Gut bacteria-derived succinate induces enteric nervous system regeneration.

Area of Science:

• Neuroscience
• Microbiology
• Gastroenterology

Background:

• Enteric neurons regulate essential gut functions like motility and secretion.
• Antibiotic-induced gut dysbiosis leads to enteric neuron loss and motility disorders.
• The mechanisms of microbiota-neuron communication remain largely unknown.

Purpose of the Study:

• To investigate the role of microbiota in enteric nervous system recovery after antibiotic-induced dysbiosis.
• To identify specific microbial signals and cellular mechanisms driving neuronal regeneration.
• To explore therapeutic strategies for peripheral neuropathies linked to gut health.

Main Methods:

• Murine gnotobiotic models were used to study the effects of microbiota restoration.
• Fecal metabolomics identified key bacterial species and metabolites involved in recovery.
• Single-nuclei RNA sequencing and genetic fate-mapping elucidated cellular mechanisms of neuronal regeneration.

Main Results:

• Antibiotic exposure caused loss of enteric neurons and glia, which recovered upon microbiota restoration.
• Specific neurogenic bacterial species and their metabolite succinate were sufficient to rescue neurons and glia.
• A novel Nav2+ neural precursor-like population and glial-to-neuron differentiation were identified as regeneration mechanisms.

Conclusions:

• Gut microbiota plays a critical role in the regeneration of the enteric nervous system.
• Succinate and specific bacterial species are key mediators of neuronal recovery.
• These findings offer potential therapeutic targets for peripheral neuropathies and gut motility disorders.