clinical applications, paving the way for more effective and individualised treatment options for those with IBD.
The study involved a multiomic analysis of 53 patients with active CD and 50 with active UC, assessing their responses to treatments over 14 weeks.
14 weeks
Congress Interviews
EMJ was delighted to interview both the President, Matthias Löhr, and the Vice President, Joost Drenth, of United European Gastroenterology (UEG), as they discuss the latest advancements in autoimmune pancreatitis, pancreatic cancer, and autoimmune hepatitis, as well as the future of UEG.
Featuring: Matthias Löhr
and Joost Drenth
Matthias Löhr
President of United European Gastroenterology (UEG); Professor of Gastroenterology, Karolinska Institutet, Stockholm, Sweden
As current President of United European Gastroenterology (UEG), what is your key goal for the future of the organisation? How are you fostering engagement and collaboration around digestive diseases in Europe and beyond?
For the organisation, we must look towards a more sustainable future for both the structures and finances of UEG. It is my goal to make the UEG fit for the future. This is a process I started when I came into office at the beginning of the year and that is ongoing, and most likely will not be finished by the time I leave office at the end of next year.
to welcome those countries, but also to have structured contracts and collaboration agreements for the mutual benefit of both UEG, and say, the Korean, Japanese, Americans, South Americans... We had presentations from our sister society, the American Gastroenterological Association (AGA), and we had another session with our Pan-American friends, from South America. So, this is a really important part of the ongoing business.
It is my goal to make the UEG fit for the future
Now, for digestive diseases across and beyond Europe, we have over 30,000 virtual myUEG Associates, and they're coming from around the globe, from beyond Europe: 500 from the USA alone, 200 or so from Asia, and South America. These international collaborations and links become more and more important for the exchange of knowledge, but also for networking. We're making an effort
Something else I do with my colleagues in the executive committee is to reach out to countries both within Europe, at the borders of Europe, and beyond, to tell them what UEG has in store for them, what offerings we have for members of UEG within both national societies and speciality societies, such as more chances to apply for and obtain grants, etc. Even for those outside Europe, we have lots of offers: they can become myUEG members, join consortia, post questions, ask for collaborations, e.g. for certain rare diseases.
Another thing, which I was pushing for and initiating already as vice president, is for UEG to engage with and be part of European research projects, like Horizon Europe. Where does UEG excel beside organising the world's best GI Congress? Dissemination and marketing. UEG has now engaged in two European projects where we are doing the dissemination part. But in the future, could that develop into taking over more and more responsibilities within such a European project? Those are my ideas and prospects for the future.
Q2 What originally sparked your interest in the pancreas, “the central organ”?
I was really puzzled by the fact that this is the only organ that has this endocrine-exocrine function, that produces the enzymes needed for digestion, as well as insulin, and I was interested in the interrelationship between those two parts. For my MD thesis, I started out with the endocrine pancreas, and then studied the relation to the exocrine pancreas, and, as is sometimes the case, I developed this into a career. Obviously,
it has to do a lot with your environment and your mentor. I recently received the Lifetime Award from the European Pancreatic Club, where I was invited to write a small piece that reflects a little bit on that journey, and how I developed my interest in the pancreas.
Q3
Your research has significantly advanced our understanding of chronic and autoimmune pancreatitis. Can you tell us more about your work in pancreatic exocrine function and the endo-exo-axis?
Apart from the Society for Digestive and Metabolic Diseases in Germany, which is an exception, the endocrine and exocrine parts of the pancreas are treated as two different specialties, one dealing with the endocrine pancreas, as in diabetes, and the other with the exocrine pancreas, as in gastroenterology. The fascinating part is how they are really connected, and this is extremely important. Insulin is produced in the islets of Langerhans and flushed out towards the liver, but the blood passes through the exocrine pancreas; so, as a result,
the highest levels of insulin are present in the pancreas. It is a prerequisite, actually, during the development of mammals, to have a pancreatic gland, because the islets need to join the exocrine pancreas to form the pancreas, and that is necessary to produce vast amounts of enzymes for digestion, particularly of proteins and fat, used to develop the brain.
Now, this is the evolutionary, developmental part, but the important thing is, what if you no longer have insulin, as in diabetes? Then you lack this trophic effect, because insulin is a growth hormone. You lack this trophic effect primarily to the pancreatic exocrine tissue, and then obviously to the rest of the body. This endo-exo axis is really pivotal to understanding consequences in patients with diabetes, but most diabetologists have no knowledge about this. One of the things my colleagues and I do is to educate diabetologists and advocate for this kind of knowledge, so that they really look out for pancreatic exocrine insufficiency in diabetic patients, which is there. There are numerous studies that have proven that point.
Q4
What research questions still remain to be addressed?
While there's lots of circumstantial evidence that is well published and understood, we still need a very large prospective study, over many years, not just the typical 6–12 months, to recruit patients with diabetes with and without exocrine pancreatic insufficiency, and look at the outcome of giving these patients pancreatic enzymes. This is a study that is lacking, and industry is hesitant, because that's a long-term commitment and costs a lot of money.
The other thing missing is broader understanding of the exocrine pancreas, and we are in the process of publishing the third guidelines, which were actually presented during the recent UEG Week by Enrique Domínguez Muñoz, from University Hospital of Santiago de Compostela, in Spain, on exocrine pancreatic insufficiency, in the sense that you lack the digestive effect, not necessarily have less secretion by the pancreatic gland. Something we would like to convey to our colleagues in gastroenterology and beyond is that there are other
conditions, such as congestive heart failure, where you could definitely develop exocrine pancreatic insufficiency.
Q5
As a key figure in the development of the first evidence-based European guidelines for chronic pancreatitis (HaPanEU), what were the biggest challenges in establishing consensus, and how do these guidelines shape clinical practice across Europe today?
The HaPanEU guidelines for the diagnosis and treatment of chronic pancreatitis were the first evidence-based guidelines that the UEG issued and approved. This is one of the things we needed, in Europe, not only for the pancreas but for other conditions. Often, for implementation of guidelines, you need to rely on national specifics, but the diagnosis around these diseases is common across European countries.
For the first time, we brought together experts not only from gastroenterology, but also oncology, endoscopy, etc. It was really a multidisciplinary, crosssectional guideline with many working parties. For the first
The HaPanEU guidelines for the diagnosis and treatment of chronic pancreatitis were the first evidencebased guidelines that the UEG issued and approved
part, we looked into diabetes. The most interesting part is, if you do any kind of guidelines, you basically detect what is lacking in the field. That led to the latest guideline, which is now dealing with pancreatic exocrine insufficiency in all conditions, both pancreatic and non-pancreatic. The paradigm shift we introduced with the latest guidelines is that we are not defining exocrine pancreatic insufficiency as just a deficit in pancreatic secretion, that is enzyme production; we're now defining it as a lack of the effect of enzymes digesting food in the intestine. That clearly can have several kinds of aetiologies, amongst them, of course, pancreatic diseases, but also
others such as Crohn's disease, coeliac disease, gastric surgery and other intestinal surgeries, some kinds of drugs, and HIV as well. All of this is covered in these guidelines, and that is really a result of the first guidelines.
Then, of course, the important question is how these guidelines did or did not shape clinical practice in Europe. We had the idea that we should analyse the implementation of these guidelines, but the Dutch Pancreatitis Study Group just beat us by maybe 2 or 3 months. They had their paper out, and we were just finishing up on ours. The Dutch Pancreatitis Study Group did a nationwide analysis about the implementation of the HaPanEU, and we did it as one centre. Now, the bottom line here is similar: we both are not perfect, neither the Dutch nor Karolinska, and there are different levels of fulfilment of the criteria in those guidelines. Diagnosis is okay, therapy maybe not so optimal, certainly not 100%, and this is a very sobering view on what we're doing.
The good news is that, slowly, the level of adherence to guidelines improved year after year after we published our guidelines. This implementation is very important, and the evidence that is coming now is a crucial part of the guidelines themselves.
Q6You were also in charge of the UEG consensus for IgG4-related diseases. Can you summarise key points and implications for clinical practice?
IgG4-related diseases encompass pancreatitis, even immune-related autoimmune cholangitis, and for that reason, some of us were invited by the American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR) to be part of a consensus. We learned a lot from the rheumatologists because this IgG4-related disease is a systemic rheumatological disease, in essence, which happens to have lots of manifestations in the GI tract. It was our idea to sum this up on the European level, and focus on GI diseases and obviously the pancreas.
Q7
Pancreatic cancer remains one of the most challenging cancers to treat. Could you tell us more about the personalised cancer medicine study you conducted in pancreatic cancer?
The driving point here is that pancreatic cancer is a terrible disease. For the time being, almost everybody who receives that diagnosis will die, and will die rather soon. The medium survival time is now less than 1 year in inoperable patients, which make up more than 80% of cases, and in operable patients, we are now reaching 2-year survival, which is good, but overall it's a very dismal prognosis.
Poor prognosis cancers are defined by a median survival of less than 2 years, and pancreatic cancer is leading this
The most important change in clinical practice that we learned from our colleagues in rheumatology is that, for secondline therapy, you no longer rely on yet another course of steroids. They switch over to biologicals quite quickly. For the time being, that was rituximab. And as a consequence of that work, another drug that already existed for some ocular disease was promoted and made available to us for a Phase III study in IgG4-related diseases, including autoimmune pancreatitis, which is going to be published very soon. So, the guidelines, number one, were very much focused on the GI tract, which I think was needed to educate our gastroenterologists about this disease in more depth; and number two, it led to a Phase III study which will bring us now the first drug ever approved and registered for IgG4-related disease. The results will be presented at the ACR meeting later this month.
From the UEG point of view, we have been pushing the European Commission in two ways. Number one, they opened up a category for ‘poor prognosis cancers’ and another for ‘neglected cancers’. Poor prognosis cancers are defined by a median survival of less than 2 years, and pancreatic cancer is leading this, together with bile duct cancer and some others. The neglected cancers are not necessarily those that have the shortest life expectancy, but receive less attention and funding. There again, pancreatic cancer is number one, and ovarian cancer number two.
One of the many reasons why pancreatic cancer has such a bad prognosis is that the tumour is rather resistant to conventional therapy. We have learned a little about molecular profiling, but if you look at its mutational profile, pancreatic cancer does not have the most genomic alterations; this would be malignant melanoma or colorectal cancer. Mutations in pancreatic cancer are very much spread across the genome, and that is the reason why targeted
therapy, like against EGFR, which works very well in colorectal cancer, doesn't work in pancreatic cancer, at least not in such a high percentage of patients. It works in a small percentage that we call the “tail” of these Kaplan–Meier curves, and these 2–5% patients have a long-term effect from these targeted therapies. So, the idea was to perform large-scale molecular profiling, not only with two or three markers, but a whole exome, and use an AI-based software to analyse the entirety of the molecular changes in a holistic view. If the patient has wild-type KRAS, for instance, you would assume receptor blockade is working, but if you then have an activating mutation further down, it wouldn't work. The software looks at all of this and gives recommendations on what drugs can be used. We published this at the beginning of this year.
Having said this, the problem in Sweden, as in Great Britain, is that even if a drug is approved, generally speaking, that doesn't mean that you will get it for your patient because then it would be off-label use. In Germany, for instance, you can have a single request to your patient’s health insurance and get that covered. In Sweden, we have to pay this out of pocket from the hospital, and apply to use a particular drug for this patient based on
the molecular profile and the evidence behind it. This personal approach is valid, and as a result, Karolinska University Hospital, our comprehensive cancer centre, is now, from the hospital side, paying the molecular profiling for pancreatic cancer and other solid cancers which have not been yet treated. So that's a very good result.
Q8
What upcoming innovations or treatments in pancreatic cancer are you most excited about?
We have just talked about individualised treatment, but I think we can look forward to two developments. One is, after decades of knowing that KRAS is the overarching driver mutation in pancreatic cancer, even of the initial malignant transformation, we now have several kinds of drugs, small inhibitors and antibodies, that address and detect mutant KRAS. Sadly, this was not developed initially for pancreatic cancer, but for colorectal cancer, and as a result, the first KRAS mutations covered were not those most prominent in pancreatic cancer. However, even in pancreatic cancer, they've worked. Now, specific KRAS inhibitors for the mutations that are most prominent in pancreatic cancer, like K12D, are in clinical studies, which is very good news. At Karolinska we are participating in these clinical studies with our Phase I unit.
and they have been working on this technology already for many years. The COVID-19 vaccine was really a ‘side track’ to serve an obviously urgent need, but they have worked in the pancreatic cancer field for years already, and that seems to work extremely well in patients who mount a particular T cell response. They had, in an adjuvant setting, a very long disease-free survival. I think that is rather exciting, and that's why this vaccination therapy works best with the lowest tumour load, which is exactly what you have after surgery of the primary tumour.
I think the personalised medicine approach will be valid. We know by now that certain drugs, even gemcitabine, work only in a particular subtype of pancreatic cancer; this is work done by David Tuveson’s group at the Sloan Kettering/Cold Spring Harbor Laboratory in New York City, USA. The knowledge for these drugs is increasing, but I think the KRAS drugs are really a breakthrough, as well as the vaccination in the adjuvant setting.
Q9
As leader of the European Educational Program for Future Pancreatologists, “Pancreas 2000”, what are your key priorities for fostering the next generation of pancreatologists?
Now, specific KRAS inhibitors for the mutations that are most prominent in pancreatic cancer, like K12D, are in clinical studies
The second thing, which was presented at last year's American Society of Clinical Oncology (ASCO) Meeting, is a vaccination strategy where you look at the molecular profile from the RNA, the expression of mutated genes and then proteins, to make a personal vaccine. This is basically the BioNTech mRNA approach,
The programme was inaugurated here at Karolinska in 1999, when the pancreatologists foresaw a shortage of experts in the pancreas, both for surgery, gastroenterology, and oncology. They started this programme with a clear vision to engage young colleagues in that field. I was leading this project until last year, and now I'm still a mentor in the programme.
The first pillar of the programme is education by the best European experts in the field, through lectures, case presentations, discussions like the multidisciplinary tumour board, and conferences. When different experts discuss a patient case, you can develop a feeling of what is really important. We have also done this during UEG Week.
The second pillar is for young colleagues to pursue a project in an interdisciplinary way. Some of them do not come from a pancreas centre, and we want to extend the network beyond the known large centres. It is amazing to see the ideas that these young colleagues, particularly those not from these centres, are coming forward with. Out of 30 participants we typically have, each provide two or three ideas, and the group of mentors then select the 15 best ones, which are then presented in person and discussed during the first meeting. Out of those 15 projects or so, we select five to six, and then the young colleagues are allocated these projects based on their interests. I always compare this to the “sorting hat” event in Harry Potter. We have been very successful in doing this. You have
a group with two mentors, which then help the young colleagues develop the idea into a study protocol, get this through the institutional review board (IRB) ethics approval, and then conduct the study, collect the results, do the statistical analysis, eventually write an abstract, present it, and write the paper.
The third pillar was revolutionary at the time. In 1999–2000, Karolinska Institutet had just started a project where they would educate the leaders and give them tools to help them develop, learn about themselves, gain discussion skills, etc. At that time, this was already standard in industry, but unknown in academia, and certainly in medicine. This is still one of the pillars that the young colleagues appreciate the most.
If you look back these 25 years, 90% of participants educated in these now 11 courses have stayed in the field. The majority have obtained leading positions as departmental heads and professors. That has really fostered the entire field of pancreatology across surgery, gastroenterology, pathology, radiology, paediatrics, oncology... The priority here is to work
together, and they also learn about the joy of doing that. It's rewarding. And as a result, we have founded the Young Pancreatologist Platform in Europe (YOUPPIE), which is now an alumni organisation carrying this on and giving young pancreatologists, or gastroenterologists interested in the pancreas, a chance to meet.
As I said, in a course we can only take about 30 participants, and this creates a network, which was a good starting point for the guidelines. If you want to conduct a study, you would turn to people with whom you have worked together for 2 or 3 years, right? This has created such momentum that most of the active researchers now in the field of pancreatology have been associated as mentors or participants in the Pancreas 2000 programme. It's a success story.
Finally, you learn to appreciate the challenges that those young colleagues come with: they have other ideas, other methods to communicate and learn. That is quite obvious looking back at the last 25 years or so. And they challenge you too, with a fresh attitude. This is what I like the most about being in academia.
Q10What advice would you give to young researchers who aspire to specialise in gastroenterology?
I think two key points are most important. Number one, you really must burn for what you're doing. Once in a while, we have colleagues who just do the research and the PhD because they know this is a prerequisite to reach a senior position. This is okay, but you should really be interested in what you choose to do, in pursuing not only a profession as a gastroenterologist, but also a career in research.
Number two is that you can't do it on your own. The key element is that you need to have a mentor, a good role model. More than half of our mentors here are female; even if I think I can accommodate female young colleagues, for them to have a female role model is extremely important. So, pick the right mentor. Sometimes there is an element of serendipity to it because when you start your career, you typically don't ask these questions. You say, “they seem like a nice person… I'm a little bit interested in GI… now I’ve ended up with the liver or the pancreas.” You don't think that
much about it. Only a minority of students come to us and say that they would like to work on the pancreas. We have a stream of students coming to us to complete their research to get the points they need to pass the course, and what you have to do is show them that it's really rewarding and fun to do research.
MyUEG, our virtual platform, has now more than 30,000 gastroenterologists across the world. It's really the largest network in GI globally
As a young colleague going into gastroenterology, you should identify something you’re interested in when you finish medical school, or as is the case in many European countries, after finishing the “common trunk” of internal medicine before going into a subspeciality. By then you should know if gastroenterology is your “thing”. Then, you should really try to find a mentor who is capable and willing to help
you, has a good track record of helping young colleagues do research and finish a PhD, and someone that you have good chemistry with.
Finally, you should also look out for others in the field. MyUEG, our virtual platform, has now more than 30,000 gastroenterologists across the world. It's really the largest network in GI globally. Not only is registration free, but you can also get educational content for free, including all content from UEG Week until the end of December. Then you can join interest groups, ask questions about patients, look for colleagues in your country, even in your particular city. So, look out for others who are interested in GI, and look for the ones who are interested in a particular disease, molecule, pathway, methodology. From my own experience, we were looking for colleagues to join a retrospective analysis for some rare diseases, such as autoimmune pancreatitis, and it is really fantastic what you can do in this safe space. It's not social media such as Twitter or LinkedIn, it is really a secure space where only you, as a professional, can enter. That is a prerequisite.
Joost Drenth
Vice President of United European Gastroenterology (UEG); Professor of Hepatology, Department of Gastroenterology and Hepatology, Amsterdam UMC, the Netherlands
You have been involved with the United European Gastroenterology (UEG) for over 15 years, and recently appointed Vice President. What is your vision for the future of UEG, including key priorities and challenges to overcome?
I believe it's important for UEG to reach out to UEG associates, because that is key to what we want to achieve. UEG is an important platform that gives room to people, societies, and network organisations where one can actually reach out to people, develop networks, and then focus on disease-specific topics or research topics. I think that is the biggest value of UEG. Our conference really puts emphasis on the newest in gastroenterology and hepatology.
Q2
What are the most exciting changes that have been made to the scientific programme for UEG Week 2024 compared to 2023?
Q3 Are there any sessions that you're particularly looking forward to at UEG Week this year? In your opinion, what are the trending topics this year in gastroenterology or hepatology?
As Editor-in-Chief, I really love the UEG Journal Awards session, which obviously is close to my heart. The opening session that we will have today is great. This brings in the best of the best, and it will also include the Lifetime Achievement Award session for Paul Fockens from the University of Amsterdam, the Netherlands, who was one of the former UEG presidents. He had a great vision to propel UEG even further, and I think he absolutely achieved it. So, his award is well deserved.
In
terms
of trending topics, I want to move away a little bit from AI
The world is in constant flux, and UEG is no exception. I really want to emphasise here that UEG and the office are working very hard to innovate the conference, as we want to stay competitive. We want to draw people in, because we know that innovations are being created here. Innovations bring people to a conference, because that is what surprises. I feel that the challenge here is to package that knowledge into the bits that people truly like and want to consume. For example, we see now that companies that bring instruments to us, such as endoscopes, want to show what they have on offer, what people can use, and have that direct interaction with consumers. That is a big value.
In terms of trending topics, I want to move away a little bit from AI because that's already discussed a lot; but what you will see here, in particular in my field, hepatology, is information on new drugs that have just been approved in the USA and are on the brink of market entry in Europe. I believe this will change the way we see and treat patients with obesity, metabolic syndrome, and liver disease. It's a huge challenge, but also an opportunity to help these patients and improve their quality of life.
Q4 What are your thoughts on the emerging role of AI in your field?
In the end, I guess the final answer is that it will stick. We will increasingly use it and already many people are using it. Let's take a topic close to my heart, the journal I run. We actually see that the quality of the papers offered to us, the style, the grammar,
have improved since the entry of ChatGPT, and we see that most authors actually use all these deep learning models as an aid. That's fine, as long as one sticks to one’s original message, and AI doesn’t overtake one’s brain.
Another example, this is a European conference, where we attract a global audience, and people speak different languages. We now have a translation model that you can put in your phone. You just scan a QR code, and then everything that's being said is translated in the language you desire; Icelandic, Finnish, Dutch, whatever you want. I That is a real advantage of AI.
Q5 What about the role of AI in diagnostics?
We see, especially in endoscopy, a real hope that models are being validated, particularly in oesophageal diseases but also in colorectal diseases. I believe that authors and researchers have made some good inroads in that area, but what is key here is that you really need to expand, to network, and collect huge data sets in order to validate these
models. I think that in the end the solution the market will take is that AI will be integrated into endoscopy and used in real time. However, we have to be careful. Any data set can be validated, but that doesn't mean that such validation can be replicated in a different situation. So, I guess that's a challenge.
Q6 Before Amsterdam UMC, you spent 30 years at Radboud University Medical Center, Nijmegen, the Netherlands, and 13 years as Head of the Gastroenterology Department. What have been your proudest achievements during that time?
I created a pipeline of junior researchers that came in, went on to do a PhD, and then were recruited to become fellows in the department and had the ability to grow on to be gastroenterologists. I am particularly very proud of them, because identifying talents is a major role for a Head of Department, and allowing other people within your department to grow and expand and find different solutions for problems that we face currently and in the future.
This was the first clinical trial in autoimmune hepatitis for more than 20 years
Q7
How are you bringing the experience from your previous positions into your new role as UEG Vice President?
That's an excellent question. Well, you have to adapt to different situations. I think that is key. It's important to facilitate others so that they can actually grow and achieve better things without me being there. So, the facilitator role I really embrace.
Moving from a position that I was in for 30 years of my career gave me the opportunity to gain new experiences and also to learn that, if you come from a different institution, you need to adapt. You should also be able to add value to your new environment, which I love. My colleagues in Amsterdam University have been very embracing. I like the atmosphere there. People were very kind and happy.
On a different note, I love my role here at UEG. And why do I do it? Because I think it really emphasises what I believe is important. It's not just the Netherlands, it's not Luxembourg, not Germany, but it's Europe. Europe is important because here you meet with your neighbours and that facilitates networking. That's what's critical in order to better tackle challenges together.
Q8
Your long-term research interest lies in rare, mainly inherited gastrointestinal diseases, such as polycystic liver disease and autoimmune hepatitis. How has your research opened up the road for novel treatment options for these patients?
I will mention two examples. First, patients with polycystic liver disease suffer from gross hepatomegaly and this causes pain, dyspnoea, and inability
to eat. We performed a clinical trial that demonstrated that with somatostatin analogues we could decrease the liver volume but also improve symptoms. This idea caught fire and now a biomedical company is running a Phase II trial with another somatostatin analogue with an aim to bring this drug to the market. On a different note, I'm proud of the trial that we published just recently for autoimmune hepatitis, where we compared conventional therapy, azathioprine combined with prednisolone, to prednisolone with mycophenolate mofetil (MMF). We showed that they are probably equal in value, with a more favourable safety profile for MMF. This was the first clinical trial in autoimmune hepatitis for more than 20 years, and was a really a great job from the researcher who led this study, Romee Snijders. It was also an achievement of the Dutch and Belgian teams that were able to find and convince patients to enter this clinical trial. Investigator-initiated trials are close to my heart.
Q9 Which rare diseases do you believe merit greater attention?
What first comes to mind is primary sclerosing cholangitis (PSC). It is a horrible disease, and we don't have any treatment. We can only follow the natural history of the disease, which is great for registering, and great for resources, but we don't have an intervention, apart from endoscopy. We can only treat the symptomatic disease and in the end, perform liver transplantation. So, it's my great desire that we see a new medical option there. There is an international PSC working group, and they're doing a great job. They have pinpointed genetic correlates but when it comes to treatment, we really need to find how we can treat PSC.
Q10Where would you say your interest for rare liver diseases came from?
When I was in medical school, I was accepted in the Internal Medicine training program. My future boss approached me when I was still serving in the military and said he had discovered a new disease that was featured by recurrent febrile episodes, termed hyper-IgD syndrome. He asked me whether I wanted to do research to better understand this enigmatic disease. I agreed and went down a very satisfying path that led me from studies to better understand the pathogenesis, to genetic studies, and ultimately trials to define a therapy for this disease. This brought immense joy and satisfaction, and I am grateful for this opportunity that was given to me. It taught me that a rare disease is a model to better understand biology and it gave me the tools to move on and study other rare gastrointestinal and liver disorders.
For me, this experience rang a bell: you can make a difference for patients with a rare disorder. For the patients with this rare febrile disorder, we have been able to
identify an effective therapy. These patients have a better life, and I have been part of that story. We now live in a world where innovation is key. As physicians and researchers, we can make a difference for these patients, and I see that as my task.
Q11Where
can we see your research focus lie in the near future?
We are expanding our research in autoimmune hepatitis, and I would really like to see new drug options. Current options like prednisolone need to be taken your whole life. Why isn't there a drug that ‘kills’ autoimmune hepatitis, similar as there is for hepatitis C? It may be a far-fetched goal, but I trust that the industry is there, the ideas are there, and so is the biology. We can make it happen, definitely.
Q12Finally,
what piece of advice would you give to young gastroenterologists or hepatologists starting out in the field?
Have a mentor! It really makes a difference for people. You don't need to have a mentor around you constantly, but someone you
can send a WhatsApp message to if you have a question that you don't know how to relate to. It's good to test that question in your own career, but it's better to reach out to somebody who has seen the world and knows what lies ahead of you.
The second advice is to join the UEG Journal. I did so 6 years ago and created a line of junior trainee editors who were given various tasks such as peer reviewing, creating visual apps, embellishing the website, and also improving titles and abstracts of articles. That has been a great success, because you get people to talk about it, it creates enthusiasm for the journal, and you create a line of talents, people who have witnessed and experienced what it’s like working with a journal. So, we have been expanding that programme ever since, and probably 40–50 people have been in that 2-year programme. This is the future for us. Those are the future editors, and I'm absolutely certain that among one of those is the future Editor-in-chief. This is what I need to do: to be a mentor and a facilitator.
This is what I need to do: to be a mentor and a facilitator
Interviews
EMJ had the pleasure of interviewing Jean-Frederic Colombel and Michael Camilleri, two leading experts in the field of gastroenterology. Colombel shares key insights in inflammatory bowel disease, including current treatment targets in Crohn’s disease and ulcerative colitis, and sheds light on the importance of early detection and prevention. Camilleri discusses the fascinating field of enteric neurosciences, with a focus on novel pharmacotherapies for disorders of gut–brain interaction, and the emerging role of GLP-1 receptor agonists in obesity management.
Featuring: Jean-Frederic Colombel and Michael Camilleri
Jean-Frederic Colombel
Professor, Icahn School of Medicine, Mount Sinai; Director of the Susan and Leonard Feinstein Inflammatory Bowel Disease Clinical Center, Mount Sinai, New York, USA
Q1What initially sparked your interest in the field of gastroenterology, inflammatory bowel disease (IBD) in particular?
I have two mottos that I always tell my fellows: don’t be a follower and think outside the box, and value collaboration and networking
Very often the biggest decisions in life occur by chance. I went into gastroenterology when I was still very young, starting a fellowship, and didn't know what to do. I spoke with one of my mentors in medical school, who told me I should go into gastroenterology because it's very diverse. And why IBD? As soon as I arrived at the department of Gastroenterology in CHU Lille, France, I was amazed by the number of young people admitted with IBD. This was very novel. The disease was originally described in North America, and now it's all over the world. What was fascinating, and this has never been published, is that in the early 70s there were already a lot of cases of IBD, mostly Crohn’s disease (CD), in Belgium and the Netherlands, and very few cases in Northern France. At that time, in the post-World War II era, we had common meetings with
gastroenterologists from Belgium, and they very often presented their cases of IBD. We didn’t have that, but then within a few years we saw this huge number of patients coming in. I thought this was very interesting and decided to focus on this disease. My goal, with the ambition of youth, would be to find the cause and the cure of IBD Interestingly, we had more cases of CD than ulcerative colitis (UC) in Northern France, which is not usual in many countries, including the UK or Scandinavia, where they have more cases of UC.
In the beginning, when I was treating patients, we had very few therapeutic options: amino salicylates, steroids, artificial nutrition, enteral and parenteral nutrition, and surgery. Patients were struggling with long term exposure to steroids, iterative surgeries, and still dying from complications. I was lucky enough to surf the wave of the development of the immunomodulators such as thiopurines, and then biologics,
and more recently small molecules. I arrived at a time when the research and the medical care for IBD exploded. With my mentor, Antoine Cortot, we launched the first epidemiological study looking at the incidence of IBD in Northern France, which comprises the departments of Nord, Pasde-Calais, Somme, and SeineMaritime. We published our first data in the 80s showing a very high incidence of CD and lower, but still quite high, incidence of UC, as well as some very interesting peculiarities, such as a high number of multiplex families with IBD.
I rapidly focused my attention on those families which were unique, including one with six out of nine children with CD, and one with the two parents and their four kids with CD. Their description raised the attention of HJ Van Kruiningen, a pathologist from Hartford, Connecticut, USA, and an IBD expert who was seeking an infectious cause for CD. We visited together these families living in rural areas of Northern France, published their pedigrees and clinical characteristics, and collected blood and stool samples, but our quest for an infectious agent was negative.
Q2You have co-authored more than 1,100 peerreviewed papers, making you one of the most published gastroenterologists in the world. What do you believe have been the most significant developments in IBD treatment in recent years?
If there is one worth mentioning, it’s the development of new drugs, biologics and small molecules, for the treatment of IBD. These drugs are now able not only to treat the clinical symptoms, but also to heal the gut mucosa of patients, thus altering their natural history and risk of disease progression towards surgery and disability.
I still think that it is the publication of a case report and a case series by Sander van Deventer from AMC in Amsterdam that revolutionised the landscape of IBD therapy. Sander was originally working on an antibody against TNF-α, the ancestor of infliximab, for the treatment of sepsis, which was a failure. He then published a case report showing the clinical efficacy of this antibody in a refractory case of CD, and subsequently with his team a case series showing not only clinical efficacy of the anti-TNF in CD, but also, for the
first time, evidence of endoscopic healing. This was so striking that the endoscopic pictures made the front cover of the journal. I believe that, at least in part, Sander’s clinical intuition opened a new era in the treatment of IBD.
Q3
Are there any areas of IBD research that merit greater attention?
There are still many, but I’d like to mention two. One major problem is that there is more and more data showing that if you treat patients early, this makes a significant difference. Often, by the time we start biologics, patients have already been suffering for several years. Retrospective data from clinical trials show that success of medications, including biologics and small molecules, especially in CD, are higher when given to patients early with relatively short disease duration compared to long disease duration.
Recently, the PROFILE study from the UK, where the median disease duration at inclusion was less than 2 weeks, showed that the clinical remission rate obtained by a combination of infliximab and thiopurines can reach 80%.
So, early diagnosis and access to the appropriate medication is key. Unfortunately, in our IBD Center, as everywhere else, we see daily patients arriving too late, when the disease has already progressed. Therefore, one area that merits much more attention is improving access to care in the very early phases of the disease, which means early diagnosis and proper management. This is a growing problem with the increasing number of IBD cases. A study we conducted with the Crohn's & Colitis Foundation in the USA 2 years ago revealed that approximately 50% of patients with CD had to wait more than 2 years to receive their diagnosis. So, we need to start by getting these patients in the clinic very early, making a proper diagnosis, and starting the medication from the beginning. This would be one of the biggest improvements in the treatment of IBD.
The second point is that, while we now have highly sophisticated techniques to look at the immune system and the microbiome, now including AI, we still need to explain some “basic” clinical questions. For instance, when scoping patients with UC, the disease often appears active in the rectum, sometimes extends to the sigmoid, and then suddenly stops. Why is there this sharp limit? Strikingly, the disease can extend within 24 hours, and these patients are the most difficult to treat, often requiring a colectomy. Nobody has yet been able to
explain this sharp demarcation.
On the other hand, when we scope a patient with CD, the pattern is different. You might see ulcerations in the rectum, then nothing, then in the right colon, then nothing, and then in the ileum. Here, again, what explains this anatomic distribution?
From an epidemiological perspective, we need to take into account that, in the near future, most cases of IBD will occur in India and Asia, shifting away from being primarily a European or American disease. This will pose a lot of problems in terms of resources and access to care.
Q4
Throughout your career, you have made important contributions to the field of IBD, including the identification of NOD2 as a susceptibility gene for CD, and the development of the anti-S. cerevisiae antibodies (ASCA) test, which is still the most sensitive and specific serologic marker for CD. Can you tell us more about these discoveries, and how they are still impacting patient care today?
Regarding the NOD2 discovery, I remember attending one Digestive Disease Week (DDW) in the 80s, where I heard a talk about discovery of genes involved in colon cancer in families. I thought, why shouldn't we do the same for CD? That was the beginning. We recruited CD families together with several European colleagues and collaborated with brilliant
geneticists in Paris, Jean-Pierre Hugot and Gilles Thomas, which eventually led to the discovery of NOD2. In our first paper in 1996 we were able to locate a CD susceptibility gene on chromosome 16, which was later identified as NOD2 in 2001.
Since then, more than 200 susceptibility genes for CD have been discovered, but NOD2 is still one of the most important. These discoveries have led to amazing progress in understanding the pathophysiology of CD, but direct translation to the treatment of patients is still lagging.
Following the genome ‘wave’, research interest then focused on the microbiome thanks to the discovery of new techniques to understand its composition and function. We contributed to this research with the discovery of a new pathovar of Escherichia coli associated with CD. The story started with our collaboration in Lille with our microbiologist Christel Neut who, when looking at samples from ileal CD, noticed that there were a lot of E. coli colonies on her dishes (it was only cultures at that time). We sent these E. coli cultures to a French international expert in E. coli, Arlette Darfeuille-Michaud from Clermont-Ferrand, and one month later, she sent us a letter confirming it was a new pathovar of E. coli with very specific adhesive and invasive properties, now known as adhesive, invasive E. coli (AIEC), strain LF82. Very few people know that LF stands for Lille, France.
This research has since blossomed under the leadership of my late friends Arlette Darfeuille-Michaud and Nicolas Barnich. The story sill goes on, and we are now working on a bacteriophage specific to AIEC that we administer orally to patients with CD, with the hope of specifically “decontaminating” their microbiome.
The story behind the ASCA discovery is also interesting. A paper published in Scotland in the 80s showed antibodies against food antigens such as Saccharomyces cerevisiae in the blood of patients with CD. I thus got in touch in Lille with Daniel Poulain and Boualem Sendid, world leading yeast experts. Their group selected several different yeasts from beers and, using the most reactive one, developed a test named ASCA, which is still the most sensitive serological test for CD. The research on ASCA is still very active with the most recent discovery we made with Salomé Pinho from Portugal, published last month, of an association between occurrence of ASCA and changes in glycosylation profiles in the blood that can precede the occurrence of CD by up to 6 years. Pinho’s group also published, in the same paper, evidence that ASCAs may play a pathogenic role in CD and are not just simple bystanders.
Q5 Can you explain the concept of ‘treat-totarget’ in IBD? What are the current treatment targets in CD and UC?
When I was still a fellow, the French Groupe d’Etude Thérapeutique des Affections Inflammatoires Digestives (GETAID), led by Robert Modigliani, conducted in the 80s a clinical trial showing that corticosteroids were able to induce clinical remission in CD. When those patients were
scoped at the end of the clinical trial, some were also in endoscopic remission, and some were not, but their long-term outcome was basically not different. The GETAID then concluded that targeting endoscopic healing beyond clinical remission was unnecessary. This later proved to be wrong.
Then, new drugs like thiopurine and infliximab came along, which were much more effective than steroids in healing the mucosa. This is where the ‘treat-to-target’ concept emerged. Along with one of my former fellows, Laurent Peyrin-Biroulet, now one of the most famous international experts in IBD, and the International Organisation for IBD (IOBD), we published the ‘treat-to-target’ guidelines proposing that the target in CD and UC should not only be clinical, but also endoscopic remission. This was mostly based on retrospective data, which showed that achieving both clinical and endoscopic remission was associated with a lower likelihood of disease progression with a lower risk of surgery and complications.
The concept is still evolving. For instance, in CD, should we aim beyond endoscopic remission to achieve transmural healing? For UC, should we go beyond endoscopic healing to histological healing? I always say to my patients that it’s like an iceberg; there are layers of healing: clinical, endoscopic, histological, and maybe even molecular. Retrospective data in UC suggest that achieving not only clinical and endoscopic but also histological healing could be associated with better long-term outcomes. However, this level of remission is difficult to achieve, and the benefit of these new targets has not yet been demonstrated in a prospective study.
There is actually an ongoing international study called VERDICT, led by Vipul Jairath from Canada, that could answer this question. In this large international prospective study, one group of patients is treated based on clinical symptoms, the second based on clinical and endoscopic remission, and the third based on clinical, endoscopic, and histological remission. The primary 2-year endpoint is lack of progression, including surgery and complications. We should know soon from this trial what is the desirable target in UC.
Q6You are a strong advocate for the prevention of IBD, as we are still far from a ‘cure’. What approaches should be taken by patients and clinicians to reduce the risk of IBD? How do these approaches vary between CD and UC?
This is my passion. As mentioned earlier, a key word in IBD is ‘early’. But even if you treat patients very early after diagnosis, it's not a cure, because cure means no disease and no need for treatment. Unfortunately, we, and others, have conducted several studies showing that, if you stop medications, even in patients in deep clinical and endoscopic remission, most of them will relapse. This is why I believe the real cure lies in catching IBD even earlier than early, meaning, before the first symptoms appear.
I believe the real cure lies in catching IBD even earlier than early, meaning, before the first symptoms appear
This concept, which was originally seen with a lot of scepticism, is now gaining momentum, not only for IBD but also for other immune-mediated diseases, such as multiple sclerosis and rheumatoid arthritis.
To me, the story started with a fascinating paper published in 2002, showing that antibodies associated with systemic lupus erythematosus can be detected in the blood of people prone to develop the disease up to 10 years before clinical symptoms. This study leveraged a unique resource which is the blood repository of the U.S. Department of Defense. This is a biobank that contains millions of sera from USA army recruits who provide blood samples starting from enrolment, and then every 2 years. Among those young people who were healthy at time of recruitment, some have developed IBD or other diseases. You can then get access to the sera of those young patients at diagnosis and back to up to 10 years earlier, allowing to trace the development of the disease using biomarkers. In close collaboration with our colleagues from the Army we have published several papers, under the acronym PREDICTS, reporting for instance the presence of microbial antibodies and proteomic and glycomic signatures preceding the development of CD. These studies are offering unique perspectives regarding what may cause the disease, but should also allow to build a serologic risk score that could be used for selecting candidates for future prevention studies.
Different designs have been used in other cohorts throughout the world, such as the Nurse Health Study Cohort (NHS) or the remarkable Genetic,
Environmental, and Microbial (GEM) cohort led by Ken Croitoru in Canada, which prospectively recruited 5,000 first-degree relatives of patients with CD and identified, after years of followup, changes in blood markers but also in the microbiome associated with the development of CD in these family members.
It is obvious that we need to work together since not one cohort will provide the answer. This is why we have established the PROMISE consortium supported by the Helmsley Foundation between PREDICTS, NHS, and GEM to validate the predictive biomarkers, identify therapeutic targets, and hopefully, in the near future, start a prevention trial. In parallel, a very ambitious project led by Geert D’Haens, from Belgium, and myself, named INTERCEPT, has recently been funded by the European Commission with the ultimate goal to launch the first prevention trial in first-degree relatives of patients with CD.
Regarding one of your questions, our search for predictive biomarkers in UC has been so far more difficult, although we recently identified the presence of antibodies against an integrin (αvβ6) in the blood of patients with UC up to 10 years before diagnosis.
Now, what does that mean today for those at risk for IBD, especially relatives of patients? Nothing concrete yet, but they should be aware of these efforts, and help us in this research. Very simple things can still be recommended for children at risk of developing IBD: anti-inflammatory diet avoiding ultra processed food as much as possible, avoiding the use of antibiotics, especially during early childhood, avoiding active and passive smoking, and
generally being aware of the risk of IBD for an early diagnosis.
Q7
You have set up an impressive network of multiple local, national, and international collaborations for IBD research, including the GETAID. You have also served as President of the European Crohn’s and Colitis Organisation (ECCO), and Chair of the International Organisation of Inflammatory Bowel Disease (IOIBD). Can you tell us more about the goals and mission of these organisations?
I have two mottos that I always tell my fellows: don’t be a follower and think outside the box, and value collaboration and networking. I think these are the two keys to a successful career. This is what I've done my whole life.
When I was in France, I was an active member and president of the GETAID, which has conducted a lot of important studies that would have never been pursued by pharmaceutical companies, such as research on the effects of stopping medications. This was networking at the national level.
At the European level, I am member and past president of ECCO. This organisation was born in the mind of my Italian friend Renzo Caprilli, who told me: “Why shouldn't we try to do something about IBD at the European level and launch ECCO?” I was telling him this would never work. I was pessimistic. The first meeting of ECCO was in Amsterdam, in the Netherlands, with few attendees. Fifteen years later, ECCO has grown tremendously and is now the number one organisation in the world for IBD, networking across European countries. Apart from the meetings, ECCO also publishes guidelines, clinical trials, and is supporting research
through multiple grants. It has even expanded beyond Europe, with a lot of members from India, Australia, Africa, and Asia. This has been an amazing success, thanks to the vision of very few people who were there at the beginning: Renzo Caprilli, Geert D’Haens from Belgium, Walter Reinisch from Austria, and Miguel Gassul from Spain. I was the first elected President of ECCO in 2009; it wasn’t very competitive back then. These days, if you want to be elected as a president, it's like the USA election; you need a campaign.
The third organisation is IOIBD, which started in the UK with very few people. It was originally created by Sidney Truelove from Oxford and was long considered an “old man’s club”. It was a very small group of key opinion leaders from all over the world, meeting once a year to discuss
IBD in a nice venue. But it has expanded a lot now, and IOIBD has become a very active international organisation. I was chair of IOIBD in 2010. IOIBD is now supporting care and research in IBD in the whole world, and actively publishing expert position papers.
In simple terms GETAID was France, ECCO was Europe, and IOIBD was the world.
Q8 What would you say your proudest achievements have been within these organisations?
By far, my proudest achievement in my career is the promotion of young people. As a testimony, I received this year the American Gastroenterology Association (AGA) Immunology, Microbiology & Inflammatory Bowel Diseases (IMIBD) Section Research Mentor Award. I've received several prizes
in my life, but maybe this is the most important one, because this is what I have been doing my whole life. It's so rewarding to see my fellows becoming IBD key opinion leaders in many countries. This is the most important to me: boosting their career, helping those people, and changing their life. I have published more than 1,100 papers but when I die, within 6 months, it will be forgotten. The only thing that remains is the life of people that you have changed: first your patients, and then your fellows. They will remember you.
Q9 Where can we expect to see your research focus lie in the near future?
I really want to focus on prediction and prevention of IBD. I'm pretty certain I will not see the end of it, but at least I will have been there at the beginning!
Michael Camilleri
Professor
of Medicine, Pharmacology,
and Physiology, Mayo Clinic College of Medicine and Science; Consultant in the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
Q1What initially sparked your interest in gastroenterology, and motivates you to continue working in this field today?
diseases, and that has continued to be a very important part of my academic activity.
Indeed, there is an interaction between the gut and the brain because, ultimately, we can only feel things because our brain senses them
I was very stimulated while I was still a medical student at the University of Malta, which is where I was born. I was exposed to a professor of surgery named Victor Griffiths, who instilled in me an interest in gastrointestinal pathophysiology. The mid-1970s was a time when there was still a lot of surgery being performed for peptic ulceration, which involved cutting the vagus nerve, truncal vagotomies, and then highly selective vagotomies. We used to do these operations almost every week on patients with chronic peptic ulcers because this was a time before we had medications like H2 receptor antagonists or proton pump inhibitors. Of course, there were pathophysiological consequences that resulted from the operations done for peptic ulceration. That immediately caught my attention when I was an undergraduate student, and then I was very fortunate to receive a Commonwealth Scholarship. So, I went to the Hammersmith Hospital in London, UK (at the time also called the Royal Postgraduate Medical School), where I trained for 6 years. I was exposed to incredible mentors; Vint Chadwick, Humphrey Hodgson, and Tim Cox are three that immediately come to my mind, and they had such a big influence on my continued interest in gastroenterology. They impressed upon me the importance of understanding the mechanisms underpinning gastrointestinal and liver
Then I was fortunate to come to the Mayo Clinic, initially just for a research fellowship, where I was exposed to two other great mentors: Juan-Ramon Malagelada and Sid Phillips. This was at the Gastrointestinal Research Unit at Mayo, which was revolutionising how we study gastrointestinal motility and neurophysiology as it applies to humans in vivo. These spheres of study continue to attract or dominate my attention. Thus, I continue to be a student of gastroenterology and of the mechanisms that cause gastrointestinal diseases.
Q2
Enteric neurosciences and gut neurohormonal activity are key areas of your expertise. Can you tell us more about your work on disorders of gut–brain interactions, and the current status of pharmacotherapies to treat these disorders?
This is a very logical extension of my good fortune of being trained in these areas. Nowadays, we talk about disorders of gut–brain interaction. And indeed, there is an interaction between the gut and the brain because, ultimately, we can only feel things because our brain senses them, but our focus has been predominantly on what's happening in the digestive tract. Indeed, we’ve learnt that there is much that we can do, not only to diagnose but also to treat patients with therapies that are directed at the gastrointestinal tract. Let's just start off, for instance, with our focus on gastrointestinal
motor function. The physiology and pathophysiology of the gut depends also on the nerves that go from the brain and the spinal cord to the gastrointestinal tract, that is the extrinsic or autonomic nervous system. So, we have appreciated the importance of vagal function, to which I was introduced during the era of vagotomy and peptic ulceration, and also the other mechanisms that result in the pathophysiology of gut function.
We also have a major interest in and continue to study problems related to diarrhoeal diseases, particularly the role of bile acids and gastrointestinal hormones in the development of chronic diarrhoeal diseases.
We also appreciated that feeling full after a meal and the function of the stomach is extremely important for satiation and weight gain, and this gastric function is dependent upon the increase in hormones that feedback not only on blood glucose control and appetite but also the effects of the same incretin hormones on how the stomach empties food. Slower emptying from the stomach can be beneficial because it may help people eat less as they feel fuller
postprandially. On the other hand, it may be that these hormones can sometimes cause adverse effects, like nausea, vomiting, and postprandial fullness, which have an impact on how patients receiving these medications present to us as doctors.
In summary, all of these studies, which emanate from understanding the gastrointestinal pathophysiology, whether it's originating from dysfunction of the muscle, the nerves, or the chemicals produced by the body, like bile acids or hormones, ultimately have an impact on the symptoms that arise. And these symptoms are very commonly encountered in the clinic: diarrhoea; constipation; symptoms suggestive of gastroparesis; and not feeling excessively full after eating, and therefore, gaining weight because we eat more.
The corollary of this greater understanding of pathophysiology is that there have been incredible advances in the treatment of these conditions over the last two or three decades. For instance, with the treatment of constipation, we now have medications that
induce the secretion of water into the small intestine or colon, or we have medications that stimulate the colon to function. I was specifically involved in the early studies documenting the proof-of-concept of medications like lubiprostone and linaclotide, both of which are secretagogues; and prucalopride, which is a prokinetic of the colon.
With regard to diarrhoeal diseases, we did the original studies that demonstrated the efficacy of the 5-HT3 antagonist alosetron. We did the proofof-concept studies regarding the 5-HT4 agonist cisapride for gastroparesis and chronic intestinal pseudo-obstruction when I was a fellow in the 1980s. Subsequently, we studied a cousin of cisapride, called prucalopride, and showed that it also worked in the colon and was approved for treating chronic idiopathic constipation. Finally, we studied incretin receptor agonists, amylin analogues, and dipeptidyl peptidase 4 in obesity, and we now know how important the glucagon-like peptide 1 (GLP-1) receptor agonists are in the management of obesity and its comorbidities.
Q3
You are also particularly interested in appetite and obesity. What is the role of the stomach in appetite regulation and obesity? Can you tell us more about the role of GLP-1 receptor agonists, such as liraglutide, semaglutide, and tirzepatide, in weight loss?
One of the wonderful opportunities I've had over the years is to interact and go across specialties, divisions, or departments. Here at Mayo Clinic, there's a wonderful legacy of cross-disciplinary research, and I was very fortunate to work with endocrinologists, specifically, Robert Rizza and Adrian Vella. More than 20 years ago, we did studies on the effects of the hormone itself, GLP-1 on gastric function. When we administered pharmacological doses of this hormone, we appreciated that the emptying of the stomach, in healthy humans, and in people with diabetes, was delayed. We also showed that this was very much dependent on the vagus nerve, which again, is the nerve that connects the stomach to
the brain. That's also important because the brain then connects back to the stomach through the same vagus nerve to induce the stomach to empty. We know GLP1 has a very important effect on appetite, and we know it is very important for insulin secretion to control blood sugar.
Subsequently, we've done studies with the GLP-1 receptor agonists exenatide and liraglutide and showed that these are associated with a significant delay in gastric emptying in non-diabetic obese participants. In the randomised placebo-controlled trial of liraglutide, we also found that the effect on stomach emptying contributes to about 25% of the total weight loss that occurs in patients treated with that specific GLP-1 receptor agonist. Does it also apply to other agents? We don't know because we haven't studied it. But as a proof of principle, it appears that the delay in gastric emptying is a significant factor. We also found that people who started with faster stomach emptying at baseline had the greatest degree of weight loss
among people with obesity. This research links, in my mind, the importance of stomach function in relation to the development of obesity because of reduced satiation, and the opportunity to change how that stomach works to induce more weight loss through slowing of emptying.
Q4 Could there be a genetic cause behind patient response to these medications?
There could certainly be a genetic cause. We tried to see whether there was a genetic variation in the GLP-1 receptor, which is the target receptor of these medications, explaining why there was a different level of weight loss in response to that medication. With a sample size of about 65 patients treated with liraglutide that we could study, we were not able to show a significant effect. On the other hand, it is conceivable that some of the factors associated with the genetics of obesity may be impacting the degree to which that weight loss will occur, or, conversely, the degree to which
weight gain occurs. Hopefully, in the future, there might be ways in which one can predict from genetic studies who might be better candidates for treatment with this and other classes of medications.
Q5You study novel approaches for the treatment of gastroparesis and dyspepsia. Can you tell us a bit more about the latest therapeutics in this field, such as ghrelin receptor agonists and 5-HT4 agonists?
Let's briefly touch upon the 5-HT4 receptor agonists. Cisapride is a medication that we studied in the 1980s, and it really was highly effective in terms of the treatment of gastroparesis, and also for symptoms arising from the small intestine in chronic intestinal pseudo-obstruction. Unfortunately, very rarely, there are cardiac side effects with that medication, and that led to its withdrawal. We're hoping that newer types of medications in the same class, which have greater safety from a cardiac standpoint, may be coming on the scene. They help to improve patients' symptoms, and for a couple of these, we've already studied the proof of concept, such as velusetrag and naronapride, both of which accelerate either gastric emptying, or gastric emptying and colonic transit in humans, even in patients with constipation. There's hope that this class of medication might still be helpful to patients.
The next class is the ghrelin agonists, and we were very excited because proof-ofconcept studies with relamorelin showed that it accelerated gastric emptying and stimulated contractile activity of the stomach to facilitate stomach emptying. There have been three Phase
III studies that, according to clinicaltrials.gov, where results have been made public, failed to reveal clinical benefit. Unfortunately, the company made the business decision to stop the development of that medication for the indication of gastroparesis, so I don't know whether that's going to move forward.
Another class of medications are the neurokinin-1 (NK-1) antagonists, and there is one that's already approved for chemotherapyinduced emesis, called aprepitant. That same medication was associated with reduced nausealike symptoms in patients with gastroparesis. Tradipitant, a new NK-1 receptor antagonist, will be reviewed for possible approval by the FDA in September 2024. The Phase III clinical trial data have been published.
And then finally, we had a National Institute of Health (NIH) grant to study cannabidiol, which is a combination cannabinoid receptor 1 and 2 modulator. We studied it in placebo-controlled clinical trials in patients with dyspepsia and in patients with gastroparesis. The latter trial suggested that there is a marked improvement in patients’ symptoms, reduction in vomiting episodes, ability to take a full meal, etc. It appears that this might be a promising approach, which needs to be replicated beyond this single-centre study at Mayo Clinic in about 45 patients. So, this trial result has to be replicated, to see whether it can go forward.
Q6 What would you currently say are the main hurdles to the clinical approval of these novel therapeutics? Is it the side effects?
The side effects are definitely important, but also, before you
consider the safety, you've got to make sure that they're efficacious. One of the nice things that's happened in the field of gastrointestinal motility is that there are now approved patient response outcomes for many of these conditions, and the regulatory agencies, such as the European Medicines Agency (EMA) or the FDA here in the USA, have given guidance on how to do the studies in Phase III, to document the benefits from a patient response outcome perspective. In other words, guidance is to document not ‘Does the stomach improve?’ but ‘Do the patient's symptoms really improve?’ I think that keeps the patient as the focus of the trials, and I applaud that approach. I also believe that proof-of-concept trials based on physiological endpoints (e.g., motility, transit) are essential to determine whether Phase II and III trials are warranted, and often provide useful information about the dose to be tested.
Q7 On average, 25% of all patients who present to gastroenterologists are suffering from irritable bowel syndrome (IBS) or chronic constipation. How important are lifestyle and dietary factors in the management of these conditions?
It's a very important question, and it's not only for gastroenterologists but even for primary care physicians. I once read that 10% of patients seen in primary care actually have these conditions. So, at a population level, it's very, very important.
First things first, lifestyle and dietary factors are very logical first steps in the management of these patients. We know, things like trying to avoid unnecessary stress, and increasing the fibre
content of the diet (e.g. 12–20 g of dietary fibre per day) will help to avoid constipation. Constipation is an extremely common problem in the general population, affecting 25% of the population, as mentioned. Now, there's been a lot of hype and information in the public domain about FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols). These are disaccharides or monosaccharides that may not be well digested, and that result in bloating, abdominal pain, discomfort, and sometimes diarrhoea.
Our approach regarding FODMAPs is rather more selective. Rather than saying that we need to stop all of these types of sugars, we really focus on two main classes. We're aware that about two-thirds of the world's population may have an intolerance to lactose. So, it makes sense to enquire about lactose intolerance when we're seeing patients. That's the first thing we ask about. The other thing we know from work done at the University of Minnesota, 75 miles north of where I am here in Rochester, Minnesota, USA, is that if you take patients with lactose intolerance who have a proven hypolactasia due to genetic defect, and you give them lactose in the form of milk, but
you give them small amounts of milk every day, you don't end up with the severe symptoms. If, on the other hand, you give all of that lactose in one setting or one meal, then they're going to develop the symptoms. We therefore teach patients how to take lactose, and if necessary, we can also manage the intolerance by supplementing the enzyme lactase.
That's one approach that we take; the second approach really refers to dietary fructans. That's the F in FODMAP. Now, fructans are types of sugars that the human gastrointestinal tract cannot digest or metabolise. So, it makes sense that foods that are rich in fructans, like onion and garlic, need to be restricted. Those are the two areas in the diet that we usually focus on.
However, our philosophy, particularly here at Mayo Clinic, has been to go beyond those first steps. There have been several guidelines recently published that suggest that we can try to use medications in an algorithmic approach: start with medication A, and if the patient doesn't respond, try medication B, and if the patient doesn't respond, try medication C, etc. Our philosophy has been very different. We like to try to identify the underlying pathophysiology in order to make
a more precise diagnosis and also to individualise treatment. We've articulated the importance of what we call actionable biomarkers and worked hard to validate diagnostic tests to identify the pathophysiology.
Our philosophy has been very different. We like to try to identify the underlying pathophysiology in order to make a more precise diagnosis
We call those actionable biomarker tests, which are important to us because we can do something about it, we can action the information that comes from these biomarkers. Examples of these would be identifying bile acid diarrhoea; we worked very hard to develop biochemical measurements in the bloodstream or in the stool in order to make the diagnosis of bile acid diarrhoea. It is a condition that doesn't always happen because your gallbladder has been removed or because you've had an intestinal resection, it can occur without those surgical procedures.
Three commonly used actionable biomarkers are: identify bile acid diarrhoea, or rectal evacuation disorders due to dysfunction of the muscles that are involved in the process of defecation, and measurement of colonic transit (too fast or too slow).
We have a very strong database of normal functions/results for all of these measurements. For instance, our chronic transit measurements are based on a comparison with 320 healthy volunteers that we have studied over the years in our laboratory. We feel quite confident when we make these pathophysiological diagnoses since we know from clinical experience that we can be much more precise in what we recommend for the individual patient's treatment.
Q8As past President of the American Gastroenterological Association (AGA) and American Neurogastroenterology and Motility Society (ANMS), what do you consider your proudest achievements to date? What key lessons did you learn from your time as president?
I was President of the ANMS before I became President of the AGA. It was actually a learning experience on how to work with committees and governing boards. One of the things that I really enjoyed in the ANMS was facilitating the interaction between clinical workers, translational researchers, and basic scientists. I think that also helped me, as I eventually graduated to the more general gastroenterology leadership position at AGA.
Within my 1-year tenure as President of the AGA, I had to focus on two or three big issues. One of those big
issues I identified was that we needed to have more timely recommendations for clinical practice. We therefore established the AGA clinical practice updates, and these were intended to complement the clinical guidelines that have been produced by the AGA, usually at a rate of about three or four clinical practice guidelines on very specific topics. I realised that it would take 25 years to cover 100 topics of interest to gastroenterologists.
There were two reasons why I felt that we really needed to have clinical practice updates. Number one is to bring timely recommendations so that doctors can use the experience of the content experts and translate that into their clinical practice. The second reason was that, when I did an analysis of the AGA guidelines, which are based on very strict evidence, based on the so called ‘Grade criteria’, it turned out that the evidence that was available for making recommendations was not always that robust. Thus,many recommendations weren't really based on a strong level of evidence, but they were based onexpert opinion.
I felt it was important that we take that component based on clinicians’ expertise and translate it into something more practical and more feasible to promote the advances in clinical practice for use by the gastroenterologist in practice. That was the first initiative, and I'm very, very glad to see that it's continued to mature, providing very important guidance in the clinical practice of gastroenterology and hepatology, as well as obesity.
The second initiative was to bring obesity to the mainstream of the activities of gastroenterologists.
This was not only because endoscopically we were able to do things like sleeve gastroplasty and other procedures like the placement of balloons to help treat obesity, but also because it became clear that there were a number of problems related to obesity that were presenting to us as gastroenterologists. For example, people who are obese are more likely to get gallstones, or patients with inflammatory bowel disease are less likely to respond to even biological therapy if they have a higher BMI. Nowadays, metabolic-associated steatotic liver disease is a major cause of cirrhosis, and incretin receptor agonists show great promise in reducing liver fat and fibrosis. I could see that this was going to come down the pike when I was President almost a decade ago, and this was an opportunity that we needed the AGA to take on, these challenges in the field of obesity that were impacting gastrointestinal diseases.
The most important lesson for me was really learning to be a servant leader, to listen, and to work with colleagues, both the lay administrative colleagues in the organisation and then my colleagues as either clinicians or scientists on the governing board. That was a very important part of my own education.
The most important lesson for me was really learning to be a servant leader, to listen, and to work with colleagues
Q9Finally, what piece of advice would you give to young gastroenterologists starting out in the field?
The first important thing that we must always do is appreciate the importance of teamwork and mutual respect, to listen attentively, and to ask for clarification where we don't completely understand what people are trying to communicate.
Second, I've always found that some of the most interesting questions I have tried to answer have emanated from observations in clinical practice. Embrace your activities as a clinician and keep an open mind; that really leads to the importance of always trying to address the mechanisms of disease or action of a treatment. I've always asked myself ‘how’ or ‘why’ rather than ‘what’ or ‘where’. ‘How’ or ‘why’ seeks answers to questions like, ‘How is that illness manifesting this way?’ Why is that illness happening? What is the mechanism that is leading to this particular illness?’ From
understanding the mechanisms, one can also develop diagnostic tests, and hopefully, treatments.
Another thing that I have benefited from tremendously is going across disciplines or specialties, that is, to interact with colleagues in hepatology, endocrinology, and surgery. And in the case of motility of the gastrointestinal tract, I've also learnt a lot from interactions with my colleagues in neurology, from the standpoint of the autonomic nervous system, and the gastrointestinal pathobiology of Parkinson's disease, which we continue to work on.
From the perspective of looking back, how does one equip oneself with the ability to pose these types of questions and to maintain one's interest and ability to do the research? I think it comes down to having the opportunity to expand one's training in methodology and scientific disciplines. As a clinician-researcher, some of the important methodological courses that I took pertain to
epidemiology, biostatistics, and clinical trial design. And from a scientific discipline standpoint, the courses I took on biochemistry, cell biology, immunology, and pharmacology, are things that I go back to, and I keep benefiting from learning how to appraise the literature on those topics.
The final thing is to always be humble and thank those who have made your career possible, particularly your families and your mentors.
Optimise Eosinophilic Oesophagitis (EoE) Care
Based on the medical symposium ‘Something to Chew On: Exploring Biologics in the Management of EoE’, presented at UEG Week, held from 4th–7th October 2024 in Vienna, Austria.
EoE, which involves Type 2 inflammation, and a predominant infiltration of eosinophils, is a chronic immune- and allergy-mediated disease that damages the oesophagus. It can be progressive, but diagnosis and treatment are often delayed, which can negatively impact physical health and quality of life.1
Symptoms
EoE symptoms vary by age and may reflect disease progression.2 Detecting them can be challenging.
• In infants and young children, symptoms can be non-specific.2
• Patients may mask the symptoms with compensating behaviours.2
The publication of this infographic was sponsored by
EoE Symptoms May Vary2
Food refusal, feeding difficulties
Patient-centred Assessment Focuses On:
Infants, Toddlers Young Children
Failure to thrive
Vomiting and regurgitation
Abdominal pain
Symptoms
Ask about adaptive behaviours.2
Long-term Follow-up of EoE is Associated With:
Endoscopy
Histology
Assess histological changes using the EoE-HSS.8
Assess endoscopic features using EoE endoscopic reference score (severity of 5 endoscopic findings: oedema, rings, exudates, furrows, strictures) (EREFS)9
After 2 years without follow-up, each additional year of absent EoE care increases the odds of stricture by 26%.6
Yet, up to 55% of patients can be lost to follow-up after presenting as an emergency with food impaction.7 Regular assessment, every 12–24 months, may detect relapses as early as possible, and minimise the risk of EoE complications.4
Identify adaptive behaviours by asking patients the right questions:2
Do you prefer creamy or smooth food to solid food?
Imbibe fluid with meals
, a non-promotional understanding of Type 2 Sanofi and Regeneron 2022;10(3):308-18. 2023;21(10):2526-33.
Do you cut your food into small pieces?
Adaptive behaviours that IMPACT symptom assessment
Modify food (cut, puree)
Prolong mealtimes
Avoid hard texture foods
Chew excessively
Do you take longer to eat than others? Do you need to drink a lot during meals?
Turn away tablets/pills
Conventional Therapies and the Importance of Maintenance and Monitoring
As relapses can occur when treatment is discontinued, maintenance may reduce the risk of complications.5 Conventional treatments have risks and benefits, so monitoring response is key.
Elimination diet: Can remove a disease trigger, but induces histological remission in less than 1/3 of adults.10
Emerging Therapies
Biologics are an emerging treatment strategy for EoE. They may be an option for those who do not respond to conventional treatments or in whom such treatments are contraindicated.
PPI: Can reduce inflammation, but around 36% of initial responders experience loss of response.11,12
STC: Can reduce inflammation, but there is a risk of cumulative exposure in the presence of comorbid Type 2 inflammatory conditions.13
Conclusions:
Endoscopic dilation: The only treatment for obstruction, but it does not address underlying inflammation10 so repeat procedures are often needed.14
• Understanding the symptoms and the importance of ongoing management is essential to avoiding complications and providing quality care to children and adults living with EoE.
• While conventional treatments have limitations, emerging biologic medicines could represent a promising option.
6. Chang NC et al. Clin Gastroenterol Hepatol. 2022;20(8):1701-8.
7. Chang JW et al. Dis Esophagus. 2019;32(12):doz056.
8. Collins MH et al. Dis Esophagus. 2017;30(3):1-8.
9. Aceves SS et al. Gastrointest Endosc. 2022;96(4):576-92.
10. Lucendo AJ et al. United European Gastroenterol J. 2017;5(3):335-58.
BY-NC 4.0 Licence
13. Hirano I. Gastroenterology. 2018;155(3):601-6.
14. Runge TM et al. Am J Gastroenterol. 2016;111(2):206-13.
15.
16.
ME et al. Lancet Gastroenterol Hepatol. 2023;8(11):990-1004.
M et al. J Allergy Clin Immunol. 2024;153(2): AB266.
2021;19(3):473-83.
Copyright
11. Amil-Dias J et al. J Pediatr Gastroenterol Nutr. 2024;79(2):394-437.
12. Lucendo AJ Molina-Infante J. Expert Rev Clin Immunol. 2022;18(8):859-72.
• Helicobacter pylori is recognised as a Class 1 carcinogen by the WHO. While it infects approximately 50% of the global population, only <3% of H. pylori-infected patients eventually develop GC.
• H. pylori initiates GC in a ‘hit and run’ manner by neutralising the gastric acidic environment via urease activity.
Legend
H. pylori
Gastric indigenous microbes
Therapeutic potential of gastric bacteria
Targeted regulation of microbiome
• Probiotics are commonly used as adjuvants in H. pylori eradication. However, H. pylori infection has been identified as a favourable factor for GC immunotherapy by shaping the “hot” TME, with higher densities of PD-L1+ immune cells and non-exhausted CD8+ T cells in TME found in H. pylori–positive GC.10
• Probiotics with beneficial bacteria, like Clostridium butyricum and Lactobacillus, can reduce post-operative inflammation in patients undergoing gastrectomy and enhance immunity.2
Abbreviations
AG: atrophic gastritis; GC: gastric cancer; IM: intestinal metaplasia; SG: superficial gastritis; TME: tumour microenvironment; WHO: World Health Organization
• Elevated gastric pH might facilitate the overgrowth of opportunistic microbes within the gastric niche. Colonisation of H. pylori has been linked to significantly reduced alpha and beta diversities in the gastric mucosa.
• The intestinal and gastric mucosal microbiota of patients with GC is often enriched in Streptococcus, Lactobacillus, and Fusobacterium, but study results remain heterogeneous.
Oral/intestinal opportunistic pathogens
Gut microbiome
Metabolites
Enhancing chemotherapy and
• Faecal microbiota transplantation prior could improve patient response and
• Butyrate-producing bacteria increase of oxaliplatin.12
• Bacteria producing short-chain fatty protective effects against radiotherapy-induced
Enhancing immunotherapy
Response rates of patients with advanced from 10–26%.2 The gut microbiota, associated microenvironment, could modulate the
• Higher abundance of Lactobacillus response to immune checkpoint blockade with GC.14
• Methylobacterium is negatively correlated of TGF-β and intratumoural infiltration memory T cells.7
• Enriched Stenotrophomonas and Selenomona increased infiltration of immunosuppressive like regulatory T cells and plasmacytoid
References
1. Shin WS et al. Cancers (Basel). 2023;15(20):4993.
2. Zeng R et al. Gut. 2024; DOI:10.1136/gutjnl-2024-332815 .
3. Liu D et al. BMC Microbiol. 2022;22:184.
4. Wu Z-F et al. A comparison of tumor-associated and non-tumorassociated gastric microbiota in gastric cancer patients. Dig Dis Sci. 2021;66:1673-82.
What Do We Know?
Diagnostic microbial biomarkers
Early diagnosis of GC is crucial to increase patient survival, and the microbiota represents a new avenue for GC diagnosis.
Panels of gastric microbial signatures and a microbial dysbiosis index based on levels of enriched or depleted microbes, have been used to distinguish GC from superficial gastritis.3,4
Collecting gastric mucosal samples remains invasive and resource-demanding; non-invasive approaches for GC diagnosis can include collecting oral or gastric fluid samples.
Microbial biomarkers in the saliva can distinguish GC from non-malignant lesions with high accuracy.5
A large-scale multicentre study reported a panel of faecal microbial signatures (Streptococcus anginosus and Streptococcus constellatus) that accurately detected both early and later stages of GC.6
Prognostic microbial biomarkers
Microbial signatures can be used to predict outcomes of patients with GC, allowing clinicians to select more appropriate therapeutics.
• Higher abundance of Methylobacterium, Prevotella, and Fusobacterium in GC tumour tissues is associated with poorer overall survival.7
• Halomonas and Shewanella are enriched in gastric mucosa of patients with poor prognosis.8
• Collinsella, Blautia, Anaerostipes, and Dorea are more abundant in patients with advanced GC than in those with early GC.9
Prognostic biomarker
Survival probability
and radiotherapy
prior to chemotherapy and survival.11 increase the efficacy
Currently, translating microbial biomarkers into clinical practice for GC faces challenges:2
• unknown confounders affecting a patient’s microbiota;
advanced GC to immunotherapy vary associated with the gastric immune the response to immunotherapy.
is associated with better blockade and survival in patients
correlated with the production infiltration of CD8+ tissue-resident
Selenomona are correlated with immunosuppressive cells into the GC TME, plasmacytoid dendritic cells.15
5. Huang K et al. Front Cell Infect Microbiol. 2021;11:640309.
6. Zhou C-B et al. Gastroenterology. 2022;162:1933-47.
7. Peng R et al. Cancer Immunol Res. 2022;10:1224-40.
8. Yang J et al. Cancer Science. 2023;114:1075-85.
9. Chen C et al. Appl Microbiol Biotechnol. 2022;106:6671-87.
10. Jia K et al. Innovation (Camb). 2024;5.
• lack of established sampling guidelines; and
• lack of consensus on the appropriate timing, location, and manner in which microbial biomarkers should be used.
Large-scale multicentre studies with standardised methodologies are needed to better understand the dynamic microbial landscape in gastric carcinogenesis.
Further research is needed to determine the dosage and safety of microbiota-targeting approaches before clinical application.
11. de Clercq NC et al. Clin Cancer Res. 2021;27:3784-92.
12. He Y et al. Cell Metab. 2021;33:988-1000.
13. Yi Y et al. Exp Hematol Oncol. 2023;12:48.
14. Han Z et al. Clin Transl Med. 2023;13:e1312.
15. Ling Z et al. Front Immunol. 2019;10:533.
Gut Bacterial Microbiome Profiles Associated with Colorectal Cancer Risk: A Narrative Review and Meta-Analysis
Authors: Christian A Russ,1 *Nicholas A Zertalis,1 Veronica Nanton1
1. Warwick Medical School, University of Warwick, UK *Correspondence to nzertalis@gmail.com
Disclosure: Russ and Zertalis are co-first authors. The authors have declared no conflicts of interest.
Received: 03.06.24
Accepted: 07.10.24
Keywords: Colorectal cancer (CRC), colorectal carcinogenesis, gut bacteria, gut microbiome, meta-analysis.
Objective: Recent studies have shown a potential link between the gut microbiome and colorectal cancer (CRC). A wide array of research into this topic was performed over the past decade, illustrating a keen interest in the potential causal relationship between the gut microbiome and CRC. However, the cancer research community is lacking a concise review of this kind, which aims to explore the evidence linking the human gut microbiome to the risk of developing CRC.
Design: This narrative review was carried out by two independent reviewers who assessed the database outcomes from Medline and EMBASE during May 2020. A meta-analysis was undertaken to study the link between Helicobacter pylori and CRC. The meta-analysis was processed through Stata (StataCorp LLC, Lakeway Drive, College Station, Texas, USA).
Results: Thirty-one papers were included in this narrative review, of which 12 were included in the meta-analysis. From these papers, Fusobacterium and Bacteroides were reported most frequently as enriched in those with CRC versus the control populations. The metaanalysis showed an odds ratio of 1.49 (95% CI: 1.19–1.86), including a total of 20,001 events. This meta-analysis concluded that H. pylori infection significantly increases the risk of CRC, albeit with evidence of publication bias.
Conclusion: Bacteria have been found to increase the risk of CRC; however, a definitive causal relationship cannot be concluded or excluded using case-control studies. To fully understand the potential link of the bacteria listed, alterations in research design and execution are required. The assessment found a need for a large-scale cohort study conducted over a significant period of time to thoroughly evaluate the potential relationship between gut microbiome and CRC risk.
Key Points
1. In the UK, 46 people per day die from colorectal cancer (CRC), with it being the third most common cancer worldwide. Increasingly, CRC has been linked to the gut microbiome, with certain genera/species linked to an increased risk of developing the disease.
2. This narrative review and meta-analysis investigated the link between CRC and the gut microbiome, with Helicobacter pylori being the subject of the meta-analysis.
3. This paper found a strong association between Fusobacterium and Bacteroides, amongst other genera, and CRC. This meta-analysis also highlights a statistically significant association between Helicobacter pylori and CRC. This may have great implications for future screening for CRC risk and provide a base for future research into the impact of the gut microbiome on CRC risk and potential for probiotics for risk reduction.
INTRODUCTION
Colorectal cancer (CRC) is the third most common cancer worldwide, accounting for 10% of all cancer deaths in the UK during the period of 2015–2017.1,2 The global burden of colorectal cancer is expected to substantially increase in the next two decades, as a result of the widening adoption of a Western lifestyle.3 Cancer Research UK estimates that 54% of CRC cases are preventable, with many studies looking into the impact that lifestyle and other preventable factors such as red meat consumption, fibre intake, and obesity, can have on CRC risk.4-7
Recently, the risk of developing CRC has been closely linked to the composition of the gut microbiome, with many papers stating evidence for and against certain commensal species normally found in the human gastrointestinal (GI) tract. It has been suggested that an understanding of this gut flora composition offers potential in terms of the identification of biomarkers and associated risk factors for early CRC.8 This may have an important impact on the future personalised management of patients, potentially improving prognoses.
The aim of this review was to determine what genera/species of bacteria in the human gut microbiome are significantly linked to increased or decreased risk of CRCs, through the evaluation of papers that have been published on this subject. The review presented here summarises the bacterial taxa associated with altered risk of CRC, in line with this paper’s research question and the PRISMA statement.9
METHODS
Data Sources and Search Strategy
This review was reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The methods used were agreed by the authors in advance:
• Develop research question
• Identification of papers
• Screening
• Critical appraisal
• Data extraction
• Narrative synthesis
• Meta-analysis
Studies that reported the association between CRC and the gut microbiome were gathered from Medline and EMBASE, with the searches adapted to utilise relevant subheadings on each database. The following variations of keywords and MeSH terms were used: colorectal, cancer, neoplasm, tumour, malignancy, carcinoma, bacteria, microbiome, gastrointestinal, colonic, faecal, gut, dysbiosis.
Selection Criteria
In accordance with the population, intervention, controls and outcomes (PICO) proforma, the criteria used for the search
and selection of papers for inclusion and exclusion in this review can be found in Supplement 1. Both reviewers agreed to base the exclusion criteria around factors that may alter the natural composition of the human gut microbiome, such as underlying conditions or medication exposure, which may inadvertently impact the composition of species. For example, a twin study by Willing et al.10 in 2010 demonstrated a significant difference in the gut microbiome of patients with inflammatory bowel disease when compared with their healthy twin, suggesting a potential for underlying conditions to alter the host microbiome.
The literature search, selection, and review were performed by two independent reviewers. Papers were removed from the selection if both reviewers agreed to exclude them at the various screening levels (title and abstract and full article eligibility), or if duplicates were found. In instances of disagreement, a resolution was reached via discussion between the two study team members. The overarching objective of the reviewers at this stage was to focus on the two absolutes of CRC risk and the gut microbiome, minimising the effect of potential microbiome-altering effects outside of these parameters (e.g. chemotherapy use, antibiotics, etc.).
Data Extraction
Data extraction was carried out independently by the two reviewers following the full article assessment and data were documented on an original electronic data extraction table. Extracted data included: author name, publication year, population location, population size, detection method, taxa enriched in CRC, and taxa enriched in control. The same data were extracted for the meta-analysis, with the number of Helicobacter pylori positive and negative patients documented for CRC, and healthy groups replacing taxa documentation.
Critical Appraisal
Two reviewers performed a critical appraisal of the selected articles. The relevant Critical Appraisal Skills Programme (CASP) checklist was used for cohort and
case-control studies. The appropriate Newcastle-Ottawa Scale (NOS) was used for cross-sectional studies.
Main Outcomes Measured
Significantly raised (p<0.05) levels of bacterial taxa in patients with and without CRC were recorded in the data extraction table. The meta-analysis was specific to H. pylori presence in patients with and without CRC.
Meta-Analysis
During the screening and eligibility phases of this review, it became apparent that several of the articles studied the association between H. pylori and CRC. To further infer significance and verify this link, a decision was made to perform a metaanalysis on the eligible papers generated from the documented search strategy. To perform the meta-analysis, StataSE 16.1 for Mac (StataCorp LLC, Lakeway Drive, College Station, Texas, USA) was used.
Significance of association was measured using odds ratio (OR) and 95% CI. A random-effects model was chosen to analyse the data due to the differences amongst studies, namely in study design. Funnel-plot and contour-enhanced funnelplots were generated to test for publication bias, alongside the use of Egger’s test and the trim-and-fill method.
RESULTS
A total of 1,058 abstracts were screened from Medline and EMBASE. The final count of articles included for this review and meta-analysis were 31 and 12, respectively. The process and numbers are documented in Figure 1.
Review
Study characteristics
A total of 30 out of the 31 articles included in this review were case-control in design, and one was a cohort study.11 The studies recruited patients from 20 countries, of which seven studies were from China, three
1: Flowchart showing the process and numbers of papers included and excluded at each stage.
from the USA, three from Japan, two from Israel, and two from Iran. The median year of publication for all articles analysed was 2016, illustrating a recent increase in the evidence for and interest in this subject.
Of the studies included, 21 of the 31 had methods enabling the detection of a vast number of bacterial genera/species, with the other 10 having a more focused approach.
Quality assessment
The table summarising the outcome of all CASP checklists can be found in Supplement 2. Three articles were excluded at the quality assessment stage, and the reasons for their exclusion are shown in Figure 1.
Significantly enriched genera in colorectal cancer and controls
Of all the taxonomic levels in the included papers, genus was most widely reported as being significantly raised in either group. Therefore, it was decided that genus and species level should be predominantly
reported to provide more specific results. Significance was determined from the p-value tests used in each paper. Any species or genus whose p-value was <0.05 in either group were recorded. The full data extraction table can be found in Supplement 3 11-41
A total of 76 genera were either recorded as being significant, or as including a species within that genus that was independently significant. When compared, 58 of those genera were recorded as enriched in patients with CRC in at least one study, compared with 35 in controls. The frequency with which a genus or species was significant is recorded in Table 1.
Fusobacterium, or a species within this genus, was recorded as statistically enriched in patients with CRC in 70.8% of all studies powered to detect it. Within these studies, the whole genus was significantly enriched in a total of 11 papers, with individual Fusobacterium species enriched in nine of these papers (one of which was
CRC: colorectal cancer.
Figure
Table 1: Number of articles in which a genus or species within a genus was statistically enriched.
Table 1: Continued.
CRC: colorectal cancer.
in a control group). Peptostreptococcus and Porphyromonas were raised in 40% of the eligible studies, Bacteroides was raised in 33.3% of the eligible studies, and Parvimonas was raised in 25% of the eligible studies. The median frequency of significance for all genera significantly enriched in the CRC group was one (interquartile range [IQR]: 2–16).
In contrast, Blautia, Eubacterium, Lachnospira, and Prevotella were significant in 20% of eligible papers in control groups. The median frequency of significance within the control groups was 1 (IQR: 1–3).
Significantly enriched species in colorectal cancer and controls
Of the Fusobacterium genus, F. nucleatum was the most commonly raised species amongst patients with CRC in the papers analysed, and was statistically enriched in seven papers. Only two individual species were identified as significantly enriched in this group, F. nucleatum and F. varium, with the latter only enriched in a single study.16 A third species, F. peridonticum, was recorded as significantly enriched in controls once.16
Bacteroides fragilis was significantly enriched among patients with CRC in five studies. Two of these papers looked for this species specifically. A total of eight other Bacteroides species were recorded as enriched in CRC compared with four in controls, however, each species was only significant once. A summary of the species reported as significantly enriched in two or more papers is provided in Supplement 4.
Both Enterococcus faecalis and Escherichia coli were significantly enriched in patients with CRC in three studies. However, two of these came from papers that were looking specifically for those bacteria.
Streptococcus bovis was specifically tested for in three studies, although only one of these studies returned a statistically significant enrichment in patients with CRC compared to controls.
Meta-analysis
The meta-analysis in this article exclusively looked at the association between H. pylori infection and the risk of CRC. A total of 12 papers, including seven case-control, two cohort and three cross-sectional, were identified from the search strategy and eligibility criteria used for this review. The meta-analysis included data of 20,001 events, out of a total of 64,027 participants.
The Forest plot (Figure 2)42-53 is split by study design for transparency with an overall OR. A full table of the study characteristics of the papers included in the meta-analysis can be found in Supplement 5. 42-53
This meta-analysis found an OR of 1.49 (95% CI: 1.19–1.86), showing a statistically significant link between H. pylori infection and increased risk of CRC (Figure 2).42-53 Upon exploration of publication bias, significant risk was found. Funnel plots proved to be asymmetrical, and Egger’s test gave a p-value of 0.0001, showing evidence of bias. When corrected for using the trimand-fill method, the calculated OR came to 1.26 (95% CI: 0.93–1.71).
An I2 result of 79.17% showed substantial heterogeneity between studies, largely arising from the case-control group. The sub-analysis by study design showed a statistically significant link with each design. The largest effect was seen amongst cross-sectional studies.
DISCUSSION
Review
Results
Some bacterial genera were featured amongst studies at a higher frequency than others. Fusobacterium was documented most frequently (n=17), and was reported as significantly enriched in patients with CRC more than twice as often as Bacteroides, Peptostreptococcus, and Porphyromonas, which were the next most commonly featured genera (n=8). Conversely, the most frequently featured genera in the control group were only significant in four studies, with 16 of the 31 studies reporting any significant enrichment in this group.
Table 1 illustrates the high disparity in the reporting of taxa significantly associated with CRC and controls, amongst the included studies. Of the 58 significant genera identified in patients with CRC, 30 of these were significant in only one paper. Similarly, 20 of the 35 significant genera identified in the controls were associated in one paper.
Additional affiliations can be seen at the species level, as 57 different species were found to be significant in patients with CRC in at least one study. The most featured of these was F. nucleatum (n=7), followed by B. fragilis (n=5; seven if including enterotoxigenic strains). The frequency of replication of these results, however, was low. Only 13 of the 57 species were featured more than once between papers, as can be seen in Supplement 4. This replication frequency was even lower for species enriched in controls, with only three of the 40 species across articles being replicated more than once.
Limitations of included studies
Recruitment methods were a limitation of many studies included in this review. Controls in most of these studies were not recruited effectively. Most studies recruited from colonoscopy waiting lists, meaning that controls were presenting with colorectal symptoms warranting further investigation. Thus, the conclusion cannot be drawn that these are truly ‘healthy’ controls, and the control microbiome may have been altered as a result of the symptoms. Cases, however, were often recruited in an acceptable way, predominantly due to their diagnosis.
Papers also failed to consider the presence or absence of blood in the stools of the patients being studied. A recent article by Chenard et al.54 showed significant differences between the gut microbiome of those with and without blood present in their stools. Specifically, Bacteroides uniformis, Clostridium symbiosum, and Collinsella aerofaciens were found to be significantly enriched in participants with bloody stools. All of these species were found to be significantly enriched in patients with CRC in this review. The Bacteroides genus was also significantly enriched in this group. Conversely, Faecalibacterium prausnitzii, Prevotella copri, and Roseburia
Figure 2: Forest Plot showing meta-analysis on association between Helicobacter pylori infection and colorectal cancer.42-53
faecis were enriched in the controls described by Chenard et al.,54 as well as the controls in this review. As blood in the stool is considered a key sign of CRC,55 this could explain some of the disparities between the microbiome profiles of patients with CRC and healthy individuals.
Many articles included in this review hypothesised that the microbiome has a causative role in CRC carcinogenesis. Causation, however, cannot be inferred through the study designs adopted. Casecontrol designs, as adopted by all but one study, cannot determine whether CRC is caused by the microbiome profile detected, or whether this profile arises due to environmental changes caused by CRC, due to testing at a set-point as opposed to testing over time. It is of no surprise that a case-control design was used in the majority of studies, as a causal relationship can often be inferred using these methods. However, in the case of studying the potential role of the microbiome in carcinogenesis, many factors may increase or decrease the abundance of different bacterial species at a set point in time. Therefore, concluding that the enrichments are purely as a result of their involvement in CRC carcinogenesis risks oversimplifying a complex array of interactions.
Microbiome sampling also differed between studies. Included in this review, Chen et al.39 performed a mix of rectal swabs, faecal sampling, and biopsy for microbiome detection, and found significant differences between each. Therefore, a truly representative microbiome profile may not have been obtained in many of the studies that used only one detection method.
There were inconsistencies in the reporting of characteristics such as sex distribution, tumour staging, and sequencing platforms used, which would have been useful in the meaningful interpretation of these results.
The studies included in this review did not routinely report on the medication use of participants. Research by Vich Vila et al.56 has shown evidence for extensive changes in the gut microbiome composition with commonly used medications such as proton
pump inhibitors, metformin, and laxatives. This interaction has the potential to further impact the risk of CRC development, and thus, requires further research.
Limitations of this review
The research included in this review originated from a wide variety of countries and the potential difference in microbiome related to diet was not thoroughly evaluated. Papers have found differences in the microbiome between patients with varying diets,57,58 which could predispose participants with certain diets to already high levels of specific bacteria, as well as a higher diversity of bacteria.59 Thus, this disparity may, in part, be due to the variations in diet between cultures.
A growing number of studies have emphasised how host genetic variations influence the gut microbial phenotype and how these multivariable interactions contribute to the development of CRC.60,61 While host genetics were outside the scope of this review, the authors recognise its potential relevance and importance as an increasing area of interest.
The focus of this article on genus and species taxonomic levels may also be seen as overly specific, when a more thorough analysis of all taxonomic levels implicated in CRC may provide a broader consensus. As this review excluded studies not written in English, due to language limitations; grey literature; and print-only journals, this decision may have excluded papers that could have enlightened further on this subject. The authors also acknowledge that more databases could have been searched as part of their research. The risk of bias amongst the included studies was also not thoroughly explored with the use of formal, published tools.
Meta-analysis Results
As can be seen in Figure 2,42-53 the OR of 1.49 (95% CI: 1.19–1.86) shows a statistically significant link between H. pylori infection and CRC. However, this meta-analysis found considerable heterogeneity, which must be considered when inferring clinical
significance. As part of the analysis, a funnel plot (Supplement 6), contour-enhanced funnel plot, Egger’s test, and the trim-and-fill method were run on the extracted data to search for evidence of publication bias.
The main sources of heterogeneity for this meta-analysis are likely due to population size differences and disparities in detection methodology. Recruitment study design also evidently contributed to the I2 statistic, shown by the moderateto-low heterogeneity within each design’s subgroup-analysis (Figure 2).42-53
This result, when taken without correction for potential publication bias, shows a considerably raised risk when compared with other known CRC risk factors. With red meat consumption at a risk ratio of 1.12 (95% CI: 1.03–1.21),62 and obesity at a risk ratior of 1.19 (95% CI: 1.11–1.29),63 H. pylori infection proves to be a significant risk for CRC carcinogenesis.
The analyses discussed in this article showed evidence of publication bias. After running the trim-and-fill method, it was calculated that the addition of the five studies theoretically missing from the results would have resulted in a statistically insignificant link between H. pylori infection and CRC. Without these studies however, it is impossible to tell whether this is correct. Therefore, the result as it stands indicates that infection with H. pylori significantly increases the risk of CRC.
Limitations of included studies
There was a variation in the methods used to detect H. pylori infection. Many used detection of IgG through ELISA, others used tests such as urease and carbon breath tests. Using IgG detection, it is impossible to work out whether the infection is active or already eradicated. Both historic and ongoing infection may increase CRC risk, however, for this hypothesis to be tested effectively, infection must be confirmed as either active or eradicated alongside IgG detection.
Limitations of this meta-analysis
As the initial aim of the paper was not to perform a meta-analysis on this subject, this search strategy was not fully comprehensive.
An extra search into H. pylori alone may have returned more papers and provided additional data for the analysis.
The large degree of heterogeneity may be a limitation, potentially affecting the clinical significance of this meta-analysis and its results. Meta-regression was also not performed by the authors, which could have further investigated this heterogeneity.
Future Research
As discussed, the case-control design is not sufficient to determine causality in this instance. This paper has identified the most frequently replicated key genera and species linked to CRC. However, due to the limitations of these study designs, it cannot be concluded that these bacteria raise the risk of developing CRC. To study this effectively, a large population, prospective cohort study should be performed, with regular colonoscopy and microbiome sampling. This sampling should be a combination of faecal, swab, and biopsy sampling. This would facilitate the representative characterisation of the microbiome profiles most commonly linked to CRC development, allowing a conclusion to be drawn as to whether there is any causative relationship between the human gut bacterial microbiome and CRC.
Implications of This Paper
To the authors’ knowledge, this is the first review of this type conducted in this topic. The results of this paper, combined with those of prospective cohort studies, as suggested, may have implications in the personalised management of patients to reduce their risk of CRC. The potential implications of the use of probiotics to lower risk has not yet been fully investigated and requires serious attention. However, this paper has identified species that may be of interest in a study of this nature.
It has been documented that probiotics could shape the intestinal microbiota.64 Knowledge of this, together with gut microbiome profiles associated with CRC, creates the potential for prophylactic probiotic administration to create a gut
microbiome with lower CRC risk. Previous studies have alluded to the effectiveness of probiotics in the treatment and prevention of CRC.65-67 If CRC-associated bacteria can be significantly reduced within the microbiome, and healthy-associated bacteria increased through the use of probiotics, for example, this may reduce an individual’s risk of developing CRC.
CONCLUSION
This narrative review demonstrates the paucity and discrepancies amongst current research into the elevated risk bacteria pose on CRC development. However, considering these limitations, certain consistencies were present within the data extracted. There is a considerable link between the Fusobacterium genus and CRC, with a possible link suggested between bacterial
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57. David LA et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;505(7484):559-63.
58. Johnson AJ et al. Daily sampling reveals personalized diet-microbiome associations in humans. Cell Host Microbe. 2019;25(6):789-802.e785.
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60. Bonder M et al. The effect of host genetics on the gut microbiome. Nat Genet. 2016;48:1407-12.
61. Colombo F et al. Gut microbiota composition in colorectal cancer patients is genetically regulated. Sci Rep. 2022;12(1):11424.
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65. Marteau P et al. Probiotics and intestinal health effects: a clinical perspective. Br J Nutr. 2002;88(S1):s51-s57.
66. Liang JQ et al. A probiotic formula for modulation of colorectal cancer risk via reducing CRC-associated bacteria. Cells. 2023;12(9):1244.
67. Shang F et al. The inhibitory effects of probiotics on colon cancer cells: in vitro and in vivo studies. J Gastrointest Oncol. 2020;11(6):1224-32.
Cytomegalovirus/Herpes Simplex Virus Co-infection with Associated Oesophageal Stricture in a Young Immunocompetent Woman: A Case Report and Literature Review
Authors: *David Godfrey,1 Ashwin
Patwardhan
1
1. Gastroenterology Department, The Royal Melbourne Hospital, Victoria, Australia
*Correspondence to david.godfrey@mh.org.au
Disclosure: The authors have declared no conflicts of interest.
The authors report the first case of oesophageal cytomegalovirus (CMV) and herpes simplex virus (HSV) co-infection in an immunocompetent patient with an associated oesophagal stricture. The authors also review the literature on oesophageal strictures related to CMV and/ or HSV oesophagitis. CMV and HSV co-infection is well documented in immunocompromised patients. The oesophagus is one of several organs known to harbour co-infection. To the knowledge of the authors’, its association with an oesophageal stricture is rare and has only been noted in patients with HIV. The authors report a case of an immunocompetent 40-yearold woman with a past history of iron deficiency anaemia and idiopathic hypertension who presented with dysphagia. Investigations revealed a circumferential oesophageal stricture, with biopsies positive for CMV and HSV. This patient was HIV-negative and had no evidence of immunodeficiency. The patient was treated successfully with valganciclovir and multiple endoscopic oesophageal dilatations. This presentation in an immunocompetent patient has not been described in the literature to the authors’ knowledge and represents a valid differential diagnosis to be recognised in clinical practice.
Key Points
1. This is the first time an oesophageal stricture related to cytomegalovirus (CMV) and herpes simplex virus (HSV) co-infection in an immunocompetent individual has been described. All cases of previously described CMV-related oesophageal strictures have been in the context of immunosuppression related to HIV or medication-related immunosuppression.
2. This study is a case report with a review of the literature on CMV-related oesophageal strictures. The review includes seven studies involving 18 patients over 33 years from being first described in 1991 (up to 2024).
3. CMV and HSV chronic infection must be considered in clinical practice and screened for in patients presenting with dysphagia secondary to an oesophageal stricture in the absence of malignancy.
CASE PRESENTATION
A 40-year-old woman presents with 3 weeks of progressive dysphagia and 10 kg of associated weight loss. Gastroscopy was performed, demonstrating an intrinsic oesophageal stricture at 23 cm from the incisors, which was unable to be traversed by a slim gastroscope (5.4 mm outer diameter), as shown in Figure 1. A subsequent CT scan revealed concentric wall thickening of the midthoracic oesophagus, raising concerns of oesophageal malignancy, also shown in Figure 1. Endoscopic biopsy was performed on the stricture revealing cytomegalovirus (CMV) and herpes simplex virus (HSV) oesophagitis with no dysplasia and no evidence of malignancy. Past medical history included iron deficiency anaemia and idiopathic hypertension, treated with amlodipine-valsartan 5-160 mg once daily. There was no history of proton pump inhibitor or significant antibiotic use. An extensive history was taken from the patient to determine the cause of immunosuppression. Most notably, there were no contributing immunosuppressant medications, relevant past medical history, prior or current malignancy, infective symptoms, or sexual history. Immunological testing revealed negative HIV serology during admission and 6 weeks postadmission and normal total levels of immunoglobulins A, M, and G, CD3+/4+/8+ T cells, CD19+ B cells, and CD3- natural killer cells. An infective screen was negative for serum HSV1/2 IgM, CMV IgM, and CMV viral load <30 IU/mL, Epstein-Barr virus IgM, and an infective screen of sexually transmitted infections was negative for Chlamydia trachomatis, Neisseria gonorrhoeae, and Syphilis. The patient did not have chronic viraemia or systemic infection with CMV or HSV. Additionally, in consultation with inpatient immunology specialists, the patient was deemed to have no immunodeficiency.
Light microscopy showed stratified squamous mucosa with underlying granulation tissue and dense mixed inflammatory infiltrate, as shown in Figure 2. Immunohistochemistry demonstrated focal positive nuclear staining for HSV-1 and HSV-2 within the epithelium and positive CMV staining in the enlarged endothelial cells. Special stains were negative for other organisms. There was no dysplasia and no evidence of malignancy. The patient was commenced on valganciclovir, a highdose proton pump inhibitor, and received optimised nutrition in conjunction with an inpatient dietician. Initially, nasogastric feeding was attempted but subsequently changed to total parenteral nutrition via a central line due to the patient not tolerating the nasogastric tube. The central line was removed following 3 kg of inpatient weight gain, and she was discharged with oral supplements. She also received an iron infusion of 1 g ferric carboxymaltose on discharge. Following discharge, the patient received weekly oesophagal dilatations via controlled radial expansion balloon in sequential increments of size for 5 weeks, also shown in Figure 1, with symptoms of dysphagia improving drastically and a further 4 kg weight gain over this time period. The patient was treated for a total of 6 weeks of oral valganciclovir and planned for ongoing outpatient follow-up.
DISCUSSION
Infectious oesophagitis is the leading cause of oesophagitis worldwide.1 CMV is a common virus affecting the general population, with 50% of people being exposed by young adulthood and 85% by the age of 40.2 In immunocompetent individuals it can present with flu-like symptoms such as fever, fatigue, and muscle aches; however, in immunosuppressed patients, it can cause more severe symptoms and affect multiple organs, including the eyes, lungs, liver, and
A) Gastroscopy image showing the oesophageal stricture during inpatient admission. B) Inpatient gastroscopy after attempt to traverse the stricture with a slim gastroscope. C) Prior to 5ᵗʰ oesophageal dilatation. D) Post 5ᵗʰ oesophageal dilatation showing marked improvement in luminal diameter. E) CT axial view of oesophageal stricture at 23 cm from the incisors showing concentric wall thickening. F) CT coronal view of oesophagal stricture.
gastrointestinal tract.3 HSV is also a common virus in the population, with HSV-1 being more common than HSV-2, 67% versus 13% in individuals under 50, respectively.4 In immunocompetent individuals, infection with HSV presents with vesicular lesions generally on mucosal surfaces in contact with the external environment such as the mouth or genitals. The presentation of HSV in immunocompromised patients is known to affect other organs as well such as the liver, brain, and lungs causing more severe symptoms.5
CMV and HSV are both known to affect the oesophagus and are routinely screened for.6 Cases of oesophageal strictures have been noted in CMV oesophagitis but only in immunosuppressed adults and children, as
seen in Table 1. 7-13 Additionally, concurrent oesophagitis with CMV and HSV is rare and is documented almost entirely in case studies of HIV, transplant, or other medication-related immunosuppression.14 An oesophageal stricture refers to the formation of granulation tissue and a narrowing of the lumen which leads to dysphagia and is associated with chronic conditions such as gastroesophageal reflux disease, oesophageal cancer, and eosinophilic oesophagitis.15 Oesophageal strictures as a result of CMV and HSV infection are extremely rare and only documented in a single case series of patients with HIV.8
The authors present a case of a circumferential oesophageal stricture with associated concurrent CMV/HSV infection
Figure 1: Gastroscopy and CT images.
A) PAS stain showing nuclear features of HSV infection: enlarged multinucleated cells with chromatin marginalisation and nuclear molding. B) HSV-1 IHC stain showing infection with HSV1. C) HSV-2 IHC stain showing infection with HSV-2. D) H&E stain showing inflamed stroma with nuclear features of CMV infection: enlarged cells with basophilic nuclei and pale perinuclear regions. E) CMV IHC stain showing infection with CMV. F) H&E stain on lower magnification showing significant inflammatory infiltrate into the stroma of the biopsied oesophagus.
CMV: cytomegalovirus; H&E stain: haematoxylin and eosin stain; HSV: herpes simplex virus; IHC: immunohistochemistry; PAS stain: Periodic acid–Schiff stain.
in a young immunocompetent woman. This is a novel presentation of viruses commonly associated with immunosuppression. Interestingly, ulceration of the oesophagus, an acute macroscopic feature of both CMV and HSV oesophagitis, was not seen on endoscopy. Acute infection was also excluded by serological testing of CMV and HSV. Histological testing, however, demonstrated clear CMV and HSV infection. As a result, the oesophageal stricture in this case is likely the result of chronic infection and subsequent fibrous healing, which has been postulated in previous case reports of CMV-related oesophageal strictures.16 However, it is unclear what the contributing factors were to CMV and HSV reactivation in this case, in the absence of clear causes of systemic immunosuppression. A control biopsy of the stricture following anti-viral treatment was not performed as the patient discharged her care to another health service internationally;
however, this would have been interesting to ascertain the persistence of CMV or HSV in the oesophagus. Instead, treatment was considered successful with a lack of stricture progression and increased patency on serial dilatations with concurrent antiviral treatment.
Local oesophageal microbiome changes have been identified in disease states of the oesophagus.17,18 A review of infectious esophagitis in children raises the possibility of local microbiome changes or dysbiosis in the oesophagus as a contributor towards eosinophilic oesophagitis, a chronic inflammatory process.19 As the presentation in this case involves a chronic inflammatory process, it is possible that dysbiosis may contribute. Influences on gastrointestinal microbiota include proton pump inhibitors, antibiotics, and diet, yet the impact of these on the oesophageal microbiome is incompletely understood.20 Additionally,
Figure 2: Histology images of oesophageal biopsy.
Table 1: Patients reported to have CMV-related strictures in the literature.
2024, Current case CMV and HSV 1 (Female aged 40 years)
2022, Tennant et al.9
2020, Mansfield et al.7
2015, Arnold et al.10
CMV 1 (Male aged 77 years)
CMV 1 (Female aged 27 years)
None
Renal transplant treated with mycophenolate 500 mg BID, tacrolimus 5 mg BID, and prednisone 10mg daily
CMV 5 (Children aged 3 days to 12 years) HIV (children)
2010, Sheth et al.11
CMV 1 (Male aged 31 years)
Valganciclovir and oesophageal dilatations
IV ganciclovir then oral valganciclovir and oesophageal dilatations
IV ganciclovir and oesophageal dilatation
Antiviral treat-ment and oesophageal dilatations
Ganciclovir then lost to follow-up, 18 months later represented with worse dysphagia and treated with esophagectomy with gastric pull-up
1999, Wilcox et al.8
1992, Churchill et al.12
CMV/HSV 5 CMV (ND) 1 HSV (ND) 1 CMV/HSV (ND)
CMV 2 (ND)
CMV 1 (Male aged 49 years)
BID: twice a day; CMV: cytomegalovirus; HSV: herpes simplex virus; IV: intravenous; ND: not disclosed. Year Infections
Recovery
Recovery
Recovery
ND but high mortality noted in patients affected with HIV in the audit
Recovery
Ganciclovir and oesophageal dilatations ND 1991, Goodgame et al.13
Ganciclovir and Oesophageal dilatations
ND
the role of dysbiosis in augmenting the immune response as it pertains to CMV and HSV infection is not well understood but warrants further investigation.
CONCLUSION
Infectious oesophagitis is associated with significant morbidity in immunosuppressed populations. Concurrent CMV and HSV infection of the oesophagus is very rare in immunocompetent patients, which
prompts the authors’ description of this case report. Oesophageal strictures are also associated with significant morbidity when symptomatic with dysphagia, weight loss, and malnutrition. Both infectious oesophagitis and oesophageal strictures warrant significant investigation to identify immunosuppression and malignancy. Further research on the role of dysbiosis in oesophageal pathology may provide insight into the pathophysiology of these diseases in the future.
References
1. Hoversten P et al. Infections of the esophagus: an update on risk factors, diagnosis, and management. Dis Esophagus. 2018;DOI: 10.1093/dote/ doy094.
2. Health NDo. Cytomegalovirus (CMV) and pregnancy fact sheet. 2017. Available at: https://www.health. nsw.gov.au/Infectious/factsheets/ Pages/cmv-and-pregnancy.aspx. Last Accessed: 17 February 2024.
3. Kudesia G, Wreghitt T, "Clinical and Diagnostic Virology," (2009), Cambridge: Cambridge University Press, pp.17-20.
4. Organisation WH. Herpes simplex virus. 2023. Available at: https://www. who.int/news-room/fact-sheets/detail/ herpes-simplex-virus. Last Accessed: 17 February 2024.
5. Singh M et al, "Herpes Simplex Virus Infections," Hoeger P et al. (eds.), Harper's Textbook of Pediatric Dermatology (2019) 4th edition, Wiley, pp.598-611.
6. Gopal P et al. Unique causes of esophageal inflammation: a histopathologic perspective. Ann N Y Acad Sci. 2018;1434(1):219-26.
7. Mansfield BS et al. Cytomegalovirusassociated esophageal stricture as a manifestation of the immune reconstitution inflammatory syndrome. IDCases. 2020;21:e00795.
8. Wilcox CM. Esophageal strictures complicating ulcerative esophagitis in patients with AIDS. Am J Gastroenterol. 1999;94(2):339-43.
9. Tennant TC et al. Esophageal stricture caused by CMV in a non-HIV-infected renal transplant patient. ACG Case Rep J. 2022;9(8):e00836.
10. Arnold M et al. Surgical manifestations of gastrointestinal cytomegalovirus infection in children: clinical audit and literature review. J Pediatr Surg. 2015;50(11):1874-9.
11. Sheth A et al. Complete esophageal obliteration secondary to cytomegalovirus in AIDS patient. Dis Esophagus. 2010;23(6):E32-4.
12. Churchill D et al. Oesophageal stricture complicating cytomegalovirus ulceration in a patient with AIDS. JInfect. 1992;25(1):108-9.
13. Goodgame RW et al. Esophageal stricture after cytomegalovirus ulcer treated with ganciclovir. J Clin Gastroenterol. 1991;13(6):678-81.
14. Bannoura S et al. Esophageal cytomegalovirus and herpes simplex virus co-infection in an immunocompromised patient: Case report and review of literature. IDCases. 2020;22:e00925.
15. Desai JP MF, Esophageal Stricture [Internet] (2002) Treasure Island: StatPearls. Available at: https://www. ncbi.nlm.nih.gov/books/NBK542209/. Last Accessed:10 February 2024.
16. Olmos M et al. Esophageal strictures complicating cytomegalovirus ulcers in patients with AIDS. Endoscopy. 2001;33(9):822.
17. Corning B et al. The esophageal microbiome in health and disease. Curr Gastroenterol Rep. 2018;20(8):39.
18. Park CH, Lee SK. Exploring esophageal microbiomes in esophageal diseases: a systematic review. J Neurogastroenterol Motil. 2020;26(2):171-9.
19. O'Donnell JEM, Krishnan U. Infectious esophagitis in children. J Pediatr Gastroenterol Nutr. 2022;75(5):55663.
20. May M, Abrams JA. Emerging insights into the esophageal microbiome. Curr Treat Options Gastroenterol. 2018;16(1):72-85.
Infective Endocarditis Following Selective Angioembolisation for Lower Gastrointestinal Tract Bleeding: A Case Report
Authors: *Michelle Bai,1,2 Ferdinand Ong,1 Daniel Kozman1
1. Department of Surgery, St George Hospital, Kogarah, Australia
2. University of New South Wales, Sydney, Australia *Correspondence to michellecbai@gmail.com
Disclosure: The authors have declared no conflicts of interest.
Received: 02.09.24
Accepted: 10.10.24
Keywords: Angioembolisation, case report, gastrointestinal bleeding, infective endocarditis.
Selective angioembolisation is a common treatment modality for lower gastrointestinal bleeding. Sepsis is an uncommon complication of the procedure, and infective endocarditis is even rarer yet. Presented here is a case of a male in his 50s who received selective angioembolisation to a branch of the right colic artery to control lower gastrointestinal bleeding. He subsequently developed sepsis and acute cardiac failure due to Enterococcus faecalis bacteraemia and infective endocarditis, requiring a valve replacement surgery and an extended course of antibiotics.
Key Points
1. Selective angioembolisation is a common and safe treatment modality for lower gastrointestinal bleeding. Sepsis is an uncommon complication of the procedure, and infective endocarditis is even rarer yet.
2. This is a case report of native aortic valve infective endocarditis following selective angioembolisation for lower gastrointestinal bleeding.
3. Bacteraemia and infective endocarditis are rare but important differential diagnoses to consider in a patient presenting with sepsis following gastrointestinal intervention.
INTRODUCTION
Selective angioembolisation is a safe and minimally invasive technique for the treatment of acute lower gastrointestinal (GI) bleeding. It is a valuable alternative treatment modality for patients who are poor surgical candidates, or refractory to transfusion resuscitation or endoscopic treatment. Technical success of this procedure has been reported to be 85–100%. Well recognised complications include rebleeding (0–20%), ischaemic complications to the bowel (0–7%), acute kidney injury, and access-site complications.1 The authors report a rare case of native aortic valve infective endocarditis following selective angioembolisation for lower GI bleeding.
PATIENT INFORMATION
A male aged in his 50s presented to the authors’ emergency department following a syncopal episode associated with rectal bleeding and vomiting without haematemesis. He denied any abdominal pain, recent change in bowel habit, weight loss, or constitutional symptoms. He was otherwise previously well and did not take any regular medications. He had a colonoscopy 2 years prior, which showed widespread diverticular disease throughout the colon, and had previously had a laparoscopic appendicectomy for appendicitis.
Clinical Findings
The patient was haemodynamically stable, and his abdominal examination was unremarkable. Digital rectal examination was painless, with blood-stained mucus on the glove. Laboratory testing revealed he had anaemia with a haemoglobin of 94 g/L. His renal function and liver function were normal.
Diagnostic Assessment
He was admitted to the authors' surgical unit for observation and was placed on a clear fluid diet. The following day, he had a further episode of large frank rectal bleeding, with a significant drop in his
haemoglobin to 74 g/L. At this time, he reported light-headedness and abdominal discomfort. An urgent CT mesenteric angiogram showed an active blush in the ascending colon, which was presumed diverticular in origin. There were no signs of colitis.
Therapeutic Intervention
The patient was resuscitated with three units of packed red bloods cells and his haemoglobin incremented to 92 g/L. He underwent urgent selective angioembolisation with digital subtraction angiography, performed by the interventional radiology department (Figure 1). A branch of the right colic artery was embolised using two Tornado® embolisation coils size 3/2 (Cook Medical, Bloomington, Indiana, USA) and this successfully controlled the bleeding. He had two episodes of self-limiting rebleeding 24 hours later, and was treated with further packed red blood cell transfusions. He was then discharged with outpatient follow-up.
Eighteen days later the patient re-presented with fevers and dyspnoea. Blood cultures returned a result of Gram-positive cocci within 24 hours. On examination, there were new pansystolic and diastolic murmurs, and peripheral oedema. Clinically, the patient was in decompensated heart failure. There were no peripheral stigmata of infective endocarditis. A chest X-ray was performed, which showed features of pulmonary oedema. He had no other focus of infection noted on history, examination, and investigations. Treatment with intravenous benzylpenicillin 2.4 g 6-hourly was commenced until identification of Enterococcus faecalis on blood cultures. At this point, the antibiotic therapy was changed to intravenous ampicillin 2.0 g 6-hourly and ceftriaxone 2.0 g 12-hourly. Transoesophageal echocardiogram revealed flail aortic valve leaflet with torrential aortic valve regurgitation and findings suspicious for an aortoatrial fistula. No obvious vegetation was identified and coronary angiogram was normal.
Figure 1: A) Digital subtraction angiography showing contrast extravasation ‘blush’ from a branch of right colic artery. B) Post embolisation, coils shown in situ and resolution of the arterial blush.
The patient underwent an emergency bioprosthetic aortic valve replacement with a 25 mm INSPIRIS RESILIA bioprosthesis (Edwards Lifesciences, Irvine, California, USA). Intraoperative findings showed an infected aortic valve, with the left coronary cusp destroyed by vegetations; the non-coronary cusp had a vegetation with perforation; and the right coronary cusp was normal. There was no aorto-atrial fistula.
He was admitted to the ICU postoperatively and was transferred to the surgical ward on post-operative Day 2. Tissue culture of the aortic valve vegetations confirmed growth of E. faecalis that was sensitive to ampicillin, gentamicin, and vancomycin. Antibiotic therapy was changed to intravenous ampicillin 2.0 g 6-hourly and gentamicin 60.0 mg 12-hourly, as per susceptibility testing. A peripherally inserted central catheter line was inserted to facilitate long-term intravenous antibiotic therapy.
Follow-up and Outcomes
The patient was discharged home on post-operative Day 14. Antibiotic therapy in the community setting comprised intravenous gentamicin 60.0 mg twice daily and benzylpenicillin infusion of
14.4 g over 24 hours. Metoprolol and aspirin were commenced as long-term therapy. Five days after discharge, gentamicin was changed to ceftriaxone 2.0 g 12-hourly due to a possible new, mild vestibulocochlear toxicity noted on examination during outpatient follow-up. In total, the patient completed 6 weeks of intravenous antibiotic therapy from the date of the operation and was discharged from the clinic.
DISCUSSION
To the best of the authors’ knowledge, the present case is the first reported case of infective endocarditis as a complication of angioembolisation to control lower GI bleeding. The presumed origin of the E. faecalis bacteraemia in this case was the GI tract, given the temporal association between the angioembolisation and infection, and the absence of other risk factors for infective endocarditis. Enterococci are Gram-positive facultative anaerobic bacteria that are normal commensal bacteria in the human GI tract.2 In the healthy state, the intestinal mucosal barrier provides physical, biochemical, and immunological defence against bacterial translocation. Insults causing tissue injury, such as ischaemia and surgical manipulation of the intestine, can
cause compromise to this protective barrier.3 Bacterial translocation of enterococci species from the GI tract to the bloodstream and lymphatics can result in bacteraemia, sepsis, and seeding of distant organs. Patients with E. faecalis bacteraemia are at high risk of infective endocarditis. In a study by Dahl et al.,4 26% of 344 patients with E. faecalis bacteraemia were found to have infective endocarditis on echocardiography. Indeed, infective endocarditis may lead to potentially fatal complications including systemic embolisation, cardiac failure, mycotic aneurysm, and neurological complications.5
The authors propose that in the case presented in this article, local ischaemia from angioembolisation resulted in disruption of the intestinal mucosal barrier, thus allowing translocation of enteric bacteria into the systemic circulation.6-8 The extent of the vascular bed embolised should be considered, particularly as even subclinical ischaemia-reperfusion injuries can result in bacterial translocation.9 It would be logical to hypothesise that the larger the vascular bed embolised, the larger the area of potential ischaemic bowel injury. The risk may be reduced with superselective angioembolisation, where the arterial recta supplying the site of haemorrhage is catheterised and embolisation performed only if the bleeding source is identified.10
In the presented case, prophylactic antibiotics were not administered during selective angioembolisation for lower GI bleeding. The patient had no identifiable risk factors for the development of postprocedure infective endocarditis, as outlined by the Society of Interventional Radiology (SIR). Current guidelines indicate that antibiotic prophylaxis for embolisation of GI bleeding is not necessary, except in cases of haemobilia.11 Additionally, the American Heart Association (AHA) guidelines indicate that antibiotic prophylaxis solely to prevent infective endocarditis is not recommended for patients undergoing GI procedures.12
In the case presented, the patient had a history of underlying diverticular disease, diagnosed on a colonoscopy performed 2years prior. Escolà-Vergé et al.13 have demonstrated that existing colonic disease
is very common amongst patients with E. faecalis endocarditis, even if the portal of entry is presumed to be known. In their study, colorectal disease was found on colonoscopy following diagnosis of E. faecalis endocarditis in 60% of cases.13 Therefore, it is possible the history of underlying diverticular disease and certainly the acute GI bleeding were important predisposing factors in the case presented in this article. Perhaps there may be a role for antibiotic prophylaxis for lower intestinal GI angioembolisation in cases with high-risk features, such as pre-existing colonic pathology or active bleeding.
There is still much to be explored regarding the role of the gut microbiome and dysbiosis in states of health and disease. Translocation of E. faecalis has been found to coincide with a threshold of enterococcal colonisation in the gut lumen in mouse models.14 E. faecalis overgrowth may also stimulate reactive oxygen species production and colonic cell genomic instability. Reactive oxygen species are known to play a role in the pathogenesis of intestinal ischaemic injury, thus increasing the risk of bacterial translocation.15,16 As such, it can be hypothesised that gut dysbiosis may predispose some individuals to the risk of bacterial translocation and the associated complications.
CONCLUSION
This case illustrates an unusual and lifethreatening complication of selective angioembolisation to control lower GI bleeding. Clinical features of bacteraemia and infective endocarditis may initially be vague; however, they are important differential diagnoses to consider in a patient presenting with sepsis following GI intervention. Compromise of the intestinal mucosal barrier may predispose to the translocation of enteric bacteria into the systemic circulation, which could lead to potential distant colonisation.
Informed Consent
The patient provided informed consent for de-identified details of this case to be published.
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