Gut Microbiota-derived Adenosine Determines the Efficacy of Electroconvulsive Therapy for Depression

Abstract

Electroconvulsive therapy (ECT) is a final procedure for major depressive disorders (MDD). However, the effectiveness of ECT in treating MDD patients varies. Here we identified gut microbiota as a potential restraining factor of ECT efficacy. By using a 5-day electroconvulsive shock (ECS) in depression mouse model of chronic restraint stress (CRS), it was observed that the antidepressant effect of ECS was suppressed after antibiotics (ABX)-induced microbiota dysbiosis, which also resulted in elevated c-Fos expression of CRH neurons in paraventricular nucleus of hypothalamus (PVN) and increased serum corticosterone levels after ECS. Metabolomic analysis revealed the critical involvement of microbiota associated purine metabolism, and the supplement of gut microbiota-derived adenosine was able to recover the antidepressant effect of ECS in ABX-treated CRS mouse model. Based on the neural tracing from colon to brain and the immunofluorescence staining, it was surmised a gut-brain axis originated from Adora1-expressing cells in colon mediate this biological process. Furthermore, adenosine supplement alleviated the further deterioration of post-ECS memory loss and impairment of synaptic plasticity induced by ABX-treatment as well. Our findings suggest a potential role of microbial adenosine metabolism in ECT efficacy determination and side effect protection, highlights potential application of adenosine supplement in antidepressant therapies of those depression patients with microbiota dysbiosis.