Gut microbial DL-endopeptidase alleviates Crohn's disease via the NOD2 pathway
Gut microbial DL-endopeptidase alleviates Crohn's disease via the NOD2 pathway
复制标题
肠道微生物 DL-内肽酶通过 NOD2 途径缓解克罗恩病
DOI：
10.1016/j.chom.2022.08.002
复制
发表时间：
2022-10-12
影响因子：
30.3
通讯作者：
Zhou, Hongwei
中科院分区：
文献类型：
--
作者：
Gao, Jie;Zhao, Xinmei;Zhou, Hongwei
模式识别受体NOD2感知细菌多肽来调节宿主免疫和维持体内平衡。NOD2的功能缺失突变与克罗恩病（CD）有关，但微生物因素的变化如何影响NOD2信号传导和宿主病理尚不清楚。我们证明厚壁菌门肽聚糖重塑酶，dl -内肽酶，增加了肠道中NOD2配体的水平，并影响结肠炎的预后。全球队列（n = 857）的宏基因组分析显示，CD患者dl -内肽酶基因丰度在全球范围内下降，与结肠炎呈负相关。dl -内肽酶活性低的乳糜泻患者的粪便微生物群使小鼠易患结肠炎。给药dl内肽酶，而不是活性位点突变，通过NOD2途径减轻结肠炎。治疗性地恢复NOD2配体，使用产生dl -内肽酶的唾液乳杆菌菌株或米法莫肽（一种穆拉迈尔二肽的临床类似物），具有有效的抗结肠炎作用。我们的研究表明，dl -内肽酶的缺失通过NOD2信号传导参与了CD的发病机制，提供了一个治疗上可改变的靶点。
The pattern-recognition receptor NOD2 senses bacterial muropeptides to regulate host immunity and maintain homeostasis. Loss-of-function mutations in NOD2 are associated with Crohn's disease (CD), but how the variations in microbial factors influence NOD2 signaling and host pathology is elusive. We demonstrate that the Firmicutes peptidoglycan remodeling enzyme, DL-endopeptidase, increased the NOD2 ligand level in the gut and impacted colitis outcomes. Metagenomic analyses of global cohorts (n = 857) revealed that DL-endopeptidase gene abundance decreased globally in CD patients and negatively correlated with colitis. Fecal microbiota from CD patients with low DL-endopeptidase activity predisposed mice to colitis. Administering DL-endopeptidase, but not an active site mutant, alleviated colitis via the NOD2 pathway. Therapeutically restoring NOD2 ligands with a DL-endopeptidase-producing Lactobacillus salivarius strain or mifamurtide, a clinical analog of muramyl dipeptide, exerted potent anti-colitis effects. Our study suggests that the depletion of DL-endopeptidase contributes to CD pathogenesis through NOD2 signaling, providing a therapeutically modifiable target.