Posts

Episode 35: Investigating gut microbiome links to chronic diseases, with Dr. Purna Kashyap MBBS

/in Podcast, Season Three /by Laura

Podcast: Play in new window | Download

Subscribe: Apple Podcasts | Spotify | RSS

In this episode, the ISAPP hosts discuss the gut microbiome’s role in chronic diseases with Dr. Purna Kashyap MBBS, from Mayo Clinic in Rochester, Minnesota, USA. Dr. Kashyap talks about how to discover the complex factors that trigger and perpetuate chronic diseases such as inflammatory bowel disease, zeroing in on the gut microbiome as a contributor to different aspects of gastrointestinal (GI) tract physiology.

Key topics from this episode:

  • Dr. Kashyap became interested in some of the initial studies linking the gut microbiome to chronic diseases around 2007-2008, and subsequently began to study the molecular mechanisms that underlie changes in GI tract physiology.
  • How can scientists figure out causality in chronic diseases and the role of gut microbes? Dr. Kashyap sees causality as an ongoing cascade of events in the GI tract, with no single causal factor. Both the initial triggers and the perpetuating factors can be considered part of what causes these diseases.
  • Microbes can help perpetuate a certain state in the host because once they establish themselves they serve to make the environment more conducive to their survival. In chronic diseases, the factor that triggers the microbial community configuration may not be as important as the factor(s) that perpetuate it on an ongoing basis.
  • The gut microbiome is changeable but not easy to change. Scientists need to know how the microbial community sustains itself and intervene there to change the community.
  • Even small microbiome studies can be informative if you look at who responds to the intervention and why. This information can be valuable for informing which treatments might work for which subgroups of people.
  • Dr. Kashyap encourages combining three types of research: large-scale studies on microbial metabolites and potential drug targets; clinical studies on the metabolites present in various subgroups; preclinical models studying the effects of individual metabolites.
  • Diet, microbes, and host uptake all contribute to the physiological effects of different metabolites. And for example, if a metabolite is low, knowing which microbes are present is not enough information to explain why it’s low.
  • In gastroenterology, clinicians primarily care about the gut microbiome in relation to the new treatments it makes possible. Now that FDA-approved treatments exist (standardized fecal microbiota transplants for recurrent C. difficile), clinicians may start paying more attention.
  • Does Dr. Kashyap recommend interventions to patients based on their gut microbiomes? A high-fiber diet is good for the gut microbiome and also for overall health, so he advises patients to adhere to dietary recommendations for their daily fiber intake.

Episode abbreviations and links:

Additional resources:

Why researchers need to understand more about the small intestinal microbiome. ISAPP blog.

About Dr. Purna Kashyap:

Dr. Purna Kashyap is practicing gastroenterologist and Professor of Medicine and Physiology, the Bernard and Edith Waterman Director of the Microbiome program, and Director of the germ-free mouse facility in the Center for Individualized Medicine at Mayo Clinic, Rochester, MN. The NIH funded Gut Microbiome laboratory led by Dr. Kashyap is focused on delineating the complex interactions between diet, gut microbiome, and host gastrointestinal physiology.  The laboratory uses germ-free mouse models in conjunction with measures of gastrointestinal physiology in vitro and in vivo to investigate effects of gut microbial products on host gastrointestinal function. In parallel, they use a systems approach incorporating multi-omics, patient metadata, and physiologic tissue responses in human studies, to aid in discovery of novel microbial drivers of disease. The overall goal of the program is to develop novel microbiota-targeted therapies. Dr. Kashyap has published nearly 100 peer reviewed articles including journals like Cell, Cell Host Microbe, Science Translational Medicine, Nature Communications, and Gastroenterology. He was inducted to American Society of Clinical Investigation in 2021. He has previously served on the scientific advisory board of American Gastroenterology Association Gut Microbiome Center, and on the council of American Neurogastroenterology and Motility Society. He now serves on the council and the research committee of AGA, in an editorial role for Gut Microbes and as an ad hoc reviewer on NIH study sections.

New global guidelines for probiotics and prebiotics for gut health and disease

/in ISAPP Science Blog /by KC

By Mary Ellen Sanders, PhD, Executive Science Officer, ISAPP

The use of probiotics and prebiotics in the practice of gastroenterology must be guided by evidence – and with new evidence continually emerging, clinicians can benefit from efforts to summarize this evidence and determine how it applies in clinical practice.

In February 2023, the World Gastroenterology Organisation provided an updated resource in this area, titled “WGO Practice Guideline. Probiotics and Prebiotics”. This project was led by Prof. Francisco Guarner MD PhD, a clinical gastroenterologist and clinical researcher in probiotics and prebiotics, and brought together experts in gastroenterology, pediatrics, family medicine, probiotics, and prebiotics. Prof. Hania Szajewska MD PhD, a clinical pediatrician and clinical researcher in probiotics from the Medical University of Warsaw, was integral to assessing evidence for pediatric populations for the guidelines. Mary Ellen Sanders PhD co-chaired the project.

For 2023 update, 800 bibliographical entries of papers published in the 2017-2021 period were scrutinized. The review team adopted the guidelines for evaluation of probiotics established by FAO/WHO experts in 2002, where at least one double blind, randomized, placebo-controlled human trial with appropriate sample size and primary outcome is required to determine if the tested product is efficacious, and qualifies as a probiotic.

ISAPP was well-represented among the experts involved on the project, as four current board members contributed. In addition to Sanders and Szajewska, Prof. Dan Merenstein MD (current ISAPP president) and Prof. Seppo Salminen PhD (current past president) populated the team.

The Guideline is intended to provide specific information on interventions that may have benefit for indicated conditions. Recommendations included probiotics or prebiotics found in at least one randomized, controlled trial showing benefit. Trials that did not show benefit were not included. The Guideline serves an important role in informing gastroenterologists around the world, especially in regions where product availability might be limited. Especially useful are Tables 8 and 9, which summarize evidence for adult and pediatric uses, respectively.

Guarner states, “We hope our WGO guideline will assist doctors, pharmacists, dietitians and other healthcare professionals all around the world to integrate probiotics and prebiotics in an evidence-based manner into their daily work of patient care.”

The Guideline provides text that introduces current understanding of probiotics and prebiotics and then comprehensively evaluates the evidence for gastrointestinal conditions. Evidence is graded from 1-3, with Level 1 referring to evidence supported by systematic review of randomized trials, Level 2 supported by randomized trials with consistent effect, without systematic review, and Level 3, supported by a single randomized controlled trial, as per the Oxford Centre for Evidence-Based Medicine.

The 2017 iteration of these guidelines was available in six languages (English, French, Portuguese, Mandarin, Russian and Spanish). This guideline is the most accessed guideline title on the WGO website,  accounting for nearly one-quarter of all visits to the site. The 2023 version is only available in English so far, but translations are underway.

Clinical conditions for which some evidence was found include:

  • Diarrheal conditions: acute, antibiotic-associated, difficile-associated, radiotherapy-associated, enteral nutrition-associated, nosocomial,
  • Diverticular disease
  • Functional abdominal pain
  • Functional constipation
  • Insulin resistance
  • Health-related quality of life
  • Helicobacter pylori infection
  • Hepatic encephalopathy
  • Infantile colic
  • Inflammatory bowel disease
  • Irritable bowel syndrome
  • Lactose maldigestion
  • Nonalcoholic fatty liver disease
  • Nonalcoholic steatohepatitis
  • Necrotizing enterocolitis

 

About WGO:
World Gastroenterology Organisation (WGO) is a federation of over 100 Member Societies and four Regional Associations of gastroenterology representing over 60,000 individual members worldwide.  The WGO Guidelines Library contains practice guidelines written from a viewpoint of global applicability. The Guidelines go through a rigorous process of authoring, editing, and peer review and are as evidence based as possible.

The gut mycobiome and misinformation about Candida

/in ISAPP Science Blog /by KC

By Prof. Eamonn Quigley, MD, The Methodist Hospital and Weill Cornell School of Medicine, Houston

As a gastroenterologist, I frequently meet with patients who are adamant that a Candida infection is the cause of their ailments. Patients experiencing a range of symptoms, including digestive problems, sometimes believe they have an overgrowth of Candida in their gastrointestinal (GI) tract and want to know what to do about it. Their insistence is perhaps not surprising, given how many many websites and social media ‘gurus’ share lists of symptoms supposedly tied to Candida infections. Even cookbooks exist with recipes specifically tailored to “cure” someone of Candida infection through dietary changes. Some articles aim to counter the hype – for example, an article titled “Is gut Candida overgrowth actually real, and do Candida diets work?” Yet patients are too often confused about the evidence on Candida and other fungi in the GI tract. In a 2021 ISAPP presentation on the gut mycobiome, I provided a clinical perspective on fungal infections and the related evidence base.

Fungal infections do occur

Much of the misinformation I encounter on Candida infections focuses on selling a story that encourages people to blame Candida overgrowth as the cause of their symptoms and undertake expensive or complicated dietary and supplement regimens to “cure” the infection. This is not to say that fungal infections do not take place in the body. Fungal infections, from Candida or other fungi, frequently occur on the nails or skin. Patients taking oral or inhaled steroids may develop Candida infections in the oropharynx and esophagus. Immunocompromised patients also face a greater risk of Candidiasis and Candidemia—these include HIV patients; patients undergoing chemotherapy; transplant patients; and patients suffering from malnutrition.

Fungal infections are rare in the GI tract

Regardless, instances of documented Candida infection in the GI tract remain few in number. One study published in the 90s reported 10 patients hospitalized with severe diarrhea1. These patients suffered from chronic illness, underwent intense antimicrobial treatment or chemotherapy, and faced severe outcomes such as dehydration—and clinicians consistently identified the growth of Candida albicans in the patient fecal samples. Other studies on the matter lack the clinical evidence to conclude that fungal infections drive GI disease. A study examining small intestinal fungal overgrowth identified instances of fungal overgrowth among 150 patients with unexplained symptoms2. However, the lack of documentation of response to an antifungal treatment protocol makes it difficult to attribute the observed symptoms to the presence of fungal organisms.

 The gut mycobiome in IBS

The gut microbiome has taken centre stage in common discourse about gut health. In line with this movement, my colleagues at Cork investigated the fungal members of the gut microbiome – that is, the gut mycobiome – in the guts of patients diagnosed with irritable bowel syndrome (IBS)3 to ascertain whether there was any correlation with symptoms. This effort revealed DNA sequences belonging to many fungal species. However, no significant differences in the number of fungal species were observed between IBS patients and volunteers. A smaller study done on a Dutch cohort, on the other hand, detected significantly reduced total fungal diversity among IBS patients4. So, it’s not yet clear whether mycobiome differences exist across populations with IBS.

Studying the gut mycobiome for further insights

The few studies that have examined the human gut mycobiome expose the need to answer basic questions about the fungal components of the gut microbiome. For instance, what is the gut mycobiome composition among people not suffering from GI-related symptoms? Efforts to answer these questions would require longitudinal sample collection to account for the high turnover of microbes in the GI tract. We would also need to perform stool measures not typically performed in the clinic to better correlate fungal overgrowth with GI-related symptoms. Overall, any gut mycobiome study requires careful and detailed experimental design.

We also have to consider where the gut mycobiome originates. A recent study in mSphere showed that the increased amount of DNA belonging to S. cerevisiae in stool samples coincided with the number of times subjects consumed bread and other fungi-rich foods5. S. cerevisiae also failed to grow in lab conditions mimicking the gut environment after 7 days of incubation. These findings suggest that the fungi identified in gut mycobiome profiles are not persistent gut colonizers, but transient members of the gut microbiome that come from the food we digest or our saliva.

A survey of the literature on the gut mycobiome and fungal infections in the GI tract highlights the need to conduct more studies on the role fungi play in gut and overall health. My clinical approach when I encounter someone claiming to have GI symptoms caused by Candida infection is a skeptical, yet empathetic response. Through proper communication of the evidence, we can investigate the origin of symptoms together and identify the best treatment methods for any GI-related disease, whether caused by fungal infections or not.

ISAPP held a mini-symposium featuring six short lectures that explore different aspects of the human mycobiome, including research, clinical and industry perspectives. See here for the replay, with Dr. Quigley’s talk at 1:12:30.

References

(1)        Gupta, T. P.; Ehrinpreis, M. N. Candida-Associated Diarrhea in Hospitalized Patients. Gastroenterology 1990, 98 (3), 780–785. https://doi.org/10.1016/0016-5085(90)90303-i.

(2)        Jacobs, C.; Coss Adame, E.; Attaluri, A.; Valestin, J.; Rao, S. S. C. Dysmotility and Proton Pump Inhibitor Use Are Independent Risk Factors for Small Intestinal Bacterial and/or Fungal Overgrowth. Aliment Pharmacol Ther 2013, 37 (11), 1103–1111. https://doi.org/10.1111/apt.12304.

(3)        Das, A.; O’Herlihy, E.; Shanahan, F.; O’Toole, P. W.; Jeffery, I. B. The Fecal Mycobiome in Patients with Irritable Bowel Syndrome. Sci Rep 2021, 11 (1), 124. https://doi.org/10.1038/s41598-020-79478-6.

(4)        Botschuijver, S.; Roeselers, G.; Levin, E.; Jonkers, D. M.; Welting, O.; Heinsbroek, S. E. M.; de Weerd, H. H.; Boekhout, T.; Fornai, M.; Masclee, A. A.; Schuren, F. H. J.; de Jonge, W. J.; Seppen, J.; van den Wijngaard, R. M. Intestinal Fungal Dysbiosis Is Associated With Visceral Hypersensitivity in Patients With Irritable Bowel Syndrome and Rats. Gastroenterology 2017, 153 (4), 1026–1039. https://doi.org/10.1053/j.gastro.2017.06.004.

(5)        Auchtung, T. A.; Fofanova, T. Y.; Stewart, C. J.; Nash, A. K.; Wong, M. C.; Gesell, J. R.; Auchtung, J. M.; Ajami, N. J.; Petrosino, J. F. Investigating Colonization of the Healthy Adult Gastrointestinal Tract by Fungi. mSphere 2018, 3 (2), e00092-18. https://doi.org/10.1128/mSphere.00092-18.

 

 

The American College of Gastroenterology recommends against use of probiotics for primary or secondary prevention of C. difficile

/in Uncategorized /by KC

By Prof. Daniel Merenstein MD, Georgetown University School of Medicine and Prof. Eamonn Quigley MD FRCP FACP MACG FRCPI,  Houston Methodist Hospital and Weill Cornell Medical College

The American College of Gastroenterology (ACG) recently published ACG Clinical Guidelines: Prevention, Diagnosis, and Treatment of Clostridioides difficile Infections. This review considers probiotics for prevention of CDI. The ACG’s recommendations regarding probiotics and C. difficile infection (CDI) are:

  1. We recommend against probiotics for the prevention of CDI in patients being treated with antibiotics (primary prevention) (conditional recommendation, moderate quality of evidence).
  2. We recommend against probiotics for the prevention of CDI recurrence (secondary prevention) (strong recommendation, very low quality of evidence).

The ACG guidelines take a different approach to the evidence relating to probiotics than that of the American Gastroenterological Association (AGA) or the Cochrane Collaboration. The most recent Cochrane review on prevention of C. difficile-associated diarrhea (CDAD) concluded in brief, “moderate certainty evidence suggests that probiotics are effective for preventing CDAD”. In the AGA Clinical Practice Guidelines on the Role of Probiotics in the Management of Gastrointestinal Disorders, the recommendation was:

In adults and children on antibiotic treatment, we suggest the use of S. boulardii; or the 2-strain combination of L. acidophilus CL1285 and Lactobacillus casei LBC80R; or the 3-strain combination of L acidophilus, Lactobacillus delbrueckii subsp bulgaricus, and Bifidobacterium bifidum; or the 4-strain combination of L. acidophilus, L. delbrueckii subsp bulgaricus, B. bifidum, and Streptococcus salivarius subsp thermophilus over no or other probiotics for prevention of C difficile infection. (Conditional recommendation, low quality of evidence.)

In both the AGA and ACG guidelines the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was used. How, then, did they come to such different conclusions and recommendations?

The ACG guideline stated,  “a meta-analysis of 19 RCTs that concluded that probiotics were helpful at prevention of CDI in hospitalized patients if given close to start of antibiotics, with a 70% lower risk if probiotics were started within 2 days but falling to a 30% risk reduction if probiotics were started after 2 days of antibiotic therapy”. But then they did not take timing of probiotic administration into account as they assessed the evidence. Instead, they use the negative PLACIDE trial to override all other evidence for primary prevention. The PLACIDE trial was a well-done trial, but participants started their probiotic treatment 3- 7 days after antibiotics. Thus, it would seem that the ACG guideline’s conclusion could favor probiotics as long as they can be started within 2 days of the antibiotic and not recommend against probiotic use.

The ACG guideline objects to combining data on different probiotic strains in meta-analyses in order to provide evidence in favor of probiotics: “Evidence to support probiotics for this indication comes mainly from meta-analyses that pool data from small trials of different probiotic formulations and methodologies.” This is true, but the Cochrane review found thirty-nine studies (8,672 participants) that met their eligibility criteria and it is noteworthy that several different probiotics were found to be effective. The Cochrane number needed to treat (NNT) to prevent CDI is 42. However, if the ACG thought this was driven by too many negative trials, they could have qualified their recommendation. The Cochrane review found in subgroup analyses that probiotics are most effective (NNT=12) among trials with a CDI baseline risk >5%. But to conclude there is no benefit of probiotics for primary CDI is not supported by the evidence.

It is puzzling that ACG insists that the probiotic literature be pooled in a strain-specific manner, yet they support conclusions on fecal microbial transplant (FMT) even though FMT interventions are much more heterogeneous than probiotics in regard to composition and mode of administration. They recommend FMT for treatment of C. difficile based on only three double-blinded randomized clinical trials (here, here and here), only one of which was positive. The positive FMT study was conducted at two sites and compared donor stool (heterologous) versus patient’s own stool (autologous) administered by colonoscopy. Overall, 91% of patients in the FMT group achieved clinical cure compared with 63% in the control group. At site #1, the cure rate with donor FMT was 90.0% (CI, 51.8% to 98.7%) versus 42.9% with autologous FMT, whereas in site #2 the cure rate was essentially identical between the two groups. At site #2, donor FMT cure rate was 91.7% (CI, 57.2% to 98.9%) compared with 90.0% (CI, 51.8% to 98.7%) after autologous FMT. We mention this to question the consistency of evidence standards that the ACG guideline authors impose. They admonish pooled data from small trials of different probiotic formulations and methodologies yet ignore heterogeneity in FMT interventions. The data reviewed for probiotics was primarily from double-blinded randomized trials, while for FMT they rely on case series, uncontrolled studies or retrospective studies.

The authors go on to state, “… high quality evidence to support probiotics for most conditions is scarce.” How do they define “scarce” and “most conditions”? As mentioned, Cochrane found thirty-nine studies (8,672 participants) for prevention of CDAD. Under “summary of evidence”, the authors address issues such as size of the market, regulatory oversight, product cost and quality control problems with commercial products, all of which may reflect practical concerns with some probiotic products in the marketplace, but have nothing to do with available evidence. Furthermore, it is the only intervention where the financial value of the industry and cost of interventions is mentioned. Why are the size of the market or costs for FMT or drugs not just as relevant to this review? Cost is discussed throughout the recommendation but without performing or citing a formal cost analysis or cost-effectiveness analysis, even though there are approaches for doing so to inform evidence-based decision-making (here).

The authors indict probiotics for concerns about safety, citing not the thorough review sponsored by AHRQ and conducted by the RAND corporation that looked at 622 studies and found no statistically significant increased relative risk of the overall number of experienced adverse events (RR 1.00; 95% confidence interval [CI]: 0.93, 1.07, p=0.999), but by referring to a review article that cites case reports of blood infections and refers to one study with microbiota, not clinical, endpoints done in Israel on one commercial product. The data actually show that for well characterized, clinically tested probiotics with high levels of quality control the evidence for infectious complications in non-vulnerable populations is virtually nil. ACG does not mention that FMT was shut down due to safety concerns as soon as the pandemic started.

In summary, we are not convinced that the authors have justified their recommendation against the use of probiotics in relation to CDI prevention. They fail to clarify why the results of their GRADE evaluation of probiotic evidence for prevention of C. difficile resulted in totally different conclusions compared to the AGA document, which found evidence sufficient for conditional recommendation of four probiotic preparations. Further,  the review of evidence for probiotics, whether in terms of efficacy or safety, should be addressed in a manner consistent with other interventions considered and editorializing on issues such as market size, profits and product cost, in the absence of an objective approach using appropriate instruments, should be avoided.

ISAPP take-home points from American Gastroenterological Association guidelines on probiotic use for gastrointestinal disorders

/in ISAPP Science Blog /by KC

By ISAPP Board of Directors

June 15, 2020

The recent American Gastroenterological Association (AGA) Clinical Practice Guidelines on the Role of Probiotics in the Management of Gastrointestinal Disorders provided the AGA’s assessment of evidence.

Considering these AGA recommendations for probiotics to prevent necrotizing enterocolitis (NEC) and C. difficile infection, all hospital formularies should stock at least one appropriately tested probiotic. Further, all physicians should consider recommending appropriately tested probiotics for their patients for whom they prescribe antibiotics.

Here are ISAPP’s other key take-home points:

  1. AGA conditionally recommends certain probiotics for 3 of 8 disease uses that they assessed*.
  2. For preterm infants, AGA conditionally recommends 13 different probiotic preparations to prevent NEC. Considering that probiotics are currently used in only 14% of US neonatal intensive care units, this is a very significant recommendation.
  3. For adults and children on antibiotics, AGA conditionally recommends certain probiotics to prevent C. difficile infection. However, AGA did not examine evidence for probiotics for managing diarrheal side effects of antibiotics, a well-studied endpoint for probiotics for which they make no recommendation.
  4. Seven of the recommended probiotics or probiotic combinations for prevention of NEC and three recommended for prevention of C. difficile infection do not specify strains, even though the AGA guidelines paper states, “Within species, different strains can have widely different activities and biologic effects.” This lack of strain specificity in the recommendations will likely lead to confusion for implementation of these recommendations.
  5. AGA did not recommend probiotics for children or adults with irritable bowel syndrome (IBS) for two endpoints, global response (overall symptoms) and abdominal pain severity. However, this should not be interpreted as a lack of evidence for ‘digestive’ symptoms, considering the exclusion criteria imposed.
    • The technical report states that 22 studies in IBS subjects were excluded from analysis, representing a potentially important gap in available evidence. Studies were excluded when no extractable data were reported and the corresponding author failed to provide data after two attempts of being contacted. Examples of excluded studies are here, here, here, and here, and this study was published after AGA’s December 2018 literature search cutoff. These studies could have been included by estimating effect sizes of interest using standard meta-analytical methods for the types of effect sizes that were reported in those excluded studies. However, because of the level of evidence AGA required, the overall conclusion may not have been different if such studies had been included.
    • Only studies on subjects diagnosed with IBS that reported on global response or abdominal pain severity were included, excluding studies on other clinically meaningful endpoints. Many studies on endpoints such as occasional diarrhea, occasional constipation, gut transit time, or individual digestive symptoms outside the context of IBS such as gas, bloating, or distension have been conducted (for example, here, here). Such benefits can be meaningful and very helpful to people afflicted with such symptoms that severely impact quality of life.
  6. AGA recommended against the use of probiotics for acute pediatric diarrhea. Although the technical report considered evidence from over 50 trials (for comparison, the European Society for Paediatric Gastroenterology, Hepatology and Nutrition working group on probiotics identified over 150 randomized, controlled trials for its document), AGA ultimately opted to base its recommendation on only trials conducted in North America, all null. Differences in rotavirus vaccination rates and time of initiation of probiotic therapy may have accounted for null results in two trials. (See rhamnosus GG for treatment of acute pediatric diarrhea: the totality of current evidence and Late initiation of probiotic therapy for acute pediatric gastroenteritis may account for null results for more on this topic.) Although AGA is an American organization, its recommendations carry weight globally, so it is unfortunate that AGA did not word its recommendation in the Summary of recommendations (Table 3) as applying only to North America.
  7. Doses were not stipulated in the recommendations.
  8. Probiotics have been studied for endpoints far beyond the eight endpoints considered by AGA (see here for a review of other evidence), including benefits for generally healthy people.
  9. AGA guidelines are not solely based on the balance between the benefits and harms of the interventions, but considered patients’ values and preferences, resource use (i.e. cost), health equity, acceptability, and feasibility (the Evidence to Decision Framework). As such, AGA’s recommendations differ in significant ways from other societies’ evidence-based recommendations, including the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), World Gastroenterology Organisation, European Crohn’s and Colitis Organization, and European Society for Primary Care Gastroenterology.

ISAPP agrees with AGA that additional human efficacy trials are needed, all human trials on probiotics should be conducted in a manner that will minimize bias, and study results should be made available to the scientific community for assessment, irrespective of outcome. Yet ISAPP also agrees with Purna Kashyap MD, a co-author of AGA’s technical report upon which their recommendations were based, who in an unrelated article states, “Diet plays a very significant role in the health of our microbiome – the food we eat provides nutrient to support both the growth and diversity of our microbiota. A diverse diet rich in prebiotic and probiotic foods is optimal.” The AGA recommendations do not address such uses of probiotics, and the negative headlines that resulted from the AGA’s press release on these guidelines may discourage probiotic use where it may be beneficial.

AGA’s recommendations sometimes lack clarity for clinicians regarding which specific strains are recommended.  Further, considering the limited scope of this review and the positive recommendations for three indications for probiotic use, ISAPP considers that conclusions such as “Probiotics don’t do much for most people’s gut health despite the hype” (CNN, June 9) leave the impression that the findings of the AGA review were broader and more negative than the data support.

 

*AGA evaluated the evidence by the GRADE criteria for use of probiotics on the following GI diseases:

  1. In symptomatic adults with confirmed Clostridioides difficile infection, should probiotics be used as part of the treatment regimen?
  2. In adults and children receiving antibiotic therapy for any indication except C. difficile infection, should probiotics be used to prevent C. difficile-associated diarrhea?
  3. In adults and children with Crohn’s disease, should probiotics be used for induction or maintenance of remission?
  4. In adults and children with ulcerative colitis, should probiotics be used for induction or maintenance of remission?
  5. In adults and children with ileal pouch-anal anastomosis for chronic ulcerative colitis, should probiotics be used for prevention or maintenance of remission of pouchitis?
  6. In symptomatic children and adults with irritable bowel syndrome, should probiotics be used to improve global response or abdominal pain severity?
  7. In children with acute infectious gastroenteritis, should probiotics be used to reduce the duration or severity of diarrhea?
  8. In preterm, low birthweight newborns, should probiotics be used to prevent necrotizing enterocolitis, sepsis, and all-cause mortality?

 

Related articles

https://www.nutraingredients-usa.com/Article/2020/06/12/AGA-issues-guidelines-for-probiotics-for-sick-at-risk-populations

The past decade of probiotics and prebiotics research: ISAPP board members share their perspectives.

/in ISAPP Science Blog, Consumer Blog /by KC

By ISAPP board members, compiled by Kristina Campbell

Scientific progress in the field of probiotics and prebiotics, as in any other field, often seems to occur one tiny step at a time. Yet over the course of several years, these tiny steps can add up to significant progress.

Current members of the ISAPP board of directors hold academic positions across North America, and Europe, representing some of the experts at the forefront of scientific innovation in probiotics and prebiotics. Their collective experience encompasses functional foods, fermentations, microbial ecology, microbial genetics, immunology, and clinical medicine, including pediatrics, family medicine and gastroenterology. As we enter into 2020 and a new decade, these board members have taken a moment to reflect on how far they and their colleagues have come over the past ten years, by answering the question: What changes have occurred in the domains of research, applications, and awareness about probiotics and prebiotics?

ISAPP board members, 2019 annual meeting

Available scientific methods and tools

The change that stood out the most to the ISAPP board members over the past decade was the rapid expansion of available scientific methods and tools – from gene sequencing technology to CRISPR-Cas to bioinformatic approaches. These exciting developments have enabled scientists to obtain more information, and to do it both quickly and economically. In the words of the board members:

“Advances in sequencing technology [have] revolutionized our ability to understand the gene repertoire of each individual probiotic strain (whole genome sequencing) and the interplay with the microbiome (metagenomics). This has been really energizing to the field, but has also meant that competence in bioinformatics has become an essential tool for probiotic and prebiotic scientists.”

“A decade ago, human studies on prebiotics would look at changes in the gut microbiota using fairly laborious procedures. Nowadays, the analysis is much more extensive and straightforward to do, and probably more accurate… The biggest change has been the capability to assess not only composition of the microbiota but also its functionality. So, today, the trials include metabonomics as well as assessments of health effects (through changes in particular symptoms and /or biomarkers such as blood lipids, microbial products, immune and inflammatory status). That way, we get a far better picture of what prebiotics can do.”

“In 2010 we only had DGGE to characterize the genome and were trying to figure out how to implement 16S amplicon sequencing. Now we are implementing shotgun & shallow shotgun sequencing for similar prices. In 2010, we did only work on 3-4 probiotic lactobacilli for molecular research, now we work on 400-500 lactobacilli. We do comparative genomics and functional analyses at much larger scale. And in 2010, we paid almost 10000 euro just to sequence one genome of lactobacilli, with limited analysis, now a few hundred euro for sequencing.”

Probiotics and prebiotics for microbiome modulation

Because of the rapid advancements in scientific tools and techniques during the past decade, as mentioned above, many more research groups are endeavoring to study the microbial communities that relate to probiotics and prebiotics. Gut microbiota are of great interest—not least because, among the strategies for microbiome modulation, probiotics and prebiotics are two of the leading candidates. Moreover, microbiome data can help researchers understand the context of probiotics and prebiotics in the gut and in different environments. In particular, many clinical trials of probiotics and prebiotics now include a microbiota-related measure. Novel species and strains for food use may be identified from gut microbiota studies, although safety and efficacy assessment will form challenges for regulatory bodies. Board members said:

“My collaborators and I initiated our first human clinical trials with prebiotics in 2008 and published several papers in 2010 and 2011. These early papers were among the first in which high throughput 16S DNA sequencing was used to assess how the human gut microbiota was affected by the prebiotic, GOS. Although this is now a routine method in the field, in 2008, having a Roche 454 pyrosequencer in the lab was very special, and we were astounded to be able to identify and measure abundances of the main members of the gut microbiota. Having these large data sets also led us to realize the importance of what was at the time the “new” field of bioinformatics that was critical in analyzing and reporting the data. This research showed that GOS was bifidogenic (with high specificity) in healthy adults, but was also subject-dependent. Thus, the results clearly showed there were prebiotic responders and non-responders. This remains an important area of research for my group.”

“The decade started with general excitement that ‘dysbiosis’ of the gut microbiota is involved in just about every human health problem, and has turned into re-remembering that correlation is not causation and microbiota patterns are often driven more by random factors or factors unrelated to disease than by microbiology.”

“It’s worth noting that in 2020, the well-controlled probiotic studies showing health benefits in humans are still more convincing and valuable than the studies showing any ‘beneficial’ effects on the human microbiota.”

“Over the past decade we have witnessed a tremendous explosion in our understanding of the microbiome and its interactions with us, its host. Progress in translating this knowledge into new treatments has been slower but glimmers of encouragement have appeared and we look forward to the next decade when interventions that modulate the microbiome to benefit our health will be based on a true understanding of how they act and will be selected to the maximal benefit of each individual.”

Probiotic mechanisms of action

Probiotic mechanisms of action are a perennial hot topic within the scientific community—and many had hoped that the new suite of scientific tools at scientists’ disposal would significantly advance this area of research during the past decade. But according to one ISAPP board member:

“In 2010 I would have confidently predicted that by 2020 we would have much more of a mechanistic understanding of probiotic mechanisms [and] the importance of strain effects… But this simply has not happened.  The field has become more biologically and computationally complex and many millions have been spent on research, but I still don’t think we can answer the fundamental question we faced in 2010, and in 2000, and in 1990 – what makes one a strain a probiotic, while another is not?”

But in the views of other board members:

“Through genomic and metabolomic studies we are identifying differences between strains that function at different sites and what properties are important for their probiotic function.”

“Identify[ing] the key effector molecules turned out to be more complex [than] we thought 10 years ago. It has become clear to me that probiotic mechanisms of action are per definition complex and multifactorial, because they are living microbes having thousands of molecules that all play a role. Yet, there is clearly an hierarchy of effector molecules.”

Probiotic and prebiotic applications

In general, microbiome studies of the past decade have led to a better appreciation of the ubiquity and complexity of microbial communities—not just those associated with different human body sites, but also those occupying every possible niche on Earth. ISAPP board members reflect:

“In 2010, I was mainly studying probiotics for the gut and vagina, now we have explored probiotics for the skin, respiratory tract, animals, plants, isolates from fermented vegetables that can boost vegan probiotic formulations etc., and other areas.”

“Two areas of research I am doing I’d never have imagined in 2010 are in honey bees and Chinook salmon and against environmental chemicals, administering probiotics.”

Public awareness of probiotics and prebiotics

Numerous studies and surveys show the general public has more awareness than ever of probiotics – and increasingly, of prebiotics too. Individuals receive their information through many different channels, both digital (e.g. blogs, websites) and non-digital (e.g. magazines, product packaging). The past decade also saw the creation of valuable evidence-based resources, such as the Clinical Guides available in the US and Canada, and resources from World Gastroenterology Organisation and from ESPGHAN (probiotics for pediatric acute gastroenteritis, pediatric nosocomial diarrhea, preterm infants, and pediatric AAD). These resources have been enabled by a critical mass of studies that have examined the efficacy of various probiotic strains for certain indications. One board member says:

“From a clinical perspective, the biggest change for us has been that the general public knows so much about probiotics; now we are doing a lot less educating of docs and patients about the concepts behind our probiotic studies.”

But there’s still work to be done:

“The term probiotic is now widely known, but still too often people are misinterpreting what it means, or generalizing the whole field instead of recognizing strain and product differences. We need to continue to educate and clarify to keep the messaging on track.”

“There is still lack of knowledge that not all probiotics are equal. The clinical effects and safety of any single probiotic or combination of probiotics should not be extrapolated to other probiotics. The same applies to prebiotics.”

“Choosing a probiotic continues to be a major hurdle for the consumer – for every probiotic strain that is well characterized, studied in detail in appropriate disease models, and shown to be effective in clinical trials there are hundreds that would fail to pass even the most basic tests of quality control. We must help the consumer to make informed choices.”

 

It seems that, while the past decade has been a fruitful time for probiotics and prebiotics research and public awareness, scientists still have a lot of work to do. In the 2020s they will use the tools available to them, and continue to develop new ones, to gain more detailed and multi-faceted information about probiotic strains and prebiotic compounds—and about the context in which they operate (for instance, the gut microbiome), to ultimately confer benefits on human health.

The small intestinal ‘mysteriome’: A potentially important but uncharted microbiome

/in Consumer Blog, ISAPP Science Blog /by KC

By Eamonn MM Quigley MD FRCP FACP MACG FRCPI, Lynda K and David M Underwood, Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital, Houston, Texas, USA

 

Over recent years, countless publications have documented the status of the microbiota of the gastrointestinal tract by examining fecal samples. While this approach does provide a “snapshot” or representation of what is going on in the gut, and especially in the colon, it is a crude measure of the complex interactions between micro-organisms in the gut, as well as between these same microorganisms and us (their hosts). Fecal samples comprise a terminal microbial ecosystem, characterized by depletion of readily fermentable substrates, with a concomitant change in microbial composition, even compared to those farther upstream in the colon. It is unlikely, for example, that studies using fecal samples provide a full picture of what happens when bacteria (or other microorganisms) “talk” to the lining of the gut (the mucosa) or interact with the immune system of the intestine. Even less likely is that they provide any insights into bacterial populations in the small intestine, where most of the digestion of food and absorption of nutrients takes place. The small intestine also possesses the most abundant immune tissue of the entire gastrointestinal tract.

Yet, details of which bacteria actually inhabit this long and important organ, the small intestine, are sketchy. This lack of knowledge has apparently not restricted much theorizing and speculation about the role of an overgrowth of colonic-type bacteria (referred to as small intestinal bacterial overgrowth – SIBO) in the small intestine in many symptoms, disorders, and diseases. According to one especially popular theory – the “leaky gut” hypothesis – the list of conditions is nearly endless. The “leaky gut” hypothesizes that dysbiosis in the small intestine (in other words SIBO) and a disruption of the gut barrier leads to “leakage” of bacteria and bacterial products into the circulation causing inflammation, allergy, and autoimmunity.

There are several leaps of faith involved in “leaky gut” including, of course, the definition and diagnosis of SIBO. Traditional methods of diagnosing SIBO (obtaining fluid samples directly from the upper small intestine or a variety of breath tests) are fraught with problems and, in essence, have precluded a universally accepted definition of SIBO.

Fundamental to this dilemma is the definition of the normal small intestinal microbiome – how can we diagnose abnormal when we do not know the limits of normality? I would contend that, while there are situations where it is undoubted (based on the clinical context and various laboratory and other findings) that SIBO is an issue, there are countless more instances where SIBO is over-diagnosed and incorrectly implicated as the cause of an individual’s symptoms. This is an important issue as it can lead to the inappropriate use of antibiotics – something we all wish to avoid.

There is some good news – clever techniques exist for obtaining uncontaminated fluid samples from the small intestine, a capsule technology that permits live sampling of intestinal gases (generated by bacteria) as it traverses the intestine and the application, at last, of high-throughput sequencing, metagenomics, metabolomics, and metatranscriptomics to small intestinal microbiota suggest that the accurate definition of the normal small intestinal microbiome is not far off. At that time, we can all agree on an accurate and clinically meaningful definition of SIBO.