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

2025 · doi:10.1101/2025.11.13.688184
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This study found that gut microbiota-derived adenosine influences electroconvulsive therapy's antidepressant efficacy by modulating a gut-brain axis, suggesting adenosine supplementation could protect against cognitive side effects.

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⚙ AI-generated deep summary by claude@2026-07, 2026-07-15 · read from full text ⓘ

The study investigated whether gut microbiota modulates the effectiveness of electroconvulsive therapy (modeled as 5-day electroconvulsive shock) for major depressive disorder using a chronic restraint stress mouse model. ECS produced antidepressant effects that were suppressed after antibiotics induced microbiota dysbiosis, which was accompanied by increased activity of CRH neurons in the hypothalamic paraventricular nucleus and higher serum corticosterone; metabolomics pointed to microbiota-associated purine metabolism as critical. Supplementing gut microbiota-derived adenosine restored the antidepressant effect of ECS in dysbiotic mice and also reduced post-ECS memory loss and synaptic plasticity impairment, with gut-brain signaling linked via neural tracing to Adora1-expressing cells in the colon. The paper’s key limitation is that findings are derived from animal models of depression and microbiota manipulation rather than direct human ECT studies. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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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.
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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. Competing Interest Statement The authors have declared no competing interest. Footnotes author order updated. author affiliations updated.

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