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Should bacteriophages be considered as a member of the biotic family?

April 25, 2024/in ISAPP Science Blog /by KC

By Prof. Colin Hill PhD DSc, University College Cork, Ireland

ISAPP has provided consensus definitions for a number of biotics that confer a health benefit on the host. These include prebiotics, probiotics, synbiotics and postbiotics, but here I want to put forward an argument that bacteriophages (phages) could qualify as a new member of the ‘biotic’ family.

Phages are bacterial viruses that infect and replicate within their bacterial victim before bursting the cell and releasing many new copies of the original virus. Phages can also integrate into the bacterial chromosome and co-exist with the living bacterium, but always with the threat that it can excise and initiate another replication-and-burst cycle. Phages are probably the most abundant biological entities on earth and are found wherever bacteria are present in the body. They are an important component of the microbiome of humans, plants and animals, and play a role in regulating bacterial community composition and function.

If phages are to fit neatly within the existing biotic family they would have to qualify as a biotic and also be shown to provide health benefits. The Oxford English Dictionary defines biotics as ‘of or relating to living organisms; caused by living organisms’. Bacteriophages (phages) are not considered as living organisms in themselves, but they easily fit within the biotic definition as they are completely dependent on living bacterial cells for their own propagation and as such certainly ‘relate to living organisms’.

There is also a significant body of evidence that some phages can confer health benefits on a host. Most of this evidence is based on using phage therapy to treat bacterial infections. This has been done in Russia for almost a century, and while the evidence may not always conform to western regulatory standards there is little doubt that phages can bring benefits such as limiting or clearing infections at various body sites. In a recent example, a randomised, controlled, blinded trial on burn wounds was conducted in Belgium and France with Pseudomonas aeruginosa as the target (1). A topically applied preparation consisting of low titres of a 12-phage cocktail was used. While the efficacy did not reach that of the standard-of-care sulfadiazine silver emulsion cream treatment, the phage treatments did lead to sustained reductions in bacterial burdens.

Phages can also be potentially used to modulate microbiomes to impact host health, as shown in a recent study I was involved in performed by Nate Ritz in the John Cryan lab where faecal virome transplants (FVT) changed the bacterial community and thus reduced the impact of stress-induced changes in behaviour and immune responses in mice (2). This paper was the topic of a recent ISAPP podcast for anyone interested in hearing more about that story. FVT has also been reported to work against Clostridioides difficile infections in humans in a small trial in Germany (3).

The term phagebiotic is perhaps the most fitting for this new type of biotic. I have always argued that we should not invent new terms for things that already have names, so why not just stick to bacteriophages or phages? It is because the term phagebiotic would be reserved for a very specific sub-category of phages. Just as all probiotics are microbes, but not all microbes are probiotics, I would suggest that phagebiotics should only be used to refer to specific phage preparations that have been shown to convincingly confer a health benefit in an appropriate properly controlled trial.

Mirroring the probiotics definition I would start with a suggested definition something like this; ‘phagebiotics are bacteriophages that, when administered in adequate amounts, confer a health benefit on the host’.

Jault P., Leclerc T., Jennes S., Pirnay J.P., Que Y.A., Resch G., Rousseau A.F., Ravat F., Carsin H., Le F.R., et al. Efficacy and tolerability of a cocktail of bacteriophages to treat burn wounds infected by Pseudomonas aeruginosa (PhagoBurn): A randomised, controlled, double-blind phase 1/2 trial. Lancet Infect. Dis. 2019;19:35–45. doi: 10.1016/S1473-3099(18)30482-1
Ritz, N.L., Draper, L.A., Bastiaanssen, T.F.S. et al. The gut virome is associated with stress-induced changes in behaviour and immune responses in mice. Nat Microbiol 9, 359–376 (2024). https://doi.org/10.1038/s41564-023-01564-y
Ott, S. J., Waetzig, G. H., Rehman, A., Moltzau-Anderson, J., Bharti, R., Grasis, J. A., et al. (2017). Efficacy of sterile fecal filtrate transfer for treating patients with Clostridium difficile Gastroenterology 152, 799.e797–811.e797. doi: 10.1053/j.gastro.2016.11.010

Microbiota-Gut-Brain Axis Researcher in Belgium Receives ISAPP’s 2024 Glenn Gibson Early Career Researcher Award

January 22, 2024/in News /by KC

The ISAPP selection committee for the Glenn Gibson Early Career Researcher Award is pleased to announce that Dr. Boushra Dalile PhD, a postdoctoral fellow at KU Leuven (Belgium), is the recipient of this year’s award.

Dr. Dalile is a researcher who moved from studying psychology and cognitive neuroscience into biomedical sciences, completing her PhD in 2021. She now focuses on the gut-brain axis – specifically, the mechanistic role of colonic short-chain fatty acids (SCFAs) as mediators of prebiotic effects on stress-related mental disorders. In one of her group’s most recent studies, she used colon-delivery capsules to approximate the metabolic effects of prebiotic administration, and found that direct delivery of SCFAs successfully reduced physiological stress response (as measured by cortisol) in humans. She is interested in continuing to explore the potential of butyrate for modulating fear as well as anxiety-related learning and memory processes.

A multilingual researcher who lived in Germany and Sweden before coming to KU Leuven, Dr. Dalile currently has a postdoc project supported by The Research Foundation – Flanders, titled “INTERFEAR – Investigating the endogenous metabolite butyrate as an epigenetic modulator of fear memory”.

The 2024 award committee, composed of ISAPP board members and affiliates, identified Dr. Dalile as making important contributions in the biotics field early in her scientific career. The award is given annually to a researcher who is no more than five years past their terminal degree, in a field of study related to probiotics, prebiotics, synbiotics, postbiotics or fermented foods. She will receive a cash prize and a speaking slot at the ISAPP annual meeting in July, 2024.

2023 in Review: Highlights in the Field of Biotic Science

December 15, 2023/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

December 12, 2023/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.

New paper outlines the value of studying probiotics in the small intestine

November 15, 2023/in ISAPP Science Blog /by KC

Even though the human digestive tract extends from the mouth down through the small and large intestines, the study of probiotics and their activities has tended to focus on the colon. While the colon (or perhaps more accurately its proxy, the faecal sample) is relatively accessible and easy to study, recently some researchers have argued that crucial information can be gained from looking at another digestive tract site: the small intestine.

A recent paper published in Cell Reports Medicine, titled Small intestine vs. colon ecology and physiology: Why it matters in probiotic administration, laid out the differences between probiotic actions and interactions in the small intestine versus the large intestine. The paper was the result of work by an expert group of the International Life Sciences Institute (ILSI) Europe – the Probiotics Taskforce.

The authors of the paper say the duodenum (the first part of the small intestine) is the most dynamic part of the digestive tract. The small intestine as a whole is the site where most of the body’s digestion and absorption takes place, it is also a site of high immune activity. Even though ingested materials move through this area more rapidly than the large intestine, the small intestine allows closer interaction between host and microbes because it has a lower rate of mucus secretion and looser gut barrier junctions. The microbiota of the small intestine is primarily shaped by the digestion and resulting abundance of simple carbohydrates and amino acids, whereas the colonic microbiota is driven by the metabolism of the remaining complex carbohydrates. These factors and others create very different environments for probiotic interaction and activity.

While the most relevant clinical question for a probiotic strain may be what health benefit it confers in the host, researchers may also be interested in gut microbiota manipulation via probiotics to transform host-microbe interactions at discrete locations in the digestive tract – potentially yielding new or improved benefits for the host. The paper raises the possibility of novel probiotics discovered or developed in the future to specifically target the small intestine.

Accessibility of the small intestine, however, remains a challenge. While animal and in vitro models can lead to valuable insights, the authors of the paper point to the need for more sensitive and cost-effective tools for sampling the small intestine in human study participants.

See this Q&A with the paper’s lead author, Dr. Arthur Ouwehand PhD, Global Health & Nutrition Sciences, International Flavors & Fragrances, Finland.

Why is it important to think about how probiotics interact at sites other than the colon?

Nutrient absorption, entero-hepatic circulation, and energy regulation are all happening in the small intestine and have a major impact on our health. Even some forms of diarrhoea originate from the small intestine. So, we should be better aware what happens in the small intestine and how probiotics may influence these processes.

What clues do we have that the small intestine is an important site for probiotic activity?

The most common argument is that the microbial numbers in the small intestine are much smaller and hence (with less competition) probiotics can better exert an effect there. Is that true? We don’t know yet, because small intestinal samples have been difficult to collect. We need to better understand what is happening in the human small intestine.

Do small intestinal interactions depend on the specific probiotic?

Very likely. Also interesting is how diet would shape the effects of the probiotic in the various parts of the small intestine.

What are some of the main questions researchers still need to address regarding how probiotics act in the small intestine?

What is the microbiota in the small intestine and how is it influenced?
What do these changes in composition and activity mean?
How can the small intestinal microbiota be influenced in a meaningful way?

How do you think researchers will overcome the challenges of gathering information about the small intestine?

Capsules that sample the small intestine are nothing new. They were already developed in the 1960s. Better and more affordable capsules are now coming on the market, so minimally invasive sampling of the human small intestine will soon be much more feasible. These new technologies should expand our understanding of the microbiota in different parts of the small intestine, and how probiotics interact in this environment.

Episode 31: Microbial species and strains: What’s in a name?

November 7, 2023/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.

Microbial species and strains: What’s in a name? with Dr. Jordan Bisanz PhD

Episode summary:

In this episode, the ISAPP podcast hosts speak with Dr. Jordan Bisanz PhD, Assistant Professor of Biochemistry and Molecular Biology at Penn State University in State College, USA. They discuss how to define a bacterial strain, the diversity of strains within a species, and how genetic differences correspond with functional differences. They also talk about manipulating microbial communities for insights about health and disease.

Key topics from this episode:

Dr. Bisanz says just because strains within a species are genetically related doesn’t mean they do the same things. Bacteria gain and lose genes rapidly, but we don’t yet know what a lot of those genes do.
Natural variation in strains can be used as a tool to find out the functions of genes.
Metagenomics illuminates strain-level differences, but that assumes we know what makes a strain. There’s no single accepted definition of a strain.
Knowing the mechanisms behind the effects of a strain on a host is important for predicting if closely related strains will have the same effect.
Moving forward, it could be useful to have functional information to go along with strains and their taxonomic descriptors.
Dr. Bisanz’s lab tests experimentally how microbial genes are gained and lost in vivo, both through wetlab experiments and computational approaches.
Experiments on strains are essential – for example, two strains with differences in 1000 SNPs might be functionally the same, while differences in 2-3 key SNPs might make a big difference.
When testing probiotic effects, you may be testing something derived from the original microbial genome but not identical. How can this be managed in industry? Understanding the mechanisms is important, strains that function similarly can qualify as the same strain.
A microbiome involves multiple microbes working together, acting differently from all the strains in isolation.
Dr. Bisanz studies tractable microbial communities: find the microorganisms that are different in a disease state compared to a healthy state, and create a synthetic community of the microbes that are absent. What are the functions of this community?
The challenge is that microbiologists need to be able to manipulate the microbes but cannot do this in a whole human fecal sample.
Is gut microbiome sequencing useful? At the level of individual, it may not provide value. But putting the data all together, in the future it may provide interesting information. The challenge with interpretation is that the microbiome is driving, but also responding to, dietary inputs.
In the microbiome field, gnotobiotic models (using humanized mice) need to be taken a step further than they currently go – specifying not only which microbes established in the host, but also how they could plausibly affect the mechanism.

Episode abbreviations and links:

Review on strain diversity co-authored by Dr. Bisanz: Challenges and opportunities of strain diversity in gut microbiome research
Computational and experimental resources for mapping phenotypes to genes: A Genomic Toolkit for the Mechanistic Dissection of Intractable Human Gut Bacteria
Example of mechanistic insights: Human gut bacteria produce ΤΗ17-modulating bile acid metabolites
Research highlight on complex synthetic microbial communities: Making gut microbiomes from scratch
Description of a defined complex microbial community: Design, construction, and in vivo augmentation of a complex gut microbiome

Additional resources:

What is a strain in microbiology and why does it matter? ISAPP blog post by Prof. Colin Hill PhD

About Dr. Jordan Bisanz PhD:

Jordan Bisanz is an assistant professor of Biochemistry and Molecular Biology at the Pennsylvania State University and the One Health Microbiome Center. The Bisanz lab combines computational analyses and wet lab experimentation to understand how gut microbes interact with each other and their host. The lab specializes in coupling human intervention studies with multi ‘omics approaches and gnotobiotic models to understand how host-microbe interactions shape health generating both mechanistic insights and translational targets.

Episode 30: A systems biology perspective on the gut microbiome

October 19, 2023/in Podcast, Season Two /by Laura

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The Science, Microbes & Health Podcast

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:

DGGE: Denaturing Gradient Gel Electrophoresis
Paper on correlation analyses: Use and abuse of correlation analyses in microbial ecology
Comment on a new approach to clinical trials required for precision medicine: Personalized medicine: Time for one-person trials
Paper on the gut microbiome and statin response: Heterogeneity in statin responses explained by variation in the human gut microbiome
Paper on developing niches in a microbial ecosystem: Orthogonal dietary niche enables reversible engraftment of a gut bacterial commensal
Paper on horizontal gene transfer in the gut microbiome: Elevated rates of horizontal gene transfer in the industrialized human microbiome

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.

Why responders and non-responders may not be the holy grail for biotics

October 15, 2023/in ISAPP Science Blog /by KC

By Prof. Dan Merenstein MD, Georgetown University Medical Center, USA

In September the New York Times published an article titled “What Obesity Drugs and Antidepressants Have in Common“. It was written by a physician who had personally struggled with weight issues and depression. In his personal journey with these health challenges, he hesitates to undergo any treatments. But he eventually does and experiences much relief from them. Why would a practicing physician hesitate to use approved drugs?

The article opens with this viewpoint: “We like to think we understand the drugs we take, especially after rigorous trials have proved their efficacy and safety. But sometimes, we know only that medications work; we just don’t know why.” He goes on to discuss selective serotonin reuptake inhibitors (SSRIs) and the recently approved weight loss drugs, such as glucagon-like peptide-1 (GLP-1) receptor agonists. The former have been widely used for over 40 years, while the weight loss drugs are more recent. For both classes of drugs, we have some ideas how they work but the exact mechanisms have not been elucidated. While this knowledge gap has not prevented wide usage, the author of the article was skeptical about using the drugs if he did not know exactly how they worked.

When I started studying probiotics 15 years ago, I began to interact with a different group of scientists than I was used to. My new collaborators were basic and applied scientists, not just clinicians. I had opportunities to attend conferences that covered bench science more than clinical evidence. My perspective as a clinical researcher was different from most of the others in attendance. I was somewhat surprised to learn how much emphasis those scientists placed on understanding mechanisms. On the one hand, intuitively it makes sense. If you know how something functions, you have a lot more confidence that it will do what you expect it to do, and more assured that it can be used safely. You also have a sense that it should work for you. But on the other hand, knowing an intervention is effective is more important than knowing how it achieves its effectiveness.

This emphasis on understanding mechanisms of action for interventions reminds me of the development of beta-blockers, a class of medicines that block epinephrine, and cause the heart to beat slower and with less force. One of the most common test questions I was asked when I was a medical student and resident is: What class of blood pressure medicines are never permissible for a patient with congestive heart failure (CHF)? Well it was obvious to all of us that the answer was clearly beta-blockers, as you wouldn’t want to slow the heart rate and reduce the force of the heart in a patient already suffering from a poorly performing heart. Yet after clinical trials were completed, beta-blockers were shown to be effective treatment for CHF patients and are now a mainstay of CHF treatment. This was counterintuitive considering the drug’s mechanism of action. So in fact, a drug’s mechanism of action does not always lead in a straightforward way to knowledge about which conditions can be treated or which individuals will respond.

Beyond mechanisms of action and individual response

In clinical medicine, we use two important statistics to capture efficacy and safety of an intervention: number needed to treat (NNT) and number needed to harm (NNH). NNT is the number of patients that need to be treated in order to have an impact on one person, while the NNH is the number of patients who must be treated with an intervention before one patient is harmed. All interventions have both an NNT and NNH. Obviously, the goal is a very low NNT and a high NNH. But we are rarely so fortunate. Take for example statins, a medicine many of us take. In patients at low risk of cardiovascular disease, the NNT is 217, which means 1 person out of 217 avoided a nonfatal heart attack by taking statins. Meanwhile, NNH for muscle pain is 21 and for developing diabetes is 204.

NNT and NNH are rarely considered in the biotics field. Yet I commonly encounter discussions about the importance of identifying responders versus non responders to biotic intervention and the need to elucidate the mechanism(s) of action for biotic substances. I believe this is because many of the scientists doing research in biotics come not from a clinical background but more bench research, where the questions really are those of mechanism. Many seem to believe that such knowledge is the Holy Grail of biotics – if only scientists could have such a good grasp of mechanism that they could figure out why certain people responded while others do not. There is nothing inherently wrong with wanting to identify reasons for differences in individual response. It is what we do in clinical practice every day. When I give someone blood pressure medicine and they don’t respond to it, I wonder – Is it a compliance issue? Is the patient’s blood pressure caused by something that the medicine does not impact? Is the patient taking the medication at the wrong time, with the wrong diet, or with other interfering medicines? Clinicians always must think about who is responding and who is not responding. However, NNT and NNH for biotics are worth prioritizing.

Data have shown that certain probiotics can get people better from an upper respiratory tract infection 26 hours earlier, or can treat infantile colic, or improve irritable bowel syndrome symptoms with a NNT respectively of 20, 15 and 100, while having a very high NNH. These are great products. But instead what I often hear at conferences is that we need to figure out why some people respond to the probiotics and others do not. I agree, go ahead and figure it out. But have realistic expectations. If two of the most widely used medicines, SSRIs and GLP-1 agonists, have an unclear mechanism, and if statins have an NNT of 217, be realistic about the impact of your probiotic. When a doc prescribes you Lipitor, he doesn’t say, “Good luck – I hope you are the 0.4% in which it helps and aren’t the 5% that gets muscle cramps.” The hope is that for you, the NNT is 1. And when your strain or product does have an impact, feel free to find ways to improve efficacy but celebrate the impact it has. If possible, maybe compare your NNTs to standard of care, or if no comparison look at your NNT versus NNH to really better understand what your biotic can do.

Episode 28: Lactobacilli in the microbiomes of the gut, skin, reproductive tract and more

September 21, 2023/in Podcast, Season Two /by Laura

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The Science, Microbes & Health Podcast

Lactobacilli in the microbiomes of the gut, skin, reproductive tract and more, with Prof. Kingsley Anukam PhD

Episode summary:

In this episode, the ISAPP podcast hosts cover a range of topics related to lactobacilli and health with Prof. Kingsley Anukam PhD from Nnamdi Azikiwe University in Nigeria. Prof. Anukam has a special interest in lactobacilli, and studies lactobacilli in microbiomes across many different contexts: fermented foods, skin, gut, and reproductive tract sites. He talks about the wide range of research he has led in Nigeria using diverse sources of funding.

Key topics from this episode:

Prof. Anukam describes his collaboration with Prof. Gregor Reid PhD early in his career, prompted by a paper claiming that African women did not have vaginal microbiomes dominated by lactobacilli. Subsequent work showed this was not the case – confounding factors contributed to the initial result.
He cautions researchers against making conclusions about race or ethnicity when geographical variations or other factors could better account for the differences between groups. In studies it’s important to specify the geography as well as the other factors (dietary, cultural) that may impact the gut microbiome in these populations.
There is a long history of fermented foods in Africa but not a lot of research has been done on them. In a 2009 paper with Prof. Reid, Prof. Anukam reported isolated lactic acid species from a fermented food called okpeye produced in Eastern Nigeria. The isolates showed potential for industrial applications.
Most of his research studies are funded from outside Nigeria, with different sources of funding.
‘Parachute’ science is common in Africa, where researchers come into an African country, obtain samples and leave. He encourages researchers to involve local scientists to build capacity and allow them to do the analysis.
Prof. Anukam describes a clinical trial he led on the skin microbiome and malodor in Nigerian youth. He found the skin microbiome in the armpit was altered if individuals used deodorants and antiperspirants; and these individuals kept having the same malodor issues. Individuals with less odor were found to have more lactobacilli on the skin, with differences in composition between men and women. They developed a topical cream to use as an intervention for 14 days, and found that lactobacilli on the skin increased and less odor was reported.
The microbiome(s) of the male reproductive organs have not been studied very much. Semen has a microbiome, and this is shown by both culture and non-culture methods. It is dominated by lactobacilli, and this corresponds with semen quality. The evidence is mixed on the existence of testes and prostate microbiomes. A gut-testes connection may exist, however, as shown in mouse studies.
Prof. Anukam says in a study of subjects seeking reproductive healthcare, different microbiomes were observed both in males and females having difficulty conceiving.
The semen microbiome could play a significant role in reproduction – for example, it may produce metabolites that could affect the female reproductive tract and influence the environment for conception to take place. When doing in vitro fertilization, evidence has shown that if the samples are contaminated by pathogens, it can be difficult to achieve conception.

Episode links:

Paper from 2009 on fermented foods: African traditional fermented foods and probiotics
Paper from 2021 on skin malodor: Topical cream containing live lactobacilli decreases malodor-producing bacteria and downregulates genes encoding PLP-dependent enzymes on the axillary skin microbiome of healthy adult Nigerians
Paper from 2021 on reproductive microbiomes: Microbiome Compositions From Infertile Couples Seeking In Vitro Fertilization, Using 16S rRNA Gene Sequencing Methods: Any Correlation to Clinical Outcomes?

About Prof. Kingsley Anukam PhD:

Kingsley C Anukam is a research scientist in human microbiome and biotherapeutics with over 20 years experience. He shares his time between Canada and Nigeria as an adjunct professor at Nnamdi Azikiwe University where he assists in the training and supervision of post graduate students working in the area of probiotics, fermented foods, human microbiome, infectious diseases, laboratory diagnostics, human genomics and forensic DNA analysis. He had his graduate education in Nigeria and post doctorate training in Dr. Gregor Reid’s Lab at Lawson Health Research Institute and Department of Microbiology and Immunology, Western University, Canada. He is the first from Africa to show that vaginal microbiome of healthy Nigerian women is similar to women from other populations irrespective of geographical location. He has sequenced and annotated the full genome of over 10 Lactobacillus species of African origin mainly from the reproductive tract and African fermented foods in collaboration with Prof. Sarah Lebeer. He played a significant role in the formation of the DORA project, an ISALA-inspired citizen science for vaginal health in Nigeria. He has over 80 scientific research publications in peer-reviewed journals and listed among first 10 most cited researcher at Nnamdi Azikiwe University by Google Scholar. He is currently the Chief Editor, Journal of Medical Laboratory Science, and a peer-reviewer of several international journals.

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

September 13, 2023/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.

Gut microbiota from a surprising source—baby kangaroos—might decrease cattle methane production

September 11, 2023/in ISAPP Science Blog /by KC

By Prof. Seppo Salminen, University of Turku, Finland

One of the major contributors to greenhouse gas production is the final stage of anaerobic fermentation in the rumen (i.e. stomach compartment) of cattle, which produces methane. The process is the top agricultural source of greenhouse gases worldwide. In addition, the formation of methane is associated with approximately 10% energy loss in animals.

To ameliorate the dangers of methanogenesis, scientists at Washington State University explored the potential of homoacetogenic microbes (i.e. those that promote the production of acetate), and especially Acetobacterium woodii, to outcompete methanogens and thereby reduce methane production in the rumen of production animals.

For this purpose, original inoculum of rumen samples were obtained from freshly slaughtered cows and developed into stable consortia of methanogens. Meanwhile, homoacetogenic cultures were developed from baby kangaroo droppings obtained from a wallaby ranch in Washington State. The original baby kangaroo sample had no methanogens present. Rumen bioreactors were inoculated with the bovine study samples and kangaroo gut microbes, and monitored for methane production and kinetics.

The investigators reported that acetogens are dominant in kangaroos, and in their presence methanogens are generally inhibited. The researchers suggested that kangaroos have interesting novel acetogens that utilize hydrogen, which rumen fermentation produces. These acetogens are potential probiotics, once they are well characterized and the benefits to rumen fermentation are documented.

This study also suggests that a variety of kangaroo acetogens should be further explored for their potential use in controlling rumen fermentation and reduction of greenhouse gas production. At the same time, additional benefits of acetogens from other marsupials could be explored and new findings are possible for potential biotic (pro-, pre-, syn- and postbiotic) development.

Episode 27: Investigating the benefits of live dietary microbes

September 7, 2023/in Podcast, Season Two /by Laura

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The Science, Microbes & Health Podcast

Investigating the benefits of live dietary microbes, with Prof. Colin Hill PhD and Prof. Dan Tancredi PhD

Episode summary:

In this episode, the ISAPP podcast hosts themselves are the experts: Prof. Colin Hill PhD from APC Microbiome Ireland / University College Cork and Prof. Dan Tancredi PhD from University of California – Davis talk about their recent work investigating the health benefits from consuming higher quantities of live dietary microbes – and not just microbes that meet the probiotic criteria.

Key topics from this episode:

Profs. Hill and Tancredi were involved with others in a recent series investigations & 3 published papers on whether there should be a recommended daily intake of live microbes.
Prof. Hill started by writing a blog, prompted by the finding that meta-analyses on probiotics tended to show some general benefits for health. Would this apply to any safe, live microbes – even those that do not meet the probiotic criteria?
Various hypotheses (hygiene hypothesis, old friends hypothesis, missing microbes hypothesis) posit that a lack of microbes is associated with poorer health.
Clean water and clean food have reduced the burden of infectious disease. But at the same time, across populations there has been an increase in chronic diseases. Could a lack of live dietary microbes be contributing to this increase in chronic disease, because the immune system lacks adequate inputs? Or in other words, could there be a general health benefit for healthy people in consuming high quantities of live microbes?
To address the hypothesis scientifically: they investigated the health status of people who eat large vs. small numbers of safe live microbes in their diets. Starting with NHANES data in the US, the researchers classified foods into categories of high / medium / low numbers of live microbes.
Note that not all fermented foods contain live microbes, but some contain high numbers of live microbes. A possible confounding factor in the analysis was that high microbe foods tend to be healthier foods.
The researchers published a series of 3 papers. The 3rd paper showed an association between intake of live microbes and various (positive) measurements of health. Consistent, modest improvements were seen across a range of health outcomes.
This is an association, but statistically the team did use regression analysis to statistically adjust for effects on health that could be due to other factors besides the live microbial intake.
The take-home is not to eat unsafe or rotten food, but rather to eat more high-microbe or fermented foods, and in general eat a healthy diet.

Episode links:

Additional Resources:

Live Dietary Microbes: A role in human health. ISAPP infographic.

About Prof. Colin Hill PhD:
Colin Hill has a Ph.D in molecular microbiology and is a Professor in the School of Microbiology at University College Cork, Ireland. He is also a founding Principal Investigator in APC Microbiome Ireland, a large research centre devoted to the study of the role of the gut microbiota in health and disease. His main interests lie in the role of the microbiome in human and animal health. He is particularly interested in the effects of probiotics, bacteriocins, and bacteriophage. In 2005 Prof. Hill was awarded a D.Sc by the National University of Ireland in recognition of his contributions to research. In 2009 he was elected to the Royal Irish Academy and in 2010 he received the Metchnikoff Prize in Microbiology and was elected to the American Academy of Microbiology. He has published more than 600 papers and holds 25 patents. More than 80 PhD students have been trained in his laboratory. He was president of ISAPP from 2012-2015.

About Prof. Dan Tancredi PhD:
Daniel J. Tancredi, PhD, is Professor in Residence of Pediatrics in the University of California, Davis School of Medicine. He has over 25 years of experience and over 300 peer-reviewed publications as a statistician collaborating on a variety of health-related research. A frequent collaborator on probiotic and prebiotic research, he has attended all but one ISAPP annual meeting since 2009 as an invited expert. In 2020, he joined the ISAPP Board of Directors. Colin Hill and Daniel co-host the ISAPP Podcast Series “Science, Microbes, and Health”. On research teams, he develops and helps implement effective study designs and statistical analysis plans, especially in settings with clusters of longitudinal or otherwise correlated measurements, including cluster-randomized trials, surveys that use complex probability sampling techniques, and epidemiological research. He teaches statistics and critical appraisal of evidence to resident physicians; graduate students in biostatistics, epidemiology, and nursing; and professional scientists. Dan grew up in the American Midwest, in Kansas City, Missouri, and holds a bachelor’s degree in behavioral science from the University of Chicago and masters and doctoral degrees in mathematics from the University of Illinois at Chicago. He lives in the small Northern California city of Davis, with his wife Laurel Beckett (UC Davis Distinguished Professor Emerita), their Samoyed dogs Simka and Milka, and near their two grandkids.

Clarifying the role of metabolites in the postbiotic definition

August 10, 2023/in ISAPP Science Blog /by KC

By Dr. Gabriel Vinderola PhD, Instituto de Lactología Industrial (CONICET-UNL), Faculty of Chemical Engineering, National University of Litoral, Santa Fe, Argentina and and Prof. Colin Hill PhD, School of Microbiology and APC Microbiome Ireland, University College Cork, Cork, Ireland

ISAPP published a definition for the term postbiotics in 2021 that states that “a postbiotic is a preparation of inanimate microorganisms and/or their components that confers a health benefit on the host” (Salminen et al., 2021). This 19-word definition had to distill the content of the accompanying article that ran to over 9,000 words (not including references) and so obviously a lot of nuance was lost. A reading of the full paper should dispel any misconceptions, but we thought it might be timely to discuss what is perhaps the most common misunderstanding.

Some of the previous definitions included metabolites (purified or semi-purified) under the postbiotic concept. We did not agree with this interpretation. For us, the term postbiotics refers to preparations that consist largely of intact microbial cells, or preparations that retain some or all of the microbial biomass contained in microbial cells. This latter concept was captured in the phrase “and/or their components” The first column of page 3 of Salminen et al., 2021 elaborates on this; “The word ‘components’ was included because intact microorganisms might not be required for health effects, and any effects might be mediated by microbial cell components, including pili, cell wall components or other structures. The presence of microbial metabolites or end products of growth on the specified matrix produced during growth and/or fermentation is also anticipated in some postbiotic preparations, although the definition would not include substantially purified metabolites in the absence of cellular biomass. Such purified molecules should instead be named using existing, clear chemical nomenclature, for example, butyric acid or lactic acid”. So, taken in context, the scope of the ISAPP definition covers inanimate, dead, non-viable microbes; either as intact whole dead cells or in the form of “their components”. We do not consider microbial metabolites to be postbiotics. Such an interpretation would, for example, make butyrate or other end-products of fermentation postbiotics (once shown to have a health benefit). The ISAPP definition does not exclude the likelihood that microbial metabolites will be present in a postbiotic preparation, but it does require that dead microbes or microbial cell fragments or structures should be present to qualify as a postbiotic.

Why did the ISAPP definition exclude purified or semi-purified metabolites in the absence of cellular components? We fully accept that metabolites or other microbe-generated functional ingredients such as lactate, butyrate, bacteriocins, defensins, neurotransmitters, and similar compounds can be present in a postbiotic preparation. But as you can see from this list, these compounds already have names that are clearly understood. The ISAPP definition of postbiotics focuses on the beneficial role of inanimate microbes and/or their components, a category that did not have a clear definition. Postbiotics are simply one category of substances that provide microbe-associated health benefits. In terms of semantics, dictionaries define the prefix ‘post’ as meaning ‘after’ and the word ‘biotic’ as meaning ‘living things’, and so a postbiotic in that context is something that was living and is now after-life, or inanimate. Metabolites are derived from living things, but never had an independent ‘life’ of their own. As a thought experiment, let us imagine a microbe that has been shown to have a health benefit and therefore qualifies as a probiotic. If the same microbe is inactivated and continues to show a health benefit, this new formulation is no longer a probiotic and qualifies as a postbiotic. If this postbiotic preparation can be further purified and it is shown that a metabolite or metabolites in the absence of cells or their components can provide the same health benefit it ceases to be a postbiotic and becomes a health-promoting metabolite. We could imagine microbially-produced vitamins as an example.

Ideally, definitions should be clear without supplemental explanation. But short, simply worded definitions that describe complex concepts must be read in a context. There is a background, they have a scope, there are things that are covered by that definition and things that are not, and of course definitions have their limitations. It would be hard, if not impossible, to include the scope, the background, the coverage and the limitations in a 19-word definition. For instance, the 15-word probiotic definition is “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host” (Hill et al, 2014). This does not include the idea that probiotics are strain-dependent, a fact that is widely accepted by the field. Other criteria for probiotics not stated in the definition include the fact that that they may be of any regulatory category, that their health benefits must be demonstrated in well-controlled trials in the target host, and that they must be safe (Binda et al. 2020).

In closing, we believe that the postbiotic concept can be an incredibly important scientific, regulatory and commercial concept. That is why we spent the time and effort to arrive at what we hope is a workable definition. We accept that the definition is not perfect but we do think it is useful, and we urge those interested in the future of this important field to read the accompanying paper carefully and to place the definition in its proper context.

See ISAPP’s Postbiotics infographic here.

Postbiotics: debate continues and the ISAPP definition gains support

July 24, 2023/in ISAPP Science Blog /by KC

By Dr. Gabriel Vinderola PhD, Instituto de Lactología Industrial (CONICET-UNL), Santa Fe, Argentina

The publication of a new definition for the term “postbiotics” by ISAPP in 2021 (Salminen et al., 2021a) spurred discussion on a variety of platforms, including scientific journals, social media and in-person debates organized at industry and scientific meetings. A couple of months after the publication of the definition, a group of scientists expressed their disagreement about the new definition (Aguilar-Toalá et al., 2021), and this was followed by a reply in support of the ISAPP definition (Salminen et al., 2021b). An example of the debate on social media is reflected in this post on LinkedIn. The comments that followed the post highlighted points of disagreement and misunderstandings about the ISAPP definition. These reactions were helpful to me in preparing for panels and debates scheduled at 2023 meetings in Amsterdam, Chicago and Bratislava, discussed more fully below.

Prior to the ISAPP panel, many terms were used to refer to non-viable microorganisms that confer a health benefit when administered in adequate amounts: heat-killed probiotics, heat-treated probiotics, heat-inactivated probiotics, tyndallized probiotics, ghost-probiotics, non-viable probiotics, paraprobiotics, cell fragments, cell lysates or postbiotics. ISAPP proposed that going forward, the single term “postbiotic” be used in scientific communications, marketing, regulatory frameworks and to counter the difficulty in tracking of papers for comprehensive systematic reviews. ISAPP’s goal was to bring focus and clarity to the term postbiotic, provide criteria for proper use of the term and set the stage for future innovation in the field.

Two competing terms

When considering preparations of non-viable microorganisms that confer a health benefit, two terms seem to have emerged most dominantly:

The term paraprobiotic was coined by Taverniti and Guglielmetti (2011) and defined as non-viable microbial cells (intact or broken) or crude cell extracts (i.e. with complex chemical composition), which, when administered (orally or topically) in adequate amounts, confer a benefit on the human or animal consumer.

The term postbiotic as proposed by Salminen et al. (2021a) refers to a preparation of inanimate microorganisms and/or their components that confers a health benefit on the host.

The definition of paraprobiotics is limiting in that it does not clarify the scope for metabolites to be present alongside non-viable cells, and this may be problematic as most products of this type developed and marketed so far contain microbial metabolites along with non-viable cells. Further, the definition of paraprobiotics refers to conferring a benefit, but not a health benefit, a divergent way of conceptualizing a ‘biotic’ substance. Probiotics, prebiotics, synbiotics, and as defined above, postbiotics, all stipulate the requirement of conferring a health benefit. In addition, embedding the term ‘probiotic’ into the term paraprobiotic may mislead some to conclude that a paraprobiotic is a dead probiotic, which places a significant burden on any live microbial precursor to first meet the probiotic definition.

Finally, the authors (Taverniti and Guglielmetti 2011) state in their paper: “In addition, once a health benefit is demonstrated, the assignation of a product into the paraprobiotic category should not be influenced by the methods used for microbial cell inactivation, which may be achieved using physical or chemical strategies, including heat treatment, or UV ray deactivation, chemical or mechanical disruption, pressure, lyophilisation or acid deactivation”. Since inactivation technology may have a significant impact on the functionality of a dead microbe, disassociating a paraprobiotic with the method used to inactivate the microbes makes it impossible to know if any given paraprobiotic preparation will be effective.

The definition of postbiotics by Salminen et al. (2021a) anticipates that metabolites may be optionally present in the finished product, requires a health benefit and does not suggest, at any point in the wording, that the progenitor strain of a postbiotic must be a probiotic. Further, although not explicitly stated in the definition, the supporting documentation for the proposal of this definition states that the process to make the postbiotic must be delineated specifically, the progenitor microorganism must be clearly identified and characterized and the final product must be safe for its intended use. This definition encompasses a meaningful and useful scope.

To add to the complexity of the existing landscape, prior to the ISAPP definition of postbiotics, six other definitions of the term postbiotic were proposed in the literature. While these are reviewed in detail in Salminen et al (2021b Supplementary information), many shared the commonality that their focus was bacterial byproducts or metabolites.

Questions about the ISAPP definition of postbiotic

A common question is, “Why did the ISAPP panel choose the term postbiotic to refer to inactivated microbes?” In short, the word seemed most appropriate since post means ‘after’ and biotic means ‘life’. Further, the panel recognized that although microbial metabolites might contribute to the health benefit conferred by a postbiotic, a preparation containing metabolites alone could be encompassed by a different term. Further, such metabolites (to the extent they are purified from the microbes that produce them) are readily referred to by their chemical names. Microbial metabolites may be present in a postbiotic preparation, but they are not required. The core of the definition of postbiotics is non-viable microbes, either as whole intact cells, disrupted cells or cell fragments. The life termination technology used to manufacture a postbiotic preparation should be stipulated. It cannot be assumed that heat inactivation, radiation, high pressure or any other technology will necessarily render an equally functional inanimate microbe.

Why use the descriptor “inanimate”? This is another common question. This word – meaning lifeless – reflects that the microorganisms should be dead, non-viable, no longer able to grow, to replicate, or, from an applied point of view, to form visible colonies in an enumeration medium or to be detected as live cells in flow cytometry techniques. It was preferred over the term “inactivated” only to call attention to the fact that postbiotics must confer a health benefit and in that sense, are active. For all practical purposes, non-viable can be used as an appropriate synonym.

Questions arise also about the breadth of definition, with concerns that “anything can be a postbiotic”. But broadness of a definition should not be seen as a disadvantage, as long as the limits to the definition are clear. Any microorganisms may be used as a postbiotic, as long as the identity is provided to the strain level, a life termination process is deliberately applied and safety and efficacy are demonstrated in a trial in the target host. Further, a postbiotic is not simply a dead probiotic. A probiotic is shown to confer a health benefit alive and it cannot be assumed that this property is retained when it is dead. Clearly, not anything can be a postbiotic.

Reflections on three recent conferences where the concept of postbiotics was debated

The first debate took place at the Beneficial Microbes conference in Amsterdam in November 2022. The outcomes were reported in a previous blog.

The second panel discussion took place in Chicago, at the Probiota 2023 conference in mid-June. After my talk, an audience poll was taken. Seventy-six out of around 250 attendees voted by an app in their cell phones to the question, How do you define a postbiotic? 68% selected the ISAPP definition, 9% said postbiotics were metabolites produced by probiotics, 4% chose the option “metabolites produced by the gut microbiota”, 14% said “none of the above” (I was curious to know what it would be for them), whereas 4% were not sure. Thus, the ISAPP definition was preferred by the majority. It is interesting to note the composition of the panel debate: three industry representatives and myself. Two of the companies represented presently market products referred to as postbiotics and containing non-viable microbes, whereas for the third company, postbiotics are “molecules created by bacteria”, according to their webpage. A discrepancy in the industry towards what postbiotics are was embodied on the stage. The preference for these meeting participants for the term postbiotic over the term paraprobiotic could be deduced from the meeting program, as the first term was mentioned 56 times, while the second had not one entry.

At Probiota 2023, an officer from Health Canada announced that the regulatory body will start considering the term postbiotics, which was defined in his presentation using the ISAPP definition. As for the quantification units for postbiotics, he indicated that milligrams would be considered currently, although he anticipated the development of more refined methodologies. The topic of what and how to quantify postbiotics is a commonly heard question. I intend to lead a Discussion Group on this topic comprising academic and ISAPP member company representatives at the 2024 ISAPP meeting July 9-11 in Cork, Ireland. If you are an academic expert or an industry member interested in joining the discussion, please reach out to me at gvinde@nullfiq.unl.edu.ar.

Panel discusson on postbiotics at the Bratislava International Probiotic Conference, 2023

A third panel discussion took place late in June in Bratislava at the 16^th edition of the International Probiotic Conference. Before the debate, presentations were made by Arthur Ouwehand (IFF Health, Finland), Wilbert Sybesma (Yoba For Life Foundation, The Netherlands) and Eva Armengol (AB-BIOTICS, Spain). These speakers presented examples of postbiotics as they perceived them, which in all cases referred to administered non-viable microbes, in most cases containing microbial metabolites, thereby fitting the ISAPP definition. The fourth speaker, Simone Guglielmetti, proposed separate terms for non-viable microbes, which he proposed to call paraprobiotics, and for metabolites, which he proposed to call postbiotics, according to previous definitions (Taverniti and Guglielmetti, 2011; Tsiliringi and Rescigno, 2013).

There was also a sense of agreement that definitions should encompass current science but not unduly restrict future innovation. Some examples of products presently available in the market that contain non-viable microbes, and have efficacy studies with a clinical endpoint or biomarker enhancement, are:

Species or strain/s	Composition	Reference
B. bifidum MIMBb75	Heat inactivated bacteria	https://pubmed.ncbi.nlm.nih.gov/32277872/
Akkermansia muciniphila	Heat inactivated bacteria	https://pubmed.ncbi.nlm.nih.gov/31263284/
L. fermentum CNCM MA65/4E-1b and L. delbrueckii CNCM MA65/4E-2z	Heat inactivated bacteria plus metabolites	https://pubmed.ncbi.nlm.nih.gov/33281937/
B. breve C50 and S. thermophilus 065	Heat inactivated bacteria plus metabolites	https://pubmed.ncbi.nlm.nih.gov/32629970/
Aspergillus oryzae	Heat inactivated fungi plus metabolites	https://pubmed.ncbi.nlm.nih.gov/33742039/
L. paracasei MCC1849	Heat inactivated bacteria plus metabolites	https://pubmed.ncbi.nlm.nih.gov/33787390/
L. sakei proBio65	Bacterial lysate plus metabolites	https://pubmed.ncbi.nlm.nih.gov/32949011/
S. cerevisiae	Heat inactivated yeasts plus metabolites	https://pubmed.ncbi.nlm.nih.gov/21501093/
Vitreoscilla filiformis	Bacterial lysate plus metabolites	https://pubmed.ncbi.nlm.nih.gov/34976852/
Mixture of pathogens	Bacterial lysate plus metabolites	https://pubmed.ncbi.nlm.nih.gov/34976852/

These ten examples of commercial products based on non-viable microbes all fit the definition of postbiotics conceptualized by Salminen et al. (2021). Only the first two fit the Taverniti and Guglielmetti (2011) definition, as these contain just non-viable microorganisms, without metabolites. This may suggest that products in the current marketplace are best described by the Salminen et al. (2021) concept, which encompasses products based on non-viable microbes, which may or may not also contain microbial metabolites.

Conclusions

In conclusion, I suggest that the term postbiotic and the definition of Salminen et al. (2021a) be used for non-viable microbes (with or without metabolites) able to confer a health benefit, as reflected by the present state of the art and products developed and marketed. If deemed useful by the field, there is room yet for a new term to encompass products developed with microbial metabolites only (devoid of cells). If we consider definitions that mutually exclude non-viable microbes or metabolites, then the vast majority of products present today in the market would not be covered, as most of them deliver non-viable microorganisms and metabolites simultaneously. My overall sense after attending the Chicago and Bratislava meetings is that the meaning of the term postbiotic as mentioned by speakers, included in the meeting programs, seen in posters (future products) and in commercial products presented in booths, refers to the ISAPP definition of non-viable microbes. Time will tell how this term and definition evolves and if a broader consensus can be reached.

References

Aguilar-Toalá, J. E., Arioli, S., Behare, P., Belzer, C., Berni Canani, R., Chatel, J. M., D’Auria, E., de Freitas, M. Q., Elinav, E., Esmerino, E. A., García, H. S., da Cruz, A. G., González-Córdova, A. F., Guglielmetti, S., de Toledo Guimarães, J., Hernández-Mendoza, A., Langella, P., Liceaga, A. M., Magnani, M., Martin, R., … Zhou, Z. (2021). Postbiotics – when simplification fails to clarify. Nature reviews. Gastroenterology & hepatology, 18(11), 825–826. https://doi.org/10.1038/s41575-021-00521-6

Salminen, S., Collado, M. C., Endo, A., Hill, C., Lebeer, S., Quigley, E. M. M., Sanders, M. E., Shamir, R., Swann, J. R., Szajewska, H., & Vinderola, G. (2021a). The International Scientific Association of Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of postbiotics. Nature reviews. Gastroenterology & hepatology, 18(9), 649–667. https://doi.org/10.1038/s41575-021-00440-6

Salminen, S., Collado, M. C., Endo, A., Hill, C., Lebeer, S., Quigley, E. M. M., Sanders, M. E., Shamir, R., Swann, J. R., Szajewska, H., & Vinderola, G. (2021b). Reply to: Postbiotics – when simplification fails to clarify. Nature reviews. Gastroenterology & hepatology, 18(11), 827–828. https://doi.org/10.1038/s41575-021-00522-5

Taverniti V, Guglielmetti S. The immunomodulatory properties of probiotic microorganisms beyond their viability (ghost probiotics: proposal of paraprobiotic concept). Genes Nutr. 2011 Aug;6(3):261-74. doi: 10.1007/s12263-011-0218-x. Epub 2011 Apr 16. PMID: 21499799; PMCID: PMC3145061.

Tsilingiri K, Rescigno M. Postbiotics: what else? Benef Microbes. 2013 Mar 1;4(1):101-7. doi: 10.3920/BM2012.0046. PMID: 23271068.

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

May 1, 2023/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

April 10, 2023/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’

April 7, 2023/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 20: How to navigate probiotic evidence and guidelines for pediatric populations

April 5, 2023/in Podcast, Season Two /by Laura

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The Science, Microbes & Health Podcast

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

Episode summary:

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

Key topics from this episode:

Guidelines exist on probiotic use for gastroenterological issues in children, but there are differences (especially regarding acute gastroenteritis) between guidelines from different medical societies: European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) and The American Gastroenterological Association (AGA).
Realistic expectations are necessary when prescribing probiotics. Different probiotics have different benefits, but they are not a ‘magic bullet’. For example, the evidence shows certain probiotics for acute gastroenteritis reduce diarrhea by an average of one day. This could have a big impact on the quality of life of the end user, but for clinicians it may not sound like a lot so they must set expectations accordingly.
The market is overflowing with probiotic products, many of which do not have proven efficacy. This makes it difficult for end users and healthcare professionals to distinguish the best products.
Always look for evidence-based probiotics with documented efficacy for the indication for which they are intended.
- Physicians have the ethical duty to prescribe evidence-based products (that is, clinically proven, effective products).
- The exact strains and doses matter.

Formal training and education of healthcare professionals regarding the beneficial effects of microbes, the microbiome, and probiotics are currently lacking.
Is it more valuable to know probiotics’ mechanism of action, or to have evidence from clinical trials that they are effective?
- Ideally we would have both, but since we don’t know the exact mechanism for all probiotics, positive evidence from clinical trials is crucial.
- We also need to make clear to healthcare professionals and end users what to expect from taking probiotics. For example, some probiotics reduce the chances of developing antibiotic-associated diarrhea by 50%. For colic, some probiotics can reduce the crying time by half an hour. These are modest benefits but for the affected individual they may be impactful.
For vulnerable populations such as preterm infants, we need high-quality products with proven safety and efficacy.

Episode abbreviations and links:

The website for the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN): https://www.espghan.org/
See here for a primer on evidence-based medicine: The Centre for Evidence-Based Medicine.
The new ESPGHAN guidelines on probiotics: Probiotics for the Management of Pediatric Gastrointestinal Disorders: Position Paper of the ESPGHAN Special Interest Group on Gut Microbiota and Modifications.
Important clinical trial on a probiotic for acute gastroenteritis: Lactobacillus GG administered in oral rehydration solution to children with acute diarrhea: a multicenter European trial.
Recently published clinical trial co-authored by Prof. Szajewska on prevention of antibiotic-associated diarrhea: Multispecies Probiotic for the Prevention of Antibiotic-Associated Diarrhea in Children: A Randomized Clinical Trial.
This paper co-authored by Prof. Szajewska shows an example of actionable evidence: Lactobacillus reuteri to Treat Infant Colic: A Meta-analysis.
Paper by ESPGHAN on the need for independent verification of probiotic quality: Commercial Probiotic Products: A Call for Improved Quality Control. A Position Paper by the ESPGHAN Working Group for Probiotics and Prebiotics. Also see Improving End-User Trust in the Quality of Commercial Probiotic Products.

About Prof. Hania Szajewska:

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

Probiotic Use in Horses: What is the Evidence?

March 14, 2023/in ISAPP Science Blog /by KC

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

Horses play a special role in many people’s lives, serving as a partner in leisure activities, therapy, various forms of work, and athletic competitions. Being large herbivores, they are adapted to a diet rich in grasses and other high-fiber forages. The complex community of microbes inhabiting the hindgut (cecum and colon) is necessary for the efficient breakdown of these fibers as well as maintaining the gastrointestinal health and overall health of horses. In recent years, a lot has been learned about the composition and activity of the gastrointestinal microbiota of horses and their role in health and disease (Kauter et al, 2019). There has also been interest in testing whether yeast- or bacteria-based probiotics may help manage equine health and disease.

Is there evidence supporting probiotic use in horses? The answer depends on the animal’s life stage, dietary and exercise strategy, and health status.

Probiotics for foals

A common target of probiotic use has been young growing foals. Similar to other host species, the gastrointestinal microbiota population of foals has a lower diversity and stability than that of adult horses (Earing et al., 2012; De La Torre et al., 2019). This instability makes foals more susceptible to pathogen-induced microbiota alterations, diarrhea, dehydration, and intestinal inflammation (Frederick et al., 2009; Schoster et al., 2017; Oliver-Espinosa, 2018). But probiotic use in foals has had both helpful and harmful outcomes. Positive results were obtained with a probiotic containing 5 Lactobacillus strains (L. salivarius YIT 0479, L. reuteri YIT 0480, L. crispatus YIT 0481, L. johnsonii YIT 0482, L. equi YIT 0483), which were shown to increase body weight and reduce diarrhea incidence in 3-4 week old foals (Yuyama et al., 2004). Similarly, a probiotic composed of 4 Lactobacillus strains (L. reuteri KK18, L. ruminis KK14, L. equi KK15, L. johnsonii KK21) and 1 Bifidobacterium strain (B. boum HU) was reported to reduce the incidence and duration of diarrhea in foals during their first 5 months of life (Tanabe et al., 2014). However, administration of a different probiotic (L. pentosus WE7) was associated with anorexia, development of diarrhea, and greater need for veterinary examination and treatment (Weese and Rousseau, 2005). Based on the evidence thus far, caution should be used when considering probiotic use in foals.

Probiotics for adult horses

Even though adult horses have a more stable and rich gastrointestinal microbiota than young animals, microbiota disruptions can occur with rapid changes in diet, transportation stress, the onset of gastrointestinal disease, or other diseases such as laminitis or grass sickness (Garrett et al., 2002; Costa et al., 2012; Moreau et al., 2014). Horses are susceptible to gastrointestinal disorders such as enterocolitis that may be due to antibiotic use, stressful conditions, or pathogen infection (e.g., Clostridioides difficile; Salmonella). Not all probiotic interventions have led to improvements, but there are examples of success. In one study, a Saccharomyces boulardii treatment reduced the severity and duration of illness in horses with acute enterocolitis (Desrochers et al., 2005). In another study, a probiotic mixture of 3 Lactobacillus strains (of the species L. plantarum, L. casei, L. acidophilus) and 1 Enterococcus strain (E. faecium) reduced the incidence of Salmonella shedding in horses admitted for routine medical and surgical treatments (Ward et al., 2004). Overall, there is weak evidence for probiotic use in horses with enterocolitis at this time.

In healthy adult horses, the reasons for using probiotics may differ depending on the fiber and starch content of the diet being fed. In horses fed a high-fiber diet composed of grasses and hay, live yeast cultures (Saccharomyces cerevisiae) have increased nutrient breakdown and energy extraction (Medina et al., 2002; Jouany et al., 2008; Garber et al., 2020). Such increased efficiency may be helpful for horses eating low-quality forages or performance animals that have higher energy requirements. To meet the energy needs of many high-energy or performance animals, grains that are rich in starch and have a higher energy content are often fed. A high-starch diet helps meet the energy requirement, but if not managed properly, it can exceed the capabilities of the horse’s small intestine, resulting in significant starch loads entering the hindgut. These starches are highly fermentable by hindgut microbiota, resulting in the rapid production of lactic acid and short-chain fatty acids. The accumulation of these acids can lead to hindgut acidosis and diseases such as colic or laminitis. Lactobacilli have been shown to modify equine microbiota populations, decreasing amylolytic bacteria and increasing lactic-acid utilizers, and ultimately attenuating starch breakdown and pH decline ex vivo (Harlow et al., 2017). Live yeast cultures have also been shown to help attenuate the hindgut lactic acid concentrations and maintain the hindgut pH of horses fed high-starch diets (Medina et al., 2002). These studies suggest that probiotics may be useful in increasing the digestive efficiency and/or maintaining the hindgut homeostasis of healthy adult horses.

Probiotics for horse athletic performance

Because probiotics have been used to support exercise performance in humans (Pyne et al., 2015), similar interventions have been tested in performance horses recently. In one study a probiotic mixture of 5 Lactobacillus strains (L. acidophilus DSM 32241, L. plantarum DSM 32244, L. casei DSM 32243, L. helveticus DSM 32242, L. brevis DSM 27961), 2 Bifidobacterium strains (B. lactis DSM 32246, B. lactis DSM 32247)), and 1 Streptococcus strain (S. thermophilus DSM 32245) reduced post-exercise blood lactate concentrations and modified blood and urinary metabolite profiles (Laghi et al., 2018). In another study, a probiotic mixture of 2 Lactobacillus strains (from the species L. plantarum and L. paracasei) increased blood oxygen saturation and reduced blood lactic acid concentrations (Zavistanaviciute et al., 2019). Because lactic acid production and accumulation results in fatigue and reduced performance, these studies suggest that probiotics may support athletic performance in horses. The results of these studies are promising, but more research is necessary.

State of the science

Data to support use of probiotics in horses is emerging, but the occurrence of harmful outcomes in at least one study reinforces the need for high quality studies that can precisely establish efficacious conditions and formulations for use. Similar to recommendations for other host species, equine probiotics should provide an effective dose, be designed for horses, target a specific life stage and condition, and be supported by evidence. It is important to remember that probiotic efficacy can depend on specific microbial strains, supplement form, storage conditions, and dosage – see ISAPP’s infographic ‘What Qualifies as a Probiotic’ for more details on probiotics.

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

Episode 18: The definition of postbiotics

March 6, 2023/in Podcast, Season Two /by Laura

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The Science, Microbes & Health Podcast

The definition of postbiotics, with Dr. Gabriel Vinderola and Prof. Seppo Salminen

Episode summary:

In this episode, the ISAPP podcast hosts join guests Gabriel Vinderola, PhD, Principal Researcher at the
National Scientific and Technical Research Council (CONICET) and Associate Professor at University of Litoral in Argentina, and Seppo Salminen, PhD, Professor at University of Turku in Finland, to discuss the relatively recent definition of postbiotics and what kinds of substances are included in this category. They talk about the criteria for something to qualify as a postbiotic, common mechanisms of action for postbiotics, and how postbiotic science has brought new perspectives on the study of probiotics.

Key topics from this episode:

What are postbiotics? Dr. Vinderola and Prof. Salminen dive deep into the definition of postbiotics created in 2021 and what it entails.
Postbiotics, similar to probiotics, prebiotics, and synbiotics, must provide health benefits to the host.
The nature of the postbiotic preparation is important for its health benefits. When the inactivation process is changed, this can lead to altered health benefits, and clinical studies must be repeated to ensure the desired health benefits are maintained.
They explain why “inanimate” was chosen to describe the microorganisms / components in a postbiotic preparation.
What is the mode of action, or how do postbiotics work?
- Postbiotics show similar mechanisms of action to probiotics, except for ones requiring viability, since postbiotics will not grow and produce metabolic byproducts in the host.
- Postbiotics can benefit the host via physical interaction with the host epithelial and immune cells.
- A primary mechanism of action is likely to be through activation of the immune system, through which postbiotics can affect inflammation and some disease conditions.
- Postbiotics may also affect the microbiome composition and ability to inhibit pathogens.
From a regulatory point of view, inanimate microorganisms may represent an easier category to prove safe for users. For industry, postbiotics may be more convenient with a longer shelf life.
Some controversy still exists around the ISAPP-led postbiotic definition, and this has led to valuable discussions that are crucial to scientific progress. So far the authors of the definition have defended their stance.

Episode abbreviations and links:

ISAPP scientific consensus definition of postbiotics, published in Nature Reviews Gastroenterology & Hepatology: The International Scientific Association of Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of postbiotics
Study on a postbiotic for addressing chronic stress in students: Health Benefits of Lactobacillus gasseri CP2305 Tablets in Young Adults Exposed to Chronic Stress: A Randomized, Double-Blind, Placebo-Controlled Study
Study using live bifidobacteria to address irritable bowel syndrome: Randomised clinical trial: Bifidobacterium bifidum MIMBb75 significantly alleviates irritable bowel syndrome and improves quality of life–a double-blind, placebo-controlled study
Study using dead bifidobacteria (same strain as above) to address irritable bowel syndrome: Heat-inactivated Bifidobacterium bifidum MIMBb75 (SYN-HI-001) in the treatment of irritable bowel syndrome: a multicentre, randomised, double-blind, placebo-controlled clinical trial
Opinion from the European Food Safety Authority (EFSA) Panel on Nutrition, Novel Foods and Food Allergens (NDA) on pasteurized Akkermansia muciniphila as a novel food (NF) pursuant to Regulation (EU) 2015/2283: Safety of pasteurised Akkermansia muciniphila as a novel food pursuant to Regulation (EU) 2015/2283

Additional Resources:

Postbiotics. ISAPP infographic (also available in Japanese and Spanish).

Behind the publication: Understanding ISAPP’s new scientific consensus definition of postbiotics. ISAPP blog post.

Definition of postbiotics: A panel debate in Amsterdam. ISAPP blog post.

About Dr. Gabriel Vinderola:

Gabriel Vinderola graduated at the Faculty of Chemical Engineering from the National University of Litoral (Santa Fe, Argentina) in 1997. He obtained his Ph.D. in Chemistry in 2002 at the same University. He collaborated with several research teams in Canada, Spain, France, Italy, Germany, Brazil and Finland. He is presently Principal Researcher of the National Scientific and Technical Research Council (CONICET) and Associate Professor at the Food Engineering Department of his home Faculty. He participated in 1999 in the development of the first commercial cheese carrying probiotic bacteria in Latin America. In 2011, he was awarded the prize in Food Technology for young scientists, by the National Academy of Natural, Physic and Exact Sciences from Argentina. He published more than 120 original scientific publications in international refereed journals and book chapters. From 2020 to present, he serves as a member of the board of directors of the International Scientific Association for Probiotics and Prebiotcis (ISAPP). He is engaged in science communication to the general public through Instagram (@gvinde).

About Prof. Seppo Salminen:

Seppo Salminen, MSc, MS, PhD, is a Senior Advisor, Functional Foods Forum (FFF) at the University of Turku. His areas of expertise are gut microbiota, probiotics and prebiotics, nutrition and food safety, and EU regulations. Seppo teaches the topics of lactic acid biotechnology, functional foods and EU legislation and conducts research into food and health, intestinal microbiota, probiotics, prebiotics, functional foods, food legislation, health claims, and novel foods.

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

February 23, 2023/in Podcast, Season Two /by Laura

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The Science, Microbes & Health Podcast

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:

Reviews on metabolic phenotyping: Metabolic phenotyping in clinical and surgical environments and Metabolic Phenotyping in Health and Disease.
Dr. Wijeyesekera’s research on how critical illness affects the gut microbiota: Multi-Compartment Profiling of Bacterial and Host Metabolites Identifies Intestinal Dysbiosis and Its Functional Consequences in the Critically Ill Child and Profiling Gut Microbiota and Bile Acid Metabolism in Critically Ill Children
Papers on how metabolic phenotyping is helping us to better understand the gut microbiota: Gut microbiota composition and activity in relation to host metabolic phenotype and disease risk and Genome-microbiome interplay provides insight into the determinants of the human blood metabolome and The fecal metabolome as a functional readout of the gut microbiome.

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 16: The honey bee microbiome and potential for probiotics

February 6, 2023/in Podcast, Season Two /by Laura

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The Science, Microbes & Health Podcast

The honeybee microbiome and potential for probiotics, with Dr. Brendan Daisley

Episode summary:

In this episode, the ISAPP podcast hosts cover the honey bee microbiome with Brendan Daisley, PhD, who is currently a post-doctoral fellow at the University of Guelph in Canada. Daisley explains how the honeybee microbiome is unique, why it’s important for bee health, and the potential for probiotic applications as well as the practicalities of how live microorganisms are delivered to hives.

Key topics from this episode:

Daisley’s research is motivated by declining bee populations and finding ways to find ways to stop this.
He originally researched how probiotics could have detoxification functions in humans; this led to the question of whether probiotics could help reduce the toxicity of pesticides in bees and possibly affect resistance to infectious diseases.
Each individual bee has a microbiome of its own. Unlike other insects, bees have a core, defined microbial community in their guts.
Surprisingly, no one has successfully derived a completely germ-free honey bee. Microbiota-depleted bees do exist, however.
Research is ongoing on how microbes may even enable life in bee species — e.g. the recent finding that pupation in stingless bees is triggered by fungi.
Bees are affected by pesticides; many pesticides also have antimicrobial effects, but regulatory agencies do not track these effects.
Supplementing bees with beneficial strains of microbes can improve bee health and resistance to infectious diseases. However, no good baseline studies have been done on the bee gut, so it’s difficult to know what’s ‘normal’ and what is missing. The Canadian Bee Gut Project aims to determine this.
It’s possible to try finding bees that may have had less exposure to pesticides, but it’s difficult to determine past exposure because bees are traded and sent all over the world.
Wolbachia is a valuable endosymbiont for bees, and acts like a ‘secondary mitochondria’ in their cells. Currently it is hardly ever found in honey bees, possibly because of chronic exposure to tetracycline.
Probiotics can be delivered to bees using a “BioPatty” or a spray-based formula; the delivery method is very important. Supplementing the hive with certain probiotics can suppress outbreaks of American Foulbrood disease when they happen.
Daisley and colleagues used 3 probiotic strains, which remain present in the bee host for several weeks.
As far as potential prebiotics for bees, it has been observed that pollen fibers can beneficially modulate the honey bee microbiome.
The healthy honey bee microbiome should be dominated by lactic acid bacteria.

Episode abbreviations and links:

This is the first paper on American foulbrood (AFB), caused by the spore-forming bacterium Paenibacillus larvae, that Daisley and colleagues captured: Novel probiotic approach to counter Paenibacillus larvae infection in honey bees
In this paper, the group showed LX3 supplementation in the BioPatty formula can decrease AFB load to near undetectable levels: Lactobacillus spp. attenuate antibiotic-induced immune and microbiota dysregulation in honey bees. This paper showed the LX3 strains can mitigate some of the negative health side effects of antibiotic exposure. Another paper from the California study, directly comparing the BioPatty and the new BioSpray, is in press.
See these reviews related to the honey bee microbiome: Missing microbes in bees: how systematic depletion of key symbionts erodes immunity, and Deteriorating microbiomes in agriculture – the unintended effects of pesticides on microbial life
Check out the website for the Canadian Bee Gut Project. The project aims to define what constitutes a “healthy” microbiome in honey bees by performing country-wide sampling in coordination with beekeepers across Canada.

About Dr. Brendan Daisley:

Dr. Brendan Daisley is a postdoc at the University of Guelph (Allen-Vercoe lab) and the current President of the Students and Fellows Association of ISAPP. He graduated from his PhD in Microbiology & Immunology at Western University in 2021 (supervisor: Dr. Gregor Reid), during which he received several national awards including the Armand Frappier Outstanding Student Award, adjudicated by The Canadian Society of Microbiologists. Brendan has a broad range of experience in environmental application of probiotics to honey bees and, notably, he was the first to introduce the theory of ‘missing microbes’ within the field of honey bee microbiome research. During his PhD, he helped coordinate several large field trials across North America (mostly in Ontario and California) showing that supplementation of probiotic lactobacilli strains to honey bees could improve colony-level health outcomes. During his postdoc work, he has developed a microbiome database tool (BEExact) for improved detection of uncultivated ‘microbial dark matter’, established a bioreactor model of the honey bee gut microbiome (the RoBEEgut), and co-founded the Canadian Bee Gut Project (https://beegutproject.uoguelph.ca) – a nationwide crowdsourcing initiative that aims to deeply sequence thousands of bee microbiome samples to increase our knowledge on the multifactorial drivers of honey bee mortality.

Episode 15: A primer on prebiotics

January 24, 2023/in Podcast, Season Two /by Laura

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The Science, Microbes & Health Podcast

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

December 13, 2022/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 20^th 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.

Episode 14: Evidence on probiotics for preterm infants

November 1, 2022/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.

Posts

Increased recognition of biotics as a category

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

Wider awareness of the postbiotic concept and definition

Advances in technologies for analyzing different sites in the digestive tract

First convincing evidence linking intake of live microbes with health benefits

Increased interest in candidate prebiotics

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

Novel findings related to lactic acid bacteria

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

Updated resource available on probiotics and prebiotics in gastroenterology

Pay attention to power

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

Improving the signal-to-noise ratio

The Science, Microbes & Health Podcast

Microbial species and strains: What’s in a name? with Dr. Jordan Bisanz PhD

The Science, Microbes & Health Podcast

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

Beyond mechanisms of action and individual response

The Science, Microbes & Health Podcast

Lactobacilli in the microbiomes of the gut, skin, reproductive tract and more, with Prof. Kingsley Anukam PhD

The Science, Microbes & Health Podcast

Investigating the benefits of live dietary microbes, with Prof. Colin Hill PhD and Prof. Dan Tancredi PhD

Two competing terms

Questions about the ISAPP definition of postbiotic

Reflections on three recent conferences where the concept of postbiotics was debated

Conclusions

References

The Science, Microbes & Health Podcast

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

Probiotics for foals

Probiotics for adult horses

Probiotics for horse athletic performance

State of the science

The Science, Microbes & Health Podcast

The definition of postbiotics, with Dr. Gabriel Vinderola and Prof. Seppo Salminen

The Science, Microbes & Health Podcast

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

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The honeybee microbiome and potential for probiotics, with Dr. Brendan Daisley

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A primer on prebiotics, with Dr. Karen Scott

The past 20 years in the biotics field

The current status of the biotics field

The future of the biotics field

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

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