Fibroblast Growth Factor 19 modulates intestinal microbiota and inflammation in presence of Farnesoid X Receptor

Background: Disruption of bile acid (BA) homeostasis plays a key role in intestinal inflammation. The gut-liver FXR-FGF19 axis is the main regulator of hepatic BA synthesis and BA pool. Recent studies have shown an important relation between FGF19 levels, BA synthetic rates and intestinal disorders. In this study we aimed to investigate for the first time the potential intestinal anti-inflammatory activity of an FGF19 analogue. Methods: A novel engineered non-tumorigenic variant of the FGF19 protein, M52-WO 2016/0168219 was generated. WT and FXRnull mice were injected with AAV-FGF19-M52 or the control AAV-GFP and subjected to Sodium Dextran Sulphate-induced colitis. Findings: FGF19-M52 reduced BA synthesis and pool size, modulated its composition and protected mice from intestinal inflammation. These events were coupled with inhibition of inflammatory immune response, direct modulation of microbiota composition and preservation of the intestinal epithelial barrier integrity. Interestingly, FGF19-M52 driven systemic and local anti-inflammatory activity was completely abolished in Farnesoid X Receptor (FXR)null mice, thus underscoring the need of FXR to guarantee enterocytes' fitness and complement FGF19 anti-inflammatory activity. Moreover, we show that circulating FGF19 levels are reduced in patients with Crohn's disease. Interpretation: Our data demonstrate that reactivation of the FXR-FGF19 axis in a murine model of intestinal inflammation could bona fide provide modulation of BA metabolism with consequent reduction of intestinal inflammation. This points to the therapeutic potential of FGF19 in the treatment of intestinal inflammation with concomitant derangement of BA homeostasis.