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Archive Highlight: Biotics in animal and human nutrition, with Prof. Kelly Swanson PhD

/in Podcast, Season Three /by Laura

 

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Completing our series on the role of biotics in animal health, we are highlighting Episode 22 from our archives. In this episode, Prof. Kelly Swanson PhD from University of Illinois at Urbana-Champaign discusses the role of biotics in animal and human nutrition. He reviews the criteria for prebiotics and synbiotics, then discusses how we gain knowledge about nutrition and the role of biotics in animals compared to humans.

Key topics from this episode:

  • A good argument can be made that biotics are essential for our diet; they are beneficial even if efficacy is sometimes difficult to prove.
  • Nutrients have an impact on the host’s health and simultaneously on the host-associated microbes.
  • Health benefits are essential to the FDA definition of fiber.
  • Antibiotics’ effect on the microbiota: short-term effects may be minor, but we still don’t know the long-term effects.
  • The synbiotics definition, criteria for products to meet this definition, and the health outcomes from using these biotic substances.
  • The difference between complementary and synergistic synbiotics.
  • When studying biotics in companion animals (cats and dogs), can results from one host be extrapolated to another host? Final studies should be in the target host.
  • Biotics are important in veterinary medicine and a popular topic of study.
  • Predictions about the future of nutrition science as informed by the microbiome.

Episode links:

Additional resources:

About Prof. Kelly Swanson:

Kelly Swanson is the Kraft Heinz Company Endowed Professor in Human Nutrition at the University of Illinois at Urbana-Champaign. His laboratory studies the effects of nutritional interventions, identifying how diet impacts host physiology and gut microbiota. His lab’s primary emphasis is on gastrointestinal health and obesity in dogs, cats, and humans. Much of his work has focused on dietary fibers and ‘biotics’. Kelly has trained over 40 graduate students and postdocs, published over 235 peer-reviewed manuscripts, and given over 150 invited lectures at scientific conferences. He is an active instructor, teaching 3-4 nutrition courses annually, and has been named to the university’s ‘List of Teachers Ranked as Excellent by Their Students’ 30 times. He serves on advisory boards for many companies in the human and pet food industries and non-profit organizations, including the Institute for the Advancement of Food and Nutrition Sciences and International Scientific Association for Probiotics and Prebiotics.

Archive Highlight: Prebiotics for animal health, with Prof. George Fahey

/in Podcast, Season Three /by Laura

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Continuing our series on the role of biotics in animal health, we are highlighting Episode 5 from our archives. This episode features a former ISAPP board member, Prof. George Fahey, giving an overview of animal prebiotic research and describing future opportunities for prebiotics in animal nutrition. Prof. George Fahey is 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.

ISAPP elaborates criteria for prebiotics

/in ISAPP Science Blog /by KC

By Mary Ellen Sanders, PhD, Mary Ellen Sanders LLC, Probiotics Consulting, Prof. Bob Hutkins, PhD, University of Nebraska and Karen Scott PhD, Rowett Institute, University of Aberdeen.

Nearly one in four Americans say digestive health is the most important aspect of their overall health, according to a 2022 International Food Information Council survey. Prebiotics – a 30-year old concept – are growing in popularity among consumers interested in digestive health, although knowledge of what they are and what they do varies. For example, 18% of American consumers have never heard of prebiotics, while 22% state they are familiar with and actively try to consume them. Those consumers who say they are ‘familiar’ with prebiotics look for them in yogurt or kefir, where they are typically not found, but also in fruits and vegetables or dietary supplements, where they may be present.

Although clearly there is a need for scientifically sound information for consumers, experts recognize that a gap in understanding exists even for scientists. To help bring some clarity to the scientific principles involved in prebiotics, a group of scientists collaborated on an Expert Recommendation published October 2, 2024 in Nature Reviews Gastroenterology and Hepatology. This paper, titled “Classifying compounds as prebiotics—scientific perspectives and recommendations”, delineated what prebiotics are and what lines of research are needed to establish their status.

This paper reinforces the 2017 definition of prebiotic, “a substrate that is selectively utilized by host microorganisms conferring a health benefit”. It further breaks down the individual criteria that are explicitly and implicitly derived from this definition, summarized in the table below. Neither ISAPP nor the authors of this paper claim to be the arbiters of whether or not a given substance satisfies the prebiotic definition.  Rather, the primary motivation for this effort was to provide researchers clearly stated criteria that aid the development of the scientific rationale for concluding that a newly proposed substance can be legitimately termed a ‘prebiotic’. In transitioning ’candidate prebiotics’ to accepted prebiotics, it is important that proposed compounds meet all aspects of the prebiotic definition. In parallel, ISAPP developed a companion prebiotic checklist.

Perhaps the most challenging issue the authors addressed was defining selectivity. Although the idea that distinct components of the microbiota respond to a prebiotic is fundamental to the prebiotic concept, the complexity of the microbiota makes such a response difficult to quantify. Selective utilization is measured by tracking prebiotic-induced changes in composition or function of the microbiota. Many different possible approaches to measuring microbial function and composition, which will continue to expand with methodological advances, inform these research efforts. The extent of the modulation could be narrow or broad, but it should be reproducible and specific. Importantly, a sound hypothesis for why any such microbiome changes would underpin the observed health effect should be advanced. The authors of this paper agreed with the importance of allowing innovation in the prebiotic field, and as such, were not prescriptive by specifying which specific analyses are required.

Unlike probiotics – where no mechanism of action leading to the health benefit is specified by the definition – the prebiotic definition stipulates one. A prebiotic-induced health benefit should derive from the modulation of the microbiome (composition or function) that is a result of selective utilization. To date, most studies on prebiotics have shown an association of microbiome modulation and the health benefit by tracking both in the same efficacy trial in the target host. Such a study shows that the health benefit and microbiome modulation are correlated, but it does not prove that the microbiome modulation causes the health benefit. Such proof is difficult to obtain, and therefore is not required for prebiotic status, a position consistent with the 2017 consensus paper. But this new paper reemphasizes the value of research to address causality, which remains a challenging issue in the microbiome field, and discusses statistical approaches that can increase confidence that the relationship is causal.  Causality studies can be informed by a variety of methods, including mining relevant microbiome databases, in silico screening, in vitro and in vivo tracking of expression of microbiota-dependent metabolic pathways, machine learning, artificial intelligence, and animal models.

The authors anticipate that this paper will encourage scientists to coalesce their understanding of prebiotics around these concepts. As pointed out in the paper, “Adherence by all stakeholders to these criteria would benefit the prebiotic field by providing cohesion in prebiotic research, principles to underpin regulatory actions, and clarity to alleviate confusion for consumers.”

Table 1: Key criteria of a prebiotic derived from the ISAPP prebiotic definitiona (From Hutkins et al. 2024)

Prebiotic criteria Comments
Substrate A prebiotic is a substance administered to a host and utilized by autochthonous microorganisms. It might be an ingredient in a diet, but ‘prebiotic’ refers to a specific substance rather than a complete diet.
Identity and characterization Prebiotic must be sufficiently described to enable robust data comparisons and reproducible manufacture of the ingredient.
Selectively utilized by host microbiota Selective utilization can be shown by one microbial change or a change in many taxa or by specific functional readouts.
Demonstrated health benefit Type of health benefit endpoint assessed depends on intended regulatory category and must be demonstrated by well controlled studies (typically RCTs) in the target population.
Hypothesis for mechanism of how microbiome modulation might lead to the health benefit A sound rationale should be developed explaining how the pattern of selective utilization by host microorganisms observed for the prebiotic could lead to the health benefit.
Health benefit in the target host must be demonstrated in the same study that demonstrates selective utilization by the microbiota It is not essential to demonstrate a causal link between the selective utilization of the prebiotic and health benefit(s), as such evidence can be very difficult to obtain experimentally. However, research aimed at this goal is encouraged, aided by causal mediation design and analysis strategies. With regard to demonstrating the health benefit, animal studies in non-target hosts as well as in vitro studies might be useful to address mechanistic questions and to plan trials in the target host but cannot in isolation provide sufficient evidence to establish claimed health benefits in the target host.
Safe for intended use Adverse events must be tracked in studies conducted in target host. Safety requirements differ for different regulatory categories and target populations.
Confirmatory evidence, beyond minimum requirements Multiple studies demonstrating reproducibility of health effects and selective utilization increase confidence in outcomes.
Administered in dose or serving size shown to elicit health benefit and selective utilization by the host microbiota in controlled studies Advice on serving size should be provided so that sufficient dose for health benefit is achieved without eliciting adverse effects, such as toxicity, gastrointestinal symptoms, or choking, among others.

aBased on the ISAPP definition of prebiotic: a substrate that is selectively utilized by host microorganisms conferring a health benefit. Not all criteria are specifically stated in the definition, but are implicit in text in the accompanying paper.

The criteria within the paper are summarized in a downloadable prebiotic evidence checklist from ISAPP.

Join ISAPP’s upcoming webinar on this topic, with the date to be announced shortly. Sign up for the ISAPP newsletter or follow our social media platforms here to be notified of the date.

REFERENCE:

Hutkins R, Walter J, Gibson GR, Bedu-Ferrari C, Scott K, Tancredi DJ, Wijeyesekera A, Sanders ME. Classifying compounds as prebiotics – scientific perspectives and recommendations. Nat Rev Gastroenterol Hepatol. 2024. doi: 10.1038/s41575-024-00981-6.

Prebiotics: Does Delivery Format Matter?

/in ISAPP Science Blog /by KC

By Kelly S. Swanson, PhD, University of Illinois Urbana-Champaign, USA

Prebiotics (1) have long been appreciated for their benefits to digestive function, immunity, energy balance, and metabolism. From a nutritionist’s perspective, the best way to consume dietary fibers and prebiotics is by eating a healthy diet comprising adequate amounts of whole grains, fruits, and vegetables. Prebiotic substances are naturally present in the food supply, with onions, garlic, Jerusalem artichoke, and bananas serving as rich sources. Prebiotic intake can also be boosted in other ways – in recent years, food companies have developed prebiotic-containing breakfast cereals and bars, muffin mixes, breads, and other food products. A variety of prebiotic dietary supplements are also available and may be used to complement dietary sources.

Most prebiotic substances are water soluble and have a slightly sweet flavor. These properties not only make it easy to incorporate prebiotics into food products, but beverages as well. In addition to dairy-based beverages, fruit juices, fruit and vegetable smoothies, iced teas, and others, prebiotics have been added to carbonated soft drinks. While a growing consumer interest in gut health products and expansion of the prebiotic food and beverage market is good to see, a recent class-action lawsuit against a producer of prebiotic soda has stirred up the field and prompted a few important questions.

What prebiotic dose is needed for a product to deliver a health benefit?

The ongoing lawsuit provides an interesting example in applying prebiotic science to a commercial product. To carry the prebiotic term, the prebiotic ingredient in a product must be provided at a dosage to deliver health benefits in the target host. When it comes to evaluating prebiotic-containing foods and beverages, the dosage per serving, effects of processing, format and stability of the final product, and presence of other nutrients and bioactive substances must all be considered.

The suit is based on the prebiotic dosage (2 grams of agave inulin/12-oz can) and high sugar content (4-5 grams/12-oz can) of the sodas in question, but the effects of processing and format/stability of the final product are also relevant. Based on the dosage and published scientific evidence (2, 3), consumers would need to drink 4 cans of soda to notice inulin’s benefits. Is the 2 gram dosage per can sufficient to carry the gut health claim?

How does delivery format shape the benefits of a prebiotic?

Another key variable is the delivery matrix of the prebiotic. In this case, what is the stability of the agave inulin during the processing and storage of the carbonated soda? Is it similar to that of a dry powder, a capsule, or the format tested in a previous study (i.e., chocolate candy chews) (2, 3) or is there degradation over time? Prebiotic functionality and efficacy is known to differ based on degree of polymerization, sugar composition, degree of branching, and the type of glycosidic bonds present (4). Because inulin-based prebiotics are known to be susceptible to structural degradation when exposed to high temperatures, high pressure, and/or low pH (5, 6, 7), ensuring integrity of the active prebiotic ingredient over shelf life is an important consideration with regards to product efficacy.

What other substances are present in the final product?

A final consideration is the presence of other nutrients and/or bioactive substances in the final product. The presence of essential nutrients and other substances may influence if and how prebiotics are modified during processing and impact the overall health implications of the final product. In regard to processing, prebiotics may participate in Maillard reactions during heat treatment, forming prebiotic-protein conjugates (8). These structures may increase stability and prebiotic functionality and be a benefit to a product as long as Maillard reaction products are not excessive. Other prebiotic-nutrient interactions may occur during food and beverage processing, but the area has not been well studied.

The nutrient content of the final product also has implications on health beyond that of the prebiotic effect. Prebiotic foods and beverages that contain essential nutrients, antioxidants, healthy fats, or functional fibers would be viewed as being beneficial. On the other hand, products low in essential nutrients but high in added sugar, unhealthy fats, salt, or caffeine may be viewed as being detrimental and could offset the benefits of the prebiotic.

Ensuring effective products to support gut health

In the case of the soda lawsuit, time will tell how the courts weigh the dosage and potential positives of the prebiotic vs. the negatives of the added sugar content of soda. Regardless of the outcome, it serves as a reminder to food and beverage producers interested in the biotic area. Products carrying biotic terms and/or structure-function claims pertaining to gut health must be carefully formulated and processed, with daily serving sizes providing sufficient dosages and functional activity in their final form throughout shelf life.

Further reading: Applying probiotics and prebiotics in new delivery formats – is the clinical evidence transferable?

Can we estimate prebiotic effects from short-chain fatty acid production?

/in ISAPP Science Blog /by KC

By Prof. Kristin Verbeke PhD, KU Leuven

Short-chain fatty acids (SCFA), primarily acetate, propionate and butyrate, are the most abundant anions in the large intestine. They are mainly produced from bacterial fermentation of undigested carbohydrates. Since SCFA were found to activate the orphan G-protein coupled receptors GPR-41 and 43 (renamed as free fatty acid receptor ffar-3 and ffar-2), research into their physiological effects on human health has increased exponentially.

SCFA production is proposed to be a mechanism for several health benefits associated with intake of dietary fiber and prebiotics, not only via local effects in the gut but also on distant organs. Molecular mechanisms explaining SCFA effects have mainly been elucidated in cell-based in vitro experiments and animal studies. However, studying the impact of SCFA on human physiology is complicated by the kinetics of these molecules.

Although fecal concentrations of SCFA are relatively easy to measure, consensus has grown that they provide little information. Fecal SCFA do not adequately reflect the production of SCFA in the proximal colon and only represent the fraction of SCFA that has been produced and not used. The capacity of the anion transporters,mainly the monocarboxylate transporter-1 (MCT-1) and sodium-coupled monocarboxylate transporter 1 (SMCT-1), that absorb SCFA into the colonocytes does not seem to be a limiting factor. More bacterial SCFA production results in more uptake of SCFA but not necessarily in a higher fecal excretion. For instance, when we administered colon-delivery capsules containing SCFA in a dose of 250 mmol (equivalent to what is produced from 20 g of fermentable fiber), fecal SCFA concentrations did not increase, indicating nearly complete absorption into the colonocytes (1).

Quantification of SCFA in serum or plasma provides a more relevant alternative, particularly for understanding effects of SCFA on distant organs. Systemic SCFA concentrations are about a 1000-fold lower than fecal concentrations, requiring more sophisticated analytical protocols for measurement. Currently, both GC-MS or LC-MS/MS protocols with or without prior derivatization are available for accurate and reliable SCFA quantification (2). However, it is important to be aware of the ubiquitous nature of acetate and to take sufficient precautions to avoid contamination. For instance, the type of blood tubes used for blood collection should be considered since EDTA-tubes induce contaminations with acetate while separator tubes result in propionate and butyrate concentrations. Also, the type of water used during sample preparation can be a source of acetate contamination, necessitating the measurement of blanks in every run to check for background acetate.

Beyond analytical challenges, uncertainties about when to measure systemic SCFA concentrations also hamper their interpretation in humans. SCFA have a plasma half-life in the order of a few minutes, causing plasma SCFA to vary during the day in response to food intake, particularly fiber. Indeed, postprandial plasma SCFA start to rise about 4 hours after the consumption of a breakfast rich in fermentable fiber and return back to baseline by the end of the day. Measured concentrations therefore depend significantly on the composition and timing of the last meal. Even when using fasting blood samples, it remains important to standardize the evening meal of the previous day to avoid residual fermentation of that meal, known as the second meal effect. Due to their short plasma half-life, SCFA do not accumulate in the circulation, explaining the lack of differences in fasting SCFA concentrations from before to after prebiotic interventions. Additionally, interindividual variation in fasting SCFA concentrations is substantial as shown in a cross-sectional study in 160 individuals (3). The factors contributing to this variability require further investigation but may include dietary habits, microbiota composition, exercise levels or host genetics. In our lab, we prefer measuring postprandial SCFA concentrations during the day and calculating the area-under-the concentration vs time curve as a measure of SCFA production rather than relying on fasting concentrations, despite the increased burden on the participants involved in clinical trials and the associated cost and effort of sample analysis.

Importantly, SCFA production may explain part of the prebiotic activity, but it likely does not provide the complete picture. For example, while the interaction of prebiotics with the immune system may be partly explained by activation of ffar2 and ffar3 receptors on immune cells by SCFA, some prebiotics such as human milk oligosaccharides or specific pectin structures directly activate immune cells via interaction with toll-like receptors 2 and 4 (4). Additionally, by altering the microbiota composition, prebiotics also indirectly alter the microbe-immune interaction. Such effects also need consideration when evaluating prebiotic interactions with host health.

Studies, preferably conducted in the target host (e.g. humans), that aim to elucidate the qualitative and quantitative contribution of SCFA to the host health benefits of prebiotics (i.e. dose-effect relationships, fraction of health benefit explained by SCFA) are highly warranted. Only then can we establish the value of SCFA as markers of prebiotic activity.

Can prebiotics benefit brain health in older adults? ISAPP experts weigh in on a recent study

/in ISAPP Science Blog /by KC

With increasing age and frailty come changes in the gut microbiota – leading scientists to ask whether targeting the gut microbiota using prebiotics could contribute to healthier aging. Of particular interest is whether prebiotics have the potential to affect brain health and cognitive performance in older adults.

An intervention study led by researchers at King’s College London (UK) explored prebiotics’ effects on both physical health and cognition in older adults. In the study, 72 adults (twin pairs) aged 60 and up consumed either a prebiotic supplement or a placebo every day for 12 weeks. The prebiotic supplement contained a mixture of inulin and fructo-oligosaccharides (FOS) totalling 7.5 grams. All participants also did resistance exercises and took a supplement containing protein components (branched-chain amino acids, or BCAAs).

The results were promising: while participants in both groups overall showed improvements in their physical strength (as measured by chair rise time), the individuals in the prebiotic group performed better than the placebo group on cognitive tests (from a computer-based battery of tests called the CANTAB) measuring executive function and memory. The result is consistent with the idea that prebiotics benefit brain health in some situations.

Two ISAPP board members and prebiotic experts, Dr. Anisha Wijeyesekera PhD and Prof. Kristin Verbeke PhD, give their perspectives on this area of research and what’s added by this recent study.

Why are prebiotics of interest for benefits to brain health?

Wijeyesekera: There is growing evidence (and interest) in the link between the gut and the brain. There are several health conditions such as irritable bowel syndrome and autism spectrum disorder where this gut-brain link is evident, as patients experience symptoms that relate to both gut and brain health. Hence, for many researchers, gut microbiota targeted dietary interventions such as prebiotics and probiotics offer an approach to improve health outcomes such as cognitive function through targeted modulation of the gut microbiota.

 

What’s known about the mechanisms by which prebiotics might improve cognition?

Wijeyesekera: This is still being studied but most likely the production of microbial metabolites (such as short-chain fatty acids, or SCFAs) are playing a crucial role here. These microbially derived small molecules enter into host physiological processes, resulting in altered metabolic mechanisms that may be contributing to the changed health outcomes.

Verbeke: The mechanisms for gut-brain signaling have been studied mainly in in vitro and animal studies. Several potential pathways have been proposed, including metabolic (SCFA production that affects the hypothalamic-pituitary-adrenal axis), endocrine (microbial production of neurotransmitters and hormones), immune (release of anti-inflammatory mediators) or neural (vagus nerve stimulation) signaling. It is hard to say whether they are all equally important in humans or whether one of those mechanisms is primary. We assume it is a combination of all those effects.

In the current study, do you think the protein intake and exercise were necessary for the beneficial effects?

Verbeke: I assume that the protein (BCAA) supplement and the exercising was intended to improve the muscle strength, which was the primary outcome of the study. Indeed, the chair rise time improved in both groups but the prebiotic did not confer an additional benefit. With respect to cognition, there was a slight effect in the placebo group that only received the protein/exercise(although it is not indicated whether that difference is statistically significant) but addition of the prebiotic significantly increased the effect. So if the effect of protein/exercise alone was not significant, the result would have been the same without that intervention; if the effect was significant, the effect of prebiotic alone might have been a bit smaller but would probably still be there.

A combination of inulin and FOS were used in the study. Do you think a different type of prebiotic would have had the same results?

Verbeke: As long as we do not know the exact working mechanism, it is hard to predict what the effect of a different prebiotic would be. I do not expect that other prebiotics would have no effect at all but the extent of the effect may (slightly) differ from one prebiotic to another. For instance, it is possible that a prebiotic that yields a different ratio of SCFA upon fermentation may have a different effect, or that a prebiotic that more selectively stimulates bacteria secreting different amounts of neurotransmitters such as GABA may also have a different effect.

What are some gaps in what researchers know about how prebiotics affect brain function?

Wijeyesekera: It would have been great if the metabolic phenotypes had also been characterised in the study, as this would be able to identify alterations to metabolic pathways as a result of the intervention. This may shed more light on the activity of the microbes that were identified to have been altered as a result of the intervention, and also the impact of the protein and exercise in general on metabolic mechanisms.

Verbeke: The effect of prebiotics/fiber on cognitive function is likely confounded by a number of individual host factors such as the baseline diet, age, lifestyle, and baseline cognitive function level. We need much more research to understand the interaction between all these factors and to be able to identify the people that would benefit most from a prebiotic/fiber intervention.

2023 in Review: Highlights in the Field of Biotic Science

/in ISAPP Science Blog /by KC

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

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

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

Increased recognition of biotics as a category

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

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

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

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

Wider awareness of the postbiotic concept and definition

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

Advances in technologies for analyzing different sites in the digestive tract

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

First convincing evidence linking intake of live microbes with health benefits

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

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

Increased interest in candidate prebiotics

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

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

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

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

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

Novel findings related to lactic acid bacteria

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

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

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

Updated resource available on probiotics and prebiotics in gastroenterology

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

Statistical considerations for the design of randomized, controlled trials for probiotics and prebiotics

/in ISAPP Science Blog /by KC

By Prof. Daniel Tancredi, UC Davis, USA

The best evidence for the efficacy of probiotics or prebiotics generally comes from randomized controlled trials. The proper design of such trials should strive to use the available resources to achieve the most informative results for stakeholders, while properly accounting for the consequences of correct and incorrect decisions. It is crucial to understand that even well-designed and -executed studies cannot entirely eliminate uncertainty from statistical inferences. Those inferences could be incorrect, even though they were made rigorously and without any procedural or technical errors. By “incorrect”, I mean that the decisions made may not correspond to the truth about those unknown population parameters. Those parameters involve the distribution of study variables in the entire population, but our inferences are inductive and based on just the fraction of the population that appeared in our sample, creating the possibility for discordance between those parameters and our inferences about them. Although rigorous statistical inference procedures can allow us to control the probabilities of certain kinds of incorrect decisions, they cannot eliminate them.

For example, consider a two-armed randomized controlled trial designed to address a typical null hypothesis, that the probability of successful treatment is the same for the experimental treatment as for the comparator. Depending on the analytical methods to be employed, that null hypothesis could also be phrased as saying that the difference in successful treatment probabilities between the two arms is zero or that the ratio of the successful treatment probabilities between the two groups is one. Suppose the study sponsor has two possible choices regarding the null hypothesis, either to reject it or fail to reject it. (The latter choice is colloquially called “accepting the null hypothesis”, but that is a bit of an overstatement, as the absence of evidence for an effect in a sample typically does not rise to the level of being convincing evidence for the absence of an effect in the population.)

With these two choices about the null hypothesis, there are two major types of “incorrect decisions” that can be made: the null hypothesis could be true for the population but the study data led to a decision to reject the null hypothesis, a result conventionally called a “Type-1” error. Or the null hypothesis could be false for the population but the study data led to a decision not to reject the null hypothesis, conventionally called a “Type-2” error. Conversely, there are also two potentially correct decisions. One could fail to reject the null hypothesis when the null hypothesis is true for the population, a so-called “true negative”, or one could reject the null hypothesis when the null hypothesis is not true, a so-called true positive.

The consequences of these four different decision classifications vary from one stakeholder to another, and thus it is unwise to rely solely and simply on commonly used error probabilities when planning studies. The wiser approach is to set the error probabilities so that they properly account for the relative gains and losses to a stakeholder that arise from correct and incorrect decisions, respectively. From long experience assessing the design of clinical trials for probiotics and prebiotics, I recommend that stakeholders in the design phase of studies give thought to the following three statistical considerations.

Pay attention to power

Power is the probability of avoiding a type-2 error—in other words, under the condition that an assumed true effect exists in a study population and that the type-1 error has been controlled at a given value, power is computed of the probability of avoiding the incorrect decision to fail to reject the null hypothesis. Standard practices are to set the type-1 error at 5% and to determine a sample size that achieves 80% power for an assumed alternative hypothesis, one stating that the true effect is of a specific given magnitude, one corresponding to a so-called meaningful effect size. That effect size is typically called a ‘minimum clinically significant difference’ (MCSD) or something similar, because ideally the assumed effect size would be the smallest of the values that would be clinically important, although as a practical matter — because the higher the magnitude of the effect size, the lower the sample size requirements and thus the better the chance of the study being perceived as “affordable” to study sponsors — the MCSDs used to power studies are often larger than some of the values that would also be clinically significant. Nevertheless, let’s consider what it means for the sponsor to accept that the study should be powered at merely the conventional 80% level. Under the assumptions that the true effect in the population is the MCSD and that the study achieves its target sample size, a sponsor of a study that has only 80% power is taking a 1-in-5 chance that the sample results would not be statistically significant (and that the null hypothesis would fail to be rejected).  Such an incorrect decision could have major adverse implications for the sponsor (and for potential beneficiaries of the intervention), particularly given the investments that have been made in the research program and the implications the incorrect decision could have for misinforming future decisions regarding the specific intervention and indeed related interventions.  A 20% risk may not be worth taking.

All other considerations being equal, the risk of a type-2 error could be lowered by increasing the sample size. Under regular asymptotic assumptions that generally apply, increasing the target sample size by about one-third would cut a 20% type-2 error risk in half, to 10%. Increasing the target sample size by two-thirds reduces it all the way to 5%.

Define the true minimum clinically significant effect size applicable to your study

Another important question is where to set the minimum clinically significant effect. Often that effect is based on prior studies without any adjustment—but this can neglect key considerations. Prior effects of an intervention are typically biased in a direction that overstates the benefits of the intervention, especially if the intervention emerged from smallish early-phase studies. More fundamentally, from the perspective of decision theory the estimated effects seen in prior studies do not specifically address what could truly be the minimum clinically meaningful effect when one considers the possible benefits, risks, and costs of the intervention. Probiotics and prebiotics are typically relatively benign interventions in terms of adverse events, so it could be that even more modest favorable impacts on health than were seen in prior studies are still worthwhile.

Powering your study based on what truly is a minimal clinically meaningful effect may lead to a better overall strategy for optimizing net gains, while giving the intervention an appropriately high chance of showing that it works. Although the smaller the assumed effect size, the larger the required sample size needed to detect it (all other factors being the same), a proper assessment of the relative risks and benefits of the intervention and, also, of correct and incorrect decisions about the intervention, may provide a strong basis for making that investment.

In addition, there is another important but often overlooked aspect when deciding on what is a worthwhile improvement. We frequently turn to clinicians to determine what would be a worthwhile improvement, and it is natural for a clinician to address that question by considering what would be a meaningful improvement for a patient who responds to the intervention. Keep in mind, though, that an intervention could be worthwhile for a population if it achieves what would be a worthwhile improvement for a single patient–say, a mean improvement of 0.2 SD on a quality-of-life scale—in only a fraction of the patients in the overall population, say 50%. There are many conditions for which having an intervention that works for only large subsets of the population could be valuable in improving the population’s overall health and wellness. Using this example, where the worthwhile improvement for an individual is 0.2 SD and the worthwhile responder percentage is 50%, then the worthwhile improvement that should be used to power the study would be 0.1 SD, which is equal to (0.2 SD * 50%) + (0 SD * 50%), with the latter product quantifying an assumed absence of a benefit in the non-responders. What should be gleaned from this example is that the minimum clinically important effect for a population is typically less than the minimum clinically important effect for an individual. The effect used to power the study should be the one that applies to the relevant population. Again, that effect should be chosen so that it balances benefits relative to the costs and harms of the intervention while accounting also for variation in whether and how much individuals in the population may respond. When study planners fail to account for this variation, the result is a study that is underpowered for detecting meaningful population-level effects.

Improving the signal-to-noise ratio

In general, effect sizes can be expressed analogously to a mean difference divided by a standard error, and thus can be thought of as a signal-to-noise ratio. Sample size requirements depend crucially on this signal-to-noise ratio. Typically, standard errors are proportional to outcome standard deviations and inversely proportional to the square root of the sample size. The latter is key because it means that in case an expected signal would be cut in half, the noise would also need to be cut in half to maintain the signal-to-noise ratio, which means that if you cannot alter the outcome standard deviation, then you would need to quadruple the sample size. This also applies in the opposite direction, happily: if you can double the expected signal-to-noise ratio, you would only need one-fourth the sample size to achieve the desired power, all other things being equal.

Signal-to-noise ratios can be optimized by designing a trial for a judiciously restricted target population (of potential responders) and by using high-quality outcome measurements for the trial to reduce noise. Although research programs may eventually aim to culminate in large pragmatic trials that show meaningful improvements associated with an intervention even in populations of individuals with wide variations in their likelihood and amount of potential response, it is generally wise up to that stage in a research program to focus trials so that they give accurate information as to whether the intervention works in populations targeted for being more apt to be responsive to an intervention. To do that, for example, the trial methods should include accurate assessments for whether potential recruits are currently experiencing, say, symptoms from whatever condition the intervention is intended to address and whether the recruit would be able to achieve the desired dose of whatever the trial assigns to them. For a truly beneficial intervention, it is easier to continue a research program advancing the development of that intervention if the intervention sustains a consecutive string of “true positive” results from when it began to undergo trials, avoiding a potentially fatal type-2 error (“false negative”).

Careful attention to the above considerations can lead to better trials, ones that combine rigor and transparency with a tailored consideration of the relative costs and benefits of potentially fallible statistical inferences, so that the resulting evidence is as informative as possible for stakeholder decision-making.

Episode 30: A systems biology perspective on the gut microbiome

/in Podcast, Season Two /by Laura

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The Science, Microbes & Health Podcast 

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

A systems biology perspective on the gut microbiome, with Dr. Sean Gibbons PhD

Episode summary:

In this episode, the ISAPP hosts discuss the microbiome and systems biology with Dr. Sean Gibbons PhD, Associate Professor at the Institute for Systems Biology in Seattle, USA. Prof. Gibbons talks about exploring and manipulating the complex ecology of the microbiome with the aim of engineering outputs of this system. He describes the utility of artificial intelligence in microbiome science and how the microbiome will play a role in personalized medicine in the future, including in the delivery of probiotics and prebiotics.

Key topics from this episode:

  • Dr. Gibbons’ lab primarily focuses on designing bioinformatic tools for exploring and manipulating the complex ecology of the microbiome, and trying to shape the outputs of the system. He emphasizes the need for computational tools alongside traditional microbiological techniques, which are needed to validate computational findings.
  • From the work so far, he says probiotics appear to be efficacious but context-specific, so the effects may appear dampened in trials with heterogeneous participants.
  • He underlines that artificial intelligence (AI) is needed to integrate complexity and predict emergent outputs of a biological system that includes a microbiome. Reductionist approaches are somewhat limited because each component of a complex system may behave differently on its own.
  • Diet is a key way to deliberately manipulate the gut microbiome. Researchers are working on how to push the system in a predictable direction. One approach is to create orthogonal niches for organisms: for example, an item in the diet (such as seaweed) that could support an organism that wouldn’t otherwise be there. His lab is working on tools that predict the likelihood of engraftment of a particular organism in a complex community.
  • Reliable tools are needed to map taxonomic composition onto functional outputs.
  • Two branches existed in the history of AI: (1) extracting new knowledge using approaches such as neural nets, and (2) A symbolic AI family of modelling, in which you already have knowledge and you can use it to make predictions about a system (making use of knowledge graphs).
  • Dr. Gibbons says microbiome measurements will likely be a part of clinical medicine in the future, because the microbiome accounts for individuals’ personalized responses to some interventions that cannot be explained by any other known factor.
  • In the future, we will be able to develop tools for precision prebiotic, probiotic, and dietary interventions through metabolic modelling work. 
  • Many probiotics have great efficacy in a particular context – so one challenge ahead is to find a rational way to deploy these organisms and to prove they work well. We will need to address the regulatory challenges inherent in personalized approaches as well.

Episode links:

About Dr. Sean Gibbons PhD:

Sean Gibbons earned his PhD in biophysics from the University of Chicago in 2015. He completed his postdoctoral work at MIT in 2018. Sean is now an associate professor at the Institute for Systems Biology, in Seattle. His lab studies the ecology and evolution of microbial communities. In particular, Sean is interested in how host-associated bacterial communities influence the health and wellness of the host organism. His group designs computational and wet-lab tools for studying these complex systems. Ultimately, the Gibbons Lab aims to develop strategies for engineering the ecology of the gut microbiome to improve human health.

Inaugural nominations open for ISAPP Award: The Sanders Award for Advancing Biotic Science

/in News /by KC

With this year’s retirement of ISAPP’s longtime Executive Science Officer, Dr. Mary Ellen Sanders PhD, the ISAPP board of directors sought a suitable way to honor her contributions in advancing scientific development in the fields of probiotics, prebiotics, synbiotics, postbiotics and fermented foods. Many scientists in these fields have commended Mary Ellen’s leadership, initiative, collaboration, and communication over the last 20 years.

Board members decided to launch a new award in Mary Ellen’s honor: The Sanders Award for Advancing Biotic Science. This award aims to promote excellence in the biotic field and recognize exceptional achievement across a range of potential endeavours including research, scientific communication and stakeholder engagement. A cash grant and travel to the ISAPP meeting will be awarded to the annual recipient starting in 2024.

Prof. Gregor Reid PhD, ISAPP co-founder and former board member, who championed the award, says: “What better way to applaud leadership and someone who has placed honesty, stewardship and evidence-based progress above all else, than to have an annual celebration of advancement in these critically important fields.”

The ISAPP board invited members of the ISAPP community to donate to a special endowment fund in order to sustain the Sanders Award over the long term, and this fund received over $34,000 of donations.

ISAPP President, Prof. Dan Merenstein MD, says: “We have really appreciated and been touched by the generous individual and company donations. But none of that is surprising because Mary Ellen has been a positive force in this field since the beginning and everyone who works with her respects and enjoys working with her.”

The award was launched in August, 2023 and nominations are open through to November, 2023.

Find out more about the award here.

Biotics in animal and human nutrition

Episode 22: Biotics in animal and human nutrition

/in Podcast, Season Two /by Laura

Biotics in animal and human nutrition

 

Podcast: Play in new window | Download

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The Science, Microbes & Health Podcast 

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

Biotics in animal and human nutrition, with Prof. Kelly Swanson

Episode summary:

In this episode, the ISAPP podcast hosts join guest Prof. Kelly Swanson PhD from University of Illinois at Urbana-Champaign, to discuss the role of biotics in animal and human nutrition. They review the criteria for prebiotics and synbiotics, then discuss how we gain knowledge about nutrition and the role of biotics in animals compared to humans.

Key topics from this episode:

  • A good argument can be made that biotics are essential for our diet; they are beneficial even if efficacy is sometimes difficult to prove.
  • Nutrients have an impact on the host’s health and simultaneously on the host-associated microbes.
  • Health benefits are essential to the FDA definition of fiber.
  • Antibiotics’ effect on the microbiota: short-term effects may be minor, but we still don’t know the long-term effects.
  • The synbiotics definition, criteria for products to meet this definition, and the health outcomes from using these biotic substances.
  • The difference between complementary and synergistic synbiotics.
  • When studying biotics in companion animals (cats and dogs), can results from one host be extrapolated to another host? Final studies should be in the target host.
  • Biotics are important in veterinary medicine and a popular topic of study.
  • Predictions about the future of nutrition science as informed by the microbiome.

Episode links:

Additional resources:

About Prof. Kelly Swanson:

Kelly Swanson is the Kraft Heinz Company Endowed Professor in Human Nutrition at the University of Illinois at Urbana-Champaign. His laboratory studies the effects of nutritional interventions, identifying how diet impacts host physiology and gut microbiota. His lab’s primary emphasis is on gastrointestinal health and obesity in dogs, cats, and humans. Much of his work has focused on dietary fibers and ‘biotics’. Kelly has trained over 40 graduate students and postdocs, published over 235 peer-reviewed manuscripts, and given over 150 invited lectures at scientific conferences. He is an active instructor, teaching 3-4 nutrition courses annually, and has been named to the university’s ‘List of Teachers Ranked as Excellent by Their Students’ 30 times. He serves on advisory boards for many companies in the human and pet food industries and non-profit organizations, including the Institute for the Advancement of Food and Nutrition Sciences and International Scientific Association for Probiotics and Prebiotics.

New global guidelines for probiotics and prebiotics for gut health and disease

/in ISAPP Science Blog /by KC

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

The use of probiotics and prebiotics in the practice of gastroenterology must be guided by evidence – and with new evidence continually emerging, clinicians can benefit from efforts to summarize this evidence and determine how it applies in clinical practice.

In February 2023, the World Gastroenterology Organisation provided an updated resource in this area, titled “WGO Practice Guideline. Probiotics and Prebiotics”. This project was led by Prof. Francisco Guarner MD PhD, a clinical gastroenterologist and clinical researcher in probiotics and prebiotics, and brought together experts in gastroenterology, pediatrics, family medicine, probiotics, and prebiotics. Prof. Hania Szajewska MD PhD, a clinical pediatrician and clinical researcher in probiotics from the Medical University of Warsaw, was integral to assessing evidence for pediatric populations for the guidelines. Mary Ellen Sanders PhD co-chaired the project.

For 2023 update, 800 bibliographical entries of papers published in the 2017-2021 period were scrutinized. The review team adopted the guidelines for evaluation of probiotics established by FAO/WHO experts in 2002, where at least one double blind, randomized, placebo-controlled human trial with appropriate sample size and primary outcome is required to determine if the tested product is efficacious, and qualifies as a probiotic.

ISAPP was well-represented among the experts involved on the project, as four current board members contributed. In addition to Sanders and Szajewska, Prof. Dan Merenstein MD (current ISAPP president) and Prof. Seppo Salminen PhD (current past president) populated the team.

The Guideline is intended to provide specific information on interventions that may have benefit for indicated conditions. Recommendations included probiotics or prebiotics found in at least one randomized, controlled trial showing benefit. Trials that did not show benefit were not included. The Guideline serves an important role in informing gastroenterologists around the world, especially in regions where product availability might be limited. Especially useful are Tables 8 and 9, which summarize evidence for adult and pediatric uses, respectively.

Guarner states, “We hope our WGO guideline will assist doctors, pharmacists, dietitians and other healthcare professionals all around the world to integrate probiotics and prebiotics in an evidence-based manner into their daily work of patient care.”

The Guideline provides text that introduces current understanding of probiotics and prebiotics and then comprehensively evaluates the evidence for gastrointestinal conditions. Evidence is graded from 1-3, with Level 1 referring to evidence supported by systematic review of randomized trials, Level 2 supported by randomized trials with consistent effect, without systematic review, and Level 3, supported by a single randomized controlled trial, as per the Oxford Centre for Evidence-Based Medicine.

The 2017 iteration of these guidelines was available in six languages (English, French, Portuguese, Mandarin, Russian and Spanish). This guideline is the most accessed guideline title on the WGO website,  accounting for nearly one-quarter of all visits to the site. The 2023 version is only available in English so far, but translations are underway.

Clinical conditions for which some evidence was found include:

  • Diarrheal conditions: acute, antibiotic-associated, difficile-associated, radiotherapy-associated, enteral nutrition-associated, nosocomial,
  • Diverticular disease
  • Functional abdominal pain
  • Functional constipation
  • Insulin resistance
  • Health-related quality of life
  • Helicobacter pylori infection
  • Hepatic encephalopathy
  • Infantile colic
  • Inflammatory bowel disease
  • Irritable bowel syndrome
  • Lactose maldigestion
  • Nonalcoholic fatty liver disease
  • Nonalcoholic steatohepatitis
  • Necrotizing enterocolitis

 

About WGO:
World Gastroenterology Organisation (WGO) is a federation of over 100 Member Societies and four Regional Associations of gastroenterology representing over 60,000 individual members worldwide.  The WGO Guidelines Library contains practice guidelines written from a viewpoint of global applicability. The Guidelines go through a rigorous process of authoring, editing, and peer review and are as evidence based as possible.

Supercharging innovation: New session at ISAPP 2023 annual meeting brings industry and student members together to scientific innovation workshop in the field of biotics

/in News /by KC

Innovation in the biotics field is an important way to address some of our most important challenges in health, and ISAPP is the organization on the forefront of this innovation. This year ISAPP members are excited to debut a new workshop focused on innovation, June 26th at the 2023 ISAPP annual meeting in Denver. For this workshop, the Industry Advisory Committee (IAC) and the Students and Fellows Association (SFA) have joined forces and initiated a new way to share knowledge and promote networking opportunities.

How did the idea of the IAC-SFA innovation workshops come about?

The Innovation Workshops evolved from interest in how SFA and IAC might gain scientific insights from each other. What they have in common is a dedication to cutting-edge science. From this emerged the idea that these groups could convene several concurrent workshop sessions during the pre-meeting program focusing on innovation in the biotic field.

What will be discussed at the workshops?

The concurrent workshops will focus on four topics:

  • Innovation in prebiotics: What’s next? Chaired by Marla Cunningham
  • Latest advances in microbiome models and biotic screening techniques. Chaired by Brendan Daisley
  • Looking to the future for food and biotics. Chaired by Daragh Hill
  • Probiotic application beyond the gut: What have we learned and what’s next? Chaired by Mariya Petrova

Guided by IAC and SFA representatives, the attendees at each workshop will discuss topics of interest and attempt to answer relevant questions in the biotics field. For example:

  • What are the latest developments in the biotic field regarding research, discoveries, and techniques?
  • What problems are we currently facing, and how will we solve them?
  • What are the future opportunities, and how can we progress?

How will this advance innovation in the field?

The Innovation Workshops will provide a platform where IAC representatives and SFA members can benefit from the exchange ideas gained from unique viewpoints expressed. Industry members can hear firsthand about innovative research that students and fellows perform in their labs, while students can gain a deeper understanding of some of the considerations for commercialization and opportunities and barriers in the marketplace. By joining forces, we believe these workshops will form a bridge between industry and young generation scientists and provide valuable insights into to the latest biotic questions.

Through initiatives such as these, ISAPP drives scientific innovation in biotics for the benefit of the entire field.

Popular media, misinformation and ‘biotics’

/in News /by KC

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

Encountering misinformation is all too easy when seeking understanding of probiotics, prebiotics, synbiotics, and postbiotics (collectively, ‘biotics’). It can be perpetuated both by proponents and detractors. Through this lens, I’m prompted to comment on some high profile pieces making news recently. A Washington Post article Probiotic supplements may do the opposite of boosting your gut health was published on March 28, 2023, by Anahad O’Connor. This author was then interviewed for a CBS video story Studies find that probiotics can harm gut health on March 30, 2023.  Then, a National Geographic article Probiotics, prebiotics, postbiotics. What’s the difference? was published on the same day.

These pieces appropriately acknowledge the availability of evidence linking probiotics to human benefits. Yet the points raised about potential harms from probiotics and a misunderstanding of what ‘biotic’ substances really are deserve comment.

Harms of probiotics

Amid a backdrop of marketing and media messaging lauding the many benefits of probiotics, reporters are understandably drawn to the counter message that ‘probiotics can harm gut health’. Safety must always be rigorously assessed, as encouraged by a 2023 ISAPP paper focused on emerging issues in probiotic safety (see here). However, the claims of harm made – although generated from studies in humans – are not based on clinical endpoints. Instead they are based on either microbiome endpoints (Suez et al. 2018) or on post hoc analysis of biomarker outcomes (Wastyk et al. 2023). The limitations of the Suez et al. 2018 study were discussed in more detail previously (See: Clinical evidence and not microbiota outcomes drive value of probiotics). This paper evaluated the effect of one multi-strain probiotic product and is the only paper I am aware of that shows that probiotics inhibit microbiome recovery after antibiotic treatment. The paucity of supporting evidence for the harm supposedly documented in this paper is not mentioned in the stories. It is noteworthy that in the Wastyk et al. 2023 paper the authors acknowledge that the study did not achieve its primary objectives, and in referring to their post hoc analysis (including the ‘evidence’ for harm), they specifically acknowledge that such analysis is not conclusive evidence:  “We next leveraged aspects of our study design … in a discovery analysis process to reveal trends that could inform possible … hypotheses for future studies.” These studies are best used for generating hypotheses requiring further study.

Another criticism that was leveraged as evidence that probiotics cause harm is that probiotics reduce microbiota diversity. Any probiotic-induced reduction in diversity of fecal microbiota has not been shown to be associated with harm. Further, most studies show no significant overall changes in microbiome composition in response to traditional probiotic administration. However, it should be understood that the value of diversity as a marker of health remains unproven. The evidence is from observational studies and only shows associations, not causality.

 You can’t both object to criticisms based only on microbiome data but then promote probiotics based on it.

As stated, relying on microbiota endpoints to advance the idea that probiotics cause harm is not justified. But I cannot escape the fact that probiotic proponents in part contribute to this thinking. When probiotics are marketed as being able to ‘balance the microbiota’, without clinical data to substantiate a benefit, aren’t they promoting the same limited science?

Adherence to definitions of biotics needed

ISAPP has rigorously considered and offered definitions for probiotics, prebiotics, synbiotics, postbiotics and fermented foods (see here for a summary), which have been presented in highly cited reviews in Nature Reviews Gastroenterology and Hepatology (see here, here, here, here and here). These efforts were undertaken to advance a common understanding of these terms, so that precision can be attained in communications on them.

This objective has been far from realized. Misuse of these terms continues on product labels, in scientific publications, and in popular press communications.

The articles cited above compelled me to offer some take home messages for those responsible for accurately communicating science:

  • “Prebiotics + probiotics = postbiotics”, a heading in the National Geographic article, is completely wrong.

Probiotics are: Live microorganisms that, when administered in adequate amounts, confer a health benefit on the host

Prebiotic is: A substrate that is selectively utilized by host microorganisms conferring a health benefit on the host

Postbiotic is: Preparation of inanimate microorganisms and/or their components that confers a health benefit on the host

  • Fermented foods are not the same as probiotics. Most fermented foods have not been proven to improve health (associative studies have suggested, but in most cases not proven, health benefits), many do not retain live microbes, and most are not made with microbes characterized to the strain level. All these are requirements to meet the definition of a probiotic. See here, here and here for clear discussions of this issue.
  • Fermented foods are not the magic bullet that many portray them as. Yes – for that subset of fermented foods that retain live microbes – they may contribute a diversity of live microbes to the diet. ISAPP has recently researched this area (see recent ISAPP publications here and here). And yes, they are tasty. However, the evidence level for benefits of traditional fermented foods is nowhere near the level for probiotics. Still, healthcare professionals critical of evidence supporting probiotic benefits commonly recommend fermented foods.
  • Postbiotics do not refer to ‘metabolites from probiotics’. See here for why ISAPP focused the definition of postbiotic on inactivated microbes with or without their metabolites.
  • In simplistic language, prebiotics can be viewed as food for beneficial microbes, but, typically, prebiotics target the normal microbes in the gut, not probiotics. See here.

Conclusion

Both the positive and negative effects of probiotics based on microbiome assembly can be misrepresented in the press, by some marketing claims, and sometimes in scientific literature. The field will benefit from communications that acknowledge the limitations of available science. Further, it’s important for clarity in communication that the field coalesces around established definitions and honor the criteria needed to meet those definitions. Additionally, scientists and medical professionals should apply the same scrutiny and critical thinking to fermented foods as they do to probiotics.

ISAPP encourages healthy debate, critical review of new studies and innovative research. Since ISAPP’s mission is focused on promoting the science of these substances, journalists are invited to reach out as needed to ISAPP for an evidence-based perspective on this evolving field (www.ISAPPscience.org).

Episode 17: Using metabolomics to learn about the activities of gut microbes

/in Podcast, Season Two /by Laura

 

Podcast: Play in new window | Download

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The Science, Microbes & Health Podcast 

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

Using metabolomics to learn about the activities of gut microbes, with Dr. Anisha Wijeyesekera

Episode summary:

In this episode, the ISAPP podcast hosts address the topic of metabolomics with Dr. Anisha Wijeyesekera, PhD, a Lecturer in the Department of Food and Nutritional Sciences at the University of Reading, United Kingdom. Dr. Wijeyesekera gives an overview of how metabolic profiling works, including the information provided by different biological samples, and discusses how metabolomics can be used to piece together the contributions of microbes to host health.

 

Key topics from this episode:

  • Dr. Wijeyesekera introduces the field of metabolomics and describes it as an essential part of systems biology. Metabolic profiling provides a real-time snapshot of the multiple metabolic processes going on in a system at the time the sample was collected.
  • Metabolites are the end products of metabolism; the gut microbiota is the most metabolically active of the microbiomes in the human body.
  • Methodology depends on what information you hope to uncover from your samples. Different biological samples (e.g. stool, urine, plasma) provide different pieces of information; this is cross-referenced with information on metabolic pathways.
  • One application of metabolomics is in identifying biomarkers that can predict patient outcomes. Identifying differences in microbes as well as metabolites could lead to the development of dietary-based supplements for patients to take alongside clinical treatments.
  • Changes in microbial composition may not be that meaningful if the bugs that change are doing the same thing in the end; this is what metabolomics helps uncover.
  • Metabolomics gives you insights into mechanisms when you have a probiotic or prebiotic trial with clinical outcomes. 
  • Short-chain fatty acids are metabolites that are frequently associated with health; changes in these is a clue that the gut microbiota has been impacted by the intervention.
  • Bile acids are metabolites that come from diet. Microbes convert primary bile acids to secondary, which circulate throughout the body. You can measure bile acids to see how gut microbiota are affected by an intervention.
  • Metabolomics is very promising and may be used in more probiotic and prebiotic studies in the future.

 

Episode abbreviations and links:

 

About Dr. Anisha Wijeyesekera:

Anisha is a Lecturer in the Department of Food and Nutritional Sciences at the University of Reading, United Kingdom. She previously worked at Imperial College London, where she also obtained her PhD (in Biochemistry). Anisha’s research applies a combined microbial and metabolic phenotyping approach, to better understand the tripartite relationship between diet, gut microbiota and human health. At the University of Reading, she conducts in vitro and in vivo studies for functional assessment of the gut microbiota, particularly in response to prebiotics and probiotics. The ultimate aim is to use this information to tailor nutritional or other interventional therapy to improve health outcomes.

Episode 15: A primer on prebiotics

/in Podcast, Season Two /by Laura

 

Podcast: Play in new window | Download

Subscribe: Apple Podcasts | Spotify | RSS

The Science, Microbes & Health Podcast 

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

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

/in ISAPP Science Blog /by KC

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

/in ISAPP Science Blog /by KC

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.

 

Watch the recording of this webinar below:

 

 

 

 

Episode 14: Evidence on probiotics for preterm infants

/in Podcast, Season One /by KC

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The Science, Microbes & Health Podcast 

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

Evidence 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

/in Podcast, Season One /by KC

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The Science, Microbes & Health Podcast 

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

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

/in Podcast, Season One /by KC

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Subscribe: Apple Podcasts | Spotify | RSS

The Science, Microbes & Health Podcast 

This podcast covers emerging topics and challenges in the science of probiotics, prebiotics, synbiotics, postbiotics and fermented foods. This is the podcast of The International Scientific Association for Probiotics and 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?

/in Consumer Blog, ISAPP Science Blog /by KC

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

/in Consumer Blog, ISAPP Science Blog /by KC

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 now closed. Please watch the recording of this webinar below.

Episode 5: Prebiotics for animal health

/in Podcast, Season One /by KC

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The Science, Microbes & Health Podcast 

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

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?

/in Consumer Blog, ISAPP Science Blog /by KC

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

 

 

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