Autotaxin, Bile Acid Profile and Effect of Ileal Bile Acid Transporter Inhibition in Primary Biliary Cholangitis Patients with Pruritus

Background And Aims: Pruritus is a common symptom in patients with primary biliary cholangitis (PBC) for which ileal bile acid transporter (IBAT) inhibition is emerging as a potential therapy. We explored the serum metabonome and gut microbiota profile in PBC patients with pruritus and investigated the effect of GSK2330672, an IBAT inhibitor.

Methods: We studied fasting serum bile acids (BAs), autotaxin and faecal microbiota in 22 PBC patients with pruritus at baseline and after 2 weeks of GSK2330672 treatment. Control group included 31 asymptomatic PBC patients and 18 healthy volunteers. BA profiling was done by ultra performance liquid chromatography coupled to a mass spectrometry (UPLC-MS). Faecal microbiomes were analysed by 16S ribosomal RNA gene sequencing.

Results: In PBC patients with pruritus, serum levels of total and glyco-conjugated primary BAs and autotaxin were significantly elevated. Autotaxin activity correlated significantly with tauro- and glyco-conjugated cholic acid (CA) and chenodeoxycholic acid (CDCA), both at baseline and after GSK2330672. GSK2330672 significantly reduced autotaxin and all tauro- and glyco- conjugated BAs and increased faecal levels of CA (P = 0.048) and CDCA (P = 0.027). Gut microbiota of PBC patients with pruritus was similar to control groups. GSK2330672 increased the relative abundance of Firmicutes (P = 0.033) and Clostridia (P = 0.04) and decreased Bacteroidetes (P = 0.033) and Bacteroidia (P = 0.04).

Conclusions: Pruritus in PBC does not show a distinct gut bacterial profile but is associated with elevated serum bile acid and autotaxin levels which decrease after IBAT inhibition. In cholestatic pruritus, a complex interplay between BAs and autotaxin is likely and may be modified by IBAT inhibition.