The International Scientific Association of Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of postbiotics

Abstract

In 2019, the International Scientific Association for Probiotics and Prebiotics (ISAPP) convened a panel of experts specializing in nutrition, microbial physiology, gastroenterology, paediatrics, food science and microbiology to review the definition and scope of postbiotics. The term 'postbiotics' is increasingly found in the scientific literature and on commercial products, yet is inconsistently used and lacks a clear definition. The purpose of this panel was to consider the scientific, commercial and regulatory parameters encompassing this emerging term, propose a useful definition and thereby establish a foundation for future developments. The panel defined a postbiotic as a "preparation of inanimate microorganisms and/or their components that confers a health benefit on the host". Effective postbiotics must contain inactivated microbial cells or cell components, with or without metabolites, that contribute to observed health benefits. The panel also discussed existing evidence of health-promoting effects of postbiotics, potential mechanisms of action, levels of evidence required to meet the stated definition, safety and implications for stakeholders. The panel determined that a definition of postbiotics is useful so that scientists, clinical triallists, industry, regulators and consumers have common ground for future activity in this area. A generally accepted definition will hopefully lead to regulatory clarity and promote innovation and the development of new postbiotic products.

Conflict of interest statement

S.S. serves on the board of ISAPP, is a board member of Yoghurt in Nutrition Initiative and has been a speaker in meetings funded by industry, Nestlé Nutrition Institute and Institute Danone. M.C.C. has participated as a speaker for HIPP, Danone, Nutricia, Nestlé Nutrition Institute and Mead Johnson. A.E. has led industry-sponsored research projects with support from B Food Science and Takanashi Milk Products, and has been a speaker for the companies. C.H. serves on the board of ISAPP, is a consultant to Artugen Therapeutics developing a live biotherapeutic, and has received research grants from several industry partners, including ADARE Pharmaceuticals, manufacturers of Lacteol. S.L. serves on the academic board of ISAPP and has received research grants from several industry partners, such as Yun. She has been compensated for speaking by Yakult. E.M.M.Q. serves on the board of ISAPP, as a consultant to 4D Pharma, Alimentary Health, Allergan, Biocodex, Ironwood, Salix, Takeda and Vibrant, and has research support from 4D Pharma, Biomerica and Vibrant. M.E.S. has been compensated for speaking engagements or for consulting from Associated British Foods, California Dairy Research Foundation, Cargill, Danone Research, Danone USA, Fairlife, General Mills, GlaxoSmithKline, JJ Heimbach, Kellogg, Kerry, Mead Johnson, Medscape, PepsiCo, Pfizer, Probi, Procter & Gamble, Sanofi, Trouw Nutrition, Visalia Dairy Company, Winclove Probiotics and Yakult. R.S. has participated as a clinical investigator, and/or advisory board member, and/or consultant, and/or speaker for Abbott, Danone and Nestlé. J.R.S. has led industry-sponsored research projects with support from AstraZeneca, Danone, Servier and Vitacress. H.S. serves on the board of ISAPP and has participated as a clinical investigator, and/or advisory board member, and/or consultant, and/or speaker for Arla, Biogaia, Biocodex, Ch. Hansen, Danone, Nestlé, Nestlé Nutrition Institute, Nutricia and Merck. G.V. has led industry-sponsored research projects on dairy products and probiotics. These projects were independently carried out and had no influence on the content of this manuscript. He is member of the Argentinian board of the Yoghurt in Nutrition Initiative (YINI Danone Argentina) and serves on the board of ISAPP. He was not a member of ISAPP Board at the time of the meeting, but has been elected as a board member as of June 2020.

© 2021. The Author(s).

Figures

Fig. 1. Total number of mentions in the literature of different terms referring to inanimate microorganisms and/or their metabolites.

Several different terms, all defined differently, have been used over the years to refer to some form of inactivated or killed microorganisms in the research literature according to a search of the literature found on PubMed for the period 1 January 2000 to 21 January 2021. Bacterial lysates were not included in the search although they may be considered postbiotics if health benefits are documented and other criteria for postbiotics are met; the isolation of lysates is also a procedure in molecular biology studies that is often used in situations unrelated to postbiotics, so the term could not be used unambiguously in this search. The data that support the plots within Fig. 1 are available from the authors upon reasonable request.

Fig. 2. Increasing use of the term postbiotics in the published literature.

Several different terms have been used over the years to refer to some form of inactivated or killed microorganisms in the research literature according to a search of the literature found on PubMed for the period 1 January 2000 to 21 January 2021. During the past 5 years, ‘postbiotics’ has emerged as the most common of these terms. The data that support the plots within Fig. 2 are available from the authors upon reasonable request.

Fig. 3. Scanning electron micrographs of Lacticaseibacillus rhamnosus GG.

Scanning electron micrographs of Lacticaseibacillus rhamnosus GG in live (part a) and processed (part b) form showing that processing steps to obtain postbiotics can have a major effect on the physical and functional properties of the bacteria, even if the overall biomass and rod shape is preserved. Inactivation was performed in this case by spray drying that resulted in a mixture of live, full piliated cells and inactivated cells lacking pili surface appendages (as described in Kiekens et al.). The bacteria were spotted on a gold-coated membrane, which is especially visible after processing. Adapted with permission from ref., Wiley.

Fig. 4. Postulated mechanisms of postbiotics and example effector molecules utilized by them.

Five mechanisms of action of postbiotics are postulated: (1) modulation of the resident microbiota; (2) enhancement of epithelial barrier functions; (3) modulation of local and systemic immune responses; (4) modulation of systemic metabolic responses; and (5) systemic signalling via the nervous system. Some examples of microbial effector molecules mediating these mechanisms are shown (non-exhaustive list). Conceptually, the activity of effector molecules could be better retained if the cellular structure of the postbiotics is preserved, for example, through increased avidity in interactions with immune receptors or through increasing the residence time of the active molecules inside the host. The cell wall protects against rapid degradation by digestive enzymes and immune attack inside the host. This aspect is similar to the situation with vaccines, which also function best if cellular structure is preserved, but with the most toxic and/or pathogenic parts being inactivated or deleted. BSH, bile salt hydrolase; EPS, exopolysaccharide; MAMP, microbe-associated molecular pattern; PRR, pattern-recognition receptor; SCFAs, short-chain fatty acids; TCR, T cell receptor; TH cell, T helper cell; Treg cell, regulatory T cell.