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

## TL;DR

Cholestyramine helps reduce itching in primary biliary cholangitis by improving gut microbiome and metabolite balance.

## Contribution

The study reveals a microbial-metabolite-clinical axis that explains cholestyramine's therapeutic effects in pruritic PBC.

## Key findings

- Pruritic PBC patients showed higher cholestasis markers and ATX levels, which were reduced by cholestyramine.
- Cholestyramine restored gut microbiome diversity and normalized metabolite levels in treated patients.
- The Romboutsia-norharman-ATX/ALP axis was identified as key in pruritic PBC pathogenesis and treatment response.

## Abstract

Emerging evidence implicates bile acid-intestinal microbiota interactions in the pathogenesis of pruritus associated with primary biliary cholangitis (PBC). Cholestyramine, a bile acid sequestrant, is clinically recommended for pruritus alleviation. This study investigates its regulatory effects on gut microbiome composition and metabolite profiles. A prospective cohort of 54 pruritic PBC patients and 25 asymptomatic controls underwent longitudinal multi-omics profiling. Fecal 16S rRNA sequencing and untargeted metabolomics were performed pre-/post-4-week cholestyramine intervention (4 g twice daily). Serum autotaxin, as a biomarker for pruritus assessment, and liver function tests were completed simultaneously. Four important findings were listed as follows. (i) Pruritus phenotype characteristics: Pruritic patients exhibited elevated cholestasis indices (total bilirubin, alkaline phosphatase [ALP], and gamma-glutamyl transferase), higher ATX levels, and increased Gp210 antibody positivity compared to controls (all P < 0.01). Cholestyramine significantly reduced 5-D pruritus scores, ATX levels, and cholestasis markers (P < 0.01). (ii) Microbial dysbiosis: Gut microbiota diversity (Shannon/Simpson indices) was markedly decreased in pruritic patients, with taxonomic enrichment of Romboutsia, Stenotrophomonas, and Achromobacter, whereas Lachnospiraceae and Bacteroidaceae predominated in controls. (iii) Metabolomic perturbations: Metabolomic analysis identified diminished medium-chain fatty acids and indole derivatives (e.g., norharman) in pruritic patients. (iv) Therapeutic efficacy: Microbial-metabolite-clinical correlations revealed the pivotal role of the Romboutsia-norharman-ATX/ALP axis in the pathogenesis of pruritic PBC. Post-treatment, cholestyramine restored microbial diversity, normalized metabolite levels, and attenuated pruritus. Enterobacteriaceae/long-chain fatty acids have been identified as a significant marker for predicting the efficiency of the response to cholestyramine.

Pruritus in primary biliary cholangitis arises from synergistic cholestasis and gut microbiome-metabolite dysregulation. Cholestyramine mitigates symptoms by modulating the microbiome-metabolite-host axis, highlighting its therapeutic potential through microbiota remodeling and metabolic homeostasis restoration.