Gut Microbiota Regulates Exercise-induced Hormetic Modulation of Cognitive Function

Lifestyle factors, particularly physical exercise, significantly influence brain structure and cognitive function through a hormetic effect dependent on exercise intensity and duration. The underlying mechanisms of this profile remain largely unexplored. Recently, the gut microbiota, has emerged a potent modulator of lifestyle-induced changes on brain and behavior. Here, we demonstrate that a 40-minute protocol of moderate exercise enhances cognitive abilities related to object recognition and memory, and increases hippocampal neurogenesis in adult mice compared to sedentary controls, but these cognitive and neurogenic benefits vanish when the exercise intensity or duration is increased. Furthermore, we identified significant alpha- and beta-diversity changes and distinct bacteria composition profiles of 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 parse causal mechanisms, fecal microbiota transplantation from exercised to sedentary mice replicated the cognitive and brain structural improvements observed in the donor animals. These findings suggest that the hormetic effects of physical exercise on cognitive function and neurogenesis are mediated by corresponding changes in the gut microbiota, indicating a novel mechanistic link between exercise, brain, and gut microbiota composition.