Terminalia bellirica ethanol extract ameliorates nonalcoholic fatty liver disease in mice by amending the intestinal microbiota and faecal metabolites

Terminalia bellirica (Gaertn.) Roxb. (TB) is a traditional Tibetan medicine used to treat hepatobiliary diseases. However, modern pharmacological evidence of the activities and potential mechanisms of TB against nonalcoholic fatty liver disease (NAFLD) are still unknown.This study aimed to evaluate the anti-NAFLD effect of ethanol extract of TB (ETB) and investigate whether its ameliorative effects are associated with the regulation of intestinal microecology.In this study, the curative effects of ETB on NAFLD were evaluated in mice fed a choline-deficient, L-amino acid defined, high fat diet (CDAHFD). Biochemical markers and hepatic histological alterations were detected. Gut microbiota and faecal metabolites were analyzed by 16S rRNA gene sequencing and liquid chromatograph mass spectrometer (LC‒MS) profiling.The results showed that oral treatment with middle- and high-dose ETB significantly improved features of NAFLD, reducing the levels of TG, LDL-C, ALT and AST, and increasing the level of HDL-C. Liver histopathologic examination demonstrated that ETB attenuated lipid accumulation and hepatocellular necrosis. ETB treatment restored the structural disturbances of gut microbiota induced by CDAHFD, reduced the levels of Intestinimonas, Lachnoclostridium, and Lachnospirace-ae_FCS020_group, and increased Akkermansia and Bifidobacterium. Moreover, untargeted metabolomics analysis revealed that ETB could restore the disrupted taurine and hypotaurine metabolism, glycine, serine and threonine metabolism, and glutathione metabolism of the intestinal bacterial community in NAFLD mice.ETB was effective in ameliorating the NAFLD, possibly by remodelling the gut microbiota composition and modulating the faecal metabolism metabolites of the host, highlighting the potential of TB as a resource for the development of anti-NAFLD drugs.