Development of targeted microbiome therapeutics and dietary interventions for potent intestinal barrier promotion to minimize GI-ARS

摘要 暴露于核事故、有预谋的核袭击或恐怖袭击产生的全身照射（TBI） 引起胃肠道（GI）急性放射综合征（GI-ARS），一种严重的肠粘膜屏障状态 损伤、组织完整性丧失和管腔内容物移位。采取措施消除 这种有害的接触对受影响者的生存和福祉至关重要。胃 微生物组（细菌和代谢物）在维持组织稳态中起着至关重要的作用。多 研究表明，特定的微生物组进化枝负责促进肠道屏障功能， 从而抵抗感染和炎性病症。这个项目的核心假设是 针对性地补充肠道细菌或益生菌的特定亚群， 通过精确的饮食干预积极产生促进屏障功能的代谢产物及其增强 改善肠上皮细胞的屏障稳态，创造一个减少GI-ARS的环境。在aim中 1.我们将开发新的活生物制剂产品，通过促进屏障功能来减少GI-ARS， 有效诱导功能性上皮表面P-糖蛋白表达。此外，我们将发现 该受体系统在临床宏基因组样品中的更广泛分布。在目标2中，我们将开发一个 益生菌E. coli Nissle 1917，其通过促进 通过琥珀酸的有效组成性产生来发挥屏障功能。最后，在目标3中，我们将评估效果 益生元强化饮食促进肠道屏障增强细菌对GI-ARS的限制。累积起来， 这项工作将产生新的微生物组治疗剂，通过特异性靶向肠屏障， 功能，最大限度地减少GI-ARS，并增加全身照射后的生存率。

ABSTRACT Exposure to total body irradiation (TBI) produced by nuclear accidents, premeditated nuclear, or terrorist attack causes gastrointestinal (GI) acute radiation syndrome (GI-ARS), a state of severe intestinal mucosal barrier damage, loss of tissue integrity, and translocation of the luminal content. Measures to counteract the effect of such detrimental exposure are critical for the survival and well-being of those impacted. The gastrointestinal microbiome (bacteria and metabolites) plays a crucial role in the maintenance of tissue homeostasis. Multiple studies have implicated specific microbiome clades as responsible for promoting intestinal barrier function and consequent resistance against infections and inflammatory conditions. The central hypothesis of this project is that targeted microbiome supplementation with specific subsets of intestinal bacteria or probiotics engineered to produce barrier function-promoting metabolites and their enhancement via precise dietary intervention actively improves barrier homeostasis in the intestinal epithelium, creating an environment that reduces GI-ARS. In Aim 1, we will develop novel live biotherapeutic products that minimize GI-ARS by promoting barrier function through the potent induction of functional epithelial surface P-glycoprotein expression. Additionally, we will uncover the broader distribution of this receptor system within clinical, metagenomic samples. In Aim 2, we will develop a novel genetically engineered strain of the probiotic E. coli Nissle 1917 that minimizes GI-ARS by promoting barrier function through the potent constitutive production of succinate. Lastly, in Aim 3 we will evaluate the effect of prebiotics-enriched diets in promoting GI-ARS limitation by barrier-enhancing intestinal bacteria. Cumulatively, this work will generate novel microbiome therapeutic agents that, by specifically targeting intestinal barrier function, minimize GI-ARS and increase survival after total body irradiation.