Deciphering the Chemical Language of the Immunomodulatory Properties of Veillonella parvula Lipopolysaccharide

Veillonella parvula, prototypical member of the oral and gut microbiota, is at times commensal yet also potentially pathogenic. The definition of the molecular basis tailoring this contrasting behavior is key for broadening our understanding of the microbiota‐driven pathogenic and/or tolerogenic mechanisms that take place within our body. In this study, we focused on the chemistry of the main constituent of the outer membrane of V. parvula, the lipopolysaccharide (LPS). LPS molecules indeed elicit pro‐inflammatory and immunomodulatory responses depending on their chemical structures. Herein we report the structural elucidation of the LPS from two strains of V. parvula and show important and unprecedented differences in both the lipid and carbohydrate moieties, including the identification of a novel galactofuranose and mannitol‐containing O‐antigen repeating unit for one of the two strains. Furthermore, by harnessing computational studies, in vitro human cell models, as well as lectin binding solid‐phase assays, we discovered that the two chemically diverse LPS immunologically behave differently and have attempted to identify the molecular determinant(s) governing this phenomenon. Whereas pro‐inflammatory potential has been evidenced for the lipid A moiety, by contrast a plausible “immune modulating” action has been proposed for the peculiar O‐antigen portion. The chemistry of lipopolysaccharides (LPS) from gut microbes might tip the delicate balance towards tolerance or inflammation. By analyzing the chemistry of LPS from two strains of the pathobiont Veillonella parvula, key and unprecedented structural differences were uncovered, which were reflected in diverse immunoactivities. Attempts were made to identify the molecular determinants governing this phenomenon.