Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease.
Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease.
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DOI：
10.1126/science.aad9948
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发表时间：
2016-05-27
期刊：
影响因子：
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通讯作者：
Mazmanian SK
中科院分区：
文献类型：
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作者：
Chu H;Khosravi A;Kusumawardhani IP;Kwon AH;Vasconcelos AC;Cunha LD;Mayer AE;Shen Y;Wu WL;Kambal A;Targan SR;Xavier RJ;Ernst PB;Green DR;McGovern DP;Virgin HW;Mazmanian SK
炎症性肠病（IBD）与人类基因组的风险变异和肠道微生物群的生态失调有关，尽管这些发现的统一原则在很大程度上仍未得到描述。人类共生的脆弱拟杆菌通过分泌外膜囊泡（omv）向免疫细胞传递免疫调节分子。我们发现omv需要ibd相关基因ATG16L1和NOD2来激活非典型自噬途径，以保护结肠炎。atg16l1缺失的树突状细胞不会诱导调节性T细胞（Treg）抑制粘膜炎症。具有ATG16L1主要风险变异的人类受试者的免疫细胞在Treg对omv的反应中存在缺陷。我们提出，易感基因的多态性通过“感知”来自微生物组的保护信号的缺陷来促进疾病，从而定义了IBD潜在的关键基因-环境病因学。
Inflammatory bowel disease (IBD) is associated with risk variants in the human genome and dysbiosis of the gut microbiome, though unifying principles for these findings remain largely undescribed. The human commensal Bacteroides fragilis delivers immunomodulatory molecules to immune cells via secretion of outer membrane vesicles (OMVs). We reveal that OMVs require IBD-associated genes, ATG16L1 and NOD2, to activate a non-canonical autophagy pathway during protection from colitis. ATG16L1-deficient dendritic cells do not induce regulatory T cells (Treg) to suppress mucosal inflammation. Immune cells from human subjects with a major risk variant in ATG16L1 are defective in Treg responses to OMVs. We propose that polymorphisms in susceptibility genes promote disease through defects in ‘sensing’ protective signals from the microbiome, defining a potentially critical gene-environment etiology for IBD.