Nod2 is required for the regulation of commensal microbiota in the intestine
Nod2 is required for the regulation of commensal microbiota in the intestine
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DOI：
10.1073/pnas.0907722106
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发表时间：
2009-09-15
影响因子：
11.1
通讯作者：
Kobayashi, Koichi S.
中科院分区：
文献类型：
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作者：
Petnicki-Ocwieja, Tanja;Hrncir, Tomas;Kobayashi, Koichi S.
NOD2基因突变是回肠克罗恩病发病机制中最强的遗传危险因素之一，但NOD2对肠粘膜稳态的确切作用尚不清楚。在这里，我们表明NOD2在控制肠道共生细菌菌群方面发挥着重要作用。对NOD2基因缺陷小鼠末端肠段的肠道细菌分析表明，它们含有更多共生细菌。此外，NOD2缺陷小鼠阻止病原菌在肠道定植的能力减弱。在体外，从NOD2基因缺陷小鼠末端肠段分离的肠隐窝不能有效杀灭细菌，提示NOD2信号在隐窝功能中起着重要作用。有趣的是，NOD2的表达依赖于共生细菌的存在，因为重新衍生到无细菌条件下的小鼠其末端Ilea中NOD2的表达显著减少，并且共生细菌补充到无菌小鼠诱导了NOD2的表达。因此，NOD2和肠道共生菌群通过反馈机制相互调节来维持平衡。NOD2的功能障碍导致了这种内稳态的破坏。
Mutations in the Nod2 gene are among the strongest genetic risk factors in the pathogenesis of ileal Crohn's disease, but the exact contributions of Nod2 to intestinal mucosal homeostasis are not understood. Here we show that Nod2 plays an essential role in controlling commensal bacterial flora in the intestine. Analysis of intestinal bacteria from the terminal ilea of Nod2-deficient mice showed that they harbor an increased load of commensal resident bacteria. Furthermore, Nod2-deficient mice had a diminished ability to prevent intestinal colonization of pathogenic bacteria. In vitro, intestinal crypts isolated from terminal ilea of Nod2-deficient mice were unable to kill bacteria effectively, suggesting an important role of Nod2 signaling in crypt function. Interestingly, the expression of Nod2 is dependent on the presence of commensal bacteria, because mice re-derived into germ-free conditions expressed significantly less Nod2 in their terminal ilea, and complementation of commensal bacteria into germ-free mice induced Nod2 expression. Therefore, Nod2 and intestinal commensal bacterial flora maintain a balance by regulating each other through a feedback mechanism. Dysfunction of Nod2 results in a break-down of this homeostasis.