https://orcid.org/0000-0001-5271-9672
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ABSTRACT
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.
Acknowledgments
We are grateful to Dimitrios Paximadas for his assistance in setting up the UK-PBC Nested Cohort Project.
Disclosure statement
The authors declare no conflicts of interest. JRM has received funds from Cultech Ltd. and Enterobiotix Ltd. for consultancy.
Author contributions
DJ, GM, SDT-R and EH conceived the study. EH, JRM, SDT-R, GM and DJ provided the necessary resources and supervised the project. MMEC, JB and GM coordinated patient recruitment and sample collection. JKD, RJ, GH, SDR, RS, SR and DT recruited participants and collected samples. AP extracted and run all metabolomics samples. AP and LMG processed the UHPLC-MS data. SB processed the NMR data. JAKM extracted and run the 16S rRNA gene sequencing samples. JAKM and LMG processed the 16S rRNA gene sequencing data. LMG performed the data integration and statistical analysis. LMG wrote the manuscript and all authors reviewed and contributed to the final version of the manuscript.
Data availability statement
16S rRNA gene amplicon sequences have been deposited in the European Nucleotide Archive database with reference PRJEB44791. Data sharing will be considered upon reasonable request. https://www.ebi.ac.uk/ena/browser/view/PRJEB44791
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2208501
Abbreviations
| 6α-H | = | 6-α hydroxylase (CYP3A4) |
| ACN | = | acetonitrile |
| ALP | = | alkaline phosphatase |
| AMA | = | anti-mitochondrial antibodies |
| APAP | = | acetaminophen (paracetamol) |
| ASV | = | amplicon sequence variant |
| AUC | = | area under the curve |
| BA | = | bile acid |
| bai | = | bile acid inducible operon |
| BMI | = | body mass index |
| Bsh | = | bile salt hydrolase |
| CA | = | cholic acid |
| CDCA | = | chenodeoxycholic acid |
| CI | = | confidence interval |
| DA | = | differential abundance |
| DCA | = | deoxycholic acid |
| DHCA | = | dehydrocholic acid |
| DKCA | = | diketocholanic acid |
| EC | = | enzyme commission |
| F | = | feces |
| G-BA | = | glycine-conjugated bile acid |
| GBM | = | Geometric Bayesian Multiplicative |
| HSDH | = | hydroxysteroid dehydrogenase |
| IPA | = | isopropanol |
| IQR | = | interquartile range |
| LCA | = | lithocholic acid |
| LOD | = | limit of detection |
| MS | = | mass spectrometry |
| NMR | = | nuclear magnetic resonance |
| NR | = | non-responder |
| Padj | = | adjusted P-value |
| PBC | = | primary biliary cholangitis |
| PCA | = | principal component analysis |
| PPI | = | proton pump inhibitor |
| PQN | = | probabilistic quotient normalisation |
| PSC | = | primary sclerosing cholangitis |
| QC | = | quality control |
| R | = | responder |
| R_BP | = | responder with bad prognosis |
| RT | = | room temperature |
| SCFA | = | short-chain fatty acid |
| STOCSY | = | statistical total correlation spectroscopy |
| U | = | urine |
| ULN | = | upper limit of normal |
| UHPLC | = | ultra-high-performance liquid chromatography |