Gut microbiome disturbances and elevated circulating levels of 2-oxoglutarate and l-glutamine partially mediate the association between residential PM2.5 and O3 exposure and cognitive dysfunction in older adults.
Key Findings
Results
Higher PM2.5 and O3 exposures were associated with disturbances in microbial composition and altered taxonomic profiles in older adults.
Study analyzed gut microbiome data from 1,027 older adults using metagenome and internal transcribed spacer (ITS) sequencing.
Both bacterial and fungal taxa were profiled along with functional pathways and enzyme abundances.
Specific taxa showing decreased abundances included Blautia obeum and Gordonibacter pamelaeae.
Statistical analyses used Microbiome Multivariable Association with Linear Models (MaAsLin) with a false discovery rate threshold of 0.25.
These findings were partially replicated in an independent population.
Results
Air pollution exposures were associated with disrupted microbial functional pathways, particularly those regulating 2-oxoglutarate metabolism.
Functional pathways and enzyme abundances were assessed via metagenomic sequencing in 1,027 older adults.
Disruptions were especially noted in anaerobic energy metabolism pathways involving 2-oxoglutarate.
The enzyme aspartate transaminase was specifically implicated in the disrupted pathways.
These functional pathway disruptions were identified as a key mechanistic link between air pollution and downstream metabolite changes.
Results
Higher air pollution levels were associated with increased circulating levels of 2-oxoglutarate and l-glutamine, which are key metabolites in neurodegenerative progression.
Targeted metabolomics quantified 195 circulating metabolites including amino acids and organic acids.
Both 2-oxoglutarate and l-glutamine were elevated in association with higher PM2.5 and O3 exposures.
The paper describes these as 'key metabolites in neurodegenerative progression.'
Annual average ambient PM2.5 and O3 exposures were estimated using satellite-based models.
Results
Elevated circulating 2-oxoglutarate and l-glutamine were associated with higher odds of concurrent mild cognitive impairment.
Odds ratios for concurrent mild cognitive impairment ranged from OR: 1.39 to 1.56.
Cognitive outcomes were assessed using the Mini-Mental State Examination and Hasegawa Dementia Scale.
Mild cognitive impairment was one of two primary cognitive outcomes examined.
Multivariate regression was used for metabolite and cognitive outcome associations.
Results
Elevated circulating 2-oxoglutarate and l-glutamine were associated with an increased 2-year risk of cognitive decline.
Odds ratios for 2-year risk of cognitive decline ranged from OR: 1.26 to 1.37.
Cognitive decline was assessed over a 2-year follow-up period using the Mini-Mental State Examination and Hasegawa Dementia Scale.
This longitudinal finding extends the cross-sectional associations with mild cognitive impairment.
Results
The association between air pollution and cognitive outcomes was partially mediated by air pollution-related changes in microbial anaerobic energy metabolism pathways.
Mediation was particularly attributed to 2-oxoglutarate metabolism and the enzyme aspartate transaminase.
The mediation was described as 'partial,' indicating that other pathways also contribute.
The gut-brain axis, involving both gut bacteria and fungi, was the primary mechanistic framework proposed.
Both bacterial and fungal microbiome components were profiled to capture this pathway.
Methods
The study population consisted of 1,027 older adults whose residential PM2.5 and O3 exposures were estimated using satellite-based models.
Annual average ambient exposures to both PM2.5 and O3 were assessed.
Both metagenome sequencing and internal transcribed spacer (ITS) sequencing were used to profile bacterial and fungal taxa respectively.
An independent population was used for partial replication of microbial findings.
The study was published in Environmental Health Perspectives (2026).
What This Means
This research suggests that breathing polluted air — specifically fine particulate matter (PM2.5) and ozone (O3) — may harm brain health in older adults partly by disrupting the community of microorganisms living in the gut. The study followed over 1,000 older adults, measuring their exposure to air pollution, analyzing their gut bacteria and fungi, testing their blood for certain chemical compounds, and assessing their memory and thinking abilities. It found that people exposed to higher levels of air pollution had altered gut microbial communities, including lower levels of specific beneficial bacteria, and disruptions in the chemical processes those microbes carry out.
These gut changes were linked to higher blood levels of two chemicals — 2-oxoglutarate and l-glutamine — that have been associated with brain degeneration. In turn, people with higher levels of these chemicals in their blood had roughly 39–56% higher odds of already having mild cognitive impairment, and a 26–37% higher risk of experiencing cognitive decline over the following two years. The connection between air pollution and these blood chemicals was partially explained by changes in how gut microbes process energy, particularly through a pathway involving a molecule called 2-oxoglutarate and an enzyme called aspartate transaminase.
This research suggests that the gut microbiome may act as an important middleman in how air pollution damages cognitive health — a pathway that has not previously been well studied. The findings point toward the gut-brain axis as a potential target for understanding, and possibly eventually addressing, air pollution's effects on dementia and cognitive decline in aging populations. The authors note these results are intended to generate new hypotheses for future research rather than establish definitive causal conclusions.
Qi W, Kong M, Meng X, Sun Z, Mei Z, Pu Y, et al.. (2026). The Role of Gut Microbiota in the Association between Air Pollution and Cognitive Function in Older Adults.. Environmental health perspectives. https://doi.org/10.1021/EHP.6c00026