Emerging Issues in Probiotic Safety: 2023 Perspectives

Contributors

• Daniel Merenstein - Georgetown University Medical Center
• Bruno Pot - Yakult Europe BV
• Gregory Leyer - Chr. Hansen
• Arthur C. Ouwehand - International Flavors & Fragrances
• Geoffrey A. Preidis - Baylor College of Medicine
• Christopher A. Elkins - CDC
• Colin Hill - University College Cork
• Zachery T. Lewis - Synbiotic Health Inc
• Andi L. Shane - Emory University
• Niv Zmora - Weizmann Institute of Science
• Mariya I. Petrova - Winclove Probiotics B.V.
• Maria Carmen Collado - IATA-CSIC
• Lorenzo Morelli - Universit Cattolica del Sacro Cuore
• Gina A. Montoya - Nestl S.A.
• Hania Szajewska - The Medical University of Warsaw
• Daniel J. Tancredi - UC Davis School of Medicine
• Mary Ellen Sanders - ISAPP

Abstract

Probiotics are widely used by healthy consumers and patients. There are both theoretical and proven adverse events associated with their use. New strains and expanding usage, especially in vulnerable populations, necessitate new safety guidelines.

Key Focus Areas:

• Acute and long-term risks of probiotics.
• Product quality tailored for vulnerable populations.
• Importance of adverse event reporting.
• Use of whole genome sequencing for virulence and antibiotic resistance monitoring.

Probiotic Safety - Context and New Findings

• Established practices address safety for general populations well.
• Stringent testing is advised for patient-targeted probiotics.
• Case-by-case assessment for probiotics from species without a history of safe use.
• Research needed on antibiotic resistance gene transfer, drug interactions, and microbiome changes.

Impact and Recommendations

• Probiotics for patients should meet biologic drug safety standards.
• Collection and reporting of adverse event data is critical.
• Understanding genetic makeup of probiotics is essential.

Background

• Probiotics defined as live microorganisms conferring health benefits.
• Growth in clinical trials assessing health benefits and risks of probiotics.
• Historically, less focus on adverse event monitoring.
• Safety issues seem minor in general populations, with better AE reporting in recent trials.
• Long-term safety impacts on microbiota and other physiological parameters are under-researched.

Safety Evaluation Frameworks

• European Food Safety Authority & Qualified Presumption of Safety approach.
• 15-step decision tree for species without an established history of safe use.
• Importance of thorough review and updated guidelines.

Fundamentals of Probiotic Safety

Concerns:

• Probiotic strains and product quality.
• Administration safety.

Essential Tools for Safety Assessment

• Whole genome sequencing.
• Strain-level identification.
• Examination of genes for toxigenicity, pathogenicity, and antibiotic resistance.

Specific Issues

• Possible transfer of antibiotic resistance genes.
• Need for tailored product testing for contamination.
• Safe administration practices.

Acute Risks

Microbiota Composition Alterations

• Microbiome profiling can inform health benefits and safety concerns.
• Potential for personalized probiotic therapy.

Antibiotic Resistance

• Regulatory focus on the horizontal transfer of AR genes.
• Importance of phenotypic and genotypic assessment.

Invasive Infection

• Rare but possible translocation from gut to cause infection.
• Monitoring and reporting invasive infections.

Long-term Risks

Long-term Colonization

• Most probiotics do not colonize long-term due to competition with resident microbiota.
• Efforts to enhance persistence raise safety questions.

Microbiome Assessments

• Profiling microbiota structure and function for hypotheses testing.
• Long-term microbiota changes need further research.

Recommendations for Study and Reporting

Probiotic Quality

• High-quality production under dietary supplement regulations.
• Independent verification for vulnerable population-targeted supplements.

Adverse Event Reporting

• Rigorous data collection in trials.
• Balanced discussion of benefits and harms.

Conclusion

• Emerging risks necessitate updated safety recommendations.
• Long-term safety to align with regulatory approaches for other biologics.
• Regulatory and research guidelines to balance benefits with patient safety.