PDF(Pubmed)
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.
摘要：
分泌的蛋白质是微生物群影响宿主的直接分子机制之一，从而构成了一个有前途的药物发现领域。这里,通过生物信息学指导筛选临床建立的乳酸菌益生菌的分泌组，我们确定了一种未表征的分泌蛋白(此处命名为LPH),该蛋白为这些益生菌菌株中的大多数(8/10)所共有,并证明它在多种模型中保护雌性小鼠免受结肠炎的侵害.功能研究表明，LPH是一种双功能肽聚糖水解酶，具有N-乙酰-β-D-muramidase和DL-内肽酶活性，可以产生胞壁酰二肽（MDP），NOD2配体。LPH的不同活性位点突变体与Nod2敲除雌性小鼠的组合证实LPH通过MDP-NOD2信号传导发挥抗结肠炎作用。此外，我们验证了LPH对雌性小鼠炎症相关结直肠癌也有保护作用.我们的研究报告了一种在雌性小鼠体内增强NOD2信号传导的益生菌酶，并描述了可能有助于传统乳酸菌益生菌作用的分子机制。
