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Postbiotics: A global perspective on regulatory progress

/in ISAPP Science Blog /by KC

By Dr. Gabriel Vinderola PhD, CONICET, National University of Litoral, Argentina

While the conceptualisation of postbiotics varies among scientists, some recent actions may suggest that regulatory agencies around the world are starting to align with the ISAPP definition (Salminen et al. 2021), understanding postbiotics as preparations of inanimate microorganisms able to confer a health benefit.

Before the May 2021 publication of the postbiotic consensus definition by an expert panel convened by ISAPP, a search in www.pubmed.com using the term postbiotics rendered around 320 entries in the period 1975-2021. Three years after the ISAPP publication, by August 2024, almost 1200 entries could be found. However, it is still to be examined how many of these entries use the term postbiotics to refer to (1) administered metabolites, (2) metabolites produced by the gut microbiota or (3) inanimate microbial preparations, the three most prevalent conceptualizations of the term. A future bibliometric analysis of the literature could be performed to shed light on this. Meanwhile outside academia, the discrepancy in postbiotic definitions continues: some companies market specific metabolites as postbiotics whereas other companies use the term postbiotics to refer to heat-inactivated lactobacilli.

The first movement I noticed towards potential regulatory adoption of the term was made by Health Canada, as suggested in a presentation by an officer at Probiota 2023 in Chicago last year. The presentation shared the ISAPP definition, stating that postbiotics would fall under the Natural and Non-Prescription Health Products Directorate (NNHPD), that some probiotic specifications may apply (strain specification, antibiotic resistance, etc,), and that quantification, in principle would be based on milligrams, expecting that more sophisticated and accurate methodologies would arise over time. This issue was addressed further in a Discussion Group in the recent ISAPP meeting at Cork (Ireland) – see the annual meeting report here. Presently, there is only one entry for the word postbiotics in the Health Canada webpage, where it is stated that “gut modifiers as livestock feed are products that, once fed, have a mode of action in the gastrointestinal tract of an animal. The gut modifier category can encompass a variety of feed ingredients, these ingredient types may include, but are not limited to viable microbial strains, prebiotics, postbiotics, enzymes, organic acids and essential oils”. However, no further indications of the meaning of the term postbiotic are stated on the website.

In January 2024, the trade journal Nutraingredients announced that the China Nutrition and Health Food Association (CNHFA) had decided to draft industry standards for quantifying postbiotics or inactivated cells and were rallying industry players and the public to take part in the draft process through a public consultation. The National Institutes for Food and Drug Control (NIFDC) was leading the process and it had drafted flow cytometry standards to measure postbiotics composed of inactivated cells of lactic acid bacteria. In addition, a fluorescent quantitative PCR detection method had been drafted for inactivated Bifidobacterium lactis cultures. In correspondence with the NIFDC, it was discussed that a direct counting method using a standard microscope for single culture postbiotics was being explored.

The TGA (Therapeutic Goods Administration) is the Australian body that regulates medicines, medical devices and biologicals. The TGA recently published a guidance to provide information for applications relating to microorganisms as active ingredients for use as new substances in listed medicines (the category which includes the majority of dietary supplements marketed in Australia), or as active ingredients in registered complementary medicines (RCM). Listed medicines and RCM containing microorganisms as active ingredients are generally referred to as probiotics or postbiotics. For the purpose of this guidance, microorganisms are whole and intact cells of bacteria and fungi (including yeasts) that are live or non-viable. This guidance is intended for the premarket assessment of new live and whole/intact non-viable microorganisms potentially used as probiotics and postbiotics. Interestingly, the guidance does not include cell fragments, which have different pharmacokinetics within the gut. It is worth noting that Australia is part of the ACCESS Consortium, consisting of Australia’s TGA, Health Canada, the UK’s MHRA, Swissmedic from Switzerland and Singapore’s Health Sciences Authority. However, it’s not yet known whether the ACCESS Consortium will take inspiration from the Australian guidance.

Which scientific publications may be influencing these regulatory directions? At the beginning of this blog I discussed the possibility of conducting a bibliometric analysis of the literature in order to find out how the term postbiotic has been used so far in relation to the different conceptualizations it may have. Surprisingly to me, a bibliometric analysis was published as a preprint last February at www.preprint.org and entitled “Who is qualified to write a review on postbiotics? A bibliometric analysis”. Authors indicated that between November 2021 and December 2023, 76 review articles were published on postbiotics, with a mean of almost 3 reviews per month. Authors concluded that a portion of this collection of work was written by first authors with no previous engagement with related research and lacking colleagues or mentors involved with microbiome/probiotics research to support them as senior authors. Our article “The Concept of Postbiotics”, in collaboration with Dr. Mary Ellen Sanders PhD and Prof. Seppo Salminen PhD ranks in third place among the top 10 publications according to the number of citations received.

While the academic and scientific sphere still debate the proper meaning of the term postbiotics, it seems the regulatory landscape for postbiotics is progressing to consider them to be preparations of inanimate microorganisms able to confer a health benefit, as proposed by ISAPP.

Clarifying the role of metabolites in the postbiotic definition

/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

/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 16th 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.

What does “gut health” mean?

/in Consumer Blog /by KC

By Prof. Maria Marco PhD, University of California – Davis

Probiotics and prebiotics are frequently marketed to consumers for their capacity to improve or support gut health. Dietitian nutritionists responding to a survey ranked fermented foods as the top superfood for the past six years explaining gut health as a primary reason for their choice. But what is gut health exactly?

As it turns out, there is not a widely accepted definition of gut health. Dr. Stephan Bischoff at the University of Hohenheim, Germany, nicely summarized the situation in a perspective back in 2011. Using criteria from the World Health Organization, he proposed that gut health be defined as “a state of physical and mental well-being in the absence of gastrointestinal complaints that require the consultation of a doctor, in the absence of indications or risks of bowel disease, and in the absence of confirmed bowel disease”. The term gut health has since been increasingly used in scientific publications. However, is gut health really only the absence of complaints or indications, risk, or disease? Is gut health a condition that requires physical and mental well-being?

For the first question, it seems reasonable that gut health would refer to an absence of bowel diseases and acute or even mild symptoms localized to the digestive tract such as food intolerance, abdominal pain, nausea, flatulence, bloating, constipation, and diarrhea. The etiology of these presentations can be traced back to disruptions in the normal functioning of the gastrointestinal tract, including undesired dietary nutrient breakdown and absorption, pathogen introduction and colonization, and intestinal inflammation. However, recent studies of the intestinal environment, encompassing both the intestinal microbiome and mucosa, suggest that an absence of complaints or disease does not directly mean our gut is healthy. Mild mucosal inflammation, increased barrier permeability, or the presence of certain potentially undesirable intestinal microorganisms may confer no overt symptoms, yet still could signify the presence of an undesired or unhealthy intestinal state. The outcomes of that imperceptible unhealthy state may not be realized until years later with the development of intestinal disease or conditions at extraintestinal sites.

This latter point evokes the second question: Is gut health a condition that requires physical and mental well-being? The answer from popular media is – yes! Diseases and chronic conditions that are not overtly related to the gastrointestinal tract, such as allergy, arthritis, obesity, cancer, mood disorders and depression, are now considered by many to be traceable back to gut health. To that regard, it is now well-established scientifically that our gastrointestinal tract is indeed an important organ, housing the majority of our microbiome and mucosal immune system and pivotal for systemic metabolism and neurological signaling. However, I wonder if the term “gut health” is at all appropriate when implying such a broad range of whole-body responses? Could it be that “gut health” is seen as the root or origin of our overall health?

One way to reconcile this broad interpretation of gut health is to consider that “gut health” has become a simple way to explain, interpret, and understand how diets intersect with overall physical and mental well-being. Our daily lives are structured around mealtimes and the foods we eat don’t just provide nutrients, but also social interactions, and can be affected by our socioeconomic status among many other factors. We connect our gut with sensations felt when hungry, full, and after drinking an alcoholic or caffeinated beverage. The gut also connects to diet-based risks for the development of non-communicable diseases over our lifetimes. The quote “all diseases begin in the gut” attributed to Hippocrates still rings true after all the medical advancements over the past 2400 years.

So, since the term “gut health” has such a broad interpretation, we should be qualifying any statement that a biotic or fermented food supports “gut health” with an explanation for the specific feature(s) of gut health that are being improved with biotic use. Perhaps in the future, good gut health, and even good health generally, can be defined. Until then, we only appreciate how we are starting to get closer to understanding the true interconnectedness of the diet-gut-microbiome axis with our overall health and well-being.

 

 

Picture of panelists on stage with conference participants in the audience

Definition of postbiotics: A panel debate in Amsterdam

/in ISAPP Science Blog /by KC

By Dr. Gabriel Vinderola, PhD,  Associate Professor of Microbiology at the Faculty of Chemical Engineering from the National University of Litoral and Principal Researcher from CONICET at the Dairy Products Institute (CONICET-UNL), Santa Fe, Argentina.

A panel debate titled “Postbiotics, definition and scopes” was convened at the 9th Beneficial Microbes conference in Amsterdam on November 14, 2022. The aim of this panel was to advance the discussion about postbiotics in the aftermath of some published disagreement (see here and here) about the definition of postbiotics produced and published by ISAPP: “a preparation of inanimate microorganisms and/or their components that confers a health benefit on the host”. The debaters included Prof. Seppo Salminen and myself (Dr. Gabriel Vinderola), both members of the board of directors of ISAPP and co-authors of the ISAPP postbiotics definition, supporting the ISAPP definition, and Prof. Lorenzo Morelli (in attendance virtually) and Dr. Guus Roeselers challenging the ISAPP definition. The debate was attended by around 150 persons, and consisted of 15-minute opening arguments on both sides, followed by a 30 min open discussion guided by the conference chair, Dr. Koen Venema.

I introduced ISAPP as a non-profit organization dedicated to advancing the science on probiotics, prebiotics and related substances. Among many other activities, ISAPP has produced 5 different consensus definitions: probiotics, prebiotics, synbiotics, postbiotics and fermented foods. Each consensus panel was composed of academic scientists with different backgrounds, expertise and perspectives, comprising at least 11 authors from 4 – 10 countries, who came together to incorporate broad perspectives and engage in thoughtful debate. To date, all 5 consensus papers have had almost half a millon accesses at Nature Reviews Gastroentetology and Hepatology, the journal where all of the definitions are published.

The discussion within ISAPP about the need for a postbiotic definition dates back to our 2019 annual meeting. Emerging research on the health benefits conferred by non-viable microbes, their fragments and metabolites was discussed at the meeting, and this planted the seed for a definition that would cover this area. Many different terms such as heat-killed probiotics, heat-treated probiotics, heat-inactivated probiotics, tyndallized probiotics, paraprobiotics, ghost probiotics, cell fragments, cell lysates and postbiotics had been used to encompass these substances.

The panel discussed these different terms and previously published definitions. Those opposed to the ISAPP definition preferred the Tsilingiri and Rescigno (2013)1 definition of postbiotics, which focuses on metabolites produced by probiotics. I reviewed the limitations of that definition, which were outlined in Salminen et al. (2021)2. One concern is that requiring a postbiotic to be derived from a probiotic creates an unnecessary burden of first meeting the criteria for a probiotic before developing a postbiotic.

Morelli emphasized the importance of definitions for regulatory bodies and stated that researchers should provide guidance on criteria to meet a definition. He quoted the first published definition of postbiotic by Tsilingiri and Rescigno in 20131: “any factor resulting from the metabolic activity of a probiotic or any released molecule capable of conferring beneficial effects to the host in a direct or indirect way”. Morelli stated that one value of this definition was that it was clear to regulators; metabolites are measurable and produced by microbes already accepted as food components with a long history of safe use. He considered this of paramount relevance as otherwise, the novel foods path would be required. He challenged the ISAPP approach as defining a substance that was unclear how to measure. Morelli showed pictures depicting the deterioration of the biomass of freeze-dried cultures during storage, to underscore the challenges of controlling the quality of products based on biomass of non-viable microbes. He added, “If we don´t know which are the components responsible for the health benefits, then it is challenging to determine what to measure.” He questioned the ability to establish the shelf life of such a product. The need to be precise in terms of how to quantify the active components of non-viable cells was essential to his criticism of ISAPP’s definition of postbiotics. Prof. Morelli concluded that researchers must address this issue of quantification methods, both to advance research and to provide regulatory bodies needed approaches to regulating non-viable microbes.

Conclusions from the debate were that the flaws of definitions previous to the ISAPP definition are apparent, and that the substance defined by ISAPP was useful to delineate, but that clear approaches to measurement of the active component(s) of non-viable microbes are needed to make the ISAPP definition workable in scientific and regulatory circles. The debate was very worthwhile, since science advances through respectful debates such as this.

It is clear that characterization of postbiotic products may be challenging, especially with increased complexity that arises by use of multiple inanimate strains, inclusion of  metabolic  endproducts, and the presence of whole and fragmented cells. But these challenges are not unique to postbiotics. Probiotic products can comprise complex mixtures of multiple strains as well as metabolic products (as the biomass during industrial production is harvested for freeze-drying, but not washed), along with significant amounts of non-viable microbes, which all may contribute to the overall health benefit. These facts are usually overlooked when relying just on viable cells for quantification.

Many commercial products carrying inanimate microbes and metabolic fermentation products, that potentially fit the ISAPP definition of postbiotics, are already available in the market. These are diverse products such as a mixture of two lactobacilli aimed at treating infant and adult diarrhea3 or a fermented infant formula to support pediatric growth4. Similar products also target animal nutrition5. A tightly controlled manufacturing process may be the path forward to warrant reproducibility of health benefits. Suitable characterization methodologies such as flow cytometry for non-viable microbes and mass spectrometry for metabolites seem to be relevant to sufficient postbiotic product characterization.

In brief, the ISAPP definition itself seemed well accepted by the meeting participants, but concerns were raised about how to quantify postbiotics according to the definition. We intend to address this point through consultations with experts, proposing scientific paths to help conceptualize factors that need to be considered for postbiotic quantification.

Picture of panelists on stage with conference participants in the audience

Panel debate about ISAPP’s definition of postbiotics held at Beneficial Microbes conference in Amsterdam on November 14th, 2022. On the stage, from left to right: Koen Venema (conference chair), Gabriel Vinderola, Seppo Salminen, Guus Roeselers and Lorenzo Morelli (on screen).

References

  1. Tsilingiri, K. & Rescigno, M. Postbiotics: What else? Benef. Microbes (2013) doi:10.3920/BM2012.0046.
  2. Salminen, S. et al. The International Scientific Association of Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of postbiotics. Nat. Rev. Gastroenterol. Hepatol. (2021) doi:10.1038/s41575-021-00440-6.
  3. Malagón-Rojas, J. N., Mantziari, A., Salminen, S. & Szajewska, H. Postbiotics for Preventing and Treating Common Infectious Diseases in Children: A Systematic Review. Nutrients 12, (2020).
  4. Béghin, L. et al. Fermented infant formula (with Bifidobacterium breve C50 and Streptococcus thermophilus O65) with prebiotic oligosaccharides is safe and modulates the gut microbiota towards a microbiota closer to that of breastfed infants. Clin. Nutr. 40, 778–787 (2021).
  5. Kaufman, J. D. et al. A postbiotic from Aspergillus oryzae attenuates the impact of heat stress in ectothermic and endothermic organisms. Sci. Rep. 11, 6407 (2021).

Additional reading:

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

Postbiotics: The concept and their use in healthy populations

 

Watch / listen to the debate here: https://youtu.be/pATNfhQY4P4

 

 

A postbiotic is not simply a dead probiotic

/in ISAPP Science Blog /by KC

By Dr. Gabriel Vinderola, PhD,  Associate Professor of Microbiology at the Faculty of Chemical Engineering from the National University of Litoral and Principal Researcher from CONICET at Dairy Products Institute (CONICET-UNL), Santa Fe, Argentina

Postbiotics, recently addressed in an ISAPP consensus panel paper, are defined as a preparation of inanimate microorganisms and/or their components that confers a health benefit on the host. Criteria to meet the postbiotic definition are summarized here. One noteworthy aspect of this definition is that the word ‘probiotic’ does not appear. Although in practice a probiotic strain may be used as a progenitor strain in the manufacture of a postbiotic, the simple process of inactivating a probiotic is not sufficient to be called a postbiotic. It cannot be assumed that any non-viable probiotic cells in a probiotic product are automatically considered a postbiotic component. If a probiotic strain is used as a progenitor of a postbiotic, an efficacy study must be redone using the inanimate preparation and a benefit must be demonstrated. A probiotic product displaying fewer than the labeled count of viable cells is merely a low-quality product; it is not a postbiotic.

Further, the ISAPP consensus definition on postbiotics recognizes that the process of making a postbiotic implies a deliberate step to inactivate the viable cells of the progenitor strain. This process can be achieved by different technological steps such as heat-treatment (perhaps the most feasible approach), high pressure, radiation or simply aerobic exposure for strict anaerobes. A corresponding efficacy study must be conducted on the preparation. Or at the very least, any postbiotic component of a probiotic product must be specifically shown to contribute to the health benefit conferred by the product.

In contrast to postbiotics, probiotics are live microorganisms which when administered in adequate amounts confer a health benefit on the host. Four minimum criteria should be met for a strain to be considered as a probiotic: (i) sufficiently characterized; (ii) safe for the intended use; (iii) supported by at least one positive human clinical trial conducted according to generally accepted scientific standards or as per recommendations and provisions of local/national authorities when applicable; and (iv) alive in the product at an efficacious dose throughout shelf life (Binda et al. 2020). This last requirement reflects the key difference between probiotics and postbiotics. Probiotics must deliver an efficacious number of viable cells through the shelf life of the product. In practice, probiotic products may display significant numbers of non-viable cells (Raymond & Champagne, 2015), as some cells may lose viability during the technological process of biomass production, while undergoing manufacture or preservation steps and through product storage prior to purchase. In order to provide the target dose until end of shelf life, an overage of 0.5 to 1 log order CFU above the expected counts of viable cells is commonly included in the product to compensate for potential losses during product storage and handling (Fenster et al. 2019).

Thus, some quantity of non-viable cells may be usually expected in certain probiotic products, especially supplement products claiming a long, room temperature stable shelf-life. However, they will be considered as probiotic products of quality as long as they are able to deliver the expected amount of viable cells until the end of the product shelf-life. It is worth mentioning that the probiotics are expected to be viable at the moment of their administration. After that, if exposure to different regions of the gut causes cells to die, it is not of consequence as long as a health effect is achieved.

Probiotics and postbiotics have things in common (the need of efficacy studies that demonstrates their benefits) and things that distinguish them (the former are administered alive, whereas the latter are administrated in their inanimate form), but no probiotic becomes a postbiotic just by losing cell viability during storage.

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

/in ISAPP Science Blog /by KC

By Mary Ellen Sanders PhD, Executive Science Officer, ISAPP

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

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

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

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

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

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

Related information:

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

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

 

 

 

 

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

/in ISAPP Science Blog /by KC

A key characteristic of a probiotic is that it remains alive at the time of consumption. Yet scientists have known for decades that some non-living microorganisms can also have benefits for health: various studies (reviewed in Ouwehand & Salminen, 1998) have compared the health effects of viable and non-viable bacteria, and some recent investigations have tested the health benefits of pasteurized bacteria (Depommier et al., 2019).

Since non-viable microorganisms are often more stable and convenient to include in consumer products, interest in these ‘postbiotic’ ingredients has increased over the past several years. But before now, the scientific community had not yet united around a definition, nor had it precisely delineated what falls into this category.

An international group of scientists from the disciplines of probiotics and postbiotics, food technology, adult and pediatric gastroenterology, pediatrics, metabolomics, regulatory affairs, microbiology, functional genomics, cellular physiology and immunology met in 2019 to discuss the concept of postbiotics. This meeting led to a recently published consensus paper, including this definition: “a preparation of inanimate microorganisms and/or their components that confers a health benefit on the host”.

Thus, a postbiotic must include some non-living microbial biomass, whether it be whole microbial cells or cell components.

Below is a Q&A with four of the paper’s seven ISAPP-linked authors, who highlight important points about the definition and explain how it will lay the groundwork for better scientific understanding of non-viable microbes and health in the years ahead.

Why was the concept of postbiotics needed?

Prof. Seppo Salminen, University of Turku, Finland:

We have known for a long time that inactivated microorganisms, not just live ones, may have health effects but the field had not coalesced around a term to use to describe such products or the key criteria applicable to them. So we felt we needed to assemble key experts in the field and provide clear definitions and criteria.

Further, novel microbes (that is, new species hitherto not used in foods) in foods and feeds are being introduced as live or dead preparations. The paper highlights regulatory challenges and for safety and health effect assessment for dead preparations of microbes.

Can bacterial metabolites be postbiotics?

Prof. Gabriel Vinderola, National University of Litoral, Argentina:

Postbiotics can include metabolites – for example, fermented products with metabolites and microbial cells or their components, but pure metabolites are not postbiotics.

Can you expand on what is not included in the category of postbiotics?

Dr. Mary Ellen Sanders, ISAPP Executive Science Officer, USA:

The term ‘postbiotic’ today is sometimes applied to components derived from microbial growth that are purified, so no cell or cell products remain. The panel made the decision that such purified, microbe-derived substances (e.g. butyrate) should be called by their chemical names and that there was no need for a single encompassing term for them. Some people may be surprised by this. But microbe-derived substances include a whole host of purified pharmaceuticals and industrial chemicals, and these are not appropriately within the scope of ‘postbiotics’.

For something to be a postbiotic, what kinds of microorganisms can it originate from?

Prof. Gabriel Vinderola, National University of Litoral, Argentina:

A postbiotic must derive from a living microorganism on which a technological process is applied for life termination (heat, high pressure, oxygen exposure for strict anaerobes, etc). Viruses, including bacteriophages, are not considered living microorganisms, so postbiotics cannot be derived from them.

Safety and benefits must be demonstrated for its non-viable form. A postbiotic does not have to be derived from a probiotic (see here for a list of criteria required for a probiotic). So the microbe used to derive a postbiotic does not need to demonstrate a health benefit while alive. Further, a probiotic product that loses cell viability during storage does not automatically qualify as a postbiotic; studies on the health benefit of the inactivated probiotic are still required.

Vaccines or substantially purified components and products (for example, proteins, peptides, exopolysaccharides, SCFAs, filtrates without cell components and chemically synthesized compounds) would not qualify as postbiotics in their own right, although some might be present in postbiotic preparations.

What was the most challenging part of creating this definition?

Dr. Mary Ellen Sanders, ISAPP Executive Science Officer, USA:

The panel didn’t want to use the term ‘inactive’ to describe a postbiotic, because clearly even though they are dead, they retain biological activity. There was a lot of discussion about the word ‘inanimate’, as it’s not so easy to translate. But the panel eventually decided it was the best option.

 Does this definition encompass all postbiotic products, no matter whether they are taken as dietary supplements or drugs?

Prof. Hania Szajewska, Medical University of Warsaw, Poland:

Indeed. However, as of today, postbiotics are found primarily in foods and dietary supplements.

Where can you currently find postbiotics in consumer products, and what are their health effects?

Prof. Hania Szajewska, Medical University of Warsaw, Poland:

One example is specific fermented infant formulas with postbiotics which have been commercially available in some countries such as Japan and in Europe, South America, and the Middle East for years. The postbiotics in fermented formulas are generally derived from fermentation of a milk matrix by Bifidobacterium, Streptococcus, and/or Lactobacillus strains.

Potential clinical effects of postbiotics include prevention of common infectious diseases such as upper respiratory tract infections and acute gastroenteritis. Moreover, fermented formulas have the potential to improve some digestive symptoms or discomfort (e.g. colic in infants). In addition, there is some rationale for immunomodulating, anti-inflammatory effects which may potentially translate into other clinical benefits, such as improving allergy symptoms. Still, while these effects are likely, more well-designed, carefully conducted trials are needed.

What do we know about postbiotic safety?

Dr. Mary Ellen Sanders, ISAPP Executive Science Officer, USA:

Living microbes have the potential, especially in people with compromised health, to cause an infection. But because the microbes in postbiotics are not alive, they cannot cause infections. This risk factor, then, is removed from these preparations. Of course, the safety of postbiotics for their intended use must be demonstrated, but infectivity should not be a concern.

What are the take-home points about the postbiotics definition?

Prof. Seppo Salminen, University of Turku, Finland:

Postbiotics, which encompass inanimate microbes with or without metabolites, can be characterized, are likely to be more stable than live counterparts and are less likely to be a safety concern, since dead bacteria and yeast are not infective.

Read the postbiotic definition paper here.

See the press release about this paper here.

View an infographic on the postbiotic definition here.

See another ISAPP publication on postbiotics here.

Video Presentation: Behind the scenes of the consensus panel discussion on the definition of fermented foods

/in ISAPP Science Blog /by KC

Numerous misunderstandings and questions exist around the concept of fermented foods. For example:

  • If a food does not contain live microorganisms, can it still be a fermented food?
  • Should the live microbes in fermented foods be called probiotics?
  • Do fermentation microbes colonize the human gut?

The first step in answering these questions is for scientists to come to agreement on what constitutes a fermented food. A new global definition of fermented foods was recently published by 13 interdisciplinary scientists from various fields—microbiology, food science and technology, immunology, and family medicine. In their paper in Nature Reviews Gastroenterology & Hepatology, fermented foods are defined as: “foods and beverages made through desired microbial growth and enzymatic conversions of food components”.

The panel discussion and the definition of fermented foods are covered in this video presentation by the paper’s first author Prof. Maria Marco, from the Department of Food Science and Technology at the University of California, Davis. This presentation was originally given at the virtual ISAPP 2020 annual meeting.

The new definition is intended to provide a clearer conceptual understanding of fermented foods for the public and industry, with the authors expecting that in the years ahead, scientists will undertake more hypothesis-driven research to determine the extent that various fermented foods improve human health and precisely how this occurs. More studies that address fermented foods in promoting health will be useful for establishing the importance of fermented foods in dietary guidelines.

The panel acknowledged that regulations on fermented foods from country to country are mainly concerned with food safety — and that, when properly made, fermented foods and their associated microorganisms have a long history of safe use.

 

Creating a scientific definition of ‘fermented foods’

/in Consumer Blog, ISAPP Science Blog /by KC

By Prof. Maria Marco, Department of Food Science and Technology, University of California Davis, USA

A panel of scientific experts was recently convened by ISAPP to discuss the state of knowledge on fermented foods. While there was much agreement on the underlying microbiological processes and health-related properties of those foods and beverages, our conversation on definitions led to sustained debate. So what exactly is a fermented food?

The word “ferment” originates from fervere, which in Latin means to boil. According to the Merriam-Webster dictionary, the verb ferment is defined as “to undergo fermentation or to be in a state of agitation or intense activity”. Fermentation is defined as both a chemical change with effervescence and as an enzymatically controlled anaerobic breakdown of energy-rich compounds (such as a carbohydrate to carbon dioxide and alcohol or to an organic acid). In biochemistry, fermentation is understood as an ATP-generating process in which organic compounds act as both electron donors and acceptors. In industry, fermentation means the intentional use of bacteria and eukaryotic cells to make useful products such as drugs or antibiotics. As you can see, there are clearly many meanings implied in “ferment” and “fermentation”. We add onto this by defining how those words apply to foods.

As our ISAPP panel began to deliberate the definition of fermented foods, it quickly became clear how difficult reaching consensus can be! Even though many panel members shared similar academic backgrounds and scientific expertise, finding agreement on the definition required several rounds of debate and some consuming of fermented foods and beverages along the way. Finally, we defined fermented foods and beverages as being “foods made through desired microbial growth and enzymatic conversions of food components” (see the published consensus paper here).

Find ISAPP’s infographic on fermented foods here.

This definition is very specific by requiring microbial growth and enzymatic processes for the making of those foods. Activity of the endogenous enzymes from the food components or enzymes added to the food is not enough for a food to be regarded as fermented. Similarly, foods made by only adding vinegar or “pickling” should not be called fermented. The definition acknowledges the essential roles of microorganisms for making fermented foods but does not require their presence or viability at the time of consumption.

On the other hand, our definition does not restrict fermented foods to only those foods and beverages made using microorganisms using metabolic pathways implicit in the strict biochemical definition. Yogurt and kimchi made using lactic acid bacteria relying on fermentative energy metabolism are included as much as koji and vinegar, foods made using fermentation processes that employ fungi and bacteria that perform aerobic respiratory metabolism.

Each word in a definition needs to be carefully calibrated. The best example of this in our definition of fermented foods is the word “desired”. Unlike a food that is spoiled as a result of microbial growth and enzymatic activity, food fermentations generate wanted attributes. Other words such as “intentional”, “desirable”, or “controlled” may also be used to describe this meaning. However, those words also have caveats that not all fermented foods are made “intentionally”, at least in the way that they were first prepared thousands of years ago. Qualities of fermented foods may be “desirable’ in some cultures but not others. While some fermentations are “controlled”, others are spontaneous, requiring little human input.

The process of discussing the definition with a group of scientific experts was enlightening because it required us to deconstruct our individual assumptions of the term in order to reach agreement on descriptions and meaning. With a definition in hand, we can use a shared language to study fermented foods and to communicate on the significance of these foods and beverages in our diets. There will also certainly be more “fermenting” of these concepts to improve our knowledge on the production and health impacting properties of fermented foods for years to come.

Find the ISAPP press release on this paper here.

Read about another ISAPP-led publication on fermented foods here.

Learn more in a webinar on the science of fermented foods here.

New synbiotic definition lays the groundwork for continued scientific progress

/in ISAPP Science Blog /by KC

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

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

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

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

A diverse panel of experts

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

An inclusive definition

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

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

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

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

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

Implications for study design

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

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

Continuing scientific progress

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

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

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

Find the ISAPP press release on this publication here.

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

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

New publication addresses the question: Which bacteria truly qualify as probiotics?

/in News, ISAPP Science Blog /by KC

Although the international scientific consensus definition of probiotics, published in 2014, is well known—”live microorganisms that, when administered in adequate amounts, confer a health benefit on the host”—the word is often used incorrectly in practice.

A recent article published in Frontiers in Microbiology builds on this definition and describes four criteria for accurate use of the word ‘probiotic’. Eight scientists co-authored the paper, including two ISAPP board members. The project was initiated by industry scientists affiliated with IPA Europe.

The authors explain why it’s important for scientists and companies to be sure the four identified criteria apply before using the term ‘probiotic’. Given the many misuses of the term that are evident today, however, consumers need to scrutinize ‘probiotic’ products to be sure they are legitimate.

Read the ISAPP press release on this publication here.

See an infographic summary of this publication here.

 

 

Highlighting the importance of lactic acid bacteria: An interview with Prof. Seppo Salminen

/in Consumer Blog, ISAPP Science Blog /by KC

By Kristina Campbell, M.Sc., science & medical writer

 

In a 2009 book called What on Earth Evolved?, British author Christopher Lloyd takes on the task of ranking the top 100 species that have influenced the planet throughout its evolutionary history.

What comes in at number 5, just slightly more influential than Homo sapiens? Lactobacilli, a diverse group of lactic-acid-producing bacteria.

The influential status of these bacteria on a global scale comes as no surprise to Prof. Seppo Salminen, ISAPP president and Professor at University of Turku (Finland), who has spent most of his career studying these microbes. He is the co-editor of the best-selling textbook Lactic Acid Bacteria: Microbiological and Functional Aspects, the fifth edition of which was released earlier this year. Salminen says the scientific community has come a long way in its understanding of lactic acid bacteria (LAB)—and in particular, lactobacilli.

Seppo Salminen at ISAPP annual meeting 2019

“If you think about the history of humankind, earlier on, more than 60% of the food supply was fermented,” explains Salminen. “On a daily basis, humans would have consumed many, many lactic acid bacteria.”

Yet 30 years ago when Salminen and his colleagues published the first edition of the textbook on lactic acid bacteria, they were working against perceptions that bacteria were universally harmful. The science on using live microorganisms to achieve health benefits was still emerging.

“Most people in food technology, they had learned how to kill bacteria but not how to keep them alive,” he explains. “They didn’t yet know how to add them to different formulations in foods and what sort of carrier they need. At that time, the safety and efficacy of probiotics was not well understood.”

Around ten years later, scientists came together to develop a definition of probiotics on behalf of the Food and Agriculture Organization of the United Nations and the WHO (FAO/WHO)—in a report that formed the basis of ISAPP Consensus meeting and today’s international consensus definition: “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host”.

With probiotics having been more precisely defined, the following years were a time of rapid scientific progress in the field. Lactobacilli became the stars of the show, as research emerged on the benefits of various strains and combinations of strains in food science and medicine.

Fast forward to today, when rapidly expanding gut microbiome research adds another dimension to what we know about these bacteria. While lactic acid bacteria are still primarily of interest for the health benefits they impart, scientists can now also study their interactions with other microorganisms in the intestinal microbiome. In some cases, this kind of research may help uncover new mechanisms of action.

After everything Salminen and his textbook co-editors (Vinderola, Ouwehand, and von Wright) have learned about lactic acid bacteria over the past few decades, Salminen says there are two main reasons for the perennial importance of the bugs. “One is their importance in food fermentation, extending the shelf life of foods, making a kind of food processing or ‘agricultural processing’ possible. To make sauerkraut shelf-stable for weeks, or to make yogurt or cheese.”

The second reason, he says, relates to their benefits for the host. “Lactic acid bacteria, especially lactobacilli, reinforce intestinal integrity. So they protect us against pathogens; and sometimes against toxins and heavy metals by binding them away.”

He continues, “The more we know, the more we understand that LAB are needed. There are very specific strains that are helpful in different conditions for animal feeds or for clinical nutrition for infants, for example.” He says the knowledge is expanding at such a rapid pace that it may only be a few more years before the textbook he co-edited will need another edition.

Salminen is currently one of the world’s most cited probiotic researchers, and has diverse ongoing research projects related to digestive health, eczema, early life, and nutrition economics—but lactic acid bacteria are the thread that weaves everything together.

“I’m proud to be working on the fifth most important factor in human evolution,” he says.

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

/in ISAPP Science Blog, News, Uncategorized /by KC

Past President and founding board member Prof. Gregor Reid is stepping down from the ISAPP Board in Banff in June 2020, as he retires from Western University and his Endowed Chair position at Lawson Health Research Institute the following month. In this blog post, he shares thoughts on his career and the opportunities for his replacement and for others to continue probiotic research. See here for information on the position of Research Chair in Human Microbiome and Probiotics at the Lawson Health Research Institute.

By Gregor Reid BSc (Hons), PhD, MBA, ARM CCM, Dr HS, FCAHS, FRSC

A mere blue dot. A pinhead, if that. But it’s us, all we have been and all we will be – for a while at least. The planet Earth.

Its magnificence is there for all to see.

Creative Commons Earth Illustration, Pixabay

Creative Commons Earth Illustration, by Pixabay

I’ve been fortunate to have visited over 60 of the countries on this majestic globe. One of the perks of being a scientist. And for those who know me well, I’ve taken my camera and my music with me on the journey. In this blog post, I’ll share some pieces of both and how they form part of who we are and what we study.

Across the vast surface of our planet, and within it, there are countless microbes. As life emerges from the surface, we shouldn’t be surprised that microbes climb on board. Whether plants, honey bees, fish, birds, lions, humans, microbes accompany each.

Photo by Andrew Pitek. Used with permission.

Just being human is a guest house1.

Understandably, since some of these microbes can be deadly to humans, our ancestors had to find ways to stop them. Whether plague, diphtheria, smallpox, influenza, wound infections, or other fatal diseases. And so, the marvels of vaccination and antibiotics were born.

Arguably, these miraculous interventions also brought complacency as a societal side-effect, despite the warnings of people like Alexander Fleming. The greatest possibility of evil in self-medication is the use of too small doses so that instead of clearing up infection the microbes are educated to resist penicillin2.

We all but ignored the collateral damage, pacified by label warnings of diarrhea and nausea until Clostridium difficile woke us from our slumber. When the antibiotics stopped working, we went out into left field and started using human poop! Too ridiculous to work, until it worked. Really well.

We’re running through the dark, and that’s how it starts. Don’t know what you’re doing to me. And it might be getting better3.

Prior to that radical step, an awakening had occurred through people like Metchnikoff but more recently Savage, Tannock, McKay, Costerton, Bruce, and others who led us to the microbes that have been helping us all along. In the case of Andrew Bruce, he wondered if replenishment of lactobacilli into the urogenital tract of women might help prevent recurrence of infection. But in the late seventies and early eighties, the collective ‘we’ wasn’t ready to listen.

You came like a comet, blazing your trail. Too high, too far, too soon, you saw the whole of the moon4.

In 2001 in the city of Cordoba, Argentina, a group of experts were assembled and asked to come up with a definition for probiotics5. This helped set a path that we remain on today.

But a definition is nothing without application and acceptance and stewardship. It requires passage to voices across the world. That is why the International Scientific Association for Probiotics and Prebiotics (ISAPP) has been a mountain overseeing the field. Led so wonderfully by Mary Ellen Sanders, Glenn Gibson and other outstanding scientists, it is symbolic of the climb many have had to make.

If you understand or if you don’t. If you believe, or if you doubt. There’s a universal justice, and the eyes of truth are always watching you6.

There’s always gonna be another mountain. I’m always gonna wanna make it move. Always gonna be an uphill battle. Sometimes I’m gonna have to lose. Ain’t about how fast I get there, ain’t about what’s waiting on the other side. It’s the climb7.

It has certainly been a climb. For each of us. Cynicism too often outweighing optimism. Hype outweighing truth. Profit ahead of science. Ignorance over understanding. But together, we have reiterated the message, the importance of studies and data. Not in experimental mice or test tubes, but in the ultimate host where benefits are sought.

The road has taught me to fight our corner, but also that there is a magnificence and mystery in this planet we share. From the birth of a baby to the honey bee that pollinates our crops, to the salmon that crosses from salt to fresh water and back. All from the Mother we share8.

I’ve been fortunate that my career has allowed me to pursue my dream, although it’s never quite as it seems9. One song sums it up for me: While I’m alive I’ll make tiny changes to earth10.

I hope that I have made some tiny changes, especially in the poorest regions of Africa where the probiotic fermented foods of Western Heads East and Yoba-for-life are impacting lives of the young and old. Such inspiring people!

I think if each person is able to make tiny changes, we can leave this life better than whence we came.

As retirement looms, it’s funny how the same question is asked repeatedly. “So, what will you do now?” My answer is I’m moving to America. It’s an empty threat11. Actually, I think back to second year of my honours’ degree at Glasgow University and second year of my PhD at Massey University when my answer was “I don’t know for sure, but I’ll do my best.” I think we need to follow the voice inside us and hope that tomorrow brings wellness and satisfaction.

I won’t fill my walls with framed degrees or awards. Those are for photo albums of a blessed past. They were made possible because of hard work, an incredible family, and a set of friends and talented colleagues too numerous to name.

I’m proud of my publications and students, and hope they inspire others. But I only have two hands12, and we need the Big Ideas for you and me13. So, the laboratory, supplies, offices, and amazing staff and students at the St. Joseph’s Hospital site in London, Ontario await a new direction and someone to carry the fire14. For whoever is my successor, I will wish that tomorrow brings another day, another ray of hope15 and that he or she remembers you only get what you give16, and you only get one shot, do not miss your chance17.

Scientific endeavour, an open mind, supportive colleagues, and taking chances all make for an exciting career. I followed a path barely walked. It ostracized me from many in mainstream microbiology. When grant panel reviewers don’t believe your work has value or is needed, life gets challenging. So, you follow your heart, you lean on those who agree with you, and publish on peripheral topics to stay noticed. Then you smile when your critics actually start studying beneficial microbes and probiotics, and understand what you’ve been saying all along.

Probiotics are more than science. They encompass a philosophy, an anthropological perspective, a bridge between past and future. They are a mountain range of possibilities. As researchers we are still people. We should never shut out the disciplines and sounds and voices that surround us. We need to awaken them like adding medium to a dried Lactobacillus and watching it grow.

The possibilities are just as endless as when I started. But they need younger hands with the latest and future technical skill-sets to pursue the big ideas and to be a steward in defending probiotic science and excellence. These are indeed exciting times.

In closing, I hope you enjoy the music selection — and the irony of some of the album names.

As for me heading into the sunset of this journey: Let the music play. I just wanna dance the night away18.

References (unlike any you’ve seen before)

  1. Coldplay. 2017. Kaleidoscope, from A Head Full of Dreams.
  2. Alexander Fleming. 1945. In, The New York Times.
  3. British Sea Power. 2017. What You’re Doing, from Let the Dancers Inherit the Party.
  4. The Waterboys. 1985. The Whole Of The Moon, from This is the Sea.
  5. Food and Agriculture Organization of the United Nations and World Health Organization. 2001. Probiotics in Food. http://www.fao.org/3/a-a0512e.pdf
  6. Enigma. 1993. The Cross Of Changes from album of the same name.
  7. Miley Cyrus. 2009. The Climb, from Hannah Montana: The Movie.
  8. Chvrches. 2013. The Mother We Share, from The Bones of What You Believe.
  9. The Cranberries. 1992. Dreams, from Everybody Else is Doing It.
  10. Frightened Rabbit. 2008. Head Rolls Off, from Midnight Organ Fight.
  11. Kathleen Edwards. 2012. Empty Threat, from Voyageur.
  12. Avicii. 2013. Wake Me Up, from True.
  13. The Boxer Rebellion. 2016. Big Ideas, from Ocean by Ocean.
  14. Editors. 2010. No Sound But The Wind, from the Twilight Saga: New Moon.
  15. Bill Nelson. 1983. Another Day, Another Ray of Hope, from Chimera.
  16. New Radicals. 1998. You Get What You Give, from Maybe You’ve Been Brainwashed Too.
  17. Eminem. 2002. Lose Yourself, from the movie 8 Mile.
  18. Barry White. 1975. Let The Music Play, from the album of the same name.

See here for a video interview with Gregor Reid on his long career in probiotic science and how the field evolved over time.