Abstract
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 associated with host genetic variations relate to behavioral outcomes is not fully understood. We investigated how Sirtuin 3 (Sirt3) deficiency is linked to altered 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 were used to assess microbiome-related contributions to behavioral differences. Transcriptomic profiling assessed region-specific gene expression in the limbic system. Metabolites in the nucleus of the solitary tract (NTS), potentially related to gut–brain vagal signaling, were analyzed. The role of the vagus nerve was further tested using subdiaphragmatic vagotomy in the Sirt3-KO mouse model, along with measurements of plasma choline levels in mice. Sirt3-KO mice displayed mood-related neurobehavioral changes and alterations in synaptic plasticity-related genes in the amygdala and the bed nucleus of the stria terminalis (BNST), accompanied by alterations in gut microbiome composition. Elevated plasma choline levels in Sirt3-KO mice, together with reduced neurotransmitter-related metabolites (e.g., γ-aminobutyric acid [GABA] in the NTS), suggest that externalizing behaviors in Sirt3-KO mice involve vagus nerve-dependent gut–brain axis signaling. Consistent with the involvement of vagal signaling, vagotomized Sirt3-KO mice were similar to WT mice in these measures, including GABA levels in the NTS and synaptic plasticity-related changes in the amygdala and BNST. Our findings support a model in which host genetic variation-associated microbiome alterations are sensed through sustained gut–vagal signaling under non-stressed conditions, correlating with NTS neurotransmitter alterations and externalizing behavioral phenotypes.