Table 2.

Summary of key recommendations regarding acute and long-term safety concerns for probiotics. AR, antibiotic resistance.

Safety risks	Recommendation
ACUTE SAFETY
Microbiome assessments	Microbiome profiling is not a required component of safety assessment for probiotics. Microbiome profiling is encouraged, as it may be useful for illuminating determinants of inter-individual differences in response to probiotics and for testing mechanisms and hypotheses.
Antibiotic resistance	All probiotic strains should be screened for AR phenotypes and genotypes. Any phenotypic resistance that is outside the norm for the species must be investigated further. If genes for antibiotics that are declared critically important by the World Health Organization (see text) are harbored, the probiotic should be subjected to a rigorous risk/benefit analysis that balances patient and consumer safety as well as public health concerns. The potential of genetic transfer via transformation poses a low risk, which nevertheless warrants further study. Manufacturers of historical strains that may not have undergone this approach to AR risk assessment should re-evaluate strains to assure compliance.
Invasive infection	Invasive infections and sepsis should be monitored diligently in clinical settings and reported fully in all probiotic trials. Using strain-level molecular techniques, clinical isolates should be compared to the administered probiotic. A molecular match of supplemented probiotic microorganism(s) to invasive clinical isolate(s) supports an association between probiotic and systemic infection. Manufacturers should identify and publicize the antibiogram of each commercialized probiotic strain, providing an empirical course of treatment if needed. When assessing the safety of any next-generation probiotic, the potential for translocation should be determined and risks weighed against benefit.
Probiotic:drug compatibility	Research has shown that probiotics encode enzymes that can interact with some drugs. Additional research is needed before recommendations can be made.
Vulnerable populations	Probiotics for mild to morbidly obese pregnant women be administered with awareness of an increased risk of pre-eclampsia. Extra monitoring is warranted when probiotics are administered to vulnerable target populations.
LONG TERM SAFETY
Long-term studies	Specific tests or length of follow-up to address long-term safety considerations are not required, as is consistent with current FDA requirements for biologic drugs, including fecal microbial transplants. Research in humans focused on determining if a probiotic changes the long-term microbiota composition or function should include collecting data on AEs, similar to acute studies. Research into animal models, especially as applied to next-generation strains, is advised to further our mechanistic understanding of how to measure potential long-term effects. In accordance with regulatory requirements for foods, supplements or drugs, companies must track and report adverse events.
Long-term colonization	Development of a long-term colonizing probiotic be done only with a clear objective of achieving benefits not easily, reliably, or economically attainable otherwise and with weighing of the risks in light of benefits. Careful consideration should be dedicated to determining what long-term safety data might be relevant to probiotic strains that persist in the host. Research should be conducted to determine relevant acute exposure tests and biomarkers that are useful for assessing safety of long-term colonizing probiotics.
Microbiome assessments	Microbiota community composition and function analyses should not be required for probiotic safety assessments. Such profiling may be useful for testing mechanisms and hypotheses. Research is needed to understand the clinical implications of any observed microbiota structure of function alterations.
Vulnerable populations	A follow-up is encouraged for a minimum of 2-year (when most outcomes are no longer corrected for prematurity) from studies of premature infants who received probiotics or not in the perinatal period to compare metabolic, allergic, immune, and other health outcomes.
GENERAL RECOMMENDATIONS
Probiotic quality	Probiotic dietary supplements targeted for vulnerable populations should undergo third-party verification of product quality (purity, potency, and identity), which are accurately communicated on product labels. Such products should undergo testing to meet quality standards appropriate for that population. Direct agreements with probiotic manufacturers may be useful for developing products to meet stricter quality control standards. Product labels would ideally communicate stricter standards.
Adverse event reporting	All clinical trials should rigorously collect and report data on adverse events. Events should be listed and defined, with reference to standardized criteria where appropriate. For each study arm, the absolute risk of each adverse event, using appropriate metrics for recurrent events, and the number of participants withdrawn due to harms should be presented. A balanced discussion of the benefits and harms should be presented.
Probiotic product labeling	Probiotic product formulations should remove probiotic products that fail to fully identify the probiotic microorganism (genus, species, and strain) and potency through the end of product shelf life.