Swertia chirayita ameliorates MAFLD by improving intestinal microenvironment and hepatic lipogenesis

Metabolic-associated fatty liver disease (MAFLD) is emerging as a very serious threat to human health. The search for effective remedies for MAFLD from natural herbs is gaining increasing attention. Swertia chirayita (SC) is a famous herb in China, India, and Nepal. It has long been employed within the traditional Tibetan medical system for managing hepatic disorders. Nevertheless, the therapeutic impacts and possible mechanisms of SC in the context of MAFLD are unclear.

This present investigation was designed to research the pharmacological influence and potential mechanisms of SC in MAFLD rats. We conducted a particular examination of its effects on the intestinal microenvironment and hepatic lipogenesis.

The pharmacological effects of SC were evaluated in MAFLD rats established through a 12-week high-fat diet (HFD) feeding. After 8 weeks of SC administration, biochemical assessments were conducted for body fat, liver function, glucose metabolism, lipid parameters, and inflammatory factors. The main chemical constituents of SC and three short-chain fatty acids (SCFAs) in rat feces were quantitatively analyzed by HPLC. Furthermore, targeted metabolomics, transcriptomics, metagenomics, and Western blotting were employed to investigate possible mechanisms by which SC improves MAFLD.

Treatment with SC significantly ameliorated excessive fat accumulation and insulin resistance in MAFLD rats. It also improved hepatic enzyme activities (AST and ALT), several lipid metrics (TG, TC, and LDL-C), and liver histopathological changes. Moreover, SC attenuated systemic inflammation, as shown by decreased circulating IL-1β, TNF-α, LPS, and IL-6. Metagenomic profiling revealed that SC administration helped reestablish the dysregulation of multiple types of gut microbiota (bacteria, fungi, archaea, and viruses) in MAFLD rats. It improved microbial diversity, community composition, and transkingdom correlations. In addition, SC enhanced gut barrier function by raising the amount of butyric acid, acetic acid, and propionic acid and upregulating the expression of several ZO-1, occludin, and claudin-1. Liver transcriptomic analysis suggested that SC could regulate the metabolism of bile acids (BAs). Importantly, targeted metabolite analysis and western blotting demonstrated that SC improved bile acid dysfunction in MAFLD rats. In particular, SC increased TCDCA, TCA, and DCA, thereby activating the FXR/FGF15 signaling axis. This activation then controlled the production of SHP and SREBP-1c proteins in the hepatic, thereby inhibiting hepatic lipogenesis to improve MAFLD.

SC has shown a good therapeutic effect on MAFLD by improving intestinal microenvironment and hepatic lipogenesis. Specifically, it improves the imbalance of multiple types of gut microbiota, restores disrupted transkingdom interactions, promotes creation of beneficial SCFAs and bile acid, protects the intestinal barrier, and inhibits hepatic lipogenesis by regulating the BAs/FXR/FGF15 and SHP/SREBP-1c signaling pathways.