Archaea methanogens are associated with cognitive performance through the shaping of gut microbiota, butyrate and histidine metabolism
Year: 2025
Type: article
Study design: Observational Study
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.
Source: Gut Microbes
Institutions: Instituto de Salud Carlos III, Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition, Institut d'Investigació Biomèdica de Girona, Hospital Universitari de Girona Doctor Josep Trueta, University of Southampton, Universitat de Girona, Parque Sanitario Pere Virgili, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana, Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública, Consejo Superior de Investigaciones Científicas, Universitat de València, Institute for Integrative Systems Biology, Universitat Pompeu Fabra, Hospital Del Mar, Municipal Institute for Medical Research, Hospital del Mar Research Institute
Language: English
Topic: Gut microbiota and health
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,060
Awards: G1204740081, G120905174, G1272927172, G1622782223, G2180888709, Papel del eje Microbioma-Intestino-Cerebro en la relación bidireccional entre obesidad y depresión: metabolitos y miRNAs como mediadores, Metabolismo del triptófano: ¿La conexión entre la microbiota intestinal y la función cognitiva en la obesidad y otras patologías relacionadas con la inflamación crónica de bajo grado?, G2830978317, G3480869486, G348919436, G357246561, G4121904980, G4442677895, G4526231891, G4616924101, G5080475149, G529962013, G531036588, G5314115342, G5404395142, G5635532810, G6874468849, G6954499072, Interrelaciones entre las reservas de hierro, el metagenoma intestinal, los niveles de glucosa y diferentes dominios cognitivos: el papel de los microARN circulantes, G7084143925, Estudio del contenido de hierro en tejido adiposo, músculo y cerebro de sujetos obesos. Interacción con la composición de la microbiota y efectos de la pérdida de peso, G7805626310, Gut-brain-axis: Targets for improvement of cognition in the elderly, G8282649436, G8355468496, Análisis integrado de las interacciones entre la glucemia y la composición de la microbiota, y de su impacto sobre el acúmulo de hierro cerebral y la cognición en sujetos obesos, G8568794117
OpenAlex ID: W4407167618