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The microbiome activates CD4 T-cell-mediated immunity to compensate for increased intestinal permeability

Edelblum, Karen L. and Sharon, Gil and Singh, Gurminder and Odenwald, Matthew A. and Sailer, Anne and Cao, Severine and Ravens, Sarina and Thomsen, Irene and El Bissati, Kamal and McLeod, Rima and Dong, Chen and Gurbuxani, Sandeep and Prinz, Immo and Mazmanian, Sarkis K. and Turner, Jerrold R. (2017) The microbiome activates CD4 T-cell-mediated immunity to compensate for increased intestinal permeability. Cellular and Molecular Gastroenterology and Hepatology, 4 (2). pp. 285-297. ISSN 2352-345X. PMCID PMC5540699.

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Background & Aims: Despite a prominent association, chronic intestinal barrier loss is insufficient to induce disease in human subjects or experimental animals. We hypothesized that compensatory mucosal immune activation might protect individuals with increased intestinal permeability from disease. We used a model in which intestinal barrier loss is triggered by intestinal epithelial-specific expression of constitutively active myosin light chain kinase (CA-MLCK). Here we asked whether constitutive tight junction barrier loss impacts susceptibility to enteric pathogens. Methods: Acute or chronic Toxoplasma gondii or Salmonella typhimurium infection was assessed in CA-MLCK transgenic or wild-type mice. Germ-free mice or those lacking specific immune cell populations were used to investigate the effect of microbial-activated immunity on pathogen translocation in the context of increased intestinal permeability. Results: Acute T gondii and S typhimurium translocation across the epithelial barrier was reduced in CA-MLCK mice. This protection was due to enhanced mucosal immune activation that required CD4^+ T cells and interleukin 17A but not immunoglobulin A. The protective mucosal immune activation in CA-MLCK mice depended on segmented filamentous bacteria (SFB), because protection against early S typhimurium invasion was lost in germ-free CA-MLCK mice but could be restored by conventionalization with SFB-containing, not SFB-deficient, microbiota. In contrast, chronic S typhimurium infection was more severe in CA-MLCK mice, suggesting that despite activation of protective mucosal immunity, barrier defects ultimately result in enhanced disease progression. Conclusions: Increased epithelial tight junction permeability synergizes with commensal bacteria to promote intestinal CD4^+ T-cell expansion and interleukin 17A production that limits enteric pathogen invasion.

Item Type:Article
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URLURL TypeDescription CentralArticle
Sharon, Gil0000-0002-4605-9943
Mazmanian, Sarkis K.0000-0003-2713-1513
Additional Information:© 2017 The Authors. Published by Elsevier Inc. on behalf of the AGA Institute. Under a Creative Commons license. Received 22 February 2017, Revised 3 April 2017, Accepted 5 June 2017, Available online 10 June 2017. The authors thank Sara McBride for help with mouse rederivation, Taren Thorn and Kimberly Ly for animal care, and the Frank W. Fitch Monoclonal Antibody Core Facility at the University of Chicago for monoclonal antibody production. Author contributions: Conceptualization, K.L.E and J.R.T.; methodology, K.L.E., G. Sharon, and S.K.M.; formal analysis, S.R. and I.T.; investigation, K.L.E., G. Sharon, G. Singh, A.S., S.C., S.G., S.R., K.E.B., and J.R.T.; resources, S.K.M., R.M., C.D., I.P., and J.R.T.; writing-original draft, K.L.E.; writing-review and editing, K.L.E., G. Sharon, S.K.M., R.M., K.E.B., I.P., S.R., and J.R.T.; visualization, K.L.E., S.R, and I.P.; supervision, K.L.E., S.K.M., and J.R.T.; funding, K.L.E., S.K.M., and J.R.T. The authors disclose no conflicts. One author (J.R.T.) is a member of the CMGH Board of Editors (BOE). In accordance with journal policy, the review process for this manuscript was managed by a Guest Associate Editor, and the author BOE member was blinded to the entire process. Funding: Supported by National Institute of Health grants K01DK093627 and F32DK084859 (K.L.E.), R01DK078938, R01GM099535 (S.K.M.), R01DK61931 and R01DK68271 (J.R.T.); Department of Defense W81XWH-09-1-0341 (J.R.T.); Crohn’s and Colitis Foundation of America (S.K.M. and J.R.T.) and Broad Medical Research Foundation (J.R.T.); The Human Frontiers Science Program - Long Term Fellowship (G. Sharon); and the Heritage Medical Research Institute (S.K.M.)
Group:Heritage Medical Research Institute
Funding AgencyGrant Number
Department of DefenseW81XWH-09-1-0341
Crohn’s and Colitis Foundation of AmericaUNSPECIFIED
Broad Medical Research FoundationUNSPECIFIED
Human Frontier Science ProgramUNSPECIFIED
Heritage Medical Research InstituteUNSPECIFIED
Subject Keywords:barrier function; tight junction; microbiota; CD4 T cell; mucosal immunity; Salmonella
Issue or Number:2
PubMed Central ID:PMC5540699
Record Number:CaltechAUTHORS:20170628-091947434
Persistent URL:
Official Citation:Karen L. Edelblum, Gil Sharon, Gurminder Singh, Matthew A. Odenwald, Anne Sailer, Severine Cao, Sarina Ravens, Irene Thomsen, Kamal El Bissati, Rima McLeod, Chen Dong, Sandeep Gurbuxani, Immo Prinz, Sarkis K. Mazmanian, Jerrold R. Turner, The Microbiome Activates CD4 T-cell–mediated Immunity to Compensate for Increased Intestinal Permeability, Cellular and Molecular Gastroenterology and Hepatology, Volume 4, Issue 2, 2017, Pages 285-297, ISSN 2352-345X, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:78637
Deposited By: Tony Diaz
Deposited On:28 Jun 2017 16:42
Last Modified:24 Feb 2020 21:27

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