Major depressive disorder (MDD) is a common, chronic, recurrent disease. The existing drugs are ineffective for approximately half of patients, so the development of antidepressant drugs with novel mechanisms is urgent. Cumulative evidence has shown neuro-inflammation plays a key role in the etiology of major depressive disorder. Clinical studies implicated that bile acids, an important component of gut-brain axis, inhibit neuro-inflammation and mediate the pathophysiology of the MDD. Here, we found that ganoderic acid A (GAA) modulated bile acid receptor FXR (farnesoid X receptor), inhibited brain inflammatory activity, and showed antidepressant effects in the chronic social defeat stress depression model, tail suspension, forced swimming, and sucrose preference tests. GAA directly inhibited the activity of the NLRP3 inflammasome, and activated the phosphorylation and expression of the AMPA receptor by modulating FXR in the prefrontal cortex of mice. If we knocked out FXR or injected the FXR-specific inhibitor z-gugglesterone (GS), the antidepressant effects induced by GAA were completely abolished. These results suggest that GAA modulates the bile acid receptor FXR and subsequently regulates neuroimmune and antidepressant behaviors. GAA and its receptor FXR have potential as targets for the treatment of MDD.

重度抑郁症 (MDD) 是一种常见的慢性复发性疾病。现有药物对大约一半的患者无效，因此开发具有新机制的抗抑郁药物迫在眉睫。累积证据表明，神经炎症在重度抑郁症的病因学中起着关键作用。临床研究表明胆汁酸是肠脑轴的重要组成部分，可抑制神经炎症并介导 MDD 的病理生理学。在这里，我们发现灵芝酸 A (GAA) 调节胆汁酸受体 FXR（法尼醇 X 受体），抑制脑炎症活动，并在慢性社交失败压力抑郁模型、悬尾、强迫游泳和蔗糖偏好测试中显示出抗抑郁作用. GAA 直接抑制 NLRP3 炎症小体的活性，并通过调节小鼠前额叶皮层中的 FXR 激活 AMPA 受体的磷酸化和表达。如果我们被淘汰FXR或注射 FXR 特异性抑制剂 z-gugglesterone (GS)，GAA 诱导的抗抑郁作用被完全消除。这些结果表明 GAA 调节胆汁酸受体 FXR 并随后调节神经免疫和抗抑郁行为。GAA 及其受体 FXR 具有作为 MDD 治疗靶点的潜力。