Gut Feeling January Edition 2020
Introduction Over the past few years, the knowledge on the gut microbiome has risen exponentially. Scientists are finding new ways on how the bacteria in our intestines are influencing the body’s immune system, metabolism and even mental health. In 2017, approximately 4000 papers focusing on the gut microbiota were published, and between the years 2013 and 2017, more than 12 900 publications were devoted to the study of the gut microbiota. This remarkable number represents more than 80% of the overall publications over the last 40 years on this topic. As you can see, the topic is very hot and that’s why we focused on it in this edition of EPSA Science! Monthly.
Josef Kunrt EPSA Science Coordinator 2019/2020
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A gut feeling for mental health It is a well-known fact that there are more bacteria than human cells in our body and it is estimated that there are 10 bacterial cells for every human cell. Furthermore, there are an estimated 3.3 million genes in the bacterial genome, which is 160 times the number of human genes. Bacteria in the gut microflora aid in digesting food, production of vitamins and also protect us from infections. But there is a growing amount of studies uncovering new and previously unheard of roles for these little helpers. There is evidence that gut bacteria can protect or predispose us for various disease states, ranging from inflammation to diabetes and obesity. As far-fetched as it sounds, a remarkable amount of data shows that they can even modify our mood and behaviour. (1) This is due to gut-microbiota-brain axis, a multidirectional network including the CNS, autonomic nervous system, enteric nervous system, hypothalamic-pituitary-adrenal axis, neural, endocrine and immune system. In a nutshell, this network provides a path for signals from the brain to influence the motor, sensory and secretory functions of the intestines and at the same time allowing signals and metabolites from the microbiome to influence brain development, biochemistry, function and behaviour. One of the most obvious associations between the gut microbiome and psychological disorders is the ability of the microbiome to change the production and action of several key neurotransmitters, through regulation of amino acid metabolism, including gamma‐aminobutyric acid (GABA), serotonin, melatonin, and dopamine. (2) The link between the gut microbiome and mental health has been previously well established in animal models, but has not been fully investigated in human studies. Researchers from the Flander Institute for Biotechnology published the first population-level study on the link between gut bacteria and mental health, specifically depression. They identified specific groups of microorganisms that are positively or negatively correlated with mental health. The authors found that two bacterial genera were consistently depleted in individuals with depression, regardless of antidepressant treatment. They also created a computational technique allowing the identification of gut bacteria that could potentially interact with the human nervous system. (3) Another recent research focused on how serotonin and fluoxetine, popular antidepressant, is affecting the gut’s microbiota. This animal study done by scientists at the University of California, USA, has identified a specific intestinal bacterium that can detect and transport serotonin into bacterial cells. When mice, the study organism, were given fluoxetine the biologists found this reduced the transport of serotonin into their cells. These findings align with a growing number of studies reporting that antidepressants can alter gut microbiota. (4) Another research team, this time from University College Cork, have focused on a wide variety of psychotropic drugs, such as antipsychotics, antidepressants, anxiolytics, anticonvulsants/mood stabilisers, opioid analgesics, drugs of abuse, alcohol, nicotine and xanthines, and their effect on the microbiome. The study itself is very broad and it is not possible to include all the findings in this article. The main outcome connected to the gut microbiome and mental health is that drugs such as lithium and fluoxetine influence the composition and richness of the gut microbiota. (5)
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Both studies have several implications for future research. First of all, some studies have shown that depressed or schizophrenic patients can have altered microbiota composition, therefore psychotropic drugs might work on intestinal microbes as part of their mechanisms of action. On the other hand, microbiome-targeting effects might be responsible for the side effects associated with these medications. All these hypotheses have to be tested in preclinical models and in humans. As you can see there is a lot to look for in the future.
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What happens with gut bacteria when we are taking antibiotics? Antibiotics are a marvellous discovery that provided us with the tools to carry out a vast range of surgical treatments and ended the age when humanity feared bacterial infections. Unfortunately, antibiotics are not completely risk averse and they come with their fare-share of complications. We may look at them as a doubleaged sword, on the one hand, they are capable of killing a wide range of bacteria that causes infections but also depleting our gut microbes, impairing our immune system and increasing vulnerability to infection by superbugs. In the past 10 years, it was established that the commensal bacteria living in our intestine help stabilise the immune system through communication with immune cells. But antibiotics are eradicating bacteria without great selectivity and thus many of their signals are lost. This leaves our immune cells without the ability to function normally. Disturbances to the human microbiota early in life have been linked to immune or metabolic difficulties, such as asthma and increased body mass, which can persist into adulthood. Evidence suggests that there are key moments when the presence of certain commensal bacteria is necessary for immune development. (6) On top of this, antibiotics act as a selection pressure on bacteria, driving antibiotic resistance. One problem with antibiotics is that by killing populations without such genes, those that survive multiply and transfer antibiotic resistance genes to other bacterial groups. Recent research has shown that the pool of antibiotic resistance genes within an individual's microbiome increases with age and is exposed to more antibiotics. (6) Another problem is that the “good” bacteria in our gut are also trying to protect themselves from the antibiotics. Scientists from Norwich BioScience Institute scanned the genome of a specific genus of bacteria that live in the intestines and they found genes that produce cephalosporinase, an enzyme that specifically destroys penicillin and similar antibiotics (cephalosporins). They also showed that the cephalosporinase are exported out of the bacterial cells, attached to the surface of special packages called Outer Membrane Vesicles (OMVs), which bacteria use to distribute compounds into the environment around them. This protective system was proven to shield ampicillin-susceptible Bifidobacterium breve. Unfortunately, the tests also showed that Salmonella bacteria were also protected. These tests were done in vitro but they pose implications for how we use antibiotics. (7) Luckily most of the time the gut microbiome is able to swiftly regenerate after antibiotic treatment. However, the bacterial diversity is not identical to the one before the treatment. One study published in the Nature Microbiology found out that six months after intensive four-day antibiotic treatment consisted of three broadspectrum antibiotics, frequently used in intensive care units, the study participants were still missing nine of their common beneficial bacteria and a few new potentially undesirable bacteria had colonized the gut. (8)
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The gut microbiome are not always able to regenerate after antibiotic treatment. This is usually the case in severely ill patients often with a compromised immune system undergoing multiple antibiotic regimens in a short time. In these cases, the microbiota often can’t regrow. This is a perfect opportunity for drug-resistant bacteria to thrive and cause severe infections. A promising treatment of these cases is faecal microbiota transplantation. Although this treatment has several promising results in animal and human studies there is still a need to advance with research on this topic to assess the efficacy and safety of this approach. (9)(10)
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When the gut microbiome damages the gut? Autoimmune diseases are a condition when an individual’s adaptive immune system is attacking the organisms own structures. The world incidence is approximated to be 3-5%. The pathogenesis is not yet fully elucidated, but it seems that environmental factors such as lifestyle, diet, medications and infections, and certain genetic backgrounds might play a role in this process. The human microbiome might have a big role in autoimmunity, as the loss of immune tolerance can be caused by microbial composition changes. (11)(12) This hypothesis was tested in the past couple of years. One research team from University of Rome Tor Vergata, Italy, found that autoantibodies directed against the cell wall mannan of the yeast Saccharomyces cerevisiae, a widespread commensal microorganism, were detected in several autoimmune diseases with different sensibilities (i.e. rheumatoid arthritis and systemic lupus erythematosus). More specifically, anti-S. cerevisiae antibodies are a specific serological marker of Crohn’s disease by appearing before CD onset in 32% of cases. (13) Numerous studies have shown that Crohn’s disease and ulcerative colitis, and other inflammatory bowel diseases, are associated with reduced complexity of the commensal microbiota and consistent shifts to a dysbiotic state. This is in a similar way which is observed during acute mucosal infections, as both of the disorders are characterised by the outgrowth of the certain bacteria, in particular from the Enterobacteriaceae and Fusobacteriaceae families. (14) But the mechanism itself is unknown. One possible mechanism is that it can be hidden in the way bacteria utilise nitrogen. In a series of human and mouse studies, the researchers from the University of Pennsylvania School of Medicine discovered that one type of non-beneficial bacteria feeding on urea played an important role in the development of dysbiosis. The "bad" bacteria, which harbour the urease enzyme, convert urea into ammonia, which is then reabsorbed by bacteria to make amino acids that are associated with dysbiosis in Crohn's disease. "Good" bacteria may not respond in a similar manner. This may hide a potential therapeutic approach to engineer the microbiome into a healthier state and treat the disease. The team is currently conducting a therapeutic clinical study in patients with refractory Crohn's disease using a strategy based on data from this study that focuses on deeply altering the gut microbiota. (15)
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Is the reason behind obesity our gut microbiome? Our gut microbiome have an irreplaceable role in the way how our bodies process food. These microbes have a number of ways to help. They produce additional sources of energy otherwise inaccessible to the host by breaking down soluble fibre, and by producing vitamins such as biotin, folate and vitamin K, and are also metabolizing xenobiotics such as the inactivation of heterocyclic amines formed in meat during cooking. The composition of gut microbiota is strongly dependent on the dietary patterns of an individual. The western diet is high in fat and sugars, and is associated with changes in the composition of the intestinal microbiome in animal models. (16) Researchers are looking for links between imbalances in the microbiome and obesity and metabolic syndrome. A recent study done by scientists from Lund University in Sweden focused metabolites in the bloodstream that are linked to obesity and investigated whether these metabolites affect the composition of the bacterial flora in stool samples. They found 19 different metabolites that could be linked to the person's BMI; glutamate and so-called BCAAs (branched-chain and aromatic amino acids) had the strongest connection to obesity. They also found that the obesity-related metabolites were linked to four different intestinal bacteria. By far the strongest risk factor for obesity in the study, glutamate, has been associated with obesity in previous studies, and BCAAs have been used to predict the future onset of type 2 diabetes and cardiovascular disease. This study also suggests that future research should focus more on how the composition of gut bacteria can be modified to reduce the risk of obesity and associated metabolic diseases and cardiovascular disease. (17) Another study found out that the healthy mice without Clostridia class of bacteria are becoming obese despite a healthy diet. The research team found that Clostridia prevents weight gain by blocking the intestine's ability to absorb fat. Furthermore, mice that were experimentally treated so that Clostridia were the only bacteria living in their gut were leaner with less fat than mice that had no microbiome at all. These insights could lead to a therapeutic approach with advantages over the faecal transplants and probiotics that are now being widely investigated as ways to restore a healthy microbiota. (18) Another possible way to tackle metabolic syndrome are compounds extracted from hops. In the most recent research, laboratory animals were given a high-fat diet exclusively, or a high-fat diet that included xanthohumol and its two hydrogenated derivatives. Scientists then measured the compounds' effects on bile acids, tissue inflammation and gut microbiome composition. Results show that each of the hops compounds decreased the amount and diversity of microbes, reduced inflammation and changed bile acid metabolism. There was a reduction in secondary bile acid production and an increase in conjugated bile acids, which are indicators of improved energy metabolism, glucose metabolism and cholesterol metabolism. The compounds previously showed antimicrobial activity so the hypothesis is that they may be killing off certain bugs that aren't beneficial and preserving other ones that are. But further research is needed to determine the precise mechanism in vitro in addition to what they are doing to the gut microbiota. (19)
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References: 1. 2. 3. 4. 5. 6.
https://www.sciencedaily.com/releases/2016/10/161020114611.htm https://onlinelibrary.wiley.com/doi/full/10.1002/brb3.1408 https://www.nature.com/articles/s41564-018-0337-x https://www.nature.com/articles/s41564-019-0540-4 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598948/ https://www.cell.com/trends/molecular-medicine/fulltext/S1471-4914(16)300077?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1 471491416300077%3Fshowall%3Dtrue 7. https://academic.oup.com/jac/article/70/3/701/776329 8. https://www.sciencedaily.com/releases/2018/10/181023110545.htm 9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6667716/ 10. https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1005132 11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4056765/ 12. https://www.sciencedirect.com/science/article/abs/pii/S1568997216301471?via%3Di hub 13. https://link.springer.com/article/10.1007%2Fs12016-012-8344-9 14. https://onlinelibrary.wiley.com/doi/full/10.1111/apt.14384 15. https://stm.sciencemag.org/content/9/416/eaah6888 16. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082693/pdf/nihms-793639.pdf 17. https://www.ncbi.nlm.nih.gov/pubmed/29409054 18. https://science.sciencemag.org/content/365/6451/eaat9351 19. https://onlinelibrary.wiley.com/doi/abs/10.1002/mnfr.201900789
Picture sources: 1. https://aanmc.org/wp-content/uploads/2019/11/iStock-1063752208.jpg 2. https://cdn.pixabay.com/photo/2018/04/19/01/47/mental-health 3332122_960_720.png 3. https://gastrotract.ru/wp-content/uploads/2018/07/21.3-2.jpg 4. https://live.staticflickr.com/1436/754962309_2dce031cd6_z.jpg 5. https://upload.wikimedia.org/wikipedia/commons/d/dc/Crohn%27s_Disease.png 6. https://cdn.pixabay.com/photo/2018/01/28/20/00/obesity-3114559_960_720.png
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