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Episode 7: Evidence for probiotic use in pediatric populations

/in Podcast, Season One /by KC

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The Science, Microbes & Health Podcast 

This podcast covers emerging topics and challenges in the science of probiotics, prebiotics, synbiotics, postbiotics and fermented foods. This is the podcast of The International Scientific Association for Probiotics and Prebiotic (ISAPP), a nonprofit scientific organization dedicated to advancing the science of these fields.

Evidence for probiotic use in pediatric populations, with Prof. Michael Cabana

Episode summary:

In this episode, the ISAPP hosts discuss probiotics for pediatric populations with Prof. Michael Cabana, MD, MPH, from Albert Einstein College of Medicine and The Children’s Hospital at Montefiore. Prof. Cabana starts by acknowledging the gap between the demand for probiotic interventions and the evidence that currently exists for their efficacy. He gives an overview of the challenges in designing trials on probiotic interventions for children, and summarizes what the evidence shows to date.

Key topics from this episode:

  • A concerning gap exists between the strength of evidence for probiotic interventions in children and the high demand by parents for these interventions.
  • A clinician supports clinical recommendations if they are based on multiple high-quality randomized, controlled trials in different settings. Unfortunately, this level of evidence is often missing for pediatric interventions, including for probiotics.
  • A clinician is less concerned about what regulatory category (drug, supplement) a recommendation falls into, and more about the level of evidence supporting its use.
  • At a minimum, a clinician looks first for evidence of no harm.
  • Conducting clinical trials in children presents many challenges. What are the “5 Ds”, which make clinical studies in children different from those in adults, as described by Forrest in 1997?
  • A lot of adult diseases have roots in childhood, so understanding pediatric health is important not just for kids, but also for adults. Preventing adult disease starts at an early age. This is the ‘delayed payoff’ that Forrest refers to.
  • Compelling evidence exists for probiotic efficacy in children for a few endpoints: colic, antibiotic-associated diarrhea, and necrotizing enterocolitis.
  • When it comes to necrotizing enterocolitis, strong evidence, reproducibility, dose-response, and biological mechanisms are what give clinicians the confidence to use probiotics.
  • An individual patient data meta-analysis (a project that emerged from an ISAPP meeting), enabled combining data from numerous studies that looked at the probiotic L. reuteri DSM17938 given to babies with colic. An overall positive effect was seen. Factors that predicted success in infants were being formula-fed, being younger, and not being on proton pump inhibitors.

 

Episode links:

  • One of many reports on the growing market for probiotic products for infants and children 
  • Information about the 2003 Pediatric Research Equity Act (PREA) and the Best Pharmaceuticals for Children Act (BPCA) mentioned in the podcast 
  • The 5 “Ds” in Pediatrics mentioned in the podcast
  • The TIPS study mentioned in the podcast is described here and here
  • The meta-analysis on colic mentioned in the podcast

 

Additional resources:

ISAPP Digs Deeper into Evidence on Probiotics for Colic with New Meta-Analysis. ISAPP blog
Probiotics to Prevent Necrotizing Enterocolitis: Moving to Evidence-Based Use. ISAPP blog

 

About Prof. Michael Cabana, MD:

Prof. Michael Cabana, MD, MPH, is a Professor of Pediatrics & the Michael I. Cohen University Chair of Pediatrics at Albert Einstein College of Medicine, as well as Physician-in-Chief, The Children’s Hospital at Montefiore (CHAM). He is also a member of the United States Preventive Services Task Force USPSTF (here), a prestigious appointment for medical personnel to weigh evidence (risk vs. harms) on prevention interventions recommended in the United States. He is a clinical trialist (see the trials listed here), with a focus on allergy in children. He has also conducted trials using probiotic interventions. Prof. Cabana served on the ISAPP board of directors from 2008 to 2018. He has an MD from University of Pennsylvania, an MPH from Johns Hopkins, and an MA in business from Wharton Business School.

Dr. Cabana’s comments do not necessarily reflect the views of the USPSTF.

What’s a Clinician to do When the Probiotic Recommendations from Medical Organizations Do Not Agree?

/in ISAPP Science Blog /by KC

By Prof. Hania Szajewska, MD, Department of Paediatrics, The Medical University of Warsaw, Poland

The scientific literature on probiotics is growing rapidly, with newly published studies continually adding to the sum of information about the probiotic strains that confer health benefits in specific populations.

In research, we make hypotheses. Eventually, they are resolved by collecting data or they are replaced by more refined, or entirely new, hypotheses. This process usually unfolds over an extended period of time. Along the way, medical and scientific organizations may decide to take ‘snapshots’ of the evidence to-date and develop guidelines based on available published studies. Unfortunately, disagreements can occur about the meaning of the data, sometimes leading to differences in the guidelines developed by various organizations.

But clinicians cannot always wait for the data to provide a crystal-clear picture. They want answers to guide their clinical practice. Hence the question: Should probiotics be used if guidelines do not agree on the use of probiotics for a certain indication, or on the strains to be used?

Take, for example, the current situation relevant to pediatric practice. Here I discuss two recommendation documents: one developed by the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), and another developed by the American Gastroenterological Association (AGA).

Acute diarrhea

In 2020, the ESPGHAN Working Group (WG) on Probiotics identified 16 systematic reviews and meta-analyses published since 2010, which included more than 150 RCTs. The WG made weak (also known as conditional) recommendations for (in descending order in terms of the number of trials evaluating any given strain):

  • S boulardii (low to very low certainty of evidence);
  • L rhamnosus GG (very low certainty of evidence); L reuteri DSM 17938 (low to very low certainty of evidence);
  • L rhamnosus 19070-2 & L reuteri DSM 12246 (very low certainty of evidence).

The WG made a strong recommendation against L helveticus R0052 & L rhamnosus R0011 (moderate certainty of evidence) and a weak (conditional) recommendation against Bacillus clausii strains O/C, SIN, N/R, and T (very low certainty of evidence)1.

In contrast, also in 2020, the AGA, based on the evaluation of 89 trials, made a conditional recommendation against the use of probiotics in children from North America with acute infectious gastroenteritis (moderate quality of evidence)2. The rationale for the negative AGA recommendation was that the majority of the studies were performed outside North America. Moreover, two large, high-quality null trials, performed in Canada and US, questioned the efficacy of the probiotics evaluated in these studies, for the management of children with acute gastroenteritis 3,4.

Prevention of necrotizing enterocolitis

Another example of discordant guidelines relates to necrotizing enterocolitis (NEC) in preterm infants. NEC is one of the most severe and life-threatening gastrointestinal diseases to occur in preterm infants, particularly those with a birth weight <1,000 g. The factors involved in the pathogenesis of NEC include formula feeding rather than breastfeeding, intestinal hypoxia–ischemia, and colonization of the gut with pathogenic microbiota5.

In 2020, both ESPGHAN6 and AGA2 published their recommendations on the use of probiotics for preventing NEC. While both were based on pair-wise systematic reviews and network meta-analyses7, their conclusions differed. The only probiotic strain that was recommended by both societies was L rhamnosus GG ATCC 53103. With regard to L reuteri DSM 17938, the ESPGHAN did not formulate a recommendation for or against it, while the AGA conditionally recommends it.

Why do guidelines differ?

Many factors contribute to the discrepancy in guidelines developed by various organizations. In the case of probiotics, they may be due to these differences:

  • Study methods. Although dozens of studies involving thousands of patients have been conducted in many indications, studies are subject to bias resulting from incorrect randomization, non-confidentiality, non-masking, or lack of intention-to-treat analysis.
  • Targeted population. The effectiveness of probiotics in different populations may vary, for example, due to differences diet or in microbiota at the start of treatment.
  • Probiotics are a heterogeneous intervention. Even if the rules for assessing individual strains, and not probiotics as a group, are followed, the effectiveness of probiotics is influenced by factors such as product quality, storage conditions, dose, timing of administration, and the duration of the intervention.
  • Outcome measures (endpoints). Studies use different outcomes to measure efficacy, and even if the same outcomes are used, their definition may differ (e.g. diarrhea duration may be defined as time to the last diarrheal stool or time to the first normal stool). Such heterogeneity in the reported outcomes, combined with the lack of standardized definitions, pose a challenge in meta-analyses and should be considered when interpreting the results.

What should clinicians do when the guidelines are not consistent?

Back to the question asked earlier: Should probiotics be routinely used if guidelines from the scientific or medical organizations do not agree on the use of probiotics?

One approach may not fit all. However, in the case of acute infectious diarrhea in children, both the AGA and ESPGHAN formulated a conditional recommendation: in the first case, it is negative; in the second, positive. It is important to note that the interpretation of a conditional recommendation for and a conditional recommendation against is similar. For clinicians, both mean that different choices will be appropriate for different people. Clinicians should help each patient make decisions consistent with the patient’s preferences. For patients, it means that the majority of individuals in this situation would want the suggested course of action, but many would not8.

Taken together, the recommendations communicate that probiotics may be beneficial, although not essential, in the treatment of acute diarrhea in young children.  The use of certain probiotics with documented efficacy may be considered in the management of acute diarrhea in young children.

With regard to the prevention of NEC, the AGA and ESPGHAN guidelines agree that certain probiotics reduce the risk of NEC in preterm infants. However, based on their analyses and the included / excluded studies they differ in the recommended strains; additionally, not all of the strain combinations are available everywhere. Therefore, it seems reasonable to choose a probiotic that is included in the recommendations of both societies (if available). One example is L. rhamnosus GG.

In general, organizations should be commended for taking on the daunting task of evaluating the probiotic evidence – both the quality of the studies and the positive or negative results – in order to generate recommendations. Until further well-conducted studies make the answer clearer, clinicians must live with some ambiguity and use the recommendations in the best way possible to inform their daily decisions with individual patients.

REFERENCES

  1. Szajewska H, Guarino A, Hojsak I, et al. Use of Probiotics for the Management of Acute Gastroenteritis in Children. An Update. J Pediatr Gastroenterol Nutr. 2020.
  2. Su GL, Ko CW, Bercik P, et al. AGA Clinical Practice Guidelines on the Role of Probiotics in the Management of Gastrointestinal Disorders. Gastroenterology. 2020.
  3. Schnadower D, Tarr PI, Casper TC, et al. Lactobacillus rhamnosus GG versus Placebo for Acute Gastroenteritis in Children. The New England journal of medicine. 2018;379(21):2002-2014.
  4. Freedman SB, Williamson-Urquhart S, Farion KJ, et al. Multicenter Trial of a Combination Probiotic for Children with Gastroenteritis. The New England journal of medicine. 2018;379(21):2015-2026.
  5. Neu J, Walker WA. Necrotizing enterocolitis. The New England journal of medicine. 2011;364(3):255-264.
  6. van den Akker CHP, van Goudoever JB, Shamir R, et al. Probiotics and Preterm Infants: A Position Paper by the European Society for Paediatric Gastroenterology Hepatology and Nutrition Committee on Nutrition and the European Society for Paediatric Gastroenterology Hepatology and Nutrition Working Group for Probiotics and Prebiotics. Journal of pediatric gastroenterology and nutrition. 2020;70(5):664-680.
  7. van den Akker CHP, van Goudoever JB, Szajewska H, et al. Probiotics for Preterm Infants: A Strain-Specific Systematic Review and Network Meta-analysis. Journal of pediatric gastroenterology and nutrition. 2018;67(1):103-122.
  8. Andrews J, Guyatt G, Oxman AD, et al. GRADE guidelines: 14. Going from evidence to recommendations: the significance and presentation of recommendations. J Clin Epidemiol. 2013;66(7):719-725.

 

See here for a published comment on this topic in The American Journal of Gastroenterology.

ISAPP’s 2019 annual meeting in Antwerp, Belgium: Directions in probiotic & prebiotic innovation

/in featured, News /by ISAPP

Kristina Campbell, Microbiome science writer, Victoria, British Columbia

We live in a time when a simple Google search for ‘probiotics’ produces over 56.8 million hits; a time when almost everyone has heard of probiotics through one channel or another, and when an ever-increasing variety of probiotic and prebiotic products is available in different regions of the world.

The next five to ten years will be telling: will probiotics and prebiotics join the ranks of other trendy health products that experienced a wave of popularity before something else took their place? Or will they be recognized as important contributors to health through the lifespan, and establish a permanent position in the clinical armamentarium?

According to the global group of 175 academic and industry scientists who met for the ISAPP annual meeting in Antwerp (Belgium) May 14-16, 2019, one thing above all is necessary for the world to recognize the significance of probiotics and prebiotics for health: scientific innovation. Not only are technological capabilities advancing quickly, but also, new products are being evaluated by better-educated consumers who demand more transparency about the health benefits of their probiotics and prebiotics.

Participants in the ISAPP conference came together to talk about some of the leading innovations in the world of probiotics and prebiotics. Here are three of the broad themes that emerged:

Better health through the gut-brain axis

Gut-brain axis research is rapidly growing, with many investigators in search of probiotic and prebiotic substances capable of modulating brain function in meaningful ways. Phil Burnett of Oxford (UK) presented on “Prebiotics, brain function and stress: To what extent will prebiotics replace or complement drug therapy for mental health?”. Burnett approached the challenge by administering prebiotics to healthy adults and giving them a battery of psychological tests; in one experiment he found people who consumed a prebiotic (versus placebo) showed benefits that included reduced salivary cortisol and positively altered emotional bias. For those with diagnosed brain disorders, Burnett concludes from the available data that prebiotics have potential anxiolytic and pro-cognitive effects in these populations, and that prebiotics may eventually be used to complement the established treatments for some mental disorders.

Short-chain fatty acids (SCFAs) are of interest as potential modulators of brain function, but so far very little research has been carried out in this area. Kristin Verbeke of Leuven (Belgium) gave a talk entitled “Short-chain fatty acids as mediators of human health”, which covered the extent to which interventions with fermentable carbohydrates can alter systemic SCFA concentrations (rather than gut SCFA concentrations)—since the former are more relevant to effects on the brain.

Also, a students and fellows feature talk by Caitlin Cowan of Cork (Ireland) explored a role for the microbiota in psychological effects of early stress. She spoke on the topic “A probiotic formulation reverses the effects of maternal separation on neural circuits underpinning fear expression and extinction in infant rats”.

A clear definition of synbiotics

Immediately before the main ISAPP meeting, a group of experts met to propose a consensus definition of ‘synbiotic’, with the objective of clarifying for stakeholders a scientifically valid approach for the use of the increasingly-popular term. A key point of discussion was whether the probiotic and prebiotic substances that make up a synbiotic are complementary or synergistic. And if the two substances have already been tested separately, must they be tested in combination to give evidence of their health effect? The group’s conclusions, which will undoubtedly steer the direction of future R&D programs, will be published in a forthcoming article in Nature Reviews Gastroenterology & Hepatology.

Probiotics and prebiotics for pediatric populations

Probiotics and prebiotics have been studied for their health benefits in pediatric populations for many years, but in this area scientists appear to have a renewed interest in exploring new solutions. Maria Carmen Collado of Valencia (Spain) covered “Probiotic use at conception and during gestation”, explaining some of the most promising directions for improving infant health through maternal consumption of probiotics.

In recent years, technical advancements have made possible the large-scale production of some human milk oligosaccharides (HMOs); it is now an option to administer them to infants. Evelyn Jantscher-Krenn of Graz (Austria) presented a novel perspective on HMOs, with “HMOs in pregnancy: Roles for maternal and infant health”, giving a broad overview of the many ways in which HMOs might signal health status and how they might be fine-tuned throughout a woman’s pregnancy.

A discussion group on “prebiotic applications in children”, chaired by Dr. Michael Cabana of San Francisco (USA) and Gigi Veereman of Brussels (Belgium), discussed evidence-based uses of prebiotics in children in three areas: (1) prevention of chronic disease; (2) treatment of disease; and (3) growth and development. While the latter category has the best support at present (specifically for bone development, calcium absorption, and stool softening), the other two areas may be ripe for more research and innovation. The chairs are preparing a review that covers the outcomes of this discussion group.

Next year in Banff

ISAPP’s next annual meeting is open to scientists from its member companies and will be held on June 2-4, 2020 in Banff, Canada.

 

Photo by http://benvandenbroecke.be/ Copyright, ISAPP 2019.

probiotics calendar

Probiotics in the Year 2018

/in featured, ISAPP Science Blog /by Mary Ellen Sanders

Prof. Daniel Merenstein MD, Georgetown University School of Medicine

Messages about probiotics seem to be everywhere. It is difficult for me to keep up with the emails, links, and stories I am sent by friends and colleagues. I am regularly asked my opinion about new studies. Null trials seem to really generate the most interest, with some people looking for limitations of the study and others generally over-extrapolating the null results, seemingly at times to generate the brashest headlines.

Today I want to take a step back and share how I see probiotics in 2018.

I just reviewed a 109-page NIH grant focused on a probiotic intervention for use in a resource poor area. Throughout the grant, the authors never once defined probiotics—presumably because the definition is so commonly known. They did define ‘prebiotics’ but they never felt the need to define probiotics. Imagine that: 2018, and probiotics no longer need to be defined lest the authors seem pedantic. This would not have been the case even five years ago.

Probiotics are backed by real science, they are here to stay, and they are impacting both how we practice medicine and how consumers care for their own health. These are real products with some robust outcomes supported by well-done, independent studies. That is worth emphasizing: there is level 1 evidence for certain products and indications. On the other hand, the use of many probiotics is not evidence-based and expectations about some are not realistic. In the real world, products do not work for every indication or study population. Effect sizes and effectiveness for most indications are often small. One of my true hesitations about fecal microbial transplantation* is how nearly every study has over 90% effectiveness. That gives me cause for concern.

Thus, when there is a null trial the skeptics shouldn’t over extrapolate and the probiotic devotees should not attack the authors. We can look to studies on other treatments as an example: In November of this year NEJM published an article that showed a new antibiotic did not work well for gonorrheal pharyngeal infections. What I didn’t see were any headlines stating, “Antibiotics don’t work for pharyngeal infections.” But headlines involving probiotics often make erroneously broad generalizations. There clearly are indications for which no probiotic has been or will be shown to work. Selling a probiotic for that indication is clearly unethical. But considering the robust evidence base we have for the indication of probiotics for gastroenteritis, it is inappropriate – after 2 null trials – for headlines to read, “Probiotics Do Not Ease Stomach Flu” or “Probiotics No Better Than Placebo for Gastroenteritis”.

This fall I spoke about probiotics at two conferences, the annual meetings of the American Academy of Family Physicians (AAFP) and the annual meeting of the Academy of Nutrition and Dietetics  (FNCE). I had never spoken at either conference. With the help of a colleague, I gave two talks at AAFP; both were over-registered with all 600+ spots taken. At the FNCE, the talk was also over-registered with 350 in attendance. The level of interest in probiotics was astonishing.

What I learned from my talks is that as long as there are well-designed studies demonstrating benefits, professionals are open to probiotics and will use them correctly. Further, both the FNCE and AAFP audiences shared similar concerns: can you trust that probiotic product labels are truthful regarding contents, and are there any safety concerns? Good science and quality oversight need to continue to address these important concerns.

2018 was a great year for the advancement of probiotics in mainstream medicine. However, I think for physicians to fully embrace probiotics, the probiotic industry will better need to police itself and make sure the products they sell are what they say they are. Then they need to communicate this on the product label, using a valid quality seal (such as offered by USP), so physicians and consumers will be confident about what they are using. If the science continues to advance and we communicate about it responsibly, the use of probiotics will be used appropriately and more frequently – as they should be.

 

*For all my colleagues in the gastroenterology world who have fallen in love with fecal transplant for recurrent C. diff,  the totality of evidence as of this writing is:  187 total patients, 5 studies (2 enema, 2 colonoscopy and 1 via-nasoduodenal tube), and punchline, TWO studies were blinded. The one with the lowest rate of success was the only one that was placebo-controlled and blinded. The other blinded study was donor versus patients’ own stools. Stew on that and feel free to correct me.  

ISAPP BOARD MEMBERS TO PARTICIPATE IN PEDIATRIC PROBIOTIC CONFERENCE IN ITALY

/in featured, News /by Mary Ellen Sanders

ISAPP Board Members, Professors Michael Cabana MD MPH and Seppo Salminen PhD, will be participating in the 4th Annual Prebiotics and Probiotics in Pediatrics conference in Bari, Italy April 12-14, 2018. Prof. Cabana will be chairing a panel on colic and will discuss findings from a meta-analysis of L. reuteri as an intervention for colic. This meta-analysis, published December 2017, was the outcome of discussion groups convened at the 2014 and 2016 ISAPP meetings, both led by Prof. Cabana of University of California, San Francisco.

Prof. Salminen will share his decades of knowledge of probiotics, colonizing microbiota and pediatric applications in his presentation titled “Bacteriome and Friends.”

Don’t miss the 4th Annual Prebiotics and Probiotics in Pediatrics conference, which is a unique opportunity to meet major experts in the field while learning the most updated basic and clinical research on prebiotics and probiotics for the developing human. The three-day meeting will cover the major novelties in pediatric gastroenterology, obesity, allergy, nephrology, neonatology and the new scenario on gut-brain communication.