Perspective | Published:

Sieving through gut models of colonization resistance


The development of innovative high-throughput genomics and metabolomics technologies has considerably expanded our understanding of the commensal microorganisms residing within the human body, collectively termed the microbiota. In recent years, the microbiota has been reported to have important roles in multiple aspects of human health, pathology and host–pathogen interactions. One function of commensals that has attracted particular interest is their role in protection against pathogens and pathobionts, a concept known as colonization resistance. However, pathogens are also able to sense and exploit the microbiota during infection. Therefore, obtaining a holistic understanding of colonization resistance mechanisms is essential for the development of microbiome-based and microbiome-targeting therapies for humans and animals. Achieving this is dependent on utilizing physiologically relevant animal models. In this Perspective, we discuss the colonization resistance functions of the gut microbiota and sieve through the advantages and limitations of murine models commonly used to study such mechanisms within the context of enteric bacterial infection.

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  1. 1.

    Hözel, D. & Barnes, R. H. Contributions of the intestinal microflora to the nutrition of the host. Vitam. Horm. 24, 115–171 (1967).

  2. 2.

    Brestoff, J. R. & Artis, D. Commensal bacteria at the interface of host metabolism and the immune system. Nat. Immunol. 14, 676–684 (2013).

  3. 3.

    Bohnhoff, M., Drake, B. L. & Miller, C. P. Effect of streptomycin on susceptibility of intestinal tract to experimental Salmonella infection. Proc. Soc. Exp. Biol. Med. 86, 132–137 (1954).

  4. 4.

    Freter, R. The fatal enteric cholera infection in the guinea pig, achieved by inhibition of normal enteric flora. J. Infect. Dis. 97, 57–65 (1955).

  5. 5.

    van der Waaij, D., Berghuis-de Vries, J. & Lekkerkerk-van der Wees, J. E. C. Colonization resistance of the digestive tract in conventional and antibiotic-treated mice. J. Hyg. Lond. 69, 405–411 (1971).

  6. 6.

    Grice, E. A. & Segre, J. A. The skin microbiome. Nat. Rev. Microbiol. 9, 244–253 (2011).

  7. 7.

    Brugger, S. D., Bomar, L. & Lemon, K. P. Commensal–pathogen interactions along the human nasal passages. PLoS Pathog. 12, e1005633 (2016).

  8. 8.

    De Cárcer, D. A. et al. Numerical ecology validates a biogeographical distribution and gender-based effect on mucosa-associated bacteria along the human colon. ISME J. 5, 801–809 (2011).

  9. 9.

    Sartor, R. B. Microbial influences in inflammatory bowel diseases. Gastroenterology 134, 577–594 (2008).

  10. 10.

    Eckburg, P. B. et al. Diversity of the human intestinal microbial flora. Science 308, 1635–1638 (2005).

  11. 11.

    Stearns, J. C. et al. Bacterial biogeography of the human digestive tract. Sci. Rep. 1, 170 (2011).

  12. 12.

    Wang, M., Ahrné, S., Jeppsson, B. & Molin, G. Comparison of bacterial diversity along the human intestinal tract by direct cloning and sequencing of 16S rRNA genes. FEMS Microbiol. Ecol. 54, 219–231 (2005).

  13. 13.

    Booijink, C. C. et al. High temporal and inter‐individual variation detected in the human ileal microbiota. Environ. Microbiol. 12, 3213–3227 (2010).

  14. 14.

    Yasuda, K. et al. Biogeography of the intestinal mucosal and lumenal microbiome in the rhesus macaque. Cell Host Microbe 17, 385–391 (2015).

  15. 15.

    Yatsunenko, T. et al. Human gut microbiome viewed across age and geography. Nature 486, 222–227 (2012).

  16. 16.

    David, L. A. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (2014).

  17. 17.

    Claesson, M. J. et al. Gut microbiota composition correlates with diet and health in the elderly. Nature 488, 178–184 (2012).

  18. 18.

    Chassaing, B. et al. Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Nature 519, 92–96 (2015).

  19. 19.

    Suez, J. et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature 514, 181–186 (2014).

  20. 20.

    Forslund, K. et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 528, 262–266 (2015).

  21. 21.

    Thaiss, C. A. et al. Transkingdom control of microbiota diurnal oscillations promotes metabolic homeostasis. Cell 159, 514–529 (2014).

  22. 22.

    Desai, M. S. et al. A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility. Cell 167, 1339–1353 (2016).

  23. 23.

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

  24. 24.

    Bellet, M. M. et al. Circadian clock regulates the host response to Salmonella. Proc. Natl Acad. Sci. USA 110, 9897–9902 (2013).

  25. 25.

    Curtis, A. M., Bellet, M. M., Sassone-Corsi, P. & O’Neill, L. A. Circadian clock proteins and immunity. Immunity 40, 178–186 (2014).

  26. 26.

    Jarchum, I. & Pamer, E. G. Regulation of innate and adaptive immunity by the commensal microbiota. Curr. Opin. Immunol. 23, 353–360 (2011).

  27. 27.

    Morgun, A. et al. Uncovering effects of antibiotics on the host and microbiota using transkingdom gene networks. Gut 64, 1674–1675 (2015).

  28. 28.

    Nguyen, K. D. et al. Circadian gene Bmal1 regulates diurnal oscillations of Ly6Chi inflammatory monocytes. Science 341, 1483–1488 (2013).

  29. 29.

    Gibbs, J. et al. An epithelial circadian clock controls pulmonary inflammation and glucocorticoid action. Nat. Med. 20, 919–926 (2014).

  30. 30.

    Morowitz, M. J. et al. Dietary supplementation with nonfermentable fiber alters the gut microbiota and confers protection in murine models of sepsis. Crit. Care Med. 45, 516–523 (2017).

  31. 31.

    Rao, S. et al. Pathogen-mediated inhibition of anorexia promotes host survival and transmission. Cell 168, 503–516 (2017).

  32. 32.

    Wang, A. et al. Opposing effects of fasting metabolism on tissue tolerance in bacterial and viral inflammation. Cell 166, 1512–1525 (2016).

  33. 33.

    Hicks, L. A. et al. US outpatient antibiotic prescribing variation according to geography, patient population, and provider specialty in 2011. Clin. Infect. Dis. 60, 1308–1316 (2015).

  34. 34.

    Langdon, A., Crook, N. & Dantas, G. The effects of antibiotics on the microbiome throughout development and alternative approaches for therapeutic modulation. Genome Med. 8, 39 (2016).

  35. 35.

    Ubeda, C. et al. Vancomycin-resistant Enterococcus domination of intestinal microbiota is enabled by antibiotic treatment in mice and precedes bloodstream invasion in humans. J. Clin. Invest. 120, 4332–4341 (2010).

  36. 36.

    Ayres, J. S., Trinidad, N. J. & Vance, R. E. Lethal inflammasome activation by a multidrug-resistant pathobiont upon antibiotic disruption of the microbiota. Nat. Med. 18, 799–806 (2012).

  37. 37.

    Pavia, A. T. et al. Epidemiologic evidence that prior antimicrobial exposure decreases resistance to infection by antimicrobial-sensitive Salmonella. J. Infect. Dis. 161, 255–260 (1990).

  38. 38.

    Lawley, T. D. et al. Antibiotic treatment of Clostridium difficile carrier mice triggers a supershedder state, spore-mediated transmission, and severe disease in immunocompromised hosts. Infect. Immun. 77, 3661–3669 (2009).

  39. 39.

    Leffler, D. A. & Lamont, J. T. Clostridium difficile infection. New Engl. J. Med. 372, 1539–1548 (2015).

  40. 40.

    Furuya-Kanamori, L. et al. Asymptomatic Clostridium difficile colonization: epidemiology and clinical implications. BMC Infect. Dis. 15, 516 (2015).

  41. 41.

    Slimings, C. & Riley, T. V. Antibiotics and hospital-acquired Clostridium difficile infection: update of systematic review and meta-analysis. J. Antimicrob. Chemother. 69, 881–891 (2014).

  42. 42.

    Ng, K. M. et al. Microbiota-liberated host sugars facilitate post-antibiotic expansion of enteric pathogens. Nature 502, 96–99 (2013).

  43. 43.

    Ferreyra, J. A. et al. Gut microbiota-produced succinate promotes C. difficile infection after antibiotic treatment or motility disturbance. Cell Host Microbe 16, 770–777 (2014).

  44. 44.

    van Nood, E. et al Duodenal infusion of donor feces for recurrent Clostridium difficile. New Engl. J. Med. 368, 407–415 (2013).

  45. 45.

    Kampmann, C., Dicksved, J., Engstrand, L. & Rautelin, H. Composition of human faecal microbiota in resistance to Campylobacter infection. Clin. Microbiol. Infect. 22, 61–68 (2016).

  46. 46.

    Barthel, M. et al. Pretreatment of mice with streptomycin provides a Salmonella enterica serovar Typhimurium colitis model that allows analysis of both pathogen and host. Infect. Immun. 71, 2839–2858 (2003).

  47. 47.

    Antonopoulos, D. A. et al. Reproducible community dynamics of the gastrointestinal microbiota following antibiotic perturbation. Infect. Immun. 77, 2367–2375 (2009).

  48. 48.

    Caballero, S. et al. Cooperating commensals restore colonization resistance to vancomycin-resistant Enterococcus faecium. Cell Host Microbe 21, 592–602 (2017).

  49. 49.

    Collins, J. W. et al. Citrobacter rodentium: infection, inflammation and the microbiota. Nat. Rev. Microbiol. 12, 612–623 (2014).

  50. 50.

    Willing, B. P., Vacharaksa, A., Croxen, M., Thanachayanont, T. & Finlay, B. B. Altering host resistance to infections through microbial transplantation. PLoS One 6, e26988 (2011).

  51. 51.

    Buffie, C. G. et al. Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile. Nature 517, 205–208 (2015).

  52. 52.

    Kim, Y.-G. et al. Neonatal acquisition of Clostridia species protects against colonization by bacterial pathogens. Science 356, 315–319 (2017).

  53. 53.

    Sprinz, H. et al. The response of the germ-free guinea pig to oral bacterial challenge with Escherichia coli and Shigella flexneri: with special reference to lymphatic tissue and the intestinal tract. Am. J. Pathol. 39, 681–685 (1961).

  54. 54.

    Nardi, R., Silva, M., Vieira, E., Bambirra, E. & Nicoli, J. Intragastric infection of germfree and conventional mice with Salmonella typhimurium. Braz. J. Med. Biol. Res. 22, 1389–1392 (1988).

  55. 55.

    Zachar, Z. & Savage, D. C. Microbial interference and colonization of the murine gastrointestinal tract by Listeria monocytogenes. Infect. Immun. 23, 168–174 (1979).

  56. 56.

    Inagaki, H., Suzuki, T., Nomoto, K. & Yoshikai, Y. Increased susceptibility to primary infection with Listeria monocytogenes in germfree mice may be due to lack of accumulation of L-selectin+ CD44+ T cells in sites of inflammation. Infect. Immun. 64, 3280–3287 (1996).

  57. 57.

    Brugiroux, S. et al. Genome-guided design of a defined mouse microbiota that confers colonization resistance against Salmonella enterica serovar Typhimurium. Nat. Microbiol. 2, 16215 (2016).

  58. 58.

    Reeves, A. E., Koenigsknecht, M. J., Bergin, I. L. & Young, V. B. Suppression of Clostridium difficile in the gastrointestinal tracts of germfree mice inoculated with a murine isolate from the family Lachnospiraceae. Infect. Immun. 80, 3786–3794 (2012).

  59. 59.

    Kernbauer, E., Ding, Y. & Cadwell, K. An enteric virus can replace the beneficial function of commensal bacteria. Nature 516, 94–98 (2014).

  60. 60.

    Schamberger, G. P. & Diez-Gonzalez, F. Selection of recently isolated colicinogenic Escherichia coli strains inhibitory to Escherichia coli O157:H7. J. Food Prot. 65, 1381–1387 (2002).

  61. 61.

    Etcheverria, A., Arroyo, G., Perdigon, G. & Parma, A. Escherichia coli with anti‐O157:H7 activity isolated from bovine colon. J. Appl. Microbiol. 100, 384–389 (2006).

  62. 62.

    Sassone-Corsi, M. et al. Microcins mediate competition among Enterobacteriaceae in the inflamed gut. Nature 540, 280–283 (2016).

  63. 63.

    Rea, M. C. et al. Thuricin CD, a posttranslationally modified bacteriocin with a narrow spectrum of activity against Clostridium difficile. Proc. Natl Acad. Sci. USA 107, 9352–9357 (2010).

  64. 64.

    Rea, M. C. et al. Antimicrobial activity of lacticin 3147 against clinical Clostridium difficile strains. J. Med. Microbiol. 56, 940–946 (2007).

  65. 65.

    Zheng, J., Gänzle, M. G., Lin, X. B., Ruan, L. & Sun, M. Diversity and dynamics of bacteriocins from human microbiome. Environ. Microbiol. 17, 2133–2143 (2015).

  66. 66.

    Cherrington, C.A., Hinton, M., Pearson, G. & Chopra, I. Short-chain organic acids at pH 5.0 kill Escherichia coli and Salmonella spp. without causing membrane perturbation. J. Appl. Bacteriol. 70, 161–165 (1991).

  67. 67.

    MacIntyre, D. L., Miyata, S. T., Kitaoka, M. & Pukatzki, S. The Vibrio cholerae type VI secretion system displays antimicrobial properties. Proc. Natl Acad. Sci. USA 107, 19520–19524 (2010).

  68. 68.

    Sana, T. G. et al. Salmonella Typhimurium utilizes a T6SS-mediated antibacterial weapon to establish in the host gut. Proc. Natl Acad. Sci. USA 113, E5044–E5051 (2016).

  69. 69.

    Chatzidaki-Livanis, M., Geva-Zatorsky, N. & Comstock, L. E. Bacteroides fragilis type VI secretion systems use novel effector and immunity proteins to antagonize human gut Bacteroidales species. Proc. Natl Acad. Sci. USA 113, 3627–3632 (2016).

  70. 70.

    Anderson, M. C., Vonaesch, P., Saffarian, A., Marteyn, B. S. & Sansonetti, P. J. Shigella sonnei encodes a functional T6SS used for interbacterial competition and niche occupancy. Cell Host Microbe 21, 769–776 (2017).

  71. 71.

    Hecht, A. L. et al. Strain competition restricts colonization of an enteric pathogen and prevents colitis. EMBO Rep. 17, 1281–1291 (2016).

  72. 72.

    Leatham, M. P. et al. Precolonized human commensal Escherichia coli strains serve as a barrier to E. coli O157:H7 growth in the streptomycin-treated mouse intestine. Infect. Immun. 77, 2876–2886 (2009).

  73. 73.

    Momose, Y., Hirayama, K. & Itoh, K. Competition for proline between indigenous Escherichia coli and E. coli O157:H7 in gnotobiotic mice associated with infant intestinal microbiota and its contribution to the colonization resistance against E. coli O157:H7. Antonie Van Leeuwenhoek 94, 165–171 (2008).

  74. 74.

    Deriu, E. et al. Probiotic bacteria reduce Salmonella typhimurium intestinal colonization by competing for iron. Cell Host Microbe 14, 26–37 (2013).

  75. 75.

    Cassat, J. E. & Skaar, E. P. Iron in infection and immunity. Cell Host Microbe 13, 509–519 (2013).

  76. 76.

    Gielda, L. M. & DiRita, V. J. Zinc competition among the intestinal microbiota. mBio 3, e00171-12 (2012).

  77. 77.

    Marteyn, B. et al. Modulation of Shigella virulence in response to available oxygen in vivo. Nature 465, 355–358 (2010).

  78. 78.

    Lopez, C. A. et al. Virulence factors enhance Citrobacter rodentium expansion through aerobic respiration. Science 353, 1249–1253 (2016).

  79. 79.

    Gantois, I. et al. Butyrate specifically down-regulates Salmonella pathogenicity island 1 gene expression. Appl. Environ. Microbiol. 72, 946–949 (2006).

  80. 80.

    Mazmanian, S. K., Liu, C. H., Tzianabos, A. O. & Kasper, D. L. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122, 107–118 (2005).

  81. 81.

    Kwon, H.-K. et al. Generation of regulatory dendritic cells and CD4+ Foxp3+ T cells by probiotics administration suppresses immune disorders. Proc. Natl Acad. Sci. USA 107, 2159–2164 (2010).

  82. 82.

    Atarashi, K. et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500, 232–236 (2013).

  83. 83.

    Sokol, H. et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc. Natl Acad. Sci. USA 105, 16731–16736 (2008).

  84. 84.

    Kobayashi, K. S. et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307, 731–734 (2005).

  85. 85.

    Levy, M. et al. Microbiota-modulated metabolites shape the intestinal microenvironment by regulating NLRP6 inflammasome signaling. Cell 163, 1428–1443 (2015).

  86. 86.

    Vaishnava, S., Behrendt, C. L., Ismail, A. S., Eckmann, L. & Hooper, L. V. Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface. Proc. Natl Acad. Sci. USA 105, 20858–20863 (2008).

  87. 87.

    Khosravi, A. et al. Gut microbiota promote hematopoiesis to control bacterial infection. Cell Host Microbe 15, 374–381 (2014).

  88. 88.

    Natividad, J. M. et al. Differential induction of antimicrobial REGIII by the intestinal microbiota and Bifidobacterium breve NCC2950. Appl. Environ. Microbiol. 79, 7745–7754 (2013).

  89. 89.

    Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).

  90. 90.

    Stecher, B. et al. Salmonella enterica serovar Typhimurium exploits inflammation to compete with the intestinal microbiota. PLoS Biol. 5, e244 (2007).

  91. 91.

    Berger, C. N. et al. Citrobacter rodentium subverts ATP flux and cholesterol homeostasis in intestinal epithelial cells in vivo. Cell Metab. (in the press).

  92. 92.

    Fabich, A. J. et al. Comparison of carbon nutrition for pathogenic and commensal Escherichia coli strains in the mouse intestine. Infect. Immun. 76, 1143–1152 (2008).

  93. 93.

    Bertin, Y. et al. Enterohaemorrhagic Escherichia coli gains a competitive advantage by using ethanolamine as a nitrogen source in the bovine intestinal content. Environ. Microbiol. 13, 365–377 (2011).

  94. 94.

    Luzader, D. H., Clark, D. E., Gonyar, L. A. & Kendall, M. M. EutR is a direct regulator of genes that contribute to metabolism and virulence in enterohemorrhagic Escherichia coli O157:H7. J. Bacteriol. 195, 4947–4953 (2013).

  95. 95.

    Thiennimitr, P. et al. Intestinal inflammation allows Salmonella to use ethanolamine to compete with the microbiota. Proc. Natl Acad. Sci. USA 108, 17480–17485 (2011).

  96. 96.

    Fox, K. A. et al. Multiple posttranscriptional regulatory mechanisms partner to control ethanolamine utilization in Enterococcus faecalis. Proc. Natl Acad. Sci. USA 106, 4435–4440 (2009).

  97. 97.

    Faber, F. et al. Host-mediated sugar oxidation promotes post-antibiotic pathogen expansion. Nature 534, 697–699 (2016).

  98. 98.

    Kelly, C. J. et al. Crosstalk between microbiota-derived short-chain fatty acids and intestinal epithelial HIF augments tissue barrier function. Cell Host Microbe 17, 662–671 (2015).

  99. 99.

    Rivera-Chávez, F. et al. Depletion of butyrate-producing Clostridia from the gut microbiota drives an aerobic luminal expansion of Salmonella. Cell Host Microbe 19, 443–454 (2016).

  100. 100.

    Winter, S. E. et al. Gut inflammation provides a respiratory electron acceptor for Salmonella. Nature 467, 426–429 (2010).

  101. 101.

    Raffatellu, M. et al. Lipocalin-2 resistance confers an advantage to Salmonella enterica serotype Typhimurium for growth and survival in the inflamed intestine. Cell Host Microbe 5, 476–486 (2009).

  102. 102.

    McClelland, M. et al. Comparison of genome degradation in Paratyphi A and Typhi, human-restricted serovars of Salmonella enterica that cause typhoid. Nat. Genet. 36, 1268–1274 (2004).

  103. 103.

    White, A. et al. Intergenic sequence comparison of Escherichia coli isolates reveals lifestyle adaptations but not host specificity. Appl. Environ. Microbiol. 77, 7620–7632 (2011).

  104. 104.

    Yang, F. et al. Genome dynamics and diversity of Shigella species, the etiologic agents of bacillary dysentery. Nucleic Acids Res. 33, 6445–6458 (2005).

  105. 105.

    Tong, Z. et al. Pseudogene accumulation might promote the adaptive microevolution of Yersinia pestis. J. Med. Microbiol. 54, 259–268 (2005).

  106. 106.

    Roxas, J. L. et al. Enterohemorrhagic E. coli alters murine intestinal epithelial tight junction protein expression and barrier function in a Shiga toxin independent manner. Lab. Invest. 90, 1152–1168 (2010).

  107. 107.

    Mundy, R., Girard, F., FitzGerald, A. J. & Frankel, G. Comparison of colonization dynamics and pathology of mice infected with enteropathogenic Escherichia coli, enterohaemorrhagic E. coli and Citrobacter rodentium. FEMS Microbiol. Lett 265, 126–132 (2006).

  108. 108.

    Wadolkowski, E. A., Burris, J. A. & O’Brien, A. D. Mouse model for colonization and disease caused by enterohemorrhagic Escherichia coli O157: H7. Infect. Immun. 58, 2438–2445 (1990).

  109. 109.

    Hapfelmeier, S. et al. The Salmonella pathogenicity island (SPI)-2 and SPI-1 type III secretion systems allow Salmonella serovar typhimurium to trigger colitis via MyD88-dependent and MyD88-independent mechanisms. J.Immunol. 174, 1675–1685 (2005).

  110. 110.

    Lindgren, S., Melton, A. & O’Brien, A. Virulence of enterohemorrhagic Escherichia coli O91: H21 clinical isolates in an orally infected mouse model. Infect. Immun. 61, 3832–3842 (1993).

  111. 111.

    Myhal, M., Laux, D. & Cohen, P. Relative colonizing abilities of human fecal and K 12 strains of Escherichia coli in the large intestines of streptomycin-treated mice. Eur. J. Clin. Microbiol. Infect. Dis. 1, 186–192 (1982).

  112. 112.

    Maltby, R., Leatham-Jensen, M. P., Gibson, T., Cohen, P. S. & Conway, T. Nutritional basis for colonization resistance by human commensal Escherichia coli strains HS and Nissle 1917 against E. coli O157: H7 in the mouse intestine. PLoS ONE 8, e53957 (2013).

  113. 113.

    Mellies, J. L., Elliott, S. J., Sperandio, V., Donnenberg, M. S. & Kaper, J. B. The Per regulon of enteropathogenic Escherichia coli: identification of a regulatory cascade and a novel transcriptional activator, the locus of enterocyte effacement (LEE)‐encoded regulator (Ler). Mol. Microbiol. 33, 296–306 (1999).

  114. 114.

    Mullineaux-Sanders, C. et al. Citrobacter rodentium relies on commensals for colonization of the colonic mucosa. Cell Rep. 21, 3381–3389 (2017).

  115. 115.

    Menzies, D. J., Dorsainvil, P. A., Cunha, B. A. & Johnson, D. H. Severe and persistent hypoglycemia due to gatifloxacin interaction with oral hypoglycemic agents. Am. J. Med. 113, 232–234 (2002).

  116. 116.

    Williams, J. Selective toxicity and concordant pharmacodynamics of antibiotics and other drugs. J. Antimicrob. Chemother 35, 721–737 (1995).

  117. 117.

    Pilot, M. A. Macrolides in roles beyond antibiotic therapy. Br. J. Surg. 81, 1423–1429 (1994).

  118. 118.

    Barnhill, A. E., Brewer, M. T. & Carlson, S. A. Adverse effects of antimicrobials via predictable or idiosyncratic inhibition of host mitochondrial components. Antimicrob. Agents Chemother. 56, 4046–4051 (2012).

  119. 119.

    Burroughs, S. & Johnson, G. Beta-lactam antibiotic-induced platelet dysfunction: Evidence for irreversible inhibition of platelet activation in vitro and in vivo after prolonged exposure to penicillin. Blood 75, 1473–1480 (1990).

  120. 120.

    McLellan, R. A., Drobitch, R. K., Monshouwer, M. & Renton, K. W. Fluoroquinolone antibiotics inhibit cytochrome P450-mediated microsomal drug metabolism in rat and human. Drug Metab. Disposition 24, 1134–1138 (1996).

  121. 121.

    Antal, E. J. et al. Linezolid, a novel oxazolidinone antibiotic: assessment of monoamine oxidase inhibition using pressor response to oral tyramine. J. Clin. Pharmacol. 41, 552–562 (2001).

  122. 122.

    Stecher, B. et al. Comparison of Salmonella enterica serovar Typhimurium colitis in germfree mice and mice pretreated with streptomycin. Infect. Immun. 73, 3228–3241 (2005).

  123. 123.

    Kamada, N. et al. Regulated virulence controls the ability of a pathogen to compete with the gut microbiota. Science 336, 1325–1329 (2012).

  124. 124.

    Lawhon, S. D., Maurer, R., Suyemoto, M. & Altier, C. Intestinal short‐chain fatty acids alter Salmonella. typhimurium invasion gene expression and virulence through BarA/SirA. Mol. Microbiol. 46, 1451–1464 (2002).

  125. 125.

    Nakanishi, N. et al. Regulation of virulence by butyrate sensing in enterohaemorrhagic Escherichia coli. Microbiology 155, 521–530 (2009).

  126. 126.

    Pacheco, A. R. et al. Fucose sensing regulates bacterial intestinal colonization. Nature 492, 113–117 (2012).

  127. 127.

    Curtis, M. M. et al. The gut commensal Bacteroides thetaiotaomicron exacerbates enteric infection through modification of the metabolic landscape. Cell Host Microbe 16, 759–769 (2014).

  128. 128.

    Maier, L. et al. Microbiota-derived hydrogen fuels Salmonella typhimurium invasion of the gut ecosystem. Cell Host Microbe 14, 641–651 (2013).

  129. 129.

    Reynolds, L. A. et al. Commensal–pathogen interactions in the intestinal tract: Lactobacilli promote infection with, and are promoted by, helminth parasites. Gut Microbes 5, 522–532 (2014).

  130. 130.

    Nguyen, T. L. A., Vieira-Silva, S., Liston, A. & Raes, J. How informative is the mouse for human gut microbiota research? Dis. Model. Mech. 8, 1–16 (2015).

  131. 131.

    Savage, D. C. & Dubos, R. Alterations in the mouse cecum and its flora produced by antibacterial drugs. J. Exp. Med. 128, 97 (1968).

  132. 132.

    Wostmann, B. & Bruckner-Kardoss, E. Cecal enlargment in germ-free animals. Am. J. Physiol. 197, 1346 (1960).

  133. 133.

    Tannock, G. W. & Savage, D. C. Indigenous microorganisms prevent reduction in cecal size induced by Salmonella typhimurium in vaccinated gnotobiotic mice. Infect. Immun. 13, 172–179 (1976).

  134. 134.

    Barbara, G. et al Interactions between commensal bacteria and gut sensorimotor function in health and disease. Am. J. Gastroenterol. 100, 2560–2568 (2005).

  135. 135.

    Kamath, P. S., Phillips, S. & Zinsmeister, A. R. Short-chain fatty acids stimulate ileal motility in humans. Gastroenterology 95, 1496–1502 (1988).

  136. 136.

    Ge, X. et al Antibiotics-induced depletion of mice microbiota induces changes in host serotonin biosynthesis and intestinal motility. J. Transl. Med. 15, 13 (2017).

  137. 137.

    Anitha, M., Vijay–Kumar, M., Sitaraman, S. V., Gewirtz, A. T. & Srinivasan, S. Gut microbial products regulate murine gastrointestinal motility via Toll-like receptor 4 signaling. Gastroenterology 143, 1006–1016 (2012).

  138. 138.

    Muller, P. A. et al. Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility. Cell 158, 300–313 (2014).

  139. 139.

    Huang, Y.-L., Chassard, C., Hausmann, M., Von Itzstein, M. & Hennet, T. Sialic acid catabolism drives intestinal inflammation and microbial dysbiosis in mice. Nat. Commun. 6, 8141 (2015).

  140. 140.

    Stefka, A. T. et al. Commensal bacteria protect against food allergen sensitization. Proc. Natl Acad. Sci. USA 111, 13145–13150 (2014).

  141. 141.

    von Schillde, M.-A. et al. Lactocepin secreted by Lactobacillus exerts anti-inflammatory effects by selectively degrading proinflammatory chemokines. Cell Host Microbe 11, 387–396 (2012).

  142. 142.

    Castagliuolo, I., Riegler, M. F., Valenick, L., LaMont, J. T. & Pothoulakis, C. Saccharomyces boulardii protease inhibits the effects of Clostridium difficile toxins A and B in human colonic mucosa. Infect. Immun. 67, 302–307 (1999).

  143. 143.

    Resta-Lenert, S. & Barrett, K. Live probiotics protect intestinal epithelial cells from the effects of infection with enteroinvasive Escherichia coli (EIEC). Gut 52, 988–997 (2003).

  144. 144.

    Mack, D. R., Michail, S., Wei, S., McDougall, L. & Hollingsworth, M. A. Probiotics inhibit enteropathogenic E. coli adherence in vitro by inducing intestinal mucin gene expression. Am. J. Physiol. Gastrointest. Liver Physiol. 276, G941–G950 (1999).

  145. 145.

    Rautava, S., Arvilommi, H. & Isolauri, E. Specific probiotics in enhancing maturation of IgA responses in formula-fed infants. Pediatr. Res. 60, 221–224 (2006).

  146. 146.

    Collins, J. W. et al Fermented dairy products modulate C. rodentium induced colonic hyperplasia. J. Infect. Dis. 210, 1029–1041 (2014).

  147. 147.

    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).

  148. 148.

    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).

  149. 149.

    Moayyedi, P. et al. Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology 149, 102–109 (2015).

  150. 150.

    Petrof, E. O. et al. Stool substitute transplant therapy for the eradication of Clostridium difficile infection: ‘RePOOPulating’ the gut. Microbiome 1, 3 (2013).

  151. 151.

    Ott, S. J. et al. Efficacy of sterile fecal filtrate transfer for treating patients with Clostridium difficile infection. Gastroenterology 152, 799–811 (2016).

  152. 152.

    Plovier, H. et al. A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nat. Med. 23, 107–113 (2017).

  153. 153.

    Thaiss, C. A. et al. Persistent microbiome alterations modulate the rate of post-dieting weight regain. Nature 540, 544–551 (2016).

  154. 154.

    Zeevi, D. et al. Personalized nutrition by prediction of glycemic responses. Cell 163, 1079–1094 (2015).

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E.E. is supported by Y. and R. Ungar; the Leona M. and Harry B. Helmsley Charitable Trust; and grants funded by the European Research Council, and is a senior fellow at the Canadian Institute for Advanced Research (CIFAR) and an International Scholar at the Bill and Melinda Gates Foundation and Howard Hughes Medical Institute (HHMI). This work was supported by grant MR/N00695X/1 from the AMR cross research council initiative under theme 1: Understanding resistant bacteria in the context of the host (C.M.S. and G.F.) and a Royal Society International Collaboration Award for Research Professors, ref: IC160080 (G.F.).

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Correspondence to Gad Frankel.

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Fig. 1: Colonization resistance in humans and mouse models.