Cellular mechanisms linking the intestine to inflammation involving non-intestinal organs

ABSTRACT Mechanisms driving inflammation, and the possibilities for therapeutic intervention, have expanded dramatically since the discovery that the intestine is linked to inflammatory diseases involving non-intestinal organs. The processes and cell types underpinning this inter-organ link are poorly understood, even for diseases which are coincident with intestinal inflammation. One prominent disease with clear links to intestinal inflammation is primary sclerosing cholangitis (PSC), an immune-mediated disease hallmarked by liver fibrosis. There is no therapy that prevents PSC from getting worse, and liver transplant is the only cure—although sometimes, PSC can return even after liver transplant. The driving forces behind PSC-linked liver fibrosis are thought to originate in the intestine and thus, understanding the inflammatory processes that link intestinal inflammation with liver fibrosis would be a breakthrough for this disease. Moreover, these fundamental discoveries would shine new light into processes that link the intestine to inflammation involving non-intestinal organs, an area that holds potential for transformative therapeutics. This project will unlock some of this potential by dissecting cellular mechanisms linking intestinal inflammation with liver fibrosis in a novel mouse model where these diseases occur concomitantly. These studies will offer specific cell types for targeted approaches to treat diseases linked to the intestine, including PSC-linked liver fibrosis, an unstoppable disease that has no cure.