NutriCology ® Newsletter | Summer 2018
The Microbiome: Before Birth and Beyond
How this collection of microbiota impacts our health, and the evidence behind the prebiotics and probiotics we use to impact it...................................... Page 2
Probiotics: An Era of Increasing Specificity
Advanced genetic identification tools enable us to dial in on benefits of unique probiotic strains, such as Lactobacillus acidophilus DDS®-1....................... Page 6
Vaginal and Urinary Tract Health: Another Case for Probiotics
Although the genitourinary tract is host to far fewer microbial species than the gut, its microbiota play an important role in common female health concerns...................................................................................Page 8
Nonalcoholic Fatty Liver Disease: The Stealth Companion of Metabolic Syndrome
The evidence behind botanicals, probiotics, and simple nutrient therapies that address this common ailment............................................................... Page 10
NutriCology ® Phone: 800.545.9960 | 510.263.2000 Fax: 800.688.7426 | 510.263.2100 2300 North Loop Road For morewww.nutricology.com information call 800.545.9960 or visit www.nutricology.com Alameda, CA 94502
The Microbiome: Before Birth and Beyond
How This Collection of Microbiota Impacts Our Health, and the Evidence Behind the Prebiotics and Probiotics We Use to Impact It By Dr. Donald Brown, ND
From the Editor‘s Desk Nowadays, probiotics seem to be everywhere: in the media, in every grocery and health-food store, and even in conventional pharmacies. Given all the genera-, species-, and now even strain-specific products out there, it’s difficult to know what has good science and what is just market hype. The “gut microbiome” was termed only as recently as 2001.1 Since then, there have been discoveries of many “biomes,” which make up the human microbiome. Examples include the skin microbiome,2 respiratory microbiome,3 placental microbiome,4 and even a brain microbiome.5 The understanding of these different biomes, and how they impact disease manifestations and may improve health outcomes, is in its infancy, as is the science of different probiotics’ genera, species, and specific strains. In this issue of IN FOCUS, we delve into the science behind some of these specific strains and how they may positively improve people’s lives. We also discuss the evidence behind non-strain-specific Bifidobacterium spp. and Lactobacillus spp. Lastly, we discuss nonalcoholic fatty liver disease (NAFLD), which has a worldwide median 20% prevalence and has been shown to affect up to 46% of the US population!6 Natural therapies (including probiotics) have proven to be helpful in this seemingly ubiquitous condition. — Dr. Todd A. Born, ND, CNS Editor-in-Chief 1 Prescott S. History of Medicine: Origin of the Term Microbiome and Why It Matters. Human Microbiome Journal. 2017 June 7;4:24-5. 2 Byrd Al, et al. The human skin microbiome. Nat Rev Microbiol. 2018 Mar;16(3):143-55. 3 Dwyer David N, et al. The Lung Microbiome, Immunity and the Pathogenesis of Chronic Lung Disease. J Immunol. 2016 Jun 15;196(12):4839-47. 4 Aagaard K, et al. The Placenta Harbors a Unique Microbiome. Sci Transl Med. 2014 May 21;6(237):237ra65. 5 Molecular Biology of Neurodegeneration Laboratory. Is there a brain microbiome? [Internet]. Boulder (CO): University of Colorado Boulder. Available from: https://www.colorado.edu/lab/neurodegeneration/therebrain-microbiome. Accessed May 21, 2018. 6 Lazo M, et al. Prevalence of nonalcoholic fatty liver disease in the United States: The Third National Health and Nutrition Examination Survey, 19881994. Am J Epidemiol. 2013;178(1):38-45.
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In recent decades there has been an explosion of information regarding the role that the human microbiota plays in both health and disease. Projects such as the National Institutes of Health Human Microbiome Project1 and similar collaborative efforts in other countries have focused on the collection of human microbiome data from large populations for the purpose of increasing our knowledge about the microbes inhabiting the body.2,3 Combined with population data, these projects offer information about the impact of host and environmental factors on microbiota in average, healthy populations, as well as microbiome-associated variables that may point to disease risks. Our microbiome includes the microbes that find their home not only in the gastrointestinal (GI) tract, but also on the skin, respiratory tract, urogenital tract, and even in the brain. These microbes predominantly consist of bacteria, although nonbacterial organisms such as viruses and fungi are also represented. The term “microbiome” refers not only to the microbiota and their habitat but also the collective genomes of the microbes, known as the “metagenome.”4 Although some references estimate that the 100 trillion organisms comprising the human microbiome represent 10 times the number of cells in the human body,5 a recent paper suggests that the ratio of microbes to human cells is closer to 1.3:1.6 Regardless, both of these estimates reflect a substantial microbial
population whose function impacts not only the interfacing epithelial tissues but also the function of our body within.
Development of the Gut Microbiota By far, the largest population of these microbes is found in the GI tract, which is home to nearly 1013 to 1014 microorganisms that represent between 500 to 1,000 unique bacterial species.7,8 As we consider how this population becomes so complex, we must roll the clock back to infancy—and, recent research suggests, even earlier. The infant gut begins as a simple ecosystem that for years was considered to be sterile in utero, only becoming colonized through the vaginal canal in the process of birth, and then through the rapid introduction of flora from breast milk, maternal skin, and the surrounding environment and individuals.9 Recent research has characterized a placental microbiome, largely similar to the oral microbiome, which may influence the infant gut through gestation.10 A concerning fact is that differences have been seen in the placental microbiome that are associated with preterm birth.11 This, of course, is an ongoing topic of research, particularly for the development of therapeutic strategies.12 The most significant influences on the development of the infant gut have been well established to be mode of birth and early feeding.13 Compared to infants born vaginally, infants born by cesarean section have decreased
bacterial diversity, or “richness” in the gut.14,15 Studies have found an increased risk of obesity in children born by cesarean section,16 and also suggest an increased risk of food allergy, atopic dermatitis, and asthma in this population.17,18,19 Infants who are formula-fed also have decreased bacterial richness in the gut compared to those who are breastfed.20 Bifidobacteria dominate the gut microbiota of breastfed infants,21 which is influenced by the presence of both bifidobacteria and prebiotic oligosaccharides, known as human milk oligosaccharides (HMOs),22 found in breast milk.23,24 The HMOs not only serve as food for bifidobacteria, but also may have antimicrobial effects and modulate the immune system response, further protecting the vulnerable infant.
Studies have found an increased risk of obesity in children born by cesarean section, and also suggest an increased risk of food allergy, atopic dermatitis, and asthma in this population. The neonatal gut continues to populate and diversify through childhood until it reaches a high level of diversity similar to the adult gut by about two to three years of age.25 It is interesting to note that a lack of bacterial richness in the adult microbiome has been associated with increased risk of obesity, metabolic syndrome, dyslipidemia, and a more pronounced inflammatory phenotype.26 This association, while not necessarily causative, nevertheless implies that augmenting microbial richness can yield positive health outcomes. What means, then, exist for us to support the microbiome?
In addition to the prebiotic HMOs found in breast milk, many substances that are found in the diet and are available as supplements serve as prebiotics; that is, food for the microbes in the gut that have been shown to confer health benefits. The 2011 practice guidelines of the World Gastroenterology Organization define prebiotics as “dietary substances (mostly consisting of nonstarch polysaccharides and oligosaccharides poorly digested by human enzymes) that nurture a selected group of microorganisms living in the gut.”27 Prebiotics include inulin, lactulose, fructooligosaccharides (FOS), xylooligosaccharides (XOS), and galactooligosaccharides (GOS). High levels of prebiotic fibers are found in foods such as onions, garlic, Jerusalem artichoke, leeks, bananas, and chicory root.28 Mechanisms of Action: Prebiotics serve as substrates for fermentation by the bacteria in the colon, and may support health by a variety of mechanisms, including: • Increasing levels of Lactobacillus and Bifidobacterium species in the colon29 • Decreasing GI transit time • Improving mineral absorption • Promoting satiety and reducing food consumption30 • Protecting against infection by inhibiting pathogen attachment and/or supporting immune function • Increasing levels of short-chain fatty acids (SCFAs) in the colon, including butyrate • Reducing cholesterol levels31 Research continues to examine the possible benefits of prebiotics as we further understand the healthand disease-related effects of the microbiome and its metabolic products. Prebiotics have been shown to potentially be beneficial in settings of inflammatory bowel disease (IBD),32 bone health,33 infant and childhood allergies and atopic
dermatitis,34,35,36 and cardiovascular disease.37 Adverse Effects: Although prebiotics are generally safe for consumption and are inherent in the diet, higher doses of prebiotic fibers can lead to undesirable effects such as flatulence, bloating, and diarrhea, particularly in sensitive individuals. These adverse effects can be averted by increasing the dosage gradually or spreading intake throughout the day. However, in some settings of diarrhea, such as that related with traveling, prebiotics have been shown to have a preventive effect, possibly due to their impact on the immune system or bacterial adhesion.38 Additionally, certain prebiotic fibers, such as XOS, have been shown to be better tolerated and require lower dosages to achieve beneficial effects on the healthy gut flora.39
Probiotics Probiotics are defined as living organisms administered to promote the health of the host. A recent revision to the original Food and Agriculture Organization (FAO) and World Health Organization (WHO) joint scientific opinion more specifically defines probiotics as “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host.”40 Much of the scientific and clinical research on probiotics has focused on their oral use for gastrointestinal and immune health. Emerging science is also exploring the use of probiotics for conditions such as female genitourinary tract health,41 atopic dermatitis,42 mood disorders,43 autoimmune disease,44 metabolic syndrome,45 and autism spectrum disorder.46 With time, we will likely see increasing conditionspecific probiotic use as evidence for it continues to develop. Mechanisms of Action: Probiotics are intended to affect the health of the host and the microbiota balance via local and systemic immune mechanisms as well as non-
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immune mechanisms. Some of these mechanisms include: • Enhancing intestinal barrier function • Stimulating production of protective epithelial mucin • Increasing production of healthpromoting SCFAs in the colon • Enhancing the local mucosal immune activity by increasing secretory IgA, which helps protect against pathogens and toxins • Lessening systemic antigen exposure (e.g., food allergens) • Systemically modulating immune system function • Protecting from microbial invaders by: ° Competition for nutrients and adhesion sites ° Production of bacteriocins, proteins which are capable of inhibiting the growth of other bacteria, including pathogens Alteration of the local pH to ° create an environment unfavorable for pathogen growth Over the past few years, researchers have also been making significant advances in their understanding of how the gut microbiota communicates with the central nervous system and influences the hypothalamic-pituitary-adrenal (HPA) axis.47 Probiotics may modulate central nervous system function via the production of neuroactive compounds that modulate signaling via the enteric nervous system,48 and have also been shown to alter neurotransmitter metabolism and receptor status in the brain.49 Research in this area may soon lead to commercially available probiotics which have evidence for modulating the stress response, reducing symptoms of anxiety or depression, and possibly treating autism spectrum disorder.50 Selected Clinical Applications The primary families of probiotics that have been studied are Lactobacillus and Bifidobacterium species (see 4
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Table 1).51 Other commonly used probiotics include Streptococcus thermophilus, Saccharomyces boulardii (a yeast), Lactococcus lactis, Enterococcus faecalis, and the spore-forming anaerobe Bacillus coagulans. Table 1 — Commonly Used Probiotic Species Lactobacillus L. rhamnosus, L. acidophilus, L. bulgaricus, L. casei, L. salivarius, L. johnsonii, L. helviticus, L. gasseri, L. brevis, L. plantarum, L. fermentum, L. paracasei Bifidobacterium B. bifidum, B. infantis, B. breve, B. lactis Other Saccharomyces boulardii, Streptococcus thermophilus, Lactococcus lactis, Enterococcus faecalis, Bacillus coagulans
Reducing Adverse Effects of Antibiotic Use: An imbalance of the healthy gut microbiota is often referred to as dysbiosis. One of the leading causes of dysbiosis is the use of antibiotics.52,53 With antibiotic use, we also often see the GI side effect of diarrhea, but even in the absence of this bothersome symptom, the gut flora balance is unavoidably affected. The estimated prevalence of antibiotic-associated diarrhea (AAD) varies greatly, being reported in 5 to 35% of patients taking antibiotics, and depends upon the specific type of antibiotic, the health of the host, and exposure to pathogens.54 Research suggests that concomitant use of probiotics during and after antibiotic use can attenuate the reduction in healthy gut microbiota.55 Multiple meta-analyses published between 2002 and 2012 indicate that probiotics can reduce the incidence of AAD by 42 to 50%.56,57,58 A 2012 meta-analysis published in the Journal of the American Medical
Association included 63 randomized, double-blind, placebo-controlled trials (RDBPCT), which encompassed 11,181 participants.59 The pooled evidence showed a 42% reduction in the incidence of AAD. Probiotic species used in these studies varied, and included Lactobacillus rhamnosus, L. casei, L. acidophilus, L. reuteri, L. plantarum, L. casei, Bifidobacterium lactis, B. infantis, B. longum, Saccharomyces boulardii, and Bacillus coagulans. Probiotic potency is typically measured in colony-forming units (CFUs), and the potencies used in these trials were 100 million to 50 billion CFUs per day. A meta-analysis looking specifically at the use of probiotics for the prevention of AAD in pediatrics (including 3,938 children and over 23 RDBPCTs) also showed significant benefits with probiotic use, finding the incidence of AAD to be 8% in the probiotic group compared to 19% in the control group.60 An a priori analysis of the data suggests that doses of probiotics greater than 5 billion CFUs/day were more effective in reducing AAD than dosages less than this threshold. While probiotics are useful in reducing side effects associated with antibiotic use, strains should only be used if they have been proven to not confer antibiotic resistance to pathogens that the antibiotics are intended to treat.61 Reliable probiotic suppliers have more recently begun to address and test for this factor due to increased awareness of this possibility. Treating Irritable Bowel Syndrome: Irritable bowel syndrome (IBS) is one of the most common functional gastroenterological diseases and is estimated to affect 11.2% of people Clinical features worldwide.62 include abdominal discomfort or pain, diarrhea, constipation, bloating, and flatulence. While the underlying pathophysiology is poorly understood, there is growing interest in the association with increased visceral sensitivity
and alterations in the intestinal microbiota, while undiagnosed food sensitivities and intolerances also may play a role.63,64,65,66 Multiple meta-analyses published between 2009 and 2016 have concluded that probiotics are an effective treatment option Perhaps the for IBS.67,68,69 most comprehensive of these meta-analyses is one published in the American Journal of Gastroenterology in 2014.70 The meta-analysis included 35 RDBPCTs with a total of 3,452 IBS patients. Nineteen trials used a combination of probiotics, while eight used single Lactobacillus (L. plantarum, L. acidophilus, L. rhamnosus, or L. reuteri) strains, three used single Bifidobacterium (B. infantis or B. bifidum) strains, two used single Streptococcus (S. thermophilus or S. faecium) strains, two used Escherichia coli Nissle 1917, and one used Saccharomyces boulardii. With the exception of two studies that used dosages greater than 200 billion CFUs/day, dosing ranged from 1 billion to 200 billion CFUs/day. Of particular note was the improvement seen in global IBS symptoms, abdominal pain, bloating, and flatulence. In individuals with chronic idiopathic constipation, the stool frequency was also increased in those taking probiotics; however, this variable was not included in the majority of the studies. A 20-week RDBPCT studied the effect of L. rhamnosus (3 billion CFUs/day) in children with IBS.71 The number of painful episodes and severity of pain were both significantly reduced in the probiotic group compared to the placebo group. At an eight-week post-treatment evaluation, these observed improvements continued to be maintained. Intestinal permeability was significantly improved in children in the probiotic group compared to placebo for those in whom this parameter was initially abnormal as well.
Preventing Atopic Dermatitis: Another area of clinical interest is the potential for probiotics to reduce the incidence of atopic disorders such as atopic dermatitis (AD) and asthma, particularly in pediatric populations, where these conditions contribute not only to discomfort in the affected individual, but also can impact the quality of life of everyone in the household. A 2013 meta-analysis published in Pediatrics reviewed the impact of probiotics on children with atopy, evaluating the outcomes of 25 studies that included a total of 4,031 children.72 Overall, probiotics significantly reduced the risk of atopic sensitization, particularly AD, when administered prenatally and postnatally. Probiotics were also found to be effective in reducing total immunoglobulin E (IgE), with the reduction being more pronounced with longer follow-up. However, probiotics were not found to significantly reduce the incidence of asthma or wheezing.
Prenatal and postnatal administration of probiotics has been shown in several RDBPCTs to significantly reduce the risk of atopic dermatitis in at-risk infants. Prenatal and postnatal administration of probiotics has been shown in several RDBPCTs to significantly reduce the risk of AD in at-risk infants (e.g., those with a parent or sibling with a history of atopy). The first of these trials was published in 2001.73 The RDBPCT included 132 pregnant women (recruited with the at-risk profile above) who were randomized to receive either 1 billion CFUs/day of L. rhamnosus or placebo beginning at 35 weeks gestation, and who continued taking the probiotic or placebo while breastfeeding. Infants began taking the probiotic or placebo when breastfeeding stopped and continued until six months of age. At a two-year follow-up, the incidence
of AD was reduced by 46% in the probiotic group. Follow-up data at four and seven years continued to show a reduced incidence of AD in the probiotic group.74,75 Another RDBPCT with a similar design included 474 mothers and infants who were randomized to one of two probiotic groups— L. rhamnosus (6 billion CFUs/day) or B. lactis (9 billion CFUs/day)—or a placebo. In this study, however, the infants received the treatment until two years rather than just six months of age.76 At two years, the incidence of AD was significantly reduced in the L. rhamnosus group but not the B. lactis group. The reduction in AD incidence in the L. rhamnosus– supplemented group persisted at four-year and six-year followups.77,78 Furthermore, at the six-year follow-up, atopic sensitization was also significantly reduced in children that had taken L. rhamnosus. Probiotic Safety Probiotic supplements from companies sourcing their strains from established probiotic strain suppliers have largely been shown to be safe for a wide age range, from infants to older adults.79 Many probiotics are made from strains of bacteria found as normal flora in healthy humans, while others are found in fermented foods that have been consumed by humans since prehistoric times.80 Probiotics are intended to colonize the intestinal tract and epithelial surfaces, not entering the bloodstream. Translocation into the bloodstream is highly unlikely in healthy humans and has not been noted in clinical trials, but with atrisk populations such as very low birth weight infants and severely immunocompromised populations, concern does exist.81 Products containing strains that have been specifically studied for use in infants, younger children, pregnant women, and the immunocompromised should be selected for use in these populations whenever possible. See pp. 14 and 15 for references.
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Probiotics: An Era of Increasing Specificity Advanced Genetic Identification Tools Enable Us to Dial In On Benefits of Unique Probiotic Strains, Such as Lactobacillus acidophilus DDS®-1
Almost anyone who is familiar with probiotics has heard of Lactobacillus acidophilus, one of the most common probiotics found both in fermented dairy products like yogurt and in supplemental probiotics that can be purchased off the shelf. However, as we move into the next era of probiotics, in part enabled by genetic identification tools,1 we now know that L. acidophilus does not uniquely identify an individual organism, but rather a family of different strains which all have distinctive characteristics and health-related benefits. Proper characterization of a probiotic down to the strain level is important for differentiating these organisms so that we may better understand and properly study the interactions among members of the gut microbiota and beyond.2 It also helps those in probiotic development to select strains that have improved tolerance to digestive secretions and challenges of temperature, and are thus more likely to survive intact and populate the gastrointestinal tract. The labeling of probiotics also reflects the value of strain specificity, with labels including information of the genus (e.g., Lactobacillus), species (e.g., acidophilus), and strain (e.g., DDS®-1) whenever possible to indicate specifically studied strains within a supplement. This will allow both clinicians and consumers to better understand the potential health-related benefits of probiotic supplements. Lactobacillus acidophilus DDS®-1 is one of these properly classified strains that has been the topic of a significant amount of research, including multiple clinical studies in children and adults. DDS®-1 6
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has been shown to be extremely tolerant to digestive secretions, including stomach acid, pepsin, bile salts, and pancreatin, allowing it to traverse through the upper GI tract to the latter parts of the small and large intestine.3 Studies show it has good adherence to human intestinal cell lines and is found in human stool samples after consumption,4,5 increasing total fecal lactobacilli counts and reducing those of opportunistic enterobacteria (Proteus, Klebsiella, Citrobacter, Enterobacter, and 6,7 Pseudomonas species). Although DDS®-1 has been shown to be tolerant of digestive secretions and to be present in the stool, enhanced survival of it (and other strains of probiotics it may be combined with) is possible with encapsulation methods that have been shown to tolerate digestive secretions and deliver their contents to the small intestine.8
Gastrointestinal Health One setting in which DDS®-1 has been well-studied and has proven to be of benefit is gastrointestinal health. Improved lactose tolerance,9 increased stool frequency in functional constipation,10 reduced symptoms of irritable bowel syndrome (IBS),11 and reduction of the occurrence of traveler’s diarrhea12 are highlights from the clinical studies pertaining to gastrointestinal health in humans. In a randomized, double-blind, placebo-controlled trial (RDBPCT) with a crossover second stage, patients who complained of lactose intolerance (confirmed by lactose challenge) were supplemented with
DDS®-1 at a dosage of 10 billion colony-forming units (CFUs) daily or placebo for a period of four weeks, followed by a two-week washout and then four weeks of the alternate intervention.9 At week four, significant reductions in diarrhea, abdominal cramping, and vomiting, as well as an improved overall symptom score, were observed in the DDS®-1 group during the sixhour lactose challenge.
DDS®-1 has been shown to be extremely tolerant to digestive secretions, including stomach acid, pepsin, bile salts, and pancreatin, allowing it to traverse through the upper GI tract to the latter parts of the small and large intestine. In another RDBPCT, a four-strain probiotic blend containing DDS®-1 as the primary strain was provided at a dosage of 15 billion CFUs daily to 100 adults having symptoms of functional constipation.10 Evaluation included detailed questionnaires at two- and four-week follow-up visits as well as study diaries through the intervention period. Compared to placebo, the group receiving the probiotic had a significant difference in stool consistency and better scores on the Bristol stool scale (a medical
aid designed to classify feces into seven groups) already at one week, with an improvement of 20% toward normal stool consistency. Within the probiotic group, significant increases in average stool consistency were seen at weeks two, three, and four as well. Trends toward improvement in the complete spontaneous bowel movement scores per week were also seen in the probiotic group compared to placebo after one week of the intervention. Twenty-five patients with IBS, as diagnosed by the Rome III criteria, were treated with a probiotic combination product that included DDS®-1, Bifidobacterium longum, B. bifidum, and B. lactis at a dosage of 12 billion CFUs daily.11 After two months of treatment, abdominal pain was improved in 84% of patients, bloating in 73.9%, belching in 92%, flatulence in 88%, diarrhea in 90.9%, and constipation in 86.9%. Each of these symptoms were also improved, but to a lesser extent, at the onemonth period of assessment. Not all patients experienced diarrhea and constipation, so these numbers reflect the percentage of individuals who complained of these symptoms.
CFUs of the combination of DDS®-1 with B. lactis UABla-12™ and fructooligosaccharides (FOS) were given twice daily to preschool children (one to three years of age) with moderate to severe AD for eight weeks.13 Children receiving the synbiotic had a significantly greater decrease in Scoring of Atopic Dermatitis (SCORAD) values, with scores reduced by 33.7% compared to 19.4% in the placebo group at the final visit, and significantly better scores at other time points as well. Correspondingly, lymphocyte subsets were normalized from the changes classically seen in AD.14,15 There also was significantly less use of topical corticosteroids, and a reduced impact on the quality of life of the family and child.
The same synbiotic combination was supplemented to children for the purpose of studying its impact on respiratory health.16 In this study, a dosage of five billion CFUs or placebo was provided once daily for 30 days to healthy children ranging in age from 3 to 12 years old. Although acute respiratory tract infection (ARTI) was experienced at a similar rate in both groups in this study, the recovery from infection was significantly faster, with children in the synbiotic group returning to normal health by day 8.5 versus day 10.7 in the control group. Nasal decongestants, throat preparations, and antipyretic medications were needed for significantly less time in the synbiotic group as well. An additional RDBPCT in a similar population of children reinforced this, with significant findings of two fewer days for the resolution of the ARTI and reduced symptom severity compared to placebo.17
In children, positive outcomes with DDS®-1 have been seen in clinical trials in settings of atopic dermatitis (AD) and respiratory tract health, and in one case report pertaining to recurrent urinary tract infections (UTIs). In one RDBPCT, five billion
Finally, DDS®-1 has been the topic of one case study in a child with recurrent UTIs.18 After clearing the third UTI in three months with appropriate antibacterial therapies, the six-year-old girl was given two billion CFUs of DDS®-1 twice daily
The probiotic DDS®-1 also was evaluated in open-label fashion in individuals traveling to regions of Guatemala, Mexico, or Nepal.12 The anticipated incidence of gastrointestinal disturbance during such travel is estimated to be 25 to 30%. Seventy healthy subjects took the probiotic DDS®-1 at a dosage of two billion CFUs daily for one week prior to and during travel, and only 3% reported gastrointestinal disturbance during their trips.
for a month and then once daily long term. The child was closely followed, and during a five-month follow-up period no recurrence was detected. Escherichia coli—which had been the causative agent of her previous infections—has been shown to be inhibited by DDS®-1, hence the selection of this probiotic. E. coli 07, which was found to be present in her stool after the completion of antibiotic therapies, was no longer detected after two months of probiotic supplementation. In this era of increasing probiotic specificity, and with the abundance of ongoing research and development, it won’t be long before we see probiotics on the market with evidence behind their use for cholesterol and blood sugar regulation,19,20 mood,21 and a multitude of other conditions. The increasing evidence behind condition-specific unique probiotic strains continues to improve the ability of clinicians and patients to understand which probiotics are best for supporting their unique health requirements. References 1 Yadav R, Shukla P. An overview of advanced technologies for selection of probiotics and their expediency: A review. Crit Rev Food Sci Nutr. 2017 Oct 13;57(15):3233-42. 2 Del Piano M, et al. Probiotics: from research to consumer. Dig Liver Dis. 2006 Dec;38 Suppl 2:S248-55. 3 Murthy M, et al. Delineation of beneficial characteristics of effective probiotics. JANA. 2000;3(2):38-43. 4 Frese SA, et al. Comparison of the colonization ability of autochthonous and allochthonous strains of lactobacilli in the human gastrointestinal tract. Adv Microb. 2012 Sep 24;2(03):399. 5 Peterson L. Studies on DDS-acidophilus at VA hospital, Minneapolis, 1998. Unpublished data. 6 Ayebo AD, et al. Effect of ingesting Lactobacillus acidophilus milk upon fecal flora and enzyme activity in humans. Milchwissenschaft. 1980;35:730-3. 7 Gerasimov SV. Treatment of atopic dermatitis in young children: Ongoing search for effective probiotic formulation. Scientific Report. UAS Labs. 2008:1-21. Unpublished data. 8 Marzorati M, et al. A novel hypromellose capsule, with acid resistance properties, permits the targeted delivery of acidsensitive products to the intestine. LWT-Food Sci Tech. 2015 Jan 1;60(1):544-51. 9 Pakdaman MN, et al. The effects of the DDS®-1 strain of lactobacillus on symptomatic relief for lactose intolerance - a randomized, double-blind, placebo-controlled, crossover clinical trial. Nutr J. 2016 May 20;15(1):56. 10 UAS Labs. Impact of a Probiotic Product on Bowel Habits and Microbial Profile in Subjects with Functional Constipation: A Randomized, Double-blind, Placebo-controlled study. L. acidophilus DDS®-1 Dossier on Safety, Efficacy and Regulatory Status, Version 1.4. December 19, 2017. Submitted for publication. 11 Nagala R, Routray C. Clinical case study: multispecies probiotic supplement minimizes symptoms of irritable bowel syndrome. UAS Labs. Apr 29, 2010. Unpublished data.
References continued on p.15.
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Vaginal and Urinary Tract Health: Another Case for Probiotics Although the Genitourinary Tract Is Host to Far Fewer Microbial Species than the Gut, Its Microbiota Play an Important Role in Common Female Health Concerns While the gut has an estimated 500 different microbial species, the number of microbial species inhabiting the vagina is thought to be approximately 50.1 The microbiota of the urogenital tract are the topic of much research surrounding not only genitourinary health, but also fertility and pregnancy,2 and even gynecological conditions such as endometriosis and adenomyosis. We now know there is a continuum of microbes that reside in the female reproductive system from the vaginal introitus to the upper reproductive tract, including the fallopian tubes and the recto-uterine peritoneal pouch.3
Normal Female Flora and Function The vaginal microbial flora of healthy women is largely dominated by the Lactobacillus genus, which typically makes up 90 to 95% of the total bacterial count of the genitourinary tract.4 The dominant species identified in healthy women have primarily been Lactobacillus gasseri, L. crispatus, L. iners, and L. jensenii, although higher levels of L. iners have also been associated with vaginal dysbosis and obesity.5,6,7,8 Other common species identified include L. acidophilus, L. rhamnosus, L. plantarum, L. fermentum, L. brevis, L. casei, L. vaginalis, L. delbrueckii, L. salivarius, and L. reuteri.9 Bifidobacterium spp. also are commonly found in the genitourinary tract, with Bifidobacterium breve and B. longum being two of those documented.10 Similar to the probiotic organisms for the gastrointestinal tract, the lactobacilli in the female genitourinary 8
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tract also have protective and healthpromoting actions. These effects have been observed to include: • Regulation of vaginal epithelial cell innate immunity11 • Production of lactic acid, hydrogen peroxide, bacteriocins, and biosurfactants that impact the pH of the vaginal canal and limit uropathogen growth and adherence12 • Disruption of the formation of uropathogen-related biofilms,13 which protect pathogens and enable colonization of normal flora such as Candida spp.14 • Disruption of yeast-to-hyphae differentiation in C. albicans15 • Competitive inhibition of binding of pathogenic bacteria, including those responsible for yeast vaginitis, bacterial vaginosis, urinary tract infections, and sexually transmitted infections16,17,18,19,20
Numerous trials have demonstrated that oral administration of specific strains of lactobacilli—in particular L. crispatus, L. rhamnosus, L. gasseri, and L. reuteri—can both maintain and restore healthy genitourinary microbiota in females. Many of the initial studies looking at the potential benefits of probiotics for female genitourinary tract health focused on the intravaginal application of lactobacilli strains.
There has been an emerging trend, however, of using oral probiotics to colonize the vagina, backed by a substantial amount of clinical research. Numerous trials have demonstrated that oral administration of specific strains of lactobacilli—in particular L. crispatus, L. rhamnosus, L. gasseri, and L. reuteri—can both maintain and restore healthy genitourinary microbiota in females.21,22,23 In one such study, healthy women took an oral daily dose of 100 million colony-forming units (CFUs) of a mixture of L. fermentum 57A, L. plantarum 57B, and L. gasseri 57C. Not only did oral supplementation result in the colonization of both vaginal and rectal epithelium by these strains for several weeks (measured by an appreciable increase in total lactobacilli counts), but it also correlated with improvement of parameters such as vaginal pH and Nugent score (a scoring system of vaginal smears to diagnose bacterial vaginosis). No adverse events were noted during the study.24
Vaginal and Urinary Tract Infections Bacterial vaginosis (BV) and vulvovaginal candidiasis (VVC) are common forms of vaginitis seen in both pregnant and nonpregnant females. BV is associated with Gardnerella vaginalis and Atopobium vaginae, while VVC is largely due to C. albicans, with C. glabrata accounting for 8 to 20%.25 Mixed infection is also not uncommon.26 Symptoms of BV may include vaginal itching, malodorous discharge, and dysuria, while VVC commonly presents with vulvar burning, soreness, and irritation.27
Almost half of all women will also be plagued by urinary tract infections (UTIs) during their lifetime, with nearly one in three women having a UTI by the age of 24.28 UTIs are most frequently caused by Escherichia coli, translocating from the colon and ascending up the urinary tract.29 Recurrence of BV, VVC, and/or UTIs is common in susceptible females, leading to repeated courses of treatment with antibiotics or antifungal medications.30,31,32 In addition to the deleterious effects on the gut, treatment with antibiotics also may lead to fungal overgrowth and subsequent need for an antifungal agent.33 Because of their ability to positively influence the vaginal environment, and the protection that they offer against pathogens, probiotics have been investigated in many clinical trials both as adjunctive and alternative treatments to the standard medication regimes for these conditions.34,35,36 Supplementation of a probiotic formula during and after antibiotic administration may also help mitigate unwanted gastrointestinal side effects from antibiotic use.37,38 In one randomized, double-blind, placebo-controlled trial, researchers explored whether probiotics could reduce the risk of recurrence of VVC after a standard course of treatment with fluconazole.39 After initial treatment with a single dose of oral fluconazole, 59 VVC patients took either an oral probiotic supplement (containing a combination of 7.5 billion CFUs of L. acidophilus, 6 billion CFUs of B. bifidum, and 1.5 billion CFUs of B. longum) or placebo capsules daily for six months. Of the women taking placebo capsules, 35.5% experienced recurrence of VVC; of the women taking probiotics, only 7.2% experienced recurrence.
Pregnancy BV has also been associated with pelvic inflammatory disease (PID), postoperative infection, and preterm
birth.40 Estimates suggest that 40% of cases of spontaneous preterm labor and preterm birth may be associated with BV.41 Forming the front line of protection in the female genitourinary mucosa, lactobacilli have been shown not only to assist in the treatment of BV, but also to improve the integrity of the cervical os.42 Similarly, vaginal colonization by healthy lactobacilli protects the uterus and upper reproductive organs from pathogenic invasion, ergo reducing the risk of adverse obstetric outcomes such as miscarriage, premature rupture of membranes (PROM), preterm birth, neonatal sepsis, and neonatal respiratory distress.43,44,45 Beyond this, the use of probiotics during pregnancy has been studied for the reduction of eczema, allergic rhinitis, and obesity in pediatric populations as well.46,47
Menopause Estrogen plays an important role in maintaining optimal vaginal ecology by thickening the vaginal epithelium, increasing the volume of vaginal secretions, and enhancing epithelial glycogen production. This glycogen (formed by many glucose molecules) serves as an important source of nutrition for lactobacilli, thereby promoting their colonization in the female reproductive tract.48 The drop in estrogen production seen in menopause, however, results in a decrease in glycogen production. This in turn shifts microbial balance, decreasing levels of healthy lactobacilli and raising vaginal pH, and leads to an increased incidence of UTIs as well as BV and VVC in menopausal women.49,50 Overall, findings from the reviews of probiotic use for female genitourinary health are positive, with some limitations. Dosage, of course, and strain are both matters to consider for the genitourinary tract, much like the gut. A 2017 review in the Journal of Menopausal Medicine of probiotic use for the treatment of vaginal infections in
postmenopausal women summarizes the potential benefits of probiotics: “Probiotics positively effects vaginal microflora composition by promoting the proliferation of beneficial microorganisms, alters the intravaginal microbiota composition, [and] prevents vaginal infections in postmenopausal [women]. Probiotics also reduce the symptoms of vaginal infections (e.g., vaginal discharge, odor, etc.), and are thus helpful for the treatment and prevention of BV and VVC.”51 A recent review concerning the treatment of BV with probiotics states: “The majority of clinical trials yielding positive results have been performed using probiotic preparations containing high doses of lactobacilli suggesting that, beside strain characteristics, the amount of exogenously applied lactobacilli could have a role in the effectiveness of the product.”35 Another review, surveying the use of probiotics for a broader range of conditions, including UTIs and VVC, concludes: “Although clinical practice recommendations were limited by the strength of evidence, probiotic interventions were effective in treatment and prevention of urogenital infections as alternatives or co-treatments.”36 Finally, a 2016 review in the journal Drugs of probiotic use for recurrent urinary tract infections concludes: “The evidence from the available studies suggests that probiotics can be beneficial for preventing recurrent UTIs in women; they also have a good safety profile.”37 However, in each of these reviews the need for further research, and the lack of homogeneity in the studies, was duly noted. Considering that lactobacilli make up over 90% of the microbial presence in the female genitourinary system, the case for probiotic supplementation in the prevention and treatment of vaginal, urinary, and reproductive infections in women—and as maintenance in pregnancy—is quite compelling. See p. 15 for references.
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Nonalcoholic Fatty Liver Disease: The Stealth Companion of Metabolic Syndrome The Evidence Behind Botanicals, Probiotics, and Simple Nutrient Therapies That Address This Common Ailment
With increasing rates of obesity and metabolic syndrome, the allied conditions of nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) have become increasingly common, such that they are now the number one cause of liver disease in Western countries.1 Nonalcoholic fatty liver disease (NAFLD) affects 10 to 46% of the United States population, while the worldwide prevalence is 6 to 35%, with a median of 20%.2 Actual numbers, of course, may be higher due to the silent nature of this metabolic syndrome companion.
If LFTs are assessed, many physicians pass off mild elevations in GGT, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) as “normal” without further screening, particularly in individuals who are overweight or obese. Even when physicians take the extra steps to rule out infectious hepatitis and biliary disease, the only recommendations typically suggested that may impact elevated liver enzymes (attributed to NAFLD) are alcohol abstinence, weight loss, and the proper medical management of blood sugar and cholesterol.3
NAFLD is subdivided into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). The former presents without significant liver inflammation, while the latter is associated with hepatic inflammation that may not be distinguishable histologically from alcoholic steatohepatitis. As NAFL and NASH are both considered “silent” liver diseases, these pathologies are often asymptomatic and easy to miss clinically in the absence of proper screening. Although liver function tests (LFTs) are a part of the comprehensive metabolic panel (CMP), which many physicians routinely assess after age 50, this profile is often not performed unless there is a problem related to the liver that presented when the patient was younger, and many times, the CMP does not include gamma-glutamyltransferase (GGT). Thus, the tissue changes and lowlevel inflammatory state of NAFLD can go undiagnosed for many years and may even progress into hepatic cirrhosis, no different than that of endstage liver disease associated with alcoholism or chronic viral hepatitis.
As we evaluate possible natural treatment strategies and interventions, it is important to consider the conditions that contribute to fatty liver changes and hepatic inflammation. It is well understood that a prolonged state of immuneled defenses contributes to oxidative stress, inflammation, and eventual hepatocellular damage and injury, but what are the factors that exacerbate this?
IN FOCUS | Summer 2018
A Gut–Liver Connection? An overlap between digestive system disease and hepatic inflammation (Figure 1) has been well documented. In embryological terms, the gut and the liver are intrinsically linked, with the liver budding directly from the foregut during development. Increasing evidence shows that the gut and liver have multiple levels of associated interdependence, and disturbance of the gut–liver axis has been implicated in several conditions linked to obesity, including NAFLD. Liver enzyme elevation and fatty liver changes are commonly seen in gastrointestinal conditions such as small intestinal bacterial overgrowth (SIBO),4 celiac disease,5 and inflammatory bowel disease (IBD), even in the absence of autoimmune liver or biliary disease.6 A recent metaanalysis also found that patients with gastroesophageal reflux disease were at a significantly increased risk of developing NAFLD (pooled odds ratio of 2.07).7 It doesn’t stop there; an association has also been shown with Helicobacter pylori infection.8
Hepatic Inflammation / NAFLD
Celiac Disease IBD
H. pylori Infection GERD
liver changes or muscle damage.18 Decreased choline intake also has been shown to be significantly associated with an increased risk of fibrosis in postmenopausal women with NAFLD.19 A recent study found that only 8% of US adults meet the recommended adequate intake (AI) of choline, with vegetarians, postmenopausal women, and men at greatest risk of inadequacy.20,21
H. pylori High- SIBO Celiac fat diet IBD disease
Hepatic Inflammation / Liver Cell Death One common denominator among these conditions is the integrity, or lack thereof, of the gut mucosal barrier. “Leaky gut,” the common term for increased intestinal permeability, has been demonstrated in each of these conditions, and it has not been a stretch for hepatologists and gastroenterologists to connect this common underpinning with NAFLD (Figure 2).9,10 With the compromised intestinal barrier that is hallmark to leaky gut, bacterialderived endotoxin, also known as lipopolysaccharide (LPS), is able to pass into circulation and trigger a defensive inflammatory response.11 In addition to alterations in the gut microbiome such as SIBO or H. pylori infection, a high-fat diet (HFD) has been shown to contribute to increased intestinal permeability and related endotoxemia.12 Endotoxemia contributes to intrahepatic cholestasis and related
hepatocyte inflammation and damage.13 However, much like the gut-brain axis, where there is communication in both directions, the cholestasis related to endotoxemia can further contribute to an altered balance of gastrointestinal flora and diminished motility.14
Fatty Liver Changes: Correlated with Phosphatidylcholine Deficiency? Phosphatidylcholine (PC), a primary component of lecithin, has been shown to protect against fibrosis associated with hepatic inflammation.15,16 PC comprises over 90% of the total bile phospholipid content17 and facilitates fat emulsification, absorption, and transport. Studies have shown that the recommended minimal dietary intake thresholds of PC may not be sufficient for prevention of symptoms of choline deficiency such as fatty
Increased intake of PC has been shown to enhance biliary lipid secretion, thereby preventing cholestasis and subsequent liver damage via numerous mechanisms, including suppression of nuclear factor kappa B (NF-κB), a well understood molecular trigger of inflammation.22,23 PC is also essential for the health of the gut and is a primary component of the protective intestinal mucus layer.24 In cell cultures, treatment with PC has been shown to reduce the migration of endotoxin through intestinal epithelial cells, further suppressing the associated inflammatory cytokine response.25 PC also reduces endotoxin translocation in the setting of alcohol-induced increases in intestinal permeability.26 This beneficial effect has been proposed as one of the mechanisms by which PC may be considered therapeutic in alcoholic liver disease.
Berberine and NAFLD Many botanicals and their extracts have demonstrated hepatoprotective actions and may reduce the risk of NAFLD as well as its progression.27 Berberine, the orangish-yellow alkaloid found in botanicals such as Oregon grape root and bark, goldenseal, and barberry, is one substance that has numerous mechanisms by which it may protect against NAFLD and support its treatment.28,29,30 There are many different means by which berberine may exert its hepatoprotective action; one is via modulation of the gut microbial
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balance.31 Berberine is also well known for its antidiabetic and lipidbalancing effects,32 both of which impact fatty liver changes. The direct actions of berberine, however, do not stop there. Berberine has been shown to alter hepatic metabolismrelated gene expression, supporting bile acid metabolism via pathways that include farnesoid X receptor (FXR).33 FXR is a key regulator of bile acid, glucose, and lipid homeostasis.34 In animal studies, berberine has been shown to have the effect of preventing HFDassociated obesity and hepatic triglyceride accumulation in wildtype (normal) mice, but not in those that had the genetic elimination of intestinal FXR expression.
In patients with NAFLD, berberine was shown to restore normal hepatic architecture, lipid, and blood sugar metabolism, with significant improvements seen over the population who only implemented lifestyle changes. Berberine also directly influences intestinal permeability, improving tight junction integrity in animals subject to endotoxemia or cell cultures treated with proinflammatory cytokines.35,36 Direct anti-inflammatory effects have also been demonstrated. Berberine has been shown to suppress obesity-associated inflammation and hepatic steatosis in mice with decreased phosphorylation of the inflammatory complex known as JNK1,37 a protein kinase implicated in the development of steatohepatitis.38 JNK1 is strongly activated by environmental stressors and pro-inflammatory cytokines. The benefits of berberine in NAFLD have also been demonstrated clinically in a randomized, parallel controlled, open-label clinical 12
IN FOCUS | Summer 2018
trial.39 In patients with NAFLD, berberine was shown to restore normal hepatic architecture, lipid, and blood sugar metabolism, with significant improvements seen over the population who only implemented lifestyle changes.
Additional HepatobiliarySupportive Botanicals Milk thistle is possibly the bestknown botanical for its potent liverprotective benefits. Silymarin, a mixture of the active constituents of milk thistle, and silibinin, the most active compound found within it, act as antioxidants and have been shown in animal studies to reduce liver injury caused by acetaminophen, alcohol, iron overload, and radiation among other known liver-toxic substances.40 Silymarin has been shown to enhance hepatic and intestinal glutathione levels, also inhibiting lipid peroxidation.41,42 Silibinin and silymarin have been shown to activate FXR as well, also inhibiting NF-κB signaling which upregulates inflammatory pathways.43 Not surprisingly, with activation of FXR in the mice, milk thistle ameliorated insulin resistance, dyslipidemia and inflammation due to HFD feeding. Agonism of FXR is one mechanism being investigated for the treatment of NAFLD and associated hepatic changes.44 Dandelion root is used by integrative practitioners to support the liver and gallbladder, and to tonify digestive health. Extracts from dandelion have been shown to be protective in settings of alcohol- or diet-induced stress on the liver.45,46 One mechanism through which dandelion root protects the liver from injury is by activating the nuclear factor E2-related factor (Nrf2) pathway,47 which promotes the body’s own production of glutathione, detoxificationrelated enzymes, and protective molecules.48
Probiotics and NAFLD Given the relationship between the many digestive system disturbances and liver enzyme elevation, it likely is not surprising that probiotics also have been studied for the purpose of addressing NAFLD. A recent meta-analysis well summarizes the collective findings.49 One-hundred thirty-four patients diagnosed with NAFLD by liver biopsy were included in this analysis, and each intervention used in the four randomized, controlled trials eligible for this meta-analysis was unique (Lactobacillus bulgaricus and Streptococcus thermophilus for three months; Lactobacillus GG for eight weeks; Bifidobacterium longum and fructooligosaccharides for 24 weeks; and a proprietary combination of Lactobacillus plantarum, L. delbrueckii, L. acidophilus, L. rhamnosus, and Bifidobacterium bifidum for six months). The dosage of probiotics ranged from 500 million to 12 billion colony-forming units (CFUs) daily. The probiotic treatments were shown to signiﬁcantly decrease ALT and AST levels by –23.71 UI/L and –19.77 UI/L, respectively. Significant improvements in total cholesterol, tumor necrosis factor alpha (TNF-α) levels, and insulin resistance were also noted.
Conclusion There is a wide range of safe and effective options available that support the restoration of health in those with NAFLD. Although each individual may have different underlying mechanisms contributing to hepatic dysfunction and inflammatory changes, each of these supportive natural agents— and many others (see Table 1, following page)—may support normal liver function in individuals with these metabolic challenges.
Table 1 — Supportive Considerations for NAFLD Note: Nutrients such as these should be used under the guidance of a qualified and licensed healthcare practitioner.
1.5 g twice daily with meals
Common dietary deficiency. Necessary for production of bile and protective gastrointestinal mucosa barrier.
Milk thistle seed
200 mg three times daily
Hepatoprotective. Supports hepatic glutathione levels, stabilizes bile salt export pump (BSEP), and activates FXR pathways.
200 mg three times daily
Hepatoprotective. Activates Nrf2 pathway, which promotes the body’s own production of glutathione, detoxification-related enzymes, and protective molecules.
500 mg three times daily50
Improves serum glucose and lipid profiles, also reducing hepatic fat content.
Probiotics, including strains such as B. longum, B. bifidum, S. thermophilus, L. rhamnosus, L. acidophilus, and L. plantarum
Minimum 12 billion CFUs daily
Improved gut epithelial barrier function and reduced intestinal and systemic inflammation.51
200 to 400 mg twice daily
Prevents cholestasis-induced Nrf2 inhibition, increasing synthesis of detoxification-related enzymes and glutathione. Methyl donor.52
300 mg daily53
Improves detoxifying ability of hepatocytes.54
500 to 600 mg twice daily, best taken on an empty stomach
NAC blocks the propagation of lipid peroxidation and supports hepatic glutathione levels.55
200 mg twice daily with food
Gamma-tocotrienol attenuates triglyceride accumulation by regulating fatty acid synthase and carnitine palmitoyltransferase enzymes, leading to a reduction of hepatic inflammation and endoplasmic reticulum stress.56,57
1 g twice daily
Plays a critical role in fatty acid oxidation and energy regulation.58
Omega-3 essential fatty acids
2 to 4 g daily, with meals
Omega-3 polyunsaturated fatty acids are known to downregulate sterol regulatory element-binding protein-1c and upregulate peroxisome proliferatoractivated receptor alpha, thus favoring fatty acid oxidation and reducing steatosis.59
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2 Lazo M, et al. Prevalence of nonalcoholic fatty liver disease in the United States: the Third National Health and Nutrition Examination Survey, 1988-1994. Am J Epidemiol. 2013;178(1):38-45.
11 Ferolla SM, et al. The role of intestinal bacteria overgrowth in obesity-related nonalcoholic fatty liver disease. Nutrients. 2014 Dec 3;6(12):5583-99.
3 Ahmed A, et al. Nonalcoholic Fatty Liver Disease Review: Diagnosis, Treatment, and Outcomes. Clin Gastroenterol Hepatol. 2015;13:2062-70.
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39 Yan HM, et al. Efficacy of Berberine in Patients with Non-Alcoholic Fatty Liver Disease. PLoS One. 2015 Aug 7;10(8):e0134172. 40 Abenavoli L, et al. Milk thistle in liver diseases: past, present, future. Phytother Res. 2010 Oct;24(10):1423-32. 41 Valenzuela A, et al. Selectivity of silymarin on the increase of the GSH content in different tissues of the rat. Planta Med. 1989 Oct;55(5):420-2.
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43 Gu M, et al. Silymarin Ameliorates Metabolic Dysfunction Associated with Diet-Induced Obesity via Activation of Farnesyl X Receptor. Front Pharmacol. 2016 Sep 28;7:345.
53 Honda Y, et al. Efficacy of glutathione for the treatment of nonalcoholic fatty liver disease: an open-label, single-arm, multicenter, pilot study. BMC Gastroenterol. 2017 Aug 8;17(1):96.
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References from p. 2, "The Microbiome: Before Birth and Beyond" 1 Turnbaugh PJ, et al. The human microbiome project. Nature. 2007 Oct 18;449(7164):804-10.
22 Bode L. Human milk oligosaccharides: every baby needs a sugar mama. Glycobiology. 2012 Sep;22(9):1147-62.
2 Qin J, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010 Mar 4;464(7285):59-65.
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