Schneider Kai Markus, Candels Lena Susanna, Hov Johannes R, Myllys Maiju, Hassan Reham, Schneider Carolin Victoria, Wahlström Annika, Mohs Antje, Zühlke Sebastian, Liao Lijun, Elfers Carsten, Kilic Konrad, Henricsson Marcus, Molinaro Antonio, Hatting Maximilian, Zaza Ayham, Drasdo Dirk, Frissen Mick, Devlin A Sloan, Gálvez Eric J C, Strowig Till, Karlsen Tom H, Hengstler Jan G, Marschall Hanns-Ulrich, Ghallab Ahmed, Trautwein Christian
Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Nat Metab. 2021 Sep;3(9):1228-1241. doi: 10.1038/s42255-021-00452-1. Epub 2021 Sep 22.
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown aetiology for which there are no approved therapeutic options. Patients with PSC display changes in gut microbiota and in bile acid (BA) composition; however, the contribution of these alterations to disease pathogenesis remains controversial. Here we identify a role for microbiota-dependent changes in BA synthesis that modulates PSC pathophysiology. In a genetic mouse model of PSC, we show that loss of microbiota-mediated negative feedback control of BA synthesis results in increased hepatic BA concentrations, disruption of bile duct barrier function and, consequently, fatal liver injury. We further show that these changes are dependent on decreased BA signalling to the farnesoid X receptor, which modulates the activity of the rate-limiting enzyme in BA synthesis, CYP7A1. Moreover, patients with advanced stages of PSC show suppressed BA synthesis as measured by serum C4 levels, which is associated with poor disease prognosis. Our preclinical data highlight the microbiota-dependent dynamics of BA metabolism in cholestatic liver disease, which could be important for future therapies targeting BA and gut microbiome interactions, and identify C4 as a potential biomarker to functionally stratify patients with PSC and predict disease outcomes.
原发性硬化性胆管炎（PSC）是一种病因不明的慢性胆汁淤积性肝病，目前尚无获批的治疗方案。PSC患者的肠道微生物群和胆汁酸（BA）组成会发生变化；然而，这些改变对疾病发病机制的作用仍存在争议。在此，我们确定了BA合成中微生物群依赖性变化在调节PSC病理生理学方面的作用。在PSC的基因小鼠模型中，我们发现微生物群介导的BA合成负反馈控制丧失会导致肝脏BA浓度升高、胆管屏障功能破坏，进而导致致命的肝损伤。我们进一步表明，这些变化依赖于BA向法尼醇X受体的信号传导减少，该受体调节BA合成中的限速酶CYP7A1的活性。此外，PSC晚期患者的血清C4水平测量显示BA合成受到抑制，这与疾病预后不良相关。我们的临床前数据突出了胆汁淤积性肝病中BA代谢的微生物群依赖性动态变化，这对于未来针对BA与肠道微生物群相互作用的治疗可能很重要，并将C4确定为一种潜在的生物标志物，用于对PSC患者进行功能分层并预测疾病结局。
