Forced treadmill running modifies gut microbiota with alleviations of cognitive impairment and Alzheimer's disease pathology in 3xTg-AD mice

•Alzheimer's disease (AD) is the most prevalent type of dementia with a devastating neurodegenerative condition.•Physical exercise has been recommended as a non-pharmacologic treatment for delaying the onset or slowing the progression of AD.•The interaction between the gut microbiota and the brain may be responsible for exercise training-induced cognitive benefits and alleviations of AD neuropathology. Physical exercise has been recommended as a non-pharmacologic treatment for delaying the onset or slowing the progression of Alzheimer's disease (AD). The therapeutic potential of exercise training-induced changes in symbiotic gut microbiota against AD neuropathology is not well understood, yet. This study investigated the effects of a 20-week forced treadmill exercise program on the makeup of the gut microbiota, the integrity of the blood-brain barrier (BBB), and the development of AD-like cognitive deficits and neuropathology in triple transgenic AD mice. Our findings show that forced treadmill running causes symbiotic changes in the gut microbiota, such as increased Akkermansia muciniphila and decreased Bacteroides species, as well as increased BBB-related protein expression and reduced AD-like cognitive impairments and neuropathology progression. The current findings of this animal study suggest that the interaction between the gut microbiota and the brain, possibly via the BBB, is responsible for exercise training-induced cognitive benefits and alleviation of AD pathology.