Institute of Cellular Medicine and NIHR Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne, UK.
Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, London, UK.
Liver Int. 2019 May;39(5):967-975. doi: 10.1111/liv.14069. Epub 2019 Feb 25.
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.
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.
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).
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.
瘙痒是原发性胆汁性胆管炎（PBC）患者的常见症状，抑制回肠胆汁酸转运体（IBAT）可能成为一种潜在的治疗方法。我们探索了瘙痒的 PBC 患者的血清代谢组和肠道微生物群特征，并研究了 IBAT 抑制剂 GSK2330672 的作用。
我们在基线和 GSK2330672 治疗 2 周后研究了 22 例瘙痒的 PBC 患者的空腹血清胆汁酸（BA）、自分泌酶和粪便微生物群。对照组包括 31 例无症状 PBC 患者和 18 名健康志愿者。BA 分析采用超高效液相色谱-质谱联用（UPLC-MS）。通过 16S 核糖体 RNA 基因测序分析粪便微生物组。
在瘙痒的 PBC 患者中，血清总胆汁酸和糖结合型初级胆汁酸以及自分泌酶的水平显著升高。自分泌酶活性与牛磺酸和糖结合型胆酸（CA）和鹅脱氧胆酸（CDCA）显著相关，在基线和 GSK2330672 后均如此。GSK2330672 显著降低了自分泌酶和所有牛磺酸和糖结合型胆汁酸，并增加了粪便 CA（P=0.048）和 CDCA（P=0.027）的水平。瘙痒的 PBC 患者的肠道微生物群与对照组相似。GSK2330672 增加了厚壁菌门（Firmicutes）（P=0.033）和梭菌科（Clostridia）（P=0.04）的相对丰度，并降低了拟杆菌门（Bacteroidetes）（P=0.033）和拟杆菌纲（Bacteroidia）（P=0.04）的相对丰度。
PBC 瘙痒并没有表现出独特的肠道细菌特征，但与血清胆汁酸和自分泌酶水平升高有关，这些水平在抑制 IBAT 后会降低。在胆汁淤积性瘙痒中，BA 和自分泌酶之间可能存在复杂的相互作用，并且可能通过 IBAT 抑制来改变。
