FXR stimulation by obethicolic acid treatment restores gut mucosa functional and structural integrity in subjects with altered glucose tolerance

The Farnesoid X receptor (FXR)-Fibroblast growth factor19 (FGF19) axis is involved in maintaining glucose homeostasis and gut tight-junction (TJ) integrity. We evaluated whether subjects with prediabetes or type 2 diabetes (T2DM) have altered intestinal FXR-FGF19 signaling and barrier function, and whether high glucose (HG) exposure may cause these aberrations. Moreover, we tested beneficial effects of the FXR agonist Obeticholic acid (OCA) on intestinal FXR signaling in subjects with prediabetes and T2DM. Sixty subjects with different glucose tolerance [normal glucose tolerance (NGT, n=25), prediabetes (n=19), T2DM (n=16)] undergone to ileocolonoscopy with collection of ileal mucosa biopsies, which were used for expression profiling analysis of FXR/FGF19/TJ axis and tissue culture experiments.

Individuals with prediabetes and T2DM displayed lower ileal levels of FXR and its target genes FGF19 and TJ proteins Zonula occludens-1, Occludin and Claudin-1 along with increased pro-inflammatory NF-kB activity and cytokines expression as compared to those with NGT. HG exposure on ileal explants collected from NGT subjects hampered FXR/FGF19/TJ axis. OCA treatment on ileal fragments of prediabetes/T2DM subjects was able to restore FGF19 synthesis and secretion, TJ expression, counteract NF-kB activity, and cytokines expression.

In conclusion, OCA treatment counteracts T2DM-related abnormalities in intestinal FXR/FGF19/TJ axis.