*Purpose: Obesity initiates a chronic inflammatory network linked to more frequent perioperative complications and increased acute rejection rates after organ transplantation. Clinically, morbidly obese transplant candidates and recipients have undergone bariatric surgery facilitating transplantation. The effects of obesity on alloimmunity and transplant outcomes have not been defined.

*Methods: We delineated the effects of obesity and bariatric surgery on alloimmunity and transplant outcomes in diet induced obese (DIO) mice. Performing allogeneic skin transplants in DIO recipient mice that underwent sleeve gastrectomies (SGx), we defined the interplay of innate and adaptive immune responses; quantitative metabolomic profiling in lean, DIO and DIO mice undergoing SGx delineated the effects of metabolic changes on alloimmunity.

*Results: Skin transplants were rejected significantly earlier in completely mismatched DIO mice (p<0.01); DIO recipients of isogeneic transplants contained their grafts indefinitely. DIO recipients that underwent SGx prior to transplantation, in contrast, demonstrated significantly prolonged graft survival times (p=0.05); SGx also attenuated alloimmune responses including reduced Th1 and Th17 frequencies (p<0.001). Additional in-vitro studies identified ameliorated alloimmune responses with a reduced IFN-γ production and higher amounts of IL-10 by CD4⁺ T cells in MLR (p<0.01). Through unbiased quantitative metabolomic profiling, we identified restored Taurodeoxycholic acid and L-Valine (TDCA/Valine) levels following SGx comparable to those in lean controls; in contrast, TDCA/Valine levels had been depleted in obese mice. Mechanistically, we identified restrained macrophage polarization through TDCA/valine via TGR5 signaling to inhibit CD4⁺ T cell activation leading to a decreased production of IL-17 and IFN-γ in vitro and in vivo.

*Conclusions: We provide novel insight into obesity induced inflammation and the consequences on allo-immunity and transplant outcomes. SGx initiated anti-inflammatory capacities on CD4⁺ T cell driven allo-immune responses through compromised macrophage polarization. Restored TDCA/Valine levels simulated the effects of bariatric surgery, suggesting those metabolites as novel treatments ameliorating obesity augmented alloimmune responses.

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