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

Elisabeth Serger, Lucia Luengo-Gutierrez, Jessica S. Chadwick, Guiping Kong, Luming Zhou, Greg Crawford, Matt C. Danzi, Antonis Myridakis, Alexander Brandis, Adesola Temitope Bello, Franziska Müller, Alexandros Sanchez-Vassopoulos, Francesco Virgiliis, Phoebe Liddell, Marc Emmanuel Dumas, Jessica Strid, Sridhar Mani, Dylan Dodd and Simone Giovanni ()
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Elisabeth Serger: Imperial College London
Lucia Luengo-Gutierrez: Imperial College London
Jessica S. Chadwick: Imperial College London
Guiping Kong: Imperial College London
Luming Zhou: Imperial College London
Greg Crawford: Imperial College London
Matt C. Danzi: University of Miami Miller School of Medicine
Antonis Myridakis: Imperial College London
Alexander Brandis: Weizmann Institute of Science
Adesola Temitope Bello: UK Dementia Research Institute, Imperial College London
Franziska Müller: Imperial College London
Alexandros Sanchez-Vassopoulos: Imperial College London
Francesco Virgiliis: Imperial College London
Phoebe Liddell: Imperial College London
Marc Emmanuel Dumas: National Heart and Lung Institute, Imperial College London
Jessica Strid: Imperial College London
Sridhar Mani: Albert Einstein College of Medicine
Dylan Dodd: Stanford School of Medicine
Simone Giovanni: Imperial College London

Nature, 2022, vol. 607, issue 7919, 585-592

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41586-022-04884-x

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