A probiotic bi-functional peptidoglycan hydrolase sheds NOD2 ligands to regulate gut homeostasis in female mice
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...
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| Format: | Article |
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Nature Portfolio
2023-06-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-38950-3 |
| _version_ | 1797806632439119872 |
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| author | Jie Gao Lei Wang Jing Jiang Qian Xu Nianyi Zeng Bingyun Lu Peibo Yuan Kai Sun Hongwei Zhou Xiaolong He |
| author_facet | Jie Gao Lei Wang Jing Jiang Qian Xu Nianyi Zeng Bingyun Lu Peibo Yuan Kai Sun Hongwei Zhou Xiaolong He |
| author_sort | Jie Gao |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-13T06:10:13Z |
| format | Article |
| id | doaj.art-2f72afde1acb4685bd9c355ec67649a1 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T06:10:13Z |
| publishDate | 2023-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-2f72afde1acb4685bd9c355ec67649a12023-06-11T11:17:54ZengNature PortfolioNature Communications2041-17232023-06-0114111510.1038/s41467-023-38950-3A probiotic bi-functional peptidoglycan hydrolase sheds NOD2 ligands to regulate gut homeostasis in female miceJie Gao0Lei Wang1Jing Jiang2Qian Xu3Nianyi Zeng4Bingyun Lu5Peibo Yuan6Kai Sun7Hongwei Zhou8Xiaolong He9Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical UniversityMicrobiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical UniversityDepartment Gerontology, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s HospitalMicrobiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical UniversityMicrobiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical UniversityDepartment of Gastroenterology, Shenzhen Hospital, Southern Medical UniversityMicrobiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical UniversityDepartment of General Surgery, Nanfang Hospital, Southern Medical UniversityMicrobiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical UniversityMicrobiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical UniversityAbstract 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.https://doi.org/10.1038/s41467-023-38950-3 |
| spellingShingle | Jie Gao Lei Wang Jing Jiang Qian Xu Nianyi Zeng Bingyun Lu Peibo Yuan Kai Sun Hongwei Zhou Xiaolong He A probiotic bi-functional peptidoglycan hydrolase sheds NOD2 ligands to regulate gut homeostasis in female mice Nature Communications |
| title | A probiotic bi-functional peptidoglycan hydrolase sheds NOD2 ligands to regulate gut homeostasis in female mice |
| title_full | A probiotic bi-functional peptidoglycan hydrolase sheds NOD2 ligands to regulate gut homeostasis in female mice |
| title_fullStr | A probiotic bi-functional peptidoglycan hydrolase sheds NOD2 ligands to regulate gut homeostasis in female mice |
| title_full_unstemmed | A probiotic bi-functional peptidoglycan hydrolase sheds NOD2 ligands to regulate gut homeostasis in female mice |
| title_short | A probiotic bi-functional peptidoglycan hydrolase sheds NOD2 ligands to regulate gut homeostasis in female mice |
| title_sort | probiotic bi functional peptidoglycan hydrolase sheds nod2 ligands to regulate gut homeostasis in female mice |
| url | https://doi.org/10.1038/s41467-023-38950-3 |
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