Select microbial metabolites in the small intestinal lumen regulates vagal activity via receptor-mediated signaling

The vagus nerve is proposed to enable communication between the gut microbiome and the brain, but activity-based evidence is lacking. We find that mice reared germ-free exhibit decreased vagal tone relative to colonized controls, which is reversed via microbiota restoration. Perfusing antibiotics into the small intestines of conventional mice, but not germ-free mice, acutely decreases vagal activity which is restored upon re-perfusion with intestinal filtrates from conventional, but not germ-free, mice. Microbiome-dependent short-chain fatty acids, bile acids, and 3-indoxyl sulfate indirectly stimulate vagal activity in a receptor- dependent manner. Serial perfusion of each metabolite class activates both shared and distinct neuronal subsets with varied response kinetics. Metabolite-induced and receptor-dependent increases in vagal activity correspond with the activation of brainstem neurons. Results from this study reveal that the gut micro- biome regulates select metabolites in the intestinal lumen that differentially activate vagal afferent neurons, thereby enabling the microbial modulation of chemosensory signals for gut-brain communication.