Obesity initiates a chronic inflammatory network linked to perioperative complications and increased acute rejection rates in organ transplantation. Bariatric surgery is the most effective treatment of obesity recommended for morbidly obese transplant recipients. Here, we delineated the effects of obesity and bariatric surgery on alloimmunity and transplant outcomes in diet-induced obese (DIO) mice. Allograft survival was significantly shorter in DIO-mice. When performing sleeve gastrectomies (SGx) prior to transplantation, we found attenuated T cell–derived alloimmune responses resulting in prolonged allograft survival. Administering taurodeoxycholic acid (TDCA) and valine, metabolites depleted in DIO-mice and restored through SGx, prolonged graft survival in DIO-mice comparable with SGx an dampened Th1 and Th17 alloimmune responses while Treg frequencies and CD4⁺ T cell–derived IL-10 production were augmented. Moreover, in recipient animals treated with TDCA/valine, levels of donor-specific antibodies had been reduced. Mechanistically, TDCA/valine restrained inflammatory M1-macrophage polarization through TGR5 that compromised cAMP signaling and inhibited macrophage-derived T cell activation. Consistently, administering a TGR5 agonist to DIO-mice prolonged allograft survival. Overall, we provide novel insights into obesity-induced inflammation and its impact on alloimmunity. Furthermore, we introduce TDCA/valine as a noninvasive alternative treatment for obese transplant patients.

中文翻译：

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牛磺脱氧胆酸和缬氨酸可逆转肥胖相关增强的同种免疫反应并延长同种异体移植物的存活率

肥胖会引发与围手术期并发症相关的慢性炎症网络，并增加器官移植中的急性排斥率。减肥手术是推荐给病态肥胖移植受者的最有效的肥胖治疗方法。在这里，我们描述了肥胖和减肥手术对饮食诱导肥胖（DIO）小鼠的同种免疫和移植结果的影响。DIO 小鼠的同种异体移植物存活时间显着缩短。在移植前进行袖状胃切除术 (SGx) 时，我们发现 T 细胞衍生的同种免疫反应减弱，导致同种异体移植物存活时间延长。给予牛磺脱氧胆酸 (TDCA) 和缬氨酸，DIO 小鼠中代谢物耗尽并通过 SGx 恢复，DIO 小鼠中的移植物存活时间与 SGx 相当，抑制 Th1 和 Th17 同种免疫反应，同时 Treg 频率和 CD4 + T 细胞衍生的 IL ^- 10产量有所增加。此外，在接受 TDCA/缬氨酸治疗的受体动物中，供体特异性抗体的水平有所降低。从机制上讲，TDCA/缬氨酸通过 TGR5 抑制炎症性 M1-巨噬细胞极化，从而损害 cAMP 信号传导并抑制巨噬细胞衍生的 T 细胞活化。一致地，对 DIO 小鼠施用 TGR5 激动剂可延长同种异体移植物的存活时间。总的来说，我们对肥胖引起的炎症及其对同种免疫的影响提供了新的见解。此外，我们引入 TDCA/缬氨酸作为肥胖移植患者的无创替代治疗。