Ingestion of Faecalibaculum rodentium causes depression-like phenotypes in resilient Ephx2 knock-out mice: A role of brain–gut–microbiota axis via the subdiaphragmatic vagus nerve

•Ephx2 KO mice do not show depression-like phenotypes after chronic social defeat stress (CSDS).•Fecal microbiota transplantation (FMT) from CSDS-susceptible mice caused depression-like phenotype in antibiotic-treated Ephx2 KO mice.•Ingestion of F. rodentium caused depression-like phenotypes in antibiotic-treated Ephx2 KO mice.•Subdiaphragmatic vagotomy did not show depression-like phenotypes in the antibiotic-treated Ephx2 mice after ingestion of F. rodentium.•The brain–gut–microbiota axis via the subdiaphragmatic vagus nerve plays an important role in susceptibility and resilience. The brain–gut–microbiota axis plays a crucial role in the bidirectional interactions between the brain and the gut. Soluble epoxide hydrolase (coded by the Ephx2 gene) plays an important role in inflammation, which has been implicated in stress-related depression. Ephx2 knock-out (KO) mice exposed to chronic social defeat stress (CSDS) did not show depression-like behaviors, indicating stress resilience. Here we examined whether the brain–gut–microbiota axis influences the resilience in Ephx2 KO mice. Effects of fecal microbiota transplantation (FMT) from CSDS-susceptible (or control) mice in wild-type (WT) mice and Ephx2 KO mice treated with an antibiotic cocktail (ABX) were investigated. Behavioral, biochemical tests and 16S ribosome RNA analysis were performed. FMT from CSDS-susceptible mice produced anhedonia-like behavior in ABX-treated WT and Ephx2 KO mice. The 16S ribosome RNA analysis showed that Faecalibaculum rodentium (F. rodentium) may be responsible for the observed anhedonia-like behavior following FMT from CSDS-susceptible mice. Ingestion of F. rodentium for 14 days produced depression- and anhedonia-like behaviors, higher blood levels of interleukin-6, and reduced expression of synaptic proteins in the prefrontal cortex of ABX-treated Ephx2 KO mice. Furthermore, subdiaphragmatic vagotomy blocked the development of these behavioral abnormalities after ingestion of F. rodentium. Detailed mechanisms are unclear. These findings suggest that F. rodentium might contribute to the conversion of resilient Ephx2 KO mice into KO mice with depression-like phenotypes. The brain–gut–microbiota axis via the subdiaphragmatic vagus nerve plays a crucial role in susceptibility and resilience to stress.