FXR agonist GW4064 improves the liver and intestinal pathology and alters bile acid metabolism in rats undergoing small intestinal resection.

Mortality associated with liver disease was observed in patients with short bowel syndrome (SBS); however, its mechanism remains unclear. Bile acid (BA) dysmetabolism may be one of the putative mechanisms, and farnesoid X receptor (FXR) is the key regulator of BA synthesis. Here, we showed that in a rat model of small bowel resection associated with liver disease (SBR-ALD), BA composition of hepatic tissues reflected a larger proportion of primary and secondary unconjugated BAs, and those of colon contents and serum showed an increased ratio of secondary unconjugated BAs. Both hepatic and intestinal regulation of BA synthesis was characterized by a blunted hepatic FXR activation response. Gene expression of the key enzymes in BA synthesis was activated. After intervention with FXR agonist GW4064, both liver histology and serum transaminase activity were improved, which demonstrated the attenuation of SBR-ALD. BA compositions of hepatic tissue, colon contents, and serum were recovered and were closer to those of the sham group. Expression levels of hepatic FXR and its target genes were activated. The study showed that FXR agonist GW4064 could balance BA dysmetabolism to alleviate hepatotoxicity in SBR animals. GW4064 intervention resulted in a decrease in fecal bile excretion and elevated plasma/hepatic conjugated BA levels. GW4064 increased the reabsorption of conjugated BAs by inducing ASBT expression in the ileum. Concomitantly, FXR activation in the presence of GW4064 decreased BA production by repressing the expression of key synthetases. These findings provide a clinical research direction for the prevention of SBS with liver disease.