Gut Microbiota and Cognitive Function in Midlife: What’s the Link?

In a cross-sectional study, researchers explored the associations between gut microbial composition and measures of cognition in midlife an established population-based study of adults.

Gut microbiota composition was found to have an association with midlife cognitive function, according to a cross-sectional study published in JAMA Network Open.

The gut-brain axis has been an area of interest for exploring the potential mechanisms that regulate brain health. Previous research has shown associations between gut microbial measures and neurological outcomes, including cognition and dementia. Although mechanisms have not been fully established, the researchers explained there is growing support for the role in microbiota-generated short-chain fatty acids.

The researchers analyzed data from the population-based, prospective Coronary Artery Risk Development in Young Adults (CARDIA) cohort of community-dwelling Black and White adults residing in 4 US metropolitan areas (Birmingham, Alabama; Chicago, Illinois; Minneapolis, Minnesota; and Oakland, California) between 2015 and 2016, with data analysis in 2019 and 2020.

They explored the associations between gut microbial composition and measures of cognition in an established population-based study of middle-aged adults. They sequenced stool DNA from samples collected in participants’ homes, to obtain the following gut microbial measures: (1) β-diversity (between-person), derived with the use of multivariate principal coordinates analysis; (2) α-diversity (within-person), defined as richness (genera count) and Shannon index (integrative measure of genera richness and evenness); and (3) taxonomy (ie, 107 genera, after filtering).

Participants’ cognitive status was evaluated with use of the following clinic-administered cognitive tests: (1) Montreal Cognitive Assessment (MoCA); (2) Digit Symbol Substitution Test (DSST); (3) Rey-Auditory Verbal Learning Test (RAVLT); (4) Stroop; (5) category fluency; and (6) letter fluency.

At the 30-year CARDIA follow-up examination in 2015 to 2016, microbiome data were available from a total of 597 CARDIA participants. The mean participant age was 55.2±3.5 years. Overall, 268 of the participants were men and 270 were Black. Per multivariable-adjusted principal coordinates analysis, permutational multivariate analysis of variance tests for β-diversity were statistically significant for all measures of cognition (principal component analysis, P =.001; MoCA, P =.001; DSST, P =.001; RAVLT, P =.001; Stroop, P =.007; and category fluency, P =.001) other than letter fluency, which did not achieve statistical significance (P =.07).

Following adjustment for sociodemographic factors (ie, age, sex, race, level of education); health behaviors (ie, diet, physical activity, medication use, smoking); and clinical variables (ie, diabetes, hypertension, body mass index), Barnesiella was positively associated with the first principal component (β, 0.16; 95% CI, 0.08 to 0.24), DSST (β, 1.18; 95% CI, 0.35 to 2.00), and category fluency (β, 0.59; 95% CI, 0.31 to 0.87). Further, Lachnospiraceae FCS020 group was positively associated with DSST (β, 2.67; 95% CI, 1.10 to 4.23). Sutterella, in contrast, was negatively associated with MoCA (β, –0.27; 95% CI, –0.44 to –0.11).

The study had several limitations, including its small sample size for epidemiologic analysis of multiple comparisons.

The researchers concluded “…microbial community composition, based on β-diversity, was associated with all cognitive measures in multivariable-adjusted analysis.”

After adjustment for multiple comparisons, several specific genera were also significantly associated with 1 or more measures of cognitive function.

Based on these findings, additional mechanistic and population studies are warranted, to elucidate the potential for gut microbiota targets for the treatment and prevention of cognitive decline.

Disclosure: None of the study authors has declared affiliations with biotech, pharmaceutical, and/or device companies.  


Meyer K, Lulla A, Debroy K, et al. Association of the gut microbiota with cognitive function in midlife. JAMA Netw Open. Published online February 8, 2022. doi:10.1001/jamanetworkopen.2021.43941