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

肠道菌群 免疫 巨噬细胞 抗生素 失调 丁酸盐 免疫学 炎症 免疫系统 生物 微生物学 体外 生物化学 食品科学 发酵
作者
Nicholas A. Scott,Anna Andrusaite,Peter Andersen,Melissa A. Lawson,Cristina Alcon‐Giner,Charlotte Leclaire,Shabhonam Caim,Gwénaëlle Le Gall,Tovah N. Shaw,James P. R. Connolly,Andrew J. Roe,H Wessel,Alberto Bravo‐Blas,Carolyn A. Thomson,Verena Kästele,Ping Wang,Daniel A. Peterson,Allison J. Bancroft,Xuhang Li,Richard K. Grencis,Allan McI. Mowat,Lindsay J. Hall,Mark A. Travis,Simon Milling,Elizabeth R. Mann
出处
期刊:Science Translational Medicine [American Association for the Advancement of Science (AAAS)]
卷期号:10 (464) 被引量:244
标识
DOI:10.1126/scitranslmed.aao4755
摘要

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.
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