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Precision approaches to microbiota modulation: Using specific fiber structures to direct the gut microbial ecosystem for better health

By now, hundreds of scientific articles show the differences in gut microbiota composition and function between states of health and disease, leading to the idea that gut microbiota modulation is a promising way to achieve better health. But in practice, changing the complex community of microbes in the gut has proved challenging—the gut microbiota of the average adult is remarkably stable.

When it comes to diet, non-digestible carbohydrates are the main way to provide nutritional support to microbial populations and to modulate these communities, either in composition or in function. Can these dietary fibers be used to modulate the gut microbiota in a precise manner, with the aim of inducing certain health effects?

Prof. Jens Walter of APC Microbiome Ireland addressed this topic in a plenary lecture at the ISAPP 2020 annual meeting, titled: Precision microbiome modulation through discrete chemical carbohydrate structures.

Walter sees the gut microbiota as an complex ecological community of interacting microbes that is remarkably stable in healthy adults (albeit with a high degree of inter-individual variation). In order to precisely modulate gut microbiomes through diet, scientists must consider the ecological principles that shape these communities and determine how they function.

In the lecture, Walter introduced a perspective for using discrete fiber substrates to precisely modulate gut microbiota – a framework first articulated in a 2014 paper by Hamaker and Tuncil. According to this framework, gut microbiomes can be precisely manipulated, whether to achieve a certain microbiota composition or the production of health-relevant metabolites, through the use of specific fiber structures that are aligned with microbes that have the ability to utilize them. Walter explains some of the main challenges of the framework, which relate to the vast inter-individual differences in the gut microbes that are present, and their response to fiber; and discovering the exact dose of a fiber required for reliable changes in a person’s gut microbiota.

At the core of the presentation is a study by the Walter Lab that systematically tested the framework through a human dose-response trial using resistant starches with slight differences in their chemical structure. The findings of the study, which were published this year, illustrate how this ecological concept can be successfully applied. This shows the colonic microbiota can be successfully shaped in a desired manner with discrete dietary fiber structures.

See Prof. Walter’s presentation in full here.

New publication co-authored by ISAPP board members gives an overview of probiotics, prebiotics, synbiotics, and postbiotics in infant formula

For meeting the nutritional needs of infants and supporting early development, human milk is the ideal food—and this is reflected in breastfeeding guidelines around the world, including the World Health Organization’s recommendation that babies receive human milk exclusively for the first six months of life and that breastfeeding be continued, along with complementary foods, up to two years of age or beyond. In certain cases, however, breastfeeding is challenging or may not even be an option. Then, parents rely on alternatives for feeding their infants.

A group of scientists, including three ISAPP board members, recently co-authored an article in the journal Nutrients entitled Infant Formula Supplemented with Biotics: Current Knowledge and Future Perspectives. In the review, they aimed to highlight the new technologies and ingredients that are allowing infant formula to better approximate the composition of human milk. They focused on four types of ingredients: probiotics, prebiotics, synbiotics, and postbiotics.

Co-author Gabriel Vinderola, 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) in Santa Fe, Argentina says, “Modern technologies have allowed the production of specific microbes, subtrates selectively used by the host microbes, and even non-viable microbes and their metabolites and cell fragments—for which scientific evidence is available on their effects on infant health, when administered in adequate amounts. Thus, this current set of gut modulators can be delivered by infant formula when breastfeeding is limited or when it is not an option.”

The authors say a well-functioning gut microbiota is essential for the overall health and proper development of the infant, and components of human milk support the development of this microbiota. They list important human milk components and the novel ingredients that aim to mimic the functions of these components in infant formulas:

  • Human milk oligosaccharides (HMOs)

HMOs are specialized complex carbohydrates found in human milk, which are digested in the infant colon and serve as substrates for beneficial microbes, mainly bifidobacteria, residing there. In recent years, prebiotic mixtures of oligosaccharides (e.g. short-chain GOS and long-chain FOS) have been added to infant formula to recapitulate the effects of HMOs. But now that it’s possible to produce several types of HMOs synthetically, some infant formulas are enriched with purified HMOs: 2’-fucosyllactose (2’FL) or lacto-N-neotetraose (LNnT). Even 3′-galactosyllactose (3′-GL) can be naturally produced by a fermentation process in certain infant formulas.

  • Human milk microbiota

Human milk has a complex microbiota, which is an important source of beneficial bacteria to the infant. Studies support the notion that the human milk microbiota delivers bioactive components that support the development of the infant’s immune system. Probiotic strains are sometimes added to infant formula in order to substitute for important members of the milk microbiota.

  • Bacterial metabolites

Human milk also contains metabolic byproducts of bacteria called “metabolites” in addition to the bacteria themselves. These components have not been fully studied to date, but bacterial metabolites such as butyrate and other short-chain fatty acids may have important health effects for the overall development of the infant. A future area of nutritional research is likely to be the addition of ‘postbiotics’ — non-viable cells, their metabolites and cell components that, when administered in adequate amounts, promote health and well-being — to infant formulas. (ISAPP convened a scientific consensus panel on the definition of postbiotics, with publication of this definition expected by the end of 2020.)

 

The precise short- and long-term health benefits of adding the above ingredients to infant formula are still under study. One pediatric society (the ESPGHAN Committee on Nutrition) examined the data in 2011 and at that time did not recommend the routine use of infant formulas with added probiotic and/or prebiotic components until further trials were conducted. A systematic review concluded that evidence for the health benefits of fermented infant formula (compared with standard infant formula) are unclear, although improvements in infant gastrointestinal symptoms cannot be ruled out. Although infant formulas are undoubtedly improving, review co-author Hania Szajewska, MD, Professor of Paediatrics at The Medical University of Warsaw, Poland, says, “Matching human milk is challenging. Any alternative should not only match human milk composition, but should also match breastfeeding performance, including how it affects infant growth rate and other functions, such as the immune response.”

 

Can the microbiota help protect against viral infections? Summary of an ISAPP discussion group

By Drs. Karen Scott, University of Aberdeen, and Sarah Lebeer, University of Antwerp

As part of the ISAPP virtual annual meeting 2020, around 85 members of the ISAPP community joined us in a Zoom discussion forum to discuss the topic: “Do our resident microbes help protect against viral infections?” A scientific perspective on this topic is especially important during the COVID-19 pandemic, when many members of the general public are wondering about actions (if any) they can take to protect themselves before a SARS-CoV-2 vaccine becomes widely available.

We introduced the topic and were joined by several invited experts, who also gave short presentations:

  • Joel Dore (INRAE France)
  • Tine Licht (Technical University of Denmark)
  • Mary O’Connell-Motherway (APC Microbiome, Cork)

The ensuing conversation, open to all participants, was wide-ranging, starting with the gut microbiota and expanding to include the microbiota at other body sites, and the effects of the gut microbiota around the body gut via transport of metabolites. Here are some of the main take-home messages from this discussion.

Components of the microbiota (bacteria, fungi, archaea, viruses and others) at a body site interact with each other. Although scientists often study one component of the (gut) microbiota at a time, members of the microbiota from different kingdoms interact with each other in ways that can be positive or negative for the host. In particular, specific activities of bacteria can be widespread, frequent or rare among members of the microbiota – and it is often the rare activities that have important impacts on the course of a disease: e.g. specific antimicrobial agents produced by some bacteria prevent Salmonella infections in pigs and cure mastitis in cows.

Mechanistic work shows bacteria in the microbiota can prevent, eliminate or promote viral infections. Studies have shown some microbes can prevent attachment of viruses to cell surfaces by offering alternative receptors. In contrast, virus particles can utilise other bacterial cells to “mask” them and facilitate entry into host cells. Other bacteria can stimulate the immune system to promote elimination of a viral infection, while under specific circumstances this same immune activation may promote viral infection. When it comes to the microbiota of the respiratory tract, studies have shown its bacterial members play a crucial defensive role. Probiotics that are already shown to be effective against other viral upper respiratory tract infections may have promise for COVID-19 (either for preventing infection or enhancing recovery), and currently studies are underway to investigate these.

Probiotics or prebiotics could be useful adjuncts to vaccination, but they are not likely to become a reality for COVID-19. Scientists are perennially interested in the topic of vaccine efficacy, and some probiotics have been shown to increase efficacy for widely available vaccines in certain populations. But in the current pandemic, developing a safe and effective vaccine (or vaccines) is the primary concern. Testing the possibility of probiotic or prebiotic combination therapies would be secondary, since the necessary testing would take longer in order to evaluate the adjuvant potential of different probiotic strains. Because the expression of cell surface molecules that can mediate adjuvant activity is strain-dependent, screening and selecting the best strains would probably take too long to become a reality for COVID-19. Certainly, participants agreed that introduction of a safe, effective vaccine was the priority, without any delays to test out ‘extras’.

A scientific rationale exists for maintaining gut microbiota diversity in order to reduce the development of diseases which, as “underlying health conditions”, may result in more severe COVID-19 outcomes. It is clear that individuals with certain underlying health conditions—related to the central nervous system and gastrointestinal system, and to metabolic and immunological dysfunction—tend to experience a more severe disease, with worse outcomes, following SARS-CoV-2 infection. Many of these conditions are also associated with a gut microbiota that is different from that of healthy controls. Research consistently shows that individuals with metabolic disease, for example, have a less diverse, lower ‘richness’ microbiota, which is often linked to increased intestinal permeability, higher gut inflammation and more oxidative stress throughout the body. This increased oxidative stress then exacerbates the microbial dysbiosis, causing more inflammation and increased intestinal permeability – creating a vicious cycle effect. This cycle is linked with obesity and metabolic disorders. In healthy individuals who are at risk of developing such conditions, the diversity of the existing resident microbiota may be increased by the application of prebiotics or synbiotics, included within a healthy, diverse, high-fibre diet. These approaches may improve bacterial fermentation in the large intestine, resulting in increased production of important bacterial metabolites that help regulate host metabolism, including short-chain fatty acids.

Until a SARS-CoV-2 vaccine is available, supporting a diverse and complex gut microbiota through diet may contribute to maintaining health in at-risk populations. Despite the intense worldwide scientific efforts and collaborations, it is unlikely that an effective vaccine against COVID-19 will be widely available soon. In the meantime, we have to protect ourselves and our local ‘at-risk’ populations as best we can. We are learning more and more about the mechanisms of dietary fibre’s health effects, in which gut bacteria play a major role. Evidence suggests that keeping our gut microbiota as complex and diverse as possible by consuming a high-fibre diet (supplemented by fermented foods, probiotics and prebiotics) might help mitigate susceptibility to infections in general.

New synbiotic definition lays the groundwork for continued scientific progress

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.

ISAPP Conference Session

New Probiotic and Prebiotic Society Among Ibero-American Countries

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

On February 8, 2019, within the framework of the X Workshop of the Spanish Society for Microbiota, Probiotics and Prebiotics (SEMiPyP), the Ibero-American Society for Microbiota, Probiotics and Prebiotics (SIAMPyP) was established, with the aim of enhancing communication among researchers and clinicians from Spain, Portugal, Mexico and several South American countries.

SIAMPyP will build on 10 years of collaboration among experts from both sides of the Atlantic, who have come together as SEMiPyP with a common interest in the potential of the microbiome in human health and disease, in promoting and disseminating scientific discovery, in rigor of scientific evidence, and facilitating future research to the benefit of Ibero-America and the globe.

Currently, the plan is for SIAMPyP to convene biennial meetings, the first being planned for March 2021 (dependent on the state of the pandemic) in Madrid and subsequently in 2023 in Mexico City.  Academic sessions of basic and clinical science will be presented in this context, taking advantage of common languages (Spanish and Portuguese) to establish synergies in Latin American countries and the Iberian Peninsula.

The SIAMPyP has fostered connections with other international academic and scientific societies with knowledge in microbiota, probiotics and prebiotics in the pediatric, gastroenterology and neurogastroenterology fields of various Spanish and Portuguese speaking countries, as well as with ISAPP. Likewise, it has the support of research-oriented pharmaceutical and food industries that seek to modulate the microbiota to benefit human health in various clinical settings with probiotics, prebiotics and postbiotics.

The current board of directors of SIAMPYP is chaired and represented by doctors from both continents, including the well-known scientists Dr. Francisco Guarner (former ISAPP board member, from Spain), Dr. Guiilermo Alvarez-Calatayud (Spain), Dr. Luis Peña (Spain), as well as Dr. Aldo Maruy (Peru), Dr. Christian Boggio (Argentina) and Dr. Ana Teresa Abreu (Mexico), in addition to members and consultants who support and strengthen it, divided by region, with Latin America being a region with several countries.

SIAMPyP welcomes scientific partners from all Ibero-American countries, at no cost. See www.siampyp.org for further information.

Hear from ISAPP board members in webinar covering probiotic and prebiotic mechanisms of action

This webinar is now complete — see the recorded version here.

New probiotic and prebiotic trials are published all the time – but when they show a health benefit, what do we know about the basic science behind it?

To provide insight into this topic, ISAPP has partnered with the International Life Sciences Institute (ILSI) Europe on a free webinar titled Understanding Prebiotic and Probiotic Mechanisms that Drive Health Benefits. This webinar helps scientists, members of the public, and media take a deep dive into what we know about the mechanisms of action of probiotics and prebiotics.

The live webinar is scheduled for Thursday, September 17, 2020 from 3 – 4:15pm Central European Time.

Short, 10-minute perspectives will be provided by the following top experts:

  • Prof. Sarah Lebeer, University of Antwerp, Belgium
  • Prof. Colin Hill, University College Cork, Ireland
  • Prof. Karen Scott, University of Aberdeen, UK
  • Prof. Koen Venema NUTRIM School of Nutrition and Translational Research in Metabolism, Venlo, The Netherlands

The presentations will be followed by a 35-minute live Q&A session, enabling participants to probe deeper into the science behind mechanisms of probiotics and prebiotics.

ILSI Europe is a non-profit organization that aims to improve public health and well-being from a science-based approach.

To learn more about probiotic mechanisms of action in advance of the webinar, see ISAPP’s blog post here.

Early career researchers discuss the future of probiotics and prebiotics in the first ISAPP-SFA paper

By Irina Spacova, ISAPP-SFA 2019 President and postdoctoral fellow at the University of Antwerp, Belgium

Early career scientists play a vital and dynamic role in research, especially in environments supporting their enthusiasm and drive for innovation. ISAPP has long been promoting young researchers through its Students and Fellows Association (ISAPP-SFA), which is a student-led branch of ISAPP established in 2009. The SFA was championed and guided from its inception through June 2020 by Prof. Gregor Reid. Together with ISAPP, the organization encourages diversity and participation through free memberships and ISAPP meeting travel grants open to all students and fellows working in research institutions. Currently, ISAPP-SFA includes 450 members from 50 countries in Asia, Africa, North and South America, Europe, and Australia.

The 2019 ISAPP meeting in Antwerp, Belgium was a milestone for ISAPP-SFA participation with 48 early career attendees from 19 countries. Facilitated by discussion clubs and poster sessions, the Antwerp meeting created an exceptional ‘melting pot’ of ideas. It was clear that young researchers had a lot to say, and the lingering idea of creating the first ISAPP-SFA paper finally took shape during the ISAPP 2019 dinner cruise of the Antwerp Harbor.

Less than a year later, the paper “Future of probiotics and prebiotics and the implications for early career researchers” was accepted in Frontiers in Microbiology, just in time for the 2020 ISAPP meeting. This initiative was driven by the ISAPP-SFA 2019 executive committee members Irina Spacova, Hemraj Dodiya, Anna-Ursula Happel, Conall Strain, Dieter Vandenheuvel, and Xuedan Wang. The core of the paper reflects what we as early career researchers believe are the biggest opportunities and challenges in advancing probiotic and prebiotic science, and summarizes a wide array of promising in vitro, in vivo and in silico tools. We emphasize the important goal of using probiotics and prebiotics to ameliorate global issues, and give examples of current initiatives in developing countries, such as Westernheadseast.ca and Yoba4Life.org. Our advice for early career researchers is to form inter-connected teams and implement the diverse toolsets to further advance the probiotics and prebiotics field.

We had a lot of fun with this paper, but also several challenges. It was not trivial to produce a concise paper with many opinions, techniques and references that would be useful to both young and established researchers. This intercontinental endeavor between young scientists working in Belgium, Japan, Ireland, South Africa, USA, and UK required a lot of early-morning and late-night meetings. Many interactions and discussions were necessary to deliver a novel perspective to add to the many excellent reviews on probiotics and prebiotics already published. Accessibility of the publication was a decisive factor, and one of the reasons why we chose to publish open access in Frontiers in Microbiology. Of course, this publication would not be possible without ISAPP, and we are especially grateful for the input and encouragement from Gregor Reid and Mary Ellen Sanders.

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

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.

 

 

 

ISAPP welcomes three new board members

By Mary Ellen Sanders, PhD, ISAPP Executive Science Officer

ISAPP is pleased to announce that Profs. Kelly Swanson PhD, Daniel Tancredi PhD, and Gabriel Vinderola PhD have joined the ISAPP board of directors. The expertise of these three globally recognized academic experts complements that of the current board members, together comprising a leading global group of distinguished scientific and clinical experts in the fields of probiotics, prebiotics, synbiotics, fermented foods, and postbiotics.

Read more about ISAPP’s newest board members:

Kelly Swanson is the Kraft Heinz Company Endowed Professor in Human Nutrition, a professor in the Department of Animal Sciences and Division of Nutritional Sciences and an adjunct professor in the Department of Veterinary Clinical Medicine at the University of Illinois at Urbana-Champaign. He is an expert in the field of fiber and prebiotics, and brings to ISAPP knowledge of application of these substances to companion and agricultural animals. Kelly, who trained with previous ISAPP Board member, George Fahey, is considered one of the top authorities in animal gut health, microbiome, and nutrition. His research has focused on testing the effects of nutritional intervention on health outcomes, identifying mechanisms by which nutrients impact gastrointestinal microbiota, host gene expression, and host physiology. Kelly served on the prebiotic consensus panel (here), led the ISAPP synbiotics consensus panel, and is lead author on the synbiotics outcome paper, currently in press with Nature Reviews Gastroenterology and Hepatology.

Dan Tancredi is a biostatistician with an appointment as an Associate Professor (full professor starting July 1, 2020) in Residence at UC Davis Department of Pediatrics, and is also with the Center for Healthcare Policy and Research. Dan works extensively on NIH-sponsored research and as an NIH scientific reviewer. He has an extensive record of collaboration with ISAPP; he has served as an invited expert and/or speaker at all but one ISAPP meeting since 2009, providing his perspectives on how to improve the quality and scientific impact of probiotic trials and how to conduct systematic reviews that rigorously and transparently synthesize the evidence from these trials. He has been a co-author on 6 ISAPP papers (here, here, here, here, here, here and here), including a 2020 paper “Probiotics as a Tx Resource in Primary Care” published in the Journal of Family Practice (see New publication gives a rundown on probiotics for primary care physicians). Dan was invited to author the Nature commentary on the landmark probiotics trial by Panigrahi, et al. for reducing newborn sepsis in the developing world—showing his reputation as a trusted voice for assessing the quality of probiotic research.

Gabriel Vinderola is a professor at National University of Litoral, Santa Fe, Argentina and Principal Researcher at CONICET, at the Dairy Products Institute (UNLCONICET). He is an expert in lactic acid bacteria, fermented foods, and probiotics. Gabriel has forged academic collaborations with academic and industrial scientists in numerous countries in Europe and with industrial colleagues in Argentina. He has been active in several countries in South America working with regulators to assure that their actions on probiotic guidelines are science-based, including his recent efforts consulting on guidelines for probiotics for the Codex Alimentarius. He has written blogs for ISAPP, translated ISAPP videos and infographics into Spanish, and was an expert on the ISAPP consensus panel on postbiotics. His research has focused on technological aspects of probiotics (biomass production, dehydration, storage, food matrices) and fermented foods. He is an active public science communicator in Argentina on the topics of probiotics, prebiotics, fermented foods, and the microbiome. See Growing interest in beneficial microbes and fermented foods in Argentina for some examples. Gabriel represents the first ISAPP board member from South America and we anticipate his involvement will help ISAPP expand its presence and connections in Latin America.

 

ISAPP provides guidance on use of probiotics and prebiotics in time of COVID-19

By ISAPP board of directors

Summary: No probiotics or prebiotics have been shown to prevent or treat COVID-19 or inhibit the growth of SARSCoV-2. We recommend placebo-controlled trials be conducted, which have been undertaken by some research groups. If being used in clinical practice in advance of such evidence, we recommend a registry be organized to collect data on interventions and outcomes.  

Many people active in the probiotic and prebiotic fields have been approached regarding their recommendations for using these interventions in an attempt to prevent or treat COVID-19. Here, the ISAPP board of directors provides some basic facts on this topic.

What is known. Some human trials have shown that specific probiotics can reduce the incidence and duration of common upper respiratory tract infections, especially in children (Hao et al. 2015; Luoto et al. 2014), but also with some evidence for adults (King et al. 2014) and nursing home residents (Van Puyenbroeck et al. 2012; Wang et al. 2018). However, not all evidence is of high quality and more trials are needed to confirm these findings, as well as determine the optimal strain(s), dosing regimens, time and duration of intervention. Further, we do not know how relevant these studies are for COVID-19, as the outcomes are for probiotic impact on upper respiratory tract infections, whereas COVID-19 is also a lower respiratory tract infection and inflammatory disease.

There is less information on the use of prebiotics for addressing respiratory issues than there is for probiotics, as they are used mainly to improve gut health. However, there is evidence supporting the use of galactans and fructans in infant formulae to reduce upper respiratory infections (Shahramian et al. 2018; Arslanoglu et al. 2008). A meta-analysis of synbiotics also showed promise in repressing respiratory infections (Chan et al. 2020).

Mechanistic underpinnings. Is there scientific evidence to suggest that probiotics or prebiotics could impact SARS-CoV-2? Data are very limited. Some laboratory studies have suggested that certain probiotics have anti-viral effects including against other forms of coronavirus (Chai et al. 2013). Other studies indicate the potential to interfere with the main host receptor of the SARS-CoV-2 virus, the angiotensin converting enzyme 2 (ACE2). For example, during milk fermentation, some lactobacilli have been shown to release peptides with high affinity for ACE (Li et al. 2019). Recently, Paenibacillus bacteria were shown to naturally produce carboxypeptidases homologous to ACE2 in structure and function (Minato et al. 2020). In mice, intranasal inoculation of Limosilactobacillus reuteri (formerly Lactobacillus reuteri) F275 (ATCC 23272) has been shown to have protective effects against lethal infection from a pneumonia virus of mice (PVM) (Garcia-Crespo et al. 2013). These data point towards immunomodulatory effects involving rapid, transient neutrophil recruitment in association with proinflammatory mediators but not Th1 cytokines. A recent study demonstrated that TLR4 signaling was crucial for the effects of preventive intranasal treatment with probiotic Lacticaseibacillus rhamnosus (formerly Lactobacillus rhamnosus) GG in a neonatal mouse model of influenza infection (Kumova et al., 2019). Whether these or other immunomodulatory effects, following local or oral administration, could be relevant to SARS-CoV-2 infections in humans is at present not known.

Our immune systems have evolved to respond to continual exposure to live microbes. Belkaid and Hand (2016) state: “The microbiota plays a fundamental role on the induction, training, and function of the host immune system. In return, the immune system has largely evolved as a means to maintain the symbiotic relationship of the host with these highly diverse and evolving microbes.” This suggests a mechanism whereby exposure to dietary microbes, including probiotics, could positively impact immune function (Sugimura et al. 2015; Jespersen et al. 2015).

The role of the gut in COVID-19. Many COVID-19 patients present with gastrointestinal symptoms and also suffer from sepsis that may originate in the gut. This could be an important element in the development and outcome of the disease. Though results from studies vary, it is evident that gastrointestinal symptoms, loss of taste, and diarrhea, in particular, can be features of the infection and may occur in the absence of overt respiratory symptoms. There is a suggestion that gastrointestinal symptoms are associated with a more severe disease course. Angiotensin converting enzyme 2 and virus nucleocapsid protein have been detected in gastrointestinal epithelial cells, and infectious virus particles have been isolated from feces. In some patients, viral RNA may be detectable in feces when nasopharyngeal samples are negative. The significance of these findings in terms of disease transmission is unknown but, in theory, do provide an opportunity for microbiome-modulating interventions that may have anti-viral effects (Cheung et al. 2020; Tian et al. 2020; Han et al. 2020).

A preprint (not peer reviewed) has recently been released, titled ‘Gut microbiota may underlie the predisposition of healthy individuals to COVID-19’ (Gao et al. 2020) suggesting that this could be an interesting research direction and worthy of further discussion. A review of China National Health Commission and National Administration of Traditional Chinese Medicine guidelines also suggested probiotic use, although more work on specific strains is needed (Mak et al. 2020).

Are probiotics or prebiotics safe? Currently marketed probiotics and prebiotics are available primarily as foods and food/dietary supplements, not as drugs to treat or prevent disease. Assuming they are manufactured in a manner consistent with applicable regulations, they should be safe for the generally healthy population and can be consumed during this time.

Baud et al. (in press) presented a case for probiotics and prebiotics to be part of the management of COVID-19. Although not fully aligned with ISAPP’s official position, readers may find the points made and references cited of interest.

Conclusion. We reiterate, currently no probiotics or prebiotics have been shown to prevent or treat COVID-19 or inhibit the growth of SARSCoV-2.

 

Connecting with the ISAPP community: Continuing to advance the science of probiotics and prebiotics

By Mary Ellen Sanders PhD, executive science officer, ISAPP

On behalf of the ISAPP board of directors, I am reaching out to the ISAPP community to say we hope you are doing well and taking all the necessary steps in your local communities to remain healthy. At present, the global ISAPP community is physically distant but digitally close, and it is important for us to remain connected and strong.

ISAPP’s activities are as important as ever during this time of increased attention to health, and ISAPP is continuing to uphold its commitment to (1) stewardship, (2) advancing the science, and (3) working with stakeholders. Although our annual meeting, which some of you may have initially planned to attend, has been cancelled, other ISAPP activities are continuing or expanding as follows:

 

  • Building on an important topic for our annual meeting, ISAPP is working to develop a strategic approach to communicating the science on probiotics, prebiotics, fermented foods, synbiotics, and postbiotics.
  • The ISAPP board of directors is pleased that our founding board members, Profs. Gregor Reid and Glenn Gibson, have agreed to remain on the board until the 2021 meeting, in particular to help with long-range planning. New academic board members will also be elected, thereby expanding the board. Working together, we will bring fresh insights, strategies and global reach.
  • The board is considering how best to approach our cancelled meeting. In lieu of re-scheduling this year’s in-person meeting, we are planning to have virtual content covering some of the originally scheduled topics. Some discussion group topics will be carried over to the 2021 meeting, while others will be addressed virtually. We will communicate further on this soon.
  • Our newsletter will continue on a monthly basis.
  • Blog postings, which are aimed at either consumers or scientists, remain timely and popular – with new contributions posted on average every 2-3 weeks. Authored by board members and other experts in the field, these blogs provide a forum for opinions and observations on current issues and controversies as well as insights on global fermented foods, critical regulatory actions, and other relevant topics.
  • ISAPP filed comments on March 17 with the American Gastroenterological Association in response to their draft recommendations for probiotic use in GI conditions.
  • Spearheaded by former ISAPP IAC representative to the board, Dr. Roberta Grimaldi, ISAPP has subtitled several of the most popular ISAPP videos in different languages, including Dutch, French, Spanish, Russian, Japanese, Italian and Indonesian. The first of these should be posted by end of April.
  • The ISAPP-Students and Fellows Association has launched a blog program to provide perspectives by young scientists on issues of importance to the probiotic and prebiotic fields. They have also submitted a manuscript to Frontiers in Microbiology discussing a toolkit needed for their future in science: “Future of probiotics and prebiotics: an early career researchers’ perspective”.
  • Three consensus panels have been conducted since May of 2019. A manuscript arising from the synbiotics panel, chaired by Prof. Kelly Swanson, is in press with Nature Reviews Gastroenterology and Hepatology. The paper summarizing the consensus panel on fermented foods, chaired by Profs. Robert Hutkins and Maria Marco, is almost ready for submission to Nature Reviews Gastroenterology and Hepatology. A manuscript from the consensus panel on postbiotics, chaired by Prof. Seppo Salminen, is currently being written. All three papers are expected to provide clarity to the field with regard to definition of terms, current evidence for health benefits, and impact on stakeholders.
  • In addition to the three consensus panel papers in progress, several different ISAPP endeavors are at different stages of publication:
    • ISAPP vice president, Prof. Dan Merenstein, and executive science officer, Dr. Mary Ellen Sanders, worked with biostatistician and frequent ISAPP contributor, Prof. Dan Tancredi, to summarize evidence for clinical endpoints for probiotics, to be published in the Journal of Family Physicians. This paper, titled “Probiotics as a Tx resource in primary care”. The paper is currently in press.
    • Several ISAPP board members and other participants in a 2019 meeting discussion group recently submitted to Current Developments in Nutrition a paper titled “Dietary Recommendation on Adequate Intake of Live Microbes: A Path Forward”.
    • Marla Cunningham, the current IAC representative to the ISAPP board, has led an effort to compile results from the IAC Learning Forum from the 2019 ISAPP meeting on the topic of matrix effects impacting probiotic and prebiotic functionality. Manuscript in preparation.
    • Colin Hill and I represented ISAPP on a paper under review at Nutrients initiated by IPA-Europe titled “Criteria to qualify microorganisms as ‘probiotic’ in foods and dietary supplements”. This paper consolidates and fleshes out minimum criteria for use of the term ‘probiotic’ published by different groups, including the 2002 FAO/WHO working group, the 2014 ISAPP consensus paper on probiotics, and the 2018 ISAPP discussion group on global harmonization.
    • Glenn Gibson and Marla Cunningham are coordinating a paper titled “The future of probiotics and prebiotics in human health” as an output from their 2019 discussion group.

See here for all published ISAPP papers.

ISAPP board members, 2019 annual meeting

Messages about probiotics and COVID-19

With many conflicting and confusing health messages circulating during this global pandemic, including some criticisms of our field as well as some unsupported claims made by certain individuals and companies, ISAPP will remain an important touchstone for scientifically accurate information. Focusing on health effects is key to demonstrating probiotic and prebiotic efficacy, and we acknowledge that human studies are the ultimate measure of efficacy, but also, elucidating mechanisms of action help us understand how these interventions interface with the immune system and other mediators of health.  Currently, there is some evidence that certain probiotics/prebiotics can reduce the risk of viral infections (discussed in other blog posts here and here), but it is important to remember that they have not been studied specifically for COVID-19 prevention or treatment. This must be acknowledged when communicating with the wider community.

We greatly appreciate the continued support of our IAC members. The ISAPP Board, colleagues, and SFA will continue to chart a course forward in preparation for life after the pandemic. Our intent is to emerge from these experiences more connected and purposeful than ever. We welcome suggestions on how collectively we can endure and strengthen the science and communications that remain foundations of our field.

 

 

 

ISAPP Students and Fellows Association announce blog posting: A new way to share our work and perspectives

By Anna-Ursula Happel, president ISAPP-SFA and postdoctoral fellow at the Faculty of Health Sciences at the University of Cape Town, South Africa

Our professors keep telling us to write, write, write. Reports, papers, reviews, presentations. You can’t blame them as that’s what most of them had to do, and in a competitive environment academic output is critical. But while professors urge students to produce academic outputs, there’s a whole world of research ‘impact’ in a digital world that is beginning to matter for career advancement. To further our reach along this axis, we as the ISAPP-Students and Fellows Association (SFA) are launching a blog platform, which will be regularly updated with perspectives from our members and ideas on recent developments in the field of probiotics and prebiotics.

Our very first blog post centered on an innovative project I never thought I would hear about. Through our SFA meeting, I had heard about the Reid lab from Western University in Canada trying to find a way to prevent the decline of honey bee populations. It was a shock, since their focus for years has been women’s health. My first question to one of Dr. Reid’s students, Brendan Daisley, was: How did this come about? It turns out, the interest in how environmental toxins affect humans led to wondering how it helped really important pollinators. Not such a tangential switch as I’d thought. But what’s this got to do with the field of probiotics and my career?

Well, it shows that probiotics, as the definition states, can be applied to many hosts. It also shows that the microbiome plays a role in the health of insects as well as humans. And many of the study tools are the same – microbiota analysis, bioinformatics, immune responses, etc., yet some are totally different – using Drosophila models, counting larvae, measuring honey volumes. Read more about it here. The lesson for me: think laterally, look at how you can apply your knowledge, think of ecosystem health, and learn lots of basic skills.

Then, I thought to myself, how can research provide me with opportunities for developing leadership, initiatives and skills that are valuable for my careers. How can I gain visibility as an early-career researcher, grow my networks, improve my writing and scientific communication skills and find a platform to highlight projects that matter to me? The new blog will be helpful for all of this.

As members of the SFA, we’re very fortunate to have our voices heard; to organize our own annual meeting (well, except for 2020 when the world shut down); to be exposed to amazing scientists and ground breaking ideas – and to communicate our work, ideas and perspectives to a broad audience through our new blog. Beyond formal networking at annual meetings, the SFA blog now offers a way to stay actively connected throughout the entire year on a more informal platform with our peers, may strengthen ties within the community and even lead to collaborations and career opportunities.

See here for the ISAPP-SFA blog — bookmark it or watch for new posts on social media!

Twitter: @ISAPPSFA

 

Growing interest in beneficial microbes and fermented foods in Argentina

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.

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

By ISAPP board members, compiled by Kristina Campbell

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

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

ISAPP board members, 2019 annual meeting

Available scientific methods and tools

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

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

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

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

Probiotics and prebiotics for microbiome modulation

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

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

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

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

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

Probiotic mechanisms of action

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

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

But in the views of other board members:

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

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

Probiotic and prebiotic applications

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

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

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

Public awareness of probiotics and prebiotics

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

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

But there’s still work to be done:

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

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

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

 

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

Probiotics, Prebiotics and Globobiotics!

By Prof. Colin Hill, PhD, APC Microbiome Ireland, University College Cork, Ireland

Growing up I could not imagine what the world would look like in 2020, but I was convinced it would be amazing. The future was exciting, new planets and solar systems would be explored, diseases would be cured, and everyone would have sufficient food and shelter.  I sometimes think my generation may have been born at the most perfect time in human history (for someone brought up in a first world country at any rate).  We avoided the major world wars which our parents and grandparents endured, we had the benefits of cheap airfares so we could travel the world as tourists, not as armies. Oil was cheap and plentiful. Access to education was widely available. We benefited from antibiotics while they were still effective.  Gender inequalities and racism began to be addressed, even though there is still a long way to go. Computers became commonplace and the internet provided access to almost unlimited sources of information.

But here we are in 2020, and now things do not look so promising. Perhaps cynicism is a natural by-product of getting older, but now the future seems to be presented in apocalyptic terms. Climate change, antibiotic resistance, ageing populations, the paradoxes of increasing obesity and increasing hunger, exploding populations, depletion of natural resources and pollution of our oceans. Watching nature programmes hosted by the incomparable David Attenborough has changed from generating a sense of awe at the wonders of the natural world to a sense of despair as to what we are doing to it. Australia is literally on fire as I write this!  Can our planet survive the onslaught of the projected 10 billion humans by 2050 – each one hungry for a share of finite resources?  Is this really going to be the legacy from my generation to the next – a dystopian future without hope and optimism?

But it’s a New Year and a new decade, and I really want to be hopeful. I am encouraged by the fact that we are gradually beginning to come to grips with this new reality. The UN Sustainable Development Goals provide a roadmap guiding societies and individuals as to how to make a contribution. Attitudes are changing.  Too slowly for sure, but we do seem to be at a tipping point.

But what has this tirade have to do with prebiotics and probiotics, you may ask? Well, everything of course. One of the things that really gives me hope is our growing understanding of how humans are simply occupying space in a microbial world. If we squander our opportunity and destroy our planet in terms of human habitation, microbes will carry on for billions of years to come. We should remember that we can only live on Earth because all of the oxygen we breathe is the result of billions of years of microbial metabolism, that most of the carbon cycling on earth is due to microbes, and that every natural system on Earth depends on microbes. Of course we are also inhabited by a vast ecosystem of microbes (our microbiomes) that are required for our health and wellbeing, and we live in environments shaped by microbes. Understanding this will help us to live in harmony with our microbial world, rather than constantly forcing our poor planet to deliver our short term needs.

How can microbes help us to achieve sustainability and restore a healthy ecosystem? I believe that there are many opportunities. By 2050 I predict that we will be using microbes to restore productivity to land damaged by excessive use and pollution.  We will be using microbes to clean our oceans of plastic waste. We will improve food production without using chemicals, and we will have certainly reduced food waste (it is estimated that one third of all the food we produce on earth is lost to spoilage, much of it caused by microbes). We will have reduced methane emissions by manipulating the rumen microbiome in domesticated ruminants. We can look forward to a world where we can work with microbes to restore and replenish our atmosphere by unlocking the enormous potential of microbes to scavenge and store carbon. We will have reduced our reliance on antibiotics and will have found microbiome-friendly solutions to prevent and treat infection. We will have developed probiotics and prebiotics that will help us to address metabolic diseases, we will be using bacteriophage to sculpt microbiomes, while psychobiotics will be helping to prevent age related loss of brain function.

Given that the world is a microbial ecosystem, I propose that in the same way we can treat our human ecosystems with prebiotics and probiotics to improve or restore health, we can think in terms of developing microbial solutions to improve or restore planetary health. Because we haven’t had one in at least a month, I propose yet another new term; globobiotics. Globobiotics would be defined as “live microorganisms, microbial products or substrates selectively utilized by microorganisms, that are used in a manner that contributes to the sustainability of our planet”.

We’ve had the Stone Age, the Iron Age, the Oil Age, the Atomic Age and the Information Age, welcome to the Microbial Age!

ISAPP helps inform UK Parliament

By Prof. Glenn Gibson, University of Reading, UK

An All Party Parliamentary Group (APPG) was inaugurated in February 2019 in the UK. Its purpose is: “to highlight the role of the gut microbiome in physical and mental health and its capacity to prevent many disorders and improve or slow others; to inform debate about how this will save money for the Treasury and NHS; and to enable communications between interested parties and relevant parliamentarians.” At this stage, over 80 MPs and Peers are currently involved, with Julie Elliott MP as chair.

iStock photo. Credit: Vladislav Zolotovby. Houses of Parliament and Big Ben at sunset, London, UK.

The APPG meetings (6 per year) provide opportunities to share information based on sound science and reality, not hype, so that parliamentarians can take appropriate action when opportunities arise. Specific experts are invited to give the evidence, and the topics discussed so far include:

  • overview of gut microbiology and health
  • potential savings for the NHS/treasury if evidenced probiotics and prebiotics were to be applied to specific clinical states
  • management of gut health in elite athletes
  • benefits of pro- and prebiotics for the wider community

Alan Barnard presents about the APPG at the 2019 ISAPP annual meeting.

Scientific advisors for the APPG are ISAPP board of directors member Dr. Glenn Gibson, Dr. Kirsty Hunter (Nottingham Trent University), and Dr. Gemma Walton (University of Reading).  The secretariat is Alan Barnard. Kirsty and Alan attended the ISAPP 2019 annual meeting in Antwerp to give an overview of the aspirations and format of the APPG. The advisors use ISAPP science to drive the communications, including the organization’s review articles, consensus statements, infographics, videos, and selected working group summaries from the annual meetings. ISAPP anticipates further involvement with the APPG, including a future meeting featuring Gregor Reid’s outstanding probiotic research in the developing world.

 

Prebiotics do better than low FODMAPs diet

By Francisco Guarner MD PhD, Consultant of Gastroenterology, Digestive System Research Unit, University Hospital Vall d’Hebron, Barcelona, Spain

Bloating and visible abdominal distention after meals is a frequent complaint of people suffering from irritable bowel syndrome, but even generally healthy people sometimes have these complaints. These symptoms are thought to be due to fermentation of food that escapes our digestive processes. Some sugars and oligosaccharides end up at the far end of our small bowel and cecum, where they become food for our resident microbes.

To manage this problem, medical organizations recommend antibiotics to suppress the microbial growth in our small intestine (known as small intestinal bacterial overgrowth or SIBO) or avoidance of foods that contain fermentable oligosaccharides, disaccharides, monosaccharides and polyols, called a low “FODMAP” diet. These approaches are generally successful in reducing symptoms, but do not provide permanent relief: symptoms typically return after the strategies are stopped.

Even worse, both approaches are known to disrupt the entire gut microbial ecosystem (not only at small bowel and cecum). Whereas a healthy microbial gut ecosystem has many different types of bacteria, antibiotics deplete them.  The low FODMAP diet deprives beneficial bacteria (such as Faecalibacterium, Roseburia, Bifidobacterium, Akkermansia, Lactobacillus and others) of the food they like to eat, and these species wane (see here).

Prof. Glenn Gibson, a founding father of prebiotic and synbiotic science, suggested that increasing ingestion of certain prebiotics could increase levels of bifidobacteria. These bifidobacteria in turn could prevent excessive gas production since they are not able to produce gas when fermenting sugars.  (Instead, bifidobacteria product short chain fatty acids, mainly lactate, which are subsequently converted to butyrate by other healthy types of bacteria, such as Faecalibacterium and Roseburia.)

Prof. Gibson’s hypothesis was tested in pilot studies where volunteers ingested a prebiotic known as galacto-oligosaccharide (Brand name: Bimuno). Healthy subjects were given 2.8 g/day of Bimuno for 3 weeks. At first, they had more gas: significantly higher number of daily anal gas evacuations than they had before taking the prebiotic (see here). The volume of gas evacuated after a test meal was also higher. However, after 3 weeks of taking the prebiotic, daily evacuations and volume of gas evacuated after the test meal returned to baseline. The microbe populations also started to recover. The relative abundance of healthy butyrate producers in fecal samples increased and correlated inversely with the volume of gas evacuated. This suggested that the prebiotic induced an adaptation of microbial metabolism, resulting in less gas.

Then researchers launched a second study, also in healthy volunteers, to look at how the metabolic activity of the microbiota changed after taking this prebiotic. They showed that adaptation to this prebiotic involves a shift in microbiota metabolism toward low-gas producing pathways (see here).

A third controlled study (randomized, parallel, double-blind), this time in patients with functional gastrointestinal disorders with flatulence, compared the effects of the prebiotic supplement (2.8 g/d Bimuno) plus a placebo diet (mediterranean-type diet) to a placebo supplement plus a diet low in FODMAPs. The study subjects were divided between these 2 diets, which they consumed for 4 weeks (see here). Both groups had statistically significant reductions in symptom scores during the 4-week intervention. Once subjects stopped taking the prebiotic, they still showed improved symptoms for 2 additional weeks (at this point, the study was completed). However, for subjects on the low-FODMAP diet, once the diet was stopped, symptoms reappeared. Very interestingly, these 2 diets had opposite effects on fecal microbiota composition. Bifidobacterium increased in the prebiotic group and decreased in the low-FODMAP group, whereas Bilophila wadsworthia (a sulfide producing species) decreased in the prebiotic group and increased in the low-FODMAP group.

The bottom line conclusion is that a diet including intermittent prebiotic administration might be an alternative to the low FODMAP diets that are currently recommended for people with functional gut symptoms, such as bloating and abdominal distention. Since low FOD MAP diets are low in fiber, the prebiotic option may provide a healthier dietary option.

 

  1. Halmos EP, Christophersen CT, Bird AR, Shepherd SJ, Gibson PR, Muir JG. Diets that differ in their FODMAP content alter the colonic luminal microenvironment. Gut. 2015;64(1):93–100.
  2. Mego M, Manichanh C, Accarino A, Campos D, Pozuelo M, Varela E, et al. Metabolic adaptation of colonic microbiota to galactooligosaccharides: a proof-of-concept-study. Aliment Pharmacol Ther. 2017;45(5):670–80.
  3. Mego M, Accarino A, Tzortzis G, Vulevic J, Gibson G, Guarner F, et al. Colonic gas homeostasis: Mechanisms of adaptation following HOST-G904 galactooligosaccharide use in humans. Neurogastroenterol Motil. 2017;29(9):e13080.
  4. Huaman J-W, Mego M, Manichanh C, Cañellas N, Cañueto D, Segurola H, et al. Effects of Prebiotics vs a Diet Low in FODMAPs in Patients With Functional Gut Disorders. Gastroenterology. 2018;155(4):1004-7.

 

Additional reading:

Halmos EP, Christophersen CT, Bird AR, Shepherd SJ, Gibson PR, Muir JG. Diets that differ in their FODMAP content alter the colonic luminal microenvironment. Gut. 2015;64(1):93–100.

Mego M, Manichanh C, Accarino A, Campos D, Pozuelo M, Varela E, et al. Metabolic adaptation of colonic microbiota to galactooligosaccharides: a proof-of-concept-study. Aliment Pharmacol Ther. 2017;45(5):670–80.

Mego M, Accarino A, Tzortzis G, Vulevic J, Gibson G, Guarner F, et al. Colonic gas homeostasis: Mechanisms of adaptation following HOST-G904 galactooligosaccharide use in humans. Neurogastroenterol Motil. 2017;29(9):e13080.

Huaman J-W, Mego M, Manichanh C, Cañellas N, Cañueto D, Segurola H, et al. Effects of Prebiotics vs a Diet Low in FODMAPs in Patients With Functional Gut Disorders. Gastroenterology. 2018;155(4):1004-7.

Halmos EP, Gibson PR. Controversies and reality of the FODMAP diet for patients with irritable bowel syndrome. J Gastroenterol Hepatol. 2019 Jul;34(7):1134-1142. doi: 10.1111/jgh.14650. Epub 2019 Apr 4.

 

 

new_website

ISAPP launches new website, furthering its mission of educating stakeholders on probiotic and prebiotic science

The ISAPP Board of Directors is pleased to announce the launch of the organization’s new website, which has now gone live at ISAPPscience.org. The website has been redesigned for easier navigation by different stakeholder groups—scientists, consumers, clinicians, and students—enabling ISAPP to continue with its mission of providing accurate, science-based information to its readers about probiotics, prebiotics and fermented foods.

ISAPP Executive Science Officer Dr. Mary Ellen Sanders says, “The scientists comprising the ISAPP Board of Directors realize that consumers and clinicians often struggle to find science-based information on probiotics and prebiotics. ISAPP is working to fill this gap, and we have streamlined our website to help individuals from each of these groups easily find the information they’re looking for.”

At the ISAPP annual meeting held earlier this year, advancing probiotic and prebiotic evidence to a variety of audiences was the topic of a special ‘springboard discussion’ session.

“Probiotic and prebiotic science has made significant progress in the past few decades,” says Sanders, “but this progress has not always been communicated effectively or correctly to those outside the scientific community.” Sanders continues, “Some studies describe an expanding array of health benefits but other studies show the limits of these interventions. Our goal is to counter the abundance of misinformation and be the go-to source of accurate materials about probiotics and prebiotics.”

ISAPP is building its capacity to produce more science-focused educational materials tailored to different audiences. Infographics, some of which are translated into 10 different languages, short videos and targeted blogs are featured on the new website. In coming weeks, ISAPP will make additional resources available on the website, including frequently asked questions about probiotics and prebiotics, and a downloadable white paper for clinicians. Signing up for the ISAPP newsletter is the best way to stay up to date on educational materials being added to the website.

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

Kristina Campbell, Microbiome science writer, Victoria, British Columbia

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

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

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

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

Better health through the gut-brain axis

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

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

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

A clear definition of synbiotics

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

Probiotics and prebiotics for pediatric populations

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

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

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

Next year in Banff

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

 

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

L. rhamnosus GG for treatment of acute pediatric diarrhea: the totality of current evidence

By Mary Ellen Sanders PhD, Executive Science Officer, ISAPP

For the past several years, studies have been adding to the evidence base on the efficacy of Lactobacillus rhamnosus GG for the treatment of pediatric diarrhea. A new systematic review and meta-analysis led by Prof. Hania Szajewska concluded that Lactobacillus rhamnosus GG is effective for treating acute diarrhea in hospitalized children, even when a 2018 null trial (Schnadower et al. 2018) was included.

“Despite a recent large RCT demonstrating no effect of L rhamnosus GG, current evidence shows that, overall, L rhamnosus GG reduced both the duration of diarrhoea (with a higher impact in European countries) and hospitalisation in inpatients.”

The authors acknowledge that the quality of evidence for this conclusion is low: 13 of 18 included studies suffered from problems with randomization, allocation concealment, blinding, and/or follow‐up. However, the rigorous process used to assess the current state of evidence provides confidence in the paper’s conclusions.

In an editorial in Alimentary Pharmacology & Therapeutics, Prof. Eamonn Quigley suggests that reports dismissing L. rhamnosus GG as ineffective (for example, see The Washington University School of Medicine opinion, “Probiotics no help to young kids with stomach virus“) were premature.

As Prof. Quigley points out, it is necessary to put the findings of the null study into context. He states several reasons why the Schnadower et al. 2018 study may not have shown an effect of L rhamnosus GG, even though previous studies had. Notably, the rotavirus vaccination status of the subjects – with two-thirds of the study population having been vaccinated – seemed important. Subgroup analysis showed that the probiotic was more effective among children who had not been vaccinated for rotavirus.

In addition, as discussed in a previous ISAPP blog, the timing of initiating probiotic therapy is likely an important factor. In the null trial, the average time of diarrhea prior to treatment was 53 hours, and subjects were enrolled up to 72 hours after onset of diarrhea – likely too late to have a possibility of positive impact by the probiotic.

For now the ESPGHAN recommendation to initiate L. rhamnosus GG treatment in conjunction with rehydration therapy early after the onset of diarrhea in children can still be supported by the totality of evidence.

Both Prof. Hania Szajewska and Prof. Eamonn Quigley serve on the ISAPP board of directors.

Effects of the food matrix on probiotic’s efficacy: how much should we care?

By Gabriel Vinderola PhD, Researcher at the Dairy Products Institute (National Scientific and Technical Research Council – CONICET) and Associate Professor at the Food Technology and Biotechnology Department, Faculty of Chemical Engineering, National University of Litoral, Santa Fe, Argentina.

The issue of to what extent food components may affect probiotic efficacy when compared to the strain delivered as supplement has lately been the subject of debate. This is especially so in the context of the Codex Alimentarius guidelines on probiotics, presently under development.

When considering the importance of the food formulation delivering the probiotic, it’s worthwhile to keep in mind that people may get their daily probiotic together with an enormous variety of foods. For instance, one person may get the probiotic at breakfast along with a yoghurt or with cereal, whereas another person may choose to consumer a fruit juice, while a third may get the probiotic dose before a meal consisting of pasta, meat and vegetables. In those cases, the same strain can undergo gastrointestinal passage in the context of very different food exposures. Does this suggest that perhaps the specific food format is not so critical? What does research tell us?

An interesting, however in vitro, study was conducted by Grześkowiak et al. (2011). In this work, Lactobacillus rhamnosus GG was recovered from more than 12 foods and supplements and its ability to inhibit food pathogens was assessed in vitro. Authors showed that even when the inhibitory capacity was quantitatively different among isolates, the qualitative probiotic capacity of inhibiting pathogens was present in all of them. That is to say, the probiotic capacity had been retained to a somewhat greater or lesser degree, regardless the matrix.

Few human studies have measured to what extent a health endpoint changes when a probiotic is delivered in different food matrixes. For instance, Saxelin et al. (2010) showed that the administration matrix (capsules, yogurt or cheese) did not influence the faecal quantity of lactobacilli, but affected faecal counts of propionibacteria and bifidobacteria. However no health endpoint was considered in this study. Several studies demonstrate that dairy products are able to confer enhanced protection during gastrointestinal transit in in vitro settings (Vinderola et al., 2000; Sagheddu et al., 2018; da Cruz Rodrigues et al., 2019), suggesting that dairy products may be better at delivering an efficacious dose of probiotic. But again, no clinical endpoint was measured in these studies.

The first comparative study on the probiotic capacity of a strain delivered in food or supplement was reported by Isolauri et al. (1991). Authors demonstrated that Lactobacillus GG either in fermented milk or freeze-dried powder was effective in shortening the course of acute diarrhea. Later on, Meng et al. (2016) found similar patterns of immune stimulation when studying the impact of Bifidobacterium animalis subsp. lactis BB12 administration in yoghurt or capsules on the upper respiratory tract of healthy adults.

As these kinds of studies are scarce, we can look to meta-analysis where the same strain is compared for the same clinical endpoint, but in studies conducted by different groups in different matrixes. For instance, Szajewska et al. (2013) concluded that Lactobacillus GG delivered in capsules or fermented milk significantly reduced the duration of diarrhea and Urbańska et al. (2016) reported that L. reuteri DSM 17938 delivered in either capsules or infant formula reduced the duration of diarrhoea and increased the chance of cure.

In vitro studies find that survival of the probiotic delivered in different food matrices through a (simulated) gastrointestinal transit may quantitatively differ, but no matrix completely eliminates probiotic capacity. Human clinical trials comparing different matrices with a clear health endpoint are scarce, but a general conclusion seems to emerge: regardless of the food matrix, the probiotic effect is achieved.  When the data are assessed through meta-analysis, the top of the “levels of evidence” in the pyramid of evidence-based studies, the probiotic capacity exists for the same strain among different studies, conducted by different research groups, using different food matrices.

In many countries regulators require that the probiotic effect be demonstrated in the same food or supplement that will be offered to consumers. This is a conservative approach in the lack of other evidence, but it may be challenging at the same time for probiotic food development, as any new food, even similar to one already existing, may require new human clinical studies to demonstrate efficacy. This approach may raise economic and ethical concerns too, and be discouraging for the future of probiotics.

Surely additional clinical trials directly comparing effects among different delivery matrices would provide clarity on the importance of this factor to probiotic functionality. Until that time, regulators should enable probiotic food manufacturers to offer a sound scientific rationale that bio-equivalency of different matrices could be expected, and thereby circumvent the requirement need to re-conduct human clinical trials on probiotics delivered in new matrices.

 

References

da Cruz Rodrigues VC, Salvino da Silva LG, Moreira Simabuco, F, Venema K, Costa Antunes AE. Survival, metabolic status and cellular morphology of probiotics in dairy products and dietary supplement after simulated digestion. J Funct. Foods, 2019, 55, 126-134.

Grześkowiak Ł, Isolauri E, Salminen S, Gueimonde M. Manufacturing process influences properties of probiotic bacteria. Br J Nutr. 2011, 105(6):887-94.

Isolauri E, Juntunen M, Rautanen T, Sillanaukee P, Koivula T. A human Lactobacillus strain (Lactobacillus casei sp strain GG) promotes recovery from acute diarrhea in children.

Meng H, Lee Y, Ba Z, Peng J, Lin J, Boyer AS, Fleming JA, Furumoto EJ, Roberts RF, Kris-Etherton PM, Rogers CJ. Consumption of Bifidobacterium animalis subsp. lactis BB-12 impacts upper respiratory tract infection and the function of NK and T cells in healthy adults. Mol Nutr Food Res. 2016, 60(5):1161-71.

Pediatrics. 1991 , 88(1):90-7.

Sagheddu V, Elli M, Biolchi C, Lucido J, Morelli L. Impact of mode of assumption and food matrix on probiotic viability. J Food Microbiol. 2018, 2.

Saxelin M, Lassig A, Karjalainen H, Tynkkynen S, Surakka A, Vapaatalo H, Järvenpää S, Korpela R, Mutanen M, Hatakka K. Persistence of probiotic strains in the gastrointestinal tract when administered as capsules, yoghurt, or cheese. Int J Food Microbiol. 2010, 144(2): 293-300.

Szajewska H, Skórka A, Ruszczyński M, Gieruszczak-Białek D. Meta-analysis: Lactobacillus GG for treating acute gastroenteritis in children-updated analysis of randomised controlled trials. Aliment Pharmacol Ther. 2013 Sep;38(5):467-76.

Urbańska M, Gieruszczak-Białek D, Szajewska H. Systematic review with meta-analysis: Lactobacillus reuteri DSM 17938 for diarrhoeal diseases in children. Aliment Pharmacol Ther. 2016, 43(10):1025-34.

Vinderola G, Prosello W, Ghiberto D, Reinheimer J. Viability of  probiotic- (Bifidobacterium, Lactobacillus acidophilus and Lactobacillus casei) and non probiotic microflora in Argentinian Fresco Cheese (2000). J Dairy Sci. 2000, 83 (9), 1905-1911.

Another day, another negative headline about probiotics?

By Prof. Colin Hill, PhD, APC Microbiome Ireland, University College Cork, Ireland

Scientists have a particular job. We try to discover what is unknown and we want to help to create a better understanding of the underlying forces, both physical and biological, that underpin our amazing universe. It is usually a slow and meticulous process. Gathering data usually takes weeks, or months, or years of work and so there is plenty of time to consider the numerous possible interpretations and the limitations and gaps in our understanding. Everything has to be repeated and subjected to statistical analysis. Finally, we publish our findings and our interpretation of that carefully accumulated data. Even this process takes weeks or months (or years) because of discussions with fellow authors and colleagues, numerous drafts of the manuscript, peer review and editorial comment. We are very aware that whatever we have published will almost certainly be repeated, or built upon, and if we are wrong (in either our data or our interpretation) that it will not withstand the test of time. Thus, we are slow and cautious and often qualify our findings with “this suggests” or “this strongly suggests” and we often finish with the unavoidable conclusion that “more research needs to be done”.

Journalists have a particular job. Journalists have to react quickly, perhaps in minutes or hours, to a breaking story or a commission from their editors, on topics with which they may not be familiar, and write short articles or present short pieces to camera that will appeal to the public and have a clear message. Nuance and complexity must often be left for long-form journalism or that as-yet unwritten novel. Being slow and complete and debating all of the possible interpretations is simply not an option. Finishing up with a cautious, equivocal “on the one hand, but also on the other hand” is also not really an option. Very few journalistic pieces end with “more journalism needs to be done”. It may also be difficult to construct a story along the lines of “some good science was well performed and led to careful and understated conclusions, which should really be repeated before we get too excited”.

It is not surprising then that scientists and journalists can sometimes find themselves at loggerheads. “Do probiotics work?” is a very reasonable question that a journalist can ask a scientist. “Well,” responds the scientist, “that depends on what you mean by ‘work’, and which probiotic you are asking about, and for what condition, and quite often strains are called probiotics but they do not fit the definition, and of course, there was that paper published last year which showed ……”. Cue frustration on both sides. Why can’t the scientist just answer the question? And why can’t the journalist understand that just because a question can be simply stated does not mean that it has a simple answer? Ask a doctor “do pills work?” and you might very well get a similarly convoluted answer, but no one would think it evasive. No wonder the scientist sometimes ends up reading the resultant article in frustration – how did the journalist come to that conclusion, where did all my careful explanations go? Of course, most scientists are imagining his or her scientific colleagues reading the article and wondering at the ‘incomplete’ or ‘trivial’ response. While the journalist may well wonder what planet the scientist lives on if he or she thinks that the editor is going to publish a long essay capturing all of the subtlety of the research.

This almost certainly comes across as me implying that scientists are impeccable purveyors of truth and that journalists are willing to sacrifice truth for simplicity, but I truly am not suggesting that. In almost every instance there is no bad faith involved from either party, it is simply the consequence of the different demands placed on two very different and very valuable roles in society.

So, these things will happen. We will see newspaper articles and online pieces (or editorial comments in journals) that do not contain all the nuance and complexity of the complex paper which it is based. We will see press articles that draw simple and reader-friendly conclusions. “Probiotics quite useless”, “Are probiotics money down the toilet? Or worse?”, etc. So, how should we respond? Do we write erudite articles pointing out the limitations of the commentator, coming across perhaps as arrogant or supercilious? [And yes, of course I use the words erudite and supercilious because it makes me feel better than you.] Do we send angry missives complaining about the article, and perhaps risk drawing further attention to it?

If you are asked by a journalist to comment on a paper, or if your local/national paper or favourite website has published an article that you think is unfair, perhaps the way to respond is to have a few simple questions of your own which can be put to journalists and/or readers. Perhaps we can use a checklist such as the following:

  • Is the article describing an original piece of research and was it published in a reputable, peer-reviewed journal?
  • What evidence is there that the strain or strain mix in question is actually a probiotic? Does it fit the very clear probiotic definition?
  • Was the study a registered human trial? How many subjects were involved? Was it blinded and conducted to a high standard?
  • What evidence was presented of the dose administered and was the strain still viable at the time of administration.
  • Were the end points of the study clear and measurable? Are they biologically or clinically significant to the subjects?
  • Did the authors actually use the words contained in the headline? “Useless”, or “waste of money”, etc?

Once these relatively simple questions are answered, then we can move on to the details and the complexities, but that is not where we should start. Of course, if a study is well performed and reaches a negative conclusion we should absolutely acknowledge that. But we can still point out that one strain or strain mix not working under one set of conditions is only evidence of the fact that one particular strain or strain mix does not work under one particular set of conditions. It does not warrant a blanket condemnation or criticism of all probiotics. Maybe ask the journalist to think about the obvious flaws in the headline ‘Headache pill does not cure cancer, all pills obviously a waste of money!”, and ask why the same standards should not be applied to probiotics?

Scientists and journalists have different roles in society, that is clear, but we can assume a priori that both have clear motives and do not want to mislead readers. Let’s start from there and make it easier for both sides to work together to make the public aware of the very real potential, and very real limitations, of probiotics and prebiotics in preserving health in a society in dire need of practical solutions.

Thank You to ISAPP’s 2019 Industry Advisory Committee Members

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

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.

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

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.