9.1 Agonists of TGR5 and FXR
Progress has been made in the study of the efficacy of natural or synthetic TGR5 and FXR agonists in the treatment of liver and intestinal diseases. In an oxazolone-induced colitis model, the GPBAR1 agonist BAR501 alleviated the symptoms of enteritis and inhibited inflammatory markers68. GW4064 activates FXR and improves LPS-induced ileocolitis by inhibiting mitochondrial dysfunction in mice118. FXR activation also inhibits endoplasmic reticulum stress and inflammation 119. In tumor-bearing models, the FXR agonist synergistically inhibited the growth of hepatocellular carcinoma with the anti-PD-1 antibody120. Obeticholic acid (OCA) is a clinically approved selective FXR agonist and Nanoemulsion-loaded OCA (OCA-NE) results in increased secretion of CXCL16, IFN-γ. The number of NKT cells in the tumor increases, resulting in a better liver tumor inhibition effect. The development of BA receptors, such as TGR5 and FXR agonists, and the targeted delivery of these drugs have greatly facilitated precision cancer therapy121. OCA is used to treat non-alcoholic steatohepatitis (NASH) by inhibiting activation of the NLRP3 inflammasome122. OCA accelerates the maturation of mouse intestinal epithelial cells in a constitutive androstane receptor (CAR)-dependent manner123. Further research on OCA is necessary to expand its application range. Salvia-Nelumbinis naturalis (SNN), a traditional Chinese medicine, is effective in the treatment of NASH. It activates the FXR-FGF15 signaling pathway in the colon by increasing BA-associated microbiome124. Research on the regulatory mechanism of traditional Chinese medicine on hepato-intestinal disease has important implications for better application of traditional Chinese medicine and the development of new targeted drugs.