Adipose-derived stem cell extracellular vesicles attenuate liver fibrosis via restoration of gut barrier function and modulation of gut microbiota

<b>Aim:</b> Liver fibrosis (LF) is a major pathological stage that may progress to end-stage chronic liver injury but currently lacks effective treatment strategies. Previous studies have shown that adipose-derived stem cell extracellular vesicles (ADSC-EVs) play crucial roles in tissue repair, immune regulation, and anti-inflammatory effects. This study aims to elucidate the therapeutic effect of ADSC-EVs in LF and reveal their regulation mechanisms in gut-liver axis dysregulation. <b>Methods:</b> The LF mouse model was established by intraperitoneal injection of diethylnitrosamine/CCl₄. LF mice for ADSC-EV treatment received ADSC-EVs (200 μg per mouse) twice a week for three weeks. Then, hepatic function tests, liver and gut histopathology, and gut microbiota analyses were performed. <b>Results:</b> ADSC-EVs effectively improved hepatic function, reduced collagen deposition and suppressed hepatic stellate cell activation, exhibiting potent anti-fibrotic potential in LF mice. Additionally, they significantly restored intestinal barrier integrity by reducing intestinal permeability and reinforcing the mucus barrier. Furthermore, ADSC-EV treatment regulated gut microbiota dysbiosis, increased the abundance of beneficial intestinal bacteria such as <i>Akkermansia muciniphila</i>. ADSC-EV intervention also elevated the level of butyric acid in cecal contents and significantly reduced systemic inflammation. <b>Conclusion:</b> Our findings suggest that ADSC-EVs represent a promising novel therapeutic strategy for LF, promoting liver tissue repair, enhancing intestinal barrier function, and maintaining gut homeostasis to establish a virtuous circle within the liver-gut axis.