Microbiota alterations in proline metabolism impact depression

Mayneris Perxachs, Jordi
Castells Nobau, Anna
Martín Sánchez, Miquel
Vega-Correa, Lisset de la
Zapata Tona, Cristina
Burokas, Aurelijus
Blasco Solà, Gerard
Coll-Martinez, Clàudia
Escrichs, Anira
Biarnés, Carles
Puig Alcántara, Josep
Serena, Joaquín
Gich Fullà, Jordi
Pérez Brocal, Vicente
Moya, Andrés
Pamplona, Reinald
Sol, Joaquim
Jové, Mariona
Ricart, Wifredo
Portero Otin, Manuel
Deco, Gustavo
Maldonado, Rafael
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 ​
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