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

Author

Listed:
  • 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
    Southern Medical University)

  • Xiaolong He

    (Southern Medical University)

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.

Suggested Citation

  • Jie Gao & Lei Wang & Jing Jiang & Qian Xu & Nianyi Zeng & Bingyun Lu & Peibo Yuan & Kai Sun & Hongwei Zhou & Xiaolong He, 2023. "A probiotic bi-functional peptidoglycan hydrolase sheds NOD2 ligands to regulate gut homeostasis in female mice," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38950-3
    DOI: 10.1038/s41467-023-38950-3
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    1. Shikha Nayar & Joshua K. Morrison & Mamta Giri & Kyle Gettler & Ling-shiang Chuang & Laura A. Walker & Huaibin M. Ko & Ephraim Kenigsberg & Subra Kugathasan & Miriam Merad & Jaime Chu & Judy H. Cho, 2021. "A myeloid–stromal niche and gp130 rescue in NOD2-driven Crohn’s disease," Nature, Nature, vol. 593(7858), pages 275-281, May.
    2. Pinaki Panigrahi & Sailajanandan Parida & Nimai C. Nanda & Radhanath Satpathy & Lingaraj Pradhan & Dinesh S. Chandel & Lorena Baccaglini & Arjit Mohapatra & Subhranshu S. Mohapatra & Pravas R. Misra &, 2017. "A randomized synbiotic trial to prevent sepsis among infants in rural India," Nature, Nature, vol. 548(7668), pages 407-412, August.
    3. Bianca Lungu & Ovidiu Georgescu & Beatrice Tudor & Roxana Buzan & Manuela Grijincu & Monica Cotarca & Carmen Panaitescu & Kuan-Wei Chen & Iuliu Torda & Calin Mircu & Ioan Hutu, 2022. "Study of some factors associated with polyclonal antibody production in rabbit," Eximia Journal, Plus Communication Consulting SRL, vol. 4(1), pages 14-18, April.
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