Exploring the role of FXR signaling in maintaining ileal mucosa integrity in subjects with altered glucose tolerance conditions

Aim: Treatment with the FXR agonist obeticholic acid (OCA) has been found to improve glucose metabolism in type 2 diabetes (T2DM) subjects with mechanisms not completely elucidated. In the gut, FXR is mainly expressed in the ileum where promotes transcription of fibroblast growth factor-19 (FGF19) having positive effects on glucose homeostasis, and maintains gut barrier integrity by regulating tight-junction (TJ) proteins expression. Herein, we evaluate whether subjects with dysglycemic conditions exhibit a down-regulation of the intestinal FXR-FGF19-TJ axis and whether treatment with OCA may revert this aberration. Methods: Levels of FXR, FGF19 and TJ proteins and pro-inflammatory cytokines were assessed in ileal mucosa specimens collected during colonoscopy from 53 subjects subdivided according to their glucose tolerance in: NGT (n=26), prediabetes (n=12) and T2DM (n=15). Effects of OCA treatment was assessed on ileal mucosa specimens of subjects with prediabetes or T2DM cultured in absence or presence of OCA for 6h. Results: Ileal FXR protein and mRNA levels were progressively decreased in prediabetes (-26%) and T2DM (-34%) as compared to the NGT group (both P<0.05). Ileal FXR downregulation was paralleled by lower FGF19 expression and circulating levels (both P<0.05). Additionally, we observed a progressive decrease of proteins and mRNA levels of the TJ zonulin (ZO)-1, occludin and claudin-1 (P<0.05 for all) with an activation of pro-inflammatory pathways in the ileal mucosa of subjects with prediabetes and T2DM as compared to the NGT group. OCA treatment resulted in an up-regulation of FGF19 expression and release (both P<0.01), mRNA and protein levels of the TJ ZO-1, occludin and claudin-1 and in reduced pro-inflammatory cytokines synthesis and release (P<0.05 for all). Conclusion: FXR stimulation by OCA treatment reverts the altered FGF-19/TJ axis in subjects with prediabetes and T2DM, indicating intestinal FXR signaling as a novel target for prevention and/or treatment of T2DM.