2. Academic Validation
  3. Gut microbial DL-endopeptidase alleviates Crohn's disease via the NOD2 pathway

Gut microbial DL-endopeptidase alleviates Crohn's disease via the NOD2 pathway

  • Cell Host Microbe. 2022 Aug 25;S1931-3128(22)00395-X. doi: 10.1016/j.chom.2022.08.002.
Jie Gao 1,  Xinmei Zhao 2,  Shixian Hu 3,  Zhenhe Huang 1,  Mengyao Hu 1,  Shaoqin Jin 4,  Bingyun Lu 5,  Kai Sun 6,  Zhang Wang 7,  Jingyuan Fu 8,  Rinse K Weersma 9,  Xiaolong He 10,  Hongwei Zhou 11
Affiliations

Affiliations

  • 1 Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510655, China.
  • 2 Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China.
  • 3 Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen 9713 AV, the Netherlands; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9713 AV, the Netherlands.
  • 4 Department of Gastroenterology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
  • 5 Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong 518101, China.
  • 6 Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China.
  • 7 Institute of Ecological Sciences, School of Life Sciences, South China Normal University, Guangzhou, Guangdong 510515, China.
  • 8 Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9713 AV, the Netherlands; Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, the Netherlands.
  • 9 Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen 9713 AV, the Netherlands. Electronic address: r.k.weersma@mdl.umcg.nl.
  • 10 Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510655, China; Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong 510515, China. Electronic address: hxl2027315@smu.edu.cn.
  • 11 Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510655, China; State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, Guangdong 510515, China. Electronic address: biodegradation@gmail.com.
PMID: 36049483 DOI: 10.1016/j.chom.2022.08.002
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; NOD2; gut microbiota; metagenomics.

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