The microbiota-gut-brain axis has emerged as a novel target in depression, a disorder with low treatment efficacy. However, the field is dominated by underpowered studies focusing on major depression not addressing microbiome functionality, compositional nature, or confounding factors. We applied a multi-omics approach combining pre-clinical models with three human cohorts including patients with mild depression. Microbial functions and metabolites converging onto glutamate/GABA metabolism, particularly proline, were linked to depression. High proline consumption was the dietary factor with the strongest impact on depression. Whole-brain dynamics revealed rich club network disruptions associated with depression and circulating proline. Proline supplementation in mice exacerbated depression along with microbial translocation. Human microbiota transplantation induced an emotionally impaired phenotype in mice and alterations in GABA-, proline-, and extracellular matrix-related prefrontal cortex genes. RNAi-mediated knockdown of proline and GABA transporters in Drosophila and mono-association with L. plantarum, a high GABA producer, conferred protection against depression-like states. Targeting the microbiome and dietary proline may open new windows for efficient depression treatment.

微生物-肠-脑轴已成为抑郁症的新靶点，抑郁症是一种治疗效果不佳的疾病。然而，该领域的研究主要集中在重度抑郁症上，而不是针对微生物组功能、成分性质或混杂因素。我们应用了一种多组学方法，将临床前模型与包括轻度抑郁症患者在内的三个人类队列相结合。微生物功能和与谷氨酸/GABA 代谢相结合的代谢物，特别是脯氨酸，与抑郁症有关。高脯氨酸摄入是对抑郁症影响最大的饮食因素。全脑动力学揭示了与抑郁症和循环脯氨酸相关的丰富的俱乐部网络中断。在小鼠中补充脯氨酸会加剧抑郁症以及微生物易位。人类微生物群移植在小鼠中诱导了情绪受损的表型以及 GABA、脯氨酸和细胞外基质相关的前额叶皮层基因的改变。RNAi介导的脯氨酸和GABA转运蛋白敲低果蝇和与高 GABA 生产者L. plantarum的单一关联赋予对抑郁样状态的保护。针对微生物组和膳食脯氨酸可能会为有效的抑郁症治疗打开新的窗口。