Intestinal Microbiota Shifts towards Elevated Commensal Escherichia coli Loads Abrogate Colonization Resistance against Campylobacter jejuni in Mice Lea-Maxie Haag 1 , Andre´ Fischer1, Bettina Otto1, Rita Plickert1, Anja A. Ku¨ hl2, Ulf B. Go¨ bel1, Stefan Bereswill1., Markus M. Heimesaat1*. 1 Department of Microbiology and Hygiene, Charite´ - University Medicine Berlin, Berlin, Germany, 2 Department of Internal Medicine, Rheumatology and Clinical Immunology/Research Center ImmunoSciences (RCIS), Charite´ - University Medicine Berlin, Berlin, Germany Abstract Background: The zoonotic pathogen Campylobacter jejuni is a leading cause of bacterial foodborne enterocolitis in humans worldwide. The understanding of immunopathology underlying human campylobacteriosis is hampered by the fact that mice display strong colonization resistance against the pathogen due to their host specific gut microbiota composition. Methodology/Principal Findings: Since the microbiota composition changes significantly during intestinal inflammation we dissected factors contributing to colonization resistance against C. jejuni in murine ileitis, colitis and in infant mice. In contrast to healthy animals C. jejuni could stably colonize mice suffering from intestinal inflammation. Strikingly, in mice with Toxoplasma gondii-induced acute ileitis, C. jejuni disseminated to mesenteric lymphnodes, spleen, liver, kidney, and blood. In infant mice C. jejuni infection induced enterocolitis. Mice suffering from intestinal inflammation and C. jejuni susceptible infant mice displayed characteristical microbiota shifts dominated by increased numbers of commensal Escherichia coli. To further dissect the pivotal role of those distinct microbiota shifts in abrogating colonization resistance, we investigated C. jejuni infection in healthy adult mice in which the microbiota was artificially modified by feeding live commensal E. coli. Strikingly, in animals harboring supra-physiological intestinal E. coli loads, colonization resistance was significantly diminished and C. jejuni infection induced enterocolitis mimicking key features of human campylobacteriosis. Conclusion/Significance: Murine colonization resistance against C. jejuni is abrogated by changes in the microbiota composition towards elevated E. coli loads during intestinal inflammation as well as in infant mice. Intestinal inflammation and microbiota shifts thus represent potential risk factors for C. jejuni infection. Corresponding interplays between C. jejuni and microbiota might occur in human campylobacteriosis. Murine models introduced here mimick key features of human campylobacteriosis and allow for further analysis of immunological and molecular mechanisms of C. jejuni – host interactions. Citation: Haag L-M, Fischer A, Otto B, Plickert R, Ku¨ hl AA, et al. (2012) Intestinal Microbiota Shifts towards Elevated Commensal Escherichia coli Loads Abrogate Colonization Resistance against Campylobacter jejuni in Mice. PLoS ONE 7(5): e35988. doi:10.1371/journal.pone.0035988 Editor: Georgina L. Hold, University of Aberdeen, United Kingdom Received February 3, 2012; Accepted March 28, 2012; Published May 1, 2012 Copyright: 2012 Haag et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by grants from the 15 German Research Foundation (DFG) to UBG (GO363/12-1, CampyGerm; SFB633, TP A7), SB (SFB633, TP A7), AK (SFB633, TP Z1), MMH (SFB633, TP B6), LMH and BO (SFB633, Immuco), and from the German Federal Ministery of Education and Research (BMBF) to SB (‘‘Lab in a hanky’’ projects TP1.1 and TP 8.2). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: Co-authors Stefan Bereswill and Markus M. Heimesaat are PLoS ONE Editorial Board members. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials. * E-mail: markus.heimesaat@charite.de . These authors contributed equally to this work. Introduction Campylobacter (C.) jejuni continues to be the most frequently reported causative agent of bacterial gastroenteritis in humans worldwide [1,2]. The gram-negative bacteria form part of the commensal flora in many wild and domestic animals. Zoonotic transmission from livestock animals via consumption of contam- inated meat products is the most common source for human C. jejuni infections [3,4,5]. Infected patients present a broad range of symptoms including abdominal pain, watery or bloody diarrhea, and fever. Histological examination of affected intestinal tissues commonly reveals crypt abscesses, ulcerations, and elevated numbers of immune cells in the colon in situ [6,7,8,9]. Although the infection is self-limiting in most cases, long-term sequelae such as reactive arthritis, gastrointestinal and neurological disorders have been reported in susceptible hosts [10,11]. C. jejuni infection correlates with reactivation of inflammatory bowel diseases (IBD), Miller-Fisher-Syndrome and Guillian-Barre´-Syndrome [10,11]. The high prevalence of campylobacteriosis poses a significant health burden and accentuates the need for further unravelling the underlying pathogenesis of C. jejuni infections. The lack of understanding mainly stems from the scarcity of suitable experimental in vivo models of human infection [12]. Although chickens allow for the investigation of colonization and transmis- PLoS ONE | www.plosone.org 1 May 2012 | Volume 7 | Issue 5 | e35988