Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
Terasaki Research Institute, Los Angeles, California, USA.
J Clin Invest. 2019 Jul 22;129(8):3420-3434. doi: 10.1172/JCI127550.
Although modifications of gut microbiota with antibiotics (Abx) influence mouse skin and cardiac allografts, its role in orthotopic liver transplantation (OLT) remains unknown. We aimed to determine whether and how recipient Abx pretreatment may affect hepatic ischemia-reperfusion injury (IRI) and OLT outcomes. Mice (C57BL/6) with or without Abx treatment (10 days) were transplanted with allogeneic (BALB/c) cold-stored (18 hours) livers, followed by liver and blood sampling (6 hours). We divided 264 human OLT recipients on the basis of duration of pre-OLT Abx treatment into control (Abx-free/Abx <10 days; n = 108) and Abx treatment (Abx ≥10days; n = 156) groups; OLT biopsy (Bx) samples were collected 2 hours after OLT (n = 52). Abx in mice mitigated IRI-stressed OLT (IRI-OLT), decreased CCAAT/enhancer-binding protein homologous protein (CHOP) (endoplasmic reticulum [ER] stress), enhanced LC3B (autophagy), and inhibited inflammation, whereas it increased serum prostaglandin E2 (PGE2) and hepatic PGE2 receptor 4 (EP4) expression. PGE2 increased EP4, suppressed CHOP, and induced autophagosome formation in hepatocyte cultures in an EP4-dependent manner. An EP4 antagonist restored CHOP, suppressed LC3B, and recreated IRI-OLT. Remarkably, human recipients of Abx treatment plus OLT (Abx-OLT), despite severe pretransplantation clinical acuity, had higher EP4 and LC3B levels but lower CHOP levels, which coincided with improved hepatocellular function (serum aspartate aminotransferase/serum aspartate aminotransferase [sALT/sAST]) and a decreased incidence of early allograft dysfunction (EAD). Multivariate analysis identified "Abx-free/Abx <10 days" as a predictive factor of EAD. This study documents the benefits of Abx pretreatment in liver transplant recipients, identifies ER stress and autophagy regulation by the PGE2/EP4 axis as a homeostatic underpinning, and points to the microbiome as a therapeutic target in OLT.
虽然抗生素（Abx）对肠道微生物群的修饰会影响小鼠皮肤和心脏移植物，但它在原位肝移植（OLT）中的作用尚不清楚。我们旨在确定受者 Abx 预处理是否以及如何影响肝缺血再灌注损伤（IRI）和 OLT 结果。用或不用 Abx 处理（10 天）的小鼠（C57BL/6）接受同种异体（BALB/c）冷存（18 小时）肝脏移植，然后进行肝脏和血液取样（6 小时）。我们根据 OLT 前 Abx 治疗的持续时间将 264 名接受 OLT 的人类患者分为对照组（Abx 无/Abx<10 天；n=108）和 Abx 治疗组（Abx≥10 天；n=156）；OLT 活检（Bx）样本于 OLT 后 2 小时采集（n=52）。Abx 减轻了 IRI-OLT，降低了 CCAAT/增强子结合蛋白同源蛋白（CHOP）（内质网[ER]应激），增强了 LC3B（自噬），并抑制了炎症，而增加了血清前列腺素 E2（PGE2）和肝 PGE2 受体 4（EP4）的表达。PGE2 以 EP4 依赖的方式增加 EP4，抑制 CHOP，并诱导肝细胞培养物中的自噬体形成。EP4 拮抗剂恢复了 CHOP，抑制了 LC3B，并重新创建了 IRI-OLT。值得注意的是，接受 Abx 治疗加 OLT（Abx-OLT）的人类患者，尽管术前临床严重程度较高，但 EP4 和 LC3B 水平较高，CHOP 水平较低，这与肝细胞功能（血清天冬氨酸氨基转移酶/血清天冬氨酸氨基转移酶[sALT/sAST]）改善和早期移植物功能障碍（EAD）发生率降低有关。多变量分析确定“Abx 无/Abx<10 天”是 EAD 的预测因素。这项研究证明了 Abx 预处理在肝移植受者中的益处，确定了 PGE2/EP4 轴对 ER 应激和自噬的调节是一种稳态基础，并指出微生物组是 OLT 的治疗靶点。
