Gut Microbiota Dysbiosis and LPS/NLRP3/GSDMD Pyroptosis Drive Hepatic Fibrosis: Therapeutic Potential of a Synbiotic Intervention.

Hepatic fibrosis (HF) is the inevitable course from chronic hepatitis to liver cirrhosis with limited treatment options. Our previous studies have found that a synbiotic alleviates autoimmune hepatitis in mice by improving the gut microbiota. However, whether this synbiotic can prevent the progression of HF and its underlying mechanism remains unclear. Therefore, we explored the effects and mechanism of this synbiotic on concanavalin A (ConA)-induced HF in mice. We found that the synbiotic not only reshaped the gut microbiota by increasing beneficial bacteria such as Bifidobacterium and reducing harmful bacteria such as Allobaculum and Dubosiella but also strengthened the intestinal barrier, reduced the hepatic transfer of lipopolysaccharide (LPS), and inhibited the LPS/NLRP3/GSDMD pyroptosis pathway. It also decreased collagen deposition and alleviated HF in mice in vivo and in LX2 cells in vitro. Fecal microbiota transplantation (FMT) experiments showed that microbiota from fibrotic mice exacerbated gut barrier dysfunction and promoted the LPS-induced pyroptosis pathway. In contrast, microbiota depletion with antibiotics alleviated these effects. In conclusion, our study indicates that gut microbiota dysbiosis and the subsequent activation of the LPS/NLRP3/GSDMD pyroptosis pathway are important factors in the progression of HF. The synbiotic, by regulating the gut microecology and inhibiting the LPS-induced pyroptosis pathway, provides a promising therapeutic strategy for inhibiting HF.