Compositional and functional differences of gut microbiome and metabolome inform pathogenesis of cholestatic liver disease.

Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are rare, idiopathic, chronic cholestatic liver diseases that respond differently to limited medical therapies and often lead to liver transplantation. We examined the compositional and functional differences in the gut microbiome, mycobiome, and metabolome of these diseases to better understand their impact on pathogenesis and outcomes. Stool sample metagenomes and metabolomes from patients with PSC (n = 245), PBC (n = 280) and matched controls (n = 245 and n = 278, respectively) were analyzed by shotgun sequencing and ultrahigh-resolution mass spectrometry. Comparisons were conducted with covariate-adjusted linear models. The gut microbiomes of patients with PSC and PBC were characterized by reduced diversity and increased abundance of pathobionts and virulence factors, coupled with altered microbial metabolism, including a reduction of short-chain fatty acids and B-vitamins. Untargeted stool metabolomics supported these results. Patients were stratified into groups using their microbial signatures, and each group had distinct patterns of microbiome-related changes. Cox regression analysis revealed that pathogenic microbial species were predictive of hepatic decompensation, whereas beneficial species had a protective effect. Based on previous groundwork and our new results, microbiome-based interventions such as probiotics, short-chain fatty acid supplementation, and phage therapy represent promising therapeutic options for cholestatic liver diseases.