Key Points
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Antibiotic treatment disrupts the native intestinal microbiota and favours infection with and the proliferation of antibiotic-resistant intestinal pathogens. Clinically important antibiotic-resistant pathogens include vancomycin-resistant Enterococcus spp., various Enterobacteriaceae and Clostridium difficile.
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The intestinal microbiota influences the development, the maintenance and the function of the innate and adaptive immune systems. Host immune function is decreased in the intestines following antibiotic therapy, and antibiotic-treated hosts are susceptible to intestinal infection.
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Microbiota-derived bacterial populations and products that enhance immune defence against intestinal pathogens are being identified. However, the precise bacterial sources of many immunomodulatory molecules remain unclear and, conversely, the molecular mechanisms by which most probiotics restore immunity have yet to be elucidated.
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In addition to indirectly enhancing colonization resistance by stimulating host immune defences, bacterial populations can directly suppress intestinal pathogens by competitive exclusion and by antimicrobial activities. The commensal populations that are responsible for direct antagonism of pathogens and indirect, immune-mediated colonization resistance may be closely related and difficult to distinguish.
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Microbiota-derived bacterial populations and products, a subset of which enhance immune defence, can also promote intestinal inflammation, whereas other microbiota components restrain effector responses and promote tolerance.
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Manipulation of the intestinal microbiota to prevent and to treat some intestinal infections, such as C. difficile, shows promise in human patients and animal models of infection. However, the specific contributions of the individual bacterial populations that constitute the consortia transferred in such studies remain mostly undefined.
Abstract
Commensal bacteria inhabit mucosal and epidermal surfaces in mice and humans, and have effects on metabolic and immune pathways in their hosts. Recent studies indicate that the commensal microbiota can be manipulated to prevent and even to cure infections that are caused by pathogenic bacteria, particularly pathogens that are broadly resistant to antibiotics, such as vancomycin-resistant Enterococcus faecium, Gram-negative Enterobacteriaceae and Clostridium difficile. In this Review, we discuss how immune- mediated colonization resistance against antibiotic-resistant intestinal pathogens is influenced by the composition of the commensal microbiota. We also review recent advances characterizing the ability of different commensal bacterial families, genera and species to restore colonization resistance to intestinal pathogens in antibiotic-treated hosts.
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References
Sensakovic, J. W. & Smith, L. G. Oral antibiotic treatment of infectious diseases. Med. Clin. North. Am. 85, 115–123, vii (2001).
Chung, H. et al. Gut immune maturation depends on colonization with a host-specific microbiota. Cell 149, 1578–1593 (2012).
Diehl, G. E. et al. Microbiota restricts trafficking of bacteria to mesenteric lymph nodes by CX3CR1hi cells. Nature 494, 116–120 (2013). This study shows that the normal microbiota stimulates MYD88-dependent pathways to restrict the delivery of commensal bacteria to the mesenteric lymph nodes.
Duan, J., Chung, H., Troy, E. & Kasper, D. L. Microbial colonization drives expansion of IL-1 receptor 1-expressing and IL-17-producing γ/δ T cells. Cell Host Microbe 7, 140–150 (2010).
Farache, J. et al. Luminal bacteria recruit CD103+ dendritic cells into the intestinal epithelium to sample bacterial antigens for presentation. Immunity 38, 581–595 (2013).
Olszak, T. et al. Microbial exposure during early life has persistent effects on natural killer T cell function. Science 336, 489–493 (2012).
Wingender, G. et al. Intestinal microbes affect phenotypes and functions of invariant natural killer T cells in mice. Gastroenterology 143, 418–428 (2012).
Hand, T. W. et al. Acute gastrointestinal infection induces long-lived microbiota-specific T cell responses. Science 337, 1553–1556 (2012). This study shows that pathogen-induced destruction of the intestinal epithelium can result in aberrant T cell responses against bystander commensal microorganisms.
Lathrop, S. K. et al. Peripheral education of the immune system by colonic commensal microbiota. Nature 478, 250–254 (2011).
Macpherson, A. J. & Uhr, T. Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science 303, 1662–1665 (2004). This study shows that immune responses to intestinal commensal bacteria remain restricted to the intestines and that they induce the production of IgA, which helps to prevent mucosal penetration by luminal bacteria.
Donskey, C. J. Antibiotic regimens and intestinal colonization with antibiotic-resistant Gram-negative bacilli. Clin. Infect. Dis. 43 (Suppl. 2), S62–S69 (2006).
Stiefel, U. & Donskey, C. J. The role of the intestinal tract as a source for transmission of nosocomial pathogens. Curr. Infect. Dis. Rep. 6, 420–425 (2004).
McDonald, L. C. et al. An epidemic, toxin gene-variant strain of Clostridium difficile. N. Engl. J. Med. 353, 2433–2441 (2005).
Owens, R. C. et al. Antimicrobial-associated risk factors for Clostridium difficile infection. Clin. Infect. Dis. 46, S19–31 (2008).
Spigaglia, P. Barbanti, F., Mastrantonio, P. & European Study Group on Clostridium difficile (ESGCD). Multidrug resistance in European Clostridium difficile clinical isolates. J. Antimicrob. Chemother. 66, 2227–2234 (2011).
Jernberg, C., Löfmark, S., Edlund, C. & Jansson, J. K. Long-term ecological impacts of antibiotic administration on the human intestinal microbiota. ISME J. 1, 56–66 (2007).
Buffie, C. G. et al. Profound alterations of intestinal microbiota following a single dose of clindamycin results in sustained susceptibility to Clostridium difficile-induced colitis. Infect. Immun. 80, 62–73 (2012).
Johnson, S. & Gerding, D. N. Clostridium difficile-associated diarrhea. Clin. Infect. Dis. 26, 1027–1036 (1998).
Chen, X. et al. A mouse model of Clostridium difficile-associated disease. Gastroenterology 135, 1984–1992 (2008).
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).
Reeves, A. E. et al. The interplay between microbiome dynamics and pathogen dynamics in a murine model of Clostridium difficile infection. Gut Microbes 2, 145–158 (2011).
Hasegawa, M. et al. Nucleotide-binding oligomerization domain 1 mediates recognition of Clostridium difficile and induces neutrophil recruitment and protection against the pathogen. J. Immunol. 186, 4872–4880 (2011).
Jarchum, I. et al. Critical role for MyD88-mediated neutrophil recruitment during Clostridium difficile colitis. Infect. Immun. 80, 2989–2996 (2012).
Hasegawa, M. et al. Protective role of commensals against Clostridium difficile infection via an IL-1β-mediated positive-feedback loop. J. Immunol. 189, 3085–3091 (2012).
Jarchum, I., Liu, M., Lipuma, L. & Pamer, E. G. Toll-like receptor 5 stimulation protects mice from acute Clostridium difficile colitis. Infect. Immun. 79, 1498–1503 (2011).
Kyne, L., Warny, M., Qamar, A. & Kelly, C. P. Asymptomatic carriage of Clostridium difficile and serum levels of IgG antibody against toxin A. N. Engl. J. Med. 342, 390–397 (2000).
Lowy, I. et al. Treatment with monoclonal antibodies against Clostridium difficile toxins. N. Engl. J. Med. 362, 197–205 (2010).
Mundy, L. M., Sahm, D. F. & Gilmore, M. Relationships between enterococcal virulence and antimicrobial resistance. Clin. Microbiol. Rev. 13, 513–522 (2000).
Arias, C. A. & Murray, B. E. The rise of the Enterococcus: beyond vancomycin resistance. Nature Rev. Microbiol. 10, 266–278 (2012).
Donskey, C. J. et al. Effect of antibiotic therapy on the density of vancomycin-resistant enterococci in the stool of colonized patients. N. Engl. J. Med. 343, 1925–1932 (2000).
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). This study shows that marked proliferation of VRE in the intestinal microbiota precedes bacteraemia in susceptible patients.
Taur, Y. et al. Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation. Clin. Infect. Dis. 55, 905–914 (2012).
Brandl, K. et al. Vancomycin-resistant enterococci exploit antibiotic-induced innate immune deficits. Nature 455, 804–807 (2008).
Kinnebrew, M. A. et al. Bacterial flagellin stimulates Toll-like receptor 5-dependent defense against vancomycin-resistant Enterococcus infection. J. Infect. Dis. 201, 534–543 (2010).
Brandl, K. et al. MyD88-mediated signals induce the bactericidal lectin RegIIIγ and protect mice against intestinal Listeria monocytogenes infection. J. Exp. Med. 204, 1891–1900 (2007).
Mundy, R. et al. Citrobacter rodentium of mice and man. Cell. Microbiol. 7, 1697–1706 (2005).
Ayabe, T. et al. Secretion of microbicidal α-defensins by intestinal Paneth cells in response to bacteria. Nature Immunol. 1, 113–118 (2000).
Vaishnava, S. et al. Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface. Proc. Natl Acad. Sci. USA 105, 20858–20863 (2008). This study definitively shows that MYD88-mediated signalling in epithelial cells drives expression of antimicrobial proteins, such as REGIIIγ.
Chu, H. et al. Human α-defensin 6 promotes mucosal innate immunity through self-assembled peptide nanonets. Science 337, 477–481 (2012).
Sotolongo, J. et al. Host innate recognition of an intestinal bacterial pathogen induces TRIF-dependent protective immunity. J. Exp. Med. 208, 2705–2716 (2011).
Niess, J. H. et al. CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 307, 254–258 (2005). This seminal study identifies the CX 3 CR1+ subset of intestinal DCs and characterizes their ability to sample commensal antigens in the intestinal lumen from the lamina propria by extending transepithelial dendrites.
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). This study identifies polysaccharide A from the intestinal commensal bacterium Bacteroides fragilis as a bacteria-derived molecule that can induce and modulate host immune development in the intestines.
Elinav, E. et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell. 145, 745–757 (2011). This study shows that inflammasomes can shape the composition of the colonic microbiota and that deficiency of the NLRP6 component can lead to a dysbiotic flora that can drive intestinal inflammation.
Sonnenburg, J. L., Chen, C. T. & Gordon, J. I. Genomic and metabolic studies of the impact of probiotics on a model gut symbiont and host. PLoS Biol. 4, e413 (2006).
Abt, M. C. et al. Commensal bacteria calibrate the activation threshold of innate antiviral immunity. Immunity. 37, 158–170 (2012). This study shows that commensal bacteria-derived signals enhance antiviral immunity.
Ferreira, R. B. et al. The intestinal microbiota plays a role in Salmonella-induced colitis independent of pathogen colonization. PLoS ONE 6, e20338 (2011).
de Sablet, T. et al. Human microbiota-secreted factors inhibit shiga toxin synthesis by enterohemorrhagic Escherichia coli O157:H7. Infect. Immun. 77, 783–790 (2009).
Kamada, N. et al. Regulated virulence controls the ability of a pathogen to compete with the gut microbiota. Science 336, 1325–1329 (2012).
Ubeda, C. et al. Intestinal microbiota containing Barnesiella cures vancomycin-resistant Enterococcus faecium colonization. Infect. Immun. 81, 965–973 (2013).
Pultz, N. J. et al. Mechanisms by which anaerobic microbiota inhibit the establishment in mice of intestinal colonization by vancomycin-resistant Enterococcus. J. Infect. Dis. 191, 949–956 (2005).
Kinnebrew, M. A. et al. Interleukin 23 production by intestinal CD103+CD11b+ dendritic cells in response to bacterial flagellin enhances mucosal innate immune defense. Immunity 36, 276–287 (2012). This study shows that CD103+ DCs in the lamina propria respond to flagellin by rapidly and transiently producing IL-23.
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).
Kankainen, M. et al. Comparative genomic analysis of Lactobacillus rhamnosus GG reveals pili containing a human- mucus binding protein. Proc. Natl Acad. Sci. USA 106, 17193–17198 (2009).
Reunanen, J. et al. Characterization of the SpaCBA pilus fibers in the probiotic Lactobacillus rhamnosus GG. Appl. Environ. Microbiol. 78, 2337–2344 (2012).
Yan, F. et al. Soluble proteins produced by probiotic bacteria regulate intestinal epithelial cell survival and growth. Gastroenterology 132, 562–575 (2007).
Banerjee, P., Merkel, G. J. & Bhunia, A. K. Lactobacillus delbrueckii ssp. bulgaricus B-30892 can inhibit cytotoxic effects and adhesion of pathogenic Clostridium difficile to Caco-2 cells. Gut. Pathog. 1, 8 (2009).
Douillard, F. P. et al. Comparative genomic and functional analysis of Lactobacillus casei and Lactobacillus rhamnosus strains marketed as probiotics. Appl. Environ. Microbiol. 79, 1923–1933 (2013).
Karlsson, H., Larsson, P., Wold, E. & Rudin, A. Pattern of cytokine responses to Gram-positive and Gram-negative commensal bacteria is profoundly changed when monocytes differentiate into dendritic cells Infect. Immun. 72, 2671–2678 (2004).
Wullt, M., Hagslätt, M. L. & Odenholt, I. Lactobacillus plantarum 299v for the treatment of recurrent Clostridium difficile-associated diarrhoea: a double-blind, placebo-controlled trial. Scand. J. Infect. Dis. 35, 365–367 (2003).
Thompson, C. L. et al. 'Candidatus Arthromitus' revised: segmented filamentous bacteria in arthropod guts are members of Lachnospiraceae. Environ. Microbiol. 14, 1454–1465 (2012).
Sczesnak, A. et al. The genome of th17 cell-inducing segmented filamentous bacteria reveals extensive auxotrophy and adaptations to the intestinal environment. Cell Host Microbe 10, 260–272 (2011).
Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011). This study identifies a consortium of Clostridia commensal bacteria that are collectively sufficient for the induction of CD4+ T Reg cells as well as resistance to colitis and allergic responses in mice.
Guinane, C. M. et al. Genome sequence of Bifidobacterium breve DPC 6330, a strain isolated from the human intestine. J. Bacteriol. 193, 6799–6800 (2011).
Huang, J. Y., Lee, S. M. & Mazmanian, S. K. The human commensal Bacteroides fragilis binds intestinal mucin. Anaerobe 17, 137–141 (2011).
Talham, G. L., Jiang, H. Q., Bos, N. A. & Cebra, J. J. Segmented filamentous bacteria are potent stimuli of a physiologically normal state of the murine gut mucosal immune system. Infect. Immun. 67, 1992–2000 (1999).
Ivanov, I. I. et al. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe 4, 337–349 (2008).
Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009). This study identifies that SFB are sufficient for the induction of CD4+ T H 17 cells and for resistance to C. rodentium infection in mice.
Gaboriau-Routhiau, V. et al. The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 31, 677–689 (2009).
Shaw, M. H., Kamada, N., Kim, Y. G. & Núñez, G. Microbiota-induced IL-1β, but not IL-6, is critical for the development of steady-state TH17 cells in the intestine. J. Exp. Med. 209, 251–258 (2012).
Stepankova, R. et al. Segmented filamentous bacteria in a defined bacterial cocktail induce intestinal inflammation in SCID mice reconstituted with CD45RBhigh CD4+ T cells. Inflamm. Bowel. Dis. 13, 1202–1211 (2007).
Kondepudi, K. K. et al. Prebiotic-non-digestible oligosaccharides preference of probiotic bifidobacteria and antimicrobial activity against Clostridium difficile. Anaerobe 18, 489–497 (2012).
Turroni, F. et al. Diversity of bifidobacteria within the infant gut microbiota. PLoS ONE 7, e36957 (2012).
Schell, M. A. et al. The genome sequence of Bifidobacterium longum reflects its adaptation to the human gastrointestinal tract. Proc. Natl Acad. Sci. USA 99, 14422–14427 (2002).
Trejo, F. M., Minnaard, J., Perez, P. F. & De Antoni, G. L. Inhibition of Clostridium difficile growth and adhesion to enterocytes by Bifidobacterium supernatants. Anaerobe 12, 186–193 (2006).
Schoster, A. et al. In vitro inhibition of Clostridium difficile and Clostridium perfringens by commercial probiotic strains. Anaerobe 20, 36–41 (2013).
Hütt, P. et al. Antagonistic activity of probiotic lactobacilli and bifidobacteria against entero- and uropathogens. J. Appl. Microbiol. 100, 1324–1332 (2006).
Gagnon, M., Kheadr, E. E., Le Blay, G. & Fliss, I. In vitro inhibition of Escherichia coli O157:H7 by bifidobacterial strains of human origin. Int. J. Food Microbiol. 92, 69–78 (2004).
Fukuda, S. et al. Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature 469, 543–547 (2011).
Fukuda, S. et al. Acetate-producing bifidobacteria protect the host from enteropathogenic infection via carbohydrate transporters. Gut Microbes 3, 449–454 (2012).
Fanning, S. et al. Bifidobacterial surface-exopolysaccharide facilitates commensal-host interaction through immune modulation and pathogen protection. Proc. Natl Acad. Sci. USA 109, 2108–2113 (2012).
Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature. 486, 207–214 (2012).
Garrett, W. S. et al. Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell 131, 33–45 (2007).
Kang, S. S. et al. An antibiotic-responsive mouse model of fulminant ulcerative colitis. PLoS Med. 5, e41 (2008).
Chen, G. Y., Shaw, M. H., Redondo, G. & Núñez, G. The innate immune receptor Nod1 protects the intestine from inflammation-induced tumorigenesis. Cancer. Res. 68, 10060–10067 (2008).
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).
Bloom, S. M. et al. Commensal Bacteroides species induce colitis in host-genotype-specific fashion in a mouse model of inflammatory bowel disease. Cell Host Microbe 9, 390–403 (2011).
Henao-Mejia, J. et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482, 179–185 (2012).
Devkota, S. et al. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10−/− mice. Nature 487, 104–108 (2012).
Morgan, X. C. et al. Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol. 13, R79 (2012).
Lupp, C. et al. Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae. Cell Host Microbe 2, 119–129 (2007).
Stecher, B. et al. Salmonella enterica serovar typhimurium exploits inflammation to compete with the intestinal microbiota. PLoS Biol. 5, 2177–2189 (2007).
Winter, S. E. et al. Gut inflammation provides a respiratory electron acceptor for Salmonella. Nature 467, 426–429 (2010).
Winter, S. E. et al. Host-derived nitrate boosts growth of E. coli in the inflamed gut. Science 339, 708–711 (2013). This study shows that intestinal inflammation can promote the expansion of low abundance populations of Proteobacteria.
Round, J. L. et al. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332, 974–977 (2011).
Mazmanian, S. K., Round, J. L. & Kasper, D. L. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453, 620–625 (2008).
Dessein, R. et al. Toll-like receptor 2 is critical for induction of Reg3β expression and intestinal clearance of Yersinia pseudotuberculosis. Gut 58, 771–776 (2009).
Chow, J. & Mazmanian, S. K. A pathobiont of the microbiota balances host colonization and intestinal inflammation. Cell Host Microbe 7, 265–276 (2010).
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).
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).
Atarashi, K. et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500, 232–236 (2013).
Negishi, H. et al. Essential contribution of IRF3 to intestinal homeostasis and microbiota-mediated Tslp gene induction. Proc. Natl Acad. Sci. USA 109, 21016–21021 (2012).
Zhang, F. et al. Should we standardize the 1,700-year-old fecal microbiota transplantation? Am. J. Gastroenterol. 107, 1755 (2012).
Bakken, J. S. et al. Treating Clostridium difficile infection with fecal microbiota transplantation. Clin. Gastroenterol. Hepatol. 9, 1044–1049 (2011).
Hamilton, M. J., Weingarden, A. R., Sadowsky, M. J. & Khoruts, A. Standardized frozen preparation for transplantation of fecal microbiota for recurrent Clostridium difficile infection. Am. J. Gastroenterol. 107, 761–767 (2012).
Hamilton, M. J. et al. High-throughput DNA sequence analysis reveals stable engraftment of gut microbiota following transplantation of previously frozen fecal bacteria Gut Microbes 4, 125–135 (2013).
van Nood, E. et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N. Engl. J. Med. 368, 407–415 (2013). This study shows that faecal microbiota transplantation is markedly more effective than standard antibiotic regimens for the treatment of recurrent C. difficile infection.
Tvede, M. & Rask-Madsen, J. Bacteriotherapy for chronic relapsing Clostridium difficile diarrhoea in six patients. Lancet 1, 1156–1160 (1989).
Petrof, E. O. et al. Stool substitute transplant therapy for the eradication of Clostridium difficile infection: 'RePOOPulating' the gut Microbiome 1, 3 (2013).
Lawley, T. D. et al. Targeted restoration of the intestinal microbiota with a simple, defined bacteriotherapy resolves relapsing Clostridium difficile disease in mice. PLoS Pathog. 8, e1002995 (2012).
Bohnhoff, M. & Miller, C. P. Enhanced susceptibility to Salmonella infection in streptomycin-treated mice. J. Infect. Dis. 111, 117–127 (1962).
van der Waaij, D. & Berghuis-de Vries, J. M. & 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).
Hentges, D. J. & Freter, R. In vivo and in vitro antagonism of intestinal bacteria against Shigella flexneri. I. Correlation between various tests. J. Infect. Dis. 110, 30–37 (1962).
Freter, R. In vivo and in vitro antagonism of intestinal bacteria against Shigella flexneri. II. The inhibitory mechanism. J. Infect. Dis. 110, 38–46 (1962).
Miller, C. P. & Bohnhoff, M. Changes in the mouse's enteric microflora associated with enhanced susceptibility to Salmonella infection following streptomycin treatment. J. Infect. Dis. 113, 59–66 (1963).
Bohnhoff, M., Miller, C. P. & Martin, W. R. Resistance of the mouse's intestinal tract to experimental Salmonella infection. I. Factors which interfere with the initiation of infection by oral inoculation. J. Exp. Med. 120, 805–816 (1964).
Bohnhoff, M., Miller, C. P. & Martin, W. R. Resistance of the mouse's intestinal tract to experimental Salmonella infection. II. Factors responsible for its loss following streptomycin treatment. J. Exp. Med. 120, 817–828 (1964).
Kobayashi, K. S. et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307, 731–734 (2005).
Cash, H. L., Whitham, C. V., Behrendt, C. L. & Hooper, L. V. Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 313, 1126–1130 (2006).
Zheng, Y. et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nature Med. 14, 282–289 (2008).
Chieppa, M., Rescigno, M., Huang, A. Y. & Germain, R. N. Dynamic imaging of dendritic cell extension into the small bowel lumen in response to epithelial cell TLR engagement. J. Exp. Med. 203, 2841–2852 (2006).
Rescigno, M., Rotta, G., Valzasina, B. & Ricciardi-Castagnoli, P. Dendritic cells shuttle microbes across gut epithelial monolayers. Immunobiology 204, 572–581 (2001).
Wei, M. et al. Mice carrying a knock-in mutation of Aicda resulting in a defect in somatic hypermutation have impaired gut homeostasis and compromised mucosal defense. Nature Immunol. 12, 264–270 (2011).
DePaolo, R. W. et al. A specific role for TLR1 in protective TH17 immunity during mucosal infection. J. Exp. Med. 209, 1437–1444 (2012).
Endt, K. et al. The microbiota mediates pathogen clearance from the gut lumen after non-typhoidal Salmonella diarrhea. PLoS Pathog. 6, e1001097 (2010).
Niess, J. H. & Adler, G. Enteric flora expands gut lamina propria CX3CR1+ dendritic cells supporting inflammatory immune responses under normal and inflammatory conditions. J. Immunol. 184, 2026–2037 (2010).
Mangan, P. R. et al. Transforming growth factor-β induces development of the TH17 lineage. Nature 441, 231–234 (2006).
Coombes, J. L. et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β and retinoic acid-dependent mechanism. J. Exp. Med. 204, 1757–1764 (2007).
Ghoreschi, K. et al. Generation of pathogenic TH17 cells in the absence of TGF-β signalling. Nature 467, 967–971 (2010).
Sun, C. M. et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J. Exp. Med. 204, 1775–1785 (2007).
Zhou, L. et al. TGF-β-induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORγt function. Nature 453, 236–240 (2008).
Chinen, T., Volchkov, P. Y., Chervonsky, A. V. & Rudensky, A. Y. A critical role for regulatory T cell-mediated control of inflammation in the absence of commensal microbiota. J. Exp. Med. 207, 2323–2330 (2010).
Sciumé, G. et al. Distinct requirements for T-bet in gut innate lymphoid cells. J. Exp. Med. 209, 2331–2338 (2012).
Sawa, S. et al. Lineage relationship analysis of RORγt+ innate lymphoid cells. Science 330, 665–669 (2010).
Spits, H. et al. Innate lymphoid cells — a proposal for uniform nomenclature. Nature Rev. Immunol. 13, 145–149 (2013).
Sonnenberg, G. F. et al. Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria. Science 336, 1321–1325 (2012).
Sonnenberg, G. F. et al. CD4+ lymphoid tissue-inducer cells promote innate immunity in the gut. Immunity 34, 122–134 (2011).
Satoh-Takayama, N. et al. Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense. Immunity 29, 958–970 (2008).
Sanos, S. L. et al. RORγt and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells. Nature Immunol. 10, 83–91 (2009).
Sonnenberg, G. F. & Artis, D. Innate lymphoid cell interactions with microbiota: implications for intestinal health and disease. Immunity 37, 601–610 (2012).
Ducluzeau, R., Dubos, F., Raibaud, P. & Abrams, G. D. Inhibition of Clostridium perfringens by an antibiotic substance produced by Bacillus licheniformis in the digestive tract of gnotobiotic mice: effect on other bacteria from the digestive tract. Antimicrob. Agents Chemother. 9, 20–25 (1976).
Honda, H. et al. Use of a continuous culture fermentation system to investigate the effect of GanedenBC30 (Bacillus coagulans GBI-30, 6086) supplementation on pathogen survival in the human gut microbiota. Anaerobe 17, 36–42 (2011).
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).
Rea, M. C. et al. Effect of broad- and narrow-spectrum antimicrobials on Clostridium difficile and microbial diversity in a model of the distal colon. Proc. Natl Acad. Sci. USA 108 (Suppl. 1), 4639–4644 (2011).
Rea, M. C. et al. Antimicrobial activity of lacticin 3,147 against clinical Clostridium difficile strains. J. Med. Microbiol. 56, 940–946 (2007).
Basler, M. et al. Type VI secretion requires a dynamic contractile phage tail-like structure. Nature 483, 182–186 (2012).
Basler, M., Ho, B. T. & Mekalanos, J. J. Tit-for-tat: type VI secretion system counterattack during bacterial cell-cell interactions. Cell. 152, 884–894 (2013).
Acknowledgements
E.G.P. receives funding from US National Institutes of Health (NIH) grants RO1 AI42135 and AI95706, and from the Tow Foundation. C.G.B. was supported by a Medical Scientist Training Program grant from the National Institute of General Medical Sciences of the NIH (award number T32GM07739, which was awarded to the Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program).
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Glossary
- Innate lymphocytes
-
Lymphoid cells that are dependent on signalling through the common cytokine receptor γ-chain but that lack recombined antigen receptors. They have important roles in mucosal defence, epithelial homeostasis and lymphoid tissue development.
- Endospores
-
Metabolically inactive bacterial forms that are resistant to chemical and physical stresses and that reactivate under specific environmental conditions.
- Vegetative bacteria
-
Metabolically active bacterial forms.
- Toxic megacolon
-
A potentially lethal complication of infectious colitis or inflammatory bowel disease that is characterized by mucosal inflammation, dilatation of the colon and systemic toxicity.
- Paneth cell
-
Specialized epithelial cell that is found at the base of crypts in the small intestine and that expresses various antimicrobial proteins.
- Cryptdins
-
Microbicidal peptides that are expressed in granules of phagocytic leukocytes and in secretory granules of Paneth cells.
- Bacteroidetes
-
A major bacterial phylum of the intestinal microbiota that comprises physiologically diverse aerobic and anaerobic Gram-negative bacteria commonly associated with the degradation of complex carbohydrates.
- Firmicutes
-
A major bacterial phylum of the intestinal microbiota that primarily comprises Gram-positive bacteria that have low guanine and cytosine DNA content. They are phenotypically diverse, commonly polyphyletic and are often distinguished by their ability to form endospores.
- Actinobacteria
-
A bacterial phylum that is abundant in the intestinal microbiota and that is primarily composed of Gram-positive bacteria that have high guanine and cytosine content in their DNA and that are commonly associated with secondary metabolite production.
- Proteobacteria
-
A bacterial phylum, which is abundant in the intestinal microbiota, that is composed of Gram-negative bacteria that can be distinguished by their collective morphological and metabolic diversity.
- Segmented filamentous bacteria
-
(SFB). Gram-positive, spore-forming, non-culturable, Clostridia-related bacteria, provisionally named Candidatus Savagella (of the Clostridiaceae family), that closely adhere to the small intestinal epithelium in various vertebrates and that stimulate immune responses.
- TRUC model
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(Tbx21−/−Rag2−/− ulcerative colitis model). A mouse model of inflammatory bowel disease that resembles human ulcerative colitis, wherein conventionally-raised mice that lack T-bet and V(D)J recombination-activating protein 2 (RAG2) spontaneously develop an aggressive, highly penetrant, communicable form of colitis.
- Type VI secretion system
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(T6SS). A protein structure that is used by Gram-negative bacteria to translocate effector proteins that are commonly involved in virulence and bacterial competition into other prokaryotic and eukaryotic cells.
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Buffie, C., Pamer, E. Microbiota-mediated colonization resistance against intestinal pathogens. Nat Rev Immunol 13, 790–801 (2013). https://doi.org/10.1038/nri3535
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DOI: https://doi.org/10.1038/nri3535
