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

开发有针对性的微生物疗法和饮食干预措施，以有效促进肠道屏障，最大限度地减少 GI-ARS

• 批准号: 10569957
• 负责人: Vanni Bucci
• 金额: $ 60.16万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-22 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569957
• 关键词: ABCB1 gene; Antibiotics; Bacteria; Bacteroides; Bile Acids; Biological Models; Biological Response Modifier Therapy; Butyrates; Cessation of life; Clinical; Data; Data Analyses; Development; Diet; Dietary Component; Dietary Intervention; Encapsulated; Engineered Probiotics; Engineering; Environment; Epithelium; Escherichia coli; Exposure to; Freeze Drying; Genetic Engineering; Homeostasis; Hour; Human; Immunity; In Vitro; Infection; Inflammatory; Intestines; Maintenance; Measures; Meditation; Metagenomics; Microbe; Mucous Membrane; Nuclear Accidents; Nuclear Warfare; Oral; Oral Administration; Pathway interactions; Personal Satisfaction; Phenotype; Physiological; Physiology; Play; Probiotics; Production; Radiation; Radiation Toxicity; Radiation exposure; Radiobiology; Recovery; Resistance; Role; Sampling; Sepsis; Succinates; Supplementation; Surface; System; Temperature; Terrorism; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Tissues; Whole-Body Irradiation; Work; beta-Glucans; dynamic system; dysbiosis; experimental study; gastrointestinal; gastrointestinal bacteria; gut colonization; gut microbiome; gut microbiota; improved; in vivo; in vivo Model; interest; intestinal barrier; intestinal epithelium; irradiation; mathematical model; medical countermeasure; member; microbiome; microbiome therapeutics; novel; permissiveness; prebiotics; receptor; synthetic biology; tissue repair; tool

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.

抽象的 暴露于核事故，预谋的核或恐怖袭击所产生的全身辐射（TBI） 引起胃肠道（GI）急性辐射综合征（GI-ARS），这是一种严重的肠粘膜屏障状态 损坏，组织完整性的丧失以及腔内含量的易位。措施抵消了 这种有害的暴露对于受影响者的生存和福祉至关重要。胃肠道 微生物组（细菌和代谢产物）在维持组织稳态中起着至关重要的作用。多种的 研究已将特定的微生物组进化枝视为促进肠道屏障功能和 因此，抵抗感染和炎症条件。该项目的中心假设是 用特定的肠道细菌或益生菌的特定亚群来靶向微生物组 通过精确的饮食干预产生障碍功能促进代谢物及其增强 改善肠上皮中的障碍稳态，从而创造了一种减少GI-ARS的环境。目标 1，我们将开发新颖的实时生物治疗产品，这些产品通过通过通过 功能上皮表面P-糖蛋白表达的有效诱导。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AIM 2中，我们将开发一个 益生菌大肠杆菌Nissle 1917的新型基因工程菌株，通过促进将GI-ARS最小化 通过有效的琥珀酸酯本构产生的屏障功能。最后，在AIM 3中，我们将评估效果 通过增强屏障的肠道细菌促进GI-AR的限制，富含益生元的饮食。累计， 这项工作将产生新型的微生物组治疗剂，通过专门针对肠道屏障 功能，最小化GI-ARS并在全身照射后增加生存率。