A probiotic bi-functional peptidoglycan hydrolase sheds NOD2 ligands to regulate gut homeostasis in female mice

Jie Gao, Lei Wang, Jing Jiang, Qian Xu, Nianyi Zeng, Bingyun Lu, Peibo Yuan, Kai Sun (), Hongwei Zhou () and Xiaolong He ()
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Jie Gao: Southern Medical University
Lei Wang: Southern Medical University
Jing Jiang: Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital
Qian Xu: Southern Medical University
Nianyi Zeng: Southern Medical University
Bingyun Lu: Southern Medical University
Peibo Yuan: Southern Medical University
Kai Sun: Southern Medical University
Hongwei Zhou: Southern Medical University
Xiaolong He: Southern Medical University

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Secreted proteins are one of the direct molecular mechanisms by which microbiota influence the host, thus constituting a promising field for drug discovery. Here, through bioinformatics-guided screening of the secretome of clinically established probiotics from Lactobacillus, we identify an uncharacterized secreted protein (named LPH here) that is shared by most of these probiotic strains (8/10) and demonstrate that it protects female mice from colitis in multiple models. Functional studies show that LPH is a bi-functional peptidoglycan hydrolase with both N-Acetyl-β-D-muramidase and DL-endopeptidase activities that can generate muramyl dipeptide (MDP), a NOD2 ligand. Different active site mutants of LPH in combination with Nod2 knockout female mice confirm that LPH exerts anti-colitis effects through MDP-NOD2 signaling. Furthermore, we validate that LPH can also exert protective effects on inflammation-associated colorectal cancer in female mice. Our study reports a probiotic enzyme that enhances NOD2 signaling in vivo in female mice and describes a molecular mechanism that may contribute to the effects of traditional Lactobacillus probiotics.

Date: 2023
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DOI: 10.1038/s41467-023-38950-3

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