Microbiota alterations in proline metabolism impact depression

• Published in: Cell metabolism 2022-05, Vol.34 (5), p.681-701.e10
• Main Authors: Mayneris-Perxachs, Jordi, Castells-Nobau, Anna, Arnoriaga-Rodríguez, María, Martin, Miquel, de la Vega-Correa, Lisset, Zapata, Cristina, Burokas, Aurelijus, Blasco, Gerard, Coll, Clàudia, Escrichs, Anira, Biarnés, Carles, Moreno-Navarrete, José María, Puig, Josep, Garre-Olmo, Josep, Ramos, Rafel, Pedraza, Salvador, Brugada, Ramón, Vilanova, Joan Carles, Serena, Joaquín, Gich, Jordi, Ramió-Torrentà, Lluís, Pérez-Brocal, Vicente, Moya, Andrés, Pamplona, Reinald, Sol, Joaquim, Jové, Mariona, Ricart, Wifredo, Portero-Otin, Manuel, Deco, Gustavo, Maldonado, Rafael, Fernández-Real, José Manuel
• Format: Article
• Language: English
• Subjects: amino acids; brain; cognition; depression; diet; gut microbiota; proline
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2022.04.001

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. [Display omitted] •High dietary and plasma proline significantly associate with depression severity•Circulating proline is dependent on microbiome composition and functionality•With FMT, depression phenocopies to mice and increases a proline transporter gene•Slc6a20 knockdown and L. plantarum supplementation protect flies from depression Mayneris-Perxachs et al. apply a multi-omics approach to study the microbiota-gut-brain axis in depression and demonstrate that microbiome-dependent elevations in plasma proline are significantly associated with depression severity in humans. Proline supplementation exacerbated depression in mice, and knockdown of proline and GABA transporters or mono-association with L. plantarum conferred protection against depression-like states in Drosophila.