Obeticholic acid beneficially affects bile composition in primary biliary cholangitis and nonalcoholic steatohepatitis

The nuclear farnesoid X receptor (FXR) agonist obeticholic acid (OCA) has promising anticholestatic and antifibrotic effects in primary biliary cholangitis (PBC) and non-alcoholic steatohepatitis (NASH), respectively. We performed pharmacokinetic profiling of biliary bile acids and duodenal signaling analysis in people with PBC and NASH in comparison to healthy volunteers (HV) before and after OCA therapy to elucidate OCA effects on human bile acid metabolism in health and chronic liver disease.

In 11 people with PBC, 7 with NASH and 11 HV, duodenal bile and tissue retrieved during gastroduodenoscopy, and blood samples were collected before and after 4 weeks of OCA treatment (10mg/d). Duodenal tissue was analyzed by quantitative polymerase chain reaction (qPCR) for expression of transporters and receptors involved in bile acid metabolism.

After 4 weeks of OCA treatment, marked improvement of all serum liver tests was observed in PBC (p<0.05, each) and of some  in NASH (γGT and ALT, p<0.05). OCA treatment reduced the plasma biomarker of bile acid synthesis, 7-alpha-hydroxy-4-cholesten-3-one (C4) in patients with PBC and NASH and in HV confirming adequate activation of FXR. Biliary UDCA enrichment in PBC patients treated with UDCA was markedly increased after 4 weeks of additional OCA treatment. The percentage of total taurine-conjugated bile acids increased in NASH patients and in healthy volunteers. An increase of organic solute transporter beta (OSTβ) activity in the duodenum was observed after 4 weeks, no changes in expression were observed in FXR, peroxisome proliferator-activated receptor (PPAR) and apical sodium bile salt transporter (ASBT).

OCA induces remarkable UDCA enrichment in bile of UDCA-treated PBC patients and a shift from glycine to less toxic taurine conjugates in NASH patients and HV.