Evaluation of butyrate and chenodeoxycholic acid (CDCA) for anti-inflammatory and hepatoprotective effects in various liver cancer models.

Abstract

e16257 Background: The gut-liver relationship plays an important role in maintaining the intestinal barrier, regulating immune response, and proliferation of hepatocytes, along with modulating the biochemical profile. Perturbation in the gut results in gut dysbiosis, leading to leaky gut, and immune disorders in the gut, liver and in the host physiology on the whole. Any or all these changes may trigger the occurrence of hepatocellular carcinoma (HCC) in the host. Butyrate (NaBu) is a potent antioxidant, anti-inflammatory, pro-apoptotic, histone deacetylase inhibitor, has a role in Cell cycle arrest, can activate the GPCR, and promotes gut health. Chenodeoxycholic acid (CDCA) can activate Farnesoid-X-Receptor, act as an anti inflammatory, inhibit angiogenesis, maintain glucose homeostasis and insulin resistance, and help in regulating the gut microbiome. NaBu is a SCFA, secondary metabolite produced by the gut microflora; and CDCA, a bile acid metabolite could restore the dysbiotic state of the gut and altered bile acid mechanism respectively and may potentially work on the Gut-Liver axis. Methods: In vitro anti-proliferative efficacy of NaBu and CDCA was determined on HepG2 cells compared with 5-flourouracil (5-FU). Various assays like Cell viability assay by MTT, gene expression study and ROS assay was performed. Reversal potentials of NaBu and CDCA was evaluated in chemical induced HCC male rats. Efficacy was determined by serum biochemical, histopathological, gene expression, HPLC and cytokine studies. Results: The IC50 of NaBu, CDCA and 5-FU are mentioned in the Table. The expression studies showed NaBu was more efficacious than CDCA and 5-FU. The potential concentration of NaBu and CDCA was further given to in-vivo model to check their efficacy and toxicity. The histopathological analysis of NaBu group when compared with diseased control showed at par results with 5-FU. The cytokine levels showed an altered in disease control and was restored in treatment groups. Gut dysbiosis as identified in HPLC analysis showed reversal in Butyrate groups as compared to CDCA group. Conclusions: We can conclude that with the treatment of Butyrate, and CDCA are beneficial for the reversal of HCC with an improved bile acid mechanism and restored gut dysbiosis. The combination effect of butyrate and CDCA showed synergistic effects which can be a potential strategy in treating liver cancer. IC 50 values for 5-fluorouracil, butyrate, and chenodeoxycholic acid (CDCA). 5-Flourouracil IC 50 Butyrate IC 50 CDCA IC 50 131 ± 21µg 672.8 ± 54µg 232.2 ± 21µg