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ISAPP’s Guiding Principles for the Definitions of ‘Biotics’

/in ISAPP Science Blog /by KC

By Mary Ellen Sanders, PhD, ISAPP Executive Science Officer

Articulating a definition for a scientific concept is a significant challenge. Inevitably, scientists have different perspectives on what falls inside and outside the bounds of a term. Prof. Glenn Gibson, ISAPP co-founder and longtime board member, recently published a paper that describes his path to coining the word ‘prebiotic’, with this observation: “One thing I have learned about definitions is that if you propose one, then be ready for it to be changed, dismissed or ignored!”

Mary Ellen Sanders with Glenn Gibson

Members of the ISAPP board, however, have remained steadfast in their belief that such definitions are worth creating. They are the basis for shared understanding and coordinated progress across a scientific field.

Developing the consensus definition papers on probiotics, prebiotics, synbiotics, postbiotics and fermented foods was demanding on the part of all involved. The objective of the panels that met to discuss these definitions was clear – to provide common ground for consistent use of this growing body of terms for all stakeholders. Although some disagreement among the broader scientific community exists about some of the definitions, ISAPP’s approach relied on important, underlying principles:

  • Don’t unnecessarily limit future innovation
  • Don’t unnecessarily limit mechanisms of action
  • Don’t unnecessarily limit scope (host, regulatory category, mechanism, site of action, etc.)
  • Require a health benefit on a target host to be demonstrated – otherwise, what is the value of these biotic substances? (Of course, fermented foods were the exception in this criterion, because the value of consuming fermented foods even in the absence of an established health benefit is evident.)
  • Limit to preparations that are administered, not substances produced by in situ activities

In my opinion, many published definitions, including previous ones for postbiotics (see supplementary table here), are untenable because they don’t recognize these principles. There may also be a tendency to rely on historical use of terms, rather than to describe what is justified by current scientific knowledge. A good example of this is provided by the first definition of probiotics, published in 1965. It was “substances secreted by one microorganism that stimulate another microorganism” (Lily and Stillwell, 1965), which is far from the current definition of “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host (Hill et al. 2014).

If you’re looking for a concise summary of the five published ISAPP definitions, see here for our definitions infographic.

Additional reflections: I noted with a smile Glenn’s views on ISAPP, specifically on the appropriate pronunciation of the abbreviation ‘ISAPP’. “My only negative is that everyone involved in the organisation aside from 2 or 3 of us pronounce its acronym wrongly.” Most board members, including myself, have always pronounced this as ‘eye-sap’. Glenn opines, “The abbreviation is not eye-SAPP, it is ISAPP (with the ‘I’ – remarkably enough – being spoken as it is in the word ‘International’).” I wonder how he pronounces IBM?

 

 

 

 

ISAPP awards the Glenn Gibson Early Career Research Prize to two diet and gut health researchers

/in ISAPP Science Blog, News /by KC

The ISAPP board of directors is pleased to announce that the 2022 Glenn Gibson Early Career Research Prize has been awarded to two promising researchers in the field of probiotics, prebiotics and related substances.

Dr. Martin Laursen, Senior Researcher at the National Food Institute, Technical University of Denmark, has demonstrated excellence in his work on the impact of probiotics and human milk oligosaccharides on infant gut microbiota and health. Dr. Eirini Dimidi, Lecturer at King’s College in London, UK, has carried out meaningful work on probiotics, prebiotics, and fermented foods and their impact on constipation.

The award criteria stipulated that the researchers must be fewer than five years from their terminal degree, and their scope of research must be basic or clinical research disciplines in the fields of probiotics, prebiotics, synbiotics, postbiotics or fermented foods. In addition, the researchers were required to show evidence of a significant research finding and its publication(s), new ideas that advance the field, and / or evidence of impact through citizenship, general outreach, social media or other means.

The prize committee chose the two recipients from among dozens of applicants and identified each of them as having made important contributions to the field at this early stage in their scientific careers. Each winner will receive a cash prize and an opportunity to speak at the ISAPP annual meeting, to be held in Spain in June, 2022.

Stay tuned to learn more about these rising star researchers!

See here for details about the 2022 Glenn Gibson Early Career Research Prize

Do fermented foods contain probiotics?

/in Consumer Blog, ISAPP Science Blog /by KC

By Prof. Maria Marco, PhD, Department of Food Science & Technology, University of California, Davis

We frequently hear that “fermented foods are rich in beneficial probiotics.” But is this actually true? Do fermented foods contain probiotics?

The quick answer to this question is no – fermented foods are generally not sources of probiotics. Despite the popular assertion to the contrary, very few fermented foods contain microbes that fit the criteria to be called probiotic. But this fact does not mean that fermented foods are bad for you. To uphold the intent of the word probiotic and to explain how fermented foods actually are healthy, we need to find better ways to describe the benefits of fermented foods.

Probiotics are living microorganisms, that when administered in adequate amounts, confer a health benefit on the host (Hill et al 2014 Nat Rev Gastroenterol Hepatol). This current definition reflects minor updates to a definition offered by an expert consultation of scientists in 2001 convened by the Food and Agriculture Organization of the United Nations (FAO) and the World Health Organization. Evident from the definition, a microbial strain is not a probiotic unless a health benefit has been found with its use. At a minimum, the strain should be proven to be beneficial in at least one randomized controlled trial (RCT). Probiotics must also be defined at the strain level through genome sequencing (a strain is a single genotype of a species).

Fermented foods, on the other hand, have no requirement to improve health. Fermented foods are foods and beverages made through desired microbial growth and enzymatic conversion of food components. This definition was recently formulated by an ISAPP consensus panel of scientific experts to affirm the common properties of all foods of this type and to differentiate foods that may look or taste similar but are not made using microbes (Marco et al 2021 Nat Rev Gastroenterol Hepatol). Fermented foods encompass an expansive variety of foods made from animal and plant sourced ingredients and produced from all types of microbial metabolism. The desired characteristics of these foods are frequently how they look, smell, and taste. There no expectation in this definition that fermented foods alter health in any way.

There is also no requirement for fermented foods contain living microbes at the time they are ingested. Foods such as bread, chocolate, and beer are fermented but then are baked, roasted, and/or filtered. This means those fermented foods cannot be probiotic.

Some fermented foods, such as kimchi and kombucha, are typically eaten with living microbes present. However, the microbes in those foods usually do not meet the criteria to be called probiotic. Whether the fermented food was made at home or purchased from the supermarket, studies investigating whether the microbes in those fermented foods are specifically responsible for a health benefit remain to be done. Those foods also do not contain microbes defined to the strain level, nor is the number of living microbes typically known. An exception to this is if specific strains previously shown to provide a health benefit in one or more RCT are intentionally used in the production of the food and remain viable at expected numbers over the shelf-life of that fermented food product. An example of this would be a commercial fermented yogurt that has an added probiotic strain remaining viable at the time of consumption, beyond the strains that carried out the fermentation.

Despite these distinctions between probiotics an fermented foods, the probiotics term has pervaded common lexicon to mean “beneficial microbes”. In contrast to pathogenic or harmful microbes, beneficial microbes are those that are understood to help rather than hurt bodily functions. However, just as we do not assume that all pathogens cause the same disease or result in the same severity of symptoms, we should also not expect that beneficial microbes all serve the same purpose. By analogy, automobiles are useful vehicles which help us to get from place to place. We do not expect that all automobiles perform like those used for Formula 1 racing. Microbes are needed to make fermented foods and may be beneficial for us, but we should not assume that those drive health benefits like established probiotic strains.

What are the consequences of calling fermented foods probiotic when they include undefined numbers of living microbes for which strain identities are not known? One can suppose that there is no harm in labeling or describing those products as “probiotic” or “containing probiotics”. However, by doing so, confusion and misunderstanding is created and too often, spread by journalists, nutritionists, scientists, and medical professionals. For example, news articles in reputable sources have written that foods like kefir, kimchi, sauerkraut made from beets or cabbage, pickles, cottage cheese, olives, bread and chocolate are rich in probiotics. As misuse perpetuates, what becomes of bona fide probiotics shown with rigorous study to benefit health, such as reducing the incidence and duration of diarrhea or respiratory infections? It becomes difficult to know which strains have scientific proof of benefit. Just as there are laws for standards of food identity, we should strive to do the same when describing microbes in fermented foods.

Avoiding the term probiotic when describing fermented foods should not stop us from espousing the myriad of positive attributes of those foods. Besides their favorable sensory qualities, fermented foods are frequently safer and better tolerated in the digestive tract than the foods they are made from. During the production of fermented foods, microbes remove or reduce toxins in the ingredients and produce bioactive compounds that persist long after the microbes that make them are gone.

Even though the living microbes in fermented foods may not rise to the standard of a probiotic, they may provide health benefits. We just don’t have the studies to prove that they do. With more study, we may find that viable microbes in fermented foods work similarly to probiotics in the digestive tract through shared mechanisms. This is already known for yogurts. Yogurt cultures share the ability to deliver lactase to the intestine, thereby improving tolerance of lactose by intolerant individuals. Clinical and epidemiological studies performed on fermented foods already suggest an association between them and different health benefits but as we recently explained (Marco et al 2021 J Nutrition), more work is needed in order to understand if and what benefits these microbes provide.

For now, we should simply continue enjoying the making and eating of fermented foods and reserve the term probiotics for those specific microbial strains which have been shown to improve our health. Marketers should resist labeling products as containing probiotics if their products do not meet the criteria for a probiotic. Indeed, the descriptor “live and active cultures” more accurately reflects the microbial composition of many fermented foods, and should be used until controlled human trials demonstrating health benefits are conducted.

 

Additional resources:

How are probiotic foods and fermented foods different? ISAPP infographic.

Fermented foods. ISAPP infographic.

What are fermented foods? ISAPP video.

Are fermented foods probiotics? Webinar by Mary Ellen Sanders, PhD.

 

New synbiotic definition lays the groundwork for continued scientific progress

/in ISAPP Science Blog /by KC

By Karen Scott, Mary Ellen Sanders, Kelly Swanson, Glenn Gibson, and Bob Hutkins

When Glenn Gibson and Marcel Roberfroid first introduced the prebiotic concept in 1995, they also conceived that prebiotics could be combined with probiotics to form synbiotics. In 2011, Gibson and Kolida described additional criteria for defining synbiotics and proposed that synbiotics could have either complementary or synergistic activities.

In the past decade, nearly 200 clinical studies on synbiotics have been reported in the literature. Nonetheless, the term itself has been open to interpretation, and the existing definition – a probiotic plus a prebiotic – was inadequate to account for the synbiotic formulations described in the literature or available in the marketplace.

To provide clarity on the definition and lay the groundwork for progress in the years ahead, scientists working on probiotics, prebiotics, and gut health came together in an expert panel. The outcome of this panel, the ISAPP consensus definition and scope of the word synbiotic, has now been published in Nature Reviews Gastroenterology & Hepatology.

A diverse panel of experts

The panel of experts who met to discuss the definition of synbiotics in May, 2019, consisted of eleven interdisciplinary scientists in the fields of microbiology and microbial ecology, gastrointestinal physiology, immunology, food science, nutritional biochemistry, and host metabolism. The panel’s range of experience was important in order to ensure the definition made sense from different scientific perspectives. The panel met under the auspices of ISAPP and was led by Prof. Kelly Swanson.

An inclusive definition

Initially, it seemed logical that synbiotic could be defined as a combination of a probiotic and a prebiotic, with each component needing to meet the criteria for either probiotic or prebiotic according to the previous scientific consensus definitions (Hill, 2014; Gibson, 2017). However, as the group discussed different scenarios and combinations, it became clear that this narrow characterization of a synbiotic could place undue emphasis on the individual components of a synbiotic rather than the combination of these components. For example, the original definition would not include a combination of inulin (a prebiotic) with live microorganisms that did not have probiotic status, even if live microbes in the host selectively utilized inulin and the combination was shown to confer a health benefit.

The definition of synbiotic agreed upon by the panel is: “A mixture, comprising live microorganisms and substrate(s) selectively utilized by host microorganisms, that confers a health benefit on the host.”

The panel discussed exactly which microorganisms must be targeted by the substrate in a synbiotic and decided that the targeted ‘host microorganisms’ can include either autochthonous microbes (those already present in the host) or allochthonous microbes (those that are co-administered).

Further, the panel defined two distinct types of synbiotics: complementary and synergistic. In a ‘synergistic synbiotic’, the substrate is designed to be selectively utilized by the co-administered microorganism(s)—and do not necessarily have to be individual probiotics or prebiotics, as long as the synbiotic itself is health promoting. In a ‘complementary synbiotic’, an established probiotic is combined with an established prebiotic designed to target autochthonous microorganisms— therefore each component of a complementary synbiotic must meet the minimum criteria for a probiotic or a prebiotic.

The definition is purposefully inclusive, so a synbiotic could be established for different hosts, e.g. humans, companion animals, or agricultural animals. Even subsets of these hosts (those of a certain age or living situation) could be targeted by synbiotic products. Moreover, products may be called synbiotics if they target areas of the host’s body outside of the gut (e.g. the skin).

Implications for study design

According to the new definition, different types of studies must be designed for synergistic synbiotics versus complementary synbiotics. For the former, a single study must demonstrate both selective utilization of the substrate and a health benefit. For complementary synbiotics, however, it is only necessary to show a health benefit of the combined ingredients; it is not necessary to show selective utilization of the prebiotic substrate, since selective utilization should have already been established.

The panel remained open to different scientifically valid approaches to demonstrate selective utilization of the substrate. Further, the nature of the ‘health benefit’ was not prescribed, but to the extent biomarkers or symptoms are used, they must be validated.

Continuing scientific progress

The field of synbiotics is evolving – some studies exist to show human health benefits deriving from synbiotic ingredients. While the studies on individual components (probiotics and prebiotics separately) may guide those in the field, there is the possibility that we will find novel uses and applications for synbiotics in the years ahead.

Causality is an important issue that scientists will need to address in this field. The definition of synbiotics rests on an important concept originally advanced in the definition of prebiotics: evidence of health benefit plus selective utilization of the substrate by microbes must be demonstrated. More investigations of causal links between these two things will have to be explored; this is closely connected with ongoing work to uncover probiotic and prebiotic mechanisms of action.

This definition is a first step—and it is fully expected that the field will evolve in the years ahead as more data are generated on the benefits of synbiotics for human and animal hosts.

Find the ISAPP press release on this publication here.

See here for a previous ISAPP blog post on the synbiotic definition.

See below for ISAPP’s new infographic explaining the concept of synbiotics.

Are prebiotics good for dogs and cats? An animal gut health expert explains

/in Consumer Blog, ISAPP Science Blog /by KC

By Kelly S. Swanson, PhD, The Kraft Heinz Company Endowed Professor in Human Nutrition, University of Illinois at Urbana-Champaign, USA

Pet dogs and cats are cherished companions. In developed countries, many households with pets treat them like family members. Similarly to humans, a high level of nutrition and veterinary care promotes health and longevity. As people become more aware of what they feed themselves and their human family, they make the same considerations for their canine and feline companions. Pet food trends have closely followed those of the human food industry over the last couple decades, with high-quality natural and organic foods gaining popularity.

One way pet food companies have enhanced their products is by incorporating functional ingredients into their formulas. Functional ingredients provide benefits beyond that of their nutrient content. One of the most popular target areas for functional ingredients is pet gastrointestinal health, with structure/function claims of “supporting digestive health”, or something similar, being quite common. Loose stools, constipation, and various gastrointestinal disorders and diseases such as inflammatory bowel diseases and irritable bowel syndrome are common in pets. The task of “poop scooping” after the dog in the park or cleaning out the cat’s litterbox provides owners with an opportunity for daily assessment of stool quality and serves as a reminder of how important diet is to gut health.

Benefits of prebiotics for pets

Many ingredients, including dietary fibers, prebiotics, probiotics, synbiotics, postbiotics, and other immunomodulators may provide gastrointestinal benefits to pets, but today we will focus on prebiotics. The most recent ISAPP expert consensus panel on prebiotics clarified that the prebiotic concept not only applies to humans, but also to companion and production animals (Gibson). Dogs and cats evolved as Carnivora, mainly consuming high-protein, high-fat diets that were low in fiber, and their short, simple gastrointestinal tracts have a limited capacity to ferment non-digestible substances. Nonetheless, they possess an active microbiota population, primarily in the colon, that may be manipulated by diet to impact health.

Most prebiotic research in pets has focused on the gastrointestinal tract. Prebiotic administration has been shown to reduce the incidence or severity of infections (Apanavicius; Gouveia), improve stool consistency (Kanakupt), and beneficially shift fecal microbiota and metabolite profiles (Propst). A few have reported the benefits that prebiotics may have on metabolic health, demonstrating improved glucose metabolism and insulin sensitivity in pets consuming prebiotics (Respondek; Verbrugghe). Since we’re looking at foods rather than at medicines that address disease, the majority of research has been conducted in healthy animals so evidence of health improvements in diseased pets is sparse.

Types of pet-friendly prebiotics

Although a few studies have tested galactooligosaccharides (GOS), mannanoligosaccharides, and other potential prebiotics, by far the most common prebiotics studied and present in pet foods are the non-digestible fructans. Natural sources, such as chicory, or isolates and extracts that have a high purity, including short-chain fructooligosaccharides (FOS), oligofructose, and inulin, are all present in pet foods.

Which pets benefit most?

Similar to dietary fiber, the need for prebiotic inclusion is dependent upon diet type and formulation. Animals consuming plant-based diets that are rich in natural fibers and non-digestible oligosaccharides likely do not require additional fermentable substrate in the formula. Dogs and cats fed high-protein, meat-based diets, however, typically have greater fecal odor, a higher colonic pH, and higher density of potential pathogens due to a high rate of protein fermentation. In those diets, prebiotic inclusion may help animals normalize their gut microbiota abundance and metabolism.

Prebiotics may be fed to all pets, but will likely provide the greatest benefits to geriatrics, animals who are or have received antibiotics, those under high stress conditions, or those with certain gastrointestinal disorders. The low caloric density of prebiotics and the metabolic benefits that come from their fermentation will be most beneficial to pets with obesity and diabetes. As for all functional ingredients, dosage is important. When comparing dogs and cats, dogs usually can tolerate a higher dosage than cats. In regard to dog size, small dogs can typically tolerate a higher dosage (per unit body weight) than large dogs, which are more susceptible to loose stools. In most commercial pet foods, prebiotic inclusion levels are <0.5% of the formula to limit side effects.

Further research on prebiotic substances

Using the powerful tools that are now available to study gut microbiota and host physiology, future research can hopefully determine what microbes are most important to the health of dogs and cats and identify mechanisms by which prebiotics provide health benefits to pets. Further testing, which may include plant-based ingredients, yeast-based products, and milk oligosaccharide mimics, will hopefully identify other prebiotic substances and continue to expand our knowledge in the field.

 

Kelly Swanson joined the ISAPP board of directors in June, 2020, providing valuable expertise in animal gut health and overall health. Swanson also chaired the 2019 ISAPP-led international consensus panel on the definition of synbiotics.

 

 

 

Growing interest in beneficial microbes and fermented foods in Argentina

/in Consumer Blog, ISAPP Science Blog /by KC

By Prof. 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

Awareness of gut microbes, fermented foods and probiotics has been on the rise in Argentina. Nutritionists and influencers, who in recent years have begun promoting a healthier lifestyle, are leveraging their social networks to post how-to instructions for making fermented foods, advice to promote a ‘healthier’ microbiota, and information on the potential role of probiotics and prebiotics in human health. But are these news items and recommendations based on science? Not always! I’ve been fortunate to have had the opportunity to make sure the science is correctly communicated to a broad audience on the microbiome, fermented foods, probiotics and prebiotics.

In Argentina, for the last 50 years, there has been on the air a TV show with a particular format: the hostess, Miss Mirtha Legrand, invites 4-6 people to have lunch every Sunday, talking about politics, economy, popular culture, arts and even science for 3 hours. According to her, this is the longest continuously running TV program in the world. Every Sunday several thousands of people from Argentina, Uruguay and Paraguay tune in. In October 2019, I was invited to join the table and to comment about the invisible world inside and around us. We discussed how we can profit from bacteria through fermented foods and probiotics, and how to feed our gut microbes with prebiotics. In fact, in 2019, I gave more than 40 talks on this topic to scientific audiences at conferences, as courses for Ph.D. students, as seminars and as workshops. These efforts are targeted not only to local scientists and students, but also to children in schools, local sport clubs in small towns, gyms and hospitals. The interest in friendly bugs is wide-ranging and varied, and fueled by information from radio and TV programs.

“Having lunch with Mirtha Legrand”, a talk show on television for more than 50 years in Argentina, where the discussion on beneficial microbes was brought to the table by Prof. Gabriel Vinderola (far right). Mirtha Legrand, now 93 years old, is in the center (October 3rd, 2019).

The enthusiasm of the audience was immediately evident. Lots of messages came by email, WhatsApp, Facebook or Instagram. People were anxious to know more, inquiring about trustworthy sources to read scientific-based but “easy-to-understand” material, posing specific questions about their gut feelings, where to get these probiotics and prebiotics or how to make fermented foods in a safe manner. Fortunately, the ISAPP infographics on probiotics and prebiotics were already available in Spanish, translated by Miguel Gueimonde (Spain) and me, and these were a welcome resource. Yet people still wanted more information, and asked more and more specific questions.

Spurred by such widespread interest, I contacted a local lawyer-turned-chef, Ana Milena Giacomini, who left behind her professional law career to open a small restaurant with a menu heavily based on fermented foods. She features such delights as home-made yoghurt, chucrut, kimchi, sugary kefir, fermented hummus, sourdough bread, pancakes made out of fermented rice flour, kombucha, kvass and a gasified drink from fermented ginger. With her, we organized 4-hour workshops, which are currently on hold due to COVID-19. These workshops feature Ana preparing some of these fermented foods live, followed by tasting, while I explain the science and microbiology behind them. I share factors related to the identity, safety, stability, and potential health effects of these products. I emphasize the differences between fermented foods and probiotics, while discussing the potential value of incorporating fermented foods, probiotics and prebiotics to the daily diet as a way to promote gut health. I provide more specific information on health effects for which robust meta-analyses are available to support the microbes’ use, such as prevention of antibiotic-associated diarrhea in children, treatment of infant colic, prevention of allergies, and downregulation of intestinal inflammation. Other workshops with different chefs from different locations in Argentina are in line for when the coronavirus pandemic ends.

Part of the four-course dinner containing fermented foods prepared by chef Martin Russo. The starter consisted of fermented carrots and hummus, served on sourdough bread (pictured).

These workshops are expected to be attended by 30-35 people each time. Nutritionists are interested in giving sound responses to their clients, who hear about these topics in the media or in social networks. But also, people come who want to learn how to make fermented foods, where to find probiotics and prebiotics, or to gain clear guidance on how to incorporate live bacteria to their diets. Other health professionals (gastroenterologists, pediatricians), educators and even people from the industry also attend.

 

The dessert was ice cream balls covered by the mother of vinegar (transparent circle on the top), rinsed and sweetened.

Most people interested in attending these workshops have narrow experience with fermented foods, only being familiar with such things as yoghurt, cheese, wine or beer. Some of them do not know that these foods are indeed fermented, or do not have a clear idea what fermentation is about. Most of them also have a very limited awareness, or even misinformation, about probiotics and prebiotics. These workshops offer the possibility for the curious to learn and to taste new foods, to get insights on the science behind fermented foods, probiotics and prebiotics, and to learn the differences between them in a science-based manner in an “easy-to-follow language”. These encounters are a great way to expand the interest by the general public on the invisible world inside and around us.

Is probiotic colonization essential?

/in Consumer Blog, ISAPP Science Blog /by KC

By Prof. Maria Marco, PhD, Department of Food Science & Technology, University of California, Davis

It is increasingly appreciated by consumers, physicians, and researchers alike that the human digestive tract is colonized by trillions of bacteria and many of those bacterial colonists have important roles in promoting human health. Because of this association between the gut microbiota and health, it seems appropriate to suggest that probiotics consumed in foods, beverages, or dietary supplements should also colonize the human digestive tract. But do probiotics really colonize? What is meant by the term “colonization” in the first place? If probiotics don’t colonize, does that mean that they are ineffective? In that case, should we be searching for new probiotic strains that have colonization potential?

My answer to the first question is no – probiotics generally do not colonize the digestive tract or other sites on the human body. Before leaping to conclusions on what this means for probiotic efficacy, “colonization” as defined here means the permanent, or at least long-term (weeks, months, or years) establishment at a specific body site. Colonization can also result in engraftment with consequential changes to the gut microbiota composition and function. For colonization to occur, the probiotic should multiply and form a stably replicating population. This outcome is distinct from a more transient, short-term (a few days to a week or so) persistence of a probiotic. For transient probiotics, it has been shown in numerous ways that they are metabolically active in the intestine and might even grow and divide. However, they are not expected to replicate to high numbers or displace members of the native gut microbiota.

Although some studies have shown that digestive tracts of infants can be colonized by probiotics (weeks to months), the intestinal persistence times of probiotic strains in children and adults is generally much shorter, lasting only few days. This difference is likely due to the resident gut microbiota that develops during infancy and tends to remain relatively stable throughout adulthood. Even with perturbations caused by antibiotics or foodborne illness, the gut microbiome tends to be resilient to the long-term establishment of exogenous bacterial strains. In instances where probiotic colonization or long-term persistence was found, colonization potential has been attributed more permissive gut microbiomes specific to certain individuals. In either case, for colonization to occur, any introduced probiotic has to overcome the significant ecological constraints inherent to existing, stable ecosystems.

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

This leads to the next question: Can probiotics confer health benefits even if they do not colonize? My answer is definitely yes! Human studies on probiotics with positive outcomes have not relied on intestinal colonization by those microbes to cause an effect. Instead of colonizing, probiotics can alter the digestive tract in other ways such as by producing metabolites that modulate the activity of the gut microbiota or stimulate the intestinal epithelium directly. These effects could happen even on short-time scales, ranging from minutes to hours.

Should we be searching for new probiotic strains that have greater colonization potential? By extension of what we know about the resident human gut microbiota, it is increasingly attractive to identify bacteria that colonize the human digestive tract in the same way. In some situations, colonization might be preferred or even essential to impacting health, such as by engrafting a microbe that performs critical metabolic functions in the gut (e.g. break down complex carbohydrates). However, colonization also comes with risks of unintended consequences and the loss of ability to control the dose, frequency, and duration of exposure to that particular microbe.

Just as most pharmaceutical drugs have a transient impact on the human body, why should we expect more from probiotics? Many medications need to be taken life-long in order manage chronic conditions. Single or even repeated doses of any medication are similarly not expected to cure disease. Therefore, we should not assume a priori that any observed variations in probiotic efficacy are due to a lack of colonization. To the contrary, the consumption of probiotics could be sufficient for a ripple effect in the intestine, subtly altering the responses of the gut microbiome and intestinal epithelium in ways that are amplified throughout the body. Instead of aiming for engraftment directly or hand-wringing due to a lack of colonization, understanding the precise molecular interactions and cause/effect consequences of probiotic introduction will lead to a path that ultimately determines whether colonization is needed or just a distraction.

Thank You to ISAPP’s 2019 Industry Advisory Committee Members

/in featured, News /by ISAPP

by Dr. Mary Ellen Sanders

This year, a record 50 companies that are dedicated to a science-based approach to the probiotic and prebiotic industries joined ISAPP. As members of the Industry Advisory Committee (IAC), these companies provide critical insights to ISAPP’s all-academic board of directors as they leverage ISAPP to address challenges facing these and related industries.

ISAPP will welcome representatives from each IAC company at the ISAPP Annual Meeting – taking place next week May 14th-16th in Antwerp, Belgium.

Industry dues provide support for ISAPP activities, which would not be possibly without funding by our IAC members. Summaries of ISAPP activities are found here.

Thank you IAC!

ISAPP Tests the Water with a New Session Format at Annual Meeting: The Springboard

/in featured, News /by ISAPP

By Mary Ellen Sanders PhD, Executive Science Officer, ISAPP

Along with more traditional lectures, the distinctive five-minute rapid-fire late breaking news session and the small, topical discussion groups have been staples of the annual ISAPP meetings. This year in Antwerp, ISAPP is trying yet another innovative approach – a session we are calling “The Springboard.” The witty Prof. Glenn Gibson will chair, sure to make the session entertaining as well as inspiring.

The Springboard is a session designed to integrate audience and facilitators’ viewpoints in an interactive format. The topic:  What can scientists and industry do to spring probiotics and prebiotics into mainstream health management? Four facilitators, each focused on a different perspective (industry, politics, medical/clinical or science/research), will present their visions. The audience, which will be divided into 10 subgroups, is challenged with the task of generating innovative ways to achieve the visions.

ISAPP plans to write up the most interesting solutions for publication. Watch for the output from this new session after the 2019 ISAPP annual meeting – May 14-16.

The Art of Interpretation

/in featured, News /by ISAPP

By Prof. Gregor Reid, BSc Hons PhD MBA ARM CCM Dr HS, Lawson Research Institute, University of Western Ontario, Canada

It takes a certain degree of intelligence to become a scientist, and certainly hard work to be able to fund a lab and students. Yet, is it not bemusing when scientists cannot interpret simple things like definitions and the results of human studies?

I’ve written repeatedly, as have others, about the definition of probiotics (in case you forgot – “Live microorganisms that, (or which) when administered in adequate amounts, confer a health benefit on the host”),1,2 and yet people look at it and must think that ‘dead’ fits, as does ‘consume’, as does ‘colonize’. It beggar’s belief how such a simple definition can be so badly interpreted by intelligent people.

Time after time papers I review mis-write and/or misinterpret the definition. Conference after conference, I hear dieticians, pharmacists, physicians, scientists not only get the definition wrong, but say things like ‘the probiotics in kombucha’ when there are none, ‘we have lots of probiotics in our gut’ when you don’t unless you consumed them, ‘the lactobacilli need to colonize’ when this was never a prerequisite nor does it happen except in rare instances.

The interpretation gets more difficult when people use terms that are completely undefined like ‘psycho-biotics’ and ‘post-biotics’. Even ‘dead probiotics’ have been used in clinical trials – God help us when the authors can’t even define it. Why stop at killing probiotic strains? Why not just kill any bacterial strain? Even the gut-brain axis which is now mentioned everywhere in the literature is undefined and unproven. The vagus nerve links to many body sites as does the nervous system, making it exceedingly difficult to prove that brain responses are only due to the gut microbes.

Everyone can site a manuscript that has been badly analyzed, interpreted or peer-reviewed, or whose findings are overblown. But let’s not excuse this as ‘it’s just science’ or ‘it’s just the way it is.’ No, it is not. When a paper uses a product that is stated to be ‘probiotic’, there is an onus on the authors to make sure the product meets the appropriate criteria. These have been stated over and over again and reiterated this March, 2019.3

If scientists and science writers are really that smart, then how do they keep getting this wrong? How do we let a poorly analyzed paper get published and allow authors to say that Bacteroides fragilis is a probiotic that can treat autism?4,5 And when this leads to companies claiming probiotics can treat autism, why do other scientists convey cynicism for the field instead of against their colleagues and specific companies making the false claims?

Where does opinion cross the line with ignorance or stupidity? Martin Luther King Jr. must have predicted life today when he said, “Nothing in all the world is more dangerous than sincere ignorance and conscientious stupidity.”

Is it envy or anger that drives the anti-probiotic sentiments? It seems to go far beyond a difference of opinion. When the BBC and JAMA fail to comment on two much better and larger studies on the effects of probiotics published6,7 at the same time as the ones in Cell8,9 that were promoted by press releases, what is driving opinion? The science or the press releases? Are the journalists and communications’ people interpreting study results vigorously? One cannot believe they are.

In an era where anyone can write anything at any time and pass it along to the world, what are we recipients to do? Just go with our instincts? Soon, we will not know the difference between fact and fake news. The avatars will be so real, we will act on falsehoods without knowing. When all news is fake, where does that leave us as people, never mind scientists?

Manuscripts are sent for peer-review but how many reviewers are experts in bioinformatics, molecular genetics, clinical medicine, biostatistics and what happens on the front line of products to consumers or patients? Like it or not, poor studies will get out there and it will be the media who will tell the story and interpret the findings or press releases.

One must hope that confirmatory science will continue and if it fails, the writers and readers will stop citing the original incorrect report. But how often does that happen? And what are we left with?

It takes effort to object or fight back, but if we don’t then the fake news will become the norm.

Try interpreting that if you will.

 

Literature Cited

  1.  FAO/WHO. 2001. Probiotics in food.  http://www.fao.org/food/food-safety-quality/a-z-index/probiotics/en/
  2. Hill C. et al. 2014. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotics. Nat. Reviews Gastroenterol. Hepatol. 11(8):506-14.
  3. Reid G. et al. 2019. Probiotics: reiterating what they are and what they are not. Front. Microbiol. 10: article 424.
  4. Hsiao et al. 2013. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell. 155(7):1451-63.
  5. Sharon G, et al. 2016. The central nervous system and the gut microbiome. Cell. 167(4):915-932.
  6. Korpela K. et al. 2018. Probiotic supplementation restores normal microbiota composition and function in antibiotic-treated and in caesarean-born infants. Microbiome. 6(1):182.
  7. De Wolfe, T.J. et al. 2018. Oral probiotic combination of Lactobacillus and Bifidobacterium alters the gastrointestinal microbiota during antibiotic treatment for Clostridium difficile infection. PLoS One. 13(9):e0204253.
  8. Suez J. et al. (2018). Post-antibiotic gut mucosal microbiome reconstitution is impaired by probiotics and improved by autologous FMT. Cell. 2018 Sep 6;174(6):1406-1423.e16.
  9. Zmora N. et al. 2018. Personalized gut mucosal colonization resistance to empiric probiotics is associated with unique host and microbiome features. Cell. Sep 6;174(6):1388-1405.e21.

University confers Distinguished University Professor status on ISAPP board of directors member Gregor Reid

/in featured, News /by Mary Ellen Sanders

ISAPP board of directors member Dr. Gregor Reid has received a Distinguished University Professorship (DUP) award from his institution, University of Western Ontario in Canada, in honour of his exceptional scholarly career achievements. Reid, a Professor of Microbiology & Immunology, and Surgery, was aptly described as ‘a Canadian and international pioneer’ in research related to probiotics and the microbiome. A special area of research focus is how these relate to women’s health.

The many letters after Reid’s name reflect his extensive qualifications: BSc Hons, PhD, MBA, ARM CCM, Dr HS, FCAHS, FRS; he also has over 500 scientific publications to his name. But more than that, the impact of Reid’s work is seen all over the world. He has researched novel probiotic therapies that are now being used in different countries and settings, and his innovations have resulted in numerous probiotic-related patents. Reid also makes a point of empowering those in need: in Uganda, Kenya, and Tanzania, for example, he participated in a project to establish probiotic yogurt kitchens that allowed local women to further build sustainable yogurt businesses.

Reid’s connection with ISAPP goes back a long way—he hosted the first ever ISAPP meeting in London, Canada in May of 2002, and served as ISAPP’s second president. Still a dedicated member of the ISAPP board of directors, he is respected for his innovative ideas to move ISAPP forward and his incredible efficiency. As his colleagues know, no one gets more done more quickly than Gregor!

Today he is known as a steward of the proper use of the term ‘probiotic,’ a fitting description since he chaired the FAO/WHO expert consensus that published the now globally-recognized definition of the word probiotic back in 2001.

The ISAPP colleagues of Dr. Gregor Reid extend a warm congratulations on his Distinguished University Professorship award; they applaud his remarkable scientific accomplishments, his energy, and his determination to help the field advance.

See here for the full news article about the award.

Probiotics: Money Well-Spent For Some Indications

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

Eamonn M M Quigley MD, Houston Methodist Hospital and Weill Cornell Medical College, Houston, Texas, USA; Hania Szajewska MD, The Medical Univesrity of Warsaw, Department of Paediatrics, Poland; Dan Merenstein MD, Department of Family Medicine, Georgetown University

We read with interest and some concern the Medical News and Perspectives article by Jennifer Abbasi titled “Are Probiotics Money Down the Toilet? Or Worse?” (Abbasi 2019).  As researchers committed to the study of fecal microbiota transplant, prebiotics and probiotics, we find the title overly sensationalist for an article that ultimately provides a more nuanced view. It is unfortunate that the author focused on studies which either did not report on any clinical outcome and hence provide limited insight on the effectiveness of probiotics, or, whose null results likely reflect the late timing of the intervention while failing to refer to many high-quality studies that illustrate the subtlety of commensal and probiotic bacterial actions or clinical efficacy. Tanoue and colleagues provide a reminder that commensal engagement with the immune system is selective and precise (Tanoue et al. 2019). As Dr Knight points out, it would be surprising to witness the same response to any intervention in all individuals (Abbasi 2019). Efforts to individualize medical interventions, including probiotics, are worthwhile, but not yet realized. Until then, available evidence must be critically considered, but not ignored.  We wholeheartedly agree with the call for high quality clinical studies of probiotics but assert that it is also important to stress the challenges of performing clinical studies that seek to demonstrate clinical benefits in healthy human subjects; they require large study populations and are consequently very expensive. That clinical studies have been performed and demonstrated robust and clinically meaningful outcomes was illustrated by the study of Panigrahi where they demonstrated that an intervention comprising a probiotic plus prebiotic reduced sepsis among high-risk infants in rural India (Panigrahi et al. 2017). In the meantime, meta-analyses of smaller studies can provide insights into clinical benefit or harm. For example, systematic reviews and meta-analyses have consistently supported a role for probiotics in the prevention of Clostridium difficile–related illness, leading a JAMA review to state: “moderate-quality evidence suggests that probiotics are associated with a lower risk of C. difficile infection” (Goldenberg et al. 2018). Balanced with the low number needed to harm, probiotic interventions are attractive clinical options. We also question Abbasi’s focus on colonization as there is little, if any, evidence that this is necessary for probiotic activity.

We stress the obligation to provide a balanced view of the field which provides equal emphasis on successes as well as failures. No two probiotics (or probiotic cocktails) are alike; we should not expect they all have the same clinical impact.

 

References

  1. Abbasi J. Are probiotics money down the toilet? Or worse. JAMA 321(7):633-635. doi:10.1001/jama.2018.20798
  2. Tanoue T, Morita S, Plichta DR, et al. A defined commensal consortium elicits CD8 T cells and anti-cancer immunity. Nature. 2019;565:600-605.
  3. Panigrahi P, Parida S, Nanda NC, et al. A randomized synbiotic trial to prevent sepsis among infants in rural India. Nature. 2017;548:407-412.
  4. Goldenberg JZ, Mertz D, Johnston BC. Probiotics to prevent Clostridium difficile infection in patients receiving antibiotics. JAMA 2018;320:499-450. 

 

Acknowledgements:

Conflicts of interest:

All three authors are members of the Board of Directors of ISAPP

Eamonn M M Quigley holds equity in Alimentary Health and has served as a consultant to Alimentary Health, Allergan, Axon Pharma, Biocodex, Glycyx, Menarini, Pharmasierra, Salix and Vibrant.

Hania Szajewska reports no conflicts

Dan Merenstein has served as a consultant to Bayer, Debevoise & Plimpton, Pharmavite and Reckitt Benckiser

New ISAPP video gives an overview of fermented foods and their health benefits

/in featured, News /by Mary Ellen Sanders

Fermented foods are not the same as probiotic-containing foods. So what’s the difference? Do both of them confer the same health benefits?

These topics are addressed in ISAPP’s latest video, which takes viewers through the scientific basics of fermented foods (see here). Yogurt, kimchi, and cheese fall into this category of foods, which are transformed by growth and metabolic activity of microbes.

Some fermented foods contain live microbes that travel through the digestive tract, interact with cells, and support the intestinal microbiota. Their potential health benefits are of interest, too: not only do fermented foods improve digestibility, but initial studies show they also improve the immune system and prevent acute illnesses.

The upshot? Naturally fermented foods are worth incorporating in your daily diet.

This educational video was commissioned by the ISAPP board of directors with input from several additional scientific experts.

Limitations of microbiome measurement: Prof. Gloor shares insights with ISAPP

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

February 20, 2019

The number of papers published on the human microbiome is growing exponentially – but not all of the studies are equally well designed or reported. Evaluating the latest research requires a basic understanding of the latest approaches to microbiome methods and data analysis.

To help equip scientists not conducting microbiome research with the tools to understand microbiome-focused publications, ISAPP hosted a webinar titled Understanding microbiome experiments: a critical assessment of methods and data analysis. The webinar featured Gregory Gloor, PhD., Professor, Department of Biochemistry, Schulich School of Medicine and Dentistry, The University of Western Ontario, Canada.

Prof. Gloor’s slides are available here.

Prof. Gloor opened his talk with a sobering perspective: the current body of microbiome publications is fraught with problems. There is a fundamental lack of reproducibility in the microbiome field (Sinha et al. 2017). This is largely due to the large number of tools available and a lack of an a priori established research plan for microbiome analysis, which should be consistently followed throughout a project. At every step of the way, many decisions must be made regarding wet lab methods, bioinformatics toolsets and statistics to use. Different choices lead to different results. Once the biological specimens are assayed, choices for bioinformatics and statistical analyses can greatly influence the conclusions. In short, it’s possible to view the data through so many different lenses that eventually a researcher can find a story worth telling. How close that story comes to the truth is a principle that sometimes is sacrificed for the sake of an interesting story.

Another important challenge to the field is representative sampling. Too few samples are typically taken, often because of cost limitations, so that the samples do not reasonably approximate the truth about the environment being sampled. Conclusions from such studies result in both many false positives and many false negatives.

Prof. Gloor also warned about outsourcing microbiome analysis. Commercial entities often use every metric, hoping the customer will get some outcome they hoped for. Further, their tools are often outdated or proprietary. So caution must be used – there is no substitute for expertise.

Some suggestions for improving outcomes were offered:

  • Each project should stipulate a research approach and outcome a priori, which is consistently followed throughout the project.
  • Methodological consistency is important within a lab, but analytical methods do not necessarily need to be standardized across all labs. If all labs use the same methods, consistent, but incorrect, outcomes may result. So use of different metrics is good, but methods should be consistent within a project. The value of different research groups using different methods to ask particular research questions is that if the same result emerges from different approaches, it increases confidence that the results are true.
  • Gloor cautioned that microbiome datasets are compositional, and compositional data approaches must be used (Gloor et al 2017).
  • Functional readouts have less methodological variation than taxonomic readouts. Therefore, functional analysis of shotgun metagenomics or shotgun metatranscriptomics is typically a more reproducible, and also more informative, readout.
  • Recent advances have significantly decreased the cost of performing shotgun metagenomics for both taxonomic and functional readouts (Hillmann et al 2018).
  • There are now near-complete microbial genomic datasets available for European, North American and Asian populations (Almeida et al 2019) that will make it easier to functionally map datasets.

Prof. Gloor mentioned an interesting aside: prior clinical trial registration, ~60% of large clinical trials showed benefit of the intervention being tested. After the registration process required declaration of primary research outcomes, that number dropped to closer to 10% (Kaplan and Irvin 2015). This suggests that primary outcomes and analysis methods need to be in place to restrict researcher bias. Right now such mechanisms are insufficient in the microbiome field.

Prof. Gloor’s paper, Microbiome Datasets Are Compositional: And This Is Not Optional, provides great background reading for this webinar.

This webinar was developed by ISAPP Industry Advisory Committee representatives as an extension of the annual IAC Learning Forum.

Dr. Gloor is a professor of biochemistry with broad experience in molecular biology, genetics and genomics. His research is focused on the development of tools to examine 16S rRNA gene composition, gene expression of mixed population samples and metabolomic analysis of clinical samples. He is currently working on developing and adapting principled methods to characterize correlation and differential abundance in sparse, high throughput sequencing data as generated in 16S rRNA gene sequencing surveys, meta-genomics and meta-transcriptomics. One of his primary contributions has been the ALDEx2 tool in Bioconductor for the analysis of high-throughput experiments that generate counts per sequence tag: 16S rRNA gene sequencing, metagenomics, transcriptomics and selex-type experiments.

ISAPP’s prebiotics & probiotics infographic now available in Russian

/in featured, News /by Mary Ellen Sanders

‘International’ is the first word in ISAPP’s title—and the organization takes seriously its commitment to advancing education about probiotics and prebiotics in countries around the world. ISAPP members are happy to announce that the infographic “Effects of Prebiotics and Probiotics on our Microbiota” is now available in Russian. See here.

In an effort to reach broader global populations with its science-based communications on probiotics, prebiotics and fermented foods, ISAPP is undertaking steps to translate its infographics into multiple languages. Expected in the next month are translations of ISAPP’s popular “Probiotics” and “Prebiotics” infographics, which will be available in Bulgarian, Chinese, Dutch, French, Indonesian, Italian, Polish, Portuguese, Russian, and Spanish. (See here for all available translations of ISAPP infographics.)

The translation efforts, led by Dr. Roberta Grimaldi from University of Reading (UK), are made possible by many translators who are contributing generously of their time and skills.

Humpty Dumpty and the Microbiome

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

Prof. Colin Hill, Microbiology Department and Alimentary Pharmabiotic Centre, University College Cork, Ireland (@colinhillucc)

“When I use a word,” Humpty Dumpty said, in rather a scornful tone, “it means just what I choose it to mean—neither more nor less.”

Microbiome science is an evolving discipline, and new terminology is an important part of any developing field.  But precise language is important, especially in a multidisciplinary field with researchers from many diverse scientific backgrounds.  Language provides us a means of communicating with brevity and accuracy, but this is effective only if the reader is deriving the correct (intended) information from the author.

For example, is there a difference between ‘microbiome’, ‘microbiota’ and ‘microflora’?  Are the terms interchangeable, or would it be useful to have them mean related but distinctly different concepts?  I have heard people state that ‘microbiota’ refers to the microbial content of an environment, whereas ‘microbiome’ refers to the microbes AND their environment (the biome).  I have heard others suggest that ‘microbiome’ actually refers to the genetic content of a particular microbiota, in the same way that the genome is the genetic content of an organism.  Some definitions assert that the microbiome/microbiota/microflora only describes the microbial cells (bacteria, archaea and fungi) in a particular niche, while others include non-cellular microbes such as viruses and bacteriophage in their definition.  It has also been pointed out that ‘microflora’ is a misnomer, since technically the term ‘flora’ is reserved for the kingdom Plantae.

A few other examples.  Do we all know what is meant when someone uses the term ‘metagenomics’?  Also, people often refer to analysing the microbiome by 16S – but they are really only analysing the bacterial fraction of the microbiome, the ‘bacteriome’.  Of course ‘16S’ itself is not a valid term – it is 16S rRNA genes that are being analysed.  Would a clear distinction between microbiome, bacteriome, phageome, mycome, virome, archaeome and all the other ‘omes’ help or hinder our understanding of the subject under discussion?  Should most studies actually use the term ‘faecal bacteriome’ rather than ‘gut microbiome’, since it is almost always faeces that is under investigation, and usually only the bacterial component?

I am not going to call out any individuals for abuse of language, since I am pretty sure I could look at my own output and find lots of examples of poorly expressed concepts.  But does any of this matter or am I simply being pedantic? I think it does matter, since if terms are poorly defined it may lead to confusion on the part of the reader (or listener), whereas the authors (or speakers) may know exactly what they mean – neither more or less, as suggested by Humpty Dumpty.

ISAPP has convened consensus panels on the meaning of some very commonly used terms such as probiotic1 and prebiotic2, but there is a limit to this activity, and consensus panels cannot be convened for every new term.  Even with these consensus papers, we still have a plethora of additional terms surrounding beneficial microbes, including paraprobiotics (killed microbes), psychobiotics (originally defined as probiotics with a mental health benefit, but the definition has recently been expanded to any exogenous influence whose effect on the brain is bacterially-mediated3), synbiotics (probiotics and prebiotics administered simultaneously – a term for which ISAPP is convening another Consensus Panel in 2019), live biotherapeutics, etc, etc.  One site I saw referred to bacteriophage as a prebiotic, using the argument that they can influence a microbiome in a selective manner to achieve a beneficial outcome.  This is surely a good example of where the ISAPP definition could provide clarity since prebiotics have to be utilised in order to qualify for the term. Other terms we often use without an agreed consensus as to their meaning are ‘dysbiotic’ (when we could use disturbed, or different, or disrupted), ‘unculturable’ (when we usually mean ‘not yet cultured as far as I know but I haven’t really tried’), ‘hypothetical genes’ (when we actually mean ‘function unknown’), ‘stability’, ‘resilience’, etc.  It may be useful to have some kind of standardised microbiome dictionary, or an accepted glossary of terms.  This is not a new idea (so few of mine ever are), and Julian Marchesi and Jacques Ravel published a lovely short paper to this effect in 20154.  The World Microbiome Day website also has a very short Glossary5.

Obviously, words must be the servants of the author and should not restrict expression or limit our ideas, and in many instances context can make it abundantly clear what meaning is intended by the author.  But in general, a strict definition is not the enemy of understanding, but makes it easier for author and reader to share common ground.

Who should create and curate such a Microbiome Glossary?  Ideally it would be interactive, perhaps along the line of a wiki page, where people could provide their newly coined terms along with a strict definition and arrive at a consensus for commonly used terms.  Reviewers of journal papers and reviews could help, by challenging authors on what terms they use, and whether or not they are the appropriate ones.

Meanwhile, I have to go back to the lab to do some comprehensive metagenomics on the gut microbiome – by which I mean that a competent scientist who works with me is going to go into the lab and conduct a particular form of 16s rRNA gene analysis to profile the more abundant members of the bacteriome of a portion of a faecal sample which has been collected, stored and extracted according to our in-house protocols.  Obviously!

 

  1. Hill et al., 2014. Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the scope and appropriate use of the term probiotic.  Nat. Rev. Gastroenterol. Hepatol. 11, 506.
  2. Gibson et al., 2017. Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics.  Nat. Rev. Gastroenterol. Hepatol. 14, 491.
  3. Sarkar et al., 2016. Psychobiotics and the Manipulation of Bacteria–Gut–Brain Signals.  Trends in Neurosciences 39, 763
  4. Marchesi JR and J. Ravel. 2015. The vocabulary of microbiome research: a proposal.  Microbiome 3, 31
  5. http://worldmicrobiomeday.com/glossary-of-microbiome-terms/

Importance of understanding probiotic mechanisms of action

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

By Prof. Sarah Lebeer, Universiteit Antwerpen, Belgium

At present, we do not fully understand the mechanistic basis of many well established probiotic health benefits. This limits our ability to predict which probiotics are likely to be effective.

For instance, prevention of antibiotic-associated diarrhea and necrotizing enterocolitis are health benefits that are well substantiated by meta-analyses, which combine results on many probiotic strains. But what the effective strains have in common from a mechanistic perspective is not known. We cannot yet pinpoint one or a few molecules produced by these strains that might drive the clinical effects. This is likely due to interplay between both host and probiotic factors. These health conditions are complex pathologies and the probiotic strains are living micro-organisms likely working through multiple mechanisms and molecules.

This is in contrast to some more clearly defined situations. Lactose maldigestion results from a deficiency in the enzyme lactase, which is required for converting lactose to glucose and galactose in the small intestine. If lactose is not broken down, it reaches the colon and is fermented by the gut microbiota, leading to symptoms. Some probiotic bacteria (including those present in yoghurt) contain lactase, which can reduce the typical symptoms of lactose digestion.

Several colleagues and I published a recent paper (Kleerebezem et al. 2019) discussing the importance of understanding mechanisms of action. We argue that such knowledge will enable: “(i) selection of more effective probiotic strains; (ii) optimization of probiotic product manufacturing and quality assurance, (iii) improved design of probiotic formulation, and (iv) support of the design of effective clinical trials with the best chance of realizing benefits to human health.”

While knowledge of the mechanism of action is not necessary for translation to effective products, it provides important insights that can improve actions throughout the translational pipeline.

The strain-specificity of different mechanisms of action is another point that will be clarified by future mechanism-focused research. Different probiotic strains clearly express different mechanisms, but some mechanisms are also shared (Sanders et al. 2018). How different host- and probiotic-specific factors interact to achieve a clinically successful intervention remains to be unraveled.

kelly_swanson

ISAPP plans consensus panel on synbiotics

/in featured, News /by Mary Ellen Sanders

The term ‘synbiotic’ – which refers to a substance that combines both a probiotic and prebiotic – lacks a concise, modern definition. Stakeholders, including researchers, regulatory experts, consumers, marketers, industry scientists and healthcare providers, would benefit from a clear definition of synbiotics, a concise review of the state of the science of synbiotics, and a clarification of what kinds of products fall under the synbiotic scope.

ISAPP will convene a panel of top scientific experts on May 13th in Antwerp to develop a consensus around this topic. This panel will be chaired by Prof. Kelly Swanson, The Kraft Heinz Company Endowed Professor in Human Nutrition, Professor in the Department of Animal Sciences and Division of Nutritional Sciences, and Adjunct Professor in the Department of Veterinary Clinical Medicine at the University of Illinois at Urbana-Champaign. Prof. Swanson is known for his research on the mechanisms by which nutritional interventions affect health outcomes in both animals and humans. He is a co-author of the 2017 ISAPP consensus statement on the definition and scope of prebiotics.

As with the ISAPP consensus statements on probiotics (Hill et al. 2014) and prebiotics (Gibson et al. 2017), ISAPP is working with Nature Reviews Gastroenterology and Hepatology to publish the outcome of the synbiotics panel.

ISAPP’s focus on the science of probiotics and prebiotics makes it uniquely positioned to champion a panel of experts to discuss the definition and scientific justification for synbiotics.

The consensus panel members are:

  • Kelly Swanson, University of Illinois at Urbana-Champaign, USA (chair)
  • Glenn Gibson, University of Reading, UK
  • Gregor Reid, University of Western Ontario, Canada
  • Kristin Verbeke, University of Leuven (KU Leuven), Belgium
  • Nathalie Delzenne, Université Catholique de Louvain, Belgium
  • Robert Hutkins, University of Nebraska-Lincoln, USA
  • Karen Scott, University of Aberdeen, UK
  • Raylene Reimer, University of Calgary, Canada
  • Hannah Holscher, University of Illinois at Urbana-Champaign, USA
  • Meghan Azad, University of Manitoba, Canada
  • Mary Ellen Sanders, ISAPP

I have IBS – should I have my microbiome tested?

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

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

I am a gastroenterologist and specialize in what is referred to as “neurogastroenterology” – a rather grandiose term to refer to those problems that arise from disturbances in the muscles or nerves of the gut or in the communications between the brain and the gut.  Yes, the gut has its own nervous system – as elaborate as the spinal cord – which facilitates the two-way communication between the brain and gut.

The most common conditions that I deal with are termed functional gastrointestinal disorders (FGIDs) among which irritable bowel syndrome (IBS) is the most frequent. I have cared for IBS sufferers and been involved in IBS research for decades. But while much progress has been made, IBS continues to be a frustrating problem for many sufferers. No, it will not kill you, but it sure can interfere with your quality of life. Dietary changes, attention to life-style issues (including stress) and some medications can help but they do not help all sufferers all of the time. It is no wonder, therefore, that sufferers look elsewhere for relief. Because, symptoms are commonly triggered by food, there are a host of websites and practitioners offering “food allergy” testing even though there is minimal evidence that food allergy (which is a real problem, causes quite different symptoms and can be fatal) has anything to do with IBS. Nevertheless, sufferers pay hundreds of dollars out of pocket to have these worthless tests performed.

Now as I sit in clinic I am confronted by a new phenomenon – microbiome testing. I cringe when a patient hands me pages of results of their stool microbiome analysis. Has their hard-earned money been well spent? The simple answer is no. Let me explain. First, our knowledge of the “normal” microbiome is still in evolution so we can’t yet define what is abnormal – unless it is grossly abnormal. Second, we have learned that many factors, including diet, medications and even bowel habit can influence the microbiome.  These factors more than your underlying IBS may determine your microbiome test results.  Third, while a variety of abnormalities have been described in the microbiome in IBS sufferers, they have not been consistent. Someday we may identify a microbiome signature that diagnoses IBS or some IBS subgroups – we, simply, are not there yet. Indeed, our group, together with researchers in Ireland and the UK, are currently involved in a large study looking at diet, microbiome and other markers in an attempt to unravel these relationships in IBS.

There have been a lot of exciting developments in microbiome research over the past few years. One that has caused a lot of excitement comes from research studies showing that the microbiome can communicate with the brain (the microbiome-gut-brain axis). It is not too great a leap of faith to imagine how such communications could disturb the flow of signals between and brain and the gut and result in symptoms that typify IBS. We also know that some antibiotics and probiotics can help IBS sufferers. Indeed, about 10% of IBS suffers can date the onset of their symptoms to an episode of gastroenteritis (so-called post-infection IBS). All of this makes it likely that the microbiome has a role in IBS; what we do not know is exactly how. Is the issue a change in the microbiome? Is it how we react to our microbiome? Is it the bacteria themselves or something that they produce? Could our microbiome pattern predict what treatments we will respond to? These are fascinating and important questions which are being actively studied. In the meantime, I feel that microbiome testing in IBS (unless conducted as part of a research study) is not helpful.

 

Related Reading:

Microbiome analysis: hype or helpful?

Why microbiome tests are currently of limited value for your clinical practice

Here’s the poop on getting your gut microbiome analyzed

 

ISAPP’s 2019 Annual Meeting Program Released

/in featured, News /by Mary Ellen Sanders

ISAPP is pleased to announce the release of the official program for its 2019 Annual Meeting, scheduled for May 14-16, 2019, in Antwerp. Unlike the 2018 ISAPP meeting in Singapore, which was an open registration meeting, the 2019 event will comprise only invited academic experts and industry scientists from member companies. For program details, see the meeting website.

The 2019 program offers a strong lineup of probiotic, prebiotic and microbiome presentations. Featured topics include human milk oligosaccharides, learnings from the Flemish Gut Flora project, and leveraging political infrastructure to advance important science and public health messaging. Half-day breakout discussion groups are scheduled for May 15th, covering timely topics relevant to both industry and clinical practice, such as recommended dietary allowance (RDA) for live cultures, and the use of probiotics and prebiotics as adjuncts to drugs. Prof. Glenn Gibson will host the “fishbowl”, a session designed to integrate audience and experts’ perspectives in an interactive format; this year’s topic is: What can scientists and industry do to spring probiotics and prebiotics into mainstream health management?

For companies interested in participating in this meeting, now’s the time to join ISAPP and become part of its active industry advisory committee. Details on industry membership can be found here. ISAPP’s industry members help ISAPP achieve its mission of advancing the science of probiotics and prebiotics—see  here for a summary of our latest accomplishments.

Students and fellows will constitute an important presence at the annual meeting. Members of the ISAPP students and fellows association (SFA) will be keen participants, having organized a poster session as well as two SFA oral presentations. The group will also run a half-day parallel student-focused program.

The local host for ISAPP’s 2019 Annual Meeting, Prof. Sarah Lebeer, University of Antwerp, is excited to welcome her ISAPP colleagues to Antwerp. The history of Antwerp goes back to the 4th century and today the city remains an important European cultural and trade center. ISAPP Annual Meeting participants are invited to join a riverboat trip and dinner to get to know this historic city.

 

 

probiotics calendar

Probiotics in the Year 2018

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

Prof. Daniel Merenstein MD, Georgetown University School of Medicine

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

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

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

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

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

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

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

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

 

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

Do you know the difference between fiber and prebiotics? A new ISAPP infographic explains

/in featured, News /by Mary Ellen Sanders

Many people think prebiotics and fiber are the same thing. But according to leading scientists, they’re not. Fiber and prebiotics are both dietary tools to promote health, but you need to know some key differences between these two types of nutrients in order to make the best decisions for your health.

This new infographic summarizes what fiber and prebiotics have in common, and how they are different (including their distinct effects on the gut microbiome). And most importantly of all: you’ll learn how to get them in your daily diet so you can take advantage of their proven health benefits.

The infographic was written by ISAPP board of directors with input from several outside experts and coordinated by the ISAPP science translation committee.

ISAPP Releases a Mission-Based Summary of 2018 Activities

/in featured, News /by Mary Ellen Sanders

The mission of ISAPP is to advance scientific excellence in probiotics and prebiotics. ISAPP is an independent, science-based voice for the probiotic and prebiotic fields. The newly released short summary details ISAPP’s accomplishments in 2018 based around the core value of Stewardship, Advancing the Science, and Education. See here for the summary, also featuring ISAPP’s recent publications.

Thank you to the ISAPP Board of Directors for their leadership, dedication and scientific expertise, making these accomplishments possible.

Thank you to the Industry Advisory Committee for their ongoing support of ISAPP, providing the resources needed for ISAPP to accomplish its mission to advance the science of probiotics and prebiotics.

Click here to see the 2018 Summary.

See all Annual Reports and Short Summaries here.

YOGURITO –the Argentinian social program with a special yogurt

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

Dra. María Pía Taranto, CERELA-CONICET, Argentina and Prof. Seppo Salminen PhD, University of Turku, Finland

It is widely accepted that technologies play a central role in the processes of social change. The Argentinian experience has documented that yogurt can be a promising tool for promoting social development.  The program is called “Scholar Yogurito, the social probiotic” and the probiotic product is called “Yogurito”. This social program began with the development of a probiotic food, in the form of yogurt. This yogurt contains the probiotic strain Lactobacillus rhamnosus CRL1505, whose functional and technological characteristics are widely documented by CERELA-CONICET researchers. These researchers conducted clinical studies that demonstrated that the consumption of this probiotic product improves natural defenses and prevents respiratory and intestinal infections, the infectious events of greatest relevance in childhood. The “Yogurito Social Program” benefits some 300,000 schoolchildren in the province of Tucumán and some 50,000 in other provinces and municipalities of Argentina. This social transfer project, implemented in 2008 in the province of Tucumán, is a paradigm of interaction between the scientific sector, the manufacturing sector and the state, to improve the quality of life of highly vulnerable populations.

The social and economic implications for such translational research are significant and especially pertinent for people living in poverty, with malnutrition and exposure to environmental toxins and infectious diseases including HIV and malaria. This example of probiotic applications illustrates the power of microbes to positively impact the lives of women, men, and children, right across the food value chain. The researchers are looking for grants that would enable them to compare outcomes of schools given Yogurito to schools with no participation in the program.

 

Additional reading:

Julio Villena, Susana Salva, Martha Núñez, Josefina Corzo, René Tolaba, Julio Faedda, Graciela Font and Susana Alvarez. Probiotics for Everyone! The Novel Immunobiotic Lactobacillus rhamnosus CRL1505 and the Beginning of Social Probiotic Programs in Argentina. International Journal of Biotechnology for Wellness Industries, 2012, 1, 189-198.

Reid G, Kort R, Alvarez S, Bourdet-Sicard R, Benoit V, Cunningham M, Saulnier DM, van Hylckama Vlieg JET, Verstraelen H, Sybesma W. Expanding the reach of probiotics through social enterprises. Benef Microbes. 2018 Sep 18;9(5):707-715. doi: 10.3920/BM2018.0015.

 Senior Researcher Maria Pia Taranto and the Yogurito product

 

Maria Luz  Ovejero, a teacher at Primary School 252 Manuel Arroyo y Pinedo, explains probiotics to 4-6 year old children in Tucuman province in Argentina

Where does our food come from – why should we care?

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

Dr. Karen Scott, The Rowett Institute, University of Aberdeen,  Scotland

The food we eat feeds our microbes, gives us energy and nutrition, and keeps us healthy. The choices we make about our food clearly affects our health, but also has a huge effect on the world around us. We need to make more effort to choose correctly.

Sometimes it seems that everywhere we look, someone has an opinion on what we should be eating. Television is full of programmes telling us how and what to cook – suitable for a range of abilities. In supermarkets we are continually targeted with special offers and promotions, encouraging us to buy things we do not need, that are not on our shopping list. In magazines there are page long adverts, letting us know many reasons why our lives will be enriched if we purchase product Y, and perhaps even how we will be missing out if we do not. Even newspapers print articles telling us which foods are “super” this week, and will endow us with youthful skin, long life, and/or a svelte figure. Next week there will be another article with a new superfood, and one demoting last week’s superfood to the “standard” food, or even demonising it completely.

Yet even with all this focus on what we should be eating, do we really care about where our food comes from? Shouldn’t we really be more concerned with the provenance and sustainability of our food, rather than whether it is “super”?

Quinoa is a grain with a high nutrient content, high protein content (including all nine essential amino acids) and is also a source of some essential micronutrients and vitamins. By popular measures, a “superfood”. Quinoa is primarily grown in South America (Peru, Chile and Bolivia) where it is an important dietary staple. The increased demand and resultant export of quinoa has contributed considerably to the Peruvian economy. On the other hand, the cost increases associated with the increased worldwide demand means that the local Andean population now struggle to afford to include this healthy food in their own diets. Additionally the enlarged land area now used for quinoa production has reduced the amount of land available to grow alternative crops, and this reduced diversity has a negative impact on soil quality and on wildlife. Not so “super”.

Another healthy food-fad with a negative environmental impact is avocado. The current demand for avocados as part of the ‘green smoothie’ revolution has resulted in considerable deforestation in Mexico to make way for avocado plantations. Avocado trees also need a lot of water, which, given that they are frequently grown in climates with problems of drought, is clearly not sustainable.

The other factor is price – we are constantly persuaded that we should be looking for the best deal, getting those “2-for-1 offers”, or buying our food in the specific supermarket “saving you the most on your weekly shop”. The reality is that we spend a smaller % of our income on food today than we ever have – and this is not because we eat less, far from it. But if we think about it, it is not the large supermarket that loses money when it introduces offers. Buy one get one free offers on, for example fruit, usually mean that the farmer is only getting paid for one of every two oranges sold. Is this fair? If you ask a people doing their food shopping if they think that milk should cost more than water – most people would say “yes of course”. Yet at the milk counter in the supermarket they automatically reach for the “special offer”, cheapest product. Sometimes the farmer gets paid less for the milk he sells the supermarket than it costs to produce. Again if you asked people in the shop if they thought this was fair, they would no doubt say no, but they still reach for the “special offer”, cheapest product. This is already driving smaller dairy farmers out of business. Is this what we want? We as consumers, as well as the supermarkets, have to take responsibility.

Similarly with meat products and eggs. Most people, when asked about the best and most humane ways to look after animals on farms, prefer the low density, outside methods often depicted in children’s story books. Yet when we reach the meat counter in the supermarket we are more likely to reach for the cheaper product than the one from the farm which assures humane conditions, but which may cost twice as much. Such farming methods are more expensive to run, so the products have to cost more. We have to make more effort to include our instinctive morality when we are actually making purchases of food.

We have also become accustomed to being able to buy anything, at any time of year. If we want to buy fruit that is out-of-season in our own country, it will be in-season somewhere else and can be flown across the world for display in our local supermarket. When we ask people if they care about global warming – most will agree that it is a big problem, threatening the world. Yet they will buy specific fruits or vegetables that have been flown 1000s of miles, in aeroplanes contributing CO2 emissions, without a thought. Locally produced food, eaten in season, completely avoids this non-essential contribution to global warming.

Feeding our microbes is easy – they just eat our leftovers. But perhaps we also need to think about them. Food produced in intensively farmed conditions contains more pesticide and antibiotic residues than foods produced less intensively. Depending where we live, imported foods may have fewer controls on additives and production methods than those produced locally. Although specific studies have not been carried out to gauge the effect of such residues on our microbes, it is likely that there will be an effect. The healthy compounds in fruits develop best when they are allowed to ripen on the bush/tree and are not harvested unripe and then transported across the world. Our ancestors ate fresh foods in season and produced locally. People living in remote areas of the modern world without access to the diverse range of foods in a supermarket have a more diverse, healthy microbiota than those of us consuming “western diets”. Our microbes do not need, and potentially do not want, intensively produced foods.

Many of us are in the fortunate position of being able to afford to pay a bit more for our food, and thus to support it being produced in the way we would prefer if we stopped to think about it. This is why we DO have to stop to think and not automatically reach for the cheapest product on the shelf.  If we do not support farmers who are producing food in the most humane way, they will go out of business and we will be left with no choice but to buy mass-produced, often imported, food. Is this really what we want?

We have become so accustomed to paying less for our food, and looking for bargains, that we seem to care less about the quality and provenance than the price. Unless we change our outlook we will affect whole populations and environments forever. We need to stop the disconnect between our thoughts about what our foods should be, and what we actually buy, and we need to do it before it is too late.