Role of gut commensal microflora in the development of experimental autoimmune encephalomyelitis.

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.

An intestinal commensal symbiosis factor controls neuroinflammation via TLR2-mediated CD39 signalling.

The mammalian immune system constitutively senses vast quantities of commensal bacteria and their products through pattern recognition receptors, yet excessive immune reactivity is prevented under homeostasis. The intestinal microbiome can influence host susceptibility to extra-intestinal autoimmune disorders. Here we report that polysaccharide A (PSA), a symbiosis factor for the human intestinal commensal Bacteroides fragilis, protects against central nervous system demyelination and inflammation during experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, through Toll-like receptor 2 (TLR2). TLR2 mediates tissue-specific expansion of a critical regulatory CD39(+) CD4 T-cell subset by PSA. Ablation of CD39 signalling abrogates PSA control of EAE manifestations and inflammatory cytokine responses. Further, CD39 confers immune-regulatory phenotypes to total CD4 T cells and Foxp3(+) CD4 Tregs. Importantly, CD39-deficient CD4 T cells show an enhanced capability to drive EAE progression. Our results demonstrate the therapeutic potential and underlying mechanism by which an intestinal symbiont product modulates CNS-targeted demyelination.

Induction of a regulatory B cell population in experimental allergic encephalomyelitis by alteration of the gut commensal microflora.

We have recently shown that alteration of the gut commensal microbiota with antibiotics can modify the susceptibility to autoimmune demyelinating processes of the central nervous system. Treatment of mice with a broad spectrum of antibiotics not only induced significant changes in the regulatory T cell populations of the gut associated lymphoid tissues (GALT) and peripheral lymphoid organs but reduced the susceptibility to EAE, the most widely used animal model for human multiple sclerosis. Here, we show further that oral antibiotic treatment of EAE mice induced a CD5(+)B cell subpopulation that conferred protection against the disease. Protection was associated with an enhanced frequency of CD5(+)B cells in distal lymphoid sites such as cervical LN. In vitro stimulation with LPS increased the production of IL-10 by splenic CD5(+)B cells. Adoptive transfer of CD5(+)B cells from antibiotic treated mice reduced significantly the severity of EAE by shifting the immune responses from Th1/Th17 towards anti-inflammatory Th2-type responses. Our results demonstrate that this specific B cell population appears to be involved in the immune regulation of autoimmunity, in particular this experimental demyelinating disease of the central nervous system by gut commensal microflora.