Decoding a Gut Commensal Signal: Structural and Immunological Profiling of Segatella Copri Lipopolysaccharide

Abstract The immunological effects of lipopolysaccharides (LPSs) from gut microbiota remain poorly explored, overshadowed by the longstanding view of LPS as a prototypical pro‐inflammatory molecule. Herein, we report the first comprehensive chemical and immunological characterization of LPS from Segatella copri DSM 18205, a prominent member of the human oral and intestinal microbiota. This LPS features a unique chemical architecture, including a mannose‐ and glucose‐rich oligosaccharide (OS) and a highly heterogeneous, hypo‐acylated lipid A domain, as elucidated by advanced mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy. Functionally, S. copri LPS displayed attenuated TLR4 activation and weak pro‐inflammatory activity. Strikingly, high‐dimensional cytometry by time‐of‐flight (CyTOF) revealed a selective preservation of CD14 + CD16 + monocytes, immune subsets typically depleted by canonical enterobacterial LPSs. These findings identify S. copri LPS as a chemically and functionally distinct microbial signature, offering new insights into host‐microbiota immune crosstalk and highlighting its potential for microbiome‐informed immunomodulatory strategies.