Delivery of butyrate to the lower gut by polymeric micelles prolongs survival of distal skin allografts

The microbiota composition is known to influence the kinetics of graft rejection, but many questions remain as to whether/how microbiota-derived metabolites affect graft outcome. We investigated the effects of the short-chain fatty acid butyrate, a product of dietary fiber fermentation. Sustained intragastric administration of a micelle-based formulation of butyrate (butyrate micelle [ButM]) that releases its cargo in the lower gastrointestinal tract elevated cecal butyrate content and significantly prolonged minor-mismatched and major-mismatched skin allograft survival in mice. While ButM did not influence regulatory T cells or the adaptive alloimmune responses we tested, it modulated the myeloid cell compartment. At steady state, ButM treatment reduced the number of circulating Ly6C^hiCD11b⁺ monocytes and other myeloid cells in secondary lymphoid organs and skin, altered their expression of genes involved in mitochondrial metabolism and key inflammatory processes, and reduced their ability to produce TNFa, likely via an indirect mechanism. ButM treatment also reduced numbers of graft-infiltrating monocytes but not T cells. Consistent with its critical effect on myeloid cells, ButM's extension of graft survival depended on the presence of CCR2⁺ cells. These findings imply that cecal ButM improves distal allograft outcomes by quantitatively and qualitatively modulating myeloid cells, thereby inhibiting the innate immune cell-mediated effector phase of alloimmunity.