Microbiota alterations in proline metabolism impact depression
Abstract & Authors:展开
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.
Jordi Mayneris-Perxachs,Rafael Maldonado,José Manuel Fernández-Real
Jordi Mayneris-Perxachs,Anna Castells-Nobau,María Arnoriaga-Rodríguez,Miquel Martin,Lisset de la Vega-Correa,Cristina Zapata,Aurelijus Burokas,Gerard Blasco,Clàudia Coll,Anira Escrichs,Carles Biarnés,José María Moreno-Navarrete,Josep Puig,Josep Garre-Olmo,Rafel Ramos,Salvador Pedraza,Ramón Brugada,Joan Carles Vilanova,Joaquín Serena,Jordi Gich,Lluís Ramió-Torrentà,Vicente Pérez-Brocal,Andrés Moya,Reinald Pamplona,Joaquim Sol,Mariona Jové,Wifredo Ricart,Manuel Portero-Otin,Gustavo Deco,Rafael Maldonado,José Manuel Fernández-Real