| 研究概要 |
The main function of the immune system is to protect the host against pathogens, such as bacteria or viruses. However, unlike the systemic immune system, the gut immune system does not eliminate microorganisms but instead nourishes rich bacterial communities and establishes advanced symbiotic relationships. Not only that the gut bacteria are essential for nutrient processing, production of vitamins and protection against pathogens (through competition for space and nutrients) but the development and maturation of the immune system depends on these bacteria. The primary individual microbiota most likely reflects the maternal hand-over during or immediately after birth. However, the subsequent shaping of the microbial community landscape is likely driven by complex interactions with the host immune system, through a network of regulatory components involving both the innate and adaptive immune system. We proposed to dissect the contribution of the adaptive immune system in establishing the symbiosis between host and bacteria in the gut.
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| 現在までの達成度 (区分) |
現在までの達成度 (区分)
2: おおむね順調に進展している
理由
Using a series of immune-deficient mice and transfer systems, we revealed an important role of the adaptive immune system in regulating the diversity and structures of microbial. In short our findings could be summarized as follows: 1) mice deficient for B cells, T cells or both, fail to support complex bacterial communities in the gut; 2) the reconstitution of T cell-deficient mice with CD4+ T cells expressing the transcription factor Foxp3 (Foxp3+ T cells) restores both the diversity and the phylogenetic structure of bacteria; 3) Foxp3+ T cells helped diversification particularly of the non-virulent Clostridia species, which were recently reported to induce Foxp3. This means that not only Clostridia induce Foxp3, but that the Foxp3+ T cells contribute to the persistence and diversification of Clostridia of the Firmicutes (the most diverse bacterial species in both mice and humans); 4) Foxp3+ T cells act outside and inside germinal centers, by preventing inflammation and by regulating selection of IgAs, respectively; 5) the coating of bacteria with selected IgAs correlates directly with bacterial diversity and inversely with bacteria abundance (again, especially of Firmicutes); therefore when IgA are non-selected we see expansion of few bacterial species; 6) the microbiota induced by Foxp3+ T cells but not by naive T cells feed-back to the immune system and increase the Foxp3+ T cell pool and induce gut germinal centers and IgA, in what appears to be a dominant regulatory loop (dominant symbiosis).
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| 今後の研究の推進方策 |
It will be important to further determine whether differences in adaptive immune system affect the resilience of bacterial communities after antibiotic treatment or dietary changes.
By resilience of bacterial communities we understand the amount of stress tolerated by the system before changing into a different equilibrium. We wish to find out whether the recovery of gut microbiota after antibiotic treatment depends on the initial diversity and composition of bacterial communities. In other words, whether diverse and balanced bacterial communities are more stable and recover quickly to their original status after antibiotics, whereas the unbalanced communities due to reduction of amount or quality of IgAs change into “alternative” pathogenic status after the same treatment. We will assess the IgA function for stabilizing consortia of commensal bacteria in the intestinal lumen and whether the unstable communities could be beneficially modified through dietary changes. Our work will be of fundamental importance for understanding the shifts in bacterial communities associated with various immunosuppressive therapies i.e. before transplantations. It is likely the recovery after such antibiotic and immune interventions will largely depend on the diversity and balance of preexisting bacterial communities.
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