Antibiotic pretreatment alleviates liver transplant damage in mice and humans
Antibiotic pretreatment alleviates liver transplant damage in mice and humans
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DOI：
10.1172/jci127550
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发表时间：
2019-08-01
影响因子：
15.9
通讯作者：
Kupiec-Weglinski, Jerzy W.
中科院分区：
文献类型：
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作者：
Nakamura, Kojiro;Kageyama, Shoichi;Kupiec-Weglinski, Jerzy W.
尽管用抗生素修饰肠道微生物区系(ABX)影响小鼠的皮肤和心脏移植物，但它在原位肝移植(OLT)中的作用仍不清楚。我们的目的是确定受体ABX预处理是否以及如何影响肝脏缺血再灌注损伤(IRI)和原位肝移植的结果。将冷藏(18h)的同种异体(BALB/c)小鼠(BALB/c)移植给经ABX处理或不经ABX处理(10d)的小鼠(C57BL/6)，然后取肝脏和血样(6h)。我们根据移植前ABX治疗的持续时间将264例人类OLT受者分为对照组(无ABX/ABX=10天；n=156)，于移植后2小时采集OLT活检(Bx)样本(n=52)。ABX可减轻IRI应激的小鼠原位肝移植(IRI-OLT)，降低CCAAT/增强子结合蛋白同源蛋白(CHOP)(内质网[ER]应激)，增强自噬(LC3B)，抑制炎症，但增加血清前列腺素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，并诱导肝细胞自噬小体的形成。EP4拮抗剂恢复CHOP，抑制LC3B，重建IRI-OLT。值得注意的是，接受ABX治疗加原位肝移植(ABX-OLT)的人，尽管移植前临床敏感度很高，但EP4和LC3B水平较高，而CHOP水平较低，这与肝细胞功能(血清天冬氨酸转氨酶/血清天冬氨酸转氨酶[SAST])的改善和早期同种异体移植功能障碍(EAD)的发生率降低是一致的。多变量分析确定“不含ABX/ABX”
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 = 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