Antibiotics induce sustained dysregulation of intestinal T cell immunity by perturbing macrophage homeostasis

Scott, N. A. et al. (2018) Antibiotics induce sustained dysregulation of intestinal T cell immunity by perturbing macrophage homeostasis. Science Translational Medicine, 10(464), eaao4755. (doi:10.1126/scitranslmed.aao4755) (PMID:30355800) (PMCID:PMC6548564)

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Abstract

Macrophages in the healthy intestine are highly specialized and usually respond to the gut microbiota without provoking an inflammatory response. A breakdown in this tolerance leads to inflammatory bowel disease (IBD), but the mechanisms by which intestinal macrophages normally become conditioned to promote microbial tolerance are unclear. Strong epidemiological evidence linking disruption of the gut microbiota by antibiotic use early in life to IBD indicates an important role for the gut microbiota in modulating intestinal immunity. Here, we show that antibiotic use causes intestinal macrophages to become hyperresponsive to bacterial stimulation, producing excess inflammatory cytokines. Re-exposure of antibiotic-treated mice to conventional microbiota induced a long-term, macrophage-dependent increase in inflammatory T helper 1 (T 1) responses in the colon and sustained dysbiosis. The consequences of this dysregulated macrophage activity for T cell function were demonstrated by increased susceptibility to infections requiring T 17 and T 2 responses for clearance (bacterial and helminth infections), corresponding with increased inflammation. Short-chain fatty acids (SCFAs) were depleted during antibiotic administration; supplementation of antibiotics with the SCFA butyrate restored the characteristic hyporesponsiveness of intestinal macrophages and prevented T cell dysfunction. Butyrate altered the metabolic behavior of macrophages to increase oxidative phosphorylation and also promoted alternative macrophage activation. In summary, the gut microbiota is essential to maintain macrophage-dependent intestinal immune homeostasis, mediated by SCFA-dependent pathways. Oral antibiotics disrupt this process to promote sustained T cell-mediated dysfunction and increased susceptibility to infections, highlighting important implications of repeated broad-spectrum antibiotic use.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Mowat, Professor Allan and Roe, Professor Andrew and Thomson, Miss Carolyn and Connolly, Dr James and Mann, Dr Elizabeth and Kaestele, Ms Verena and Andrusaite, Anna and Milling, Professor Simon and Wessel, Miss Hannah
Authors: Scott, N. A., Andrusaite, A., Andersen, P., Lawson, M., Alcon-Giner, C., Leclaire, C., Caim, S., Le Gall, G., Shaw, T., Connolly, J. P.R., Roe, A. J., Wessel, H., Bravo-Blas, A., Thomson, C. A., Kästele, V., Wang, P., Peterson, D. A., Bancroft, A., Li, X., Grencis, R., Mowat, A. M., Hall, L. J., Travis, M. A., Milling, S. W.F., and Mann, E. R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:Science Translational Medicine
Publisher:American Association for the Advancement of Science
ISSN:1946-6234
ISSN (Online):1946-6242
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Science Translational Medicine 10(464): eaao4755
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
618121The Functions of Migrating Intestinal Dendritic Cells in Tolerance and Immunity.Simon MillingMedical Research Council (MRC)MR/K021095/1III -IMMUNOLOGY
715631Defining mechanisms that control T cell migrationSimon MillingMedical Research Council (MRC)MR/N023625/1III -IMMUNOLOGY