The intermittent fasting-dependent gut microbial metabolite indole-3 propionate promotes nerve regeneration and recovery after injury

Abstract The regenerative potential of mammalian peripheral nervous system (PNS) neurons after injury is critically limited by their slow axonal regenerative rate 1 . Since a delayed target re-innervation leads to irreversible loss of function of target organs 2 , accelerated axonal regeneration is required to enhance functional outcomes following injury. Regenerative ability is influenced by both injury-dependent and injury-independent mechanisms 3 . Among the latter, environmental factors such as exercise and environmental enrichment have been shown to affect signalling pathways that promote axonal regeneration 4 . Several of these pathways, including modifications in gene transcription and protein synthesis, mitochondrial metabolism and release of neurotrophins, can be activated by intermittent fasting (IF) 5,6 . IF has in turn been shown to increase synaptic plasticity 7,8 and neurogenesis 9 , partially sharing molecular mechanisms with axonal regeneration. 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 the mouse via an unexpected mechanism that relies upon the gram + gut microbiome and an increase of 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 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 that was confirmed by the inhibition of neutrophil chemotaxis. Our results demonstrate for the first time the ability of a microbiome derived metabolite, such as IPA, in facilitating regeneration and functional recovery of sensory axons via an immune-mediated mechanism. Since IPA is a naturally occurring metabolite with a very favourable toxicity profile, it represents a realistic translational possibility for human axonal injuries.