Developing therapies to target the microbiota

描述(申请人提供)：哺乳动物是一个共生微生物群落的家园，被称为微生物区系。最近的数据提供了令人信服的证据，表明哺乳动物身上的微生物对适当的发育和健康至关重要。事实上，肠道微生物群落的变化与炎症性肠病(IBD)、糖尿病、过敏、肥胖、多发性硬化症甚至自闭症有关。最近的研究，包括我们自己的研究，已经证明在动物模型系统中，替换有益的细菌物种或删除致病微生物可以保护甚至治愈疾病。虽然有益细菌的存在可以预防或治愈疾病，但这些细菌的丧失或特定的“坏”共生细菌的产生可能会诱发疾病。因此，似乎维持共生生物体的适当平衡或群落结构对健康至关重要。这突显了开发允许对微生物区系进行治疗性操作的方法的迫切需要。目前的方法，如抗生素或抗微生物药物，针对的是大群细菌，没有提供足够的特异性水平。事实上，众所周知，使用抗生素清除病原体会扰乱有益的共生群落，导致微生物区系中特定成员的永久丧失，并为病原体创造生态位，这一过程被称为生态失调。此外，抗生素的大量使用与自身免疫发病率的增加相关，这可能是因为我们拥有的有益生物体受到破坏。因此，迫切需要新的治疗方法来控制细菌种群并针对特定的生物。这项提案将提出实验，以更好地了解我们的微生物区系中的一个重要成员--我们的病毒生物群，以此作为开发新的治疗策略以操纵健康微生物群落的一种手段。虽然微生物区系的数量比我们自己的细胞多一个数量级，但病毒区系主要由噬菌体组成，噬菌体的数量是微生物区系的10倍。这意味着噬菌体是我们体内最丰富的外来物质之一。虽然噬菌体只捕食细菌作为宿主，但在人和鼠的粘液分泌物中都发现了大量的游离噬菌体，这表明噬菌体本身就有能力影响免疫系统的发育。因此，这些研究有可能为识别新的方法奠定基础，有选择地获得致病微生物群的致病成员的ri，并探索这些微小的细菌捕食者可能如何塑造人类的进化和健康。

DESCRIPTION (provided by applicant): Mammals are home to a commensal microbial community referred to as the microbiota. Recent data has provided compelling evidence that microbial residents on mammals are crucial for proper development and health. Indeed, changes in intestinal microbial communities have been associated with inflammatory bowel disease (IBD), diabetes, allergies, obesity, multiple sclerosis and even autism. Recent research, including our own, has demonstrated that replacement of beneficial bacterial species or deletion of pathogenic microbes can protect and even cure diseases in animal model systems. While the presence of beneficial bacteria can prevent or cure disease the loss of these bacteria or the outgrowth of particular 'bad' commensal bacteria can induce disease. Therefore, it appears that maintaining the proper balance, or community structure, of commensal organisms is critical to health. This highlights the critical need to develop methodologies that allow for therapeutic manipulation of the microbiota. Current methodologies such as antibiotics or anti-microbials target large groups of bacteria and do not provide a sufficient level of specificity. Indeed, antibiotic use to clear a pathogen is well known to disrupt beneficial commensal communities, leading to permanent loss of particular members of the microbiota and creating niches for pathogens, a process referred to as dysbiosis. Moreover, greater antibiotic use has been correlated with increasing incidence of autoimmunity, likely because of disruptions to the beneficial organisms that we harbor. Thus, novel therapies to control bacterial populations and target specific organisms is sorely needed. This proposal will set forth experiments to better understand a numerically prominent member of our microbiota, our virobiota as a means to develop novel therapeutic strategies to manipulate health microbial communities. While the microbiota outnumbers our own cells by an order of magnitude, the virobiota is mainly composed of bacteriophages that outnumber the microbiota by estimated factor of 10. This means that bacteriophages represent one of the most abundant forms of foreign material on our bodies. While bacteriophages solely prey on bacteria as their hosts, an abundance of free phage has been found in both human and mouse mucus secretions, suggesting that phage has the capacity to influence immune system development on its own. Therefore, these studies have the potential to lay the foundation for the identification of novel ways to selectively get ri of pathogenic members of the microbiota that induce disease and exploring how these tiny bacterial predators may have shaped human evolution and health.