ena-STUDY-CUSB-HM-06-05-2021-09:40:48:002-239
Metabolic and bacterial phenotypes associated with inadequate ursodeoxycholic acid treatment response in patients with primary biliary cholangitis
BACKGROUND & AIMS: Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease with ursodeoxycholic acid (UDCA) as first-line treatment. An incomplete treatment response means higher risk of progressing to cirrhosis. The mechanism for UDCA non-response is unclear. We characterized the bile acid (BA) and bacterial profiles of PBC patients treated with UDCA to assess whether a different treatment response associates with a different phenotype.METHODS: Patients (n=454) from the UK-PBC cohort were treated with UDCA for a minimum of 12 months, and their response to therapy assessed. BA from serum, urine and faeces were analysed using Ultra-Performance Chromatography-Mass Spectrometry and faecal bacterial composition measured using 16S rRNA gene sequencing.RESULTS: We found distinct stool BA signatures in UDCA non-responders (n= 214), complete-responders (responders with a good prognosis; n= 224) and a newly identified group of partial-responders (responders with a bad prognosis; n= 16), with the two responder sub-groups showing opposite trends. BA in urine were higher in non-responders, and only 12-dehydrocholate was increased in urine of complete-responders. Differences in bacterial composition were found in confounder-matched sub-analyses after adjusting for bacterial load; complete-responders had lower abundance of Oscillospirales and a predicted increase in a gene of the 7alpha-dehydroxylation pathway. Partial-responders had differences in bacteria involved in BA deconjugation including Bacteroides and Parabacteroides.CONCLUSION: UDCA response failure was associated with a specific bacterial-derived secondary bile acid signature. Modest differences in bacterial taxonomy indicate that the phenotype of non-responders does not rely on specific microorganisms, but rather on a decreased capacity to generate and excrete oxo- and epimerised secondary bile acids.
BACKGROUND & AIMS: Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease with ursodeoxycholic acid (UDCA) as first-line treatment. An incomplete treatment response means higher risk of progressing to cirrhosis. The mechanism for UDCA non-response is unclear. We characterized the bile acid (BA) and bacterial profiles of PBC patients treated with UDCA to assess whether a different treatment response associates with a different phenotype.METHODS: Patients (n=454) from the UK-PBC cohort were treated with UDCA for a minimum of 12 months, and their response to therapy assessed. BA from serum, urine and faeces were analysed using Ultra-Performance Chromatography-Mass Spectrometry and faecal bacterial composition measured using 16S rRNA gene sequencing.RESULTS: We found distinct stool BA signatures in UDCA non-responders (n= 214), complete-responders (responders with a good prognosis; n= 224) and a newly identified group of partial-responders (responders with a bad prognosis; n= 16), with the two responder sub-groups showing opposite trends. BA in urine were higher in non-responders, and only 12-dehydrocholate was increased in urine of complete-responders. Differences in bacterial composition were found in confounder-matched sub-analyses after adjusting for bacterial load; complete-responders had lower abundance of Oscillospirales and a predicted increase in a gene of the 7alpha-dehydroxylation pathway. Partial-responders had differences in bacteria involved in BA deconjugation including Bacteroides and Parabacteroides.CONCLUSION: UDCA response failure was associated with a specific bacterial-derived secondary bile acid signature. Modest differences in bacterial taxonomy indicate that the phenotype of non-responders does not rely on specific microorganisms, but rather on a decreased capacity to generate and excrete oxo- and epimerised secondary bile acids.