Toggle Main Menu Toggle Search

Open Access padlockePrints

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

Lookup NU author(s): James Connolly

Downloads


Licence

This is the authors' accepted manuscript of an article that has been published in its final definitive form by American Association for the Advancement of Science, 2018.

For re-use rights please refer to the publisher's terms and conditions.


Abstract

Copyright © 2018 The Authors. 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 (TH1) 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 TH17 and TH2 responses for clearance (bacterial Citrobacter rodentium and helminth Trichuris muris 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.


Publication metadata

Author(s): Scott NA, Andrusaite A, Andersen P, Lawson M, Alcon-Giner C, Leclaire C, Caim S, Le Gall G, Shaw T, Connolly JPR, Roe AJ, Wessel H, Bravo-Blas A, Thomson CA, Kastele V, Wang P, Peterson DA, Bancroft A, Li X, Grencis R, McI Mowat A, Hall LJ, Travis MA, Milling SWF, Mann ER

Publication type: Article

Publication status: Published

Journal: Science Translational Medicine

Year: 2018

Volume: 10

Issue: 464

Print publication date: 24/10/2018

Acceptance date: 28/09/2018

Date deposited: 23/09/2019

ISSN (print): 1946-6234

ISSN (electronic): 1946-6242

Publisher: American Association for the Advancement of Science

URL: https://doi.org/10.1126/scitranslmed.aao4755

DOI: 10.1126/scitranslmed.aao4755

PubMed id: 30355800


Altmetrics

Altmetrics provided by Altmetric


Actions

Find at Newcastle University icon    Link to this publication


Share