The regenerative potential of mammalian peripheral nervous system neurons after injury is critically limited by their slow axonal regenerative rate¹. Regenerative ability is influenced by both injury-dependent and injury-independent mechanisms². Among the latter, environmental factors such as exercise and environmental enrichment have been shown to affect signalling pathways that promote axonal regeneration³. Several of these pathways, including modifications in gene transcription and protein synthesis, mitochondrial metabolism and the release of neurotrophins, can be activated by intermittent fasting (IF)^4,5. However, whether IF influences the axonal regenerative ability remains to be investigated. Here we show that IF promotes axonal regeneration after sciatic nerve crush in mice through an unexpected mechanism that relies on the gram-positive gut microbiome and an increase in the gut bacteria-derived metabolite indole-3-propionic acid (IPA) in the serum. IPA production by Clostridium sporogenes is required for efficient axonal regeneration, and delivery of IPA after sciatic injury significantly enhances axonal regeneration, accelerating the recovery of sensory function. Mechanistically, RNA sequencing analysis from sciatic dorsal root ganglia suggested a role for neutrophil chemotaxis in the IPA-dependent regenerative phenotype, which was confirmed by inhibition of neutrophil chemotaxis. Our results demonstrate the ability of a microbiome-derived metabolite, such as IPA, to facilitate regeneration and functional recovery of sensory axons through an immune-mediated mechanism.

哺乳动物周围神经系统神经元损伤后的再生潜力受到其缓慢的轴突再生速率的严重限制¹ 。再生能力受到损伤依赖性和损伤无关机制的影响² 。其中，运动和环境富集等环境因素已被证明会影响促进轴突再生的信号通路³ 。其中一些途径，包括基因转录和蛋白质合成、线粒体代谢和神经营养素释放的修饰，可以通过间歇性禁食 (IF) 激活^4,5 。然而，IF是否影响轴突再生能力仍有待研究。在这里，我们发现 IF 通过一种意想不到的机制促进小鼠坐骨神经挤压后的轴突再生，该机制依赖于革兰氏阳性肠道微生物组和血清中肠道细菌衍生的代谢物吲哚-3-丙酸 (IPA) 的增加。产孢梭菌产生的 IPA 是有效轴突再生所必需的，坐骨神经损伤后 IPA 的输送可显着增强轴突再生，加速感觉功能的恢复。从机制上讲，坐骨背根神经节的 RNA 测序分析表明中性粒细胞趋化性在 IPA 依赖性再生表型中发挥作用，这一点通过中性粒细胞趋化性的抑制得到证实。我们的结果证明了微生物组衍生的代谢物（例如 IPA）能够通过免疫介导的机制促进感觉轴突的再生和功能恢复。