Enhancing the Cognitive Effects of Flavonoids With Physical Activity: Is There a Case for the Gut Microbiome?

Abstract

Age-related cognitive changes can be the first indication of the progression to dementias, such as Alzheimer's disease. These changes may be driven by a complex interaction of factors including diet, activity levels, genetics, and environment. Here we review the evidence supporting relationships between flavonoids, physical activity, and brain function. Recent in vivo experiments and human clinical trials have shown that flavonoid-rich foods can inhibit neuroinflammation and enhance cognitive performance. Improved cognition has also been correlated with a physically active lifestyle, and with the functionality and diversity of the gut microbiome. The great majority (+ 90%) of dietary flavonoids are biotransformed into phytoactive phenolic metabolites at the gut microbiome level prior to absorption, and these prebiotic flavonoids modulate microbiota profiles and diversity. Health-relevant outcomes from flavonoid ingestion may only be realized in the presence of a robust microbiome. Moderate-to-vigorous physical activity (MVPA) accelerates the catabolism and uptake of these gut-derived anti-inflammatory and immunomodulatory metabolites into circulation. The gut microbiome exerts a profound influence on cognitive function; moderate exercise and flavonoid intake influence cognitive benefits; and exercise and flavonoid intake influence the microbiome. We conclude that there is a potential for combined impacts of flavonoid intake and physical exertion on cognitive function, as modulated by the gut microbiome, and that the combination of a flavonoid-rich diet and routine aerobic exercise may potentiate cognitive benefits and reduce cognitive decline in an aging population, via mechanisms mediated by the gut microbiome. Mechanistic animal studies and human clinical interventions are needed to further explore this hypothesis.

Keywords: age-related; cognition; exercise; microbiome; neuroprotective; phenolic metabolites; prebiotic flavonoids.

FIGURE 1

Change (delta) in speed of processing by age group across the 6-month intervention in the CANTAB rapid visual processing task (left frame; negative is better, F(2,110) = 4.14, p < 0.05). Recognition memory (right frame; positive is better) as tested by ERP (delta across 6 months) improved in the blueberry group to the level of the reference group, whereas the placebo group did significantly worse [Group: F(8,83) = 2.63, p = 0.01].

FIGURE 2

Cognitive scores (CANTAB) related to the gut microbiome diversity score Shannon Alpha [Multivariate Model F(2,56) = 4.846, R² = 0.117] on spatial working memory (left–longer times to success relate to lower diversity; p = 0.025) and paired associates learning (right-higher errors on the task relate to lower diversity; p = 0.024). Reprinted from Canipe et al. (2021).

FIGURE 3

Post-exercise change for 15 selected and grouped plasma gut-derived phenolics. P-values indicate contrasts with the placebo–sit group. Data are represented as means with standard errors of the mean. *indicates a significant difference with the placebo-sit group (P values).

FIGURE 4

Higher flavonoid intake may influence cognitive function by augmenting gut microbial diversity and functionality and increasing circulating levels of gut-derived phenolic metabolites. Moderate-to-vigorous physical activity (MVPA) adds to this effect by enhancing the release of gut-derived metabolites and improving cognitive function.