BACKGROUND: Growing evidence links air pollution to cognitive dysfunction in older adults. The gut microbiome and circulating metabolites present an important yet unexplored pathway given their crucial role in the gut-brain axis. OBJECTIVES: We aimed to explore the potential roles of gut bacteria, fungi, microbial functional potentials, and circulating metabolites in the association of residential PM2.5 and O3 exposure with cognitive dysfunction. METHODS: We analyzed gut microbiome data from 1,027 older adults using metagenome and internal transcribed spacer sequencing to profile bacterial and fungal taxa, functional pathways, and enzyme abundances. Targeted metabolomics quantified 195 circulating metabolites, such as amino acids and organic acids. Annual average ambient PM2.5 and O3 exposures were estimated by using satellite-based models. Cognitive outcomes, including mild cognitive impairment and cognitive decline, were assessed using the Mini-Mental State Examination and Hasegawa Dementia Scale. Statistical analyses included Microbiome Multivariable Association with Linear Models (with a false discovery rate threshold of 0.25) for microbial associations and multivariate regression for metabolites and cognitive outcomes. RESULTS: Higher PM2.5 and O3 exposures were associated with disturbances in microbial composition, altered taxonomic profiles (e.g., decreased abundances of Blautia obeum and Gordonibacter pamelaeae), and disrupted functional pathways, particularly those regulating 2-oxoglutarate. These findings were partially replicated in an independent population. Higher air pollution levels were associated with increased circulating levels of 2-oxoglutarate and l-glutamine (key metabolites in neurodegenerative progression), which were further linked to higher odds of concurrent mild cognitive impairment (OR: 1.39-1.56) and an increased 2-year risk of cognitive decline (OR: 1.26-1.37). These associations were partially mediated by air pollution-related changes in microbial anaerobic energy metabolism pathways, especially involving 2-oxoglutarate metabolism and the enzyme aspartate transaminase. CONCLUSIONS: Our findings highlight the role of the gut microbiome and microbial metabolites in mediating the detrimental impact of air pollution on cognitive health in older adults, providing new insights into the underlying etiology for future hypothesis generation.
