Arctigenin-mediated gut microbiota and metabolite butyric acid positively affect the intestinal barrier and hepatic lipid metabolism in diet-induced metabolic dysfunction-associated fatty liver disease

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common chronic disease and a major cause of liver-related morbidity and mortality. Alcohol consumption and high-fat diet (HFD) often co-exist and are common risk factors in the development of MAFLD. However, there are still no effective therapeutic treatments. Gut microbiota plays a crucial role in the pathogenesis of fatty liver and have emerged as potential therapeutic targets. Arctium lappa L. is widely consumed and arctigenin (AG) is its major bioactive components. We aimed to assess the protective effects of AG on 3 MAFLD models induced by ethanol, HFD, and combined ethanol and HFD and investigate the underlying mechanisms focusing on the gut-liver axis. Our results showed that AG effectively ameliorated serum lipid profile, hepatic lipid accumulation and fibrosis, and attenuated intestinal barrier breakdown, inflammatory response and Th17/Treg immune imbalance in 3 MAFLD models. In addition, AG reversed gut microbiota dysbiosis and enriched short-chain fatty acids (SCFA) producers such as Muribaculum, Alloprevotella, Rikenellaceae and Butyricimonas. Correspondingly, AG increased SCFA levels, especially butyric acid, activated the its receptors G protein-coupled receptor (GPR) 41, GPR43 and GPR109a, inhibited histone deacetylase 3 (HDAC3) protein levels and toll-like receptor 4 (TLR4)-nuclear factor kappa-B (NFκB) signaling, which facilitated the intestinal homeostasis. Moreover, AG promoted the absorption of SCFA and activates the GPR43-adenosine 5'-monophosphate-activated protein kinase (AMPK)-signaling axis to regulates the process of fatty acid synthesis and oxidation, lipid uptake and transport, and cholesterol synthesis and secretion. These findings reveal for the first time the mechanism of AG ameliorating MAFLD by regulating the microbiota and metabolite butyric acid-gut-liver axis, supporting the great potential of AG as a novel prebiotic against MAFLD.