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Can intestinal metabolites promote peripheral nerve regeneration ?


As described in my recently published book on nerve regeneration from p. 75, attempts have been made for many years to increase the efficiency and specificity of peripheral nerve regeneration. There are pharmacological approaches, but the use of neurotrophic factors as well as cellular and gene therapy methods have also been proposed. These have often shown astonishing success in preclinical animal experiments. Unfortunately, however, despite numerous clinical trials, which must precede any approval of new therapies, no new drug has yet made it into everyday clinical practice. However, electrical and manual stimulation therapies are used in addition to the generally recognized rehabilitation measures, as they improve the reinnervation of the paralyzed muscles.

In addition, our eating habits probably also play a role, as intermittent fasting not only reduces body weight in the long term, but also promotes axon regeneration (at least in animal experiments). Apparently, gram-positive bacteria in the gut produce regeneration-promoting metabolites during starvation, with the commercially available indole-3-propionic acid (IPA) playing a key role.

The production of IPA by the intestinal bacterium Clostridium sporogenes is required for efficient axonal regeneration, as Simone Di Giovanni's team demonstrated in Nature in 2022. After administration of IPA, the regeneration and functional recovery of injured sciatic nerves in mice improved significantly. Based on RNA sequencing of the dorsal sciatic root ganglia, they demonstrated a significant role of neutrophil chemotaxis in this context, i.e. the recruitment of immune cells with phagocytic function into the injured nerve through activation of the IPA receptor pregnane X (PXR).

Neutrophil granulocytes are required for axonal regeneration in the peripheral and central nervous system by transmitting regenerative signals, e.g. interferons (IFNγ), to the injured neurons. Potentially, the identification of bacterial fatty acids for oral or intravenous administration could therefore offer promising new therapeutic opportunities to promote axonal regeneration.

Reference:


Serger E, Luengo-Gutierrez L, Chadwick JS, ..., Di Giovanni S (2022) The gut metabolite indole-3 propionate promotes nerve regeneration and repair. Nature 607:585


Image credit: iStock/alex-mit

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