Probiotic and Prebiotic Definitions: Where do we stand?

Transcription

1 Probiotic and Prebiotic Definitions: Where do we stand? MARY ELLEN SANDERS, PH.D. E X E C U T I V E S C I E N C E O F F I C E R, I N T E R N A T I O N A L S C I E N T I F I C A S S O C I A T I O N F O R P R O B I O T I C S A N D P R E B I O T I C S W W W. I S A P P S C I E N C E. O R G F O R I L S I - N O R T H A M E R I C A G U T M I C R O B I O M E C O M M I T T E E J U L Y 2 3,

2 Why do definitions matter? Stakeholders need a common language - agreed-upon definitions - that enables us to be precise when discussing an issue Figure from Hill et al Nat Rev Gastro Hepatol 11,

3 Why do definitions matter? Consumers should be clear what probiotic and prebiotic mean on a label Regulators should be clear what substances they are regulating and therefore what types of regulations make sense Without clear definitions, no path to global harmonization

4 Why do definitions matter? Scientists should be consistent with word usage in publications to avoid confusion Industry benefits Overall impression of the field is higher quality if all stakeholders can agree Adherence to definitions avoids the appearance of fraud

5 Blog about misuse of term probiotic Usprobiotics.org

6 Probiotics Live microorganisms that, when administered in adequate amounts, confer a health benefit on the host 2014 Definition, updated from 2002 WHO/FAO Photo, courtesy of G. Gibson Hill et al Nature Rev Gastroenterol Hepatol. 11,

7 Live microorganisms that, when administered in adequate amounts, confer a health benefit on the host The value of this definition is that it is clear, actionable and inclusive Not unduly restrictive in terms of what can be considered a probiotic Safety for intended use (dose, population, etc) not stipulated but is implied by requirement of health benefit Let s look at characteristics of historic probiotic definitions and compare to this definition

8 Characteristic Mechanism Type of benefit Pr0biotic definitions Examples in historical probiotic definitions Alter the microflora Improve microbial balance Implantation or colonization Improving the properties of the indigenous microflora Modulating mucosal and systemic immunity Improving nutritional and microbial balance in the intestinal tract ISAPP consensus definition Not stipulated* Not stipulated* Health benefit shown Not required Required Regulatory category Foods Not stipulated* Site of action Gut Not stipulated* Means of application Orally consumed Not stipulated* Live microbes Required by most historical definitions Required GMOs Silent Silent but OK Defined Not stipulated Implied Host Human Not stipulated* *Allows for innovation; is not needlessly proscriptive; does not rely on un-validated characterizations

9 Minimum criteria for commercial probiotic for human use Identification to the strain level Naming according to valid nomenclature Safe for intended use Provide sufficient levels of live microorganisms until the end of shelf life to deliver the health benefit Accurate labelling Providing evidence of health benefit from a human study Deposit in an international culture collection From 2018 ISAPP meeting, discussion group on global harmonization

10 What a probiotic is and is not Two basic ways to NOT be a probiotic: 1. Don t meet definition 2. Don t meet label claim Sanders, M.E How do we know when something called probiotic is really a probiotic? A guideline for consumers and healthcare professionals. Functional Food Rev 1:3-12.

11 Probiotics: what is encompassed under this term Dead microbes, microbial endproducts, microbial components and undefined microbial mixes

12 Term probiotic on wide range of products Lawn products Mattresses Cleaners Air sprays Cosmetics Huge array of foods And others How is confer a health benefit defined?

13 Challenges of establishing health benefits How many studies needed? Few recognized biomarkers for many probiotic endpoints Mixed results (some positive, some negative studies) Magnitude of effect may be small Numerous confounders Background diet, baseline microbiota, placebo effect Choice of placebo Choosing study populations Effects in healthy people difficult to establish Choosing patient population triggers drug status Unknown criteria for responders/non-responders Dose response studies rare, but can be convincing

14 Probiotic Must contain live microbes Must be tested and shown to have health benefit Must deliver level of live microbes shown to confer benefit Fermented Food vs. Probiotic Fermented Food Made by live microbes Live microbes might not survive into the food you consume (postfermentation processing) May not have been tested for health benefits beyond basic nutritional value Likely healthy dietary components, but may not meet the bar to be called a probiotic Probiotic Fermented Food Must contain live microbes meeting probiotic definition Must be tested and shown to have health benefit The health benefit must result, at least in part, from the live microbes present The health benefit must go beyond meeting basic microand macro-nutrient nutritional needs Must deliver level of live microbes shown to confer benefit

15 Prebiotics Substrate that is selectively utilized by host microorganisms conferring a health benefit Gibson et al The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nature Rev Gastroenterol Hepatol. 14(8):

16 Bindels, et al A non-digestible compound that, through its metabolization by microorganisms in the gut, modulates the composition and/or activity of the gut microbiota, thus, conferring a beneficial physiological effect on the host

17 Prebiotic definitions Characteristic Previous definitions ISAPP consensus definition Mechanism Selective stimulation Selective fermentation Composition and/or activity in the GI microflora Target: beneficial microbes Selectively utilized by host microbes (including coadministered probiotics) Broader range of impacted microbes recognized Nature of substances Ingredient or food ingredient Not stipulated* Regulatory category Foods Not stipulated* Site of action Colon or GI tract Not stipulated* Means of application Orally consumed Not stipulated* Host Human or not stipulated Not stipulated* Health benefit Required Required *Allows for innovation; is not needlessly proscriptive

18 Minimum criteria for prebiotic for human use Adequate chemical characterization Naming according to valid chemical nomenclature Safe for intended use Selectively utilized by host microbes Sufficient amount until the end of shelf-life to deliver the health benefit Evidence of health benefit from a human study The benefit is mediated by a positive impact on the microbiota The microorganisms that utilize the prebiotic should be identified and evidence of selective utilization by host microorganisms should be provided. From 2018 ISAPP meeting, discussion group on global harmonization

19 Synbiotic A mixture of probiotics and prebiotics that beneficially affects the host by improving the survival and implantation of live microbial dietary supplements in the gastrointestinal tract, by selectively stimulating the growth and/or activating the metabolism of one or a limited number of health-promoting bacteria, and thus improving welfare. G.R. Gibson and M.B. Roberfroid, 1995, J. Nutr., 125, 1401.

20 Synbiotics may be either synergistic or complementary Images courtesy of Glenn Gibson

21 Emerging terms in microbiota space Probiotic Prebiotic Definition Live microorganisms that, when delivered in adequate amounts, confers a health benefit on the host A substrate that is selectively utilized by host/commensal microorganisms conferring a health benefit Comment/Reference (Hill et al. 2014) (Gibson et al. 2017) Synbiotic Combinations of prebiotics and probiotics Prebiotic may (synergistic synbiotic) or may not (complementary synbiotic) be utilized by the probiotic Abiotic, Postbiotic Pharmabiotic Immunobiotic Psychobiotic Live biotherapeutic agents Non-viable probiotic organisms or cellular components thereof that exert beneficial effects on health or well-being Any form of therapeutic exploitation of the commensal flora, including the use of live probiotic bacteria, probiotic-derived biologically active metabolites, prebiotics, synbiotics or genetically modified commensal bacteria. Bacteria that promote health through activation of the mucosal immune apparatus Live organism that, when ingested in adequate amounts, produces a health benefit in patients suffering from psychiatric illness. (Shortt 1999) (Patel & Denning 2013) (O'Hara & Shanahan 2007) (Clancy 2003) (Sarkar et al. 2016) Probioceutical Probiotic-derived factors (Howarth 2010) A biological product that contains live organisms, such as bacteria; is applicable to the prevention, treatment, or cure of a disease or condition of human beings; and is not a vaccine. (Food and Drug Administration 2016) Submitted, Food Microbiology: Fundamentals and Frontiers, 5th edition, C Hill, Ed., Chapter: Probiotics and Prebiotics, ASM Press

22 Taxonomy changes for Lactobacillus genus The taxonomy of Lactobacillus genus is abnormally heterogeneous Currently 231 Lactobacillus species range from a genome size of megabases, have a GC content of 32-57% and an average nucleotide identity that is typical for a family or worse Such ranges are far beyond what is acceptable for a bacterial genus Experts are recommending that the current genus should be split into 12 new genera The genus of some well-known Lactobacillus species would be re-named (reuteri, rhamnosus, casei/paracasei, plantarum) Acidophilus group would remain Lactobacillus Sure to have important repercussions commercially

23 - Nomenclature changes are formally proposed in the IJSEM - The authors will decide on the names International Journal of Systematic and Evolutionary Microbiology (formerly International Journal of Systematic Bacteriology) Official journal of record for novel prokaryotic taxa Official publication of: International Committee on Systematics of Prokaryotes and the Bacteriology Applied Microbiology Division of the International Union of Microbiological Societies

24 LABIP Expert Workshop LABIP: Industry Platform for EU-sponsored research programs on lactic acid bacteria LABIP : European Economical Association, founded in 1994 Members are companies that produce or use LAB and have production or research facilities within the EU Major changes in the taxonomy of Bifidobacterium and Lactobacillus; consequences for industry 4-5 October 2018 Verona, Italy 34 people invited including academic, EFSA and industry members (all of whom are members of the LABIP) The meeting is by invitation Program focuses on the science and the consequences for probiotic safety (QPS), legal/ip, and industry I will attend on behalf of ISAPP

25 ISAPP response to nomenclature changes Embrace the changes Advocate for assuring that new names are not objectionable from a marketing point of view Can species names be retained? Can new genus names begin with L? Can new genus names be some variation of Lactobacillus? Advocate for a transition period for commercial products to comply Develop clear communications to consumers, healthcare providers and regulatory Key point: the microbes are not changed, but the names are different Collaborate with stakeholders Open mind as to formats and means of dissemination: Webinar, infographic, video, blogs

26 ISAPP Perspective on the IPA Codex Proposal Proposal: Development of Codex Alimentarius guidance or standard to more clearly define the required characteristics of safe and efficacious probiotics, and to ensure the same level of quality and manufacturing requirements for all operators on the global market Justification: Global occurrence of products sold as probiotics that do not meet the accepted probiotic definition Overall, global harmonization likely good for field Carrying this forward will be in Argentina s hands Unintended negative consequences Possible lack of consensus of what Argentina will ultimately propose IPA proposal presents some real challenges in certain sections Definition Criteria Safety Manufacturing Efficacy

27 A few points Safety Efforts should focus on adopting QPS approach Animal testing and/or phase 1 safety tests for QPS strains are not needed Manufacturing GMPs are likely straightforward How to handle product labeling of multi-strain products? Is total count enough? Should dead microbes resulting from overages be considered a functional ingredient? Efficacy What bar for efficacy? Highest possible standard? Competent and reliable scientific evidence? Qualified claims? When do human studies need to be repeated to confirm that changes in manufacturing or product haven t impacted efficacy?

28 Conclusions Clear, actionable and inclusive definitions, which allow for innovation, exist for probiotics and prebiotics New terms, needing consensus definitions, are emerging Lactobacillus genus taxonomy will change soon and companies will need to react and comply An avenue for global harmonization of probiotic definition and standards is available through Codex