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

: 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.