Variation in microbiome and metabolites is associated with advantageous effects of cholestyramine on primary biliary cholangitis with pruritus.

Pruritic PBC patients exhibited elevated cholestasis indices and higher autotaxin (ATX) levels compared to asymptomatic controls.

• Pruritic patients showed elevated total bilirubin, alkaline phosphatase (ALP), and gamma-glutamyl transferase compared to controls (all P < 0.01)
• Higher ATX levels and increased Gp210 antibody positivity were observed in pruritic patients versus controls (all P < 0.01)
• The study included 54 pruritic PBC patients and 25 asymptomatic controls in a prospective cohort design
• Serum autotaxin was used as a biomarker for pruritus assessment alongside liver function tests

Cholestyramine significantly reduced pruritus scores, ATX levels, and cholestasis markers after 4 weeks of treatment.

• Cholestyramine was administered at 4 g twice daily for 4 weeks
• Cholestyramine significantly reduced 5-D pruritus scores, ATX levels, and cholestasis markers (P < 0.01)
• Fecal 16S rRNA sequencing and untargeted metabolomics were performed pre- and post-intervention
• Liver function tests and serum autotaxin measurements were completed simultaneously with microbiome profiling

Gut microbiota diversity was markedly decreased in pruritic PBC patients, with distinct taxonomic differences compared to controls.

• Shannon and Simpson diversity indices were markedly decreased in pruritic patients compared to controls
• Pruritic patients showed taxonomic enrichment of Romboutsia, Stenotrophomonas, and Achromobacter
• Lachnospiraceae and Bacteroidaceae predominated in asymptomatic controls
• Post-treatment with cholestyramine restored microbial diversity

Metabolomic analysis identified diminished medium-chain fatty acids and indole derivatives in pruritic PBC patients.

• Pruritic patients showed reduced levels of medium-chain fatty acids compared to controls
• Indole derivatives, including norharman, were diminished in pruritic patients
• Post-treatment, cholestyramine normalized metabolite levels
• Untargeted metabolomics was used to profile metabolite changes pre- and post-intervention

The Romboutsia-norharman-ATX/ALP axis was identified as pivotal in the pathogenesis of pruritic PBC.

• Microbial-metabolite-clinical correlations revealed the role of this axis in pruritic PBC pathogenesis
• Romboutsia was enriched in pruritic patients and associated with reduced norharman levels
• Norharman levels were inversely correlated with ATX and ALP levels
• This axis links gut microbial dysbiosis to cholestasis and pruritus biomarkers

Enterobacteriaceae and long-chain fatty acids were identified as significant markers for predicting the efficiency of cholestyramine response.

• Enterobacteriaceae abundance was identified as a predictive marker for cholestyramine treatment response
• Long-chain fatty acid levels were also identified as predictive markers for treatment efficacy
• These markers were identified through microbial-metabolite-clinical correlation analyses
• The finding suggests that baseline microbiome and metabolite profiles may stratify patients likely to respond to cholestyramine

Emerging evidence implicates bile acid-intestinal microbiota interactions in the pathogenesis of pruritus associated with primary biliary cholangitis.

• Cholestyramine is a bile acid sequestrant clinically recommended for pruritus alleviation in PBC
• The study investigated regulatory effects of cholestyramine on gut microbiome composition and metabolite profiles
• Pruritus in PBC is proposed to arise from synergistic cholestasis and gut microbiome-metabolite dysregulation
• A prospective longitudinal multi-omics design was used to characterize these interactions