Impact of Diet on Intestinal Microbiota-Host Dynamics

人类肠道中有一个密集而复杂的微生物群落，被称为肠道微生物区系。一个 破坏或破坏微生物生态系统与多种疾病有关，包括炎症性疾病 肠道疾病、代谢综合征和结肠癌。肠道微生物区系的治疗操作有 对人类健康的广泛影响。然而，寄生在细菌体内的大量细菌菌株 个体在很大程度上是随着时间的推移而稳定的，并且很难在可预测的、健壮的和可重现的 时尚。粪便微生物区系移植越来越多地被用于修复非生物微生物区系，然而， 引入的菌株的命运是不可预测的，并且在很大程度上是个性化的(即，受接受者的 微生物区系)。如果微生物区系重新编程要成为一种治疗广泛疾病的有效方法， 更好地理解控制治疗菌株整合的因素和饮食的作用 在加固新菌株方面至关重要。在目标1中，微生物区系可获得的碳水化合物 (MACs)，微生物区系组成和功能的强大杠杆，将被用来通过 哪些外源细菌物种扎根于已建立的微生物区系中。此外，新的环境 将通过新的饮食碳水化合物来建立生态位，以取代致病细菌菌株 共生同基因菌株。将使用最先进的合成生物学工具和成像技术来量化 新侵袭的菌株在结肠内的生物地理位置。在目标2中，微生物和遗传位点 将从狩猎-采集种群的微生物群中分离出同源多糖 已确认身份。由于饮食和碳水化合物利用酶编码在传统的微生物区系中 人口与美国居民不同，这些工业化前的微生物群拥有大量的 碳水化合物活性酶在西方世界中并不存在或非常罕见。分离利用 将对独特的Mac进行测试，以实现已被设计用于使用的治疗菌株的植入 这些碳水化合物。使用多个特权Mac是否是巩固和控制 在多个已建立的微生物群中独立地测试多种物种的丰度将在 人源化小鼠模型(拥有人类微生物区系的小鼠)。这项提议建立了一个新的范例 对非生物微生物区系进行重新编程，这使得坚固和可复制的 外源细菌菌株。这一战略的最终目标是使新物种能够稳定地融合。 以及可以根据个人特定的微生物区系和疾病状态量身定做的功能。

The human gut harbors a dense and complex community of microbes known as the intestinal microbiota. A disrupted or dysbiotic microbial ecosystem has been connected to several diseases including inflammatory bowel diseases, metabolic syndrome, and colon cancer. Therapeutic manipulation of the gut microbiota has broad implications for human health. However, the abundance of bacterial strains that reside within an individual is largely stable over time and can be difficult to alter in a predictable, robust, and reproducible fashion. Fecal microbiota transplants are being increasingly used to repair a dysbiotic microbiota, however, the fate of the introduced strains is unpredictable and largely individualized (i.e., influenced by the recipient's microbiota). If microbiota reprogramming is to become an effective therapy for a broad range of diseases, a better understanding of the factors that control entrenchment of therapeutic strain integration and the role of diet in the reinforcement of new strains is critically important. In Aim 1, microbiota accessible carbohydrates (MACs), powerful levers on microbiota composition and function, will be used to elucidate the mechanisms by which exogenous bacterial species entrench within an established microbiota. Furthermore, new environmental niches will be established through novel dietary carbohydrates to replace pathogenic bacterial strains with commensal isogenic strains. State-of-the-art synthetic biology tools and imaging will be employed to quantify the biogeographical location of newly entrenching strains within the colon. In Aim 2, microbes and genetic loci will be isolated from the microbiomes of hunter-gatherer populations and cognate polysaccharides will be identified. Since the diet and carbohydrate utilization enzymes encoded within the microbiota of traditional populations is distinct from that of US residents, these pre-industrialized microbiomes possess a large collection of carbohydrate active enzymes not present or exceedingly rare in the Western world. Isolation and utilization of unique MACs will be tested to enable engraftment of therapeutic strains that have been engineered to utilize these carbohydrates. Whether using multiple privileged MACs is an effective strategy to entrench and control the abundance of multiple species independently within multiple established microbiotas will be tested in a humanized mouse model (mice harboring a human microbiota). This proposal establishes a new paradigm for reprogramming a dysbiotic microbiota, which makes possible the robust and reproducible entrenchment of exogenous bacterial strains. The ultimate goal of this strategy is to enable stable incorporation of new species and functions that could be tailored to an individual's specific microbiota and disease state.