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、预谋核或恐怖袭击产生的全身照射(TBI) 引起胃肠道(GI)急性辐射综合征(GI-ARS)，一种严重的肠道粘膜屏障状态 损伤、组织完整性丧失和腔内容物移位。采取措施抵消 这种有害的暴露对受影响者的生存和福祉至关重要。胃肠道 微生物组(细菌和代谢物)在维持组织内环境平衡方面起着至关重要的作用。多重 研究表明，特定的微生物群分支负责促进肠道屏障功能和 由此产生对感染和炎症条件的抵抗力。这个项目的中心假设是 以肠道细菌或益生菌的特定亚群为靶点的微生物补充剂 通过精准膳食干预主动产生屏障功能促进代谢物及其增强作用 改善肠道上皮屏障的动态平衡，创造一个减少GI-ARS的环境。在AIM 1、我们将开发新的活体生物治疗产品，通过以下途径促进屏障功能，最大限度地减少GI-ARS 有效地诱导功能性上皮细胞表面P-糖蛋白的表达。此外，我们还将揭开 这一受体系统在临床和后基因组样本中的广泛分布。在目标2中，我们将制定一个 益生菌E.ColiNissle 1917的新型基因工程菌株通过促进 通过琥珀酸的有效构成产物起到阻隔作用。最后，在目标3中，我们将评估效果 益生素强化饮食在促进屏障增强肠道细菌限制GI-ARS方面的作用。累积起来， 这项工作将产生新的微生物治疗药物，通过专门针对肠道屏障 功能，最大限度减少GI-ARS，提高全身照射后的存活率。

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.