Bacterial and metabolic phenotypes associated with inadequate response to ursodeoxycholic acid treatment in primary biliary cholangitis
Laura Martinez-Gili,
Alexandros Pechlivanis,
Julie A.K. McDonald,
Sofina Begum,
Jonathan Badrock,
Jessica K. Dyson,
Rebecca Jones,
Gideon Hirschfield,
Stephen D. Ryder,
Richard Sandford,
Simon Rushbrook,
Douglas Thorburn,
Simon D. Taylor-Robinson,
Mary M.E. Crossey,
Julian R. Marchesi,
George Mells,
Elaine Holmes,
David Jones
Affiliations
Laura Martinez-Gili
Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
Alexandros Pechlivanis
Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
Julie A.K. McDonald
Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
Sofina Begum
Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
Jonathan Badrock
Academic Department of Medical Genetics, Cambridge University, Cambridge, UK
Jessica K. Dyson
Liver Unit, Freeman Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
Rebecca Jones
Leeds Liver Unit, St James’s University Hospital, Leeds, UK
Gideon Hirschfield
Center for Liver and Gastroenterology Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, UK
Stephen D. Ryder
NIHR Biomedical Research Centre at Nottingham University Hospitals NHS Trust, University of Nottingham, Nottingham, UK
Richard Sandford
Academic Department of Medical Genetics, Cambridge University, Cambridge, UK
Simon Rushbrook
Department of Gastroenterology, Norfolk and Norwich University Hospital, Norwich, UK
Douglas Thorburn
UCL Royal Free Campus, Royal Free Hospital, University College London Institute of Liver and Digestive Health, London, UK
Simon D. Taylor-Robinson
Department of Electrical and Electronic Engineering, Imperial College London, London, UK
Mary M.E. Crossey
Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
Julian R. Marchesi
Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
George Mells
Academic Department of Medical Genetics, Cambridge University, Cambridge, UK
Elaine Holmes
Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
David Jones
Liver Unit, Freeman Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
ABSTRACTPrimary 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.
