Bacterial and metabolic phenotypes associated with inadequate response to ursodeoxycholic acid treatment in primary biliary cholangitis

• Published in: Gut microbes 2023-12, Vol.15 (1), p.2208501-2208501
• Main Authors: Martinez-Gili, Laura, Pechlivanis, Alexandros, McDonald, Julie A.K., Begum, Sofina, Badrock, Jonathan, Dyson, Jessica K., Jones, Rebecca, Hirschfield, Gideon, Ryder, Stephen D., Sandford, Richard, Rushbrook, Simon, Thorburn, Douglas, Taylor-Robinson, Simon D., Crossey, Mary M.E., Marchesi, Julian R., Mells, George, Holmes, Elaine, Jones, David
• Format: Article
• Language: English
• Subjects: Bacteria - genetics; Bile acids; Bile Acids and Salts - therapeutic use; Biomarkers; Cholagogues and Choleretics - therapeutic use; Dehydrocholic Acid - therapeutic use; Gastrointestinal Microbiome; gut-liver-kidney axis; Humans; Liver Cirrhosis, Biliary - drug therapy; microbiota; PBC; Phenotype; Research Paper; RNA, Ribosomal, 16S - genetics; UDCA; Ursodeoxycholic Acid - therapeutic use
• ISSN: 1949-0976; 1949-0984
• DOI: 10.1080/19490976.2023.2208501

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease with ursodeoxycholic acid (UDCA) as first-line treatment. Poor response to UDCA is associated with a higher risk of progressing to cirrhosis, but the underlying mechanisms are unclear. UDCA modulates the composition of primary and bacterial-derived bile acids (BAs). We characterized the phenotypic response to UDCA based on BA and bacterial profiles of PBC patients treated with UDCA. Patients from the UK-PBC cohort (n = 419) treated with UDCA for a minimum of 12-months were assessed using the Barcelona dynamic response criteria. BAs from serum, urine, and feces were analyzed using Ultra-High-Performance Liquid Chromatography-Mass Spectrometry and fecal bacterial composition measured using 16S rRNA gene sequencing. We identified 191 non-responders, 212 responders, and a subgroup of responders with persistently elevated liver biomarkers (n = 16). Responders had higher fecal secondary and tertiary BAs than non-responders and lower urinary bile acid abundances, with the exception of 12-dehydrocholic acid, which was higher in responders. The sub-group of responders with poor liver function showed lower alpha-diversity evenness, lower abundance of fecal secondary and tertiary BAs than the other groups and lower levels of phyla with BA-deconjugation capacity (Actinobacteriota/Actinomycetota, Desulfobacterota, Verrucomicrobiota) compared to responders. UDCA dynamic response was associated with an increased capacity to generate oxo-/epimerized secondary BAs. 12-dehydrocholic acid is a potential biomarker of treatment response. Lower alpha-diversity and lower abundance of bacteria with BA deconjugation capacity might be associated with an incomplete response to treatment in some patients.