Archaea methanogens are associated with cognitive performance through the shaping of gut microbiota, butyrate and histidine metabolism

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• dc.contributor.author Fumagalli, Andrea
• dc.contributor.author Castells-Nobau, Anna
• dc.contributor.author Trivedi, Dakshat
• dc.contributor.author Garre-Olmo, Josep
• dc.contributor.author Puig, Josep
• dc.contributor.author Ramos, Rafel
• dc.contributor.author Ramió-Torrentà, Lluís
• dc.contributor.author Pérez Brocal, Vicente
• dc.contributor.author Moya, Andrés
• dc.contributor.author Swann, Jonathan Richard
• dc.contributor.author Martín García, Elena, 1975-
• dc.contributor.author Maldonado, Rafael, 1961-
• dc.contributor.author Fernández Real, Jose M.
• dc.contributor.author Mayneris Perxachs, Jordi
• dc.date.accessioned 2025-03-21T08:33:11Z
• dc.date.available 2025-03-21T08:33:11Z
• dc.date.issued 2025
• dc.description.abstract The relationship between bacteria, cognitive function and obesity is well established, yet the role of archaeal species remains underexplored. We used shotgun metagenomics and neuropsychological tests to identify microbial species associated with cognition in a discovery cohort (IRONMET, n = 125). Interestingly, methanogen archaeas exhibited the strongest positive associations with cognition, particularly Methanobrevibacter smithii (M. smithii). Stratifying individuals by median-centered log ratios (CLR) of M. smithii (low and high M. smithii groups: LMs and HMs) revealed that HMs exhibited better cognition and distinct gut bacterial profiles (PERMANOVA p = 0.001), characterized by increased levels of Verrucomicrobia, Synergistetes and Lentisphaerae species and reduced levels of Bacteroidetes and Proteobacteria. Several of these species were linked to the cognitive test scores. These findings were replicated in a large-scale validation cohort (Aging Imageomics, n = 942). Functional analyses revealed an enrichment of energy, butyrate, and bile acid metabolism in HMs in both cohorts. Global plasma metabolomics by CIL LC-MS in IRONMET identified an enrichment of methylhistidine, phenylacetate, alpha-linolenic and linoleic acid, and secondary bile acid metabolism associated with increased levels of 3-methylhistidine, phenylacetylgluamine, adrenic acid, and isolithocholic acid in the HMs group. Phenylacetate and linoleic acid metabolism also emerged in the Aging Imageomics cohort performing untargeted HPLC-ESI-MS/MS metabolic profiling, while a targeted bile acid profiling identified again isolithocholic acid as one of the most significant bile acid increased in the HMs. 3-Methylhistidine levels were also associated with intense physical activity in a second validation cohort (IRONMET-CGM, n = 116). Finally, FMT from HMs donors improved cognitive flexibility, reduced weight, and altered SCFAs, histidine-, linoleic acid- and phenylalanine-related metabolites in the dorsal striatum of recipient mice. M. smithii seems to interact with the bacterial ecosystem affecting butyrate, histidine, phenylalanine, and linoleic acid metabolism with a positive impact on cognition, constituting a promising therapeutic target to enhance cognitive performance, especially in subjects with obesity.
• dc.description.sponsorship (ISCIII, Madrid, Spain) through the projects PI15/01934, PI18/01022 and PI21/01361 to J.M.F-R and the project PI20/01090 and PI23/00575 (co-funded by the European Union under the European Regional Development Fund (FEDER) “A way to make Europe”) to J.M-P, the project CNS2023-144218 funded by MCIN/AEI/10.13039/501100011033 and the European Union NextGenerationEU/PRTR to J.M-P, and (2021 SGR 01263). This work has also been co-financed by the Spanish Ministry of Science, Innovation and Universities with funds from the European Union NextGenerationEU, from the Recovery, Transformation and Resilience Plan (PRTR-C17.I1) and from the Autonomous Community of Catalonia within the framework of the Biotechnology Plan Applied to Health through the project PPCC-ADGUT to J.M.-P. J.M-P and A.C.N are funded by (Madrid, Spain) through the Miguel Servet Program CP18/00009 and CP24/00033 (co-funded by the European Union under the European Social Fund “Investing in your future”), respectively. A.F. is funded by Girona Biomedical Research Institute (Girona, Spain) through the Horizon 2020 Framework Programme of the European Union under the Marie Skłodowska-Curie Innovative Training Network grant agreement No 859890. This study was conducted using samples/data from the Aging Imageomics Study, supported by the through the Strategic Plan for Health Research and Innovation (PERIS) 2016–2020 (SLT002/16/00250). We want to particularly acknowledge the participants, to the IDIBGI Horizontal Aging Program and the IDIBGI Biobank (Biobanc IDIBGI, B.0000872), integrated in the Platform ISCIII Biomodels and Biobanks, for their collaboration. JRS is supported by the NIHR Southampton Biomedical Research Centre, and the Biotechnology and Biological Sciences Research Council (BB/W00139X/1).
• dc.format.mimetype application/pdf
• dc.identifier.citation Fumagalli A, Castells-Nobau A, Trivedi D, Garre-Olmo J, Puig J, Ramos R, et al. Archaea methanogens are associated with cognitive performance through the shaping of gut microbiota, butyrate and histidine metabolism. Gut Microbes. 2025 Dec;17(1):2455506. DOI: 10.1080/19490976.2025.2455506
• dc.identifier.doi http://dx.doi.org/10.1080/19490976.2025.2455506
• dc.identifier.issn 1949-0976
• dc.identifier.uri http://hdl.handle.net/10230/69986
• dc.language.iso eng
• dc.publisher Taylor & Francis
• dc.relation.ispartof Gut Microbes. 2025 Dec;17(1):2455506
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/859890
• dc.rights © 2025 The Author(s). Published with license by Taylor & Francis Group, LLC. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Microbiota
• dc.subject.keyword Archaea
• dc.subject.keyword Cognition
• dc.subject.keyword Cognitive flexibility
• dc.subject.keyword Executive function
• dc.title Archaea methanogens are associated with cognitive performance through the shaping of gut microbiota, butyrate and histidine metabolism
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion