Exercise influences the brain in a hormetic way, and it happens through the microbiota

In today’s post, we would like to present our latest work published by our laboratory.

In this study, we sought to shed light on a key question in the Neurobiology of physical exercise: how do intensity and duration of exercise modulate its beneficial effects on cognitive function and hippocampal neurogenesis? Our results, published this month in eBioMedicine (The Lancet, 2025), uncover the mediating role of the gut microbiome in this relationship, revealing not only the importance of dosing exercise, but also how our intestinal flora acts as a fundamental axis in mediating the beneficial effects of exercise on the brain. https://www.csic.es/es/actualidad-del-csic/la-microbiota-modula-el-impacto-positivo-del-ejercicio-fisico-moderado-sobre-la-memoria-segun-un-estudio-del-csic

We employed a mouse model subjected to different aerobic exercise protocols: one moderate, another prolonged, and one at higher running speed. The most striking finding is that only moderate exercise—running 40 minutes per day at an average pace—improved memory and facilitated neurogenesis in the subgranular zone of the dentate gyrus. By contrast, increasing either duration or intensity abolished these benefits, showing a clear hormetic curve: moderate doses of exercise trigger positive responses, whereas excessive stimuli may result in neutral or even negative outcomes.

Behavioral results demonstrated that mice exposed to moderate exercise showed significant improvements in object recognition and spatial location tasks, both hippocampus-dependent. These cognitive enhancements were accompanied by an increase in neural precursor cells and in the population of immature neurons, indicators of active neurogenesis. In contrast, mice subjected to prolonged or high-intensity exercise did not exhibit these increases, demonstrating that the exercise–neurogenesis relationship is not linear but rather modulated by the dose of stimulation.

Yet, the most novel and fascinating aspect of the study is the integration of the microbiota–gut–brain axis as a key agent in this dynamic. Significant changes in both diversity and composition of the gut microbiome were detected with each specific exercise regime, and certain bacterial groups correlated with enhanced cognitive performance. For example, genera such as Lachnospiraceae or Acetatifactor were positively linked with cognitive function, whereas others, like Angelakisella or Coriobacteriaceae, showed negative correlations.

To further probe causality, we conducted a fecal transplant experiment, transferring gut microbiota from moderately running mice into sedentary mice. Remarkably, the recipients of the transplant acquired similar cognitive improvements and neurogenesis increases as their donors, strongly supporting the role of the microbiota as a mediator of the hormetic effects of exercise on the brain. Conversely, microbiota from high-intensity exercise mice failed to induce any cognitive or neurogenic changes in transplant recipients.

In summary, this work delivers two major insights for the neurobiology of exercise within a neurohormetic framework: first, that intensity and duration of exercise are crucial in determining cognitive and neurogenic benefits; and second, that the gut microbiota is not a mere bystander, but rather a sufficient mediator of these effects, capable of even transferring them through fecal transplantation. These findings open the door to conceiving personalized training strategies to optimize brain health via precise microbiome modulation, and suggest a pathway toward future preventive and rehabilitative therapies for cognitive disorders, arising from the synergy between exercise, microbiota, and brain plasticity.

Thus, exercise hormesis emerges as a complex, multifactorial phenomenon, where what matters is not only how much or how fast we run, but also how we interact with our inner microbial ecosystem—an authentic player in brain biology. Here you have the link to the article: https://www.thelancet.com/action/showPdf?pii=S2352-3964%2825%2900320-2

At NeuroHormesis, we will continue to advance this research to better understand how the right dose of stimulus can become our best ally for a healthier and more resilient brain.