Prevotella histicola improves metabolic-associated fatty liver disease by promoting lipid droplet autophagy and inhibiting ER stress.

Metabolically associated fatty liver disease (MAFLD), a prevalent chronic liver disorder linked to metabolic dysfunction, is marked by hepatic lipid accumulation and inflammatory response. Treatment options are limited, yet probiotics show potential in modulating the gut-liver axis. Prevotella histicola (P. histicola), known for its anti-oxidant and anti-inflammatory features, provides protection against metabolic diseases, but its role in MAFLD remains unclear. This study explored P. histicola in mice with high-fat diet (HFD)-induced MAFLD, revealing that oral administration of P. histicola reduced HFD-induced weight gain, fasting hyperglycemia, hepatic steatosis, and liver damage, with histology indicating diminished hepatic lipid droplets and inflammation. In vitro, P. histicola supernatant reversed free fatty acid-induced lipid accumulation, apoptosis, and oxidative stress in HepG2 cells. Mechanistically, P. histicola upregulated autophagy markers, downregulated p62, STX18, promoted lipid autophagy, and inhibited IRE1α-JNK signaling. Furthermore, ATG14 knockdown partially reversed the protective effects of P. histicola, leading to increased lipid accumulation, impaired autophagic activity, and enhanced endoplasmic reticulum (ER) stress responses, indicating that ATG14-dependent lipid droplet autophagy contributes to the beneficial effects of P. histicola. In addition, pharmacological inhibition of autophagic flux using bafilomycin A1 attenuated the protective effects of P. histicola, resulting in increased lipid accumulation, enhanced ER stress responses, and activation of the IRE1α-JNK pathway. In conclusion, P. histicola mitigates MAFLD partially through promoting ATG14-dependent lipid droplet autophagy, thereby inhibiting ER stress-associated IRE1α-JNK activation, underscoring its potential as a probiotic for MAFLD and providing insights for gut microbiota-targeted therapies.