Vagal Sensing of Altered Gut Microbiota Links to Externalizing Behaviors

Interoceptive brain responses triggered by intestinal microbiota influence mood-related behaviors such as anxiety and depression. Although genetic mutations can alter the gut microbiome, how alterations in the gut microbiome caused by host genetic variations affect behavioral outcomes is not fully understood. We investigated how Sirtuin 3 ( Sirt3 ) deficiency affects gut–brain interactions and mood-related behaviors. Gut microbiota composition and behavior were compared between Sirt3 -knockout (KO) and wild-type (WT) mice. Cohousing and heterozygous littermate controls distinguished microbiome-driven from genetic effects. Transcriptomic profiling assessed region-specific gene expression in the limbic system. Metabolites in the nucleus of the solitary tract (NTS), reflecting gut–brain vagal signaling, were analyzed. The role of the vagus nerve was further tested via vagotomy, with comparative analyses of choline levels in mice and mood disorder patients. Sirt3 -KO mice appeared mood-related neurobehavioral changes and alterations in synaptic plasticity-related genes in the amygdala and BNST, dependent on gut microbiome composition. Elevated plasma choline levels in both mood disorder patients and Sirt3 -KO mice, together with reduced neurotransmitter-related metabolites (e.g., γ-aminobutyric acid [GABA] in the NTS), suggested that externalizing behaviors in Sirt3 -KO mice are mediated by vagus nerve-dependent gut–brain axis signaling. Consistent with this, vagotomy abolished these changes, including GABA in the NTS, as well as alterations in synaptic plasticity in the amygdala and BNST. Our findings suggest the novel finding that an altered gut microbiome caused by a host genetic change, namely a Sirt3 deficiency, is sensed in the NTS of the brain via the vagus nerve, leading to externalizing behaviors.