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

Abstract

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 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.

Species differences in immune‐mediated CNS tissue injury and repair: A (neuro)inflammatory topic

“…Microbiome transplants from MS patients to mice have differential effects on subsequent susceptibility to EAE (Berer et al, ). Modulation of specific species of bacteria has a significant impact on the susceptibility to the development of EAE (Yadav et al, ); clinical trials are ongoing in MS.…”

“…Microbiome transplants from MS patients to mice have differential effects on subsequent susceptibility to EAE(Berer et al, 2017). Modulation of specific species of bacteria has a significant impact on the susceptibility to the development of EAE(Yadav et al, 2017); clinical trials are ongoing in MS.The above focus on the EAE model does not negate the utility of other animal or in vitro models in helping define the mechanisms of many of the individual components or processes that comprise the total picture of MS. Toxic and hypoxic/ischemic models may shed light on oligodendrocyte damage with consequent demyelination and remyelination, while there are many experimental manipulations which help us understand, for example, the breakdown of the BBB or astrogliosis.…”

Differences in Gut Microbiota Profiles between Autoimmune Pancreatitis and Chronic Pancreatitis

“…For example, imbalance of gut microbiota, referred to as dysbiosis, is associated with multiple sclerosis, a chronic demyelinating disease triggered by an autoimmune mechanism (Yadav et al 2017). Subgingival dysbiosis has been reported in patients with systemic lupus erythematosus, another autoimmune disease (Correa et al 2017).…”

Treating impulsivity with probiotics in adults (PROBIA): study protocol of a multicenter, double-blind, randomized, placebo-controlled trial

“…This system is connected to the central nervous system through hormonal or innate neuronal pathways [51] that are critical for its development and vice versa [52]. Furthermore, studies have shown that the gut flora is critically involved in immunoregulation [53][54][55], whereas some reports have shown the immune system as an important regulator of neurodevelopment and synaptic function in the brain [56]. In line with this, immune dysfunction and/or autoimmunity have been speculated to be associated with many neuropsychiatric and neurodevelopmental disorders, such as ADHD [57,58].…”