High-fat diet promotes T cell–mediated synaptic dysfunction in multiple sclerosis

Early glutamatergic synaptopathy contributes to disease progression in multiple sclerosis (MS), leading to excitotoxic synaptic damage. Although high-fat diet (HFD)–associated peripheral inflammation has been linked to central nervous system dysfunction, how metabolic and immune signals converge to drive central synaptic alterations remains unclear. Here, we showed that overweight or obese patients with relapsing–remitting MS exhibited greater disability and elevated cerebrospinal fluid glutamate levels, indicative of enhanced excitotoxicity. We substantiated this clinical evidence using a multidisciplinary and multi-omics approach in the MOG₃₅–₅₅-induced experimental autoimmune encephalomyelitis (EAE) model. In EAE mice, HFD exacerbated disease severity and induced a metabolic rewiring that specifically potentiates glutamatergic transmission. Remarkably, HFD alone was sufficient to recapitulate EAE-like glutamatergic synaptic alterations in the absence of overt autoimmunity, via interleukin‐1β and tumour necrosis factor. Mechanistic investigations revealed that HFD reshapes gut microbiota composition, increasing the Bacillota/Bacteroidota ratio and reducing Lactobacillus species, thereby promoting T-cell activation and trafficking to the brain, particularly of CD4⁺ effector T cells, and increasing blood–brain barrier permeability, ultimately establishing a synaptotoxic milieu . Pharmacological blockade of T-cell infiltration mitigated HFD-induced synaptic alterations, while Lactobacillus-based probiotic intervention reduced T-cell infiltration, and improved synaptic and clinical outcomes. Transcriptomic profiling further showed that microbiota modulation attenuated striatal immune-inflammatory programs while enriching neuronal and synaptic programs. Collectively, these findings identify a gut microbiota–T cell axis by which dietary fat drives immune–metabolic signaling underlying synaptotoxicity, defining modifiable pathways with therapeutic potential.