Hundreds of bacterial species make up the mammalian intestinal microbiota. Following perturbations by antibiotics, diet, immune deficiency or infection, this ecosystem can shift to a state of dysbiosis. This can involve overgrowth (blooming) of otherwise under-represented or potentially harmful bacteria (for example, pathobionts). Here, we present evidence suggesting that dysbiosis fuels horizontal gene transfer between members of this ecosystem, facilitating the transfer of virulence and antibiotic resistance genes and thereby promoting pathogen evolution.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Wildlife gut microbiomes of sympatric generalist species respond differently to anthropogenic landscape disturbances
Animal Microbiome Open Access 06 April 2023
Mucosal Immunology Open Access 03 November 2022
Animal Microbiome Open Access 09 August 2022
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Berg, R. D. The indigenous gastrointestinal microflora. Trends Microbiol. 4, 430–435 (1996).
The Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012).
Arumugam, M. et al. Enterotypes of the human gut microbiome. Nature 473, 174–180 (2011).
Yatsunenko, T. et al. Human gut microbiome viewed across age and geography. Nature 486, 222–227 (2012).
Wu, G. D. et al. Linking long-term dietary patterns with gut microbial enterotypes. Science 334, 105–108 (2011).
Cho, I. & Blaser, M. J. The human microbiome: at the interface of health and disease. Nature Rev. Genet. 13, 260–270 (2012).
Sharon, I. et al. Time series community genomics analysis reveals rapid shifts in bacterial species, strains, and phage during infant gut colonization. Genome Res. 23, 111–120 (2013).
Dethlefsen, L. & Relman, D. A. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc. Natl Acad. Sci. USA 108 (Suppl. 1), 4554–4561 (2011).
Walker, A. W. et al. Dominant and diet-responsive groups of bacteria within the human colonic microbiota. ISME J. 5, 220–230 (2011).
Kelly, B. G., Vespermann, A. & Bolton, D. J. Gene transfer events and their occurrence in selected environments. Food Chem. Toxicol. 47, 978–983 (2009).
Smillie, C. S. et al. Ecology drives a global network of gene exchange connecting the human microbiome. Nature 480, 241–244 (2011).
Stecher, B. et al. Salmonella enterica serovar Typhimurium exploits inflammation to compete with the intestinal microbiota. PLoS Biol. 5, 2177–2189 (2007).
Barman, M. et al. Enteric salmonellosis disrupts the microbial ecology of the murine gastrointestinal tract. Infect. Immun. 76, 907–915 (2008).
Ubeda, C. et al. Familial transmission rather than defective innate immunity shapes the distinct intestinal microbiota of TLR-deficient mice. J. Exp. Med. 209, 1445–1456 (2012).
Stecher, B. et al. Gut inflammation can boost horizontal gene transfer between pathogenic and commensal Enterobacteriaceae. Proc. Natl Acad. Sci. USA 109, 1269–1274 (2012).
Doucet-Populaire, F., Trieu-Cuot, P., Dosbaa, I., Andremont, A. & Courvalin, P. Inducible transfer of conjugative transposon Tn1545 from Enterococcus faecalis to Listeria monocytogenes in the digestive tracts of gnotobiotic mice. Antimicrob. Agents Chemother. 35, 185–187 (1991).
Jones, B. V., Sun, F. & Marchesi, J. R. Comparative metagenomic analysis of plasmid encoded functions in the human gut microbiome. BMC Genomics 11, 46 (2010).
Dagan, T., Artzy-Randrup, Y. & Martin, W. Modular networks and cumulative impact of lateral transfer in prokaryote genome evolution. Proc. Natl Acad. Sci. USA 105, 10039–10044 (2008).
Llosa, M., Schroder, G. & Dehio, C. New perspectives into bacterial DNA transfer to human cells. Trends Microbiol. 20, 355–359 (2012).
Claverys, J. P., Prudhomme, M. & Martin, B. Induction of competence regulons as a general response to stress in gram-positive bacteria. Annu. Rev. Microbiol. 60, 451–475 (2006).
Dorer, M. S., Fero, J. & Salama, N. R. DNA damage triggers genetic exchange in Helicobacter pylori. PLoS Pathog. 6, e1001026 (2010).
Meibom, K. L., Blokesch, M., Dolganov, N. A., Wu, C. Y. & Schoolnik, G. K. Chitin induces natural competence in Vibrio cholerae. Science 310, 1824–1827 (2005).
Mirold, S. et al. Isolation of a temperate bacteriophage encoding the type III effector protein SopE from an epidemic Salmonella typhimurium strain. Proc. Natl Acad. Sci. USA 96, 9845–9850 (1999).
Waldor, M. K. & Friedman, D. I. Phage regulatory circuits and virulence gene expression. Curr. Opin. Microbiol. 8, 459–465 (2005).
Brussow, H., Canchaya, C. & Hardt, W. D. Phages and the evolution of bacterial pathogens: from genomic rearrangements to lysogenic conversion. Microbiol. Mol. Biol. Rev. 68, 560–602 (2004).
Waldor, M. K. & Mekalanos, J. J. Lysogenic conversion by a filamentous phage encoding cholera toxin. Science 272, 1910–1914 (1996).
Duerkop, B. A., Clements, C. V., Rollins, D., Rodrigues, J. L. & Hooper, L. V. A composite bacteriophage alters colonization by an intestinal commensal bacterium. Proc. Natl Acad. Sci. USA 109, 17621–17626 (2012).
Canchaya, C., Fournous, G., Chibani-Chennoufi, S., Dillmann, M. L. & Brussow, H. Phage as agents of lateral gene transfer. Curr. Opin. Microbiol. 6, 417–424 (2003).
Rey, F. E. et al. Dissecting the in vivo metabolic potential of two human gut acetogens. J. Biol. Chem. 285, 22082–22090 (2010).
Brown Kav, A. et al. Insights into the bovine rumen plasmidome. Proc. Natl Acad. Sci. USA 109, 5452–5457 (2012).
Frost, L. S., Leplae, R., Summers, A. O. & Toussaint, A. Mobile genetic elements: the agents of open source evolution. Nature Rev. Microbiol. 3, 722–732 (2005).
Stotzky, G. & Babich, H. Survival of, and genetic transfer by, genetically engineered bacteria in natural environments. Adv. Appl. Microbiol. 31, 93–138 (1986).
Sommer, M. O., Dantas, G. & Church, G. M. Functional characterization of the antibiotic resistance reservoir in the human microflora. Science 325, 1128–1131 (2009).
Salyers, A. A., Gupta, A. & Wang, Y. Human intestinal bacteria as reservoirs for antibiotic resistance genes. Trends Microbiol. 12, 412–416 (2004).
Frye, J. G. et al. Related antimicrobial resistance genes detected in different bacterial species co-isolated from swine fecal samples. Foodborne Pathog. Dis. 8, 663–679 (2011).
Aminov, I. R. in Horizontal Gene Transfer in Microorganisms (ed. Francino, M. P.) 93–130 (Caister Academic, 2012).
Dionisio, F., Matic, I., Radman, M., Rodrigues, O. R. & Taddei, F. Plasmids spread very fast in heterogeneous bacterial communities. Genetics 162, 1525–1532 (2002).
Peterson, G., Kumar, A., Gart, E. & Narayanan, S. Catecholamines increase conjugative gene transfer between enteric bacteria. Microb. Pathog. 51, 1–8 (2011).
Whitman, W. B., Coleman, D. C. & Wiebe, W. J. Prokaryotes: the unseen majority. Proc. Natl Acad. Sci. USA 95, 6578–6583 (1998).
Matsuo, J. et al. Ciliates rapidly enhance the frequency of conjugation between Escherichia coli strains through bacterial accumulation in vesicles. Res. Microbiol. 161, 711–719 (2010).
Crippen, T. L. & Poole, T. L. Conjugative transfer of plasmid-located antibiotic resistance genes within the gastrointestinal tract of lesser mealworm larvae, Alphitobius diaperinus (Coleoptera: Tenebrionidae). Foodborne Pathog. Dis. 6, 907–915 (2009).
Hinnebusch, B. J., Rosso, M. L., Schwan, T. G. & Carniel, E. High-frequency conjugative transfer of antibiotic resistance genes to Yersinia pestis in the flea midgut. Mol. Microbiol. 46, 349–354 (2002).
Salyers, A. A. Gene transfer in the mammalian intestinal tract. Curr. Opin. Biotechnol. 4, 294–298 (1993).
Sears, C. L. Enterotoxigenic Bacteroides fragilis: a rogue among symbiotes. Clin. Microbiol. Rev. 22, 349–369 (2009).
Hehemann, J. H. et al. Transfer of carbohydrate-active enzymes from marine bacteria to Japanese gut microbiota. Nature 464, 908–912 (2010).
Hehemann, J. H., Kelly, A. G., Pudlo, N. A., Martens, E. C. & Boraston, A. B. Bacteria of the human gut microbiome catabolize red seaweed glycans with carbohydrate-active enzyme updates from extrinsic microbes. Proc. Natl Acad. Sci. USA 109, 19786–19791 (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).
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).
Wohlgemuth, S., Haller, D., Blaut, M. & Loh, G. Reduced microbial diversity and high numbers of one single Escherichia coli strain in the intestine of colitic mice. Environ. Microbiol. 11, 1562–1571 (2009).
Carvalho, F. A. et al. Transient inability to manage proteobacteria promotes chronic gut inflammation in TLR5-deficient mice. Cell Host Microbe 12, 139–152 (2012).
Winter, S. E. et al. Host-derived nitrate boosts growth of E. coli in the inflamed gut. Science 339, 708–711 (2013).
Stecher, B. & Hardt, W. D. Mechanisms controlling pathogen colonization of the gut. Curr. Opin. Microbiol. 14, 82–91 (2011).
Stecher, B. et al. Like will to like: abundances of closely related species can predict susceptibility to intestinal colonization by pathogenic and commensal bacteria. PLoS Pathog. 6, e1000711 (2010).
Mason, T. G. & Richardson, G. Escherichia coli and the human gut: some ecological considerations. J. Appl. Bacteriol. 51, 1–16 (1981).
Rasko, D. A. et al. The pangenome structure of Escherichia coli: comparative genomic analysis of E. coli commensal and pathogenic isolates. J. Bacteriol. 190, 6881–6893 (2008).
Ohnishi, M., Kurokawa, K. & Hayashi, T. Diversification of Escherichia coli genomes: are bacteriophages the major contributors? Trends Microbiol. 9, 481–485 (2001).
Allen, H. K. et al. Antibiotics in feed induce prophages in swine fecal microbiomes. mBio 2, e00260-11 (2011).
Bina, J. et al. ToxR regulon of Vibrio cholerae and its expression in vibrios shed by cholera patients. Proc. Natl Acad. Sci. USA 100, 2801–2806 (2003).
Lepage, P. et al. Dysbiosis in inflammatory bowel disease: a role for bacteriophages? Gut 57, 424–425 (2008).
Brown, S. P., Le Chat, L. & Taddei, F. Evolution of virulence: triggering host inflammation allows invading pathogens to exclude competitors. Ecol. Lett. 11, 44–51 (2008).
Thiennimitr, P., Winter, S. E. & Baumler, A. J. Salmonella, the host and its microbiota. Curr. Opin. Microbiol. 15, 108–114 (2012).
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).
Sorsa, L. J., Dufke, S., Heesemann, J. & Schubert, S. Characterization of an iroBCDEN gene cluster on a transmissible plasmid of uropathogenic Escherichia coli: evidence for horizontal transfer of a chromosomal virulence factor. Infect. Immun. 71, 3285–3293 (2003).
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).
Watson, P. R., Galyov, E. E., Paulin, S. M., Jones, P. W. & Wallis, T. S. Mutation of invH, but not stn, reduces Salmonella-induced enteritis in cattle. Infect. Immun. 66, 1432–1438 (1998).
Hensel, M. et al. Analysis of the boundaries of Salmonella pathogenicity island 2 and the corresponding chromosomal region of Escherichia coli K-12. J. Bacteriol. 179, 1105–1111 (1997).
Li, J. et al. Relationship between evolutionary rate and cellular location among the Inv/Spa invasion proteins of Salmonella enterica. Proc. Natl Acad. Sci. USA 92, 7252–7256 (1995).
Ochman, H. & Groisman, E. A. Distribution of pathogenicity islands in Salmonella spp. Infect. Immun. 64, 5410–5412 (1996).
Crawford, R. W. et al. Very long O-antigen chains enhance fitness during Salmonella-induced colitis by increasing bile resistance. PLoS Pathog. 8, e1002918 (2012).
Stelter, C. et al. Salmonella-induced mucosal lectin RegIIIβ kills competing gut microbiota. PLoS ONE 6, e20749 (2011).
Jacobsen, A., Hendriksen, R. S., Aaresturp, F. M., Ussery, D. W. & Friis, C. The Salmonella enterica pan-genome. Microb. Ecol. 62, 487–504 (2011).
Hardt, W. D., Urlaub, H. & Galan, J. E. A substrate of the centisome 63 type III protein secretion system of Salmonella typhimurium is encoded by a cryptic bacteriophage. Proc. Natl Acad. Sci. USA 95, 2574–2579 (1998).
Mirold, S. et al. Salmonella host cell invasion emerged by acquisition of a mosaic of separate genetic elements, including Salmonella pathogenicity island 1 (SPI1), SPI5, and sopE2. J. Bacteriol. 183, 2348–2358 (2001).
Hardt, W. D., Chen, L. M., Schuebel, K. E., Bustelo, X. R. & Galan, J. E. S. typhimurium encodes an activator of Rho GTPases that induces membrane ruffling and nuclear responses in host cells. Cell 93, 815–826 (1998).
Hapfelmeier, S. et al. Role of the Salmonella pathogenicity island 1 effector proteins SipA, SopB, SopE, and SopE2 in Salmonella enterica subspecies 1 serovar Typhimurium colitis in streptomycin-pretreated mice. Infect. Immun. 72, 795–809 (2004).
Muller, A. J. et al. The S. Typhimurium effector SopE induces caspase-1 activation in stromal cells to initiate gut inflammation. Cell Host Microbe 6, 125–136 (2009).
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).
Winter, S. E. et al. Gut inflammation provides a respiratory electron acceptor for Salmonella. Nature 467, 426–429 (2010).
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).
Garrett, W. S. et al. Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell 131, 33–45 (2007).
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).
Jernberg, C., Lofmark, S., Edlund, C. & Jansson, J. K. Long-term impacts of antibiotic exposure on the human intestinal microbiota. Microbiology 156, 3216–3223 (2010).
Britton, R. A. & Young, V. B. Interaction between the intestinal microbiota and host in Clostridium difficile colonization resistance. Trends Microbiol. 20, 313–319 (2012).
Hill, D. A. et al. Metagenomic analyses reveal antibiotic-induced temporal and spatial changes in intestinal microbiota with associated alterations in immune cell homeostasis. Mucosal Immunol. 3, 148–158 (2010).
Scott, K. P. The role of conjugative transposons in spreading antibiotic resistance between bacteria that inhabit the gastrointestinal tract. Cell. Mol. Life Sci. 59, 2071–2082 (2002).
Jakobsson, H. E. et al. Short-term antibiotic treatment has differing long-term impacts on the human throat and gut microbiome. PLoS ONE 5, e9836 (2010).
Jernberg, C., Lofmark, 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).
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).
Ayres, J. S., Trinidad, N. J. & Vance, R. E. Lethal inflammasome activation by a multidrug-resistant pathobiont upon antibiotic disruption of the microbiota. Nature Med. 18, 799–806 (2012).
Woodford, N., Turton, J. F. & Livermore, D. M. Multiresistant Gram-negative bacteria: the role of high-risk clones in the dissemination of antibiotic resistance. FEMS Microbiol. Rev. 35, 736–755 (2011).
Weinstock, G. M. Genomic approaches to studying the human microbiota. Nature 489, 250–256 (2012).
Zaneveld, J. R., Nemergut, D. R. & Knight, R. Are all horizontal gene transfers created equal? Prospects for mechanism-based studies of HGT patterns. Microbiology 154, 1–15 (2008).
Kennemann, L. et al. Helicobacter pylori genome evolution during human infection. Proc. Natl Acad. Sci. USA 108, 5033–5038 (2011).
Holt, K. E. et al. High-resolution genotyping of the endemic Salmonella Typhi population during a Vi (typhoid) vaccination trial in Kolkata. PLoS Negl. Trop. Dis. 6, e1490 (2012).
Prakash, T. et al. Complete genome sequences of rat and mouse segmented filamentous bacteria, a potent inducer of Th17 cell differentiation. Cell Host Microbe 10, 273–284 (2011).
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).
De Paepe, M. et al. Trade-off between bile resistance and nutritional competence drives Escherichia coli diversification in the mouse gut. PLoS Genet. 7, e1002107 (2011).
Leatham-Jensen, M. P. et al. The streptomycin-treated mouse intestine selects Escherichia coli envZ missense mutants that interact with dense and diverse intestinal microbiota. Infect. Immun. 80, 1716–1727 (2012).
Stepanauskas, R. Single cell genomics: an individual look at microbes. Curr. Opin. Microbiol. 15, 613–620 (2012).
Metchnikoff, E. The Prolongation of Life: Optimistic Studies, Revised Edition of 1907. (Heinemann,1910).
Hill, D. A. & Artis, D. Intestinal bacteria and the regulation of immune cell homeostasis. Annu. Rev. Immunol. 28, 623–667 (2010).
Manichanh, C. et al. Reduced diversity of faecal microbiota in Crohn's disease revealed by a metagenomic approach. Gut 55, 205–211 (2006).
Ley, R. E. et al. Obesity alters gut microbial ecology. Proc. Natl Acad. Sci. USA 102, 11070–11075 (2005).
Moore, W. E. & Moore, L. H. Intestinal floras of populations that have a high risk of colon cancer. Appl. Environ. Microbiol. 61, 3202–3207 (1995).
Bollyky, P. L. et al. The Toll-like receptor signaling molecule Myd88 contributes to pancreatic beta-cell homeostasis in response to injury. PLoS ONE 4, e5063 (2009).
Penders, J. et al. Gut microbiota composition and development of atopic manifestations in infancy: the KOALA Birth Cohort Study. Gut 56, 661–667 (2007).
Hajishengallis, G., Darveau, R. P. & Curtis, M. A. The keystone-pathogen hypothesis. Nature Rev. Microbiol. 10, 717–725 (2012).
Devkota, S. et al. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10−/− mice. Nature 487, 104–108 (2012).
Arthur, J. C. et al. Intestinal inflammation targets cancer-inducing activity of the microbiota. Science 338, 120–123 (2012).
Haag, L. M. et al. Intestinal microbiota shifts towards elevated commensal Escherichia coli loads abrogate colonization resistance against Campylobacter jejuni in mice. PLoS ONE 7, e35988 (2012).
Barnich, N. & Darfeuille-Michaud, A. Adherent-invasive Escherichia coli and Crohn's disease. Curr. Opin. Gastroenterol. 23, 16–20 (2007).
Chow, J. & Mazmanian, S. K. A pathobiont of the microbiota balances host colonization and intestinal inflammation. Cell Host Microbe 7, 265–276 (2010).
Arboleya, S. et al. Establishment and development of intestinal microbiota in preterm neonates. FEMS Microbiol. Ecol. 79, 763–772 (2012).
Palmer, C., Bik, E. M., DiGiulio, D. B., Relman, D. A. & Brown, P. O. Development of the human infant intestinal microbiota. PLoS Biol. 5, e177 (2007).
Ventura, M., Turroni, F., Motherway, M. O., MacSharry, J. & van Sinderen, D. Host–microbe interactions that facilitate gut colonization by commensal bifidobacteria. Trends Microbiol. 20, 467–476 (2012).
Work in the W.D.H. laboratory is supported by the Swiss National Science foundation (SNF). Work in the B.S. laboratory is supported by the German Research Foundation (DFG) and the German Federal Ministry of Education and Research (BMBF).
The authors declare no competing financial interests.
About this article
Cite this article
Stecher, B., Maier, L. & Hardt, WD. 'Blooming' in the gut: how dysbiosis might contribute to pathogen evolution. Nat Rev Microbiol 11, 277–284 (2013). https://doi.org/10.1038/nrmicro2989
This article is cited by
Wildlife gut microbiomes of sympatric generalist species respond differently to anthropogenic landscape disturbances
Animal Microbiome (2023)
Nature Reviews Microbiology (2023)
Antigenotoxicity and Cytotoxic Potentials of Cell-Free Supernatants Derived from Saccharomyces cerevisiae var. boulardii on HT-29 Human Colon Cancer Cell Lines
Probiotics and Antimicrobial Proteins (2023)
Animal Microbiome (2022)
Nature Biomedical Engineering (2022)