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Should everyone take a probiotic? Assessment of evidence of probiotics for healthy people

/in ISAPP Science Blog /by KC

By Prof. Daniel Merenstein MD and Dr. Mary Ellen Sanders PhD

During the ISAPP 2024 meeting, an article titled, “Is there evidence to support probiotic use for healthy people?” was published. The authors concluded, “…we did not find a high level of evidence to support recommendations for other endpoints we reviewed for healthy people. Although evidence for some indications is suggestive of preventive benefits of probiotics, additional research is needed.”

Those in the probiotic field are used to headlines critical of probiotics meant to sensationalize rather than accurately reflect the evidence. But this article takes a careful look at if probiotics should be used by everyone regardless of indication. 

Scientific grounding for the paper

This article is an ISAPP output derived from an ISAPP 2023 discussion group that included academic and industry scientists, including the nine authors. The discussion group aimed to examine the evidence that probiotics are beneficial to healthy people at a population recommendation level.

We assembled probiotic and evidence-based medicine experts to review the literature. We chose preventative indications that we felt had some compelling evidence that healthy people would benefit from probiotics. Thus, we examined the evidence that probiotics could reduce urinary, vaginal, gastrointestinal, and respiratory infections, reduce antibiotic use, and improve risk factors associated with cardiovascular health. Populations included certain groups of individuals, including generally healthy people, those at risk for recurrent urinary and vaginal infections, and children taking antibiotics. We considered that the evidence was too nascent for this exercise for endpoints such as cognitive function, athletic performance, and dental health, and therefore did not review these endpoints. 

The challenges of studying prevention

We undertook this effort to address the common question, “Should everyone take a probiotic?” In fact, there are few recommendations for any intervention for people free of underlying disease. Such interventions must have sufficient evidence of benefit and of relatively little to no risk of harm.

In raising this question for probiotics, we took inspiration from the approach of an organization tasked with evaluating preventive evidence: the United States Preventive Services Task Force (USPSTF). Since an important component of a USPSTF review is potential for harm, it is important to note here that experts considering the safety of probiotics recently concluded that commonly used probiotic strains are safe for use in the general population.

The USPSTF recognizes that preventive measures are difficult and expensive to study. Healthy populations are difficult to define and not uniformly defined across studies. The physiology of healthy people recruited into a study is generally unlikely to change, especially over the short term. So efficacy studies must either be long-term or must identify more accessible endpoints, such as validated biomarkers of disease or reduction of infectious disease, as targets for prevention. Further, the threshold of evidence for recommending any intervention to a healthy population has to be very high, partially due to the potential risk of harm. In a patient with an illness, a risk of harm may be tolerable if the benefit outweighs the risk. But in an asymptomatic individual this threshold is more difficult to determine. 

It is noteworthy that some preventive measures are widely believed by the general public to be effective, but upon scrutiny of the data have been found to lack supporting evidence. For example, for healthy adults younger than 75 years of age, the Endocrine Society recently recommended against Vitamin D supplementation above the current RDA. The USPSTF has concluded that there is insufficient evidence to recommend a daily multivitamin for the prevention of cancer or cardiovascular disease, to screen for skin cancer,  or to screen for speech and language delay disorders in children 5 years or younger or eating disorders in adolescents. Even diet and exercise counseling for the prevention of cardiovascular risk in healthy people received only a level C recommendation. As one would expect for recommendations for healthy people, the USPSTF imposes a high bar for required evidence. This group of experts aimed to apply a similar high bar for evidence on probiotic indications.  

Meeting the strict criteria for an effective preventative measure

We reviewed data for indications where there were compelling studies on essentially healthy individuals showing some benefit from probiotics. But we wanted to determine if it was plausible that this body of evidence would meet a USPSTF-level of evidence for a recommendation for all healthy people. We recognized that there is sufficient evidence of efficacy to consider using specific probiotics for some indications for certain people. For example, evidence reviews have found that certain probiotics can be effective to prevent necrotizing entercolitis, reduce incidence of antibiotic associated diarrhea, reduce crying time in breast-fed colicky infants, improve therapeutic effectiveness of antibiotics to treat bacterial vaginosis, reduce risk for Clostridioides difficile infections, treat acute pediatric diarrhea, and manage symptoms of constipation. However:

Sufficient evidence of benefit to support the recommendation that “everyone should take a probiotic” is not yet available.

At ISAPP 2024 (held July 9-11), we heard from experts about the promise of probiotics for our skin as we age, for social anxiety, for immune function in children  and for helping undernourished kids thrive. Those who understand the evidence level for probiotics recognize the proven and potential role for probiotics in health. Our paper does not change that. There is evidence for many individuals to take daily probiotics due to conditions they have. But for those out there lucky enough to be totally healthy, the evidence is not yet sufficient to say they would benefit from daily probiotic use.  

Woman holding yogurt. In the US, yogurt now has an approved Qualified Health Claim.

A guide to the new FDA Qualified Health Claim for yogurt

/in ISAPP Science Blog /by KC

Fermented foods such as yogurt, kimchi, and fermented pickles have traditionally been associated with health benefits in countries around the world, but the science that backs these health benefits is relatively new.

Amidst a growing number of scientific studies examining the health benefits of specific fermented foods, a new Food and Drug Administration (FDA) announcement in the US marks an advance in how the potential benefits of fermented foods can be portrayed to the general public.

In response to a petition by Danone North America, the FDA announced that it will allow the first Qualified Health Claim related to a fermented food – yogurt. The new Qualified Health Claim is worded as follows:

Eating yogurt regularly, at least 2 cups (3 servings) per week, may reduce the risk of type 2 diabetes. FDA has concluded there is limited information supporting this claim.

Or Eating yogurt regularly, at least 2 cups (3 servings) per week, may reduce the risk of type 2 diabetes according to limited scientific evidence.

The claim was announced in a letter of enforcement discretion on March 1st, and can be applied to any yogurt product on the US market that meets the FDA’s standards of identity.

Qualified Health Claims and why they’re important

A Qualified Health Claim is a statement that makes a connection between a substance and a disease-related or health-related condition, is supported by scientific evidence, but does not meet the more rigorous “significant scientific agreement” standard required for an Authorized Health Claim.

Currently, approximately one dozen Authorized Health Claims and around 30 Qualified Health Claims exist in the US for different nutritional and food substances. For example, an Authorized Health Claim exists for soluble fiber from whole oats; Qualified Health Claims exist for walnuts, green tea, and a list of other foods.

To ensure that these claims are not misleading, they must be accompanied by a disclaimer or other qualifying language to accurately communicate to consumers the level of scientific evidence supporting the claim.

According to Bob Hutkins, Professor Emeritus at the University of Nebraska-Lincoln, such claims are important when considered within the context of what Americans currently eat.

He says, “We come nowhere close to eating the recommended amounts of fiber, whole grains, and fruits and vegetables. Indeed, according to the USDA Healthy Eating Index, the average consumer scores a 60 on a 100 point scale. When considering our overall eating habits in the US, I don’t know that this one claim will actually move the needle very much. But in my view, health claims, whether ‘Authorized’ or ‘Qualified’, may help nudge consumers to make informed decisions when deciding what to eat.”

The path to Qualified Health Claim

Dr. Miguel Freitas PhD, VP Health and Scientific Affairs at Danone North America, whose team led the petition, says the company’s efforts were motivated by the observation that, over time, evidence supporting the potential of yogurt to reduce the risk of type 2 diabetes grew more and more compelling.

In December 2018, Danone North America first submitted the Qualified Health Claim petition to the FDA. The petition was put on hold during the height of the COVID-19 pandemic and the evidence was reviewed again in 2023 by the FDA.

In total, more than 85 related studies were considered in support of the claim, with 30 being deemed high or moderate quality.

The FDA gave recognition of the claim in March 2024. Dr. Freitas says, “Now that the claim has been announced, our hope is that it will give consumers simple, actionable information they can use to reduce their risk of developing type 2 diabetes through an easily achievable, realistic dietary modification.”

Scientific support

Prof. Hutkins says the FDA has a high bar even for Qualified Health Claims, requiring a substantial level of scientific evidence to support them. He says that regarding this yogurt claim, “The FDA conducted an exhaustive review of studies that were included in the petition. Many of the studies were not considered rigorous enough and were excluded. In my view, they were very conservative in their analysis of the data.”

Both intervention studies and observational studies were considered in the FDA’s evaluation of the evidence linking yogurt and type 2 diabetes. Pro. Hutkins says that while randomized, controlled trials (RCTs) are considered the gold standard, well-conducted observational studies in large human cohorts can be very informative. The latter ended up being the sole basis of the FDA decision.

“The FDA identified 20 relevant intervention studies, but none were considered sufficiently rigorous to draw meaningful conclusions,” he says. “The FDA identified 28 relevant observational studies, which were then critically reviewed. Ultimately they concluded there was sufficient credible data to suggest associations of yogurt consumption on reduced incidence type 2 diabetes.”

The language for Qualified Health Claims includes any relevant qualifications indicated by the evidence. The FDA claim wording does not differentiate between sweetened and unsweetened yogurt products, with the evaluation noting that the beneficial association was observed irrespective of fat or sugar content. Nevertheless, Prof. Hutkins advises paying attention to the overall nutritional profile of different yogurt products, “In my view consumers could gain the benefits of yogurt without the extra calories and refined carbohydrates by choosing unsweetened yogurts.”

Implications for the food industry

Dr. Freitas says, “Our hope is that this new Qualified Health Claim will inspire the food industry as a whole to increase its focus on yogurt innovation and research, to continue unlocking the full extent of its potential benefits.”

Meanwhile, Prof. Hutkins hopes to see more RCTs on yogurt in the future. “It should be possible to design RCTs that would satisfy the FDA,” he says. “I hope funding agencies will agree.”

Prof. Seppo Salminen PhD, from University of Turku (Finland), says this approval may mark the beginning of a trend in developing claims for individual fermented foods. Such is the goal of a European project called Promoting Innovation of ferMENTed fOods (PIMENTO), which acknowledges the high consumer interest in fermented foods and the potential benefits of these foods for nutrition, sustainability, and more. Prof. Salminen points out that yogurt is leading the way, given the new US claim as well as the existing European Union claim regarding yogurt with live cultures and improved lactose digestion.

2023 in Review: Highlights in the Field of Biotic Science

/in ISAPP Science Blog /by KC

By Kristina Campbell, Prof. Colin Hill PhD, Prof. Sarah Lebeer PhD, Prof. Maria Marco PhD, Prof. Dan Merenstein MD, Prof. Hania Szajewska MD PhD, Prof. Dan Tancredi PhD, Prof. Kristin Verbeke PhD, Dr. Gabriel Vinderola PhD, Dr. Anisha Wijeyesekera PhD, and Marla Cunningham

Biotic science is an active field, with over 6,600 scientific papers published in the past year. The scientific work that emerged in 2023 covered many diverse areas – from probiotic mechanisms of action to the use of biotics in clinical populations. In parallel with the scientific advancements, consumer interest in gut health and biotics is at an all-time high. A recent survey showed that 67 percent of consumers are familiar with the concept of probiotics and 51 percent of those who consume probiotics do so with the aim of supporting gut health.

Several ISAPP-affiliated experts took the time to reflect on 2023 and identify the most important directions in the fields of probiotics, prebiotics, synbiotics, postbiotics, and fermented foods. Below are these experts’ picks for the top developments in biotic science and application during the past year.

Increased recognition of biotics as a category

After ISAPP’s publication of the recent synbiotics and postbiotics definitions in 2020-2021, board members and others began referring to probiotics, prebiotics, synbiotics, and postbiotics collectively as “biotics”. 2023 has seen the term being used more widely (for example, in article headlines and communications from major organizations) to refer to these substances as a broad group.

Steps forward and steps back in the regulation of live microbial interventions

The actions of regulators have a profound impact on how biotic science is applied and how products can reach consumers. On the positive side, 2023 heralded the regulatory approval of two live microbial drug products for recurrent C. difficile infection by the US Food and Drug Administration (FDA). Both products are derived from fecal samples, but one is delivered to the patient gastrointestinal (GI) tract by enema, and the other is delivered orally.

Meanwhile, a case of fatal bacteremia in a preterm infant who had been given a probiotic product prompted the FDA to issue a warning letter to healthcare practitioners about probiotics in preterm infants, as well as warning letters to two probiotic manufacturers. These actions had the concerning effect of reducing access to probiotics for this population, despite the accumulated evidence that probiotics effectively prevent necrotizing enterocolitis in preterm infants. As outlined in ISAPP’s scientific statement on the FDA’s actions, the regulatory decision weighting the risks of commission over omission did not reflect the wealth of evidence for probiotic efficacy in this population and the low risk of harm.

Wider awareness of the postbiotic concept and definition

Scientific discussions on postbiotics continued throughout 2023, with several debates and conference sessions devoted to discussion of the postbiotic concept – including the status of metabolites in the definition. According to ISAPP board member Dr. Gabriel Vinderola PhD, who was a co-author on the definition paper and an active participant in many of these debates, the ISAPP definition is gaining traction and the debates have been useful in pinpointing further areas of clarification for the sake of regulators and other stakeholders. As shared with the audience at Probiota Americas 2023 in Chicago, Health Canada became the first regulatory agency to address the definition, and has started considering the term postbiotics under the ISAPP definition.

Advances in technologies for analyzing different sites in the digestive tract

When studying how biotics interface with the host via the gut microbiota, the science has relied mainly on analysis of fecal samples, with the majority of the GI tract remaining a ‘black box’. But a 2023 paper by Shalon et al., which was discussed at the ISAPP meeting in Denver, describes a device able to collect intestinal samples from different regions in the GI tract. Analysis of the metabolites and microbes indicated clear regional differences, as well as marked differences between samples in the GI tract versus fecal samples (for example, with respect to bile acids); an accompanying paper revealed novel insights into diet and microbially-derived metabolites. Efforts are underway across the world to develop smart pills or robotic pills that take samples all along the GI tract. Some devices have sensors that immediately signal to a receiver and others have been engineered to release therapeutic contents. Although these technologies may need more validation before they are useful in research or clinical contexts, they may greatly expand knowledge of the intestinal microbial community and how it interacts with biotic substances.

First convincing evidence linking intake of live microbes with health benefits

When an ISAPP discussion group in 2019 delved into the question of whether a higher intake of safe, uncharacterized live microbes had the potential to confer health benefits, it spurred a program of scientific work to follow. Efforts of this group in subsequent years led to the publication of an important study in 2023: Positive Health Outcomes Associated with Live Microbe Intake from Foods, Including Fermented Foods, Assessed using the NHANES Database. Researchers analyzed data from a large US dietary database and found clear but modest health benefits associated with consuming higher levels of microbes in the daily diet.

The benefits of live dietary microbes are being explored further in the scientific literature (for example, here, here, and here) and are likely to remain an exciting topic of study in the years ahead, building evidence globally for the health benefits of consuming a higher quantity of live microbes.

Increased interest in candidate prebiotics

Polyphenols have long been studied for their health benefits, but newer evidence suggests they may have prebiotic effects, achieving their health benefits (in part) through interactions with the gut microbiota. A theme at conferences and in the scientific literature has been the use of polyphenols to modulate the gut microbiota for specific health benefits. More than a dozen reviews on this topic were published in 2023, and several of them focused on how polyphenols may achieve health benefits in very specific conditions, such as diabetes or inflammatory bowel disease.

Another substrate receiving much attention for its prebiotic potential are human milk oligosaccharides (HMOs). HMOs, found in human milk, support a nursing infant’s health by encouraging the growth of beneficial gut microbes. Several articles in 2023 have delved into the mechanisms of HMO metabolism by the gut microbiota, and explored its potential as a dietary intervention strategy to improve gut health in adults.

Sharper focus on evidence for the health and sustainability benefits of fermented foods

Fermented foods are popular among consumers, despite only early scientific knowledge on whether and how they might confer health benefits (see ‘First convincing evidence linking intake of live microbes with health benefits’, above). ISAPP board member Prof. Maria Marco PhD co-authored a review led by Dr. Paul Cotter PhD in Nature Reviews Gastroenterology and Hepatology on the GI-related health benefits of fermented foods. The paper clearly lays out the potential mechanisms under investigation and identifies gaps to be addressed in the ongoing study of fermented foods.

As calls for reducing carbon footprints continue across the globe, plant-based fermented foods are being singled out as an area for innovation and expansion. One example of how these foods are being explored is through the HealthFerm project, a 4-year, 13.1 million Euro project involving 23 partners from 10 countries, which is focused on understanding how to achieve more sustainable, healthy diets by leveraging fermented foods and technologies.

Novel findings related to lactic acid bacteria

Lactic acid bacteria (LAB) are some of the most frequently-studied microbial groups, but scientists have only begun to uncover the workings of this diverse group of bacteria and how they affect a variety of hosts. These bacteria are used as probiotics and are often beneficial members of human and animal microbiomes, and they are also essential to making fermented foods. This year marked the first ever Gordon Research Conference on LAB in California, USA. Attendees showcased the diversity of research on lactic acid bacteria, and the meeting was energized by the early investigators present and by the interest in LAB in other disciplines including medicine, ecology, synthetic biology, and engineering. One example of a scientific development in this area was the further elucidation of the mechanism of Lactiplantibacillus plantarum’s extracellular electron transfer.

Progress on the benefits and mechanisms of action for probiotics to improve the effectiveness of cancer immunotherapies

Researchers have known for several years that the gut microbiota can be a determinant of the efficacy of cancer immunotherapy drugs that involve immune checkpoint blockade, but interventions that target the gut microbiota to improve response to immunotherapies have been slower to develop. This year saw encouraging progress in this important area, with probiotic benefits and mechanisms of action being demonstrated in several papers. Two of the most highly cited probiotics papers of the year centered on this topic: one showing how a tryptophan metabolite released by Limosilactobacillus reuteri (formerly Lactobacillus reuteri — see this ISAPP infographic) improves immune checkpoint inhibitor efficacy, and another paper that reviewed how gut microbiota regulates immunity in general, and immune therapies in particular.

Updated resource available on probiotics and prebiotics in gastroenterology

This year the World Gastroenterology Organisation (WGO) guidelines on probiotics and prebiotics were updated to reflect the latest evidence, with contributions from ISAPP board member Prof. Hania Szajewska MD PhD and former board member Prof. Francisco Guarner MD PhD. The guideline lists indications for probiotic and prebiotic use, and how the use of these substances may differ in pediatric versus adult populations. Find the guideline here.

Episode 24: Reflections on the probiotic field and ISAPP’s role

/in Podcast, Season Two /by Laura

 

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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 Prebiotics (ISAPP), a nonprofit scientific organization dedicated to advancing the science of these fields.

Reflections on the probiotic field and ISAPP’s role, with Dr. Mary Ellen Sanders PhD

Episode summary:

In this episode, the ISAPP podcast hosts talk about how the probiotic field has evolved over the past 20 years with Dr. Mary Ellen Sanders PhD, ISAPP’s outgoing executive director. She describes how ISAPP is a unique organization advancing the science in the field, highlights what she has enjoyed about being a part of the ISAPP community, and looks ahead to the future of the field.

Key topics from this episode:

  • Sanders describes her career path and how it led to her role with ISAPP. 
  • Both ISAPP and Sanders’ role have changed over time, but she always appreciated two things: great scientific discussions, and interacting with an excellent board of directors.
  • ISAPP has always been dedicated to following the science, highlighting where the evidence is but also the shortcomings of the evidence.
  • The development of microbiome science changed the field of probiotics but it remains important to focus on what probiotics can do for health, rather than what they can do for the microbiome.
  • Mechanisms are important to elucidate, but the most important thing is whether a product impacts health.
  • Sanders says regulations are needed and in the future she hopes regulators will reach out to the expert scientists more frequently and be clear about the standards they expect for a claim.
  • ISAPP meetings are unique–both scientifically enlightening and a lot of fun. Longtime ISAPP board member Gregor Reid had the initial idea for the successful ‘discussion groups’ held every year. 
  • In the future, Sanders thinks probiotics will be used more precisely, like medicines. But also the concept of live dietary microbes may become more popular, with quantities of safe microorganisms being consumed for health benefits.

Episode links:

About Dr. Mary Ellen Sanders PhD:

Mary Ellen Sanders, PhD has served in several roles within ISAPP. She was the founding president, executive science officer and executive director and has retired from ISAPP as of June 30, 2023. She is also a consultant in the area of probiotic microbiology. She works internationally with food and supplement companies to develop new probiotic products and offers perspective on paths to scientific substantiation of probiotic product label claims. She is the current chair of the United States Pharmacopeia’s Probiotics Expert Panel, was a member of the working group convened by the FAO/WHO that developed guidelines for probiotics and serves on the World Gastroenterology Organisation Guidelines Committee preparing practice guidelines for the use of probiotics and prebiotics for gastroenterologists.

How to navigate probiotic evidence and guidelines for pediatric populations

Episode 20: How to navigate probiotic evidence and guidelines for pediatric populations

/in Podcast, Season Two /by Laura

How to navigate probiotic evidence and guidelines for pediatric populations

 

Podcast: Play in new window | Download

Subscribe: Apple Podcasts | Spotify | RSS

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 Prebiotics (ISAPP), a nonprofit scientific organization dedicated to advancing the science of these fields.

How to navigate probiotic evidence and guidelines for pediatric populations, with Dr. Hania Szajewska

Episode summary:

In this episode, the ISAPP podcast hosts talk about evidence and guidelines for probiotics in pediatric populations, with Prof. Hania Szajewska MD PhD, of the Department of Paediatrics at the Medical University of Warsaw, Poland. They talk about some of the inconsistencies between different medical organizations’ guidelines for pediatric probiotic use, and how clinicians can move forward with recommendations based on the best available evidence.

 

Key topics from this episode:

  • Guidelines exist on probiotic use for gastroenterological issues in children, but there are differences (especially regarding acute gastroenteritis) between guidelines from different medical societies: European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) and The American Gastroenterological Association (AGA).
  • Realistic expectations are necessary when prescribing probiotics. Different probiotics have different benefits, but they are not a ‘magic bullet’. For example, the evidence shows certain probiotics for acute gastroenteritis reduce diarrhea by an average of one day. This could have a big impact on the quality of life of the end user, but for clinicians it may not sound like a lot so they must set expectations accordingly.
  • The market is overflowing with probiotic products, many of which do not have proven efficacy. This makes it difficult for end users and healthcare professionals to distinguish the best products.
  • Always look for evidence-based probiotics with documented efficacy for the indication for which they are intended.
    • Physicians have the ethical duty to prescribe evidence-based products (that is, clinically proven, effective products).
    • The exact strains and doses matter.
  • Formal training and education of healthcare professionals regarding the beneficial effects of microbes, the microbiome, and probiotics are currently lacking.
  • Is it more valuable to know probiotics’ mechanism of action, or to have evidence from clinical trials that they are effective?
    • Ideally we would have both, but since we don’t know the exact mechanism for all probiotics, positive evidence from clinical trials is crucial. 
    • We also need to make clear to healthcare professionals and end users what to expect from taking probiotics. For example, some probiotics reduce the chances of developing antibiotic-associated diarrhea by 50%. For colic, some probiotics can reduce the crying time by half an hour. These are modest benefits but for the affected individual they may be impactful.
  • For vulnerable populations such as preterm infants, we need high-quality products with proven safety and efficacy.

 

Episode abbreviations and links:

 

About Prof. Hania Szajewska: 

Hania Szajewska, MD, is Professor and Chair of the Department of Paediatrics at the Medical University of Warsaw and the Chair of the Medical Sciences Council. Among her various functions, she served as the Editor-in-Chief of the Journal of Pediatric Gastroenterology and Nutrition; a member of the Council and then as the General Secretary of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN); the Secretary of the ESPGHAN Committee on Nutrition. Most recently, she joined the Board of Directors of the International Scientific Association for Probiotics and Prebiotics (ISAPP). Prof. Szajewska has broad interests in pediatric nutrition but her research focuses on the effects of early nutritional interventions on later outcome; and the gut microbiota modifications such as with various biotics (probiotics, prebiotics, synbiotics, postbiotics). She is or has been actively involved in several European Union-funded research projects. She is an enthusiastic advocate for the practice of evidence-based medicine. Prof. Szajewska has co-authored more than 400 peer-reviewed publications and 30 book chapters. Citations >18,141. Hirsch index 72 (WoS, March 2023).

Questioning the existence of a fetal microbiome, with Dr. Kate Kennedy

Episode 19: Questioning the existence of a fetal microbiome

/in Podcast, Season Two /by Laura

Questioning the existence of a fetal microbiome, with Dr. Kate Kennedy

 

Podcast: Play in new window | Download

Subscribe: Apple Podcasts | Spotify | RSS

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 Prebiotics (ISAPP), a nonprofit scientific organization dedicated to advancing the science of these fields.

Questioning the existence of a fetal microbiome, with Dr. Kate Kennedy

Episode summary:

In this episode, the ISAPP podcast hosts tackle the debate on the existence of a fetal microbiome, with guest Kate Kennedy PhD of McMaster University in Canada. They talk about Kennedy’s recent co-first-authored paper in Nature, which concludes that it is not biologically plausible that the fetus harbors live microorganisms, and that previous microbial sequencing studies on the fetal microbiome did not account for the many sources of contamination.

 

Key topics from this episode:

  • During the last 10 years, a lively debate has emerged on whether humans harbor living microorganisms prior to birth. Some scientists have looked at fetal and placental tissues and amniotic fluid, and have ostensibly detected microbial DNA. But those results are being questioned, with the argument that the signals being found are not biologically plausible.
  • Kennedy et al. published an article in Nature that re-analyzed data and brought in experts from different related fields to help interpret the data. The conclusion is that the fetal microbiome does not exist. Previous studies have likely seen contamination during sampling, since it’s nearly impossible to collect samples in a sterile way following vaginal delivery; contamination can happen at different stages so stringent controls are needed across all these areas of potential contamination. Furthermore, live microorganisms in the fetus does not fit with what we already know in related fields of science.
  • The popularity of microbiome research may have made scientists interested in this topic, although sequencing by itself may not be sufficient to settle the question of whether a fetal microbiome exists.
  • Human cells have Mitochondrial DNA, which is bacterial in origin. In 16S rRNA gene sequencing, there is some overlap in what is amplified, and this could include mitochondrial DNA, giving misleading results. This was not accounted for in some of the initial fetal microbiome studies.
  • Bringing together disparate disciplines is inherently challenging. It’s very important to work to understand each other and understand the host and biological situation you’re dealing with.
  • If there were even small numbers of bacteria present in the fetus it would have huge implications for our understanding of fetal biology and immunology. One question would be: how is the fetus limiting growth of any microbes it harbors?
  • Despite the likelihood that the fetal microbiome does not exist, the fetus is not unprepared for the microbial onslaught after birth. The maternal microbiota and immune system can educate the fetus immunologically in the absence of fetal colonization.

 

Episode abbreviations and links:

 

About Dr. Kate Kennedy: 

Kate completed her PhD on the role of the maternal gut microbiome in perinatal programming in the lab of Dr. Deborah Sloboda at McMaster University. She previously completed her BSc and MSc in Biology at the University of Waterloo. Her research explores host-microbiome relationships in pregnancy, early-life, and aging to understand their role in modulating health and disease risk.  

Can Probiotics Cause Harm? The example of pregnancy

/in ISAPP Science Blog /by KC

By Prof. Dan Merenstein MD, Georgetown University School of Medicine, Washington DC, USA and Dr. Maria Carmen Collado, Institute of Agrochemistry and Food Technology-National Research Council (IATA-CSIC), Valencia, Spain

Limiting excessive weight gain and controlling blood pressure during pregnancy are important to prevent pre-eclampsia and other complications of pregnancy. Researchers have examined if there is a role for probiotics in maintaining a healthy pregnancy. A recent Cochrane review, which evaluated evidence on probiotics for preventing gestational diabetes (GDM), concluded, “Low-certainty evidence from six trials has not clearly identified the effect of probiotics on the risk of GDM. However, high-certainty evidence suggests there is an increased risk of pre-eclampsia with probiotic administration.” This was an unexpected conclusion, which raised concerns about probiotic safety. A close look at the basis for this statement is warranted to determine if certain strains of probiotics are contraindicated for pregnant women.

Most people familiar with probiotic science understand that giving anyone live bacteria carries some risk. The definition of probiotics is live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. It is not live microorganisms that, when administered in adequate amounts, confer a health benefit on the host that outweighs potential adverse events. But clinicians understand that risk versus benefit must be considered for all interventions.

Many interventions associated with significant positive outcomes also are associated with some adverse events, some quite significant. For example, a recent United States Preventive Services Task Force report found that beta carotene, with or without vitamin A, was significantly associated with an increased risk of lung cancer and cardiovascular disease mortality. Aspirin kills thousands of people each year, with many more hospitalized with significant bleeds. While for an exercise doctors recommend all the time, biking, the CDC reports nearly 1,000 bicyclists die and over 130,000 are injured in crashes every year in the US.

Studies that led to the Cochrane conclusion

But let’s get back to trying to understand what made the Cochrane review come out with this warning about probiotics and pre-eclampsia. Turns out the conclusion was based on four randomized clinical trials which reported pre-eclampsia as an adverse event. All four studies were well done with low risk of bias per the Cochrane report.

Here is a summary of the four studies that collected preeclampsia data, included in the Cochrane review:

Callaway et al.(2019) studied  a mixture of Lactobacillus rhamnosus (LGG) and Bifidobacterium animalis subspecies lactis BB-12 for the prevention of gestational diabetes The reported pre-eclampsia in the probiotic group was 19 (9.2%) participants compared to 10 (4.9%) in the placebo group, p-value=0.09. This was in an obese cohort, with an average BMI of both groups near 32 (kg/m2).

Lindsay et al. (2014) evaluated the effect of Lactobacillus salivarius UCC118 on maternal fasting glucose. They reported preeclampsia in 3/62 in the probiotic group versus 2/74 in the placebo group (p-value >0.366).  Again, this was in an obese cohort with early pregnancy BMIs in the probiotic group, averaging 32.9 versus 34.1 in the placebo group.

Pellonpera et al. (2019) conducted a 4-arm study to determine if fish oil and or Lactobacillus rhamnosus HN001 and Bifidobacterium animalis ssp. lactis 420 could prevent gestational diabetes. In total there were 10 cases of pre-eclampsia among the four groups as shown below, (each group had about 95 total participants) and no significant differences between them, p value=0.80.

  • Fish oil + placebo, 1 of 95 participants (1.1%)
  • Probiotics + placebo, 4 of 96 participants (4.2%)
  • Fish oil + probiotics 3, of 96 participants (3.1%)
  • Placebo + placebo, 2 of 93 participants (2.2%)

Okesene-Gafa et al. (2019) published in the American Journal of Obstetrics and Gynecology in 2019 looking at culturally tailored dietary intervention and or daily probiotic capsules containing lactobacillus rhamnosus GG and Bifidobacterium lactis BB12 impact pregnancy weight-gain and birthweight. (This was also an obese cohort with an average BMI of 38.8.) They found pregnancy induced hypertension in the probiotic group in 4/96 (4.2%) of women versus 2/93 (2.2%) in the placebo group (p value=0.31).

Is there a rationale for the preeclampsia warning?

The increased rate of preeclampsia in probiotic groups was only with studies using obese subjects. Importantly, obesity has been associated with a higher risk of preeclampsia (see here and here). A recent meta-analysis, which included 86 studies representing 20,328,777 pregnant women, showed that higher BMI is associated with adverse pregnancy outcomes, among them, gestational diabetes and preeclampsia. Furthermore, the adjusted risk of preeclampsia is estimated to be double for overweight mothers and almost triple for obese mothers, compared to normal weight mothers.

It has been reported that pro-inflammatory signals (TNF-alpha, IL6) produced in adipose tissue of obese individuals induces a proinflammatory state characterized by insulin resistance and altered endothelial function. The gut microbiota is also disrupted in these individuals, consistent with observations that report an altered gut microbiota composition in obese versus lean individuals (see here, and the effects on offspring here and here). This suggests that obese mothers may have an increased risk of adverse events, but still the evidence supports that the addition of certain strains of probiotics may exacerbate this risk. Furthermore, it is relevant to mention the accumulating data showing that during gestation in parallel to the physiological, immune and metabolic adaptations, gut microbiota changes over the pregnancy (see here, here, here and here) although little is known on the impact of pre-gestational BMI on gut microbiota changes during pregnancy. However, specific microbial shifts have been reported to be predictive of GDM and also, gut microbial differences in women with and without GDM have been reported (here and here) . It has been also reported that the gut microbiota shifts (in composition and activity metabolites) in women with preeclampsia (see here). Thus, it is quite possible that the women in these studies, obese women, react to gut-microbiota-related interventions differently than non-obese women and that their pre-pregnancy weight puts them at an increased risk of complications.

It is worth noting that the total number of cases cited in the Cochrane review supporting their conclusion was 31 cases of preeclampsia in 472 women who took probiotics versus 17 in 483 women in the placebo groups. Thus, 14 more women who experienced preeclampsia, 9 of whom came from one of the studies [“probiotics increase the risk of pre-eclampsia compared to placebo (RR 1.85, 95% CI 1.04 to 3.29; p-value=0.04; 4 studies, 955 women; high-certainty evidence”] This is not a very large number of subjects for such a strong conclusion. The authors don’t mention if this high-certainty evidence is in all women or just obese women. By combining four studies, in which none found a significant increase in preeclampsia, the authors did find significance. Is this a convincing number of subjects? The Cochrane author, Dr. Marloes Dekker Nitert replied to an inquiry from us that she believes that this difference makes it unethical to conduct further studies in pregnant women, stating, “I think that there now is a lack of clinical equipoise to do an RCT on a combination of Lactobacillus/Bifidobacterium.”

This is a strong statement but is consistent with their high-certainty of evidence statement. We acknowledge that something does appear to be going on. It is possible that certain populations react differentially to certain strains. Thus, maybe mild to morbidly obese women are a subgroup that needs closer monitoring during pregnancy and maybe even in non-pregnant settings, as they may react differently to probiotic interventions. Maybe it is just certain strains, as the Cochrane author was very clear in her email to state, “a combination of Lactobacillus/Bifidobacterium” and not generalize to all probiotics. We agree and in fact it is possible that different strains of Lactobacillus/Bifidobacterium will have different outcomes. Pregnancy is also a continuum and to think that giving an intervention during the first trimester is the same as during the third makes little scientific or clinical sense. Along these lines, one study showed the association of probiotic intake with different effects in early versus late pregnancy; an analysis that specifically focused on women in the third trimester of pregnancy found no association between probiotics and adverse fetal outcomes.

Conclusions

In summary, we must recognize that certain strains of probiotics may cause harm in certain populations. This reinforces the importance of diligent collection of adverse event data during all clinical trials. Although Cochrane is renowned to conduct analyses of the highest caliber, we wonder if four studies of 955 mostly obese women, in which 14 more in the probiotic group than the placebo group have a secondary outcome of harm, warrant the conclusion that there is “high-certainty evidence” that probiotics cause harm. This seems overstated based on our review of the literature. Should women and clinicians pay particular attention to this subgroup (obese pregnant women) and this outcome (preeclampsia, hypertension)? We think the answer is yes. But we do not conclude that all women at all stages of pregnancy need to refrain from probiotics. Fortunately, at the time of writing there appear to be 87 trials listed on clinicaltrials.gov looking at probiotics and pregnancy. As in many things the details still need to be further elucidated and we expect more clarification on this issue over the next 5-10 years.

Probiotics vs. prebiotics: Which to choose? And when?

/in Consumer Blog, ISAPP Science Blog /by KC

By Dr. Karen Scott, PhD, Rowett Institute, University of Aberdeen, Scotland

As consumers we are constantly bombarded with information on what we should eat to improve our health. Yet the information changes so fast that it sometimes seems that what was good for us last week should now be avoided at all costs!

Probiotics and prebiotics are not exempt from such confusing recommendations, and one area lacking clarity for many is which of them we should pick, and when. In this blog I will consider the relative merits of probiotics and prebiotics for the gut environment and health.

By definition, both probiotics and prebiotics should ‘confer a health benefit on the host’. Since an improvement in health can be either subjective (simply feeling better) or measurable (e.g. a lowering in blood pressure) it is clear that there is not a single way to define a ‘health benefit’. This was discussed nicely in a previous blog by Prof Colin Hill.

Although consumption of both probiotics and prebiotics should provide a health benefit, this does not mean that both need to act through the gut microbiota. Prebiotics definitively need to be selectively utilised by host microorganisms – they are food for our existing microbiota. However, depending on the site of action, this need not be the gut microbiota, and prebiotics targeting other microbial ecosystems in or on the body are being developed. Traditionally prebiotics have specifically been used to boost numbers of gut bacteria such as Bifidobacterium and the Lactobacilliaceae family, but new prebiotics targeting different members of the gut microbiota are also currently being researched.

Probiotics are live bacteria and despite a wealth of scientific evidence that specific probiotic bacterial strains confer specific health benefits, we often still do not know the exact mechanisms of action. This can make it difficult both to explain how or why they work, and to select new strains conferring similar health benefits. Many probiotics exert their effects within the gut environment, but they may or may not do this by interacting with the resident gut microbiota. For instance probiotics that reduce inflammation do so by interacting directly with cells in the mucosal immune system. Yet strains of lactobacilli (see here for what’s included in this group of bacteria) may do this by modulating cytokine production while Bifidobacterium strains induce tolerance acquisition. These very different mechanisms are one reason why mixtures containing several probiotic species or strains may in the end prove the most effective way to improve health. On the other hand, some probiotics do interact with the resident gut microbes: probiotics that act by inhibiting the growth of pathogenic bacteria clearly interact with other bacteria. Sometimes these may be potential disease-causing members of the resident microbiota, normally kept in check by other commensal microbes that themselves have become depleted due to some external impact, and some may be incoming pathogens. Such interactions can occur in the gut or elsewhere in the body.

This brings me back to the original question, and one I am frequently asked – should I take a probiotic or a prebiotic? The true and quick answer to this question is ‘it depends’! It depends why you are asking the question, and what you want to achieve. Let’s think about a few possible reasons for asking the question.

I want to improve the diversity of my microbiota. Should I take a prebiotic or a probiotic?

My first reaction was that there is an easy answer to this question – a prebiotic. Prebiotics are ‘food’ for your resident bacteria, so it follows that if you want to improve the diversity of your existing microbiota you should take a prebiotic. However, in reality this is too simplistic. Since prebiotics are selectively utilised by a few specific bacteria within the commensal microbiota to provide a health benefit, taking a prebiotic will boost the numbers of those specific bacteria. If the overall bacterial diversity is low, this may indeed improve the diversity. However, if the person asking the question already has a diverse microbiota, although taking one specific prebiotic may boost numbers of a specific bacterium, it may not change the overall diversity in a measurable way. In fact the best way to increase the overall diversity of your microbiota is to consume a diverse fibre-rich diet – in that way you are providing all sorts of different foods for the many different species of bacteria living in the gut, and this will increase the diversity of your microbiota.  Of course, if you already consume a diverse fibre-rich diet your microbiota may already be very diverse, and any increased diversity may not be measurable.

I want to increase numbers of bifidobacteria in my microbiota. Should I take a prebiotic or a probiotic?

Again, I initially thought this was easy to answer – a prebiotic. There is a considerable amount of evidence that prebiotics based on fructo-oligosaccharides (FOS or inulin) boost numbers of bifidobacteria in the human gut. But this is only true as long as there are bifidobacteria present that can be targeted by consuming suitable prebiotics. Some scientific studies have shown that there are people who respond to prebiotic consumption and people who do not (categorised as responders and non-responders). This can be for two very different reasons. If an individual is devoid of all Bifidobacterium species completely, no amount of prebiotic will increase bifidobacteria numbers, so they would be a non-responder. In contrast if someone already has a large, diverse bifidobacteria population, a prebiotic may not make a meaningful impact on numbers – so they may also be a non-responder.

However, for those people who do not have any resident Bifidobacterium species, the only possible way to increase them would indeed be to consume a probiotic- specifically a probiotic containing one or several specific Bifidobacterium species. Consuming a suitable diet, or a prebiotic alongside the probiotic, may help retention of the consumed bifidobacteria, but this also depends on interactions with the host and resident microbiota.

I want to increase numbers of ‘specific bacterium x’ in my microbiota. Should I take a prebiotic or a probiotic?

The answer here overlaps with answer 2, and depends on the specific bacterium, and what products are available commercially, but the answer could be to take either, or a combination of both – i.e. a synbiotic.

If bacterium x is available as a probiotic, consuming that particular product could help. If bacterium x has been widely researched, and the specific compounds it uses for growth have been established, identifying and consuming products containing those compounds could boost numbers of bacterium x within the resident microbiota. Such research may already have identified combination products – synbiotics – that could also be available.

One caveat for the answers to questions 2 and 3 is that probiotics do not need to establish or alter the gut microbiota to have a beneficial effect on health. In fact, a healthy large intestine has a microbial population of around 1011-1012 bacterial cells per ml, or up to 1014 cells in total, while a standard pot of yogurt contains 1010 bacterial cells (108 cells/ml). Assuming every probiotic bacterial cell reaches the large intestine alive, they would be present in a ratio of 1: 10,000. This makes it difficult for them to find a specific niche to colonise, so consuming a probiotic may not “increase numbers of ‘specific bacterium x’ in my microbiota”, but this does not mean that the function of the probiotic within the gut ecosystem would not provide a health benefit. Many probiotics act without establishing in the microbiota.

I’ve been prescribed antibiotics. Should I take a prebiotic or a probiotic?

In this case the answer is clear cut – a probiotic.

There is a lot of evidence that consumption of probiotics can alleviate symptoms of, or reduce the duration of, antibiotic associated diarrhoea. From what we know about mechanisms of action, consumption of antibiotics kills many resident gut bacteria, reducing the overall bacterial population and providing an opportunity for harmful bacteria to become more dominant. Consuming certain probiotics can either help boost bacterial numbers in the large intestine, preventing the increased growth in pathogenic bacteria until the resident population recovers, or can increase production of short chain fatty acids, decreasing the colonic pH, preventing growth of harmful bacteria. Ideally probiotics would be taken alongside antibiotics, from day 1, to avoid the increase in numbers of the potentially harmful bacteria in the first place. This has been shown to be more effective. Consuming the probiotic alongside prebiotics that could help the resident microbiota recover more quickly may be even more effective. Even if you’ve already started the course of antibiotics, it’s not too late to start taking probiotics to reduce any side-effects. Always remember to complete taking the course of antibiotics as prescribed.

 

 

Putting all of this together to answer the initial question of whether it’s better to take probiotics or prebiotics, a better answer may in fact be take both to cover the different effects each has, maximising the benefit to health. There are specific times when probiotics are better, and other times when prebiotics are better, and consuming both together may make each more effective. In any case care has to be taken to consume a product that has been confirmed through robust studies to have the specific benefit that is required.

 

ISAPP’s 2021 year in review

/in ISAPP Science Blog /by KC

By Mary Ellen Sanders, PhD, ISAPP Executive Science Officer

The upcoming year-end naturally leads us to reflect about what has transpired over the past 12 months. From my perspective working with ISAPP, I witnessed ISAPP board members and the broader ISAPP community working creatively and diligently to find solutions to scientific challenges in probiotics, prebiotics and related fields. Let’s look back together at some of the key developments of 2021.

ISAPP published outcomes from two consensus panels this year, one on fermented foods and one on postbiotics. The popularity of these articles astounds me, with 49K and 29K accesses respectively, as of this writing. I think this reflects recognition on the part of the scientific community of the value – for all stakeholders – of concise, well-considered scientific definitions of terms that we deal with on a daily basis. If we can all agree on what we mean when we use a term, confusion is abated and progress is facilitated. The postbiotics definition was greeted with some resistance, however, and it will remain to be seen how this is resolved. But I think ISAPP’s response about this objection makes it clear that productive definitions are difficult to generate. Even if the field ultimately embraces another definition, it is heartening to engage in scientific debate about ideas and try to find alignment.

Keeping with the idea of postbiotics, a noteworthy development this year was the opinion from the European Food Safety Authority that the postbiotic made from heat-treated Akkermansia muciniphila is safe for use as a novel food in the EU. Undoubtedly, this development is a bellwether for likely future developments in this emerging area as some technological advantages to postbiotics will make these substances an attractive alternative to probiotics IF the scientific evidence for health benefits becomes available.

Recognizing the existing need for translational information for clinicians, ISAPP developed a continuing education course for dietitians. Published in March, it has currently reached close to 6000 dietitians. This course focused on probiotics, prebiotics and fermented foods: what they and how they might be applied in dietetic practice. It is a freely available, self-study course and completion provides two continuing education credits for dietitians.

On a sad note, in March of this year, ISAPP suffered the loss of Prof. Todd Klaenhammer. Todd was a founding ISAPP board member, and directed many of our activities over the course of his 18-year term on the board. He was also my dear friend and major advisor for my graduate degrees at NC State many years ago.  As one former collaborator put it, “I was not prepared to finish enjoying his friendship and mentorship.” See here for a tribute to Prof. Klaenhammer on the ISAPP blog: In Memoriam: Todd Klaenhammer.

So where will 2022 lead ISAPP? The organization has now published five consensus definitions: probiotics, prebiotics, synbiotics, postbiotics and fermented foods – extending its purview beyond where it started, with probiotics and prebiotics. Through the year ahead, ISAPP is committed to providing science-based information on the whole ‘biotics’ family of substances as well as fermented foods. Our Students and Fellows Association is growing, supported by the opportunity for young scientists to compete for the Glenn Gibson Early Career Researcher Prize. We continue to see our industry membership expand. Through our new Instagram account and other online platforms, our overall community is increasing. The ISAPP board of directors continues to evolve as well, with several long-term members leaving the board to make room for younger leaders in the field who will direct the future of the organization. This applies to me as well, as I have made the difficult decision to depart ISAPP in June of 2023. Thus, hiring a new executive director/executive science officer is an important priority for ISAPP in 2022. My 20 years with ISAPP have seen the organization evolve tremendously, through the hard work of incredible board members as well as many external contributors. We will strive to make 2022 – our 20th anniversary – ISAPP’s best year yet.

ISAPP board members give a scientific overview of synbiotics in webinar

/in Consumer Blog, ISAPP Science Blog /by KC

Many kinds of products are labeled as synbiotics – but how do they differ from each other? And do they all meet the scientific criteria for synbiotic ingredients?

To demystify the science of synbiotics – including ISAPP’s definition published in 2020 – ISAPP is holding a free webinar: Synbiotics: Definitions, Characterization, and Assessment. Two ISAPP board members, Profs. Bob Hutkins and Kelly Swanson, present on the implications of the synbiotic definition for science and industry. They clarify the difference between ‘complementary’ and ‘synergistic’ synbiotics and cover the basics of meeting the criteria for synbiotic efficacy and safety. One challenge is learning when a synbiotic is required to have demonstrated both selective utilization of the microbiota in the same study that measures the health outcome. A Q&A is scheduled for the last 20 minutes of the webinar.

This webinar is for scientists, members of the public, and media who want a scientific overview on synbiotics as they appear in more and more consumer products.

The live webinar was broadcast on Friday, January 28th, 2022, from 10:00 am – 11:10 New York (Eastern) time.

Find the webinar recording here.

A postbiotic is not simply a dead probiotic

/in ISAPP Science Blog /by KC

By Dr. Gabriel Vinderola, PhD,  Associate Professor of Microbiology at the Faculty of Chemical Engineering from the National University of Litoral and Principal Researcher from CONICET at Dairy Products Institute (CONICET-UNL), Santa Fe, Argentina

Postbiotics, recently addressed in an ISAPP consensus panel paper, are defined as a preparation of inanimate microorganisms and/or their components that confers a health benefit on the host. Criteria to meet the postbiotic definition are summarized here. One noteworthy aspect of this definition is that the word ‘probiotic’ does not appear. Although in practice a probiotic strain may be used as a progenitor strain in the manufacture of a postbiotic, the simple process of inactivating a probiotic is not sufficient to be called a postbiotic. It cannot be assumed that any non-viable probiotic cells in a probiotic product are automatically considered a postbiotic component. If a probiotic strain is used as a progenitor of a postbiotic, an efficacy study must be redone using the inanimate preparation and a benefit must be demonstrated. A probiotic product displaying fewer than the labeled count of viable cells is merely a low-quality product; it is not a postbiotic.

Further, the ISAPP consensus definition on postbiotics recognizes that the process of making a postbiotic implies a deliberate step to inactivate the viable cells of the progenitor strain. This process can be achieved by different technological steps such as heat-treatment (perhaps the most feasible approach), high pressure, radiation or simply aerobic exposure for strict anaerobes. A corresponding efficacy study must be conducted on the preparation. Or at the very least, any postbiotic component of a probiotic product must be specifically shown to contribute to the health benefit conferred by the product.

In contrast to postbiotics, probiotics are live microorganisms which when administered in adequate amounts confer a health benefit on the host. Four minimum criteria should be met for a strain to be considered as a probiotic: (i) sufficiently characterized; (ii) safe for the intended use; (iii) supported by at least one positive human clinical trial conducted according to generally accepted scientific standards or as per recommendations and provisions of local/national authorities when applicable; and (iv) alive in the product at an efficacious dose throughout shelf life (Binda et al. 2020). This last requirement reflects the key difference between probiotics and postbiotics. Probiotics must deliver an efficacious number of viable cells through the shelf life of the product. In practice, probiotic products may display significant numbers of non-viable cells (Raymond & Champagne, 2015), as some cells may lose viability during the technological process of biomass production, while undergoing manufacture or preservation steps and through product storage prior to purchase. In order to provide the target dose until end of shelf life, an overage of 0.5 to 1 log order CFU above the expected counts of viable cells is commonly included in the product to compensate for potential losses during product storage and handling (Fenster et al. 2019).

Thus, some quantity of non-viable cells may be usually expected in certain probiotic products, especially supplement products claiming a long, room temperature stable shelf-life. However, they will be considered as probiotic products of quality as long as they are able to deliver the expected amount of viable cells until the end of the product shelf-life. It is worth mentioning that the probiotics are expected to be viable at the moment of their administration. After that, if exposure to different regions of the gut causes cells to die, it is not of consequence as long as a health effect is achieved.

Probiotics and postbiotics have things in common (the need of efficacy studies that demonstrates their benefits) and things that distinguish them (the former are administered alive, whereas the latter are administrated in their inanimate form), but no probiotic becomes a postbiotic just by losing cell viability during storage.

Pharmacists as influencers of probiotic use

/in ISAPP Science Blog /by KC

By Kristina Campbell, science writer

It’s not an uncommon scene in a pharmacy: someone standing in front of the shelf of probiotic products, picking up various bottles and reading the labels, looking uncertain. The person’s doctor may have recommended a certain brand of probiotic to prevent diarrhea with a prescribed course of antibiotics—but they’ve just noticed that the store-brand probiotic, with different strains, is half the price.

Dragana Skokovic-Sunjic

According to Dragana Skokovic-Sunjic, clinical pharmacist and author of the ‘Clinical Guide to Probiotic Products Available in Canada/US’, pharmacists can play an important and influential role helping patients make informed decisions about the available products. “Pharmacists provide a ‘last check validation’ before the patient actually decides to purchase a product,” she says. “And we proactively seek to assist those patients who need help.”

Nardine Nakhla

Nardine Nakhla, clinical pharmacist and Clinical Lecturer at the University of Waterloo School of Pharmacy, says pharmacists often have the knowledge and experience to zero in on which over-the-counter product(s) will or will not work for a certain individual. “Pharmacists have the knowledge and skills to individualize the recommendation based on patient-specific and disease-specific factors, and that is so very important with non-prescription and natural health products because there is no one-size-fits-all approach,” she says.

Can pharmacists apply their knowledge and skills to make specific probiotic recommendations? While it can be hard to narrow the evidence down on specific products, pharmacists can certainly play a role in helping patients understand the evidence for the products they encounter. In a recent interview with ISAPP, Skokovic-Sunjic and Nakhla explained why pharmacists in Canada and elsewhere have the potential to steer people’s choice of over-the-counter and natural health products – including probiotics.

Pharmacists have knowledge about the products on their shelves.

“Advising patients on self-care, which includes over-the-counter and natural health product use, is a key responsibility of Canadian pharmacists. We have North American survey data that shows, for patients who go out and buy non-prescription and natural health products, over 80% never read the label,” says Nakhla.

This means that having a pharmacist available at the point-of-purchase to answer questions can go a long way toward educating people about what’s actually in their hands and how to optimize use, if warranted.

“Having the pharmacist present lets you access somebody who can help inform your decisions—someone who can perhaps steer you away from products that may not be appropriate for you,” she says.

“Pharmacists need to be familiar with the products they are selling at their pharmacies,” adds Skokovic-Sunjic. “They are skilled at asking suitable questions to ensure the patient’s needs and wishes are understood and then to help them choose appropriate over-the-counter, ‘self-selection’ therapy.”

Pharmacists are unique in having non-prescription products within their standards of practice.

As a faculty member at the school of pharmacy, Nakhla emphasizes the requirement for pharmacists to know how to assess and manage patients seeking self-care in the community. She says, “We have a unique body of knowledge where we study non-prescription therapeutics and other self-care measures of disease management and health maintenance,” she says. “Pharmacists are trained to know about these and to recommend evidence-based and cost-effective measures individualized for each patient.”

“It’s explicitly stated under our Standards of Practice that we must be proficient in providing information on non-prescription products, natural health products, and on non-pharmacological measures to enable patients to receive the intended benefit of the therapies, whereas physicians are far more focused on the diagnosis and prescription therapies,” she says.

Pharmacists can identify patients who could benefit from probiotics

Both Nakhla and Skokovic-Sunjic emphasize that pharmacists frequently identify people who could potentially benefit from self-care products, even if they don’t come in looking for them.

Nakhla mentions the probiotic guide authored by Skokovic-Sunjic, and how it helps pharmacists provide helpful solutions to common problems that present in the community. “I think a good strategy is looking at the conditions listed in the probiotic guide and the subsequent products indicated for use for them, and then work backwards to try to identify patients who may benefit from the listed therapies, rather than just wait for them to present asking you questions.”

Pharmacists are in a position to encourage prevention.

“Pharmacy has historically focused on providing reactive healthcare rather than proactive or preventative care,” says Nakhla. But this has recently changed, with a growing emphasis on preventing chronic disease through ongoing health maintenance and self-care strategies. She cites pharmacists as qualified health professionals who encounter many generally healthy people throughout the course of their day, and who are therefore well-positioned to advise the public on how to remain healthy.

Skokovic-Sunjic gives some examples: “If the consumer will be travelling, we might suggest a specific probiotic to prevent traveller’s diarrhea. Or if we are coming to the cold and flu season, we may recommend a product they can take to reduce the risk of developing common infectious diseases.”

Pharmacists can conduct brief or lengthy assessments before providing recommendations.

Skokovic-Sunjic says, “A pharmacist can provide specific recommendations that could really make a big difference in the patient’s experience by quickly asking a few targeted questions. This strategy may save the patient time, money, frustration and sub-optimal health outcomes. When consumers self-select inappropriate products, they will not experience benefits they seek. Determined to choose a natural product, some consumers will try a second or even third product but will not get the symptom relief they are looking for. An unintended consequence of this is that the patient may dismiss the probiotics as ineffective not because they did not work, but because it was the wrong product for the desired effect.”

Brief assessment questions are especially important for probiotics, she adds, because specificity can ‘make or break’ how useful they are to an individual. “In my consultations with patients, I quite often include questions about bowel movements and I know they are questioning why I am asking. Understanding gut function can be extremely helpful in providing appropriate probiotic recommendations.”

Pharmacists can help people understand the concept of ‘evidence-based’.

Nakhla acknowledges it’s difficult for the average person to confront a shelf of probiotic products and delineate between the ones that have evidence backing their use, and the ones that do not. “That’s where I really think a pharmacist needs to intervene and to help them balance out the pros and the cons,” she says.

“If patients are looking for a probiotic to relieve a specific symptom, then looking for an evidence-based recommendation for that specific symptom is needed,” says Skokovic-Sunjic. “If they pick something that’s not supported by evidence, it may not provide symptom relief or the benefit they expect. This may be in addition to wasted funds and mounting frustration.”

Thus, pharmacists are in a unique position to contribute to enhanced awareness about efficacy and “evidence-based self-care” as they explain these concepts to consumers at the point of sale.

 

Given all the potential ways for pharmacists to guide consumer decisions about probiotics, both Skokovic-Sunjic and Nakhla agree that keeping up on the latest probiotic evidence is of high importance.

Through ISAPP’s new efforts to engage with pharmacists, the organization plans to gauge how pharmacists in various parts of the world approach probiotic recommendations, and to support the ‘best case scenario’ of pharmacists providing evidence-based information about probiotics directly to consumers.

Sign up here for ISAPP’s newsletter for pharmacists.

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.

What’s the evidence on ‘biotics’ for health? A summary from five ISAPP board members

/in Consumer Blog, ISAPP Science Blog /by KC

Evidence on the health benefits of gut-targeted ‘biotics’ – probiotics, prebiotics, synbiotics, and postbiotics – has greatly increased over the past two decades, but it can be difficult to sort through the thousands of studies that exist today to learn which of these ingredients are appropriate in which situations. At a recent World of Microbiome virtual conference, ISAPP board members participated in a panel that provided an overview of what we currently know about the health benefits of ‘biotics’ and how they are best used.

Here’s a summary of what the board members had to say:

Dr. Mary Ellen Sanders: Probiotics and fermented foods

  • Probiotics are “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host”.
  • Unfortunately, published assessments of probiotic products available on the market show that these products often fall short of required evidence. For example, their labels may not adequately describe the contents (including genus / species / strain in the product); they may not guarantee the efficacious dose through the end of the shelf life.
  • Contrary to common belief, probiotics do not need to colonize in the target site (e.g. the gut), impact gut microbiota composition, be derived from humans, or be resistant to stomach acid and other gut secretions such as bile.
  • Fermented foods are those made “through desired microbial growth and enzymatic conversions of food components”. The recent increased interest in fermented foods may come from people’s increased awareness of the role of gut microbes in overall health, but it is important to note that we have little direct evidence that the transient effects of fermented food microbes on the gut microbiota actually lead to health benefits. With that said, observational studies suggest that consuming some traditional fermented foods is associated with improved health outcomes.

Prof. Dan Merenstein, MD: Probiotics – How do I know what to prescribe for adult health?

  • A (limited) survey showed that most dietary supplement probiotic products cannot be linked to evidence because they do not provide enough information to determine what evidence exists to support their use – especially strains in the product. However, there are some probiotic products that have robust evidence.
  • Should every adult take a probiotic? The best evidence supports probiotics for improved lactose digestion and for prevention of difficile infection. Probiotics have also been shown to prevent common illnesses; reduce the duration of gut symptoms; and perhaps even reduce antibiotic consumption.
  • Studies will reveal more about the microbiome and about how probiotics work, for whom and for what indications. As with diet, the answer will most likely not be same for each person.

Prof. Glenn Gibson: Prebiotics and Synbiotics

  • A prebiotic is “a substrate that is selectively utilized by host microorganisms conferring a health benefit”. Researchers can test these substances’ activity in various ways: batch cultures, micro batch cultures, metabolite analysis, molecular microbiology methods, CF gut models, with in vivo (e.g. human) studies being required. Prebiotics appear to have particular utility in elderly populations, and may be helpful in repressing infections, inflammation and allergies. They have also been researched in clinical states such as IBS, IBD, autism and obesity related issues (Gibson et al., 2017).
  • A synbiotic is “a mixture, comprising live microorganisms and substrate(s) selectively utilized by host microorganisms, that confers a health benefit on the host.” While more studies are needed to say precisely which are useful in which situations, synbiotics have shown promise for several aspects of health in adults (Swanson et al. 2020): surgical infections and complications, metabolic disorders (including T2DM and glycaemia), irritable bowel syndrome, Helicobacter pylori infection and atopic dermatitis.

Prof. Hania Szajewska, MD: Biotics for pediatric use

  • Beneficial effects of ‘biotics’ are possible in pediatrics, but each ‘biotic’ needs to be evaluated separately. High-quality research is essential.
  • It is important that we view the use of ‘biotics’ in the context of other things in a child’s life and other interventions.
  • Breast milk is the best option for feeding infants
  • If breastfeeding is not an option, infant formulae supplemented with probiotics and/or prebiotics and/or postbiotics are available on the market.
  • Pro-/pre-/synbiotic supplemented formulae evaluated so far seem safe with some favorable clinical effects possible, but the evidence is not robust enough overall to be able to recommend routine use of these formulae.
  • Evidence is convincing on probiotics for prevention of necrotizing enterocolitis in preterm infants.
  • Medical societies differ in their recommendations for probiotics to treat acute gastroenteritis in children – they appear beneficial but not essential.
  • Synbiotics are less studied, but early evidence indicates they may be useful for preventing sepsis in infants and preventing / treating allergy and atopic dermatitis in children.

Prof. Gabriel Vinderola: Postbiotics

  • The concept of non-viable microbes exerting a health benefit has been around for a while, but different terms were used for these ingredients. Creating a scientific consensus definition will improve communication with health professionals, industry, regulators, and the general public. It will allow clear criteria for what qualifies as a postbiotic, and allow better tracking of scientific papers for future systematic reviews and meta-analyses.
  • The ISAPP consensus definition (in press) of a postbiotic is: “A preparation of inanimate microorganisms and/or their components that confers a health benefit on the host”.
  • Postbiotics are stable, so no cold-chain is needed to deliver them to the consumer. Safety is of less concern because the microbes are not alive and thus cannot cause bacteraemia.
  • Research in the coming years will reveal more about postbiotics and the ways in which they can promote human health.

See here for the entire presentation on Biotics for Health.

Probiotics and fermented foods, by Dr. Mary Ellen Sanders (@1:15)

Postbiotics, by Prof. Gabriel Vinderola (@18:22)

Prebiotics and synbiotics, by Prof. Glenn Gibson (@33:24)

‘Biotics’ for pediatric use, by Prof. Hania Szajewska (@47:55 )

Probiotics: How do I know what to prescribe for adult health? by Prof. Dan Merenstein (@1:04:51)

Q&A (@1:20:00)

 

New ISAPP-led paper calls for investigation of evidence for links between live dietary microbes and health

/in ISAPP Science Blog, Consumer Blog /by KC

The past two decades have brought a massive increase in knowledge about the human gut microbiota and its links to human health through diet. And although many people perceive that regular consumption of safe, live microbes will benefit their health, the scientific evidence to date has not been sufficiently developed to justify adding a daily recommended intake of live microbes to food guides for different populations.

Recently, a group of seven scientists, including six ISAPP board members, published their perspective about the value of establishing the link between live dietary microbes and health. They conclude that although the scientific community has a long way to go to build the evidence base, efforts to do this are worthwhile.

The collaboration on this review was rooted in an ISAPP expert discussion group held at the 2019 annual meeting in Antwerp, Belgium. During the discussion, various experts presented evidence from their fields—addressing the potential health benefits of live microbes in general, rather than the narrow group of microbial strains that qualify as probiotics.

Below, the authors of this new review answer questions about their efforts to quantify the relationship between greater consumption of live microbes and human health.

Why is it interesting to look at the potential importance of live microbes in nutrition?

Prof. Joanne Slavin, PhD, RD, University of Minnesota

Current recommendations for fiber intake are based on protection against cardiovascular disease—so can we do something similar for live microbes? We know that intake of live microbes is thought to be health promoting, but actual recommended intakes for live microbes are missing.  Bringing together a talented group of microbiologists, epidemiologists, nutritionists, and food policy experts moves this agenda forward.

Humans need proper nutrition to survive, and a lack of certain nutrients creates a ‘deficiency state’. Is this the case for live microbes?

Dr. Mary Ellen Sanders, PhD, ISAPP Executive Science Officer

I don’t think we’ll find that live microbes are essential in the same way that vitamins and minerals lead to deficiency diseases. After all, gnotobiotic animal colonies are viable. But I believe there is enough evidence to suggest that consumption of live microbes will promote health. Exactly how and to what extent remains to be established.

Why think about intake of ‘live microbes’ in general, rather than intake of probiotic & fermented foods specifically?

Prof. Maria Marco, PhD, University of California Davis

We are constantly exposed to microorganisms in our foods and beverages, in the air, and on the things we touch. While much of our attention has been on the microbes that can cause harm, most of our microbial exposures may not affect us at all or, quite the opposite, be beneficial for maintaining and improving health. Research on probiotic intake as a whole supports this possibility. However, probiotic-containing foods and dietary supplements are only a part of our dietary connection with live microbes. Non-pasteurized fermented foods (such as kimchi and yogurts) can contain large numbers of non-harmful bacteria (>10^7 cells/g). Fruits and vegetables are also sources of living microbes when eaten raw.  Although those raw foods they may contain lower numbers of microbes, they may be more frequently eaten and consumed in larger quantities. Therefore, our proposal is that we take a holistic view of our diets when weighing the potential significance of live microbe intake on health and well-being.

What are dietary sources of live microbes? And do we get microbes in foods besides fermented & probiotic foods?

Prof. Bob Hutkins, PhD, University of Nebraska Lincoln

For tens of thousands of years, humans consumed large amounts of microbes nearly every time they ate food or drank liquids. Milk, for example, would have been unheated and held at ambient temperature with minimal sanitation and exposed to all sorts of microbial environments.  Thus, a cup of this milk could easily have contained millions of bacteria. Other foods like fruits and vegetables that were also exposed to natural conditions could have also contained similar levels of microbes. Even water would have contributed high numbers of live microbes.

Thanks to advances in food processing, hygiene, and sanitation, the contemporary western diet generally contains low levels of microbes. Consider how many foods we eat that are canned, pasteurized, or cooked – those foods will contain few, in any live microbes. Fresh produce can serve as a source of live microbes, but washing, and certainly cooking, will reduce those levels.

For sure, the most reliable sources of dietary microbes are fermented foods and beverages. Even if a fresh lettuce salad were to contribute a million bacteria, a single teaspoon of yogurt could contain 100 times more live bacteria. Other popular fermented foods like kefir, kimchi, kombucha, and miso, can contain a large and relatively diverse assortment of live microbes. Other fermented foods, such as cheese and sausage, are also potential sources, but the levels will depend on manufacturing and aging conditions. Many fermented, as well as non-fermented foods are also supplemented with probiotics, often at very high levels.

What’s the evidence that a greater intake of live microbes may lead to health benefits?

Prof. Dan Merenstein, MD, Georgetown University

Studies have shown that fermented foods are linked to a reduced risk of cardiovascular disease, reduced risk of weight gain, reduced risk of type 2 diabetes, healthier metabolic profiles (blood lipids, blood glucose, blood pressure and insulin resistance), and altered immune responses. This link is generally from associative studies on certain fermented foods. Many randomized controlled trials on specific live microbes (probiotics and probiotic fermented foods) showing health benefits have been conducted, but randomized controlled trials on traditional fermented foods (such as kimchi, sauerkraut, kombucha) are rare. Further, no studies have aimed to assess the specific contribution of safe, live microbes in diets as a whole on health outcomes.

Why is it difficult to interpret past data on people’s intake of live microbes and their health?

Prof. Colin Hill, PhD, University College Cork

It would be wonderful if there were a simple equation linking the past intake of microbes in the diet and the health status of an individual (# MICROBES x FOOD TYPE = HEALTH). In reality, this is a very complex challenge. Microbes are the most diverse biological entities on earth, our consumption of microbes has not been deliberately recorded and can only be estimated, and even the concept of health has defied precise definitions for centuries. To further confuse the situation microbes meet the host in the gastrointestinal tract, the site of our enormously complex mucosal immune system and equally complex microbiome.  But the complexity of the problem should not prevent us from looking for prima facie evidence as to whether or not such a relationship is likely to exist.

Databases of dietary information have data on people’s intake of live microbes, but what are the limitations of our available datasets?

Prof. Dan Tancredi, PhD, University of California Davis

Surveys often rely on food frequency questionnaires or diaries to determine consumption of specific foods. These are notoriously prone to recall error and/or other types of measurement error. So, even just measuring consumption of foods is difficult. For researchers seeking to quantify survey respondents’ consumption of live microbes, these challenges become further aggravated because the respondents would not typically know the microbial content in the foods they consumed. Instead, we would have to have them tell us the types and amounts of the foods they ate, and then we would need to translate that into approximate microbial counts—but even within a particular food, the microbial content can vary, depending on how it was processed, stored, and/or prepared prior to consumption.

See ISAPP’s press release on this paper here.

60 Minutes’ 13 minutes on probiotics

/in ISAPP Science Blog /by KC

By Mary Ellen Sanders, PhD, ISAPP Executive Science Officer 

On June 28, 60 Minutes aired a 13-minute segment about probiotics titled, “Do Probiotics Actually Do Anything?” Unfortunately the media segment did not provide listeners with a nuanced perspective.

‘Probiotics’ were treated as if they were one entity, ignoring the best approach to addressing the topic of what probiotics do: evaluate the evidence for specific strains, doses and endpoints, and then make a conclusion based on the totality of the evidence. They would have found that many experts agree that actionable evidence exists for certain probiotics to prevent antibiotic associated diarrhea (here, here), prevent upper respiratory tract infections (here), prevent morbidity and mortality associated with necrotizing enterocolitis (here,), treat colic (here), and treat acute pediatric gastroenteritis (here). (For an overall view of evidence, see here.)

Importantly, not all retail probiotics have evidence (at least evidence that is readily retrievable, see here and here). But that does not mean that none do.

The 60 Minutes segment also highlighted questions about probiotic safety. No intervention is without risk, and no one claims as much for probiotics. Prof. Dan Merenstein, MD, just one clinical investigator of probiotics, has collected over 20,000 pediatric clinical patient days’ worth of safety data over the past eight years of clinical investigation, with no indication of safety concerns. In fact, participants in the placebo group generally have more adverse events than in the probiotic groups. But importantly, the safety standard for probiotics was mischaracterized by 60 Minutes. According to Dr. James Heimbach, a food safety expert (not interviewed in the segment) who has conducted 41 GRAS determinations on probiotics, over 25 of them notified to the FDA, he objects to the statement that GRAS is a lower safety bar than a drug. He clarifies:

“The safety standard that applies to food additives and GRAS substances, “reasonable certainty of no harm,” is a far higher standard than that applying to drugs. Drugs are judged against a risk/benefit standard, which can potentially allow quite dangerous drugs on the market provided they offer a significant benefit. The safety standard for drugs also applies only to prescribed doses for specific individuals over prescribed durations. The food-additive/GRAS substance standard, on the other hand, requires safety at any biologically plausible level of intake, for any person (child, adult, elderly; pregnant; etc.), over a lifetime. And it is a risk-only standard—no potential benefit is allowed to override the “reasonable certainty of no harm” standard. Additionally, in the case of GRAS substances (which includes most probiotics), the evidence of safety must be published in the peer-reviewed scientific literature and be widely accepted by the scientific community as well as by government regulators.”

Finally, the story implied that benefits people claim for themselves when using probiotics are due to a placebo effect. This ignores the many properly controlled studies directly comparing the effects of specific probiotics to placebos. A positive trial on probiotics, such as observed in this recent trial on irritable bowel syndrome symptoms (here) and in most trials included in Cochrane meta-analyses on prevention of C. difficile-associated diarrhea (here), means that positive effects were observed beyond any placebo effect. The placebo effect is real, equally applicable to probiotics and drugs, but as with all clinically evaluated substances, properly controlled trials control for this effect.

The probiotic field has come a long way over the past 20 years with regard to number and quality of clinical trials. In that time, well-done systematic reviews of the evidence have found benefits for specific probiotics for specific conditions, while also finding a lack of evidence for beneficial effects in other contexts. There are of course well-conducted clinical trials that have failed to demonstrate benefit (here, here, here). This should not be equated to mean that probiotics do not do anything.

Many challenges remain for improving the quality of the evidence across the wide range of different strains, doses, endpoints and populations. More clinical research needs to be conducted in a manner that minimizes bias and is reported according to established standards. Confidence in the quality of commercial products could be improved by industry adopting third party verification (here), and the quality of products targeting compromised populations need to be fit for purpose (here). Companies should stop using the term ‘probiotic’ on products that have no evidence warranting that description. We need to understand much better how a person’s individual situation, such as diet, microbiome, use of medications and fitness, impact the ability of a probiotic to promote health. Much remains to be learned in this evolving and exciting field. As Dr. Merenstein says, “The key question is not, ‘Do probiotics actually do anything?’, as that is easily answered ‘yes’ when you look at robust placebo-controlled trials of specific probiotics. Better questions are ‘Which probiotics do anything, and for what?’”

Further reading:

Misleading press about probiotics: ISAPP responses

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

New publication gives a rundown on probiotics for primary care physicians

Safety and efficacy of probiotics: Perspectives on JAMA viewpoint

New publication gives a rundown on probiotics for primary care physicians

/in News, ISAPP Science Blog /by KC

With an increasing number of patients becoming aware of the human microbiome and its role in health, primary care physicians are faced with questions about probiotics as a possible strategy for maintaining health. Patients may see conflicting messages in the news and on product labels – so how can they know which probiotic benefits are scientifically proven?

A new publication in the Journal of Family Practice provides a quick update on evidence for the use of probiotics in different indications, so primary care physicians can equip themselves to provide evidence-based recommendations and to answer patients’ most commonly asked questions about probiotics.

Written by ISAPP board members Daniel J. Merenstein, MD and Mary Ellen Sanders, PhD, along with Daniel J. Tancredi, PhD, the article provides practical advice in the form of practice recommendations, along with comments about safety data from numerous clinical trials.

As Dr. Merenstein stated, “We wrote this article for working clinicians. They are interested in the science but are busy and want a straightforward evidence-based resource. We are hopeful this will be a go-to resource during the busy clinic day.”

Verbatim from the article are the following practice recommendations:

  • Consider specific probiotics to prevent antibiotic-associated diarrhea, reduce crying time in colicky infants, and improve therapeutic effectiveness of antibiotics for bacterial vaginosis.
  • Consider specific probiotics to reduce the risk for Clostridioides (formerly Clostridium) difficile  infections, to treat acute  pediatric diarrhea, and to manage symptoms of constipation.
  • Check a product’s label to ensure that it includes the probiotic’s genus, species, and strains; the dose delivered in colony-forming units through the end of shelf life; and expected benefits.

The full text can be accessed by logging into Medscape.

A Miracle Treatment! Or Not?

/in ISAPP Science Blog /by KC

By Daniel J. Merenstein, MD, Professor, Department of Family Medicine and Director of Research Programs, Georgetown University Medical Center, Washington DC

Here’s a scenario for a physician: A drug rep walks into your office. She has a new product she wants to talk to you about. You are super excited to talk to her as you have heard all about this product from many other sources. The data that are being reported are amazing. There are hundreds if not many more case reports of it working. People were dying and then totally recovered after being given this product. It has been witnessed and published! The efficacy is well over 90%. You are not sure there is any intervention you have ever heard of that has such amazing efficacy.  She tells you that in some of the cases, the patients were very sick and despite numerous courses of antibiotics they did not improve until this new product was given. You ask for more information as you are starting to think this must be like when doctors first heard of penicillin.

The product can be taken orally but that is not the way it is generally given. She tells you that although there are 2-3 ways to administer, most hospitals are doing it the most expensive way now. (You later learn that the typical– and most expensive – approach to administering the product may not even be the best approach.) But you withhold judgement as this sounds exciting. And remember, you have been hearing all about this from so many different sources.

But as you listen, it gets a little confusing. She tells you that the makeup of the product is different in nearly every application. This makes it exciting to use, as one really never knows what is in it. It is also relatively cheap to obtain, as the patient can have a friend just bring it in for them.

Since you are trained in evidence-based medicine, you ask a few questions. It is exciting there are all sorts of case reports but what about the randomized controlled trials, and what does the FDA say about it? You ask if you can look at the trials—there is no way you can review hundreds of studies now but if she leaves them for you, you will look at them this weekend. But before she leaves you ask a few quick questions. How many of these studies are randomized? She says 10. How many use a placebo? She says 6. You tell her what you really want to do is review all the randomized placebo-controlled blinded studies, if she can just leave those.

Later in the week you go pick up the folder she left and right away are a little surprised at how light it is. It looks like there are only 3 randomized placebo-controlled blinded studies, only two of which are peer-reviewed and published. One was a positive study; overall, 91% of patients in the new drug group achieved clinical cure compared with 63% in the control group. But you realize this is not exactly a placebo-controlled trial. What they did is compare two types of the new application. Furthermore, this study was conducted at two sites and at one of the sites both the new application and the control had nearly identical rates of improvement, both over 90%. Okay so this was not a perfect study, only 46 total participants, but still pretty exciting with over 90% improvement.

The second study had three groups of 83 people. Group A (2 doses of new drug), B (2 doses of placebo) and C (1 dose of new drug and 1 placebo dose). The efficacy for these three groups was 61%, 45%, and 67%, respectively. The primary endpoint was not met (P = .152). Interestingly, Group C, which included one dose of placebo, was superior to all placebo (group B) but Group A, in which the drug was given two times, was not superior to placebo.

The third study, a Phase II trial, appears to not be peer-reviewed or published, but just reported online. However, it does appear this was far from a positive study, with 44% of subjects (26 of 59) who received the new application improving versus 53% of subjects (16 of 30) who received placebo. I have been told that this study will be published soon and that a Phase III study of this intervention was also undertaken.

Well now you are getting a little more confused. You have heard from fellow docs, the lay press, medical literature and the drug rep that this new application was over 90% effective. But it appears in the three reasonably well controlled studies, the ones from which we can really draw conclusions, only one was positive and in that study the control was not a real placebo.

Besides efficacy, you remember that one has to always consider the cost and adverse events. Maybe this new application is like recommending the Mediterranean Diet, where the efficacy from studies is limited but the adverse events are nearly non-existent. But when you do a quick PubMed search you learn that this is far from the case with this product. This application has been reported to cause very serious adverse events, including extended-spectrum beta-lactamase (ESBL)–producing Escherichia coli bacteremia resulting in one death. You look online expecting that the FDA must have some serious warnings about this new drug. You don’t find any such warnings.

You may have guessed that the product is in fact a Fecal Microbiota Transplant (FMT). Besides having a professional interest in this much-discussed treatment, I have a personal interest. Last year my son was in a Johns Hopkins Hospital with a central line and two broad-spectrum antibiotics for a bone infection. I asked them to provide him with probiotics since the number needed to treat to prevent pediatric antibiotic associated diarrhea is 9, per a 2019 Cochrane review. This review included 20 randomized, placebo-controlled studies of a single strain. However, I was told no Hopkins hospital will administer probiotics, and further, that we could not even bring in our own because of concerns for the safety of others. But no worries – if my son got recurrent C. diff infection, Hopkins would allow this great new procedure, FMT.

In medicine I cannot truly imagine a probiotic with the same evidence base as FMT receiving such widespread acceptance and escaping regulatory scrutiny. And currently used probiotics have an excellent safety record. Just imagine, if this were a new drug being sold there would be widespread condemnation of the attempt to get approval mainly based on anecdotal case reports.  Shockingly, based on the level of evidence I have described many experts now think a randomized placebo-controlled trial is not even ethical for the placebo group, as of course they know FMT works.

It is a quandary. I am not opposed to FMT; I find it fascinating. But why has it been so widely accepted and why has the FDA, which in general has been very careful with probiotic applications in medicine, allowed this to proceed for recurrent C diff infection with only enforcement discretion? Both treatments administer live microorganisms, one with 31 placebo controlled randomized trials, including 8672 subjects [of C. diff prevention (number needed to prevent=42), not treatment like FMT], the other with pretty limited data.  I have my thoughts, but better for you to ponder it.

Additional related content:

Webinar presenting current level of evidence for FMT: FECAL MICROBIOTA TRANSPLANTATION, AM I SURE IT WORKS? Oct 29, 2020. Presented by Prof. Daniel Merenstein, introduced by Prof. Hania Szajewska, sponsored by Centro Studi Scientifici, La Marcigliana.

 

 

 

thumbnail of Clinical Guide Canada 2018

Updated Clinical Guide to Probiotics Now Available

/in featured, News /by Mary Ellen Sanders

Want some guidance on knowing which probiotic products have been tested for which clinical benefits, and understand the level of evidence supporting those benefits? Check out the 2018 versions of Clinical Guide to Probiotic Products Available in USA and Clinical Guide to Probiotic Products Available in Canada. Currently, these are the only 2 geographical regions covered by this initiative, although they are considering expanding to other regions. This guide is updated annually. Some changes for 2018 include addition of new indications ‘Mood and affect’, ‘Liver health’, ‘Weight management’ (Canada) and ‘Seasonal allergies’ and ‘Eczema/Dermatitis-Adult’ (United States). Evidence is reviewed independently by six academic experts and graded as Level I (highest), II or III. A grade of Level I requires evidence from at least one properly designed randomized human trial. This guide is produced by the Alliance for Education on Probiotics, and is an industry funded effort (see industry sponsors for US and Canadian versions).