Developing therapies to target the microbiota

描述（由申请人提供）：哺乳动物是被称为微生物群的共生微生物群落的家园。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正常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疗疾病，但这些细菌的丧失或特定“坏”共生细菌的生长可诱发疾病。因此，维持共生生物的适当平衡或群落结构似乎对健康至关重要。这突出了开发允许对微生物群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，并没有提供足够的特异性。事实上，众所周知，使用抗生素清除病原体会破坏有益的共生群落，导致微生物群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的发病率增加有关，这可能是因为我们所拥有的有益生物受到破坏。因此，迫切需要新的治疗方法来控制细菌种群和靶向特定生物体。该提案将提出实验，以更好地了解我们的微生物群中数字突出的成员，我们的病毒群，作为开发新的治疗策略来操纵健康微生物群落的手段。虽然微生物群的数量比我们自己的细胞多出一个数量级，但病毒群主要由噬菌体组成，其数量比微生物群多出约10倍。这意味着噬菌体是我们体内最丰富的外来物质之一。虽然噬菌体只捕食作为宿主的细菌，但在人类和小鼠的粘液分泌物中都发现了大量的游离噬菌体，这表明噬菌体本身具有影响免疫系统发育的能力。因此，这些研究有可能为鉴定有选择性地获得诱发疾病的微生物群致病性成员的新方法以及探索这些微小的细菌捕食者如何影响人类进化和健康奠定基础。

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.