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bioRxiv · 10.1101/2024.10.03.616279

Gut Microbial Impact on Colitis and Colitis-Associated Carcinogenesis in a Primary Sclerosing Cholangitis-IBD Model

Awoniyi, M.·Meadows, V.·Ngo, B.·Conskuner, D.·Montgomery, S. A.·Farmer, M.·Liu, B.·Zhou, H.·Roach, J.·Stappenbeck, T.·Sartor, B.
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Abstract

Background and AimsPrimary sclerosing cholangitis (PSC) associated inflammatory bowel diseases (IBD) increase colorectal dysplasia and malignancy risk. Current mouse models do not adequately replicate human PSC-IBD, limiting mechanistic understanding and therapeutic development. This study uses Mdr2/Il10 double knockout (DKO) mice to examine microbiota roles in mediating colitis, colitis-associated colorectal dysplasia and hepatobiliary inflammation/fibrosis. GoalDevelop and phenotype a chronic spontaneous PSC-IBD mouse model, emphasizing colitis, colonic dysplasia, hepatobiliary inflammation/ fibrosis and the functional roles of resident microbiota. MethodsWe utilized germ-free (GF) and specific-pathogen-free Mdr2/Il10 DKO, Il10-/- and Mdr2-/- mice to model PSC-IBD. We monitored colonic dysplasia progression, colitis kinetics and severity by lipocalin-2, cytokine measurement, and tissue evaluations of colon and liver. We manipulated the microbiome to assess its functional effects. ResultsDKO mice exhibited age- and region-specific accelerated colitis and spontaneous colonic dysplasia progressing to high-grade invasive adenocarcinomas. Despite aggressive colonic inflammation, DKO mice showed reduced hepatic fibrosis, increased hepatic reparative macrophages, and matrix metalloproteinase activity compared to Mdr2-/- mice. GF DKO had heightened liver inflammation and mortality with absent colitis and colonic dysplasia, reversed with microbial reconstitution from DKO mice. Changes in DKO primary/secondary bile acid profiles mirrored those in PSC-IBD. ConclusionThe Mdr2/Il10 DKO model mirrors key factors in PSC-IBD patients in terms of inflammation and carcinogenesis. We found an important role for the dysbiotic microbiota in DKO mice for disease onset and progression. Targeting microbiota and bile acid metabolism may provide promising strategies for developing effective PSC-IBD therapies.

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Awoniyi, M., Meadows, V., Ngo, B., Conskuner, D., Montgomery, S. A., Farmer, M., Liu, B., Zhou, H., Roach, J., Stappenbeck, T., Sartor, B.. 2024-10-03. Gut Microbial Impact on Colitis and Colitis-Associated Carcinogenesis in a Primary Sclerosing Cholangitis-IBD Model. https://doi.org/10.1101/2024.10.03.616279

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