High-intensity exercise training alters gut microbiota to mitigate the development of experimental autoimmune encephalomyelitis

Exercise training (ET) has demonstrated beneficial effects in autoimmune and neurological disorders, including multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). ET modulates the gut microbiota, which influences neuroimmune interactions via the microbiota-gut-brain and microbiota-gut-immune system axes. However, the role of gut microbiota in mediating ET’s protective effects in autoimmune neuroinflammation remains unclear. We investigated whether gut microbiota mediates the beneficial effects of ET on EAE development. Healthy mice underwent high-intensity continuous training (HICT). Fecal microbiota from HICT and sedentary mice were transplanted into naïve recipients, followed by proteolipid protein (PLP) immunization to induce EAE. Disease severity, gut microbial composition (16S rDNA sequencing), short-chain fatty acid (SCFA) levels (LC–MS), and autoreactive T-cell proliferation (flow cytometry) were assessed. Faecal microbiota transplantation (FMT) from HICT donors significantly reduced EAE severity, delaying onset and decreasing CNS inflammation, demyelination, and axonal damage. These effects correlated with distinct microbial signatures, including increased Faecalimonas and Escherichia genera, and decreased Mucispirillum genus. HICT-FMT mice exhibited higher Faecalimonas abundance and reduced serum SCFA levels. PLP-reactive T-cell proliferation was suppressed in HICT-FMT recipients. Gut microbiota from HICT mice confers protection against EAE development, associated with microbial-metabolic shifts and modulation of autoreactive T-cell responses.