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Episode 15: A primer on prebiotics

 

The Science, Microbes & Health Podcast 

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

A primer on prebiotics, with Dr. Karen Scott

Episode summary:

In this episode, the ISAPP podcast hosts talk about prebiotics with Karen Scott, PhD, who is an ISAPP board member and Senior Research Fellow at Rowett Institute, University of Aberdeen, Scotland. Scott describes what prebiotics are, as well as the latest thinking about how they fit within an overall healthy diet and how they confer health benefits through the gut microbiota.

Key topics from this episode:

  • Dr. Scott and colleagues at the Rowett Institute began many years ago by working on anaerobic bacteria from the rumen of animals, then started to focus on the bacteria in the human large intestine.
  • Prebiotics (see definition below) stimulate the growth of beneficial bacteria in the human gut, and in doing so, benefit host health.
    Prebiotics alone cannot guarantee health: they must be consumed in addition to a healthy regular diet, which helps support thediversity of all gut microbes.
  • Prebiotics are not necessarily supplements; they are found in high amounts in many foods such as bulb-based vegetables, banana, and plantain. Around 5g of prebiotic per days is beneficial for health.
  • Not all prebiotics are equal: they each stimulate the growth of particular groups of bacteria. By definition, they must be selectively utilized (that is, some bacteria but not others must use them), and this differentiates prebiotics from fiber.
  • Some prebiotics are shown to improve gut transit (i.e. reduce constipation). One common example of the benefit of prebiotics has to do with bone health: metabolism of prebiotics in the colon tends to lower the pH; this increases calcium absorption for supporting bone health. Other benefits involve the production of short-chain fatty acids.
  • Bifidobacterium have traditionally been a group of bacteria targeted by prebiotics. Some Bifidobacterium produce lactate, and other bacteria produce butyrate (important for colonic health) from lactate. In healthy adults, there are bacteria that are equally or more important than bifidobacteria, however.
  • Prebiotics can target other body sites besides the gut.
  • Prebiotics that can be used by a bacteria in pure culture are not necessarily used by those bacteria within the ecosystem of the human gut.
  • New experimental platforms exist to see which bacteria are producing specific compounds on the growth of a specific substrate. But a model may not represent what is happening in the host, so this must be specifically tested.
  • Human milk oligosaccharides are a great example of how prebiotics are important to human health. Formula is often supplemented with prebiotics because of ample evidence that oligosaccharides (naturally present in human milk, but mimicked synthetically) enable growth of specific bacteria in the baby’s gut that are very important for immunity and other aspects of health.
  • Overall, to support bacteria in your gut and overall health, Dr. Scott recommends consuming a diverse diet: “eat a rainbow”. If you cannot, a prebiotic supplement is advisable.*

Episode abbreviations and links:

Dr. Karen Scott works at the Rowett Institute, a renowned centre focused on nutrition and human health.

ISAPP published the scientific consensus definition of prebiotics.

An early review co-authored by Dr. Scott, covering gut microbiota functions and their impact on host health via diet.

A review on prebiotics to support calcium absorption and therefore bone health.

Dr. Scott refers to a new tool: the Exploris 240 Orbitrap mass spectrometer, which is interfaced with an atmospheric pressure matrix assisted laser desorption ionisation (AP-MALDI) source and direct infusion. This theoretically allows scientists to measure the distribution and composition of complex gut bacterial communities, whilst simultaneously assessing metabolite production from the constituent microbes, allowing them to better understand the cooperation and competition between different human gut microbiota species.

Additional resources:

Prebiotics. ISAPP infographic.

Understanding prebiotics and fiber. ISAPP infographic.

The many functions of human milk oligosaccharides: A Q&A with Prof. Ardythe Morrow. ISAPP blog post.

 

About Dr. Karen Scott:

Dr. Karen Scott is a Senior Research Fellow at the Rowett Institute, University of Aberdeen. She leads a research team investigating the (molecular) mechanisms by which key members of the gut microbiota interact with the diet and host, at different life-stages. The fermentation products of gut bacteria contribute to gut health, and are differentially expressed on different substrates, including prebiotics. In vitro bacterial growth studies utilising our large culture collection of gut anaerobes (in pure culture, mixed culture, fermentor systems, and also with human cells) and bioinformatic analyses illustrate niche-specific processes and bacterial interactions. Resident bacteria are also an important reservoir of transferable antimicrobial resistance genes, and other work investigates the evolution and spread of resistance from farm to fork.

Looking back and looking ahead: ISAPP session focuses on the past, present, and future of the biotics field

Kristina Campbell, MSc, and Prof. Dan Tancredi, PhD, Professor of Pediatrics, UC Davis School of Medicine and Center for Healthcare Policy and Research

Twenty years ago, in 2002, the first ISAPP meeting was held in London, Canada. At the time, the field was much less developed: only small human trials on probiotics or prebiotics had been published, no Nutrition and Health Claims legislation existed in the EU, and the human microbiome project hadn’t been conceived.

Now in ISAPP’s 20th year, the scientific landscape of probiotics and prebiotics is vastly different. For one thing, probiotics and prebiotics now form part of the broader field of “biotics”, which also encompasses both synbiotics and postbiotics. Hundreds of trials on biotics have been published, regulations on safety and health claims has evolved tremendously globally, and ”biotics” are go-to interventions (both food and drug) to modulate the microbiota for health.

At the ISAPP annual meeting earlier this year, scientists across academia and industry joined together for an interactive session discussing the past, present and future of the biotics field. Three invited speakers set the stage by covering some important advancements in the field. Then session chair (Prof. Daniel Tancredi) invited the participants to divide into 12 small groups to discuss responses to a set of questions. The session was focused on generating ideas, rather than achieving consensus.

The following is a summary of the main ideas generated about the past, present and future of the biotics field. Many of the ideas, naturally, were future-focused – participants were interested in how to move the field of biotics forward with purpose.

The past 20 years in the biotics field

Prof. Eamonn Quigley had the challenge of opening the discussion about the past by summing up the last 20 years in the biotics field. He covered early microbiological progress in the biotics field, such as the production of antimicrobials and progress in understanding the biology of lactic acid bacteria and their phages. In the modern era, scientists made strides in understanding the role of gut bacteria and metabolites in hepatic encephalopathy; the role of C. difficile in pseudo-membranous colitis; and in the 90s, the concept of bacterial translocation in the intestines. Prof. Quigley summarized the progress and challenges in advancing the underlying science and in developing actionable clinical evidence. He noted that more high-quality clinical trials are being published lately.

The discussion participants noted the following achievements in the field over the past two decades:

Recognition that microbes can be ‘good’. A massive shift in public consciousness has taken place over the past 20 years: the increased recognition that microorganisms are not just pathogens, they have a role to play in the maintenance of health. This added impetus to the idea that consuming beneficial microbes or other biotics is desirable or even necessary.

The high profile of biotics. An increasing number of people are familiar with the basic idea of biotics. Especially for probiotics, there is a strong legacy of use for digestive health; they are also widely available to consumers all around the world.

ISAPP’s published papers. Participants appreciated the papers published as a result of ISAPP’s efforts, including the five scientific consensus definition papers. These have raised the profile of biotics and clarified important issues.

Connections between basic and clinical scientists. Collaborations between biotics scientists and clinicians have been increasing over the past two decades, leading to better questions and higher quality research. ISAPP is one of the leading organizations that provides opportunities for these two groups to interact.

These were among the challenges from the past two decades, as identified by discussion participants:

Lack of understanding among those outside the probiotic/prebiotic field. Although the science has advanced greatly over the past 20 years, some outside the biotics field continue to believe the evidence for probiotic efficacy is thin. It appears some early stereotypes about probiotics and other biotics persist, especially in some clinical settings. This also leads to consumer misunderstandings and affects how they use biotics substances.

Too many studies lacking in quality. In the past, many studies were poorly designed; and sometimes the clinical research did not follow the science. Further, a relative lack of mechanistic research is evident in the literature.

Lack of regulatory harmony. Probiotics and other biotics are regulated in different ways around the world. The lack of harmonized regulations (for example, EFSA and FDA having different regulatory approaches) has led to confusion about how to scientifically substantiate claims in the proper way to satisfy regulators.

Lack of standardized methodologies. Many scientific variables related to biotics, such as microbiome measurements, do not have standardized methodologies, making comparability between studies difficult.

Not having validated biomarkers. The absence of validated biomarkers was noted as a potential impediment to conducting feasible clinical research studies.

The current status of the biotics field

At the moment, the biotics field is more active than ever. The industry has grown to billions of dollars per year and microbial therapeutics are in development all across the globe. The number of published pro/prebiotic papers is over 40K and the consensus definitions alone have been accessed over half a million times.

Prof. Kristin Verbeke spoke at the interactive session about the biotics field at present. She noted that the field has faced the scientific reality that there is no single microbiota configuration exclusively associated with health. The current trajectory is to develop and expand systems biology approaches for understanding the taxonomic and functional composition of microbiomes and how those impact health. Scientists are increasingly making use of bioinformatics tools to improve multi-omic analyses, and working toward proving causation.

The future of the biotics field

Prof. Clara Belzer at the ISAPP 2022 annual meeting

Prof. Clara Belzer spoke on the future of the biotics field, focusing on a so-called “next-generation” bacterium, Akkermansia muciniphila. She covered how nutritional strategies might be based on improved understanding of the interplay between microbes and mucosal health via mucin glycans, and the potential for synthetic microbial communities to lead to scientific discoveries in microbial ecology and health. She also mentioned some notable citizen science education and research projects, which will contribute to overall knowledge in the biotics field.

Participants identified the following future directions in the field of biotics:

Expanding biotics to medical (disease) applications. One group discussed at length the potential of biotics to expand from food applications (for general overall health) to medical applications. The science and regulatory frameworks will drive this shift. They believed this expansion will increase the credibility of biotics among healthcare practitioners, as the health benefits will be medical-condition-specific and will also have much broader applicability.

As for which medical conditions are promising, the group discussed indications for which there are demonstrated mechanistic as well as clinical effects: atopic diseases, irritable bowel syndrome, and stimulating the immune system to boost vaccine efficacy. In general, three different groups of medical conditions could be targeted: (1) common infections, (2) serious infectious diseases, and (3) chronic diseases for which drugs are currently inadequate, such as metabolic disorders, mental health disorders and autoimmune diseases.

Using biotics as adjuncts to medical treatments. An area of huge potential for biotics is in complementing existing medical treatments for chronic disease. There is evidence suggesting in some cases biotics could be used to increase the efficacy of drugs or perhaps reduce side effects, for example with proton pump inhibitors, statins, NSAIDs, metformin, or cancer drugs. Biotics are not going to replace commonly used drugs, but helping manage certain diseases is certainly within reach.

Using real-world data in studies. Participants said more well-conducted studies should be done using real world data. This seems in line with the development of citizen science projects as described by Clara Belzer and others at the ISAPP meeting. Real-world data is particularly important in the research on food patterns/dietary habits as they relate to biotics.

Considering new probiotic formulations. In some cases, a cocktail of many strains (50-60, for example) may be necessary for achieving a certain health effect. Using good models and data from human participants, it may be possible to create these multi-strain formulations with increased effects on the gut microbial ecosystem and increased efficacy.

Embracing omics technology and its advancement. Participants thought the next five years should see a focus on omics data, which allows for stratifying individuals in studies. This will also help increase the quality of RCTs.

More mechanism of action studies. Several groups expressed the importance of investing in understanding mechanisms of action for biotic substances. Such understandings can help drive more targeted clinical studies, providing a rationale for the exact type of intervention that is likely to be effective. Thus, clinical studies can be stronger and have more positive outcomes.

Increased focus on public / consumer engagement. Educational platforms can engage consumers, providing grassroots support for more research resources as well as advancing regulatory frameworks. Diagnostic tools (e.g. microbiome tests with validated recommendations) will help drive engagement of consumers. Further, science bloggers are critical for sharing good-quality information, and other digital channels can have great impact.

Defining and developing “precision biotics”. One group talked about “precision biotics” as solutions that target specific health benefits, which also have a well-defined or unique mechanism of action. At present, this category of biotics is in its very early stages; a prerequisite would be to better define the causes and pathways of gastrointestinal diseases.

Increasing incentives for good science. Participants discussed altering the regulatory and market environments so that good science and proper randomized, controlled trials on biotics are incentivized. Regulators in particular need to change their approaches so that companies are driven primarily by the science.

Precise characterization of responders and non-responders. The responder and non-responder phenomenon is seen with many biotic interventions. Across the field, deep characterization of subjects using multi-omics approaches with a high resolution is needed to determine what factors drive response and non-response to particular biotics substances.

Overall, participants’ ideas centered around the theme of leaning into the science to be able to create better-quality biotics products that support the health of different consumer and patient groups.

 

Special thanks to the table discussion leaders: Irene Lenoir-Wijnkoop, Zac Lewis, Seema Mody, David Obis, Mariya Petrova, Amanda Ramer-Tait, Delphine Saulnier, Marieke Schoemaker, Barry Silkington, Stephen Theis, Elaine Vaughan and Anisha Wijeyesekera.

The many functions of human milk oligosaccharides: A Q&A with Prof. Ardythe Morrow

Human milk is the ‘gold standard’ of infant nutrition—and some scientists have set their sights on working towards that standard to improve the health of infants who are not breastfed. Among the many important components of human milk are human milk oligosaccharides (HMOs): complex carbohydrates that are 3-32 sugars in length. Over 200 different HMO molecules have been discovered, but a mother typically has between 12 and 20 in her milk. Some types of HMOs are affected by genetic polymorphisms – for example, only those who have the FUT2 (secretor) gene have breast milk containing HMOs called 2′-fucosylated (2’-FL) glycans.

ISAPP held a webinar in October, 2022 featuring Prof. Ardythe Morrow, University of Cincinnati College of Medicine, speaking about the latest research on HMOs and their health effects in both infants and adults.

HMOs as prebiotics

Prof. Morrow emphasized that research to date on HMOs shows they clearly fit the scientific consensus definition for prebiotics: a “substrate that is selectively utilized by host microorganisms conferring a health benefit”. HMOs are utilized by bacteria in the infant gut—mainly bifidobacteria, but also other genera (Yu, Chen & Newburg, 2013)—producing end-products that benefit infant health. B. longum subsp. infantis are the quintessential bacteria that grow on HMOs; pathogens do not typically grow on them.

Within the prebiotic category, HMOs are unique. Unlike other prebiotic substances they are structurally similar to gut oligosaccharides, which populate the surface of mucosal surfaces of the GI tract and are abundant in the mucin layer. They also can function via mechanisms that do not require utilization by gut microbes.

Beyond prebiotic function

Prof. Morrow emphasized that HMOs are multi-functional agents: in addition to their prebiotic functions, they have direct functions in the infant gut that are not mediated by microbes. First, individual HMOs have been shown to bind pathogens and inhibit infections and bind to immune cells to optimize their function (Triantis, Bode & van Neerven, 2018). Further, they can enhance neurodevelopment and brain function (Furness, Kunze & Clerc 1999; Sharon et al, 2016). The latter is a more recent domain of research, but so far it is known that basic neurodevelopmental processes are modulated in animals that are germ-free or have a depleted gut microbiota.

Certain HMOs (notably 2’-FL) can be produced synthetically and are being tested in infant formulas, and more recently for healthy adults (Elison et al., 2016). Prof. Morrow noted HMOs also have potential as novel therapeutics for various indications, such as inflammatory bowel disease (IBD). Determining which specific HMOs are most effective in these outcomes, and the dose needed, is an active area of research.

The webinar participants generated some interesting questions, some of which Prof. Morrow answers below.

Are 2’FL and LNnT (Lacto-N-neotetraose) found in cow’s milk?

2′-FL is not found in cow’s milk. Other oligosaccharides, especially sialyl oligosaccharides, are present but generally at very low levels.

How similar to HMOs are the glycosylation patterns on gut mucin?

Mucin glycosylation is not identical to human milk. But there are structural motifs that recur in both milk and gut mucin.

Do the more abundant HMOs have more potential for health benefit, compared with those at lower abundances in human milk?

We do not know that more abundance means more functionality or importance. But it is a reasonable place to start with the research. Also, several of the most abundant HMOs are trisaccharides (2’FL, 3FL, 3′-SL, and 6′-SL), and these are the most manageable to synthesize and start with.

For non-secretors, HMO complexity in milk is around 30% lower than for secretors. Does this factor affect the beneficial functions of non-secretor HMOs?

Having lower HMO content might be an issue in some circumstances. But we cannot say that it is a general problem. Furthermore, if non-secretors have more sialyloligosaccharides and 3-FL instead of 2′-FL, for example, perhaps this helps protect against viruses that bind to sialic acid epitopes (for example, influenza). Or perhaps this helps with increasing sialic acid to the brain (see Mudd et al., 2017). So, my argument is that at this point in our knowledge, we should avoid any idea of “superior” or “inferior” milk for the general healthy public. More likely, there are situation-specific benefits or disadvantages for different milk oligosaccharide phenotypes.

What do you think is more important for infant formula, more HMO complexity or more structure-function relations?

A set of HMOs for normal infant nutrition will be important, and these include fucosyllactoses, sialyllactoses, and neutral oligosaccharide with neither sialic acid nor fucose. Structure-function orientation is important to guide use in special populations with specific health needs.

Long term, will HMOs replace FOS and GOS in infant formulas?

All of the efforts in making infant formula have the goal of doing the best possible job of mimicking the physiological function of breastmilk, but cost and function are also relevant factors to consider in this process. It’s important that babies get some form of prebiotic. GOS is structurally more similar to HMOs, but it’s not enough on its own. Ideally, we’d hope for a rational mixture of different oligosaccharides backed by research confirming their combined functions.

Can we really replicate HMOs with synthetic formula, given the large number of diverse HMOs present in human milk?

I do not foresee ever achieving full replication, no. But getting closer to mother’s milk, yes, over time.

How is the dosing of HMOs in clinical trials for adults being determined? Should it be based on human milk concentration?

Elison et al. published a dosing study based on tolerance and shift of microbiota. A dosing study is now underway in Cincinnati, too.

Since it is fairly difficult to manufacture HMOs, do you think they provide sufficient advantages compared to GOS to justify their use as prebiotics in adults?

We do not yet know whether HMOs might have enough advantage over GOS in some situations, or whether prebiotic combinations might be best. This is research in progress! The reason for testing 2′-FL in IBD is because of the structure-function evidence. IBD is increased in non-secretors, and is associated with dysbiosis, inflammation, and so on. We will learn from the ongoing research.

Do you think adults will differ in response to HMOs therapeutically, possibly based on genetic differences?

I don’t yet have data on this, but have a study ongoing that I hope will be able to address this very question.

 

 

 

 

Episode 14: Evidence on probiotics for preterm infants

The Science, Microbes & Health Podcast 

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

Evidence on probiotics for preterm infants, with Dr. Geoffrey A. Preidis

Episode summary:

In this episode, the ISAPP podcast hosts talk about probiotics for preterm infants with Geoff Preidis, MD, PhD, a pediatric gastroenterologist and researcher at Baylor College of Medicine & Texas Children’s Hospital. Predis describes the evidence on probiotics for prevention of necrotizing enterocolitis, the challenges in interpreting the evidence that exists, and using the evidence to make clinical decisions.

Key topics from this episode:

  • Dr. Preidis works mostly with preterm infants, a population that didn’t exist just a few decades ago.
  • In the totality of evidence on probiotics for treating or preventing certain health conditions, the largest body of evidence is on whether probiotics can prevent negative health outcomes in preterm infants. Large meta-analyses (>15,000 preterm infants, >60 RCTs) conclude that overall, probiotics reduce the risk of necrotizing enterocolitis (NEC) by ~50%.
  • Probiotics do not appear to increase the risk of sepsis. In one case, contamination during the manufacturing process led to a severe infection and death. Although there is a very low risk of this happening, it highlights that a pharmaceutical grade probiotic is not available to give infants.
  • Many caveats accompany these findings, however. Trials use a wide range of products, as well as different strains, doses, durations of treatment, preterm infant populations, etc. Trials vary in their quality.
  • The body of evidence on probiotics for preventing NEC is convincing but far from perfect. Future trials need to continue reporting details on safety.
  • Some leading professional societies have issued guidelines that contradict each other.
  • How should clinicians make a decision, then? One way of choosing one therapy over another is to use network meta-analysis, which  ranks therapies according to which product might have greater efficacy than another. However, the most studied therapies tend to rank higher. 
  • Another way to make a decision is to consider looking at mechanisms. This is challenging with NEC, since we don’t know exactly what causes it.
  • Dr. Preidis is doing research on the association between early life undernutrition and increased risk of metabolic disorders later in life, what is known as the “thrifty phenotype” hypothesis. The mechanism may involve an epigenetic switch, whereby early life nutritional insult affects gene expression and metabolism in a long-lasting way.

 

Episode abbreviations and links:

This 2020 Cochrane Library review of probiotics for preventing NEC, mortality, and invasive infection (i.e. sepsis), found that “Combined analyses showed that giving very preterm and very low birth weight infants probiotics may reduce the risk of necrotizing enterocolitis, and probably reduces the risk of death and serious infection,” but also noted important concerns about the quality of the trials used to support these conclusions,  that, “further, large, high-quality trials are needed to provide evidence of sufficient quality and applicability to inform policy and practice.”

Study in JPGN showing metabolites and fecal microbiota in preterm infants are modulated according to the probiotics they are exposed to.

Network meta-analysis on how probiotics affect morbidity and mortality in preterm infants.

A recent commentary by Dr. Preidis on rational selection of a probiotic for preventing necrotizing enterocolitis

 

Additional resources:

Probiotics and Necrotizing Enterocolitis. ISAPP infographic.

Probiotics to Prevent Necrotizing Enterocolitis: Moving to Evidence-Based Use. ISAPP blog.

 

About Dr. Geoff Preidis:

Dr. Preidis received his undergraduate degree in Physics from Harvard University, then completed his medical degree, residency in Pediatrics, fellowship in Pediatric Gastroenterology, Hepatology & Nutrition, and Ph.D. in Translational Biology and Molecular Medicine from Baylor College of Medicine. Now an Assistant Professor at Baylor College of Medicine and Texas Children’s Hospital, Dr. Preidis leads the Nutritional Physiology Research Laboratory and serves as an attending physician on both the Neonatal Gastroenterology, Hepatology & Nutrition Consultation Service and the Transplant Hepatology Service.

Dr. Preidis’s laboratory seeks to define mechanisms through which early life malnutrition impairs intestinal and liver function, leading to both short-term and long-term medical problems. Current studies focus on how malnutrition slows gastrointestinal motility, alters the gut microbiome, and inhibits the liver’s ability to synthesize important substances including bile acids – all of which adversely impact child growth. This research aims to help children suffering from nutritional deficiencies caused by a wide range of medical and socioeconomic factors, including premature newborns in the neonatal intensive care unit.

Episode 13: The history of ISAPP

The Science, Microbes & Health Podcast 

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

The history of ISAPP, with Drs. Glenn Gibson, Mary Ellen Sanders and Irene Lenoir-Wijnkoop

Episode summary:

In this episode, the ISAPP podcast hosts talk about the history of the ISAPP organization with the organization’s three co-founders: Glenn Gibson, Mary Ellen Sanders and Irene Lenoir-Wijnkoop. The three guests recount the origins of ISAPP and the state of probiotic and prebiotic science 20 years ago when the organization was founded. They speak about some of the successes and challenges they encountered along the way, and highlight what they see as some of the key achievements of ISAPP.

Key topics from this episode:

  • The origin of the idea for ISAPP back in 1999: an organization dedicated to the science of pro- and prebiotics.
  • The annual meeting proved a key mechanism to gathering the multi-disciplinary scientists together to talk about and advance the science.
  • How ISAPP walks the line between receiving funding from industry members yet protecting scientific credibility.
  • The value that ISAPP has provided to industry members and the academic scientific community over the years.
  • How research in the field developed in the last 20 years and the questions that remain unanswered.
  • How industry members understood the importance of science 20 years ago and still do today, respecting the line between science and marketing.
  • Challenges from the last 20 years and where the field is going.

 

About Irene Lenoir-Wijnkoop:

Irene Lenoir-Wijnkoop is affiliated with the Utrecht University, specialized in public health nutrition and she provides independent consultancy services in related areas. She acts as associate editor in the Drugs Outcomes Research & Policies section of Frontiers. Through her passion for tackling preventable food-related diseases, which jeopardize healthcare resources, societies and human equity, she pioneered the field of nutrition economics.

After a first experience in clinical nutrition, she successively held assignments at the Dutch and the French subsidiaries of The Upjohn Company. When food industries initiated clinical research activities, she joined management and executive positions at the Danone Group. Besides her responsibilities, she got actively involved in ILSI Europe, in many international societies and advisory boards, primarily in the field of probiotics. She co-conceived ISAPP by enabling the first -seminal- meeting in 1999 in New York. In 2010 she was awarded with the Elie Metchnikoff Prize of Recognition.

 

About Mary Ellen Sanders:

Mary Ellen Sanders, PhD serves as the Executive Science Officer for the International Scientific Association of Probiotics and Prebiotics. She is also a consultant in the area of probiotic microbiology (www.mesanders.com). She is the current chair of the United States Pharmacopeia’s Probiotics Expert Panel, was a member of the working group convened by the FAO/WHO that developed guidelines for probiotics, and co-chairs the World Gastroenterology Organisation Guidelines Committee for practice guidelines for the use of probiotics and prebiotics for gastroenterologists. She lives in Colorado with her husband, where she enjoys her 2 grandchildren, hiking and riding her aging Morgan horse.

 

About Glenn Gibson:

Born in an ambulance parked on a roundabout outside Littlethorpe Maternity Hospital near Sunderland, UK (his dad fainted). Failed scientist at school – a trait he has successfully continued to this very day. Has poked around in people’s faeces for over 30 years and as a result, has published over 500 research papers but do not waste your time reading any of them, as you will learn nothing. Before that he did a PhD on sediment microbiology and learnt a lot about what the great population (or poopulation) of Dundee flush down their toilets. 

He has supervised over 80 PhD students and 40 postdocs, who all said he was an absolute pleasure to work with and they wished their projects had lasted 10 times as long as they did. He is a compulsive fantasist. He thinks h-factor is a hat size. Has not done a day’s work in the last decade, largely because he spends all his time reading refereeing requests from journals he has never heard of, or grant bodies wanting reviews after spending decades bouncing every single one of his*, or conference organisers asking him to travel across the world (at his own expense) to give a talk or chair a session on anything whatsoever. Helped Mary Ellen, Irene and Gregor found the organisation most people call EYE-SAPP. 

Episode 11: How to build a satisfying scientific career and make a difference

The Science, Microbes & Health Podcast 

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

How to build a satisfying scientific career and make a difference, with Prof. Gregor Reid

Episode summary:

In this episode, the ISAPP podcast hosts talk about how to succeed as a scientist in the fields of probiotics and prebiotics with Gregor Reid, professor emeritus at Western University, Canada. Prof. Reid, who is ISAPP’s former president and host of the first ISAPP meeting 20 years ago, tells about his career path and shares ways to make a difference outside of the scientific laboratory.

Key topics from this episode:

  • The importance of keeping a sense of humor as a scientist
  • Sometimes it pays to do something unconventional: early in his career, Reid decided to work with a urologist who had a hunch that lactobacilli were important in women’s health; they had difficulty getting funding to investigate further but they persisted over a number of years and eventually published some landmark work
  • Reid (with others) investigated on how biofilms impacted clinical antibiotic treatments
  • When clinical problems drive the research, it can have great impact on people’s lives, yet it can take many years to progress from observation to mechanism to better clinical treatments
  • Probiotics are “an ecological approach to an ecological problem” but often the structures (funding, regulatory, etc.)  are not in place for scientists to study them or pursue them as interventions in industry
  • Prof. Reid has worked in South Africa, led by local people, helping them obtain tools for making fermented yogurt (Yoba-For-Life)
  • For early career scientists who want to make a difference in science beyond publishing papers, it’s important to be proactive and go after what you want
  • The right lab and the right environment are essential
  • Reflect on the personal connection to your work that “makes you almost unstoppable”
  • Partnerships are key for international impacts
  • Those involved in ISAPP can champion a cause that’s important to them within the organization
  • Flexibility will be key for probiotics (and other ‘biotics’) companies in the future
  • The field is poised to expand; all kinds of organisms will benefit from probiotics in the future

 

Episode abbreviations and links:

Landmark papers related to vaginal lactobacilli, biofilms and health:

Recurrent urethritis in women

Bacterial biofilm formation in the urinary bladder of spinal cord injured patients

Bacterial biofilms: influence on the pathogenesis, diagnosis and treatment of urinary tract infections

Ultrastructural study of microbiologic colonization of urinary catheters

 

Additional resources:

Reflections on a career in probiotic science, from ISAPP founding board member Prof. Gregor Reid. ISAPP blog

The Children of Masiphumelele Township. ISAPP blog

 

About Prof. Gregor Reid:

Gregor Reid is a Fellow of the Royal Society of Canada and Canadian Academy of Health Sciences, and Distinguished Professor Emeritus at Western University. 

Born and raised in Scotland, he did his PhD in New Zealand and immigrated to Canada in 1982. His research, most recently at Lawson Health Research Institute, has focused on the role of beneficial microbes in the health of humans and other life forms. He has produced 32 patents, 586 peer-reviewed publications cited over 50,000 times, has a Google Scholar H index of 116 and has given over 650 talks in 54 countries. He is ranked #3 in Canada and #59 in the world for  Microbiology Scientists by research.com. In 2001, he chaired the UN/WHO Expert Panel that defined the term probiotic. In 2004, he helped introduce probiotic yoghurt to East Africa as a means for women to create microenterprises that by 2019 reached 260,000 adults and children. 

He has received an Honorary Doctorate from Orebro University, Sweden, a Distinguished Alumni award from Massey University, New Zealand, a Canadian Society for Microbiologists Career Award and Western University’s highest accolade of Distinguished Professor. He is Chief Scientific Officer for Seed, a Californian start-up. 

Can diet shape the effects of probiotics or prebiotics?

By Prof. Maria Marco PhD, University of California – Davis and Prof. Kevin Whelan PhD, King’s College London

If you take any probiotic or prebiotic product off the shelf and give it to several different people to consume, you might find that each person experiences a different effect. One person may notice a dramatic reduction in gastrointestinal symptoms, for example, while another person may experience no benefit. On one level this is not surprising, since every person is unique. But as scientists, we are interested in finding out exactly what makes a person respond to a given probiotic or prebiotic to help healthcare providers know which products to recommend to which people.

Among factors that might impact someone’s response to a probiotic or prebiotic – such as baseline microbiota, medications, and host genetics – diet emerges as a top candidate. Ample evidence has emerged over the past ten years that diet has direct and important effects on the structure and function of the gut microbiome. Overall the human gut microbiome is shaped by habitual diet (that is, the types of foods consumed habitually over time), but the microbes can also can fluctuate in response to short-term dietary shifts. Different dietary patterns are associated with distinct gut microbiome capabilities. Since probiotics and prebiotics may then interact with gut microbes when consumed, it is plausible that probiotic activity and prebiotic-mediated gut microbiome modulation may be impacted by host diet.

A discussion group convened at ISAPP’s 2022 annual meeting brought together experts from academia and industry to address whether there is evidence to support the impact of diet on the health effects of probiotics and prebiotics. To answer this question, we looked at how many probiotic or prebiotic studies included data on subjects’ diets.

  • Prebiotics: Our review of the literature showed that only a handful of prebiotic intervention studies actively measured background diet as a potential confounder of the effect of the prebiotic. One such study (Healey, et al., 2018) classified individuals based on habitual fiber intake, and in doing so found that the gut microbiome of individuals consuming high fiber diets exhibited more changes to microbiome composition than individuals with low fiber intake. While both groups consuming prebiotics showed enrichment of Bifidobacterium, those with high fiber intake uniquely were enriched in numerous other taxa, including butyrate-producing groups of microbes. Prebiotics also resulted in improved feelings of satiety, but only among the high fiber diet consumers.
  • Probiotics: We found no evidence of published human RCTs on probiotics that investigated diet as a possible confounding factor. This is a significant gap, since we know from other studies that host diet affects the metabolic and functional activity of probiotic lactobacilli in the digestive tract. Moreover, the food matrix for the probiotic may further shape its effects, via the way in which the probiotic is released in situ.

Our expert group agreed that diet should be included in the development of new human studies on probiotics and prebiotics, as well as other ‘-biotics’ and fermented foods. These data are urgently needed because although diet may be a main factor affecting outcomes of clinical trials for such products, it is currently a “hidden” factor.

We acknowledge there will be challenges in taking diet into account in future trials. For one, should researchers merely record subjects’ habitual dietary intake, or should they provide a prescribed diet for the duration of the trial? The dietary intervention (nutrient, food, or whole diet) must also be clearly defined, and researchers should carefully consider how to measure diet (e.g. using prospective or retrospective methods). In the nutrition field, it is well known that there are challenges and limitations in the ways dietary intake is recorded as well as the selection of dietary exclusion criteria. Hence, it is crucial that dietitians knowledgeable in dietary assessment and microbiome research contribute to the design of such trials.

If more probiotic and prebiotic trials begin to include measures of diet, perhaps we will get closer to understanding the precise factors that shape someone’s response to these products, ultimately allowing people to have more confidence that the product they consume will give them the benefits they expect.

Human milk oligosaccharides as prebiotics to be discussed in upcoming ISAPP webinar

Human milk oligosaccharides (HMOs), non-digestible carbohydrates found in breast milk, have beneficial effects on infant health by acting as substrates for immune-modulating bacteria in the intestinal tract. The past several years have brought an increase in our understanding of how HMOs confer health benefits, prompting the inclusion of synthetic HMOs in some infant formula products.

These topics will be covered in an upcoming webinar, “Human milk oligosaccharides: Prebiotics in a class of their own?”, with a presentation by Ardythe Morrow PhD, Professor of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine. The webinar will provide an overview of what HMOs are, how they are breaking new ground with the types of health benefits they can provide to infants and the recent technological innovations that will facilitate their translation into new infant formulas.

Dr. Karen Scott, Rowett Institute, University of Aberdeen, and Dr. Margriet Schoterman, FrieslandCampina, will host the webinar. All are welcome to join this webinar, scheduled for Wednesday, Oct 19th, 2022, from 10-11 AM Eastern Daylight Time. Registration is free of charge. Spaces may be limited.

Register here.

Episode 5: Prebiotics for animal health

The Science, Microbes & Health Podcast 

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

Prebiotics for animal health, with Prof. George Fahey

Episode summary:

The hosts discuss prebiotics for animals with Prof. George Fahey, a prominent animal nutrition scientist who is currently Professor Emeritus at University of Illinois. Fahey explains how animal nutrition research relates to human nutrition research, and the changes in the field he has seen over the course of his long career. He describes the research on prebiotics for animal nutrition, covering both livestock and companion animals.

Key topics from this episode:

  • A short history of animal prebiotics research as well as future opportunities in animal nutrition.
  • Pro- and prebiotics are being explored as an alternative to antibiotic treatment in production animals. Antibiotics are overused, leading to an increase in antibiotic resistance; the “biotics” therefore have great potential in animal nutrition.
  • Probiotics can potentially be used instead of antibiotics to inhibit pathogens and support the gut microbiota in animals.
  • Prebiotics possibly have high nutritional value and beneficial effects in animals, especially in poultry and pigs.
  • There are limitations to using prebiotics in the animal industry, especially for some animals such as horses and ruminants.
  • There has been increased use of prebiotics for companion animals (pets) in the past few years. Now many pet foods contain prebiotics.
  • Benefits of using prebiotics in companion animals:
    •  Support digestive health
    •  Improve stool quality
    • Support the gut microbiota, which also translates to good stool quality
  • A short overview of how companion animals’ food is produced, and the timing of adding prebiotics.
  • Wild animals’ diet has low nutrition with limited to no prebiotic intake, resulting in a shorter lifespan in comparison with companion animals
  • Some take-home points from animal models and animal nutrition research.

 

Episode links:

Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics
The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic

 

Additional resources:

Are prebiotics good for dogs and cats? An animal gut health expert explains. ISAPP blog post
Using probiotics to support digestive health for dogs. ISAPP blog post
Prebiotics. ISAPP infographic

 

About Prof. George Fahey:

George C. Fahey, Jr. is Professor Emeritus of Animal Sciences and Nutritional Sciences at the University of Illinois at Urbana-Champaign. He served on the faculty since 1976 and held research, teaching, and administrative appointments. His research was in the area of carbohydrate nutrition of animals and humans. He published numerous books, book chapters, journal articles, and research abstracts.

He currently serves on two editorial boards, numerous GRAS expert panels, and is scientific advisor to both industry and governmental organizations. He retired from the University in 2010 but continues to serve on graduate student committees and departmental search committees. He owns Fahey Nutrition Consulting, Inc. that provides services to the human and pet food industries.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

 

 

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

 

ISAPP’s 2021 year in review

By Mary Ellen Sanders, PhD, ISAPP Executive Science Officer

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

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

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

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

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

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

Hands holding mobile phone

Virtual events continue to fill gaps as in-person meetings are being planned

Prof. Bob Hutkins, PhD, University of Nebraska – Lincoln, USA

For scientists, annual meetings provide coveted opportunities to hear about the latest scientific advances from expert researchers, and they are where students and trainees get to present their research, often for the first time. Of course, meeting and socializing with colleagues, both new and old, during breaks and evening sessions is also an important part of these conferences.

Yet over the past two years, most occasions to meet face-to-face were canceled. Virtual meetings became the new normal and, even though a poor substitute for in-person gatherings, provided opportunities to connect and share emerging science. As we anticipate being together again in person – hopefully for 2022 meetings – take note of three upcoming conferences to fill the gap. Each of these feature meetings are related to the gut microbiome, diet, and health.

(1) In October, the Agriculture and Health Summit: Cultivating Gut Health at the Crossroads of Food & Medicine is a FREE three-day virtual conference that brings together a unique combination of researchers, industry leaders and thought leaders from the biomedical and agricultural sectors for important conversations about the future of human health. The event will provide a rare opportunity for individuals with diverse areas of expertise to discuss opportunities and challenges in creating ‘foods for health’ through the gut microbiome, working toward solutions in nutrition and medicine. More information can be found here. Among the presenters are ISAPP Executive Science Officer, Mary Ellen Sanders, and board members, Dan Merenstein and Bob Hutkins.

 

(2) Then in November, a Nature-sponsored online conference called Reshaping the Microbiome through Nutrition will be held. According to the website, “this conference will bring together researchers working on the microbiome and nutrition to discuss how our microbiota use and transform dietary components, and how these nutrients and their products influence host health throughout life, including effects on development and infectious and chronic diseases. A central theme of the meeting will be how diet and dietary supplements could be harnessed to manipulate the microbiome with the aim of maintaining health and treating disease”More information is found here.

(3) Another meeting in November is organized across ten centers/institutes at the NIH and the Office of Dietary Supplements and the Office of Nutrition Research. This two-day conference November 5 and 8, titled Precision Probiotic Therapies—Challenges and Opportunities, features a Keynote address by Prof. Jeff Gordon, from the Washington University School of Medicine. ISAPP president Prof. Dan Merenstein, Georgetown University School of Medicine, is also presenting. To register for this FREE meeting, see here.

 

In this current era, interest in how diet (including probiotics, prebiotics, and fermented foods) influences the microbiome and affects human and animal health has never been greater, as is evident by these and other similarly-themed conferences.

ISAPP is planning its next annual by-invitation meeting, to be held in person.

 

Using probiotics to support digestive health for dogs

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

Because dogs are considered to be members of the family by most pet owners today, their health and well-being is a top priority. As with humans, nutritional products supporting gastrointestinal health are some of the most popular. Many pets are healthy, but loose stools, constipation, and various gastrointestinal disorders and diseases such as inflammatory bowel disease and irritable bowel syndrome are common. In fact, within the pet food conversation, digestive health improvements have been the most discussed health benefits among social media discussion posts over the past 2 years (see here). Given the high interest in digestive health, it is not surprising that the canine microbiome has been of great interest over the past decade, with many recent reviews reporting on the overall composition of the gastrointestinal microbiota and how it is impacted by diet (Barko et al., 2018; Alessandri et al., 2020; Wernimont et al., 2020). Gastrointestinal microbiome changes contributing to or resulting from digestive diseases have also been documented in dogs (Redfern et al., 2017; Ziese and Suchodolski, 2021). Animals under high levels of stress or undergoing antibiotic therapy are also known to have poor stool quality and an altered gut microbiota (i.e., dysbiosis) (Pilla et al., 2020).

Dietary fibers and prebiotics are commonly used in complete and balanced diets to improve or maintain stool quality, provide laxation, and positively manipulate the microbiota of healthy animals. The use of probiotics is also popular in dogs, but the route of administration, efficacy, and reason for use is usually different than that of fiber and prebiotics. Probiotics are usually provided in the form of supplements (e.g., powders, capsules, pastes) and are most commonly used to treat animals with gastrointestinal disease rather than support the healthy condition. Live microbes are added to many dry extruded foods as ‘probiotics’, but in many cases, maintaining viability and evidence for a health benefit for dogs is lacking for these products. Such microbes would not meet the minimum criteria to be called a ‘probiotic.’ Viability is a challenge because most HACCP plans for producing complete and balanced pet foods include a kill step that inactivates all microorganisms. Therefore, inclusion must be applied post-extrusion on the outside of the kibble. Even if applied in this way, low numbers of viable organisms are common (Weese and Arroyo, 2003). Post-production inclusion is not possible for other diet formats (e.g., cans, pouches, trays). Although spore-forming bacteria that may survive the extrusion process have been of interest lately, evidence of efficacy is lacking thus far.

Picture of Simka (a Samoyed) courtesy of ISAPP board member Dr. Daniel Tancredi

Even though health benefits coming from the inclusion of live microorganisms in dog foods is not supported by the peer-reviewed literature, such evidence exists for many probiotic supplements. The clinical effects of probiotics in the prevention or treatment of gastrointestinal diseases in dogs have been reviewed recently (Schmitz and Suchodolski, 2016; Suchodolski and Jergens, 2016; Jensen and Bjornvad, 2018; Schmitz, 2021). Although some similarities exist, recent research has shown that distinct dysbiosis networks exist in dogs compared to humans (Vazquez-Baeza et al., 2016), justifying unique prevention and/or treatment strategies for dogs.

One population of dogs shown to benefit from probiotics has been those with acute idiopathic diarrhea and gastroenteritis, with a shorter time to resolution and reduced percentage of dogs requiring antibiotic administration being reported (Kelley et al., 2009; Herstad et al., 2010; Nixon et al., 2019). Probiotic administration has also been shown to benefit dogs undergoing antibiotic therapy and those engaged in endurance exercise – two conditions that alter the gastrointestinal microbiota and often lead to loose stools. In those studies, consumption of a probiotic helped to minimize gastrointestinal microbiome shifts and reduced the incidence and/or shortened the length of diarrhea (Gagne et al., 2013; Fenimore et al., 2017). Dogs diagnosed with inflammatory bowel disease have also been shown to benefit from probiotic consumption (Rossi et al., 2014; White et al., 2017). In these chronic conditions, drug therapy is almost always required, but probiotics have been shown to help normalize intestinal dysbiosis, increase tight junction protein expression, and reduce clinical and histological scores.

So what is the bottom line? Well, for dogs with a sensitive stomach and/or digestive health issues, probiotics may certainly help. Rather than relying on live microbes present in the dog’s food or adding a couple spoonfuls of yogurt to the food bowl each day, it is recommended that owners work with their veterinarian to identify a probiotic that has the best chance for success. The probiotic selected should provide an effective dose, be designed for dogs, target the specific condition in mind, and be backed by science. As summarized here, it is important to remember that all probiotics are different so the specific microorganism(s), supplement form, storage conditions, and dosage are all important details to consider.

 

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 board member Prof. Dan Tancredi kindly provided pictures of Simka, pet Samoyed, for the post.

 

Follow up from ISAPP webinar – Probiotics, prebiotics, synbiotics, postbiotics and fermented foods: how to implement ISAPP consensus definitions

By Mary Ellen Sanders PhD, Executive Science Officer, ISAPP

On the heels of the most recent ISAPP consensus paper – this one on postbiotics – ISAPP sponsored a webinar for industry members titled Probiotics, prebiotics, synbiotics, postbiotics and fermented foods: how to implement ISAPP consensus definitions. This webinar featured short presentations outlining definitions and key attributes of these five substances. Ample time remained for the 10 ISAPP board members to field questions from attendees.

When considering the definitions, it’s important to remember that the definition is a starting point – not all criteria can be included. Using the probiotic definition as an example, Prof. Colin Hill noted that the definition is only 15 words – Live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. This is a useful definition, stipulating the core characteristics of a probiotic. However, important criteria such as safety and identity are not specified in the definition yet are clearly delineated in the full paper on probiotics.

Several interesting topics emerged from this discussion, which will be explored in future blog posts. These include:

  • What is meant by host health? Microbe mediated benefits are numerous. But not all benefits are a benefit to host health. Benefits for user appearance, pets and potentially livestock may be measurable, economically important and desirable, but may not encompass ‘host health’.
  • What types of endpoints are appropriate for studies to meet the requirement of a health benefit? Endpoints that indicate improved health (such as symptom alleviation, reduced incidence of infections or quality of life measures) are targeted. Some physiological measures that may be linked to health (such as increased fecal short chain fatty acids or changes in microbiota composition) may not be sufficient.
  • What are the regulatory implications from these definitions? As suggested by the National Law Review article on the ISAPP consensus definitions, attorneys are interested in the scientific positions on how these terms are defined and characterized. Further, some regulatory actions – such as by Codex Alimentarius in defining probiotics – are underway. ISAPP is open to suggestions about the best way to communicate these definitions to regulators.
  • Is any follow-up by ISAPP to these papers anticipated in order to clarify criteria and provide simple guidance to their implementation?

Simple guidance to these substances can be found in the infographics: probiotics, probiotic criteria, prebiotics, fermented foodshow are probiotic foods and fermented foods different, synbiotics, and postbiotics. As mentioned above, watch for blog updates on implementation of the definitions for different stakeholder groups.

The recording of this webinar is available here under password protection for ISAPP industry members only.

Related information:

Consensus panel papers, all published in Nature Reviews Gastroenterology and Hepatology:

A roundup of the ISAPP consensus definitions: probiotics, prebiotics, synbiotics, postbiotics and fermented foods

 

 

 

 

ISAPP thanks Prof. Glenn Gibson as he retires from the organization’s board of directors

By Mary Ellen Sanders, PhD, ISAPP Executive Science Officer

Glenn Gibson – co-founder and backbone of ISAPP for over 20 years – has retired from the ISAPP board of directors.

In 1999, Glenn, Irene Lenoir-Wijnkoop and I conceived of ISAPP as a scientific ‘home’ for the multidisciplinary scientists involved in probiotic and prebiotic research. In 2002, ISAPP was incorporated as a non-profit, public service organization.

Colin Hill and Glenn Gibson

Through all the years, Glenn supported ISAPP beyond measure. His scientific acumen led to many insightful ideas for discussion groups and scientific speakers. He brought ISAPP and probiotic / prebiotic science to the attention of UK political strategists. He hosted meetings, chaired panels, authored publications, provided steady guidance and leadership, and helped keep the board focused on the mission at hand. He also promptly answered my interminable shower of emails for 20+ years. Highlights of his service include:

  • Co-founded ISAPP in 1999
  • Served as Vice President, President and Past President
  • Hosted ISAPP’s 2003 meeting in Henley, UK and 2007 in London, UK
  • Chaired 12 discussion groups
  • Chaired 2 ISAPP consensus panels, on probiotics (2013) and prebiotics (2016)
  • Co-authored 18 ISAPP publications (https://isappscience.org/publications/)
  • Chaired the innovative Springboard session at the Antwerp meeting (2019)
  • And so much more!

Glenn Gibson, Gregor Reid, Mary Ellen Sanders

What is more difficult to catalogue is how thoroughly enjoyable Glenn was to work with over the years. He did so much with an air of ease and joy, making it fun for everyone around him.

Glenn also masterfully decoupled ego from accomplishments. A person less dedicated to this principle would have reminded us ‘early and often’ (as they say) of his scientific stature in the field. Glenn remained approachable despite being one of the ‘greats’ – he started the field of prebiotics, a term addressed in over 9000 papers (close to 200 being his), and coined ‘synbiotics’, a term with 1700 papers currently published. I marvel at how many researchers and companies these two ideas have kept busy over the past 30 years. He developed a validated in vitro gut model, enabling mechanistic studies of the effects of dietary ingredients on gut microbiota, while conducting over 50 human studies, showing his commitment to move the science into the human so we can understand how it can make a difference in people’s lives. Yet still, his penchant was always to give others the credit, the limelight, the microphone, the opportunities.

His incredible stature in the field could have led him to dedicate his precious time to organizations much better established than ISAPP. But to the benefit of all of us, he was ISAPP’s greatest champion. His commitment radiated out to many academic experts who thought hey, if Glenn is in, I’ll be in, too, and to many industry scientists who simply relished the opportunity to network and collaborate with him under the ‘ISAPP umbrella’.

Gabriel Vinderola and Glenn Gibson, Singapore, 2018

Glenn believes that the right thing to do now is let ISAPP move into its next phase as he retires from board membership. I’ll be following his example in 3 years. Meanwhile, my challenge is to figure out how to find opportunities to keep him connected to the busy and dynamic ISAPP community.

As Glenn steps away, ISAPP would like to honor him by naming the Early Career Researcher Prize, which Glenn initiated, after him. The 2022 edition of the prize will be called the Glenn Gibson Early Career Researcher Prize. It’s a small gesture, as it’s impossible to thank Glenn sufficiently for all he has done for the ISAPP community. But we know he will continue to inspire the next generation of probiotic and prebiotic researchers! As his dedicated colleagues and friends, we wish him all the best as he brings his formidable talents to bear on other projects in the months and years ahead.

Enjoy this candid interview with Glenn.

 

A roundup of the ISAPP consensus definitions: probiotics, prebiotics, synbiotics, postbiotics and fermented foods

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

ISAPP has long recognized the importance of precise definitions of the ‘biotic’ family of terms. As a scientific organization working to advance global knowledge about probiotics, prebiotics, synbiotics, postbiotics and fermented foods, we believe carrying out rigorous scientific studies—and comparing one result to another—is more difficult if we do not start with a clear definition of what we are studying.

Over the past 8 years, ISAPP has endeavored to bring clarity to these definitions for scientists and other stakeholders. ISAPP board members have met with other top experts representing multiple perspectives and specialties in the field to develop precise, useful and appropriate definitions of the terms probiotics, prebiotics, synbiotics, postbiotics and fermented foods. The definitions of these first four terms have all entailed the requirement that the substance be shown to confer a health benefit in the target host. Fermented foods have multitudes of sensorial, nutritional and technological benefits, which drive their utility. A health benefit is not required.

The problem with health benefits

The definitions provide significant advantages for the scientific community in terms of clarity but complexity arises when the same definitions are accepted by regulatory agencies. This requirement for a health benefit as part of the probiotic definition has been rigorously implemented in the European Union. Currently, with the exception of a few member states, the term probiotic is prohibited. The logic is that since a health benefit is inherent to the term probiotic and since there are no approved health claims for probiotics in the EU*, the term ‘probiotic’ is seen to be acting as a proxy for a health claim. This has frustrated probiotic product companies who believe they have met the scientific criteria for probiotics, yet cannot identify their product as a probiotic in the marketplace because they have not received endorsement of their claims by the EU. This is not an issue resulting from an unclear definition, since probiotics surely should provide a health benefit, but rather from a lack of agreement as to what level of evidence is sufficient to substantiate a health benefit.

ISAPP remains committed to the importance of requiring a health benefit for the ‘biotic’ family of terms (outlined in the table below). It’s clear that all of these definitions are meaningless unless the requirement that they confer a health benefit is considered as essential by all stakeholders. One could reasonably discuss whether the required levels of evidence for foods and supplements are too high in some regulatory jurisdictions, but the value of these substances collapses in the absence of a health benefit.

Summary of ISAPP consensus definitions

With the publication of the most recent ISAPP consensus paper, this one on postbiotics, I offer a summary below of the five consensus definitions published by ISAPP. Each definition is part of a comprehensive paper resulting from focused discussions among experts in the field and published in Nature Reviews Gastroenterology and Hepatology (NRGH). These papers are among the top most viewed of all time on the NRGH website and are increasingly cited by scientists and regulators.

Table. Summary of ISAPP Consensus Definitions of the ‘Biotics’ Family of Substances. Probiotics, prebiotics, synbiotics and postbiotics have in common the requirement for a health benefit. They may apply to any target host, any regulatory category and must be safe for their intended use. Fermented foods fall only under the foods category and no health benefit is required.

Definition Key features of the definition Reference
Probiotics Live microorganisms that, when administered in adequate amounts, confer a health benefit on the host Grammatical correction of the 2001 FAO/WHO definition.

No mechanism is stipulated by the definition.

 

Hill et al. 2014
Prebiotics A substrate that is selectively utilized by host microorganisms conferring a health benefit Prebiotics are distinct from fiber. Beneficial impact on resident microbiota and demonstration of health benefit required in same study. Gibson et al. 2017
Synbiotics A mixture comprising live microorganisms and substrate(s) selectively utilized by host microorganisms that confers a health benefit on the host Two types of synbiotics defined: complementary and synergistic. Complementary synbiotics comprise probiotic(s) plus prebiotic(s), meeting requirements for criteria for each. Synergistic synbiotics comprise substrate(s) selectively utilized by co-administered live microbe(s), but independently, the components do not have to meet criteria for prebiotic or probiotic. Swanson et al. 2020
Postbiotics Preparation of inanimate microorganisms and/or their components that confers a health benefit on the host Postbiotics are prepared from live microbes that undergo inactivation and the cells or cellular structures must be retained. Filtrates or isolated components from the growth of live microbes are not postbiotics. A probiotic that is killed is not automatically a postbiotic; the preparation must be shown to confer a health benefit, as well as meet all other criteria for a postbiotic. Salminen et al. 2021
Fermented Foods Foods made through desired microbial growth and enzymatic conversions of food components Fermented foods are not the same as probiotics. They are not required to have live microbes characterized to the strain level nor have evidence of a health benefit. Types of fermented foods are many and are specific to geographic regions. Compared to the raw foods they are made from, they may have improved taste, digestibility, safety, and nutritional value. Marco et al. 2021

 

 

*Actually, there is one approved health claim in the EU for a probiotic: Scientific Opinion on the substantiation of health claims related to live yoghurt cultures and improved lactose digestion (ID 1143, 2976) pursuant to Article 13(1) of Regulation (EC) No 1924/2006

 

Further reading: Defining emerging ‘biotics’

ISAPP publishes continuing education course for dietitians

For dietitians, it’s often difficult to find practical, up-to-date resources with a scientific perspective on probiotics, prebiotics, synbiotics and fermented foods. ISAPP is pleased to announce a new resource to fill this need – a Special Continuing Education Supplement in Today’s Dietitian titled, “Evidence-based use of probiotics, prebiotics and fermented foods for digestive health”. This free continuing education course also includes infographic summaries, links to supplementary information, and even some favourite recipes. US dietitians can earn 2.0 CPEUs for completing this self-study activity.

The resource was written by dietitian and assistant professor Dr. Hannah D. Holscher, along with two ISAPP board members, Prof. Robert Hutkins, a fermented foods and prebiotics expert, and Dr. Mary Ellen Sanders, a probiotic expert.

“We hope this course will give dietitians an overview of the evidence that exists for probiotics, prebiotics, synbiotics and fermented foods, and help explain some of the practical nuances around incorporating them into their practice,” says Sanders. “In addition, we believe that this course will be a scientifically accurate overview that can counter prevalent misinformation. It can serve as a useful resource for diverse array of professionals active in this field.”

Find the supplement here.

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

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

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

Dr. Mary Ellen Sanders: Probiotics and fermented foods

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

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

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

Prof. Glenn Gibson: Prebiotics and Synbiotics

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

Prof. Hania Szajewska, MD: Biotics for pediatric use

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

Prof. Gabriel Vinderola: Postbiotics

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

See here for the entire presentation on Biotics for Health.

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

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

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

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

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

Q&A (@1:20:00)

 

Five things scientists should know about the future of probiotics and prebiotics

By Marla Cunningham​, Metagenics Global R&D Innovation Manager and 2021 ISAPP Industry Advisory Committee representative

As anyone connected with probiotics and prebiotics knows – there’s a lot happening in this space.

After a well-attended discussion group at the 2019 ISAPP Annual Meeting in Antwerp, a collaboration of 16 industry and academic scientists came together to produce a broad overview of current and emerging trends that were covered in this discussion. Just released online by Trends in Microbiology, the open access paper identifies some top trends across multiple spheres of influence on the future of probiotics and prebiotics.

  1. Discovery: Prebiotics and probiotics are emerging from unexpected sources – naturally occurring as well as synthesised or engineered. Food, human and animal microbiome-derived probiotics feature heavily in probiotic development through top-down microbiome data-driven approaches as well as physiological target-driven screening approaches. Prebiotic sources have expanded beyond traditional plant sources to include food waste streams, animal gut-derived glycans and mammalian milk as well as increasingly sophisticated synthesis techniques, involving sonication, high pressure, acid, enzyme and oxidation treatments. A growing understanding of the implications of carbohydrate structure on microbial metabolism is driving the emergence of designer prebiotics, as specific substrates for microbes of interest or the production of target metabolites, such as polyphenol-derived bioactives.
  2. Evaluation: Calls for integrated systems biology -omic approaches to the evaluation of probiotic and prebiotics effects continue to increase, utilising whole genome and metabolite approaches, with a focus on better understanding of mode of action as well as differential host and microbial responses that serve to improve host health.
  3. Product development: Quality assurance techniques continue to undergo evolution as the challenges of divergent product formats and increasingly complex formulations necessitate innovation in the field. There is a focus on techniques beyond cell culture enumeration for probiotic product verification as well as on the identification of functional markers of probiotic and prebiotic activity, which can be applied in complex food matrices.
  4. Regulation: Recent regulatory challenges with claim approval are understood to have driven corresponding evolution in clinical science and an increased focus on mechanistic elucidation. However, the converse is also occurring, with the development of novel probiotic species, therapeutics for disease treatment and increasingly microbiome-driven modes of action having implications for regulatory frameworks. This ‘give and take’ between science and regulatory requirements will likely accelerate into the future as the field continues to evolve.
  5. Implementation: Interest continues to grow in precision and personalised approaches to nutrition and healthcare, especially in the field of microbiome-related interventions where there is significant appreciation of host-to-host variability. The identification of putative microbial signatures of health and disease continues to fuel the development of health-associated microbes as candidate probiotics and as targets for novel prebiotic substrates. Further, a focus beyond microbial composition and into microbial function is driving interest in interventions which can correct metabolomic profiles, such as probiotics with specific enzyme activity to boost synthesis or catabolism of key microbial metabolites in vivo, including purine and monoamine compounds.

These and other trends create a rich and evolving landscape for scientists within the field and provide the promise of a bright future for prebiotics and probiotics.

Read the full paper here

Reference:

Cunningham, M., Azcarate-Peril, M. A., Barnard, A., Benoit, V., Grimaldi, R., Guyonnet, D., Holscher, H. D., Hunter, K., Manurung, S., Obis, D., Petrova, M. I., Steinert, R. E., Swanson, K. S., van Sinderen, D., Vulevic, J., & Gibson, G. R. (2021). Shaping the Future of Probiotics and Prebiotics. Trends in microbiology, S0966-842X(21)00005-6. Advance online publication. https://doi.org/10.1016/j.tim.2021.01.003

 

 

 

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.