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Interactions between the microbiota and pathogenic bacteria in the gut

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Abstract

The microbiome has an important role in human health. Changes in the microbiota can confer resistance to or promote infection by pathogenic bacteria. Antibiotics have a profound impact on the microbiota that alters the nutritional landscape of the gut and can lead to the expansion of pathogenic populations. Pathogenic bacteria exploit microbiota-derived sources of carbon and nitrogen as nutrients and regulatory signals to promote their own growth and virulence. By eliciting inflammation, these bacteria alter the intestinal environment and use unique systems for respiration and metal acquisition to drive their expansion. Unravelling the interactions between the microbiota, the host and pathogenic bacteria will produce strategies for manipulating the microbiota against infectious diseases.

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Figure 1: The impact of antibiotics on the microbiota and the expansion of enteric pathogens.
Figure 2: Modulation of enterohaemorrhagic E.coli virulence through nutrients provided by the microbiota.
Figure 3: The effect of intestinal inflammation on nutrient availability.

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References

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

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  2. Frank, D. N. et al. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc. Natl Acad. Sci. USA 104, 13780–13785 (2007).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  3. The Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012).

  4. Ley, R. E., Peterson, D. A. & Gordon, J. I. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 124, 837–848 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Yurist-Doutsch, S., Arrieta, M. C., Vogt, S. L. & Finlay, B. B. Gastrointestinal microbiota-mediated control of enteric pathogens. Annu. Rev. Genet. 48, 361–382 (2014).

    Article  CAS  PubMed  Google Scholar 

  6. Sassone-Corsi, M. & Raffatellu, M. No vacancy: how beneficial microbes cooperate with immunity to provide colonization resistance to pathogens. J. Immunol. 194, 4081–4087 (2015).

    Article  CAS  PubMed  Google Scholar 

  7. Cameron, E. A. & Sperandio, V. Frenemies: signaling and nutritional integration in pathogen–microbiota–host interactions. Cell Host Microbe 18, 275–284 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Pacheco, A. R. & Sperandio, V. Enteric pathogens exploit the microbiota-generated nutritional environment of the gut. Microbiol. Spectr. 3, MBP-0001-2014 (2015).

  9. 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).

    Article  CAS  PubMed  Google Scholar 

  10. Ferreira, R. B. et al. The intestinal microbiota plays a role in Salmonella-induced colitis independent of pathogen colonization. PLoS ONE 6, e20338 (2011).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  11. Sprinz, H. et al. The response of the germfree guinea pig to oral bacterial challenge with Escherichia coli and Shigella flexneri. Am. J. Pathol. 39, 681–695 (1961).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kamada, N. et al. Regulated virulence controls the ability of a pathogen to compete with the gut microbiota. Science 336, 1325–1329 (2012). This study showed that enteric pathogens use virulence genes to compete with the microbiota for nutrients in the gut.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  14. Ghosh, S. et al. Colonic microbiota alters host susceptibility to infectious colitis by modulating inflammation, redox status, and ion transporter gene expression. Am. J. Physiol. Gastrointest. Liver Physiol. 301, G39–G49 (2011).

    Article  CAS  PubMed  ADS  Google Scholar 

  15. 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).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  16. Kampmann, C., Dicksved, J., Engstrand, L. & Rautelin, H. Composition of human faecal microbiota in resistance to Campylobacter infection. Clin. Microbiol. Infect. 22, 61.e1–61.e8 (2016).

    Article  CAS  Google Scholar 

  17. Kau, A. L., Ahern, P. P., Griffin, N. W., Goodman, A. L. & Gordon, J. I. Human nutrition, the gut microbiome and the immune system. Nature 474, 327–336 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zumbrun, S. D. et al. Dietary choice affects Shiga toxin-producing Escherichia coli (STEC) O157:H7 colonization and disease. Proc. Natl Acad. Sci. USA 110, E2126–E2133 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wlodarska, M., Willing, B. P., Bravo, D. M. & Finlay, B. B. Phytonutrient diet supplementation promotes beneficial Clostridia species and intestinal mucus secretion resulting in protection against enteric infection. Sci. Rep. 5, 9253 (2015).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  20. Modi, S. R., Collins, J. J. & Relman, D. A. Antibiotics and the gut microbiota. J. Clin. Invest. 124, 4212–4218 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Leffler, D. A. & Lamont, J. T. Clostridium difficile infection. N. Engl. J. Med. 373, 287–288 (2015).

    CAS  PubMed  Google Scholar 

  22. 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).

    Article  CAS  PubMed  Google Scholar 

  23. Ng, K. M. et al. Microbiota-liberated host sugars facilitate post-antibiotic expansion of enteric pathogens. Nature 502, 96–99 (2013). This study showed that treatment with antibiotics enhances the abundance of host sialic acid that can be harvested by the microbiota, which promotes the expansion of enteric pathogens.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  24. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ferreyra, J. A., Ng, K. M. & Sonnenburg, J. L. The enteric two-step: nutritional strategies of bacterial pathogens within the gut. Cell. Microbiol. 16, 993–1003 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rakoff-Nahoum, S., Coyne, M. J. & Comstock, L. E. An ecological network of polysaccharide utilization among human intestinal symbionts. Curr. Biol. 24, 40–49 (2014).

    Article  CAS  PubMed  Google Scholar 

  27. Alverdy, J., Chi, H. S. & Sheldon, G. F. The effect of parenteral nutrition on gastrointestinal immunity. The importance of enteral stimulation. Ann. Surg. 202, 681–684 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Fischbach, M. A. & Sonnenburg, J. L. Eating for two: how metabolism establishes interspecies interactions in the gut. Cell Host Microbe 10, 336–347 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chow, W. L. & Lee, Y. K. Free fucose is a danger signal to human intestinal epithelial cells. Br. J. Nutr. 99, 449–454 (2008).

    Article  CAS  PubMed  Google Scholar 

  30. Bourlioux, P., Koletzko, B., Guarner, F. & Braesco, V. The intestine and its microflora are partners for the protection of the host: report on the Danone Symposium “The Intelligent Intestine,” held in Paris, June 14, 2002. Am. J. Clin. Nutr. 78, 675–683 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Bry, L., Falk, P. G., Midtvedt, T. & Gordon, J. I. A model of host–microbial interactions in an open mammalian ecosystem. Science 273, 1380–1383 (1996).

    Article  CAS  PubMed  ADS  Google Scholar 

  32. Hooper, L. V., Xu, J., Falk, P. G., Midtvedt, T. & Gordon, J. I. A molecular sensor that allows a gut commensal to control its nutrient foundation in a competitive ecosystem. Proc. Natl Acad. Sci. USA 96, 9833–9838 (1999).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  33. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Autieri, S. M. et al. L-fucose stimulates utilization of D-ribose by Escherichia coli MG1655 ΔfucAO and E. coli Nissle 1917 ΔfucAO mutants in the mouse intestine and in M9 minimal medium. Infect. Immun. 75, 5465–5475 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Pacheco, A. R. et al. Fucose sensing regulates bacterial intestinal colonization. Nature 492, 113–117 (2012). This paper showed that sugars from the mucus that are released by the microbiota can be perceived as signals by enteric pathogens to regulate the expression of virulence genes.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  36. Schauer, D. B. & Falkow, S. Attaching and effacing locus of a Citrobacter freundii biotype that causes transmissible murine colonic hyperplasia. Infect. Immun. 61, 2486–2492 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Szabady, R. L., Lokuta, M. A., Walters, K. B., Huttenlocher, A. & Welch, R. A. Modulation of neutrophil function by a secreted mucinase of Escherichia coli O157:H7. PLoS Pathog. 5, e1000320 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  38. 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). This study revealed that metabolites that are produced by the microbiota can be exploited as cues to increase the virulence of enteric pathogens.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Macy, J. M., Ljungdahl, L. G. & Gottschalk, G. Pathway of succinate and propionate formation in Bacteroides fragilis. J. Bacteriol. 134, 84–91 (1978).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Carter, P. B. & Collins, F. M. The route of enteric infection in normal mice. J. Exp. Med. 139, 1189–1203 (1974).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 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).

    Article  CAS  PubMed  Google Scholar 

  42. Takao, M., Yen, H. & Tobe, T. LeuO enhances butyrate-induced virulence expression through a positive regulatory loop in enterohaemorrhagic Escherichia coli. Mol. Microbiol. 93, 1302–1313 (2014).

    CAS  PubMed  Google Scholar 

  43. Karmali, M. A., Petric, M., Lim, C., Fleming, P. C. & Steele, B. T. Escherichia coli cytotoxin, haemolytic-uraemic syndrome, and haemorrhagic colitis. Lancet 2, 1299–1300 (1983).

    Article  CAS  PubMed  Google Scholar 

  44. Fukuda, S. et al. Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature 469, 543–547 (2011). This study showed that the acetate that is produced by certain probiotic bacteria can enhance the barrier function of the gut epithelium to protect the host from enteric infections.

    Article  CAS  PubMed  ADS  Google Scholar 

  45. 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).

    Article  CAS  PubMed  Google Scholar 

  46. Garsin, D. A. Ethanolamine utilization in bacterial pathogens: roles and regulation. Nature Rev. Microbiol. 8, 290–295 (2010).

    Article  CAS  Google Scholar 

  47. Korbel, J. O. et al. Systematic association of genes to phenotypes by genome and literature mining. PLoS Biol. 3, e134 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. 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).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  49. Joseph, B. et al. Identification of Listeria monocytogenes genes contributing to intracellular replication by expression profiling and mutant screening. J. Bacteriol. 188, 556–568 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kendall, M. M., Gruber, C. C., Parker, C. T. & Sperandio, V. Ethanolamine controls expression of genes encoding components involved in interkingdom signaling and virulence in enterohemorrhagic Escherichia coli O157:H7. mBio 3, 00050-12 (2012).

    Article  CAS  Google Scholar 

  51. Anderson, C. J., Clark, D. E., Adli, M. & Kendall, M. M. Ethanolamine signaling promotes Salmonella niche recognition and adaptation during infection. PLoS Pathog. 11, e1005278 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  53. 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).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  54. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Hsiao, A. et al. Members of the human gut microbiota involved in recovery from Vibrio cholerae infection. Nature 515, 423–426 (2014).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  56. Hughes, D. T. et al. Chemical sensing in mammalian host–bacterial commensal associations. Proc. Natl Acad. Sci. USA 107, 9831–9836 (2010).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  57. Bachmann, V. et al. Bile salts modulate the mucin-activated type VI secretion system of pandemic Vibrio cholerae. PLoS Negl. Trop. Dis. 9, e0004031 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Hörger, S., Schultheiss, G. & Diener, M. Segment-specific effects of epinephrine on ion transport in the colon of the rat. Am. J. Physiol. 275, G1367–G1376 (1998).

    PubMed  Google Scholar 

  59. Yano, J. M. et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 161, 264–276 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Asano, Y. et al. Critical role of gut microbiota in the production of biologically active, free catecholamines in the gut lumen of mice. Am. J. Physiol. Gastrointest. Liver Physiol. 303, G1288–G1295 (2012).

    Article  CAS  PubMed  Google Scholar 

  61. Furness, J. B. Types of neurons in the enteric nervous system. J. Auton. Nerv. Syst. 81, 87–96 (2000).

    Article  CAS  PubMed  Google Scholar 

  62. Curtis, M. M. & Sperandio, V. A complex relationship: the interaction among symbiotic microbes, invading pathogens, and their mammalian host. Mucosal Immunol. 4, 133–138 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Moreira, C. G., Weinshenker, D. & Sperandio, V. QseC mediates Salmonella enterica serovar Typhimurium virulence in vitro and in vivo. Infect. Immun. 78, 914–926 (2010).

    Article  CAS  PubMed  Google Scholar 

  64. Sperandio, V., Torres, A. G., Jarvis, B., Nataro, J. P. & Kaper, J. B. Bacteria–host communication: the language of hormones. Proc. Natl Acad. Sci. USA 100, 8951–8956 (2003). This paper describes how signals from the microbiota and host converge to enhance virulence in enteric pathogens.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  65. Nakano, M., Takahashi, A., Sakai, Y. & Nakaya, Y. Modulation of pathogenicity with norepinephrine related to the type III secretion system of Vibrio parahaemolyticus. J. Infect. Dis. 195, 1353–1360 (2007).

    Article  CAS  PubMed  Google Scholar 

  66. Clarke, M. B., Hughes, D. T., Zhu, C., Boedeker, E. C. & Sperandio, V. The QseC sensor kinase: a bacterial adrenergic receptor. Proc. Natl Acad. Sci. USA 103, 10420–10425 (2006).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  67. Reading, N. C., Rasko, D. A., Torres, A. G. & Sperandio, V. The two-component system QseEF and the membrane protein QseG link adrenergic and stress sensing to bacterial pathogenesis. Proc. Natl Acad. Sci. USA 106, 5889–5894 (2009).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  68. Seksik, P. et al. Alterations of the dominant faecal bacterial groups in patients with Crohn's disease of the colon. Gut 52, 237–242 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Gophna, U., Sommerfeld, K., Gophna, S., Doolittle, W. F. & Veldhuyzen van Zanten, S. J. Differences between tissue-associated intestinal microfloras of patients with Crohn's disease and ulcerative colitis. J. Clin. Microbiol. 44, 4136–4141 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Baumgart, M. et al. Culture independent analysis of ileal mucosa reveals a selective increase in invasive Escherichia coli of novel phylogeny relative to depletion of Clostridiales in Crohn's disease involving the ileum. ISME J. 1, 403–418 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Walker, A. W. et al. High-throughput clone library analysis of the mucosa-associated microbiota reveals dysbiosis and differences between inflamed and non-inflamed regions of the intestine in inflammatory bowel disease. BMC Microbiol. 11, 7 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Gevers, D. et al. The treatment-naive microbiome in new-onset Crohn's disease. Cell Host Microbe 15, 382–392 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Chiodini, R. J. et al. Microbial population differentials between mucosal and submucosal intestinal tissues in advanced Crohn's disease of the ileum. PLoS ONE 10, e0134382 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Lupp, C. et al. Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae. Cell Host Microbe 2, 119–129; corrigendum 2, 204 (2007). This paper reported that the induction of inflammation in the host disrupts the microbiota and promotes a bloom of Enterobacteriaceae.

    Article  CAS  PubMed  Google Scholar 

  75. Garrett, W. S. et al. Enterobacteriaceae act in concert with the gut microbiota to induce spontaneous and maternally transmitted colitis. Cell Host Microbe 8, 292–300 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Raffatellu, M. et al. Simian immunodeficiency virus-induced mucosal interleukin-17 deficiency promotes Salmonella dissemination from the gut. Nature Med. 14, 421–428 (2008).

    Article  CAS  PubMed  Google Scholar 

  77. Godinez, I. et al. T cells help to amplify inflammatory responses induced by Salmonella enterica serotype Typhimurium in the intestinal mucosa. Infect. Immun. 76, 2008–2017 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Pickard, J. M. et al. Rapid fucosylation of intestinal epithelium sustains host–commensal symbiosis in sickness. Nature 514, 638–641 (2014). This paper showed that cytokines that are induced by enteric infection promote fucosylation in the host.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  79. Pham, T. A. et al. Epithelial IL-22RA1-mediated fucosylation promotes intestinal colonization resistance to an opportunistic pathogen. Cell Host Microbe 16, 504–516 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Sonnenburg, J. L. et al. Glycan foraging in vivo by an intestine-adapted bacterial symbiont. Science 307, 1955–1959 (2005).

    Article  CAS  PubMed  ADS  Google Scholar 

  81. Ansong, C. et al. Studying Salmonellae and Yersiniae host–pathogen interactions using integrated 'omics and modeling. Curr. Top. Microbiol. Immunol. 363, 21–41 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Harper, R. W. et al. Differential regulation of dual NADPH oxidases/peroxidases, Duox1 and Duox2, by Th1 and Th2 cytokines in respiratory tract epithelium. FEBS Lett. 579, 4911–4917 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Haberman, Y. et al. Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature. J. Clin. Invest. 124, 3617–3633 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Salzman, A. et al. Induction and activity of nitric oxide synthase in cultured human intestinal epithelial monolayers. Am. J. Physiol. 270, G565–G573 (1996).

    CAS  PubMed  Google Scholar 

  85. Palmer, R. M., Rees, D. D., Ashton, D. S. & Moncada, S. L-arginine is the physiological precursor for the formation of nitric oxide in endothelium-dependent relaxation. Biochem. Biophys. Res. Commun. 153, 1251–1256 (1988).

    Article  CAS  PubMed  Google Scholar 

  86. Lundberg, J. O., Weitzberg, E., Lundberg, J. M. & Alving, K. Intragastric nitric oxide production in humans: measurements in expelled air. Gut 35, 1543–1546 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Singer, I. I. et al. Expression of inducible nitric oxide synthase and nitrotyrosine in colonic epithelium in inflammatory bowel disease. Gastroenterology 111, 871–885 (1996).

    Article  CAS  PubMed  Google Scholar 

  88. Enocksson, A., Lundberg, J., Weitzberg, E., Norrby-Teglund, A. & Svenungsson, B. Rectal nitric oxide gas and stool cytokine levels during the course of infectious gastroenteritis. Clin. Diagn. Lab. Immunol. 11, 250–254 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Bai, P. et al. Protein tyrosine nitration and poly(ADP-ribose) polymerase activation in N-methyl-N-nitro-N-nitrosoguanidine-treated thymocytes: implication for cytotoxicity. Toxicol. Lett. 170, 203–213 (2007).

    Article  CAS  PubMed  Google Scholar 

  90. Dudhgaonkar, S. P., Tandan, S. K., Kumar, D., Raviprakash, V. & Kataria, M. Influence of simultaneous inhibition of cyclooxygenase-2 and inducible nitric oxide synthase in experimental colitis in rats. Inflammopharmacology 15, 188–195 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. Winter, S. E. et al. Host-derived nitrate boosts growth of E. coli in the inflamed gut. Science 339, 708–711 (2013). This study revealed that nitrate respiration drives the expansion of commensal E. coli during colitis.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  92. Winter, S. E. & Baumler, A. J. Why related bacterial species bloom simultaneously in the gut: principles underlying the 'like will to like' concept. Cell. Microbiol. 16, 179–184 (2014).

    Article  CAS  PubMed  Google Scholar 

  93. Rivera-Chávez, F. & Baumler, A. J. The pyromaniac inside you: Salmonella metabolism in the host gut. Annu. Rev. Microbiol. 69, 31–48 (2015).

    Article  PubMed  CAS  Google Scholar 

  94. Galán, J. E. & Curtiss, R., III. Cloning and molecular characterization of genes whose products allow Salmonella typhimurium to penetrate tissue culture cells. Proc. Natl Acad. Sci. USA 86, 6383–6387 (1989).

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  95. Hensel, M. et al. Simultaneous identification of bacterial virulence genes by negative selection. Science 269, 400–403 (1995).

    Article  CAS  PubMed  ADS  Google Scholar 

  96. Tsolis, R. M., Adams, L. G., Ficht, T. A. & Baumler, A. J. Contribution of Salmonella typhimurium virulence factors to diarrheal disease in calves. Infect. Immun. 67, 4879–4885 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Coburn, B., Li, Y., Owen, D., Vallance, B. A. & Finlay, B. B. Salmonella enterica serovar Typhimurium pathogenicity island 2 is necessary for complete virulence in a mouse model of infectious enterocolitis. Infect. Immun. 73, 3219–3227 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Stecher, B. et al. Salmonella enterica serovar Typhimurium exploits inflammation to compete with the intestinal microbiota. PLoS Biol. 5, 2177–2189 (2007).

    Article  CAS  PubMed  Google Scholar 

  100. Lawley, T. D. et al. Host transmission of Salmonella enterica serovar Typhimurium is controlled by virulence factors and indigenous intestinal microbiota. Infect. Immun. 76, 403–416 (2008).

    Article  CAS  PubMed  Google Scholar 

  101. Lopez, C. A. et al. Phage-mediated acquisition of a type III secreted effector protein boosts growth of Salmonella by nitrate respiration. mBio 3, e00143-12 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Lopez, C. A., Rivera-Chavez, F., Byndloss, M. X. & Baumler, A. J. The periplasmic nitrate reductase NapABC supports luminal growth of Salmonella enterica serovar Typhimurium during colitis. Infect. Immun. 83, 3470–3478 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Levitt, M. D., Furne, J., Springfield, J., Suarez, F. & DeMaster, E. Detoxification of hydrogen sulfide and methanethiol in the cecal mucosa. J. Clin. Invest. 104, 1107–1114 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Harris, J. C., Dupont, H. L. & Hornick, R. B. Fecal leukocytes in diarrheal illness. Ann. Intern. Med. 76, 697–703 (1972).

    Article  CAS  PubMed  Google Scholar 

  105. Loetscher, Y. et al. Salmonella transiently reside in luminal neutrophils in the inflamed gut. PLoS ONE 7, e34812 (2012).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  106. Winter, S. E. et al. Gut inflammation provides a respiratory electron acceptor for Salmonella. Nature 467, 426–429 (2010). This paper showed that tetrathionate is a unique electron acceptor that is induced through inflammation that promotes expansion of S . Typhimurium.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  107. Muller, H. J. Partial list of biological institutes and biologists doing experimental work in Russia at the present time. Science 57, 472–473 (1923).

    Article  CAS  PubMed  ADS  Google Scholar 

  108. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Behnsen, J. et al. The cytokine IL-22 promotes pathogen colonization by suppressing related commensal bacteria. Immunity 40, 262–273 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Goetz, D. H. et al. The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition. Mol. Cell 10, 1033–1043 (2002).

    Article  CAS  PubMed  Google Scholar 

  111. Flo, T. H. et al. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 432, 917–921 (2004).

    Article  CAS  PubMed  ADS  Google Scholar 

  112. Deriu, E. et al. Probiotic bacteria reduce Salmonella typhimurium intestinal colonization by competing for iron. Cell Host Microbe 14, 26–37 (2013). This paper revealed that probiotic strains of E. coli restrict infection of the gut with S . Typhimurium by competing for sources of iron.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Cascales, E. et al. Colicin biology. Microbiol. Mol. Biol. Rev. 71, 158–229 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Guterman, S. K. Colicin B: mode of action and inhibition by enterochelin. J. Bacteriol. 114, 1217–1224 (1973).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Cardelli, J. & Konisky, J. Isolation and characterization of an Escherichia coli mutant tolerant to colicins Ia and Ib. J. Bacteriol. 119, 379–385 (1974).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Patzer, S. I., Baquero, M. R., Bravo, D., Moreno, F. & Hantke, K. The colicin G, H and X determinants encode microcins M and H47, which might utilize the catecholate siderophore receptors FepA, Cir, Fiu and IroN. Microbiology 149, 2557–2570 (2003).

    Article  CAS  PubMed  Google Scholar 

  117. Hooper, L. V. et al. Molecular analysis of commensal host–microbial relationships in the intestine. Science 291, 881–884 (2001). This was the first report to show that the microbiota can change the expression of mammalian genes to modulate the immune system of the host.

    Article  CAS  PubMed  ADS  Google Scholar 

  118. Wu, M. et al. Genetic determinants of in vivo fitness and diet responsiveness in multiple human gut Bacteroides. Science 350, aac5992 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Earle, K. A. et al. Quantitative imaging of gut microbiota spatial organization. Cell Host Microbe 18, 478–488 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Bouslimani, A. et al. Molecular cartography of the human skin surface in 3D. Proc. Natl Acad. Sci. USA 112, E2120–E2129 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. 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 

  122. Lau, W., Fischbach, M. A., Osbourn, A. & Sattely, E. S. Key applications of plant metabolic engineering. PLoS Biol. 12, e1001879 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Marcobal, A. et al. Metabolome progression during early gut microbial colonization of gnotobiotic mice. Sci. Rep. 5, 11589 (2015).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  124. Rath, C. M. et al. Molecular analysis of model gut microbiotas by imaging mass spectrometry and nanodesorption electrospray ionization reveals dietary metabolite transformations. Anal. Chem. 84, 9259–9267 (2012). This study used imaging mass spectrometry to map differences in the gut metabolic landscape that are promoted by the microbiota.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Dorrestein, P. C., Mazmanian, S. K. & Knight, R. Finding the missing links among metabolites, microbes, and the host. Immunity 40, 824–832 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Antunes, L. C. et al. Antivirulence activity of the human gut metabolome. mBio 5, e01183-14 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Antunes, L. C. et al. Impact of Salmonella infection on host hormone metabolism revealed by metabolomics. Infect. Immun. 79, 1759–1769 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Buffie, C. G. et al. Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile. Nature 517, 205–208 (2015). This paper showed that the introduction of a single species of bacteria that can produce secondary bile salts confers the host with resistance to the expansion of C. difficile after treatment with antibiotics.

    Article  CAS  ADS  PubMed  Google Scholar 

  129. Koenigsknecht, M. J. & Young, V. B. Faecal microbiota transplantation for the treatment of recurrent Clostridium difficile infection: current promise and future needs. Curr. Opin. Gastroenterol. 29, 628–632 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Sekirov, I. et al. Antibiotic-induced perturbations of the intestinal microbiota alter host susceptibility to enteric infection. Infect. Immun. 76, 4726–4736 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Louis, E., Libioulle, C., Reenaers, C., Belaiche, J. & Georges, M. Genomics of inflammatory bowel diseases: basis for a new molecular classification and new therapeutic strategies of these diseases [in French]. Rev. Med. Liege 64 S1, 24–28 (2009).

    CAS  PubMed  Google Scholar 

  132. Meynell, G. G. Antibacterial mechanisms of the mouse gut. II. The role of Eh and volatile fatty acids in the normal gut. Br. J. Exp. Pathol. 44, 209–219 (1963).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Donohoe, D. R., Wali, A., Brylawski, B. P. & Bultman, S. J. Microbial regulation of glucose metabolism and cell-cycle progression in mammalian colonocytes. PLoS ONE 7, e46589 (2012).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  134. Atarashi, K., Umesaki, Y. & Honda, K. Microbiotal influence on T cell subset development. Semin. Immunol. 23, 146–153 (2011).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  ADS  Google Scholar 

  136. Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450 (2013).

    Article  CAS  ADS  PubMed  Google Scholar 

  137. Spees, A. M. et al. Streptomycin-induced inflammation enhances Escherichia coli gut colonization through nitrate respiration. mBio 4, e00430-13 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  138. Itoh, K. & Freter, R. Control of Escherichia coli populations by a combination of indigenous clostridia and lactobacilli in gnotobiotic mice and continuous-flow cultures. Infect. Immun. 57, 559–565 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Wells, J. E. & Hylemon, P. B. Identification and characterization of a bile acid 7α-dehydroxylation operon in Clostridium sp. strain TO-931, a highly active 7α-dehydroxylating strain isolated from human feces. Appl. Environ. Microbiol. 66, 1107–1113 (2000).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  140. Wilson, K. H. Efficiency of various bile salt preparations for stimulation of Clostridium difficile spore germination. J. Clin. Microbiol. 18, 1017–1019 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Sorg, J. A. & Sonenshein, A. L. Bile salts and glycine as cogerminants for Clostridium difficile spores. J. Bacteriol. 190, 2505–2512 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Theriot, C. M. et al. Antibiotic-induced shifts in the mouse gut microbiome and metabolome increase susceptibility to Clostridium difficile infection. Nature Commun. 5, 3114 (2014).

    Article  ADS  CAS  Google Scholar 

  143. Weingarden, A. R. et al. Microbiota transplantation restores normal fecal bile acid composition in recurrent Clostridium difficile infection. Am. J. Physiol. Gastrointest. Liver Physiol. 306, G310–G319 (2014).

    Article  CAS  PubMed  Google Scholar 

  144. Bernstein, H., Bernstein, C., Payne, C. M., Dvorakova, K. & Garewal, H. Bile acids as carcinogens in human gastrointestinal cancers. Mutat. Res. 589, 47–65 (2005).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Work in the V.S. laboratory is supported by US National Institutes of Health (NIH) grants AI053067, AI077613, AI05135 and AI114511. Work in the A.J.B. laboratory is supported by US Department of Agriculture grant 2015-67015-22930 and NIH grants AI044170, AI096528, AI112445, AI114922 and AI117940. The contents of this Review are solely the responsibility of the authors and do not necessarily represent the official views of the NIH National Institute of Allergy and Infectious Diseases.

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Bäumler, A., Sperandio, V. Interactions between the microbiota and pathogenic bacteria in the gut. Nature 535, 85–93 (2016). https://doi.org/10.1038/nature18849

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