Microbiota alterations in proline metabolism impact depression

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  • dc.contributor.author Mayneris Perxachs, Jordi
  • dc.contributor.author Martin, Miquel
  • dc.contributor.author Burokas, Aurelijus, 1982-
  • dc.contributor.author Escrichs, Anira
  • dc.contributor.author Deco, Gustavo
  • dc.contributor.author Maldonado, Rafael, 1961-
  • dc.contributor.author Fernández Real, Jose M.
  • dc.date.accessioned 2022-06-17T05:51:56Z
  • dc.date.available 2022-06-17T05:51:56Z
  • dc.date.issued 2022
  • dc.description.abstract 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.
  • dc.description.sponsorship This work was partially supported by Instituto de Salud Carlos III (Madrid, Spain) through the research grants PI15/01934, PI18/01022, and PI21/01361 to J.M.F.-R. and PI20/01090 (co-funded by the European Regional Development Fund. “A way to make Europe”) to J.M.-P.; the Catalan Government (AGAUR, #SGR2017-0734, ICREA Academia Award 2021) to J.M.F.-R.; the Spanish Ministry of Science, Innovation and Universities (PID2019-105969GB-I00); Generalitat Valenciana (Prometeo/2018/133), Spain; and Fondo Europeo de Desarrollo Regional (FEDER) funds to A.M. This work was also supported by the European Commission (FP7, NeuroPain #2013-602891); the Catalan Government (AGAUR, #SGR2017-669, ICREA Academia Award 2020) to R.M.; the Spanish Instituto de Salud Carlos III (RTA, #RD16/0017/0020) to R.M.; Ministry of Science and Innovation and State Research Agency (#PID2020- 120029GB-I00/MICIN/AEI/10.13039/501100011033) to R.M.; the European Regional Development Fund (project no. 01.2.2-LMT-K-718-02-0014) under grant agreement with the Research Council of Lithuania (LMTLT); and the Project ThinkGut (EFA345/19), 65% co-financed by the European Regional Development Fund (ERDF) through the Interreg V-A Spain-France-Andorra program (POCTEFA, 2014–2020). We also acknowledge funding from the Spanish Ministry of Science, Innovation and Universities (RTI2018-099200-B-I00) and the Generalitat of Catalonia (Agency for Management of University and Research Grants [2017SGR696] and Department of Health [SLT002/16/00250]) to R.P. M.A.-R. is funded by Instituto de Salud Carlos III, Río Hortega (CM19/00190). J.M.-P. is funded by a Miguel Servet contract (CP18/00009) from the Instituto de Salud Carlos III. J.S. is funded by a predoctoral PERIS contract (SLT002/16/00250) from the Catalan Government. M.J. is a professor under “Serra Hunter” program (Generalitat de Catalunya). The graphical abstract was created with BioRender.com. We would like to thank Martijn Eidhof for his help in building the stress treatment machine for Drosophila.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Mayneris-Perxachs J, Castells-Nobau A, Arnoriaga-Rodríguez M, Martin M, de la Vega-Correa L, Zapata C et al. Microbiota alterations in proline metabolism impact depression. Cell Metab. 2022 May 3;34(5):681-701.e10. DOI: 10.1016/j.cmet.2022.04.001
  • dc.identifier.doi http://dx.doi.org/10.1016/j.cmet.2022.04.001
  • dc.identifier.issn 1550-4131
  • dc.identifier.uri http://hdl.handle.net/10230/53513
  • dc.language.iso eng
  • dc.publisher Elsevier
  • dc.relation.ispartof Cell Metab. 2022 May 3;34(5):681-701.e10
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-105969GB-I00
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-120029GB-I00
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-099200-B-I00
  • dc.rights © 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
  • dc.subject.keyword Amino acids
  • dc.subject.keyword Brain
  • dc.subject.keyword Cognition
  • dc.subject.keyword Depression
  • dc.subject.keyword Diet
  • dc.subject.keyword Gut microbiota
  • dc.subject.keyword Proline
  • dc.title Microbiota alterations in proline metabolism impact depression
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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