Role of Gut Commensal Microflora in the Development of Experimental Autoimmune Encephalomyelitis

Abstract

Mucosal tolerance has been considered a potentially important pathway for the treatment of autoimmune disease, including human multiple sclerosis and experimental conditions such as experimental autoimmune encephalomyelitis (EAE). There is limited information on the capacity of commensal gut bacteria to induce and maintain peripheral immune tolerance. Inbred SJL and C57BL/6 mice were treated orally with a broad spectrum of antibiotics to reduce gut microflora. Reduction of gut commensal bacteria impaired the development of EAE. Intraperitoneal antibiotic-treated mice showed no significant decline in the gut microflora and developed EAE similar to untreated mice, suggesting that reduction in disease activity was related to alterations in the gut bacterial population. Protection was associated with a reduction of proinflammatory cytokines and increases in IL-10 and IL-13. Adoptive transfer of low numbers of IL-10-producing CD25+CD4+ T cells (>75% FoxP3+) purified from cervical lymph nodes of commensal bacteria reduced mice and in vivo neutralization of CD25+ cells suggested the role of regulatory T cells maintaining peripheral immune homeostasis. Our data demonstrate that antibiotic modification of gut commensal bacteria can modulate peripheral immune tolerance that can protect against EAE. This approach may offer a new therapeutic paradigm in the treatment of multiple sclerosis and perhaps other autoimmune conditions.

The role of gut microbiota (commensal bacteria) and the mucosal barrier in the pathogenesis of inflammatory and autoimmune diseases and cancer: contribution of germ-free and gnotobiotic animal models of human diseases

“…102 The role of the components of the microbiota in the pathogenesis of disease using this experimental model has recently been documented by Kasper's group, and the results of this study have been used to propose a novel treatment. 103,104 The gut-brain axis is a bidirectional communication system through which the brain modulates gastrointestinal function and through which the gastrointestinal system is monitored by the brain. Neural and immunological and endocrine mechanisms are involved in this communication.…”

The Microbiome and Neurologic Disease: Past and Future of a 2-Way Interaction

“…Although genetic susceptibility is a factor that may determine disease, other risk factors are also necessary, in particular, environmental triggers such as those associated with known risk factors. We, among other investigators, explored the effects of the gut microbiota in experimental autoimmune encephalomyelitis (EAE) models of MS and proposed the idea that the composition of the gut microbiota is relevant for the balance of the proinflammatory and anti-inflammatory cell subpopulations that result in disease induction or protection [9][10][11][12][13][14][15][16][17]. This special issue covers the most recent literature on the experimental models and the clinical evidence for changes in the gut microbiota observed in patients with MS. Tremlett and Waubant [18] explore the microbiota of pediatric MS cases.…”

Homeostatic IL-23 receptor signaling limits Th17 response through IL-22–mediated containment of commensal microbiota

“…It is thought that diseases such as inflammatory bowel disease and atopic dermatitis result, in part, from barrier defects, leading to bacterial invasion, breakdown of tolerance, and inflammation. Interestingly, germ-free mice or antibiotic-treated mice are resistant to intestinal as well as extraintestinal autoimmune diseases and defective in the generation of Th17 cells, a lineage of CD4 + T cells contributing to autoimmune pathologies (4)(5)(6), suggesting that immune cell education takes place in colonized tissues and may have consequences elsewhere in the organism.…”