Microbes modulate sympathetic neurons via a gut-brain circuit

Microbial density and diversity increases from proximal to distal regions of the intestine, affecting tissue physiology, metabolism, and function of the immune and nervous systems. Both intrinsic and extrinsic enteric-associated neurons (EAN) continuously monitor and modulate homeostatic intestinal functions, including nutrient absorption and motility. However, a systemic and circuit-based link between gut microbes and the nervous system has yet to be established. Through a combination of molecular, anatomic and functional approaches, we characterized the influence of the microbiota on EAN. We found that intrinsic EAN are functionally adapted to the specific intestinal region they occupy in a microbiota-dependent manner. Furthermore, we observed that gut-extrinsic sympathetic neurons are hyperactivated in the absence of microbes, while the production of butyrate is sufficient to suppress sympathetic activity. Finally, retrograde polysynaptic neuronal tracing from the intestinal wall revealed that brainstem GABAergic neurons are a potential central hub for modulation of gut-specific sympathetic neurons. These results reveal that commensal microbiota imprint gut-intrinsic neuronal gene programs and control extrinsic sympathetic activity through a metabolite-mediated gut-brain circuit.