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Clonal Parabacteroides from Gut Microfistulous Tracts as Transmissible Cytotoxic Succinate-Commensal Model of Crohn's
Abstract:
Crohn'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 on Parabacteroides 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-derived E. coli , but not to cells from healthy mice. With unique genomic features supporting recent genetic exchange with Bacteroides fragilis -BGF539, evidence of international presence in primarily human metagenome databases, these CavFT Pdis isolates could represent to a new opportunistic Parabacteroides species, or subspecies (' cavitamuralis' ) adapted to microfistulous niches in CD.
Insights
Certain Parabacteroides distasonis strains, found in Crohn's disease (CD) fistulas, act as pathobionts. These bacteria promote inflammation and gut damage in mouse models, suggesting a novel role in CD pathogenesis.
Area of Science:
- Microbiology
- Gastroenterology
- Immunology
Background:
- Crohn's disease (CD) pathogenesis remains incompletely understood, with mechanisms causing gut wall thickening and fistulas unclear.
- Parabacteroides distasonis, a succinate-producing commensal, was investigated in the context of CD-associated microfistulas.
- Cavernous fistulous micropathologies (CavFT) were identified as potential intermediates between mucosal fissures and fistulas in CD.
Conclusions:
- CavFT-derived P. distasonis isolates exhibit pathogenic/pathobiont characteristics relevant to Crohn's disease.
- These findings suggest a potential role for specific P. distasonis strains in driving CD-associated ileitis and microfistula formation.
- Genomic analysis indicates potential for a new opportunistic Parabacteroides subspecies, 'cavitamuralis', adapted to microfistulous environments in CD.
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