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Do polyphenols qualify as prebiotics? The latest scientific perspectives

/in ISAPP Science Blog, Consumer Blog /by KC

Kristina Campbell, Consulting Communications Director, ISAPP

When the ISAPP scientific consensus definition of ‘prebiotic’ was published in 2017, the co-authors on the paper included polyphenols as potential prebiotic substances. At the time, the available data on the effect of polyphenols on the gut microbiota were insufficient to show a true prebiotic effect.

An ISAPP webinar held in April 2022, aimed to give an update on the health effects of polyphenols and their mechanisms of action, along with how well polyphenols fit the prebiotic definition. Prof. Daniele Del Rio from University of Parma, Italy, and Prof. Yves Desjardins from Université Laval, Canada, presented the latest perspectives in the field.

What are polyphenols?

Polyphenols are a group of compounds found in plants, with over 6000 types identified to date. They can be divided into two main categories, flavonoids and non-flavonoids.

Polyphenols are absorbed in two different ways in the body. A very small fraction is absorbed in the small intestine, but 95% of them reach the lower gut and interact with gut microbiota. Although polyphenols have a special capacity to influence the activities of microorganisms, some resident microorganisms, in turn, can change the chemical structure of polyphenols through enzymatic action. These interactions produce a unique array of metabolites, which may be responsible for some of polyphenols’ prebiotic effects.

What are the health effects of polyphenols?

Epidemiological studies show that polyphenols in the diet are associated with many health benefits, including prevention of cardiovascular disease, certain cancers, and metabolic disease. These effects occur through various mechanisms. However, association is not proof of causation. So how good is the evidence that polyphenols can lead to health benefits?

Numerous human studies exist, but the most robust study to date for the health benefits of polyphenols is a randomized, controlled trial of over 20,000 adults, published in 2022, which showed supplementation with cocoa extract reduced death from cardiovascular events (although it did not reduce the number of cardiovascular events).

What are the mechanisms of action for polyphenols?

Polyphenols have multiple mechanisms of action. Del Rio focuses on the metabolites produced from dietary polyphenols called flavan-3-ols, which are found in red wine, grapes, tea, berries, chocolate and other foods. Along with colleagues, he showed that the metabolites produced in response to a polyphenol-rich food occur two ‘waves’: a small wave in the first 2 hours after ingestion, and a larger wave 5-35 hours after ingestion. The second wave is produced when flavan-3-ols reach the colon and interact with gut microbiota.

Work is ongoing to link these metabolites to specific health effects. Along these lines, Del Rio described a study showing how cranberry flavan-3-ol metabolites help defend against infectious Escherichia coli in a model system of bladder epithelial cells. These polyphenols are transformed by the gut microbiota into smaller compounds that are absorbed—so the health benefit comes not from the activity of polyphenols directly, but from the molecule(s) that the gut microbiota has produced from the polyphenols.

How else do polyphenols work? Ample evidence suggests polyphenols interact in different ways with gut microbes: they have direct antimicrobial effects, they affect quorum sensing, they compete with bacteria for some minerals, and/or they modify ecology, thereby affecting biofilm formation. Desjardins explained that these interactions may occur in parallel: for example, polyphenols may exert antimicrobial effects when they reach the colon, and at the same time, microorganisms in the gut begin to degrade them.

The mode of action of polyphenols Desjardins studies is the prebiotic mode of action—or as he describes it, “prebiotic with a twist”. A landmark paper from 2015 showed how cranberry polyphenols had protective effects on metabolism and obesity through the creation of mucin in the intestine, which formed a good niche for Akkermansia muciniphila, a keystone bacterial species for good metabolic health. Other polyphenols have since been shown to work the same way: by stimulating production of mucin, thereby providing ideal conditions for beneficial bacteria to grow. In this way, polyphenols appear to show small-scale effects comparable to the effects of probiotics, by inducing a host response that alters the bacterial niche.

Are the effects of polyphenols individual?

Del Rio offered some evidence that the health effects of polyphenols, via metabolites, is personalized: a study showed the existence of three distinct patterns of metabolite production in response to dietary polyphenols (ellagitannins). These may depend on the particular microbes of the gut and their ability to produce the relevant metabolites—so in essence, in each case the gut microbiota is equipped to produce a certain set of metabolites in response to polyphenols. More work is needed, however, to be able to personalize polyphenol intake.

Do polyphenols qualify as prebiotic substances?

Polyphenols clearly interact with gut microbiota to influence human health. The definition of a prebiotic is “a substrate that is selectively utilized by host microorganisms conferring a health benefit”. Given the available evidence that polyphenols are not metabolized or utilized by bacteria in all cases in the same direct way as carbohydrate prebiotics, Desjardins sees them as having a “prebiotic-like effect”. Rather, polyphenols are transformed into other biologically active molecules that ultimately provide health benefits to the host. These prebiotic-like properties of polyphenols are nicely summarized in a 2021 review paper and include decreasing inflammation, increasing bacteriocins and defensins, increasing gut barrier function (thereby reducing low-grade inflammation), modulating bile acids, and increasing gut immuno-globulins.

Overall, the speakers showed that polyphenols exert their health effects in several ways—and while the gut microbiota are important for their health effects, polyphenols, as a heterogenous group, may not strictly meet the criteria for prebiotics. Clearly, more research on polyphenols may reveal other mechanisms by which these important nutrients influence the gut microbiome and contribute to host health, and they may someday be regarded as prebiotics.

Watch the replay of the ISAPP webinar here.

ISAPP’s Guiding Principles for the Definitions of ‘Biotics’

/in ISAPP Science Blog /by KC

By Mary Ellen Sanders, PhD, ISAPP Executive Science Officer

Articulating a definition for a scientific concept is a significant challenge. Inevitably, scientists have different perspectives on what falls inside and outside the bounds of a term. Prof. Glenn Gibson, ISAPP co-founder and longtime board member, recently published a paper that describes his path to coining the word ‘prebiotic’, with this observation: “One thing I have learned about definitions is that if you propose one, then be ready for it to be changed, dismissed or ignored!”

Mary Ellen Sanders with Glenn Gibson

Members of the ISAPP board, however, have remained steadfast in their belief that such definitions are worth creating. They are the basis for shared understanding and coordinated progress across a scientific field.

Developing the consensus definition papers on probiotics, prebiotics, synbiotics, postbiotics and fermented foods was demanding on the part of all involved. The objective of the panels that met to discuss these definitions was clear – to provide common ground for consistent use of this growing body of terms for all stakeholders. Although some disagreement among the broader scientific community exists about some of the definitions, ISAPP’s approach relied on important, underlying principles:

  • Don’t unnecessarily limit future innovation
  • Don’t unnecessarily limit mechanisms of action
  • Don’t unnecessarily limit scope (host, regulatory category, mechanism, site of action, etc.)
  • Require a health benefit on a target host to be demonstrated – otherwise, what is the value of these biotic substances? (Of course, fermented foods were the exception in this criterion, because the value of consuming fermented foods even in the absence of an established health benefit is evident.)
  • Limit to preparations that are administered, not substances produced by in situ activities

In my opinion, many published definitions, including previous ones for postbiotics (see supplementary table here), are untenable because they don’t recognize these principles. There may also be a tendency to rely on historical use of terms, rather than to describe what is justified by current scientific knowledge. A good example of this is provided by the first definition of probiotics, published in 1965. It was “substances secreted by one microorganism that stimulate another microorganism” (Lily and Stillwell, 1965), which is far from the current definition of “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host (Hill et al. 2014).

If you’re looking for a concise summary of the five published ISAPP definitions, see here for our definitions infographic.

Additional reflections: I noted with a smile Glenn’s views on ISAPP, specifically on the appropriate pronunciation of the abbreviation ‘ISAPP’. “My only negative is that everyone involved in the organisation aside from 2 or 3 of us pronounce its acronym wrongly.” Most board members, including myself, have always pronounced this as ‘eye-sap’. Glenn opines, “The abbreviation is not eye-SAPP, it is ISAPP (with the ‘I’ – remarkably enough – being spoken as it is in the word ‘International’).” I wonder how he pronounces IBM?

 

 

 

 

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

/in ISAPP Science Blog /by KC

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

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

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

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

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

Read the full paper here

Reference:

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

 

 

 

Current status of research on probiotic and prebiotic mechanisms of action

/in ISAPP Science Blog /by KC

By Mary Ellen Sanders, PhD, ISAPP Executive Science Officer

Human intervention studies in the fields of probiotics and prebiotics assess the health effects of these ingredients, whether it’s improving specific symptoms or preventing the occurrence of a health condition. Yet scientists in the field recognize the importance of learning the ‘chain of events’ by which probiotics and prebiotics are able to confer health benefits. Such mechanistic insights allow better probiotic selection and development of therapeutic approaches, as well as more precise dosing.

Mechanisms of action for probiotics and prebiotics are complex and often difficult to pinpoint, especially since any given health benefit may derive from multiple co-functioning mechanisms. However, scientists have made incremental gains in understanding these mechanisms. This scientific progress was covered in a recent webinar co-presented by ISAPP and ILSI-Europe, titled Understanding Prebiotic and Probiotic Mechanisms that Drive Health Benefits. Speakers for the webinar were:

  • Sarah Lebeer, University of Antwerp, Belgium
  • Colin Hill, University College Cork, Ireland
  • Karen Scott, University of Aberdeen, UK
  • Koen Venema, Maastricht University – campus Venlo, The Netherlands

The webinar was held live on September 17, 2020. Of the 499 webinar registrants, 357 attended the webinar live from 57 countries, from Australia to the US. ISAPP and ILSI-Europe hope the webinar will serve as a resource for people who want a rapid overview about mechanisms of action.

Watch the full webinar here, and read further for a summary of key points from these experts.

Prebiotic benefits and mechanisms of action

Prebiotics are defined as substrates that are “selectively utilized by host microorganisms conferring a health benefit”. ‘Utilization’ in the gut may involve crossfeeding, which means products produced by the first microbes degrading the prebiotic can then be used by different members of the host microbiota – so it may take a series of complex steps to get to a final health outcome. However, selective utilization and health benefit are always required for a substance to meet the definition of a prebiotic.

The health benefit of a prebiotic can be local (in the gut) or systemic. Locally, prebiotics can act via fecal bulking, as they are typically types of fiber. In addition, they can produce short-chain fatty acids (SCFAs), which reduce gut pH and thereby can discourage pathogenic and toxigenic activity of gut microbes, increase calcium ion absorption and provide energy for gut epithelial cells.

Systemic functions of prebiotic metabolism include them being used as substrates for microbes that produce or interact with host cells to produce molecules with neurochemical, metabolic or immune activity. Further, SCFAs can end up in the blood and can reach the liver, muscles and the brain. The SCFAs interact with specific host receptors and can lead to the release of satiety hormones or interact with receptors in the liver, adipose tissue and muscle tissue, leading to reduced inflammation. Prebiotics can also interact directly with immune cells.

Probiotic health effects and mechanisms of action

Health and disease are the end results of complex interactions on a molecular scale within a human or animal host.  Host molecules also interact with microbial molecules, including those molecules introduced with or produced by probiotics. Designing studies to discover probiotic mechanisms in human research is extremely challenging because both host and probiotic are very complex systems that most probably engage with one another on multiple levels. Probiotic molecules can have direct effects and downstream effects, and we are aware of only a few cases where a health effect can be tied to one specific probiotic molecule.

Probiotics can interact directly with the host, but also can act indirectly by influencing the microbiome. There may be many different mechanisms by which a given probiotic interacts with the host.

It is interesting to note that probiotics use some of the same types of mechanisms (pili, small molecule production, etc.) that are used by pathogens, microbes that have a detrimental effect on the host.  But these shared mechanisms are usually connected to surviving or colonising strategies, not those that cause damage to the host.

L. rhamnosus GG is a well-researched model probiotic, for which many mechanisms have been identified, including pili, immune modulators and lactic acid production, some mechanisms shared with other probiotic strains and species. Other studies have identified mechanisms for novel types of probiotics. For example, in mice and humans taking a strain of Akkermansia, heat killed cells had the same or even better effect on markers of metabolic health, which implies that the molecules (perhaps proteins in the bacteria, unaffected by heat treatment) are mediating the effect in this case.

See here to watch the webinar in full.