Jiangzhi granule attenuates non-alcoholic steatohepatitis through modulating bile acid in mice fed high-fat vitamin D deficiency diet

Vitamin D deficiency is a common phenomenon in non-alcoholic fatty liver disease (NAFLD) and the progressive non-alcoholic steatohepatitis (NASH). Jiangzhi Granule (JZG) formula is a Traditional Chinese medicine prescription, and has been found effective against NAFLD/NASH. Here we showed that vitamin D deficiency could accelerate NASH development, and reduce vitamin D receptor (VDR) expression. JZG treatment alleviated high-fat vitamin D deficient (HF-VDD) diet-induced NASH in C57BL/6 J mice, and up-regulated both the liver and intestinal VDR expression independent of 1,25-dihydroxy-vitamin D3 level. We analyzed the fecal BA profile using liquid chromatography coupled with triple quadrupole mass spectrometry (UPLC-TQMS) -based metabolomics, and found that JZG modulated fecal BA profile, predominantly increased the ratio of secondary BA species, as well as the expression of tight junction proteins Zona occludens 1(ZO-1) and occludin in the colon. In vitro experiment further confirmed the representative secondary BA species lithocholic acid (LCA) and keto-LCA upregulated the expression of and ZO-1 through VDR in LPS-stressed Caco-2 cells. Our results identified the endogenous VDR activation by JZG through modulating BA species in vitamin D deficiency-related NASH mice, thus providing evidence for the clinical application of JZG in treating NASH.