Gut Microbial Metabolites Induce Donor-Specific Tolerance of Kidney Allografts through Induction of T Regulatory Cells by Short-Chain Fatty Acids

Significance Statement The gut microbiome is known to affect immune responses in autoimmunity and cancer, but little is known about its role in transplant immunity. In a mouse model, the authors observed dysbiosis after kidney transplantation in the absence of antibiotics or other drugs. A high-fiber diet prevented dysbiosis and afforded protection against allograft rejection, as did supplementation with the short-chain fatty acids sodium acetate or sodium butyrate, microbial metabolites produced by gut fermentation of dietary fiber. This protection was dependent on the G protein–coupled receptor GPR43 and T regulatory cells. These findings show how the microbiome can be modified to retard alloimmunity in a mouse model of kidney transplantation, and provide a rationale to explore this strategy in humans as a means to facilitate transplant acceptance. Background Short-chain fatty acids derived from gut microbial fermentation of dietary fiber have been shown to suppress autoimmunity through mechanisms that include enhanced regulation by T regulatory cells (Tregs). Methods Using a murine kidney transplantation model, we examined the effects on alloimmunity of a high-fiber diet or supplementation with the short-chain fatty acid acetate. Kidney transplants were performed from BALB/c(H2 d ) to B6(H2 b ) mice as allografts in wild-type and recipient mice lacking the G protein–coupled receptor GPR43 (the metabolite-sensing receptor of acetate). Allograft mice received normal chow, a high-fiber diet, or normal chow supplemented with sodium acetate. We assessed rejection at days 14 (acute) and 100 (chronic), and used 16S rRNA sequencing to determine gut microbiota composition pretransplantation and post-transplantation. Results Wild-type mice fed normal chow exhibited dysbiosis after receiving a kidney allograft but not an isograft, despite the avoidance of antibiotics and immunosuppression for the latter. A high-fiber diet prevented dysbiosis in allograft recipients, who demonstrated prolonged survival and reduced evidence of rejection compared with mice fed normal chow. Allograft mice receiving supplemental sodium acetate exhibited similar protection from rejection, and subsequently demonstrated donor-specific tolerance. Depletion of CD25 + Tregs or absence of the short-chain fatty acid receptor GPR43 abolished this survival advantage. Conclusions Manipulation of the microbiome by a high-fiber diet or supplementation with sodium acetate modified alloimmunity in a kidney transplant model, generating tolerance dependent on Tregs and GPR43. Diet-based therapy to induce changes in the gut microbiome can alter systemic alloimmunity in mice, in part through the production of short-chain fatty acids leading to Treg cell development, and merits study as a potential clinical strategy to facilitate transplant acceptance.