The gut metabolite indole-3 propionate promotes nerve regeneration and repair

• Published in: Nature (London) 2022-07, Vol.607 (7919), p.585-592
• Main Authors: Serger, Elisabeth, Luengo-Gutierrez, Lucia, Chadwick, Jessica S., Kong, Guiping, Zhou, Luming, Crawford, Greg, Danzi, Matt C., Myridakis, Antonis, Brandis, Alexander, Bello, Adesola Temitope, Müller, Franziska, Sanchez-Vassopoulos, Alexandros, De Virgiliis, Francesco, Liddell, Phoebe, Dumas, Marc Emmanuel, Strid, Jessica, Mani, Sridhar, Dodd, Dylan, Di Giovanni, Simone
• Format: Article
• Language: English
• Subjects: 13/31; 13/51; 38; 38/91; 631/250; 631/378; 631/378/340; Acids; Animals; Axons; Axons - drug effects; Axons - physiology; Bacteria; Chemotaxis; Chemotaxis, Leukocyte; Chromatography; Clostridium - metabolism; Dorsal root ganglia; Drug resistance; Enrichment; Environmental factors; Exercise; Fasting; Ganglia; Ganglia, Spinal - metabolism; Gastrointestinal Microbiome; Gene sequencing; Genotype & phenotype; Gram-positive bacteria; Humanities and Social Sciences; Indoles - blood; Indoles - metabolism; Indoles - pharmacology; Injuries; Injury prevention; Intestinal microflora; Leukocytes (neutrophilic); Life Sciences; Mass spectrometry; Metabolism; Metabolites; Mice; Microbiomes; Microbiota; Mitochondria; multidisciplinary; Nerve Crush; Nerve Growth Factors - metabolism; Nerve Regeneration - drug effects; Nerves; Nervous system; Neurons; Neurotrophic factors; Neutrophils; Neutrophils - cytology; Neutrophils - immunology; Peripheral nervous system; Phenotypes; Propionates - blood; Propionates - metabolism; Propionates - pharmacology; Propionic acid; Protein biosynthesis; Protein synthesis; Protein turnover; Recovery; Recovery of Function; Regeneration; Sciatic nerve; Sciatic Nerve - injuries; Science; Science (multidisciplinary); Scientific imaging; Sensory neurons; Sequence analysis; Sequence Analysis, RNA; Signal transduction; Wound Healing - drug effects
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-022-04884-x

The regenerative potential of mammalian peripheral nervous system neurons after injury is critically limited by their slow axonal regenerative rate 1 . Regenerative ability is influenced by both injury-dependent and injury-independent mechanisms 2 . Among the latter, environmental factors such as exercise and environmental enrichment have been shown to affect signalling pathways that promote axonal regeneration 3 . 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.