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Gut dysbiosis breaks immunological tolerance toward the central nervous system during young adulthood

Significance Multiple sclerosis (MS) is classified as an autoimmune disease of the central nervous system (CNS). Alterations of gut microbiota (gut dysbiosis) are frequently observed in MS patients. It is still unknown how gut dysbiosis contributes to development of MS. We report here that gut dysbiosis, which we attribute to expansion of enteric pathogenic bacteria, triggers and/or exacerbates the spontaneous development of experimental autoimmune encephalomyelitis, an animal model of MS. This occurs during the period of young adulthood by reducing development of Foxp3+ Treg cells and expression of E3 ubiquitin ligase genes involved in protection from autoimmune diseases. This study suggests that gut dysbiosis may play a pathological role in the initiation and/or progression of MS during a defined age window. Multiple sclerosis (MS) is an autoimmune disease targeting the central nervous system (CNS) mainly in young adults, and a breakage of immune tolerance to CNS self-antigens has been suggested to initiate CNS autoimmunity. Age and microbial infection are well-known factors involved in the development of autoimmune diseases, including MS. Recent studies have suggested that alterations in the gut microbiota, referred to as dysbiosis, are associated with MS. However, it is still largely unknown how gut dysbiosis affects the onset and progression of CNS autoimmunity. In this study, we investigated the effects of age and gut dysbiosis on the development of CNS autoimmunity in humanized transgenic mice expressing the MS-associated MHC class II (MHC-II) gene, HLA-DR2a, and T-cell receptor (TCR) genes specific for MBP87-99/DR2a that were derived from an MS patient. We show here that the induction of gut dysbiosis triggers the development of spontaneous experimental autoimmune encephalomyelitis (EAE) during adolescence and early young adulthood, while an increase in immunological tolerance with aging suppresses disease onset after late young adulthood in mice. Furthermore, gut dysbiosis induces the expression of complement C3 and production of the anaphylatoxin C3a, and down-regulates the expression of the Foxp3 gene and anergy-related E3 ubiquitin ligase genes. Consequently, gut dysbiosis was able to trigger the development of encephalitogenic T cells and promote the induction of EAE during the age window of young adulthood.