Akebia trifoliata extracts attenuate liver injury via gut-liver axis in a murine model of nonalcoholic fatty liver disease with low-grade colitis.

Abstract

Perturbations in intestinal homeostasis can significantly influence the pathophysiology of metabolic disorders through the gut-liver axis, with nonalcoholic fatty liver disease (NAFLD) being a prime example. Our previous study demonstrated that Akebia trifoliata extracts (APE) exhibit significant anti-inflammatory activity; however, their protective effect on the intestinal barrier and liver remain unclear. In this study, we established a TNF-α-induced Caco-2 cell monolayer model and a mouse model of NAFLD with DSS-induced low grade colitis. Serum, intestinal tissue, and liver samples were used to assess the effects of APE effects on inflammation, gut barrier integrity, and hepatic lipid metabolism. 16S rRNA sequencing, targeted metabolomics, and RNA sequencing were employed to examine gut microbiota composition, short-chain fatty acid metabolism, and liver gene expression profiles. Results indicated that APE effectively alleviates hepatic steatosis induced by HFD and DSS reducing by hepatocellular lipid accumulation. APE treatment also reduced inflammatory cytokine levels, including TNF-α, IL-6, and IL-1β. Additionally, APE restored the impaired intestinal barrier by reducing intestinal permeability, enhancing tight junction protein expression, and modulating gut microbiota composition. Notably, APE reduced the abundance of Verrucomicrobia and Prevotellaceae, while increasing the abundance of Proteobacteria, Lachnospiraceae, Ruminococcaceae, and Bifidobacterium. Correlation analysis indicated that the abundance of Ruminococcaceae was negatively correlated with levels of d-mannitol, liver LPS, and IL-6, while it was positively correlated with butyrate concentration. Furthermore, liver inflammatory factors, TG, TC, IL-6 and LPS levels were positively correlated with serum d-mannitol levels, but negatively correlated with intestinal ZO-1 expression and acetic and propionic acid levels. This study is the first to explore the hepatoprotective effects of bioactives from Akebia trifoliata via the gut-liver axis, thereby broadening the application value of Akebia trifoliata.