Metabolites Linked to Bariatric Surgery Prolong Allograft Survival in Obese Recipients

Abstract

Introduction: In transplantation, obesity has become a common co-morbidity linked to inferior transplant outcome through far-reaching effects on the complex network of metabolism, inflammation and immunity. Methods: Fully mismatched skin transplantations were performed in diet-induced obese (DIO) C57/Bl6 mice and lean littermates. Sleeve gastrectomies (SGx) were performed prior to transplantation to induce weight loss. Results: Obese graft recipients showed significantly accelerated allograft rejection when compared to lean littermates (p < 0.001), associated with increased IFN-γ expression in splenic CD4+ T cells. Bariatric surgery, on the other hand, prolonged allograft survival even beyond that of lean animals (p = 0.005) and promoted protective IL-10-skewed conditions with reduced alloreactivity as confirmed by ELISPOT. Of note, sham procedures and dietary weight loss showed inferior results in allograft survival and weight loss when compared to bariatric surgery. Quantitative metabolomic profiling identified a secondary bile acid and a proteinogenic amino acid as upregulated subsequent to bariatric surgery. Strikingly, combined application reduced obesity and resulted in significant prolongation of graft survival (p = 0.005; Fig.1). Metabolic treatment was also associated with reduced pro-inflammatory responses in splenic CD4+ T cells and a significant reduction in splenic M1-like antigen-presenting cells (Fig. 2). Mechanistically, metabolic treatment reduced M1-polarization of monocytes/macrophages through activation of the bile acid receptor TGR5. Activation of TGR5 through a specific agonist blocked M1-polarization in vitro and prolonged allograft survival to levels comparable to metabolic treatment, while disruption of intracellular signaling of TGR5 during metabolic treatment abrogated these effects. Of note, studies in metabolic cages demonstrated a reduced oral intake of treated obese animals while maintaining regular physical activity, indicating that weight loss was not induced through toxic side-effects of metabolic treatment. Conclusion: Obesity augments alloimmune responses resulting in accelerated graft rejection, while bariatric surgery induced a change in cytokine balances with transplant outcome superior even to lean controls. Two metabolic compounds were identified as key mediators skewing the interplay of metabolism and inflammation towards anti-inflammatory conditions, providing unique insights linking obesity, metabolism and immunity.FigureFigure