Neuroinflammation through the vagus nerve-dependent gut-microbiota-brain axis in treatment-resistant depression.

Neuroinflammation is central to major depressive disorder (MDD) and treatment-resistant depression (TRD), with patients showing higher inflammatory biomarkers. The gut-microbiota-brain axis, mediated by the vagus nerve, contributes to neuroinflammation. Fecal microbiota transplantation (FMT) from depressed humans or rodents induces depression-like behaviors and systemic inflammation in rodents, effects blocked by subdiaphragmatic vagotomy. Vagotomy also blocks antidepressant effects of serotonergic drugs. The antidepressant arketamine may restore altered gut microbiota in depressed rodents. This chapter reviews the vagus nerve-dependent gut-microbiota-brain axis in depression and discusses FMT, vagus nerve stimulation, and arketamine as potential TRD treatments.

Study at a glance

Abstract

Neuroinflammation plays a key role in the pathogenesis of major depressive disorder (MDD), including treatment-resistant depression (TRD). Patients with TRD have higher levels of inflammatory biomarkers compared with responders to antidepressants. Multiple lines of evidence suggest that the gut-microbiota-brain axis via the vagus nerve plays a key role in neuroinflammation. Preclinical and clinical data suggest that fecal microbiota transplantation (FMT) from MDD patients or rodents with depression-like behaviors cause depression-like behaviors in rodents through systemic inflammation. Importantly, subdiaphragmatic vagotomy blocked these depression-like phenotypes and systemic inflammation in rodents after FMT of depression-related microbes. Subdiaphragmatic vagotomy also blocked the antidepressant-like effects of serotonergic antidepressants in rodents. Preclinical findings suggest that the new antidepressant, (R)-ketamine (or arketamine), may restore the altered composition of gut microbiota in rodents with depression-like behaviors, contributing to the beneficial effects of arketamine. In this chapter, the author reviews the role of the vagus nerve-dependent gut-microbiota-brain axis in depression (including TRD), and also discuss the potential of FMT, vagus nerve stimulation, and arketamine for the treatment of TRD.