This study aimed to dissect the relationship between specific gut commensal bacterial subgroups, their functional metabolic pathways, and their impact on skin allograft outcome and alloimmunity. We previously showed that oral broad-spectrum antibiotic (Abx) pretreatment in mice delayed skin, heart, and lung allograft rejection and dampened alloimmune responses. Here, rationally designed Abx combinations targeting major bacterial groups were used to elucidate their individual contribution to modulating alloimmune responses. Abx cocktails targeting intestinal gram-negative, gram-positive, or anaerobic/gram-positive bacteria by oral gavage, all delayed skin allograft rejection, and reduced alloreactive T cell priming to different extents. Notably, the most pronounced extension of skin allograft survival and attenuation of alloimmunity were achieved when all gut bacterial groups were simultaneously targeted. These results suggest a model in which the strength of the alloimmune response is additively tuned up by gut microbial diversity. Shotgun metagenomic sequencing enabled strain-level resolution and identified a shared commensal, as the most enriched following all Abx treatments. Oral administration of to mice harboring a diverse microbiota significantly prolonged skin allograft survival, identifying a probiotic with therapeutic benefit in transplantation.

中文翻译：

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协调消除细菌类群可最佳地减弱同种免疫并延长同种异体移植物的存活

本研究旨在剖析特定肠道共生细菌亚群之间的关系、它们的功能代谢途径以及它们对皮肤同种异体移植结果和同种免疫的影响。我们之前表明，对小鼠进行口服广谱抗生素（Abx）预处理可延迟皮肤、心脏和肺同种异体移植物的排斥反应并抑制同种免疫反应。在这里，针对主要细菌群的合理设计的 Abx 组合被用来阐明它们对调节同种免疫反应的个体贡献。 Abx 鸡尾酒通过口服管饲法针对肠道革兰氏阴性、革兰氏阳性或厌氧/革兰氏阳性细菌，均延迟了皮肤同种异体移植排斥，并不同程度地减少了同种异体反应性 T 细胞启动。值得注意的是，当同时靶向所有肠道细菌群时，可实现皮肤同种异体移植存活率的最显着延长和同种免疫的减弱。这些结果表明了一个模型，其中同种免疫反应的强度是通过肠道微生物多样性进行额外调节的。鸟枪法宏基因组测序实现了菌株水平的分辨率，并确定了一个共享的共生体，这是所有 Abx 处理后最富集的共生体。对含有多种微生物群的小鼠口服益生菌可显着延长同种异体皮肤移植物的存活率，从而确定了一种在移植中具有治疗效果的益生菌。