Translational Hepatology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Hepatol Commun. 2024 Jul 5;8(7). doi: 10.1097/HC9.0000000000000478. eCollection 2024 Jul 1.
BACKGROUND: Bile acids mediate gut-liver cross-talk through bile acid receptors. Serum, hepatic, and microbial bile acid metabolism was evaluated in HCV-compensated chronic liver disease. METHODS: Patients underwent liver biopsy; portal and peripheral blood were obtained before (HCVi), and 6 months after sustained virologic response (SVR), splenic blood was obtained only after SVR. The fecal microbiome and liver transcriptome were evaluated using RNA-Seq. Twenty-four bile acids were measured in serum, summed as free, taurine-conjugated bile acids (Tau-BAs), and glycine-conjugated bile acids. RESULTS: Compared to SVR, HCVi showed elevated conjugated bile acids, predominantly Tau-BA, compounded in HCVi cirrhosis. In the liver, transcription of bile acids uptake, synthesis, and conjugation was decreased with increased hepatic spillover into systemic circulation in HCVi. There was no difference in the transcription of microbial bile acid metabolizing genes in HCVi. Despite an overall decrease, Tau-BA remained elevated in SVR cirrhosis, mainly in splenic circulation. Only conjugated bile acids, predominantly Tau-BA, correlated with serum proinflammatory markers and hepatic proinflammatory pathways, including NLRP3 and NFKB. Among hepatic bile acid receptors, disease-associated conjugated bile acids showed the strongest association with hepatic spingosine-1-phosphate receptor 2 (S1PR2). CONCLUSIONS: Enhanced expression of hepatic S1PR2 in HCVi and HCVi-cirrhosis and strong associations of S1PR2 with Tau-BAs suggest pathological relevance of Tau-BA-hepatic S1PR2 signaling in chronic liver disease. These findings have therapeutic implications in chronic liver diseases.
背景：胆汁酸通过胆汁酸受体介导肠-肝相互作用。评估了 HCV 代偿性慢性肝病患者的血清、肝脏和微生物胆汁酸代谢。
方法：患者接受肝活检；门静脉和外周血分别在（HCVi）之前和持续病毒学应答（SVR）后 6 个月采集，仅在 SVR 后采集脾血。使用 RNA-Seq 评估粪便微生物组和肝转录组。在血清中测量了 24 种胆汁酸，总和为游离、牛磺酸结合胆汁酸（Tau-BAs）和甘氨酸结合胆汁酸。
结果：与 SVR 相比，HCVi 显示出结合胆汁酸升高，主要是 Tau-BA，在 HCVi 肝硬化中更为严重。在肝脏中，胆汁酸摄取、合成和结合的转录物减少，而 HCVi 中肝溢出到体循环增加。HCVi 中微生物胆汁酸代谢基因的转录没有差异。尽管总体下降，但 Tau-BA 在 SVR 肝硬化中仍然升高，主要在脾循环中。只有结合胆汁酸，主要是 Tau-BA，与血清促炎标志物和肝炎症途径相关，包括 NLRP3 和 NFKB。在肝脏胆汁酸受体中，与疾病相关的结合胆汁酸与肝鞘氨醇 1-磷酸受体 2（S1PR2）的相关性最强。
结论：HCVi 和 HCVi 肝硬化中肝 S1PR2 的表达增强，以及 S1PR2 与 Tau-BAs 的强烈关联表明 Tau-BA-肝 S1PR2 信号在慢性肝病中的病理相关性。这些发现对慢性肝病具有治疗意义。
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