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The secreted protein is 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, an uncharacterized secreted protein (named LPH here) shared by most of these probiotic strains (8/10) was identified and proved to protect mice from colitis in multiple models. Functional studies showed LPH is a bi-functional peptidoglycan hydrolase (PGH) with both N-Acetyl-β-D-muramidase and DL-endopeptidase activities that could generate muramyl dipeptide (MDP), a NOD2 ligand with high efficiency. Different active site mutants of LPH in combination with Nod2 knockout mice confirmed that LPH exerts colitis-protective effects through MDP-NOD2 signaling. Furthermore, we validated that LPH could also exert protective effects on other NOD2-associated diseases such as colitis-associated colorectal cancer. Our study provides a new probiotic enzyme to efficiently enhance the NOD2 signaling in vivo and reveals a molecular mechanism of traditional probiotics.