GUT MICROBIOTA–T CELL AXIS LINKS HIGH-FAT DIET TO CENTRAL SYNAPTOPATHY IN MULTIPLE SCLEROSIS

Early glutamatergic synaptopathy contributes to disease course in multiple sclerosis (MS), but the impact of lifestyle factors, like high-fat diet (HFD), remains poorly understood.We investigated whether HFD promotes synaptic inflammatory damage in patients with relapsing–remitting MS (pwRRMS) and in the MOG₃₅–₅₅ experimental autoimmune encephalomyelitis (EAE) model. Clinical evaluation of pwRRMS (n=226) showed that overweight/obese individuals exhibited greater disability and higher cerebrospinal fluid glutamate levels, suggesting enhanced neuro-excitotoxicity. In mice, HFD initiated three weeks before EAE induction (45%vs10%kcal from fat) exacerbated disease severity. Integrated analyses combining electrophysiology, flow cytometry, metabolomics, molecular profiling, and 16S metagenomics revealed that HFD disrupted gut microbiota composition and striatal metabolism, thereby amplifying neuroinflammation and driving corticostriatal glutamatergic hyperactivity. HFD-induced dysbiosis was marked by an increased Firmicutes/Bacteroidetes ratio, which correlated with elevated interleukin-1beta (IL-1b) and tumor necrosis factor (TNF) levels and increased CD3⁺ T-cell infiltration in the striatum. HFD also significantly reduced the abundance of beneficial Lactobacillus genus within the Firmicutes phylum. Even in non-autoimmune mice, HFD alone triggered gut dysbiosis, T-cell activation, glycolytic reprogramming and increased blood–brain barrier permeability, facilitating striatal T-cell infiltration and inducing IL-1b- and TNF-mediated glutamatergic synaptic dysfunction, recapitulating EAE-like alterations. Restoring microbial balance through a biphasic Lactobacillus-based probiotic supplementation counteracted these effects, reducing systemic and central inflammation, normalizing synaptic transmission, and improving motor performance. Together, these findings delineate a gut microbiota–T cell axis linking dietary fat to central synaptopathy in MS and support microbiota-targeted nutritional strategies as promising complementary approaches to limit neuroinflammatory synaptic damage.