Impact of Diet on Intestinal Microbiota-Host Dynamics

人类肠道内有一个密集而复杂的微生物群落，称为肠道微生物群。一 微生物生态系统的破坏或失调与几种疾病有关， 肠道疾病、代谢综合征和结肠癌。对肠道微生物群的治疗操作 对人类健康的广泛影响。然而，大量的细菌菌株存在于 个体在很大程度上随时间稳定，并且可能难以以可预测、稳健和可再现的方式改变。 时尚.粪便微生物群移植越来越多地用于修复生态失调的微生物群，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体化的（即，受接受者的影响 微生物群）。如果微生物群重编程要成为广泛疾病的有效疗法， 更好地了解控制治疗菌株整合巩固的因素和饮食的作用 在新菌株的强化中至关重要。在目标1中，微生物群可获得的碳水化合物 （MAC），微生物组成和功能的强大杠杆，将用于阐明机制， 所述外源性细菌物种在已建立的微生物群中扎根。此外，新环境 将通过新的饮食碳水化合物来建立生态位， 同源同基因株。将采用最先进的合成生物学工具和成像技术来量化 结肠内新形成的菌株的地理位置。在目标2中，微生物和遗传基因座 将从狩猎采集者群体的微生物组中分离出来， 鉴定由于饮食和碳水化合物利用酶编码的微生物群的传统 人口与美国居民不同，这些工业化前的微生物组拥有大量的 碳水化合物活性酶在西方世界不存在或非常罕见。分离利用 将对独特的MAC进行测试，以使已被工程化以利用的治疗菌株能够植入。 这些碳水化合物。使用多个特权MAC是否是一种有效的策略， 在多个已建立的微生物群落中独立地检测多个物种的丰度， 人源化小鼠模型（携带人微生物群的小鼠）。这一建议为以下方面建立了一个新的范例： 重新编程一个生态失调的微生物群，这使得强大的和可再生的防御成为可能。 外源菌株这一策略的最终目标是使新物种能够稳定掺入 以及可以针对个体特定微生物群和疾病状态定制的功能。

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.