Intestinal ischemia is a potentially catastrophic emergency, with a high rate of morbidity and mortality. Currently, no specific pharmacological treatments are available. Previous work demonstrated that pre-treatment with obeticholic acid (OCA) protected against ischemia reperfusion injury (IRI). Recently, a more potent and water-soluble version has been synthesized: Intercept 767 (INT-767). The aim of this study was to investigate if intravenous treatment with INT-767 can improve outcomes after IRI. In a validated rat model of IRI (60 min ischemia + 60 min reperfusion), three groups were investigated (n = 6/group): (i) sham: surgery without ischemia; (ii) IRI + vehicle; and (iii) IRI + INT-767. The vehicle (0.9% NaCl) or INT-767 (10 mg/kg) were administered intravenously 15 min after start of ischemia. Endpoints were 7-day survival, serum injury markers (L-lactate and I-FABP), histology (Park–Chiu and villus length), permeability (transepithelial electrical resistance and endotoxin translocation), and cytokine expression. Untreated, IRI was uniformly lethal by provoking severe inflammation and structural damage, leading to translocation and sepsis. INT-767 treatment significantly improved survival by reducing inflammation and preserving intestinal structural integrity. This study demonstrates that treatment with INT-767 15 min after onset of intestinal ischemia significantly decreases IRI and improves survival. The ability to administer INT-767 intravenously greatly enhances its clinical potential.

中文翻译：

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INT-767—双法尼醇 X 受体 (FXR) 和武田 G 蛋白偶联受体 5 (TGR5) 激动剂可提高大鼠的存活率并减轻肠缺血再灌注损伤

肠缺血是一种潜在的灾难性紧急情况，发病率和死亡率很高。目前，没有特定的药物治疗方法。先前的工作表明，奥贝胆酸（OCA）预处理可预防缺血再灌注损伤（IRI）。最近，合成了一种更有效的水溶性版本：Intercept 767 (INT-767)。本研究的目的是调查 INT-767 静脉注射治疗是否可以改善 IRI 后的预后。在经过验证的 IRI 大鼠模型（60 分钟缺血 + 60 分钟再灌注）中，对三组进行了研究（n = 6/组）： (i) 假手术：无缺血的手术；(ii) IRI + 车辆；(iii) IRI + INT-767。缺血开始后 15 分钟，静脉注射载体（0.9% NaCl）或 INT-767（10 mg/kg）。终点包括 7 天生存、血清损伤标志物（L-乳酸和 I-FABP）、组织学（Park-Chiu 和绒毛长度）、通透性（跨上皮电阻和内毒素易位）和细胞因子表达。如果不进行治疗，IRI 会引发严重炎症和结构损伤，从而导致易位和败血症，因此都是致命的。INT-767 治疗通过减少炎症和保持肠道结构完整性显着提高生存率。这项研究表明，肠缺血发作 15 分钟后使用 INT-767 治疗可显着降低 IRI 并提高生存率。静脉注射 INT-767 的能力大大增强了其临床潜力。