Although obesity has been linked to impaired transplant outcomes, underlying mechanisms and consequences of obesity on alloimmunity are only poorly understood.

Allogenic skin transplantations were performed in diet-induced obese (DIO) C57BL/6 mice, lean littermates and animals following sleeve gastrectomy (SGx). Quantitative metabolomic and extensive immune profiling were performed to characterize consequences of obesity on alloimmunity and to dissect the role of endogenous metabolites in obesity.

Obese animals exhibited accelerated allograft rejection linked to increased IFN-γ expression in splenic CD4⁺ T cells (n=4-6/group by POD 6; p<0.001). In contrast, bariatric surgery prolonged allograft survival beyond that observed in both, obese and lean animals by promoting protective, IL-10-dominated conditions (median graft survival: 7 d obese vs. 9 d lean vs. 11 d SGx; Log-rank test: p=0.005; n=5/group). Of note, a sham procedure group and a weight loss group that was switched to a normal chow diet showed both inferior results in allograft survival and weight loss when compared to SGx. In addition, bariatric surgery was also linked to a significantly reduced alloreactivity confirmed by ELISPOT analysis (n=6/group by POD 6; p<0.05). Metabolomic profiling identified a secondary bile acid and proteinogenic amino acid as mediators of alloimmunity subsequent to bariatric surgery. Strikingly, combined application of these compounds resulted in significant prolongation of graft survival (p=0.005); treatment also reflected less potent alloimmune responses in obese animals. On a mechanistic level, treatment with bile acid/proteinogenic amino acid had been linked to a significant reduction of splenic dendritic cells (n=4-6/group by POD 6; p<0.01). Of additional relevance, these effects were accompanied by a substantial weight loss that was comparable to the weight loss observed after bariatric surgery (-34.17% obese treated vs. -34.24% SGX by day 14; n=3-7/group; p=ns).

In conclusion, obesity augments alloimmune responses. Bariatric surgery is linked to metabolic changes that affect alloimmunity. Bile acid signaling represents a key mechanism impacting both, alloimmune response and metabolism.

CITATION INFORMATION: Quante M, ElKhal A, Seyda M, Schuitenmaker J, Uehara H, Tullius S. Bile Acid Signaling Affects Metabolism and Prolongs Allograft Survival in Obese Recipients. Am J Transplant. 2016;16 (suppl 3).

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