Emerging issues in probiotic safety: 2023 perspectives

ABSTRACT

Probiotics are used for both generally healthy consumers and in clinical settings. However, theoretical and proven adverse events from probiotic consumption exist. New probiotic strains and products, as well as expanding use of probiotics into vulnerable populations, warrants concise, and actionable recommendations on how to work toward their safe and effective use. The International Scientific Association for Probiotics and Prebiotics convened a meeting to discuss and produce evidence-based recommendations on potential acute and long-term risks, risks to vulnerable populations, the importance for probiotic product quality to match the needs of vulnerable populations, and the need for adverse event reporting related to probiotic use. The importance of whole genome sequencing, which enables determination of virulence, toxin, and antibiotic resistance genes, as well as clear assignment of species and strain identity, is emphasized. We present recommendations to guide the scientific and medical community on judging probiotic safety.

Plain Language Summary

What is the context? Probiotics, available to healthy consumers as both dietary supplements and foods, are also used by some patient populations. The goal of this paper is to determine if any new factors have emerged that would impact current views about probiotic safety for both these populations.

What is new? The authors conclude that established practices are sensibly addressing factors important to the safety of traditional probiotics used by the general population. They also make recommendations regarding emerging safety considerations. Probiotics targeted for patient populations should undergo stringent testing to meet quality standards appropriate for that population, preferably verified by an independent third party. The safety of probiotics derived from species without a history of safe use must be considered on a case-by-case basis. Research is needed to address some gaps, for example which best animal models to use for safety assessment of live microbes, the possibility of antibiotic resistance gene transfer via transformation, and potential impact of probiotic-induced changes in microbiomes, interactions with drugs, and probiotic colonization.

What is the impact? Probiotics of sufficient quality for patient populations are being developed and should be used accordingly. Long-term safety assessments for probiotics should be consistent with, and not more stringent than, current regulatory requirements for biologic drugs, including fecal microbial transplants. Rigor in collecting and reporting data on adverse events is needed. The authors confirm the need for understanding the entire genetic makeup of a probiotic as a cornerstone for assessing its safety.

KEYWORDS:

• Probiotic
• safety
• next-generation probiotics
• antibiotic resistance
• microbiome
• microbiota
• genome sequencing
• live biotherapeutic products
• International Scientific Association for Probiotics and Prebiotics
• ISAPP

Disclosure statement

DM has been a paid consultant for HowarU and Bayer, has done legal work for VSL#3, and is President of the ISAPP board, a non-paid position. CH has consulted for Kyowa Hakko, Adiso Therapeutics and Winclove BV and serves as a non-paid member of the Board of Directors of ISAPP. GAP declares no conflicts of interest. ALS declares no conflicts of interest. NZ declares no conflicts of interest. MCC has been paid to speak at meetings by HIPP, Danone, Nutricia, Nestlé Nutrition Institute and Mead Johnson. LM has been a paid consultant for Sanofi, Bayer, Danone, and Hamni. CAE declares no conflicts of interest. Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention. The use of trade names is for identification only and does not imply endorsement by the Centers for Disease Control and Prevention. C.A. Elkins contributions are primarily attributed to the section titled “ What long-term safety studies are indicated?” and conceptual elements within the section titled “AR Horizontal transfer of antibiotic resistance genes.” GAM is employed by the Société des Produits Nestlé S.A. ZTL is an employee of Synbiotic Health, Inc. BP is employed by Yakult Europe BV and serves in non-remunerated positions as president of the Pharmabiotics Research Institute, board member of Lactic Acid Bacteria Industrial Platform and board chair of International Life Sciences Institute - EU. GL is employed by Chr. Hansen. MIP is employed by Winclove Probiotics and serves as a consultant for academic and industrial representatives in the field of microbiome and probiotics. Her consultancy clients had no role in drafting this manuscript or the decision to submit the work for publication. ACO is employed by International Flavors & Fragrances. HS has participated as a clinical investigator, and/or advisory board member, and/or consultant, and/or speaker for: Arla, BioGaia, Biocodex, Danone, Dicofarm, Nestlé, NNI Nutricia, Mead Johnson and serves as a non-paid member of the Board of Directors of ISAPP. DJT has been a paid consultant for Synbiotic Health, Inc., and International Fragrance & Flavors and serves as a non-paid member of the Board of Directors of ISAPP. MES has been a paid consultant for Bayer, Bill and Melinda Gates Foundation, California Dairy Research Foundation, Danone North America, Pepsico, Smith, Gambrell & Russell, LLP, and Winclove, has received honoraria for speaking from Associated British Foods, Biocodex, European Federation of Associations of Dietitians, fairlife, Allergosan, Probi, and Sanofi, is paid as the executive science officer of International Scientific Association for Probiotics and Prebiotics, and has served on advisory boards for Cargill, Danone North America, Danone, Yakult, and Winclove.

Abbreviations

AE	=	adverse event
AR	=	antibiotic resistance
GMP	=	good manufacturing requirements
MIC	=	minimum inhibitory concentration
FDA	=	U.S. Food and Drug Administration

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

ISAPP provided travel funding for non-industry-affiliated members of this expert panel. ISAPP is funded by equal contributions from member companies involved in the development, assessment, or marketing of probiotic or prebiotic products. Although ISAPP receives funds to support its activities from commercial sources, its activities and positions are set by an all-academic, volunteer board of scientists. Industry members have no control over the positions of the organization.