Human cognitive performance-associated gut microbiota influences learning and memory in mice through arginine and pterin metabolism.

Abstract

The human gut microbiome undergoes changes across the lifespan and has been implicated in age-related decline. The symbol digit modalities test (SDMT) is a measure of information processing speed and is sensitive to mild cognitive impairment. Here, we assessed SDMT scores and fecal shotgun metagenomics in older individuals from the Imageomics cohort (n = 867) and performed fecal microbiota transplantation (FMT) from human donors to male C57BL/6 mouse recipients. In mice, we evaluated cognitive performance using the Morris water maze (MWM) and measured neurone density, fecal shotgun metagenomics, hippocampal metabolomics, and cortical gene expression to identify microbial-derived functional properties related to cognitive performance. In humans, both microbial species composition and functional profiles were associated with cognitive performance. FMT from high-SDMT donors improved cognitive performance and increased neuronal density in recipient mice compared with FMT from low-SDMT donors. In both humans and mice, higher cognitive performance was associated with arginine and proline metabolism and pterin-related pathways. In mice receiving microbiota from high-SDMT donors, cortical gene expression showed enrichment of dopamine receptor pathways and reduced dopamine reuptake and catecholamine biosynthesis. Our findings highlight the potential role of the gut microbiome in cognitive performance among older individuals, particularly information processing speed, and identify potential mechanisms involving alterations in arginine and pterin metabolism. Integrating human and mouse data supports a model in which microbiota-associated metabolic remodeling influences cognitive performance.

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