The gut-microbiota-brain axis mediates the neuroprotective effects of exercise against microgravity-induced cognitive...

Prolonged exposure to microgravity is associated with gastrointestinal dysfunction and cognitive decline, both of which are critically regulated by the gut-microbiota-brain axis. This study aimed to investigate whether exercise mitigates microgravity-induced cognitive deficits by restoring gut homeostasis.

The hindlimb unloading (HU) mouse model, a well-established ground-based analog of microgravity, was used in this study. HU mice underwent 4-week weight-loaded treadmill running. After the intervention, gut homeostasis, hippocampal neuroplasticity, and cognitive function were assessed. To establish causality, fecal microbiota transplantation (FMT) from exercised donor mice to HU recipient mice was performed.

HU mice exhibited gut microbial dysbiosis, increased circulating lipopolysaccharide (LPS) levels, reduced short-chain fatty acids (SCFAs), and impaired learning and memory. Exercise intervention restored intestinal barrier integrity by upregulating zonula occludens-1 (ZO-1) and Occludin, normalized gut microbiota composition and diversity, enhanced hippocampal neuroplasticity by increasing postsynaptic density protein 95 (PSD95), growth associated protein 43 (GAP43), phosphorylated cAMP response element-binding protein (P-CREB), and the brain-derived neurotrophic factor (BDNF)/ tropomyosin receptor kinase B (TrkB) pathway, and improved cognitive function. FMT from exercised donors to HU recipients recapitulated these benefits.

These results support that physical activity counteracts microgravity-induced neural dysfunction via the gut-microbiota-brain axis, suggesting that microbiome-targeted interventions may help preserve cognitive health in extreme environments such as spaceflight.