Treadmill exercise attenuates neuroinflammation in APP/PS1 mice via gut microbiota remodeling: Evidence from fecal microbiota transplantation.

Alzheimer's disease is associated with gut microbiota dysbiosis, intestinal barrier dysfunction, lipopolysaccharide (LPS) translocation, and neuroinflammation. However, it is unclear whether exercise-induced gut microbiota remodeling causally contributes to the neuroprotective effects of exercise in AD. Herein, APP/PS1 mice underwent 12 weeks of treadmill exercise, and fecal microbiota transplantation (FMT) was used to determine whether exercise-related benefits could be transferred to the recipient mice. Behavioral performance was assessed using the Morris water maze and open-field test. Gut microbial profiles were analyzed by 16S rDNA sequencing. Intestinal barrier integrity was evaluated using histology, AB-PAS staining, and tight-junction protein expression, while plasma and brain LPS levels were measured by enzyme-linked immunosorbent assay. Neuroinflammation was examined with immunofluorescence and Western blotting. It was found that treadmill exercise improved spatial learning, memory, and anxiety-like behavior in APP/PS1 mice. These benefits were partly reproduced in recipients of microbiota from exercised donors. Exercise also restored gut microbial diversity and composition, increased the abundance of taxa including Dubosiella and UBA1819, alleviated colonic injury, enhanced mucus secretion, upregulated ZO-1, Occludin, and Claudin-1, and reduced plasma and brain LPS levels. In parallel, exercise and FMT from exercised donors decreased brain TLR4 expression, attenuated microglial and astrocytic activation, and suppressed TLR4/NF-κB signaling and downstream inflammatory cytokines. These findings indicate that treadmill exercise alleviates neuroinflammation in APP/PS1 mice, at least in part, through gut microbiota remodeling, improved intestinal barrier integrity, and reduced LPS-driven inflammatory signaling.