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  • Perspective
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The pros, cons, and many unknowns of probiotics

Nature Medicine volume 25, pages 716–729 (2019)Cite this article

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Abstract

Consumption of over-the-counter probiotics for promotion of health and well-being has increased worldwide in recent years. However, although probiotic use has been greatly popularized among the general public, there are conflicting clinical results for many probiotic strains and formulations. Emerging insights from microbiome research enable an assessment of gut colonization by probiotics, strain-level activity, interactions with the indigenous microbiome, safety and impacts on the host, and allow the association of probiotics with physiological effects and potentially useful medical indications. In this Perspective, we highlight key advances, challenges and limitations in striving toward an unbiased interpretation of the large amount of data regarding over-the-counter probiotics, and propose avenues to improve the quality of evidence, transparency, public awareness and regulation of their use.

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Fig. 1: Precision aspects of probiotics.
Fig. 2: Mechanistic interactions between probiotics and the host and its microbiome.

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References

  1. Hill, C. et al. Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat. Rev. Gastroenterol. Hepatol. 11, 506–514 (2014).

    Article  PubMed  Google Scholar 

  2. Global Probiotic Market Is Set For Rapid Growth and is Expected To Reach Value Around USD 65.87 Billion by 2024 (Zion Market Research, 2018).

  3. Clarke, T. C., Black, L. I., Stussman, B. J., Barnes, P. M. & Nahin, R. L. Trends in the use of complementary health approaches among adults: United States, 2002–2012. Natl. Health Stat. Report. 79, 1–16 (2015).

  4. Hoffmann, D. E. et al. Probiotics: achieving a better regulatory fit. Food Drug Law J. 69, 237–272 (2014).

    PubMed  PubMed Central  Google Scholar 

  5. Draper, K., Ley, C. & Parsonnet, J. Probiotic guidelines and physician practice: a cross-sectional survey and overview of the literature. Benef. Microbes 8, 507–519 (2017).

    Article  CAS  PubMed  Google Scholar 

  6. Williams, M. D., Ha, C. Y. & Ciorba, M. A. Probiotics as therapy in gastroenterology: a study of physician opinions and recommendations. J. Clin. Gastroenterol. 44, 631–636 (2010).

    PubMed  PubMed Central  Google Scholar 

  7. Rijkers, G. T. et al. Health benefits and health claims of probiotics: bridging science and marketing. Br. J. Nutr. 106, 1291–1296 (2011).

    Article  CAS  PubMed  Google Scholar 

  8. Saldanha, L. G. US Food and Drug Administration regulations governing label claims for food products, including probiotics. Clin. Infect. Dis. 46, S119–121 (2008).

    Article  PubMed  Google Scholar 

  9. Degnan, F. H. Clinical studies involving probiotics: when FDA’s investigational new drug rubric applies-and when it may not. Gut Microbes 3, 485–489 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Sniffen, J. C., McFarland, L. V., Evans, C. T. & Goldstein, E. J. C. Choosing an appropriate probiotic product for your patient: an evidence-based practical guide. PLoS One 13, e0209205 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. El Hage, R., Hernandez-Sanabria, E. & Van de Wiele, T. Emerging trends in “smart probiotics”: functional consideration for the development of novel health and industrial applications. Front. Microbiol. 8, 1889 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Panigrahi, P. et al. A randomized synbiotic trial to prevent sepsis among infants in rural India. Nature 548, 407–412 (2017).

    Article  CAS  PubMed  Google Scholar 

  13. Kruis, W. et al. Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine. Gut 53, 1617–1623 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Canani, R. B. et al. Probiotics for treatment of acute diarrhoea in children: randomised clinical trial of five different preparations. Br. Med. J. 335, 340 (2007).

    Article  Google Scholar 

  15. Ruszczyński, M., Radzikowski, A. & Szajewska, H. Clinical trial: effectiveness of Lactobacillus rhamnosus (strains E/N, Oxy and Pen) in the prevention of antibiotic-associated diarrhoea in children. Aliment. Pharmacol. Ther. 28, 154–161 (2008).

    Article  PubMed  Google Scholar 

  16. Gao, X. W., Mubasher, M., Fang, C. Y., Reifer, C. & Miller, L. E. Dose–response efficacy of a proprietary probiotic formula of Lactobacillus acidophilus CL1285 and Lactobacillus casei LBC80R for antibiotic-associated diarrhea and Clostridium difficile–associated diarrhea prophylaxis in adult patients. Am. J. Gastroenterol. 105, 1636–1641 (2010).

    Article  PubMed  Google Scholar 

  17. Fujimori, S. et al. A randomized controlled trial on the efficacy of synbiotic versus probiotic or prebiotic treatment to improve the quality of life in patients with ulcerative colitis. Nutrition 25, 520–525 (2009).

    Article  PubMed  Google Scholar 

  18. Benton, D., Williams, C. & Brown, A. Impact of consuming a milk drink containing a probiotic on mood and cognition. Eur. J. Clin. Nutr. 61, 355–361 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Kekkonen, R. A. et al. Probiotic intervention has strain-specific anti-inflammatory effects in healthy adults. World J. Gastroenterol. 14, 2029–2036 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Simon, M. C. et al. Intake of Lactobacillus reuteri improves incretin and insulin secretion in glucose-tolerant humans: a proof of concept. Diabetes Care 38, 1827–1834 (2015).

    Article  CAS  PubMed  Google Scholar 

  21. Pereg, D. et al. The effect of fermented yogurt on the prevention of diarrhea in a healthy adult population. Am. J. Infect. Control 33, 122–125 (2005).

    Article  PubMed  Google Scholar 

  22. Dietrich, C. G., Kottmann, T. & Alavi, M. Commercially available probiotic drinks containing Lactobacillus casei DN-114001 reduce antibiotic-associated diarrhea. World J. Gastroenterol. 20, 15837–15844 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Gareau, M. G., Sherman, P. M. & Walker, W. A. Probiotics and the gut microbiota in intestinal health and disease. Nat. Rev. Gastroenterol. Hepatol. 7, 503–514 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Begley, M., Hill, C. & Gahan, C. G. Bile salt hydrolase activity in probiotics. Appl. Environ. Microbiol. 72, 1729–1738 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. de Vrieze, J. The metawars. Science 361, 1184–1188 (2018).

    Article  PubMed  Google Scholar 

  26. Moayyedi, P. et al. The efficacy of probiotics in the treatment of irritable bowel syndrome: a systematic review. Gut 59, 325–332 (2010).

    Article  CAS  PubMed  Google Scholar 

  27. Shimizu, M., Hashiguchi, M., Shiga, T., Tamura, H. O. & Mochizuki, M. Meta-analysis: effects of probiotic supplementation on lipid profiles in normal to mildly hypercholesterolemic individuals. PLoS One 10, e0139795 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lu, C. et al. Probiotic supplementation does not improve eradication rate of Helicobacter pylori infection compared to placebo based on standard therapy: a meta-analysis. Sci. Rep. 6, 23522 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lü, M. et al. Efficacy of probiotic supplementation therapy for Helicobacter pylori eradication: a meta-analysis of randomized controlled trials. PLoS One 11, e0163743 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kolber, M. R., Vandermeer, B. & Allan, G. M. Funding may influence trial results examining probiotics and Clostridium difficile diarrhea rates. Am. J. Gastroenterol. 109, 1081–1082 (2014).

    Article  PubMed  Google Scholar 

  31. Allen, S. J., Martinez, E. G., Gregorio, G. V. & Dans, L. F. Probiotics for treating acute infectious diarrhoea. Cochrane Database Syst. Rev. 11, CD003048 (2010).

  32. Feizizadeh, S., Salehi-Abargouei, A. & Akbari, V. Efficacy and safety of Saccharomyces boulardii for acute diarrhea. Pediatrics 134, e176–e191 (2014).

    Article  PubMed  Google Scholar 

  33. Szajewska, H., Skórka, A., Ruszczyński, M. & Gieruszczak-Białek, D. Meta-analysis: Lactobacillus GG for treating acute gastroenteritis in children—updated analysis of randomised controlled trials. Aliment. Pharmacol. Ther. 38, 467–476 (2013).

    Article  CAS  PubMed  Google Scholar 

  34. Van Niel, C. W., Feudtner, C., Garrison, M. M. & Christakis, D. A. Lactobacillus therapy for acute infectious diarrhea in children: a meta-analysis. Pediatrics 109, 678–684 (2002).

    Article  PubMed  Google Scholar 

  35. Goldenberg, J. Z. et al. Probiotics for the prevention of pediatric antibiotic-associated diarrhea. Cochrane Database Syst. Rev. 11, CD004827 (2015).

  36. Hempel, S. et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis. J. Am. Med. Assoc. 307, 1959–1969 (2012).

    Article  CAS  Google Scholar 

  37. Jafarnejad, S. et al. Probiotics reduce the risk of antibiotic-associated diarrhea in adults (18–64 years) but not the elderly (>65 years): a meta-analysis.Nutr. Clin. Pract. 31, 502–513 2016).

    Article  PubMed  Google Scholar 

  38. Hickson, M. et al. Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial. Br. Med. J. 335, 80 (2007).

    Article  Google Scholar 

  39. Olek, A. et al. Efficacy and safety of Lactobacillus plantarum DSM 9843 (LP299V) in the prevention of antibiotic-associated gastrointestinal symptoms in children-randomized, double-blind, placebo-controlled study. J. Pediatr. 186, 82–86 2017).

    Article  CAS  PubMed  Google Scholar 

  40. Allen, S. J. et al. Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in older inpatients (PLACIDE): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 382, 1249–1257 (2013).

    Article  PubMed  Google Scholar 

  41. Freedman, S. B. et al. Multicenter trial of a combination probiotic for children with gastroenteritis. N. Engl. J. Med. 379, 2015–2026 2018).

    Article  CAS  PubMed  Google Scholar 

  42. Schnadower, D. et al. Lactobacillus rhamnosus GG versus placebo for acute gastroenteritis in children. N. Engl. J. Med. 379, 2002–2014 2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Freedman, S. B. et al. Gastroenteritis therapies in developed countries: systematic review and meta-analysis. PLoS One 10, e0128754 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Khanna, R., Lakhanpaul, M., Burman-Roy, S. & Murphy, M. S. Diarrhoea and vomiting caused by gastroenteritis in children under 5 years: summary of NICE guidance. Br. Med. J. 338, b1350 (2009).

    Article  Google Scholar 

  45. Szajewska, H. et al. Use of probiotics for management of acute gastroenteritis: a position paper by the ESPGHAN Working Group for Probiotics and Prebiotics. J. Pediatr. Gastroenterol. Nutr. 58, 531–539 (2014).

    Article  PubMed  Google Scholar 

  46. Li, S. T., Klein, E. J., Tarr, P. I. & Denno, D. M. Parental management of childhood diarrhea. Clin. Pediatr. (Phila.) 48, 295–303 (2009).

    Article  Google Scholar 

  47. Goldenberg, J. Z. et al. Probiotics for the prevention of Clostridium difficile–associated diarrhea in adults and children. Cochrane Database Syst. Rev. 5, CD006095 (2013).

  48. Shen, N. T. et al. Timely use of probiotics in hospitalized adults prevents Clostridium difficile infection: a systematic review with meta-regression analysis. Gastroenterology 152, 1889–1900 e1889 (2017).

    Article  PubMed  Google Scholar 

  49. Goldenberg, J. Z. et al. Probiotics for the prevention of Clostridium difficile–associated diarrhea in adults and children. Cochrane Database Syst. Rev. 12, CD006095 (2017).

    PubMed  Google Scholar 

  50. McFarland, L. V. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease. Am. J. Gastroenterol. 101, 812–822 (2006).

    Article  PubMed  Google Scholar 

  51. Szajewska, H. & Kołodziej, M. Systematic review with meta-analysis: Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea. Aliment. Pharmacol. Ther. 42, 793–801 (2015).

    Article  CAS  PubMed  Google Scholar 

  52. Szajewska, H.et al. Probiotics for the prevention of antibiotic-associated diarrhea in children. J. Pediatr. Gastroenterol. Nutr. 62, 495–506 2016).

    Article  CAS  PubMed  Google Scholar 

  53. Georgieva, M. et al. Use of the probiotic Lactobacillus reuteri DSM 17938 in the prevention of antibiotic-associated infections in hospitalIzed Bulgarian children: a randomized, controlled trial. J. IMAB–Annu. Proc. Sci. Pap. 21, 895–900 (2015).

    Google Scholar 

  54. Ouwehand, A. C. et al. Probiotics reduce symptoms of antibiotic use in a hospital setting: a randomized dose response study. Vaccine 32, 458–463 (2014).

    Article  PubMed  Google Scholar 

  55. Klarin, B. et al. Lactobacillus plantarum 299v reduces colonisation of Clostridium difficile in critically ill patients treated with antibiotics. Acta Anaesthesiol. Scand. 52, 1096–1102 (2008).

    Article  CAS  PubMed  Google Scholar 

  56. Morrow, L. E., Kollef, M. H. & Casale, T. B. Probiotic prophylaxis of ventilator-associated pneumonia: a blinded, randomized, controlled trial. Am. J. Respir. Crit. Care Med. 182, 1058–1064 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Shan, L. S. et al. Prevention and treatment of diarrhoea with Saccharomyces boulardii in children with acute lower respiratory tract infections. Benef. Microbes 4, 329–334 (2013).

    Article  PubMed  Google Scholar 

  58. Rafiq, R. et al. in Gastroenterology, Vol. 132. A187 (WB Saunders Co–Elsevier, 2007).

  59. Lemann, M., Cezard, J., Ruemmele, F. & Turck, D. European Society for Paediatric Gastroenterology, Hepatology, and Nutrition Annual Meeting June 3–6, 2009 Budapest, Hungary. J. Pediatr. Gastroenterol. Nutr. 48, E1–E149 (2009).

    Article  Google Scholar 

  60. Viggars, A. P., Gracie, D. J. & Ford, A. C. Use of probiotics in hospitalized adults to prevent Clostridium difficile infection: downgrade the quality of evidence?. Gastroenterology 153, 1451–1452 (2017).

    Article  PubMed  Google Scholar 

  61. McFarland, L. V. Deciphering meta-analytic results: a mini-review of probiotics for the prevention of paediatric antibiotic-associated diarrhoea and Clostridium difficile infections. Benef. Microbes 6, 189–194 (2015).

    Article  CAS  PubMed  Google Scholar 

  62. Guyonnet, D. et al. Effect of a fermented milk containing Bifidobacterium animalis DN-173 010 on the health-related quality of life and symptoms in irritable bowel syndrome in adults in primary care: a multicentre, randomized, double-blind, controlled trial. Aliment. Pharmacol. Ther. 26, 475–486 (2007).

    Article  CAS  PubMed  Google Scholar 

  63. Ford, A. C., Harris, L. A., Lacy, B. E., Quigley, E. M. M. & Moayyedi, P. Systematic review with meta-analysis: the efficacy of prebiotics, probiotics, synbiotics and antibiotics in irritable bowel syndrome. Aliment. Pharmacol. Ther. 48, 1044–1060 (2018).

    Article  PubMed  Google Scholar 

  64. McKenzie, Y. A., Thompson, J., Gulia, P. & Lomer, M. C. British Dietetic Association systematic review of systematic reviews and evidence-based practice guidelines for the use of probiotics in the management of irritable bowel syndrome in adults (2016 update). J. Hum. Nutr. Diet. 29, 576–592 (2016).

    Article  CAS  PubMed  Google Scholar 

  65. Olsen, R., Greisen, G., Schrøder, M. & Brok, J. Prophylactic probiotics for preterm infants: a systematic review and meta-analysis of observational studies. Neonatology 109, 105–112 (2016).

    Article  PubMed  Google Scholar 

  66. Rao, S. C., Athalye-Jape, G. K., Deshpande, G. C., Simmer, K. N. & Patole, S. K. Probiotic supplementation and late-onset sepsis in preterm infants: a meta-analysis. Pediatrics 137, e20153684 (2016).

    Article  PubMed  Google Scholar 

  67. Ganguli, K. et al. Probiotics prevent necrotizing enterocolitis by modulating enterocyte genes that regulate innate immune-mediated inflammation. Am. J. Physiol. Gastrointest. Liver Physiol. 304, G132–G141 (2013).

    Article  CAS  PubMed  Google Scholar 

  68. Yan, F. et al. Neonatal colonization of mice with LGG promotes intestinal development and decreases susceptibility to colitis in adulthood. Mucosal Immunol. 10, 117–127 (2017).

    Article  CAS  PubMed  Google Scholar 

  69. Costeloe, K., Hardy, P., Juszczak, E., Wilks, M. & Millar, M. R. Bifidobacterium breve BBG-001 in very preterm infants: a randomised controlled phase 3 trial. Lancet 387, 649–660 (2016).

    Article  PubMed  Google Scholar 

  70. AlFaleh, K. & Anabrees, J. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database Syst. Rev. 4, CD005496 (2014).

  71. Aceti, A. et al. Probiotics prevent late-onset sepsis in human milk-fed, very low birth weight preterm infants: systematic review and meta-analysis. Nutrients 9, 904 (2017).

  72. Dermyshi, E. et al. The “golden age” of probiotics: a systematic review and meta-analysis of randomized and observational studies in preterm infants. Neonatology 112, 9–23 (2017).

    Article  CAS  PubMed  Google Scholar 

  73. Zhang, G. Q., Hu, H. J., Liu, C. Y., Shakya, S. & Li, Z. Y. Probiotics for preventing late-onset sepsis in preterm neonates: A PRISMA-compliant systematic review and meta-analysis of randomized controlled trials. Med. (Baltim.) 95, e2581 (2016).

    Article  Google Scholar 

  74. Sommer, F. & Bäckhed, F. The gut microbiota—masters of host development and physiology. Nat. Rev. Microbiol. 11, 227–238 (2013).

    Article  CAS  PubMed  Google Scholar 

  75. King, S. et al. Does probiotic consumption reduce antibiotic utilization for common acute infections? A systematic review and meta-analysis. Eur. J. Public Health https://doi.org/10.1093/eurpub/cky185 (2018).

  76. Hao, Q., Dong, B.R. & Wu, T. Probiotics for preventing acute upper respiratory tract infections. Cochrane Database Syst. Rev. 2, CD006895 (2015).

  77. Vouloumanou, E. K., Makris, G. C., Karageorgopoulos, D. E. & Falagas, M. E. Probiotics for the prevention of respiratory tract infections: a systematic review. Int. J. Antimicrob. Agents 34, 197.e1–197.e10 (2009).

    Article  CAS  Google Scholar 

  78. Merenstein, D. et al. Use of a fermented dairy probiotic drink containing Lactobacillus casei (DN-114 001) to decrease the rate of illness in kids: the DRINK study. A patient-oriented, double-blind, cluster-randomized, placebo-controlled, clinical trial. Eur. J. Clin. Nutr. 64, 669–677 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. de Vrese, M. et al. Effect of Lactobacillus gasseri PA 16/8, Bifidobacterium longum SP 07/3, B. bifidum MF 20/5 on common cold episodes: a double blind, randomized, controlled trial. Clin. Nutr. (Edinb., Scotl.) 24, 481–491 (2005).

    Article  Google Scholar 

  80. Smith, T. J., Rigassio-Radler, D., Denmark, R., Haley, T. & Touger-Decker, R. Effect of Lactobacillus rhamnosus LGG® and Bifidobacterium animalis ssp. lactis BB-12® on health-related quality of life in college students affected by upper respiratory infections. Br. J. Nutr. 109, 1999–2007 (2013).

    Article  CAS  PubMed  Google Scholar 

  81. Shinkai, S. et al. Immunoprotective effects of oral intake of heat-killed Lactobacillus pentosus strain b240 in elderly adults: a randomised, double-blind, placebo-controlled trial. Br. J. Nutr. 109, 1856–1865 (2013).

    Article  CAS  PubMed  Google Scholar 

  82. Hatakka, K. et al. Effect of long term consumption of probiotic milk on infections in children attending day care centres: double blind, randomised trial. Br. Med. J. 322, 1327 (2001).

    Article  CAS  Google Scholar 

  83. West, N. P. et al. Lactobacillus fermentum (PCC®) supplementation and gastrointestinal and respiratory-tract illness symptoms: a randomised control trial in athletes. Nutr. J. 10, 30 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Murata, M. et al. Effects of paraprobiotic Lactobacillus paracasei MCC1849 supplementation on symptoms of the common cold and mood states in healthy adults. Benef. Microbes 9, 855–864 (2018).

  85. Atarashi, K. et al. TH17 cell induction by adhesion of microbes to intestinal epithelial cells. Cell 163, 367–380 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Thaiss, C. A. et al. Microbiota diurnal rhythmicity programs host transcriptome oscillations. Cell 167, 1495–1510.e12 (2016).

    Article  CAS  PubMed  Google Scholar 

  87. Uchimura, Y. et al. Antibodies set boundaries limiting microbial metabolite penetration and the resultant mammalian host response. Immunity 49, 545–559.e5 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Mattar, A. F. et al. Probiotics up-regulate MUC-2 mucin gene expression in a Caco-2 cell-culture model. Pediatr. Surg. Int. 18, 586–590 (2002).

    Article  CAS  PubMed  Google Scholar 

  89. Zmora, N. et al. Personalized gut mucosal colonization resistance to empiric probiotics is associated with unique host and microbiome features. Cell 174, 1388–1405.e21 (2018).

    Article  CAS  PubMed  Google Scholar 

  90. Turroni, F. et al. Role of sortase-dependent pili of Bifidobacterium bifidum PRL2010 in modulating bacterium-host interactions. Proc. Natl Acad. Sci. USA 110, 11151–11156 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Van Tassell, M. L. & Miller, M. J. Lactobacillus adhesion to mucus. Nutrients 3, 613–636 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Fujimura, S. et al. Detection of Lactobacillus gasseri OLL2716 strain administered with yogurt drink in gastric mucus layer in humans. Lett. Appl. Microbiol. 43, 578–581 (2006).

    Article  CAS  PubMed  Google Scholar 

  93. Valeur, N., Engel, P., Carbajal, N., Connolly, E. & Ladefoged, K. Colonization and immunomodulation by Lactobacillus reuteri ATCC 55730 in the human gastrointestinal tract. Appl. Environ. Microbiol. 70, 1176–1181 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Johansson, M. L. et al. Administration of different Lactobacillus strains in fermented oatmeal soup: in vivo colonization of human intestinal mucosa and effect on the indigenous flora. Appl. Environ. Microbiol. 59, 15–20 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Shibahara-Sone, H. et al. Living cells of probiotic Bifidobacterium bifidum YIT 10347 detected on gastric mucosa in humans. Benef. Microbes 7, 319–326 (2016).

    Article  CAS  PubMed  Google Scholar 

  96. Yang, Y., Galle, S., Le, M. H., Zijlstra, R. T. & Gänzle, M. G. Feed fermentation with reuteran- and levan-producing Lactobacillus reuteri reduces colonization of weanling pigs by enterotoxigenic Escherichia coli. Appl. Environ. Microbiol. 81, 5743–5752 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Riboulet-Bisson, E. et al. Effect of Lactobacillus salivarius bacteriocin Abp118 on the mouse and pig intestinal microbiota. PLoS One 7, e31113 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Crittenden, R. et al. Lactobacillus paracasei subsp. paracasei F19: Survival, ecology and safety in the human intestinal tract-A survey of feeding studies within the PROBDEMO project. Microb. Ecol. Health Dis. 14, 22–26 (2002).

    Article  Google Scholar 

  99. Goossens, D. A., Jonkers, D. M., Russel, M. G., Stobberingh, E. E. & Stockbrügger, R. W. The effect of a probiotic drink with Lactobacillus plantarum 299v on the bacterial composition in faeces and mucosal biopsies of rectum and ascending colon. Aliment. Pharmacol. Ther. 23, 255–263 (2006).

    Article  CAS  PubMed  Google Scholar 

  100. Alander, M. et al. Persistence of colonization of human colonic mucosa by a probiotic strain, Lactobacillus rhamnosus GG, after oral consumption. Appl. Environ. Microbiol. 65, 351–354 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Gianotti, L. et al. A randomized double-blind trial on perioperative administration of probiotics in colorectal cancer patients. World J. Gastroenterol. 16, 167–175 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Suez, J., Zmora, N. & Elinav, E. Probiotics in the next-generation sequencing era. Gut Microbes 5, 1–17 (2019).

    Article  CAS  Google Scholar 

  103. Zhang, C. et al. Ecological robustness of the gut microbiota in response to ingestion of transient food-borne microbes. ISME J. 10, 2235–2245 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Charbonneau, D., Gibb, R. D. & Quigley, E. M. Fecal excretion of Bifidobacterium infantis 35624 and changes in fecal microbiota after eight weeks of oral supplementation with encapsulated probiotic. Gut Microbes 4, 201–211 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Alander, M. et al. Effect of galacto-oligosaccharide supplementation on human faecal microflora and on survival and persistence of Bifidobacterium lactis Bb-12 in the gastrointestinal tract. Int. Dairy J. 11, 817–825 (2001).

    Article  CAS  Google Scholar 

  106. Firmesse, O., Mogenet, A., Bresson, J. L., Corthier, G. & Furet, J. P. Lactobacillus rhamnosus R11 consumed in a food supplement survived human digestive transit without modifying microbiota equilibrium as assessed by real-time polymerase chain reaction. J. Mol. Microbiol. Biotechnol. 14, 90–99 (2008).

    Article  CAS  PubMed  Google Scholar 

  107. Rochet, V. et al. Effects of orally administered Lactobacillus casei DN-114 001 on the composition or activities of the dominant faecal microbiota in healthy humans. Br. J. Nutr. 95, 421–429 (2006).

    Article  CAS  PubMed  Google Scholar 

  108. Garrido, D., Suau, A., Pochart, P., Cruchet, S. & Gotteland, M. Modulation of the fecal microbiota by the intake of a Lactobacillus johnsonii La1-containing product in human volunteers. FEMS Microbiol. Lett. 248, 249–256 (2005).

    Article  CAS  PubMed  Google Scholar 

  109. Goossens, D. et al. The effect of Lactobacillus plantarum 299v on the bacterial composition and metabolic activity in faeces of healthy volunteers: a placebo-controlled study on the onset and duration of effects. Aliment. Pharmacol. Ther. 18, 495–505 (2003).

    Article  CAS  PubMed  Google Scholar 

  110. Smith, T. J., Anderson, D., Margolis, L. M., Sikes, A. & Young, A. J. Persistence of Lactobacillus reuteri DSM17938 in the human intestinal tract: response to consecutive and alternate-day supplementation. J. Am. Coll. Nutr. 30, 259–264 (2011).

    Article  PubMed  Google Scholar 

  111. Jacobsen, C. N. et al. Screening of probiotic activities of forty-seven strains of Lactobacillus spp. by in vitro techniques and evaluation of the colonization ability of five selected strains in humans. Appl. Environ. Microbiol. 65, 4949–4956 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Sierra, S. et al. Intestinal and immunological effects of daily oral administration of Lactobacillus salivarius CECT5713 to healthy adults. Anaerobe 16, 195–200 (2010).

    Article  PubMed  Google Scholar 

  113. Frese, S. A., Hutkins, R. W. & Walter, J. Comparison of the colonization ability of autochthonous and allochthonous strains of lactobacilli in the human gastrointestinal tract. Adv. Microbiol. 2, 399 (2012).

    Article  Google Scholar 

  114. Tannock, G. W. et al. Analysis of the fecal microflora of human subjects consuming a probiotic product containing Lactobacillus rhamnosus DR20. Appl. Environ. Microbiol. 66, 2578–2588 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Maldonado-Gómez, M. X. et al. Stable engraftment of Bifidobacterium longum AH1206 in the human gut depends on individualized features of the resident microbiome. Cell Host Microbe 20, 515–526 (2016).

    Article  CAS  PubMed  Google Scholar 

  116. Suez, J. et al. Post-antibiotic gut mucosal microbiome reconstitution is impaired by probiotics and improved by autologous FMT. Cell 174, 1406–1423.e16 (2018).

    Article  CAS  PubMed  Google Scholar 

  117. Chung, H. et al. Gut immune maturation depends on colonization with a host-specific microbiota. Cell 149, 1578–1593 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Dogi, C. A. & Perdigón, G. Importance of the host specificity in the selection of probiotic bacteria. J. Dairy Res. 73, 357–366 (2006).

    Article  CAS  PubMed  Google Scholar 

  119. Marcobal, A. et al. A metabolomic view of how the human gut microbiota impacts the host metabolome using humanized and gnotobiotic mice. ISME J. 7, 1933–1943 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. de Vrese, M. et al. Probiotics—compensation for lactase insufficiency. Am. J. Clin. Nutr. 73, 421S–429S (2001).

    Article  PubMed  Google Scholar 

  121. Bonder, M. J. et al. The effect of host genetics on the gut microbiome. Nat. Genet. 48, 1407–1412 (2016).

    Article  CAS  PubMed  Google Scholar 

  122. Macho Fernandez, E. et al. Anti-inflammatory capacity of selected lactobacilli in experimental colitis is driven by NOD2-mediated recognition of a specific peptidoglycan-derived muropeptide. Gut 60, 1050–1059 (2011).

    Article  CAS  PubMed  Google Scholar 

  123. Lin, Y. P., Thibodeaux, C. H., Peña, J. A., Ferry, G. D. & Versalovic, J. Probiotic Lactobacillus reuteri suppress proinflammatory cytokines via c-Jun. Inflamm. Bowel Dis. 14, 1068–1083 (2008).

    Article  PubMed  Google Scholar 

  124. Lavasani, S. et al. A novel probiotic mixture exerts a therapeutic effect on experimental autoimmune encephalomyelitis mediated by IL-10 producing regulatory T cells. PLoS One 5, e9009 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Thomas, C. M. & Versalovic, J. Probiotics–host communication: modulation of signaling pathways in the intestine. Gut Microbes 1, 148–163 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  126. van Baarlen, P. et al. Differential NF-κB pathways induction by Lactobacillus plantarum in the duodenum of healthy humans correlating with immune tolerance. Proc. Natl Acad. Sci. USA 106, 2371–2376 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Matsuguchi, T. et al. Lipoteichoic acids from Lactobacillus strains elicit strong tumor necrosis factor alpha-inducing activities in macrophages through Toll-like receptor 2. Clin. Diagn. Lab. Immunol. 10, 259–266 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Medina, M., Izquierdo, E., Ennahar, S. & Sanz, Y. Differential immunomodulatory properties of Bifidobacterium logum strains: relevance to probiotic selection and clinical applications. Clin. Exp. Immunol. 150, 531–538 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Schiavi, E. et al. The surface-associated exopolysaccharide of Bifidobacterium longum 35624 plays an essential role in dampening host proinflammatory responses and repressing local Th17 responses. Appl. Environ. Microbiol. 82, 7185–7196 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. von Ossowski, I. et al. Using recombinant Lactococci as an approach to dissect the immunomodulating capacity of surface piliation in probiotic Lactobacillus rhamnosus GG. PLoS One 8, e64416 (2013).

    Article  CAS  Google Scholar 

  131. Ardita, C. S. et al. Epithelial adhesion mediated by pilin SpaC is required for Lactobacillus rhamnosus GG–induced cellular responses. Appl. Environ. Microbiol. 80, 5068–5077 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Yanagihara, S. et al. Uromodulin-SlpA binding dictates Lactobacillus acidophilus uptake by intestinal epithelial M cells. Int. Immunol. 29, 357–363 (2017).

    Article  CAS  PubMed  Google Scholar 

  133. Konieczna, P. et al. Bifidobacterium infantis 35624 administration induces Foxp3 T regulatory cells in human peripheral blood: potential role for myeloid and plasmacytoid dendritic cells. Gut 61, 354–366 (2012).

    Article  CAS  PubMed  Google Scholar 

  134. Fukushima, Y., Kawata, Y., Hara, H., Terada, A. & Mitsuoka, T. Effect of a probiotic formula on intestinal immunoglobulin A production in healthy children. Int. J. Food Microbiol. 42, 39–44 (1998).

    Article  CAS  PubMed  Google Scholar 

  135. Galdeano, C. M. & Perdigón, G. The probiotic bacterium Lactobacillus casei induces activation of the gut mucosal immune system through innate immunity. Clin. Vaccin. Immunol. 13, 219–226 (2006).

    Article  CAS  Google Scholar 

  136. Gueimonde, M., Margolles, A., de los Reyes-Gavilán, C. G. & Salminen, S. Competitive exclusion of enteropathogens from human intestinal mucus by Bifidobacterium strains with acquired resistance to bile—a preliminary study. Int. J. Food Microbiol. 113, 228–232 (2007).

    Article  PubMed  Google Scholar 

  137. Tsai, C. C. et al. Antagonistic activity against Salmonella infection in vitro and in vivo for two Lactobacillus strains from swine and poultry. Int. J. Food Microbiol. 102, 185–194 (2005).

    Article  PubMed  Google Scholar 

  138. Kim, Y., Kim, S. H., Whang, K. Y., Kim, Y. J. & Oh, S. Inhibition of Escherichia coli O157:H7 attachment by interactions between lactic acid bacteria and intestinal epithelial cells. J. Microbiol. Biotechnol. 18, 1278–1285 (2008).

    CAS  PubMed  Google Scholar 

  139. Fukuda, S. et al. Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature 469, 543–547 (2011).

    Article  CAS  PubMed  Google Scholar 

  140. Cotter, P. D., Hill, C. & Ross, R. P. Bacteriocins: developing innate immunity for food. Nat. Rev. Microbiol. 3, 777–788 (2005).

    Article  CAS  PubMed  Google Scholar 

  141. Corr, S. C. et al. Bacteriocin production as a mechanism for the antiinfective activity of Lactobacillus salivarius UCC118. Proc. Natl Acad. Sci. USA 104, 7617–7621 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Medellin-Peña, M. J., Wang, H., Johnson, R., Anand, S. & Griffiths, M. W. Probiotics affect virulence-related gene expression in Escherichia coli O157:H7. Appl. Environ. Microbiol. 73, 4259–4267 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Yun, B., Oh, S. & Griffiths, M. W. Lactobacillus acidophilus modulates the virulence of Clostridium difficile. J. Dairy Sci. 97, 4745–4758 (2014).

    Article  CAS  PubMed  Google Scholar 

  144. Li, J., Wang, W., Xu, S. X., Magarvey, N. A. & McCormick, J. K. Lactobacillus reuteri-produced cyclic dipeptides quench agr-mediated expression of toxic shock syndrome toxin-1 in staphylococci. Proc. Natl Acad. Sci. USA 108, 3360–3365 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Miller, M. B. & Bassler, B. L. Quorum sensing in bacteria. Annu. Rev. Microbiol. 55, 165–199 (2001).

    Article  CAS  PubMed  Google Scholar 

  146. Lagrafeuille, R. et al. Opposing effect of Lactobacillus on in vitro Klebsiella pneumoniae in biofilm and in an in vivo intestinal colonisation model. Benef. Microbes 9, 87–100 (2018).

    Article  CAS  PubMed  Google Scholar 

  147. Thompson, J. A., Oliveira, R. A., Djukovic, A., Ubeda, C. & Xavier, K. B. Manipulation of the quorum sensing signal AI-2 affects the antibiotic-treated gut microbiota. Cell Rep. 10, 1861–1871 (2015).

    Article  CAS  PubMed  Google Scholar 

  148. Ohland, C. L. & Macnaughton, W. K. Probiotic bacteria and intestinal epithelial barrier function. Am. J. Physiol. Gastrointest. Liver Physiol. 298, G807–G819 (2010).

    Article  CAS  PubMed  Google Scholar 

  149. Miyamoto, J. et al. A gut microbial metabolite of linoleic acid, 10-hydroxy-cis-12-octadecenoic acid, ameliorates intestinal epithelial barrier impairment partially via GPR40–MEK–ERK pathway. J. Biol. Chem. 290, 2902–2918 (2015).

    Article  CAS  PubMed  Google Scholar 

  150. Kaikiri, H. et al. Supplemental feeding of a gut microbial metabolite of linoleic acid, 10-hydroxy-cis-12-octadecenoic acid, alleviates spontaneous atopic dermatitis and modulates intestinal microbiota in NC/nga mice. Int. J. Food Sci. Nutr. 68, 941–951 (2017).

    Article  CAS  PubMed  Google Scholar 

  151. Yamada, M. et al. A bacterial metabolite ameliorates periodontal pathogen-induced gingival epithelial barrier disruption via GPR40 signaling. Sci. Rep. 8, 9008 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Yan, F. et al. Soluble proteins produced by probiotic bacteria regulate intestinal epithelial cell survival and growth. Gastroenterology 132, 562–575 (2007).

    Article  CAS  PubMed  Google Scholar 

  153. Mack, D. R., Ahrne, S., Hyde, L., Wei, S. & Hollingsworth, M. A. Extracellular MUC3 mucin secretion follows adherence of Lactobacillus strains to intestinal epithelial cells in vitro. Gut 52, 827–833 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Gaudier, E., Michel, C., Segain, J. P., Cherbut, C. & Hoebler, C. The VSL# 3 probiotic mixture modifies microflora but does not heal chronic dextran-sodium sulfate-induced colitis or reinforce the mucus barrier in mice. J. Nutr. 135, 2753–2761 (2005).

    Article  CAS  PubMed  Google Scholar 

  155. Caballero-Franco, C., Keller, K., De Simone, C. & Chadee, K. The VSL#3 probiotic formula induces mucin gene expression and secretion in colonic epithelial cells. Am. J. Physiol. Gastrointest. Liver Physiol. 292, G315–G322 (2007).

    Article  CAS  PubMed  Google Scholar 

  156. Persborn, M. et al. The effects of probiotics on barrier function and mucosal pouch microbiota during maintenance treatment for severe pouchitis in patients with ulcerative colitis. Aliment. Pharmacol. Ther. 38, 772–783 (2013).

    Article  CAS  PubMed  Google Scholar 

  157. Jones, C. et al. Modulation of gut barrier function in patients with obstructive jaundice using probiotic LP299v. Eur. J. Gastroenterol. Hepatol. 25, 1424–1430 (2013).

    Article  PubMed  Google Scholar 

  158. Zeng, J. et al. Clinical trial: effect of active lactic acid bacteria on mucosal barrier function in patients with diarrhoea-predominant irritable bowel syndrome. Aliment. Pharmacol. Ther. 28, 994–1002 (2008).

    Article  CAS  PubMed  Google Scholar 

  159. Sabico, S. et al. Effects of a multi-strain probiotic supplement for 12 weeks in circulating endotoxin levels and cardiometabolic profiles of medication naïve T2DM patients: a randomized clinical trial. J. Transl. Med. 15, 249 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  160. Wilms, E. et al. Effects of supplementation of the synbiotic ecologic® 825/FOS P6 on intestinal barrier function in healthy humans: a randomized controlled trial. PLoS One 11, e0167775 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Horvath, A. et al. Randomised clinical trial: the effects of a multispecies probiotic vs. placebo on innate immune function, bacterial translocation and gut permeability in patients with cirrhosis. Aliment. Pharmacol. Ther. 44, 926–935 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Stadlbauer, V. et al. Lactobacillus casei shirota supplementation does not restore gut microbiota composition and gut barrier in metabolic syndrome: a randomized pilot study. PLoS One 10, e0141399 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Joyce, S. A. et al. Regulation of host weight gain and lipid metabolism by bacterial bile acid modification in the gut. Proc. Natl Acad. Sci. USA 111, 7421–7426 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Costabile, A. et al. An in vivo assessment of the cholesterol-lowering efficacy of Lactobacillus plantarum ECGC 13110402 in normal to mildly hypercholesterolaemic adults. PLoS One 12, e0187964 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Sun, L. et al. Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. Nat. Med. 24, 1919–1929 (2018).

  166. Sarkar, A. et al. Psychobiotics and the manipulation of bacteria–gut–brain signals. Trends Neurosci. 39, 763–781 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Bravo, J. A. et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc. Natl Acad. Sci. USA 108, 16050–16055 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  168. Kelly, J. R. et al. Lost in translation? The potential psychobiotic Lactobacillus rhamnosus (JB-1) fails to modulate stress or cognitive performance in healthy male subjects. Brain Behav. Immun. 61, 50–59 (2017).

    Article  CAS  PubMed  Google Scholar 

  169. Buffington, S. A. et al. Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring. Cell 165, 1762–1775 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Perez-Burgos, A. et al. The TRPV1 channel in rodents is a major target for antinociceptive effect of the probiotic Lactobacillus reuteri DSM 17938. J. Physiol. (Lond.) 593, 3943–3957 (2015).

    Article  CAS  Google Scholar 

  171. Rousseaux, C. et al. Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nat. Med. 13, 35–37 (2007).

    Article  CAS  PubMed  Google Scholar 

  172. Reis, D. J., Ilardi, S. S. & Punt, S. E. W. The anxiolytic effect of probiotics: a systematic review and meta-analysis of the clinical and preclinical literature. PLoS One 13, e0199041 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Kristensen, N. B. et al. Alterations in fecal microbiota composition by probiotic supplementation in healthy adults: a systematic review of randomized controlled trials. Genome Med. 8, 52 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. McFarland, L. V. Use of probiotics to correct dysbiosis of normal microbiota following disease or disruptive events: a systematic review. BMJ Open 4, e005047 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  175. Jakobsson, H. E. et al. Short-term antibiotic treatment has differing long-term impacts on the human throat and gut microbiome. PLoS One 5, e9836 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Sommer, F., Anderson, J. M., Bharti, R., Raes, J. & Rosenstiel, P. The resilience of the intestinal microbiota influences health and disease. Nat. Rev. Microbiol. 15, 630–638 (2017).

    Article  CAS  PubMed  Google Scholar 

  177. Bruzzese, E. et al. Disrupted intestinal microbiota and intestinal inflammation in children with cystic fibrosis and its restoration with Lactobacillus GG: a randomised clinical trial. PLoS One 9, e87796 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Zoppi, G., Cinquetti, M., Benini, A., Bonamini, E. & Minelli, E. B. Modulation of the intestinal ecosystem by probiotics and lactulose in children during treatment with ceftriaxone. Curr. Ther. Res. Clin. Exp. 62, 418–435 (2001).

    Article  CAS  Google Scholar 

  179. Wang, Z. J. et al. Effects of anti–Helicobacter pylori concomitant therapy and probiotic supplementation on the throat and gut microbiota in humans. Microb. Pathog. 109, 156–161 (2017).

    Article  CAS  PubMed  Google Scholar 

  180. Khalesi, S. et al. A review of probiotic supplementation in healthy adults: helpful or hype?. Eur. J. Clin. Nutr. 73, 24–37, doi: (2019).

    Article  CAS  PubMed  Google Scholar 

  181. Ricci, A. et al. Update of the list of QPS‐recommended biological agents intentionally added to food or feed as notified to EFSA 8: suitability of taxonomic units notified to EFSA until March 2018. EFSA Journal 16, e05315 (2018).

    PubMed  PubMed Central  Google Scholar 

  182. Quin, C. et al. Probiotic supplementation and associated infant gut microbiome and health: a cautionary retrospective clinical comparison. Sci. Rep. 8, 8283 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Topcuoglu, S., Gursoy, T., Ovali, F., Serce, O. & Karatekin, G. A new risk factor for neonatal vancomycin-resistant Enterococcus colonisation: bacterial probiotics. J. Matern. Fetal Neonatal Med. 28, 1491–1494 (2015).

    Article  CAS  PubMed  Google Scholar 

  184. Didari, T., Solki, S., Mozaffari, S., Nikfar, S. & Abdollahi, M. A systematic review of the safety of probiotics. Expert Opin. Drug Saf. 13, 227–239 (2014).

    Article  PubMed  Google Scholar 

  185. Carvour, M. L. et al. Predictors of Clostridium difficile infection and predictive impact of probiotic use in a diverse hospital-wide cohort. Am. J. Infect. Control 47, 2–8, doi: (2019).

    Article  PubMed  Google Scholar 

  186. Besselink, M. G. et al. Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial. Lancet 371, 651–659 (2008).

    Article  PubMed  Google Scholar 

  187. Hempel, S. et al. Safety of probiotics used to reduce risk and prevent or treat disease. Evid. Rep. Technol. Assess. (Full Rep.) 1–645 (2011).

  188. Bafeta, A., Koh, M., Riveros, C. & Ravaud, P. Harms reporting in randomized controlled trials of interventions aimed at modifying microbiota: a systematic review. Ann. Intern. Med. 169, 240–247 (2018). .

  189. US Food & Drug Administration. Development & approval process (drugs). https://www.fda.gov/drugs/developmentapprovalprocess/default.htm (2018).

  190. Grazul, H., Kanda, L. L. & Gondek, D. Impact of probiotic supplements on microbiome diversity following antibiotic treatment of mice. Gut Microbes 7, 101–114 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  191. Kabbani, T. A. et al. Prospective randomized controlled study on the effects of Saccharomyces boulardii CNCM I-745 and amoxicillin-clavulanate or the combination on the gut microbiota of healthy volunteers. Gut Microbes 8, 17–32 (2017).

    Article  CAS  PubMed  Google Scholar 

  192. De Wolfe, T. J. et al. Oral probiotic combination of Lactobacillus and Bifidobacterium alters the gastrointestinal microbiota during antibiotic treatment for Clostridium difficile infection. PLoS One 13, e0204253 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Brecht, M., Garg, A., Longstaff, K., Cooper, C. & Andersen, C. Lactobacillus sepsis following a laparotomy in a preterm infant: a note of caution. Neonatology 109, 186–189 (2016).

    Article  PubMed  Google Scholar 

  194. Spinler, J. K. et al. Administration of probiotic kefir to mice with Clostridium difficile infection exacerbates disease. Anaerobe 40, 54–57 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Oliveira, B. C. M. & Widmer, G. Probiotic product enhances susceptibility of mice to cryptosporidiosis. Appl. Environ. Microbiol. 84, e01408–18 (2018).

  196. He, F. et al. Differences in composition and mucosal adhesion of Bifidobacteria isolated from healthy adults and healthy seniors. Curr. Microbiol. 43, 351–354 (2001).

    Article  CAS  PubMed  Google Scholar 

  197. Kankaanpää, P. E., Salminen, S. J., Isolauri, E. & Lee, Y. K. The influence of polyunsaturated fatty acids on probiotic growth and adhesion. FEMS Microbiol. Lett. 194, 149–153 (2001).

    Article  PubMed  Google Scholar 

  198. Shepherd, E. S., DeLoache, W. C., Pruss, K. M., Whitaker, W. R. & Sonnenburg, J. L. An exclusive metabolic niche enables strain engraftment in the gut microbiota. Nature 557, 434–438 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Andriantsoanirina, V., Teolis, A. C., Xin, L. X., Butel, M. J. & Aires, J. Bifidobacterium longum and Bifidobacterium breve isolates from preterm and full term neonates: comparison of cell surface properties. Anaerobe 28, 212–215 (2014).

    Article  CAS  PubMed  Google Scholar 

  200. Roessler, A. et al. The immune system in healthy adults and patients with atopic dermatitis seems to be affected differently by a probiotic intervention. Clin. Exp. Allergy 38, 93–102 (2008).

    CAS  PubMed  Google Scholar 

  201. Pelto, L., Isolauri, E., Lilius, E. M., Nuutila, J. & Salminen, S. Probiotic bacteria down-regulate the milk-induced inflammatory response in milk-hypersensitive subjects but have an immunostimulatory effect in healthy subjects. Clin. Exp. Allergy 28, 1474–1479 (1998).

    Article  CAS  PubMed  Google Scholar 

  202. Hod, K. et al. The effect of a multispecies probiotic on microbiota composition in a clinical trial of patients with diarrhea-predominant irritable bowel syndrome. Neurogastroenterol. Motil. 30, e13456 (2018).

    Article  CAS  PubMed  Google Scholar 

  203. Suwal, S. et al. The probiotic effectiveness in preventing experimental colitis is correlated with host gut microbiota. Front. Microbiol. 9, 2675 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  204. Abildgaard, A., et al. The antidepressant-like effect of probiotics and their faecal abundance may be modulated by the cohabiting gut microbiota in rats. Eur. Neuropsychopharmacol. 29, 98–110 (2019).

  205. Ferrario, C. et al. Modulation of fecal Clostridiales bacteria and butyrate by probiotic intervention with Lactobacillus paracasei DG varies among healthy adults. J. Nutr. 144, 1787–1796 (2014).

    Article  CAS  PubMed  Google Scholar 

  206. Knight, R. et al. Best practices for analysing microbiomes. Nat. Rev. Microbiol. 16, 410–422 (2018).

    Article  CAS  PubMed  Google Scholar 

  207. Degirolamo, C., Rainaldi, S., Bovenga, F., Murzilli, S. & Moschetta, A. Microbiota modification with probiotics induces hepatic bile acid synthesis via downregulation of the Fxr–Fgf15 axis in mice. Cell Rep. 7, 12–18 (2014).

    Article  CAS  PubMed  Google Scholar 

  208. García-Albiach, R. et al. Molecular analysis of yogurt containing Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus in human intestinal microbiota. Am. J. Clin. Nutr. 87, 91–96 (2008).

    Article  PubMed  Google Scholar 

  209. Ouwehand, A. C. et al. Bifidobacterium microbiota and parameters of immune function in elderly subjects. FEMS Immunol. Med. Microbiol. 53, 18–25 (2008).

    Article  CAS  PubMed  Google Scholar 

  210. Korpela, K. et al. Probiotic supplementation restores normal microbiota composition and function in antibiotic-treated and in caesarean-born infants. Microbiome 6, 182 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  211. Wang, C. et al. Intestinal microbiota profiles of healthy pre-school and school-age children and effects of probiotic supplementation. Ann. Nutr. Metab. 67, 257–266 (2015).

    Article  CAS  PubMed  Google Scholar 

  212. Mohan, R. et al. Effects of Bifidobacterium lactis Bb12 supplementation on intestinal microbiota of preterm infants: a double-blind, placebo-controlled, randomized study. J. Clin. Microbiol. 44, 4025–4031 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  213. Veiga, P. et al. Changes of the human gut microbiome induced by a fermented milk product. Sci. Rep. 4, 6328 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Brahe, L. K. et al. Dietary modulation of the gut microbiota—a randomised controlled trial in obese postmenopausal women. Br. J. Nutr. 114, 406–417 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. McNulty, N. P. et al. The impact of a consortium of fermented milk strains on the gut microbiome of gnotobiotic mice and monozygotic twins. Sci. Transl. Med. 3, 106ra106 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Eloe-Fadrosh, E. A. et al. Functional dynamics of the gut microbiome in elderly people during probiotic consumption. mBio 6, e00231-15 (2015).

  217. Martin, F. P. et al. Probiotic modulation of symbiotic gut microbial–host metabolic interactions in a humanized microbiome mouse model. Mol. Syst. Biol. 4, 157 (2008).

    PubMed  PubMed Central  Google Scholar 

  218. Burton, K. J. et al. Probiotic yogurt and acidified milk similarly reduce postprandial inflammation and both alter the gut microbiota of healthy, young men. Br. J. Nutr. 117, 1312–1322 (2017).

    Article  CAS  PubMed  Google Scholar 

  219. Kajander, K. et al. Effects of multispecies probiotic supplementation on intestinal microbiota in irritable bowel syndrome. Aliment. Pharmacol. Ther. 26, 463–473 (2007).

    Article  CAS  PubMed  Google Scholar 

  220. Donaldson, G. P., Lee, S. M. & Mazmanian, S. K. Gut biogeography of the bacterial microbiota. Nat. Rev. Microbiol. 14, 20–32 (2016).

    Article  CAS  PubMed  Google Scholar 

  221. Uronis, J. M. et al. Gut microbial diversity is reduced by the probiotic VSL#3 and correlates with decreased TNBS-induced colitis. Inflamm. Bowel Dis. 17, 289–297 (2011).

    Article  PubMed  Google Scholar 

  222. Arthur, J. C. et al. VSL#3 probiotic modifies mucosal microbial composition but does not reduce colitis-associated colorectal cancer. Sci. Rep. 3, 2868 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  223. Kühbacher, T. et al. Bacterial and fungal microbiota in relation to probiotic therapy (VSL#3) in pouchitis. Gut 55, 833–841 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank the members of the Elinav and Segal laboratories for discussions and apologize to authors whose work was not included due to space constraints. J.S. is the recipient of the Strauss Institute research fellowship. N.Z. is supported by the Gilead Sciences International Research Scholars Program in Liver Disease. E.S. is supported by the Crown Human Genome Center; the Else Kroener Fresenius Foundation; Donald L. Schwarz, Sherman Oaks, CA; Jack N. Halpern, NY, NY; Leesa Steinberg, Canada; and grants funded by the European Research Council and the Israel Science Foundation. E.E. is supported by Y. and R. Ungar, the Abisch Frenkel Foundation for the Promotion of Life Sciences, the Gurwin Family Fund for Scientific Research, the Leona M. and Harry B. Helmsley Charitable Trust, the Crown Endowment Fund for Immunological Research, the estate of J. Gitlitz, the estate of L. Hershkovich, the Benoziyo Endowment Fund for the Advancement of Science, the Adelis Foundation, J. L. and V. Schwartz, A. and G. Markovitz, A. and C. Adelson, the French National Center for Scientific Research (CNRS), D.L. Schwarz, the V.R. Schwartz Research Fellow Chair, L. Steinberg, J. N. Halpern, A. Edelheit, grants funded by the European Research Council, a Marie Curie Integration grant, the German-Israeli Foundation for Scientific Research and Development, the Israel Science Foundation, the Minerva Foundation, the Rising Tide Foundation, the Helmholtz Foundation, and the European Foundation for the Study of Diabetes.

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Author notes

  1. These authors contributed equally: Jotham Suez, Niv Zmora.

Authors and Affiliations

  1. Immunology Department, Weizmann Institute of Science, Rehovot, Israel

    Jotham Suez, Niv Zmora & Eran Elinav

  2. Digestive Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Niv Zmora

  3. Internal Medicine Department, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Niv Zmora

  4. Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel

    Eran Segal

  5. Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel

    Eran Segal

  6. Cancer-Microbiome Research Division, DKFZ, Heidelberg, Germany

    Eran Elinav

Authors
  1. Jotham Suez
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  2. Niv Zmora
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  3. Eran Segal
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  4. Eran Elinav
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All authors have researched data for the article, made substantial contributions to discussion of content and wrote, reviewed and edited the manuscript before submission.

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Correspondence to Eran Segal or Eran Elinav.

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Declaration of interests

E.S. and E.E. are paid consultants at DayTwo and BiomX. None of their work on microbial therapies is related to, funded or endorsed by, shared or discussed with or licensed to any commercial entity.

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Suez, J., Zmora, N., Segal, E. et al. The pros, cons, and many unknowns of probiotics. Nat Med 25, 716–729 (2019). https://doi.org/10.1038/s41591-019-0439-x

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