Gut microbiota modulates CNS barrier function in murine model for multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disease that has been associated with dysfunction of the protective barriers in the central nervous system (CNS), allowing harmful immune cells to enter. Growing evidence implicates gut microbiota dysbiosis in MS pathogenesis, yet its connection to CNS barrier integrity is not fully understood. To address this, we investigated the role of gut microbiota in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, by depleting intestinal microbes using a broad-spectrum antibiotic (ABX) regimen. Our results indicate that ABX-mediated gut microbiota depletion was associated with a milder EAE disease course, accompanied by reduced immune cell infiltration and attenuation of EAE-associated loss of barrier integrity. These improvements coincided with preserved expression and localization of tight junction (TJ) proteins, vital for maintaining barrier integrity. While these data support a microbiota-mediated effect, ABX compounds may also exert microbiota-independent immunomodulatory actions. Importantly, although ABX treatment proved beneficial in the inflammatory EAE setting, antibiotics are also known to disrupt immune and barrier homeostasis under steady-state conditions, highlighting their dual and context-dependent nature. To further look into this, we transferred gut microbiota between EAE and healthy mice and observed a microbiota-dependent effect on CNS barrier integrity. Next, treatment with SCFAs partly restored the disrupted CNS barriers and was linked to reduced disease development in EAE. Altogether, our findings suggest that the gut microbiota has dual role in the CNS barriers in MS. These findings align with emerging literature identifying gut-derived signals, particularly under antibiotic perturbation or through microbial metabolites, as critical modulators of neuroimmune homeostasis. Additionally, our results highlight the potential of microbiota-targeted interventions and SCFAs to influence CNS barrier integrity and disease outcomes.