Faecal Cathepsin B and S Are Associated With Liver Disease Severity and Adiposity in MASLD

BACKGROUND & AIMS: Dysregulation of hepatic cathepsins contributes to metabolic dysfunction-associated steatotic liver disease (MASLD) by promoting inflammation, apoptosis, and fibrosis. However, the role of intestinal cathepsins in MASLD has not been investigated. Given the central role of the gut-liver axis in disease progression, this represents an important knowledge gap. METHODS: Faecal cathepsin B and S activity was measured in 95 patients with MASLD and 18 healthy controls. Cathepsin activity was correlated with liver disease severity, metabolic parameters, and gut microbiome composition. RESULTS: Faecal cathepsin B and S activity was higher in patients with MASLD than in healthy controls. Cathepsin B activity was further increased in patients with metabolic dysfunction-associated steatohepatitis. Cathepsin B and S activity correlated with serum transaminases and hepatic steatosis, while cathepsin B activity was additionally associated with liver stiffness. Cathepsin B and S activity correlated with adiposity but showed no associations with other metabolic dysfunction-related parameters. Moreover, gut microbiome composition differed between patients with low vs. high faecal cathepsin B or S activity, respectively. CONCLUSION: Increased faecal cathepsin B and S activity is associated with liver disease severity and adiposity in MASLD and is linked to alterations of the gut microbiome, suggesting a potential role of intestinal cathepsins in gut-liver axis dysfunction.