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

Autor: Serger E; Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, UK.; Graduate School for Neuroscience, Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, UK., Luengo-Gutierrez L; Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, UK., Chadwick JS; Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, UK., Kong G; Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, UK., Zhou L; Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, UK., Crawford G; Department of Immunology and Inflammation, Imperial College London, London, UK., Danzi MC; Dr. John T. MacDonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA., Myridakis A; Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK., Brandis A; Targeted Metabolomics Unit, Weizmann Institute of Science, Rehovot, Israel., Bello AT; UK Dementia Research Institute, Imperial College London, London, UK., Müller F; Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, UK., Sanchez-Vassopoulos A; Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, UK., De Virgiliis F; Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, UK., Liddell P; Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, UK., Dumas ME; National Heart and Lung Institute, Imperial College London, London, UK.; European Genomic Institute for Diabetes, UMR1283 INSERM, UMR8199 CNRS, Institut Pasteur de Lille, University of Lille, Lille, France., Strid J; Department of Immunology and Inflammation, Imperial College London, London, UK., Mani S; Departments of Medicine, Molecular Pharmacology and Genetics, Albert Einstein College of Medicine, Bronx, NY, USA., Dodd D; Department of Pathology, Stanford School of Medicine, Stanford, CA, USA.; Department of Microbiology & Immunology, Stanford School of Medicine, Stanford, CA, USA., Di Giovanni S; Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, UK. s.di-giovanni@imperial.ac.uk.
Jazyk: angličtina
Zdroj: Nature [Nature] 2022 Jul; Vol. 607 (7919), pp. 585-592. Date of Electronic Publication: 2022 Jun 22.
DOI: 10.1038/s41586-022-04884-x
Abstrakt: 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.
(© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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