Abstract

Liver injury and persistent inflammation are common processes underlying liver disease pathogenesis, ultimately leading to fibrosis/cirrhosis and carcinoma. Clostridium sporogenes , a commensal gut bacterium, can produce bioactive metabolites to inhibit colon inflammation and promote neuronal repair. However, there is little information on how C. sporogenes affects injury and inflammation in the liver. Here, we found that live C. sporogenes supplementation significantly attenuates hepatic injury across multiple animal models. Including acute and chronic carbon tetrachloride (CCl 4 ) induced liver damage, as well as methionine-choline-deficient (MCD) diet-induced steatohepatitis. Metabolomics analysis in the supernatants and fecal sample of mice treated with C. sporogenes revealed that live C. sporogenes was able to generate a vital bioactive molecule 5-aminovaleric acid (5-AVA). 5-AVA exerted protective effects against liver damage in both acute and chronic liver models. Furthermore, both C. sporogenes and 5-AVA significantly prevented LPS-induced M1 macrophage activation in vivo and in vitro . The hepatoprotective effects of C. sporogenes in CCl 4 -exposed mice were abolished with macrophage depletion. Mechanistically, 5-AVA upregulated interferon-induced protein with tetratricopeptide repeats 1 (IFIT1), which inhibited NF-κB pathway activation, suppressed pro-inflammatory cytokine expression, and attenuated liver inflammation. These findings demonstrate that C. sporogenes and 5-AVA ameliorate hepatic injury by suppressing M1 macrophage activation via the IFIT1-NF-κB signaling pathway, highlighting their potential as novel therapeutic candidates after successful translation into clinical applications. Synopsis Clostridium sporogenes alleviates acute and chronic liver injury and inflammation through its metabolite 5-aminovaleric acid (5-AVA). 5-AVA suppresses M1 macrophage activation by upregulating IFIT1, inhibiting the NF-κB pathway, and exerti