Li Chenyu, Adamson Christopher, Ng Allan Wee Ren, Liang Yaquan, Hong Zebin, Loh Jia Tong, Ng Siu-Kin, Kwan Jeric Mun Chung, Feng Shiliu, Ng Evan Wei Long, Nair Sajith, Ruedl Christiane, Wong Sunny Hei, Lam Kong-Peng, Qiao Yuan
School of Chemistry, Chemical Engineering and Biotechnology (CCEB), Nanyang Technological University, 21 Nanyang Link, Singapore, 637371, Singapore.
Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Singapore, 138673, Singapore.
Nat Commun. 2025 Jul 1;16(1):5577. doi: 10.1038/s41467-025-60678-5.
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.
肠道微生物群衍生的肽聚糖片段（PGNs）是调节宿主健康多个方面的关键信号分子。然而，宿主中天然PGNs的确切结构尚未完全阐明。在此，我们开发了一种LC-HRMS/MS分析平台，用于对宿主肠道和血清中的天然PGN亚型进行全面定量和分析，意外地发现了大量与哺乳动物NOD1/2受体的典型配体不同的PGN衍生糖部分。聚焦于不激活NOD1/2但仍在宿主免疫细胞中表现出免疫刺激作用的二糖GlcNAc-MurNAc（GM），我们确定GM为一种温和的TLR4激动剂，阐明了一种不同于NOD信号传导的PGN感知机制。重要的是，GM的给药通过TLR4依赖性方式减轻了小鼠DSS诱导的结肠炎模型中的结肠炎症，突出了肠道微生物群衍生的PGN糖类在维持宿主肠道稳态中的体内意义。
