Clonal Parabacteroides from Gut Microfistulous Tracts as Transmissible Cytotoxic Succinate-Commensal Model of Crohn's Disease Complications

Singh, V.; West, G.; Fiocchi, C.; Good, C. E.; Katz, J.; Jacobs, M. R.; Dichosa, A. E. K.; Flask, C.; Wesolowski, M.; McColl, C.; Grubb, B.; Ahmed, S.; Bank, N. C.; Thamma, K.; Bederman, I.; Erokwu, B.; Yang, X.; Sundrud, M. S.; Menghin, P.; Basson, A. R.; Ezeji, J.; Viswanath, S. E.; Veloo, A.; Sykes, D. B.; Cominelli, F.; Rodriguez-Palacios, A.

doi:10.1101/2024.01.09.574896

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bioRxiv · 10.1101/2024.01.09.574896

Clonal Parabacteroides from Gut Microfistulous Tracts as Transmissible Cytotoxic Succinate-Commensal Model of Crohn's Disease Complications

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Abstract

Crohns 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.

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Singh, V., West, G., Fiocchi, C., Good, C. E., Katz, J., Jacobs, M. R., Dichosa, A. E. K., Flask, C., Wesolowski, M., McColl, C., Grubb, B., Ahmed, S., Bank, N. C., Thamma, K., Bederman, I., Erokwu, B., Yang, X., Sundrud, M. S., Menghin, P., Basson, A. R., Ezeji, J., Viswanath, S. E., Veloo, A., Sykes, D. B., Cominelli, F., Rodriguez-Palacios, A.. 2024-01-10. Clonal Parabacteroides from Gut Microfistulous Tracts as Transmissible Cytotoxic Succinate-Commensal Model of Crohn's Disease Complications. https://doi.org/10.1101/2024.01.09.574896

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