Human gut commensalAlistipes timonensismodulates the host lipidome and delivers anti-inflammatory outer membrane vesicles to suppress colitis in anIl10-deficient mouse model

Abstract

Correlative studies have linked human gut microbes to specific health conditions.Alistipesis one such microbial genus negatively linked to inflammatory bowel disease (IBD). However, the protective role ofAlistipesin IBD has not been studied and the underlying molecular mechanisms also remain unknown. In this study, colonization ofIl10-deficient mice withAlistipes timonensisDSM 27924 delays the development of colitis. Colonization withAlistipesdoes not significantly alter the gut microbiome composition during colitis development, but instead shifts the host plasma lipidome, increasing phosphatidic acids while decreasing triglycerides. Outer membrane vesicles (OMVs) derived fromAlistipesare also detected in the plasma of colonized mice, which carry metabolites with immunomodulatory potential into the host circulatory system. We further demonstrate that fractions ofA. timonensisOMVs suppress LPS-inducedIl6,Il1b, andTnfaexpressionin vitroin murine macrophages. We detect immunomodulatory sulfonolipids (SoLs) in the active fraction, which are also increased in the blood ofA. timonensis-colonized mice; and we identify other putative bioactive lipids in theA. timonensisOMVs. Thus,A. timonensisOMVs represent a potential mechanism forAlistipes-mediated delay of colitis progression inIl10-deficient mice through the delivery of immunomodulatory lipids, including SoLs, and modulation of the host plasma lipidome.