@article{d89848d005824963a327e05b7869f42c,
title = "Gut microbial DL-endopeptidase alleviates Crohn's disease via the NOD2 pathway",
abstract = "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.",
keywords = "Crohn's disease, DL-endopeptidase, gut microbiota, metagenomics, NOD2",
author = "Jie Gao and Xinmei Zhao and Shixian Hu and Zhenhe Huang and Mengyao Hu and Shaoqin Jin and Bingyun Lu and Kai Sun and Zhang Wang and Jingyuan Fu and Weersma, {Rinse K.} and Xiaolong He and Hongwei Zhou",
note = "Funding Information: We thank Professor Yu Guangchuang for guidance on plotting. This work was supported by the following funders: National Natural Science Foundation of China ( 81925026 , 82130068 , 31900101 , and 32170111 ); Dutch Heart Foundation IN-CONTROL ( CVON2018-27 ); ERC Consolidator grant (grant agreement no. 101001678 ); NWO -Vici grant ( VI.C.202.022 ); the Netherlands Organ-on-Chip Initiative , an NWO Gravitation project ( 024.003.001 ); Natural Science Foundation of Guangdong Province of China ( 2021A1515010455 and 2021A1515010429 ); and Medical Scientific Research Foundation of Guangdong Province , China ( A2020104 and A2020124 ). Funding Information: We thank Professor Yu Guangchuang for guidance on plotting. This work was supported by the following funders: National Natural Science Foundation of China (81925026, 82130068, 31900101, and 32170111); Dutch Heart Foundation IN-CONTROL (CVON2018-27); ERC Consolidator grant (grant agreement no. 101001678); NWO-Vici grant (VI.C.202.022); the Netherlands Organ-on-Chip Initiative, an NWO Gravitation project (024.003.001); Natural Science Foundation of Guangdong Province of China (2021A1515010455 and 2021A1515010429); and Medical Scientific Research Foundation of Guangdong Province, China (A2020104 and A2020124). Conceptualization, H.Z. X.H. J.G. and R.K.W.; methodology, X.H. J.G. S.H. Z.H. and M.H.; clinical samples, K.S. X.Z. B.L. R.K.W. and S.J.; visualization, X.H. J.G. Z.H. S.H. X.Z. and M.H.; funding acquisition, H.Z. J.G. X.H. and J.F.; supervision, H.Z. X.H. J.G. R.K.W. and J.F.; writing – original draft, X.H. Z.H. J.G. S.H. and Z.W.; writing – review & editing, H.Z. X.H. Z.W. J.G. S.H. J.F. and R.K.W. H.W.Z. is listed as an inventor on patents related to the anti-colitis effect of the isolated L. salivarius and mifamurtide. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = oct,
day = "12",
doi = "10.1016/j.chom.2022.08.002",
language = "English",
volume = "30",
pages = "1435–1449.e1–e9",
journal = "Cell Host and Microbe",
issn = "1931-3128",
publisher = "Cell Press",
number = "10",
}