Gut microbiota regulates exercise-induced hormetic modulation of cognitive function.

Background: Lifestyle factors, particularly physical exercise, significantly influence brain structure and cognitive function through a hormetic effect -a phenomenon where low to moderate doses of a stimulus (in this case, exercise) induce beneficial adaptations, while excessive doses could lead to detrimental effects. This effect depends on exercise intensity and duration, though the underlying mechanisms remain largely unexplored. Recently, the gut microbiota has emerged as potent modulator of lifestyle-induced changes in brain and behaviour.

Methods: We used a 40-min, 1200 cm/min exercise protocol. We measured cognition through several tests and analysed microbiota composition comparing adult exercised animals to sedentary controls. Finally, we performed fecal microbiota transplantation from exercised to sedentary mice.

Findings: Exercise enhances cognitive abilities related to object recognition and object location memory, as well as increases hippocampal neurogenesis. However, these cognitive and neurogenic benefits vanish when the exercise intensity or duration is increased. Furthermore, we identified significant changes in alpha and beta diversity and distinct bacteria composition profiles in the gut microbiota associated with different exercise regimens. Specific bacterial families showed altered relative abundances depending on exercise intensity and duration, with certain families' quantities significantly correlating with cognitive performance (Angelakisella, Acetatifactor, Erysipelatoclostridium, and Coriobacteriaceae UCG-002.). To explore causal mechanisms, we performed fecal microbiota transplantation from exercised to sedentary mice, which replicated the cognitive and neurogenic changes observed in the donor animals.

Interpretation: These findings suggest that the hormetic effects of physical exercise on cognitive function and neurogenesis are mediated by corresponding changes in the gut microbiota, highlighting a novel mechanistic link between exercise, brain function, and gut microbiota composition.

Funding: E.C. and P.M. were funded by predoctoral fellowship (FPI) grants from the Spanish Ministry of Economy and Competitiveness (BES-2017/080415 E.C.) and the Spanish Ministry of Science and Innovation (PRE2020/093032 P.M.), and P.T. by a predoctoral fellowship (FPU) from the Spanish Ministry of Universities (18/00069). Work was supported by project grants PID2019-110292RB-100 and PID2022-136891NB-I00 (from Spanish Ministry of Science and Innovation), (to J.L.T.).