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、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) 急性辐射综合征 (GI-ARS)，这是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易位。抵消影响的措施 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（细菌和代谢物）在维持组织稳态中发挥着至关重要的作用。多种的 研究表明特定的微生物组负责促进肠道屏障功能和 由此产生的对感染和炎症的抵抗力。该项目的中心假设是 针对微生物群补充特定的肠道细菌或益生菌子集 积极产生促进屏障功能的代谢物，并通过精准饮食干预增强代谢物 改善肠上皮屏障稳态，创造减少 GI-ARS 的环境。瞄准 1，我们将开发新型活体生物治疗产品，通过促进屏障功能来最大限度地减少 GI-ARS 有效诱导功能性上皮表面 P-糖蛋白表达。此外，我们还将揭开 该受体系统在临床宏基因组样本中分布更广泛。在目标 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，可通过促进 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 富含益生元的饮食通过增强屏障的肠道细菌促进 GI-ARS 限制。累计起来， 这项工作将产生新型微生物组治疗剂，通过专门针对肠道屏障 功能，最大限度地减少 GI-ARS 并提高全身照射后的生存率。