Antibiotics induce sustained dysregulation of intestinal T cell immunity by perturbing macrophage homeostasis.
Antibiotics induce sustained dysregulation of intestinal T cell immunity by perturbing macrophage homeostasis.
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DOI：
10.1126/scitranslmed.aao4755
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发表时间：
2018-10-24
影响因子：
17.1
通讯作者：
Mann ER
中科院分区：
文献类型：
--
作者：
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;Kästele V;Wang P;Peterson DA;Bancroft A;Li X;Grencis R;Mowat AM;Hall LJ;Travis MA;Milling SWF;Mann ER
健康肠道中的巨噬细胞是高度特化的，通常对肠道微生物群作出反应，而不会引起炎症反应。这种耐受性的破坏会导致炎症性肠病（IBD），但肠道巨噬细胞通常习惯于促进微生物耐受性的机制尚不清楚。强有力的流行病学证据表明，早期使用抗生素对肠道微生物群的破坏与IBD有关，这表明肠道微生物群在调节肠道免疫方面发挥着重要作用。在这里，我们发现抗生素的使用导致肠道巨噬细胞对细菌刺激产生过度反应，产生多余的炎症细胞因子。将抗生素治疗的小鼠再次暴露于传统的微生物群中，会导致结肠中炎症性T辅助1 （TH1）反应的长期、巨噬细胞依赖性增加和持续的生态失调。巨噬细胞活性失调对T细胞功能的影响可以通过对需要TH17和TH2应答才能清除的感染（细菌啮齿柠檬酸杆菌和蠕虫感染）的易感性增加来证明，这与炎症增加相对应。短链脂肪酸（SCFAs）在给药过程中被耗尽；抗生素与SCFA丁酸酯的补充恢复了肠道巨噬细胞的特征性低反应性，并防止T细胞功能障碍。丁酸改变巨噬细胞的代谢行为，增加氧化磷酸化，并促进巨噬细胞的选择性活化。总之，肠道微生物群对于维持巨噬细胞依赖的肠道免疫稳态至关重要，这是由scfa依赖途径介导的。口服抗生素破坏这一过程，促进持续的T细胞介导的功能障碍和增加对感染的易感性，强调重复使用广谱抗生素的重要意义。
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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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
29
作者：
Donohoe DR;Garge N;Zhang X;Sun W;O'Connell TM;Bunger MK;Bultman SJ
通讯作者：
Bultman SJ
影响因子：
--
作者：
Herrmann E;Young W;Rosendale D;Reichert-Grimm V;Riedel CU;Conrad R;Egert M
通讯作者：
Egert M
影响因子：
2.3
作者：
Greetham, HL;Gibson, GR;Collins, MD
通讯作者：
Collins, MD