Gut microbiota-derived GlcNAc-MurNAc is a TLR4 agonist that protects the host gut

Chenyu Li, Christopher Adamson, Allan Wee Ren Ng, Yaquan Liang, Zebin Hong, Jia Tong Loh, Siu-Kin Ng, Jeric Mun Chung Kwan, Shiliu Feng, Evan Wei Long Ng, Sajith Nair, Christiane Ruedl, Sunny Hei Wong, Kong-Peng Lam and Yuan Qiao ()
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Chenyu Li: Nanyang Technological University
Christopher Adamson: Nanyang Technological University
Allan Wee Ren Ng: Nanyang Technological University
Yaquan Liang: Nanyang Technological University
Zebin Hong: Agency for Science, Technology and Research (A*STAR)
Jia Tong Loh: Nanyang Technological University
Siu-Kin Ng: Nanyang Technological University
Jeric Mun Chung Kwan: Nanyang Technological University
Shiliu Feng: Nanyang Technological University
Evan Wei Long Ng: Nanyang Technological University
Sajith Nair: Nanyang Technological University
Christiane Ruedl: Nanyang Technological University
Sunny Hei Wong: Nanyang Technological University
Kong-Peng Lam: 8A Biomedical Grove
Yuan Qiao: Nanyang Technological University

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Gut microbiota-derived peptidoglycan fragments (PGNs) are key signaling molecules that regulate multiple aspects of the host’s health. Yet the exact structures of natural PGNs in hosts have not been fully elucidated. Herein, we developed an LC-HRMS/MS analytical platform for global quantification and profiling of natural PGN subtypes in host gut and sera, unexpectedly revealing the abundance of PGN-derived saccharide moieties that do not resemble canonical ligands of mammalian NOD1/2 receptors. Focusing on the disaccharide GlcNAc-MurNAc (GM), which does not activate NOD1/2 yet still exhibits immunostimulatory effects in host immune cells, we established GM as a mild TLR4 agonist, illustrating an alternate PGN sensing mechanism other than NOD signaling. Importantly, the administration of GM mitigates colonic inflammation in the DSS-induced colitis model in mice via a TLR4-dependent manner, highlighting the in vivo significance of gut microbiota-derived PGN saccharides in maintaining host intestinal homeostasis.

Date: 2025
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DOI: 10.1038/s41467-025-60678-5

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