Beneficial effects of arketamine on the reduced bone mineral density in susceptible mice after chronic social defeat stress: Role of the gut–microbiota–bone–brain axis

Patients with depression exhibit reduced bone mineral density (BMD). We previously reported that the new antidepressant arketamine improved the reduced BMD seen in chronic social defeat stress (CSDS) susceptible mice and ovariectomized mice. Considering the role of the gut microbiota in maintaining bone health, the current study investigated whether the gut microbiota, along with metabolites derived from the microbiome, play a role in the beneficial actions of arketamine with respect to the anhedonia-like behavior and reduced BMD seen in CSDS susceptible mice. A single administration of arketamine (10 mg/kg) ameliorated anhedonia-like behavior and decreased femoral neck cortical (and total) BMD in CSDS susceptible mice. There was a negative correlation between anhedonia-like behavior and BMD. Furthermore, significant differences in the abundance of microbiota (and plasma metabolites) were found between the CSDS + saline and CSDS + arketamine groups. Correlations were observed between the abundance of certain microbiota (and plasma metabolites) and cortical (and total) BMD. These data suggest that, in addition to its anti-anhedonia effect, arketamine might ameliorate the reduced cortical (and total) BMD seen in CSDS susceptible mice through the gut–microbiota–bone–brain axis. Therefore, arketamine could serve as a drug therapy for depressed patients with low BMD. This article is part of the Special Issue on “Ketamine and its Metabolites”.