Depression-like phenotypes in mice with hepatic ischemia/reperfusion injury: A role of gut–microbiota–liver–brain axis via vagus nerve

Depression is a frequent symptom in patients with chronic liver disease; however, the mechanisms underlying this association remain unclear. Dysbiosis of gut microbiota plays a critical role in depression through the gut–brain axis via the vagus nerve. In this study, we investigated whether the gut–microbiota–liver–brain axis plays a role in depression-like phenotypes in mice with hepatic ischemia/reperfusion (HI/R) injury via the vagus nerve. Behavioral tests for depression-like behaviors were performed 7 days after sham or HI/R injury surgery. Mice with HI/R injury exhibited splenomegaly, systemic inflammation, depression-like behaviors, reduced expression of synaptic proteins in the prefrontal cortex (PFC), abnormal composition of gut microbiota, and altered blood metabolites and lipids. Furthermore, there were positive or negative correlations between the relative abundance of microbiome and behavioral data or blood metabolites (or lipids). Moreover, subdiaphragmatic vagotomy significantly blocked these changes in mice with HI/R injury. Notably, depression-like phenotypes in mice with HI/R injury were ameliorated after subsequent single injection of the new antidepressant arketamine. The current findings suggest that HI/R injury induces depression-like phenotypes in mice through the gut–microbiota–liver–brain axis via the subdiaphragmatic vagus nerve. Furthermore, arketamine may have therapeutic potential in the treatment of depression in patients with chronic liver disease.