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Sci Transl Med. 2018 Oct 24;10(464). pii: eaao4755. doi: 10.1126/scitranslmed.aao4755.

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

Author information

1
Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester M13 9PT, UK.
2
Manchester Collaborative Centre for Inflammation Research, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, UK.
3
Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary Medicine and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK.
4
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
5
Quadram Institute Bioscience, Norwich Research Park, Norwich NR4 7UA, UK.
6
Eli Lilly and Company, Indianapolis, 46285 IN, USA.
7
Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester M13 9PT, UK.
8
Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester M13 9PT, UK. elizabeth.mann@manchester.ac.uk.

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 (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.

PMID:
30355800
PMCID:
PMC6548564
DOI:
10.1126/scitranslmed.aao4755
[Indexed for MEDLINE]
Free PMC Article

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