Association of the Gut Microbiota With Cognitive Function in Midlife

Abstract

Importance: Animal experiments and small clinical studies support a role for the gut microbiota in cognitive functioning. Few studies have investigated gut microbiota and cognition in large community samples.

Objective: To examine associations of gut microbial composition with measures of cognition in an established population-based study of middle-aged adults.

Design, setting, and participants: This cross-sectional study analyzed data from the prospective Coronary Artery Risk Development in Young Adults (CARDIA) cohort in 4 US metropolitan centers between 2015 and 2016. Data were analyzed in 2019 and 2020.

Exposures: Stool DNA were sequenced, and the following gut microbial measures were gathered: (1) β-diversity (between-person) derived with multivariate principal coordinates analysis; (2) α-diversity (within-person), defined as richness (genera count) and the Shannon index (integrative measure of genera richness and evenness); and (3) taxonomy (107 genera, after filtering).

Main outcomes and measures: Cognitive status was assessed using 6 clinic-administered cognitive tests: Montreal Cognitive Assessment (MoCA), Digit Symbol Substitution Test (DSST), Rey-Auditory Verbal Learning Test (RAVLT), Stroop, category fluency, and letter fluency. A global score measure derived using principal components analysis was also assessed; the first principal component explained 56% of variability.

Results: Microbiome data were available on 597 CARDIA participants; mean (SD) age was 55.2 (3.5) years, 268 participants (44.7%) were men, and 270 (45.2%) were Black. In multivariable-adjusted principal coordinates analysis, permutational multivariate analysis of variance tests for β-diversity were statistically significant for all cognition measures (principal component analysis, P = .001; MoCA, P = .001; DSST, P = .001; RAVLT, P = .001; Stroop, P = .007; category fluency, P = .001) with the exception of letter fluency (P = .07). After adjusting for sociodemographic variables (age, race, sex, education), health behaviors (physical activity, diet, smoking, medication use), and clinical covariates (body mass index, diabetes, hypertension), Barnesiella was positively associated with the first principal component (β, 0.16; 95% CI, 0.08-0.24), DSST (β, 1.18; 95% CI, 0.35-2.00), and category fluency (β, 0.59; 95% CI, 0.31-0.87); Lachnospiraceae FCS020 group was positively associated with DSST (β, 2.67; 95% CI, 1.10-4.23), and Sutterella was negatively associated with MoCA (β, -0.27; 95% CI, -0.44 to -0.11).

Conclusions and relevance: In this cross-sectional study, microbial community composition, based on β-diversity, was associated with all cognitive measures in multivariable-adjusted analysis. These data contribute to a growing body of literature suggesting that the gut microbiota may be associated with cognitive aging, but must be replicated in larger samples and further researched to identify relevant pathways.

Figure.. Multivariable-Adjusted Associations Between Specific Genera and Measures of Cognitive Function

Genera are restricted to those associated with at least 1 cognitive measure with an FDR-adjusted P < .20. Colors reflect direction of β coefficients (blue indicates positive; orange, negative). Stroop is on its natural scale, with lower values reflecting higher cognitive scores. Patterning indicates the highest level of multivariable adjustment for which results were statistically significant, as follows: solid indicates results were significant after adjustment for sequencing batch, age, race, sex, study center; dotted, results remained significant after additional adjustment for education; horizontal lines, results were significant after further adjustment for physical activity, diet, smoking, medication use, body mass index, diabetes, and hypertension.