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Cited by 481Probiotics and Fermented FoodsComplementary and Alternative Medicine StudiesGut microbiota and health

Emerging issues in probiotic safety: 2023 perspectives

Open access
Merenstein, Daniel, Pot, Bruno, Leyer, Gregory, Ouwehand, Arthur C., Preidis, Geoffrey A., Elkins, Christopher A., Hill, Colin, Lewis, Zachery T. +9 more·2023·Gut Microbes
DOI 10.1080/19490976.2023.2185034PMC PMC10026873
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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.

AI snapshot

Written from the paper’s full text.

TL;DR

This ISAPP expert panel paper reviews emerging acute and long-term safety issues for probiotics and offers recommendations on strain screening, vulnerable populations, product quality, and adverse event reporting. It emphasizes whole genome sequencing, antibiotic resistance assessment, and cautious use in high-risk groups while noting limited long-term safety data.

Key findings

  • In the earlier AHRQ review cited, only 235 of 622 studies (37%) provided nonspecific safety statements, and probiotic use was not associated with a statistically significant increase in overall adverse events (RR 1.00; 95% CI 0.93, 1.07, p = 0.999). A systematic review of children from 1995–2021 found 49 invasive infections, mostly sepsis, with most affected children under two years old and having a predisposing condition; 94% were treated successfully with antimicrobial therapy.
  • All probiotic strains should be screened for antibiotic resistance phenotypes and genotypes; if genes for antibiotics declared critically important by WHO are harbored, the probiotic should undergo rigorous risk/benefit analysis. Horizontal transfer via transformation is considered low risk but warrants further study.
  • In pregnancy, of 100 eligible studies, only 28 reported adverse events and 11 reported events potentially causally related, with no serious health concerns for mother or infant; however, a Cochrane review pooling four trials in obese women found 31 pre-eclampsia cases in 472 probiotic-treated women versus 17 in 483 placebo women, leading the authors to recommend monitoring for pre-eclampsia risk in mild to morbidly obese pregnant women.
  • Long-term colonization examples include *Bifidobacterium longum* subsp. *longum* AH1206 persisting for 6 months in some adults, *Bifidobacterium adolescentis* IVS-1 for 4 weeks, *B. longum* subsp. *infantis* EVC001 for approximately one year in infants, and *Lactiplantibacillus plantarum* ATCC 202195 for nearly 6 months in infants. Microbiome profiling is not recommended as a required component of probiotic safety assessment.

Methods

  • The International Scientific Association for Probiotics and Prebiotics convened an expert panel at its 2022 annual meeting; the authors met for a half-day, discussed information presented by panelists, and reached general agreement on key conclusions and recommendations.
  • Individuals authored sections related to their expertise, and the text was compiled, reviewed, and edited by all authors.
  • The paper is a narrative expert consensus/recommendation document based on literature and panel discussion, with recommendations summarized in Table 2; no systematic review or new primary data collection is described.

Limitations

  • The paper states that long-term safety studies for probiotics are much less well defined than acute safety studies, that data are limited, that no specific tests or length of follow-up are recommended, that clinical implications of microbiota alterations are unclear, and that the true frequency of probiotic-associated invasive infection remains uncertain.
  • The paper notes that harms reporting in probiotic trials is often incomplete and that long-term safety endpoints are seldom tracked by trialists.
  • Evident from the text: this is an expert panel consensus/narrative review rather than a systematic review or meta-analysis, so recommendations may rely on expert opinion and available literature rather than formal quantitative synthesis.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1080/19490976.2023.2185034

Cites

136 of 136 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 62 cited sources checked · 0 supported · 0 flagged

  • Interpretationnone given

    On rare occasions, probiotics may translocate from the gastrointestinal tract, resulting in invasive infection.

    “On rare occasions, probiotics may translocate from the gastrointestinal tract, resulting in invasive infection.”
    Quote in the paperSubstantial claim
  • Interpretationreasoning

    The ability of probiotics to impact drug function may have safety consequences.

    “The ability of probiotics to impact drug function may have safety consequences.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Evidence accumulated to-date on recovery of probiotics from feces indicates that most current probiotics do not colonize.

    “Evidence accumulated to-date on recovery of probiotics from feces indicates that most current probiotics do not colonize.75,, 76”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [75] Sanders ME, Heimbach JT, Pot B, Tancredi DJ, Lenoir-Wijnkoop I, Lahteenmaki-Uutela A, Gueimonde M, Bañares S. Health claims substantiation for probiotic and prebiotic products. Gut Microbes. 2011; 2(3): 127– 133. doi: 10.4161/gmic.2.3.16174. 21646865 source

      Not checked in the free run.

    • cites [76] Khalesi S, Bellissimo N, Vandelanotte C, Williams S, Stanley D, Irwin C. A review of probiotic supplementation in healthy adults: helpful or hype? Eur J Clin Nutr. 2019; 73(1): 24– 37. doi: 10.1038/s41430-018-0135-9. 29581563 source

      Not checked in the free run.

  • Premisecitation

    Among the general population and in patients who are not immunocompromised or severely debilitated, acute safety issues appear to be minor, especially when considering the large global use of probiotics in foods and nutritional supplements.

    “Among the general population and in patients who are not immunocompromised or severely debilitated, acute safety issues appear to be minor, especially when considering the large global use of probiotics in foods and nutritional supplements.2–5”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [2] Mogensen G, Salminen S, O’brien J, Ouwehand AC, Holzapfel W, Shortt C, et al. Food microorganisms - health benefits, safety evaluation and strains with documented history of use in foods. Bulletin of the IDF. 2002; 377: 4– 9.

      Not checked in the free run.

    • cites [3] Goldenberg JZ, Yap C, Lytvyn L, Lo CK, Beardsley J, Mertz D, Johnston BC. Probiotics for the prevention of clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev. 2017; 12: CD006095. doi: 10.1002/14651858.CD006095.pub4. PMC6486212 29257353 source

      Not checked in the free run.

    • cites [4] Guo Q, Goldenberg JZ, Humphrey C, El Dib R, Johnston BC. Probiotics for the prevention of pediatric antibiotic-associated diarrhea. Cochrane Database Syst Rev. 2019; 4: CD004827. doi: 10.1002/14651858.CD004827.pub5. PMC6490796 31039287 source

      Not checked in the free run.

    • cites [5] Hempel S, Newberry S, Ruelaz A, Wang Z, Miles JN, Suttorp MJ, Johnsen B, Shanman R, Slusser W, Fu N, et al. Safety of probiotics used to reduce risk and prevent or treat disease. Evid Rep Technol Assess (Full Rep). 2011;200: 1– 645. PMC4780970 23126627

      Not checked in the free run.

  • Interpretationreasoning

    A complete genome sequence is a foundation to assessing the safety of any given probiotic strain.

    “A foundation to assessing the safety of any given probiotic strain is a complete genome sequence.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 8
  • May combine two claims. 18

  • Classified as probably not a substantial claim.

    Premisecitation

    Probiotic-borne AR genes could be transferred to resident potential pathogens, other microbes harbored by the host, and/or environmental microbes, thereby increasing the ecological pool of antimicrobial resistance genes.

    “one concern is the theoretical situation in which probiotic-borne AR genes could be transferred to resident potential pathogens, other microbes harbored by the host, and/or environmental microbes, thereby increasing the ecological pool of antimicrobial resistance genes.15–17”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [15] Cohen PA. Probiotic safety—no guarantees. JAMA Intern Med. 2018; 178(12): 1577– 1578. doi: 10.1001/jamainternmed.2018.5403. 30242393 source

      Not checked in the free run.

    • cites [16] Freedman SB, Schnadower D, Tarr PI. The probiotic conundrum: regulatory confusion, conflicting ctudies, and safety concerns. JAMA. 2020; 323(9): 823– 824. doi: 10.1001/jama.2019.22268. 32125410 source

      Not checked in the free run.

    • cites [17] Poindexter B, Committee on F, Hand, Newborn I, Adams-Chapman I, Aucott SW, Puopolo KM, Goldsmith JP, Kaufman D, Martin C, et al. Use of probiotics in preterm infants. Pediatrics. 2021; 147(6). doi: 10.1542/peds.2021-051485. 34031231 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Hempel et al. concluded that, from the available evidence, although interventions and AEs were poorly documented, there was no statistically significant increase of the relative risk (RR) of the overall number of experienced AEs (RR 1.00; 95% confidence interval: 0.93, 1.07, p = 0.999) associated with probiotic use.

    “Hempel et al. concluded that, from the available evidence, although interventions and AEs were poorly documented, there was no statistically significant increase of the relative risk (RR) of the overall number of experienced AEs (RR 1.00; 95% confidence interval: 0.93, 1.07, p = 0.999) associated with probiotic use.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Hempel S, Newberry S, Ruelaz A, Wang Z, Miles JN, Suttorp MJ, Johnsen B, Shanman R, Slusser W, Fu N, et al. Safety of probiotics used to reduce risk and prevent or treat disease. Evid Rep Technol Assess (Full Rep). 2011;200: 1– 645. PMC4780970 23126627

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Culture-proven invasive infection is studied as a primary or secondary outcome in most trials that administer probiotics to preterm neonates, and network meta-analyses suggest that probiotic administration does not increase rates of sepsis in this vulnerable population.

    “Nonetheless, culture-proven invasive infection is studied as a primary or secondary outcome in most trials that administer probiotics to preterm neonates, and network meta-analyses suggest that probiotic administration does not increase rates of sepsis in this vulnerable population.59”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Morgan RL, Preidis GA, Kashyap PC, Weizman AV, Sadeghirad B, McMaster Probiotic P, Florez ID, Foroutan F, Shahid S, Zeraatkar D. Probiotics reduce mortality and morbidity in preterm, low-birth-weight infants: a systematic review and network meta-analysis of randomized trials. Gastroenterology. 2020; 159(2): 467– 480. doi: 10.1053/j.gastro.2020.05.096. 32592699 PMC8014956 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In vivo transfer via conjugation of AR genes from viable probiotic bacteria acting as donors was documented in 1998 and several papers since have confirmed the transferability of AR genes within the gut.

    “In vivo transfer via conjugation of AR genes from viable probiotic bacteria acting as donors was documented in 199833 and several papers since have confirmed the transferability of AR genes within the gut for a recent review see.34”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [33] Morelli L, Sarra PG, Bottazzi V. In vivo transfer of pAmβ1 from Lactobacillus reuteri to Enterococcus faecalis. J Appl Bacteriol. 1988; 65(5): 371– 375. doi: 10.1111/j.1365-2672.1988.tb01905.x. 2976754 source

      Not checked in the free run.

    • cites [34] Crits-Christoph A, Hallowell HA, Koutouvalis K, Suez J. Good microbes, bad genes? the dissemination of antimicrobial resistance in the human microbiome. Gut Microbes. 2022; 14(1): 2055944. doi: 10.1080/19490976.2022.2055944. 35332832 PMC8959533 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The gut microbiota can have both direct and indirect effects on the metabolism of drugs, with consequences for both efficacy and toxicity.

    “The gut microbiota can have both direct and indirect effects on the metabolism of drugs, with consequences for both efficacy and toxicity.60, 61”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [60] Wilson ID, Nicholson JK. Gut microbiome interactions with drug metabolism, efficacy, and toxicity. Transl Res. 2017; 179: 204– 222. doi: 10.1016/j.trsl.2016.08.002. 27591027 PMC5718288 source

      Not checked in the free run.

    • cites [61] Dashnyam P, Mudududdla R, Hsieh TJ, Lin TC, Lin HY, Chen PY, Hsu C-Y, Lin C-H. β-Glucuronidases of opportunistic bacteria are the major contributors to xenobiotic-induced toxicity in the gut. Sci Rep. 2018; 8(1): 16372. doi: 10.1038/s41598-018-34678-z. 30401818 PMC6219552 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Even in the absence of risk of conjugal transfer of non-intrinsic AR genes, there is also a possibility of transfer via transformation of naked DNA or transduction via phage.

    “Even in the absence of risk of conjugal transfer of non-intrinsic AR genes, there is also a possibility of transfer via transformation of naked DNA46, 47 or transduction via phage.48”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [46] McInnes RS, McCallum GE, Lamberte LE, van Schaik W. Horizontal transfer of antibiotic resistance genes in the human gut microbiome. Curr Opin Microbiol. 2020; 53: 35– 43. doi: 10.1016/j.mib.2020.02.002. 32143027 source

      Not checked in the free run.

    • cites [47] Winter M, Buckling A, Harms K, Johnsen PJ, Vos M. Antimicrobial resistance acquisition via natural transformation: context is everything. Curr Opin Microbiol. 2021; 64: 133– 138. doi: 10.1016/j.mib.2021.09.009. 34710742 source

      Not checked in the free run.

    • cites [48] Cj VW, Penders J, Jm VN, Nd M, Majumder S, Lb VA, Savelkoul PHM, Wolffs PFG. Dissemination of antimicrobial resistance in microbial ecosystems through horizontal gene transfer. Front Microbiol. 2016; 7: 173. doi: 10.3389/fmicb.2016.00173. 26925045 PMC4759269 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    There is no clear link between the microbiota alterations caused by the probiotic blend after antibiotics and clinical adverse events, nor evidence that this observation can be extended to other probiotic preparations.

    “However, there is no clear link between these alterations and clinical AEs nor is there evidence that this observation can be extended to other probiotic preparations.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Of 100 eligible studies of probiotic administration during pregnancy, only 28 reported adverse events; of these, only 11 reported adverse events potentially causally related to treatment, including gastrointestinal problems, nausea, and headache, but no serious health concerns were reported for mother or infant.

    “Of 100 eligible studies of probiotic administration during pregnancy, only 28 reported AEs. Of these, only 11 reported AEs that potentially could have a causal relationship with the treatment, including gastrointestinal problems, nausea, and headache; but no serious health concerns were reported for mother or infant.117”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [117] Sheyholislami H, Connor KL. Are probiotics and prebiotics safe for use during pregnancy and lactation? A systematic review and meta-analysis. Nutrients. 2021; 13(7): 2382. doi: 10.3390/nu13072382. 34371892 PMC8308823 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A small but significant increase in Lactobacillus bacteremia was observed in intensive care unit patients receiving probiotics in a Boston hospital, albeit this was not linked directly to colonization of the probiotic.

    “This last example was observed in a small but significant increase in Lactobacillus bacteremia in intensive care unit patients receiving probiotics in a Boston hospital, albeit this was not linked directly to colonization of the probiotic.92”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [92] Yelin I, Flett KB, Merakou C, Mehrotra P, Stam J, Snesrud E, Hinkle M, Lesho E, McGann P, McAdam AJ, et al. Genomic and epidemiological evidence of bacterial transmission from probiotic capsule to blood in ICU patients. Nat Med. 2019; 25(11): 1728– 1732. doi: 10.1038/s41591-019-0626-9. 31700189 PMC6980696 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Adverse events from probiotic strains in vulnerable populations include life-threatening pneumonia, endocarditis, and sepsis.

    “AEs include life-threatening pneumonia,106 endocarditis,107–111 and sepsis.112–115”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [106] Doern CD, Nguyen ST, Afolabi F, Burnham CA, Carroll KC. Probiotic-associated aspiration pneumonia due to Lactobacillus rhamnosus. J Clin Microbiol. 2014; 52(8): 3124– 3126. doi: 10.1128/JCM.01065-14. 24899028 PMC4136183 source

      Not checked in the free run.

    • cites [107] Shinar E, Leitersdorf E, Yevin R. Lactobacillus plantarum endocarditis. Klin Wochenschr. 1984; 62(24): 1173– 1174. doi: 10.1007/BF01712185. 6530891 source

      Not checked in the free run.

    • cites [108] Ze-Ze L, Tenreiro R, Duarte A, Salgado MJ, Melo-Cristino J, Lito L, et al. Case of aortic endocarditis caused by Lactobacillus casei. J Med Microbiol. 2004; 53(5): 451– 453. doi: 10.1099/jmm.0.05328-0. 15096557 source

      Not checked in the free run.

    • cites [109] Franko B, Vaillant M, Recule C, Vautrin E, Brion JP, Pavese P. Lactobacillus paracasei endocarditis in a consumer of probiotics. Med Mal Infect. 2013; 43(4): 171– 173. doi: 10.1016/j.medmal.2013.01.007. 23622954 source

      Not checked in the free run.

    • cites [110] Encarnacion CO, Loranger AM, Bharatkumar AG, Almassi GH. Bacterial endocarditis caused by lactobacillus acidophilus leading to rupture of sinus of valsalva aneurysm. Tex Heart Inst J. 2016; 43(2): 161– 164. doi: 10.14503/THIJ-15-5121. 27127435 PMC4845580 source

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    • cites [111] Boumis E, Capone A, Galati V, Venditti C, Petrosillo N. Probiotics and infective endocarditis in patients with hereditary hemorrhagic telangiectasia: a clinical case and a review of the literature. BMC Infect Dis. 2018; 18(1): 65. doi: 10.1186/s12879-018-2956-5. 29390976 PMC5796351 source

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    • cites [112] Kunz AN, Noel JM, Fairchok MP. Two cases of Lactobacillus bacteremia during probiotic treatment of short gut syndrome. J Pediatr Gastroenterol Nutr. 2004; 38(4): 457– 458. doi: 10.1097/00005176-200404000-00017. 15085028 source

      Not checked in the free run.

    • cites [113] Guenther K, Straube E, Pfister W, Guenther A, Huebler A. Sever sepsis after probiotic treatment with escherichia coli NISSLE 1917. Pediatr Infect Dis J. 2010; 29(2): 188– 189. doi: 10.1097/INF.0b013e3181c36eb9. 20118747 source

      Not checked in the free run.

    • cites [114] Vahabnezhad E, Mochon AB, Wozniak LJ, Ziring DA. Lactobacillus bacteremia associated with probiotic use in a pediatric patient with ulcerative colitis. J Clin Gastroenterol. 2013; 47(5): 437– 439. doi: 10.1097/MCG.0b013e318279abf0. 23426446 source

      Not checked in the free run.

    • cites [115] Zbinden A, Zbinden R, Berger C, Arlettaz R. Case series of bifidobacterium longum bacteremia in three preterm infants on probiotic therapy. Neonatology. 2015; 107(1): 56– 59. doi: 10.1159/000367985. 25402825 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a post-hoc analysis of the previous study, probiotics administered after antibiotics caused an expansion in antibiotic resistance genes within the mucosal microbiota, in particular to vancomycin, but this in-silico finding was not confirmed in-vivo.

    “Furthermore, a post-hoc analysis of the previous study revealed that probiotics administered after antibiotics caused an expansion in antibiotic resistance genes within the mucosal microbiota, in particular to vancomycin; however, this in-silico finding was not confirmed in-vivo.54”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Montassier E, Valdes-Mas R, Batard E, Zmora N, Dori-Bachash M, Suez J, Elinav E. Probiotics impact the antibiotic resistance gene reservoir along the human GI tract in a person-specific and antibiotic-dependent manner. Nat Microbiol. 2021; 6: 1043– 1054. doi: 10.1038/s41564-021-00920-0. 34226711 PMC8318886 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    In vulnerable populations, the presence of a single major risk factor, such as immunocompromised state, or more than one minor risk factor, merits caution in using probiotics.

    “In general, it has been suggested that in vulnerable populations, the presence of a single major risk factor, such as immunocompromised state, or more than one minor risk factor, merits caution in using probiotics.116”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [116] Boyle RJ, Robins-Browne RM, Tang ML. Probiotic use in clinical practice: what are the risks? Am J Clin Nutr. 2006; 83(6): 1256– 1257. doi: 10.1093/ajcn/83.6.1256. 16762934

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    Translating the preclinical framework to next-generation live biotherapeutics, which lack history of safe use, suggests that 12-month studies in humans would be in line with expectations for new molecular agents/targets when little-to-no post-market experience is available and should potentially be conducted concurrently with Phase III clinical trials.

    “Translating this preclinical framework to next-generation live biotherapeutics, which lack history of safe use, would suggest that 12-month studies in humans would be in line with expectations for new molecular agents/targets when little-to-no post-market experience is available and should potentially be conducted concurrently with Phase III clinical trials.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    The relevance of established toxicological frameworks to probiotics that do not generally enter the bloodstream or exhibit traditional small-molecule decay rates is not clearly apparent.

    “However, their relevance to probiotics that do not generally enter the bloodstream or exhibit traditional small-molecule decay rates is not clearly apparent.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Probiotics do not generally enter the bloodstream or exhibit traditional small-molecule decay rates.

  • May combine two claims.

    Premisecitation

    Subacute and chronic toxicity studies are usually conducted in animal models using validated procedures designed to provide insight into risk for humans, and are inherent to the drug development process prior to clinical use.

    “These types of studies are usually conducted in animal models using validated procedures designed to provide insight into risk for humans. These studies are inherent to the drug development process prior to clinical use.97”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [97] Dorato MA, Buckley LA. Toxicology testing in drug discovery and development. Curr Protoc Toxicol. 2007; 31(1). 19.1.1-.1.35. doi: 10.1002/0471141755.tx1901s31. 23045141 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationcitation

    The safety challenge is defining relevant outcomes and pathways that may span the cadre of intended organisms and their metabolic potentials within a microbial community setting of the gut.

    “Given this backdrop, the safety challenge is defining relevant outcomes and pathways that may span the cadre of intended organisms and their metabolic potentials within a microbial community setting of the gut.102”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] Veiga P, Suez J, Derrien M, Elinav E. Moving from probiotics to precision probiotics. Nat Microbiol. 2020; 5(7): 878– 880. doi: 10.1038/s41564-020-0721-1. 32393856 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Based on traditional toxicological designs for small molecules, long-term chronic studies in animal models are defined typically as 6 months to 1 year in duration with a priori experiential knowledge or predisposition toward affected organs, reversibility of toxicity, (no) observed effect levels, and quantifying clinical risk at expected dose for long-term treatment.

    “Based on the traditional toxicological designs used to assess the safety of small molecules, long-term chronic studies in animal models are defined typically as 6 months to 1 year in duration with a priori experiential knowledge or predisposition toward affected organs, reversibility of toxicity, (no) observed effect levels, and quantifying clinical risk at expected dose for long-term treatment.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [100] Colerangle JB. Chapter 25 - preclinical development of nononcogenic drugs (small and large molecules). In: Faqi A editor. A comprehensive guide to toxicology in nonclinical drug development. Second. Boston: Academic Press; 2017. pp. 659– 683.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [101] U.S. Food and drug administration, center for food safety and applied nutrition, office of food additive safety. Redbook 2000: IV.C.5.a. Chronic Toxicity Studies with Rodents. 2007. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/redbook-2000-ivc5a-chronic-toxicity-studies-rodents

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    A large cohort study of 333,353 children in the United States reported that prescriptions of antibiotics and acid-suppressive medications in the first two years of life are associated with obesity later in childhood; these associations were strengthened with each additional class of these microbiota-altering drugs and with each additional 30-day prescription.

    “A large cohort study of 333,353 children in the United States reported that prescriptions of antibiotics and acid-suppressive medications in the first two years of life are associated with obesity later in childhood; these associations were strengthened with each additional class of these microbiota-altering drugs and with each additional 30-day prescription.131”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [131] Stark CM, Susi A, Emerick J, Nylund CM. Antibiotic and acid-suppression medications during early childhood are associated with obesity. Gut. 2019; 68(1): 62– 69. doi: 10.1136/gutjnl-2017-314971. 30377188 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In general, high quality, safe probiotic products are produced under dietary supplement and food regulations, although there have been incidences of noncompliance documented for supplements and calls for improved product quality.

    “In general, high quality, safe probiotic products are produced under dietary supplement and food regulations, although there have been incidences of noncompliance documented for supplements15 and calls for improved product quality.135”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [15] Cohen PA. Probiotic safety—no guarantees. JAMA Intern Med. 2018; 178(12): 1577– 1578. doi: 10.1001/jamainternmed.2018.5403. 30242393 source

      Not checked in the free run.

    • cites [135] Jackson SA, Schoeni JL, Vegge C, Pane M, Stahl B, Bradley M, Goldman VS, Burguière P, Atwater JB, Sanders ME. Improving end-user trust in the quality of commercial probiotic products. Front Microbiol. 2019; 10: 739. doi: 10.3389/fmicb.2019.00739. 31105649 PMC6499161

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lack of data in preterm infants led to a caution about using D-lactate-producing probiotics in this population, although a controlled trial in healthy full-term infants showed that D-lactate-producing L. reuteri DSM-17938 did not result in acidosis and probiotic-containing infant formulas were not associated with acidosis.

    “Lack of data in preterm infants led to a caution about using D-lactate-producing probiotics in this population,125 although a controlled trial in healthy full-term infants showed that D-lactate-producing L. reuteri DSM-17938 did not result in acidosis126 and probiotic-containing infant formulas were not associated with acidosis.127”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [125] Chp VDA, Jb VG, Szajewska H, Nd E, Hojsak I, Reid D, Shamir R. Probiotics for preterm infants: a strain-specific systematic review and network meta-analysis. J Pediatr Gastroenterol Nutr. 2018; 67(1): 103– 122. doi: 10.1097/MPG.0000000000001897. 29384838 source

      Not checked in the free run.

    • cites [126] Papagaroufalis K, Fotiou A, Egli D, Tran LA, Steenhout P. A randomized double blind controlled safety trial evaluating d-lactic acid production in healthy infants fed a Lactobacillus reuteri-containing formula. Nutr Metab Insights. 2014; 7: 19– 27. doi: 10.4137/NMI.S14113. 24812520 PMC3999946 source

      Not checked in the free run.

    • cites [127] Lukasik J, Salminen S, Szajewska H. Rapid review shows that probiotics and fermented infant formulas do not cause d-lactic acidosis in healthy children. Acta Paediatr. 2018; 107(8): 1322– 1326. doi: 10.1111/apa.14338. 29603358 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Probiotic safety encompasses properties inherent to the probiotic, to the consumer/patient, and to the manufacturing process, with contaminated probiotic products representing a safety concern.

    “Probiotic safety encompasses properties inherent to the probiotic, to the consumer/patient, and to the manufacturing process (contaminated probiotics products represent a safety concern).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The safety standard for dietary supplements requires that they be reasonably expected to be safe under the labeled conditions of use, but they do not need to be established as safe for more vulnerable patient populations.

    “This is important because while the safety standard for dietary supplements requires that they will reasonably expected to be safe under the labeled conditions of use, they do not need to be established as safe for more vulnerable patient populations.9”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Rouanet A, Bolca S, Bru A, Claes I, Cvejic H, Girgis H, Harper A, Lavergne SN, Mathys S, Pane M, et al. Live biotherapeutic products, a road map for safety assessment. Front Med (Lausanne). 2020; 7: 237. doi: 10.3389/fmed.2020.00237. 32637416 PMC7319051 source

      Not checked in the free run.

22 of 22

  • The paper relies on this without support.

    Long-term safety studies for probiotics are much less well defined than those addressing acute safety issues.

    “Long-term safety studies for probiotics are much less well defined than those addressing acute safety issues.”

  • The paper relies on this without support.

    Few clinical trials on probiotics follow study cohorts long-term, leaving a gap in long-term data.

    “Few clinical trials on probiotics follow study cohorts long-term, leaving a gap in long-term data.”

  • The paper relies on this without support.

    Long-term studies designed to demonstrate probiotic safety in populations at risk (such as individuals with weakened/impaired immune function, aged people, newborns, particularly preterm infants) are scarce.

    “Long-term studies designed to demonstrate probiotic safety in populations at risk (such as individuals with weakened/impaired immune function, aged people, newborns, particularly preterm infants) are scarce.”

  • The paper relies on this without support.

    The state of science and understanding of key metrics for safety in specialized population or disease states (and associated model systems) have not yet achieved a literature base or consensus for establishing long-term safety recommendations for probiotics.

    “It is clear that the state of science and understanding of key metrics for safety in specialized population or disease states (and associated model systems) have not yet achieved a literature base or consensus for establishing long-term safety recommendations for probiotics.”

  • The paper relies on this without support.

    Probiotics do not generally enter the bloodstream or exhibit traditional small-molecule decay rates.

    “However, their relevance to probiotics that do not generally enter the bloodstream or exhibit traditional small-molecule decay rates is not clearly apparent.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Food probiotics require proof of safe use or QPS status, while LBPs require controlled clinical trials, detailed manufacturing and quality control documentation, and extensive genomic and pharmacovigilance data.

    “While food probiotics require proof of safe use or QPS status, LBPs require controlled clinical trials, detailed manufacturing and quality control documentation, and extensive genomic and pharmacovigilance data [20].”

    From Current Concepts in Probiotic Safety and Efficacy (2026) · cites this paper as [20]

    The Background section describes QPS as an approach for recognizing microorganisms with a history of safe use in foods. Probiotic quality considerations distinguishes food from drug manufacturing controls, and What long-term safety studies are indicated? says live biotherapeutic products have more rigorous post-market safety reporting requirements than supplements. The paper does not establish the claimed blanket requirement for controlled clinical trials, detailed manufacturing documentation, and extensive genomic data specifically for LBPs; it also does not say all food probiotics must have QPS status or proof of safe use. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Higher CFU doses may increase the likelihood of gastrointestinal upset or infections in susceptible populations.

    “Higher CFU doses, while potentially beneficial for increased efficacy, may increase the likelihood of gastrointestinal upset or infections in susceptible populations [20].”

    From Current Concepts in Probiotic Safety and Efficacy (2026) · cites this paper as [20]

    The Vulnerable target populations and Acute risks > Invasive infection sections describe rare probiotic-associated infections and advise caution for susceptible people. Fundamentals of probiotic safety says products should be delivered at a dose shown to be safe, but the passages do not establish that higher CFU doses increase infection risk or gastrointestinal upset. No page numbers are available in our copy. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Inadequate harm data plague many treatments, not just probiotics.

    “Others note that inadequate harm data plague many treatments, not just probiotics [20].”

    From Current Concepts in Probiotic Safety and Efficacy (2026) · cites this paper as [20]

  • Whole-genome sequencing-based genomic screening allows in silico detection of antibiotic resistance genes, virulence-associated factors, and mobile genetic elements, providing a basis for modern probiotic safety evaluation.

    “Whole-genome sequencing-based genomic screening allows for the in silico detection of antibiotic resistance genes, virulence-associated factors, and mobile genetic elements, thus providing a basis for modern probiotic safety evaluation [20,133,155,156].”

    From Current Concepts in Probiotic Safety and Efficacy (2026) · cites this paper as [20]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Year of the cited gene-transfer study differs

    Minor

    The text says the study documented transfer in 1998, but the cited reference is dated 1988.

  • Percentage of studies with safety statements is miscalculated

    Minor

    The stated 235 studies are 37.78% of 622 studies, which rounds to 38%, not 37%.

    Reported 37 · recomputed 37.78135

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. EFSA Panel on Nutrition NFaFAN. Safety of pasteurisedAkkermansia muciniphilaas a novelfood pursuant to Regulation (EU) 2015/2283. EFSA J. 2021;19:6780.
  2. National Institutes of Health. National Database of Antibiotic Resistant Organisms (NDARO). National Library of Medicine; 2022. https://www.ncbi.nlm.nih.gov/pathogens/antimicrobial-resistance/

Cited by

Sorted by citations

Related

Authors
Merenstein, D., Pot, B., Leyer, G., Ouwehand, A. C., Preidis, G. A., Elkins, C. A., Hill, C., Lewis, Z. T., Shane, A. L., Zmora, N., Petrova, M. I., Collado, M. C., Morelli, L., Montoya, G. A., Szajewska, H., Tancredi, D. J., & Sanders, M. E.
Affiliations
  • Georgetown University Medical Center (US)
  • Yakult (Netherlands) (NL)
  • Scientific Affairs, Chr. Hansen, Milwaukee, WI, USA
  • Global Health & Nutrition Sciences, International Flavors & Fragrances, Kantvik, Finland
  • Baylor College of Medicine (US)
  • Centers for Disease Control and Prevention (US)
  • University College Cork (IE)
  • Synbiotic Health Inc, Lincoln, NE, USA
  • Emory University (US)
  • Weizmann Institute of Science (IL)
  • Winclove Probiotics (Netherlands) (NL)
  • Institute of Agrochemistry and Food Technology-National Research Council (IATA-CSIC), Valencia, Spain
  • Università Cattolica del Sacro Cuore (IT)
  • Nestlé (Switzerland) (CH)
  • Medical University of Warsaw (PL)
  • University of California Davis Medical Center (US)
  • International Scientific Association for Probiotics and Prebiotics, Centennial, CO, USA
Corresponding author
Sanders, Mary Ellen
ORCID
Venue
Gut Microbes
Publisher
Informa UK Limited
Published
2023-03-15
Volume
15
Issue
1
Pages
2185034-2185034
ISSN
  • 1949-0976 (ISSN-L)
  • 1949-0984
DOI
10.1080/19490976.2023.2185034
PMC
PMC10026873
OpenAlex
W4324304780
Semantic Scholar
c3ba807ba8cdd7ae2f573d56eb4d93185f6e7956
Cited by
481
References
136
Citations by year
2026: 154 · 2025: 187 · 2024: 104 · 2023: 36
FWCI
69.46
Type
journal article
Language
en
Open access
Licence
Locations
  • Gut Microbes (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • VUBIR (Vrije Universiteit Brussel) (submittedVersion)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Lenus, The Irish Health Repository (Dr Steevens Hospital Library) (submittedVersion, cc-by)
Funders
International Scientific Association for Probiotics and Prebiotics
Topics
  • Life Sciences › Agricultural and Biological Sciences › Food Science › Probiotics and Fermented Foods
  • Health Sciences › Medicine › Complementary and alternative medicine › Complementary and Alternative Medicine Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
Keywords
probiotic safety, vulnerable populations, adverse event reporting, whole genome sequencing, virulence genes, toxin genes, antibiotic resistance genes, strain identity, evidence-based recommendations
MeSH terms
Gastrointestinal Microbiome, Anti-Bacterial Agents, Probiotics, Prebiotics

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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