ClonalParabacteroidesfrom Gut Microfistulous Tracts as Transmissible Cytotoxic Succinate-Commensal Model of Crohn’s Disease Complications

Abstract

AbstractCrohn’s disease (CD) has been traditionally viewed as a chronic inflammatory disease that cause gut wall thickening and complications, including fistulas, by mechanisms not understood. By focusing onParabacteroides distasonis(presumed modern succinate-producing commensal probiotic), recovered from intestinal microfistulous tracts (cavernous fistulous micropathologies CavFT proposed as intermediate between ‘mucosal fissures’ and ‘fistulas’) in two patients that required surgery to remove CD-damaged ilea, we demonstrate that such isolates exert pathogenic/pathobiont roles in mouse models of CD. Our isolates are clonally-related; potentially emerging as transmissible in the community and mice; proinflammatory and adapted to the ileum of germ-free mice prone to CD-like ileitis (SAMP1/YitFc) but not healthy mice (C57BL/6J), and cytotoxic/ATP-depleting to HoxB8-immortalized bone marrow derived myeloid cells from SAMP1/YitFc mice when concurrently exposed to succinate and extracts from CavFT-derivedE. coli, but not to cells from healthy mice. With unique genomic features supporting recent genetic exchange withBacteroides fragilis-BGF539, evidence of international presence in primarily human metagenome databases, these CavFTPdisisolates could represent to a new opportunisticParabacteroidesspecies, or subspecies (‘cavitamuralis’) adapted to microfistulous niches in CD.