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 Ly6ChiCD11b+ 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.

中文翻译：

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通过聚合物胶束将丁酸盐递送到下肠道可延长远端皮肤同种异体移植物的存活时间


已知微生物群组成会影响移植物排斥的动力学，但关于微生物群衍生的代谢物是否/如何影响移植物结果，仍然存在许多问题。我们研究了膳食纤维发酵产物短链脂肪酸丁酸盐的影响。基于胶束的丁酸盐制剂 （丁酸盐胶束 [ButM]）的持续胃内给药，在下消化道中释放其货物，盲肠丁酸盐含量升高，并显着延长小鼠轻微错配和严重错配皮肤同种异体移植物的存活率。虽然 ButM 不会影响调节性 T 细胞或我们测试的适应性同种免疫反应，但它调节了髓系细胞区室。在稳态下，ButM 治疗减少了次级淋巴器官和皮肤中循环 Ly6ChiCD11b+ 单核细胞和其他髓系细胞的数量，改变了它们参与线粒体代谢和关键炎症过程的基因表达，并降低了它们产生 TNFa 的能力，可能是通过间接机制。ButM 治疗还减少了移植物浸润单核细胞的数量，但没有减少 T 细胞的数量。与其对骨髓细胞的关键作用一致，ButM 对移植物存活的延伸取决于 CCR2 + 细胞的存在。这些发现意味着盲肠 ButM 通过定量和定性调节髓系细胞来改善远端同种异体移植物的结果，从而抑制同种异体免疫的先天免疫介导的效应期。