High-fat diet promotes T cell–mediated synaptic dysfunction in multiple sclerosis
Year: 2026
Type: article
Abstract: 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.
Source: Journal of Neuroinflammation
Authors: Sara Balletta, Silvia Caioli, Alessandra Musella, Federica Palmerio, Diego Fresegna, Alice Tartacca, Fabrizio Mariani, Antonio Fiorenza, Adriana la Candia, Veronica Ceci, Fortunata Carbone, Claudio Procaccini, Alessandro Moscatelli, Marta Tiberi, Giulia Carrera, Teresa Micillo, Giusy De Rosa, Claudia Russo, Carmen Marino, Raffaella di Vito, Alessandro Matteocci, Valerio Licursi, Vincent Escarrat, Luana Gilio, Antonio Bruno, Ettore Dolcetti, Fabio Buttari, Roberta Fantozzi, Valentina Rovella, Marco Salvetti, Antonella Conte, Anna Maria D’Ursi, Alessandro Usiello, Valerio Chiurchiù, Giuseppe Matarese, Georgia Mandolesi, Diego Centonze, Francesca De Vito
Institutions: Istituti di Ricovero e Cura a Carattere Scientifico, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele, Istituto Neurologico Mediterraneo, San Raffaele University of Rome, University of Rome Tor Vergata, UniNettuno University, Istituto di Farmacologia Traslazionale, Fondazione Santa Lucia, National Research Council, Azienda Ospedaliera Universitaria Università degli Studi della Campania Luigi Vanvitelli, University of Naples Federico II, Federico II University Hospital, University of Salerno, University of Campania "Luigi Vanvitelli", CEINGE Biotecnologie Avanzate Franco Salvatore (Italy), Institute of Molecular Biology and Pathology, Azienda Ospedaliera Sant'Andrea, Sapienza University of Rome
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,090
OpenAlex ID: W7214062276
FWCI:
Cites:
Cited by:
Related to: