Kuhuang alleviates liver fibrosis by modulating gut microbiota-mediated hepatic IFN signaling and bile acid synthesis

Abstract

Background: Liver fibrosis is a common outcome of the pathological progression of chronic liver disease; however, no specific and effective therapeutic agent has been approved for its treatment. We investigated the effects of Kuhuang on liver fibrosis and the underlying mechanisms of action.Materials and methods: To induce hepatic fibrosis, either 3,5-diethoxycarbonyl-1,4-dihydro-collidine (DDC) diet was administered, or bile duct ligation (BDL) surgery was performed on C57BL/6 mice. Kuhuang was orally administered to mice for 7 days before and after bile duct ligation or 4 weeks with a DDC diet. Hematoxylin and eosin, Sirius red staining, and immunohistochemical analyses were performed to evaluate hepatic pathology. Hepatic interferon-β (IFN-β) levels were measured using an enzyme-linked immunosorbent assay. RNA sequencing was performed to examine the gene expression profiles of liver tissues. The mRNA expression of inflammatory, profibrotic, and bile acid (BA)-related genes was further validated by qRT-PCR. A targeted metabolomics assay revealed the alteration of the hepatic bile acid (BA) composition. The composition of the gut microbiota was determined via 16S rRNA sequencing.Results: Treatment with Kuhuang attenuated liver fibrosis and reduced the inflammatory response in bile duct ligation and DDC mouse models. In addition, the hepatic IFN signaling pathway was activated following Kuhuang treatment. Kuhuang treatment also significantly decreased hepatic levels of both primary and secondary BAs. In addition, Kuhuang treatment altered gut microbiota composition, with an increased abundance of interferon-inducing Akkermansia and decreased abundance of bile salt hydrolase-producing Lactobacillus, Clostridium, and Bifidobacterium. Furthermore, the abundance of Akkermansia was positively correlated with the hepatic mRNA expression levels of Ifna4, Ifnb, and Isg15, whereas that of Lactobacillus, Clostridium-sensu-stricto-1, and Bifidobacterium was positively correlated with levels of bile acid synthesis-related genes.Conclusion: Our results suggest that Kuhuang plays a protective role during the progression of liver fibrosis, potentially by altering the composition of the gut microbiota, which consequently activates interferon signaling and inhibits bile acid synthesis in the liver.

Blueberry and Blackberry Anthocyanins Ameliorate Metabolic Syndrome by Modulating Gut Microbiota and Short-Chain Fatty Acids Metabolism in High-Fat Diet-Fed C57BL/6J Mice

“…Meanwhile, the abundance of Actinobacteria in the HFD group significantly increased compared to that in the Chow group, which is consistent with some previous studies. , However, the effect of HFD on the abundance of Actinobacteria is not entirely clear, as there is some inconsistency in the results reported by previous studies, variations in experimental design, sample sources, or other factors among studies may account for the inconsistencies observed. , At the genus level, administration of VA and RA led to the decrease of the abundance of Bifidobacterium induced by HFD, which is capable of fermenting polysaccharides and other complex carbohydrates, producing SCFAs and other beneficial metabolites, and Bifidobacterium is important for the immune system . The increase in the abundance of Bifidobacterium might be a result of gut microbiota imbalance or the host’s response to inflammation induced by HFD . VA and RA also decreased the abundance of Allobaculum belonging to the phylum Firmicutes, which is positively related to lipid metabolism, glucose metabolism, and the progression of inflammation. , Additionally, the administration of the HFD could decrease the abundance of Prevotella , which belongs to the Bacteroidetes phylum.…”

“…65 The increase in the abundance of Bif idobacterium might be a result of gut microbiota imbalance or the host's response to inflammation induced by HFD. 66 VA and RA also decreased the abundance of Allobaculum belonging to the phylum Firmicutes, which is positively related to lipid metabolism, glucose metabolism, and the progression of inflammation. 67,68 Additionally, the administration of the HFD could decrease the abundance of Prevotella, which belongs to the Bacteroidetes phylum.…”

Dietary Methionine Restriction Improves Gut Health and Alters the Plasma Metabolomic Profile in Rats by Modulating the Composition of the Gut Microbiota

“…Moreover, TCA and TCDCA downregulate the expression of hepatic FXR and are positively associated with pro-inflammatory cytokines, such as TNF-α [42,43], supporting our observation in this study. It has been reported that bile salt hydrolase-producing bacteria such as Clostridium_sensu_stricto_1 and Bacteroidetes hydrolyze taurine-and glycine-conjugated BAs to unconjugated free forms, which can be further converted to secondary BAs [40,44]. Therefore, the increased abundance of Clostridium_sensu_stricto_1 and Bacteroidetes in the cecal contents may account for the depleted taurine-conjugated BAs in the MetR-fed rats.…”