Identification of bacterial strains for development of an oral probiotic aimed at increasing nitric oxide bioavailability

鉴定用于开发口服益生菌的菌株，旨在提高一氧化氮的生物利用度

• 批准号: 10666185
• 负责人: DANIEL B KIM-SHAPIRO
• 金额: $ 19.78万
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666185
• 关键词: Adherence; Anemia; Animal Model; Anions; Antibiotic Resistance; Atherosclerosis; Back; Bacteria; Biological Assay; Biological Availability; Blood; Cell Line; Cells; Clinical; Clinical Research; Clinical Trials; Congestive Heart Failure; Control Animal; Data; Development; Diabetes Mellitus; Disease; Epithelium; Genomics; Goals; Heart failure; Hemolytic Anemia; Homeostasis; Human; Hypertension; Individual; Intake; Intervention; Lead; Link; Malaria; Methods; Microbial Biofilms; Molecular; Nerve Degeneration; Nitrates; Nitric Oxide; Nitrites; Nutrient; Obesity; Oral; Oral Administration; Oral Characters; Oral cavity; Oral mucous membrane structure; Organ; Outcome; Pathogenicity; Pathology; Patients; Phase; Physiological; Physiology; Pilot Projects; Plasma; Play; Probiotics; Reporting; Role; Route; Safety; Saliva; Salivary Glands; Signaling Molecule; Source; System; Testing; Therapeutic Intervention; Tissues; Tongue; Transfusion; base; candidate identification; cohort; culture plates; design; dietary nitrate; efficacy evaluation; exercise capacity; high throughput screening; human disease; improved; innovation; microbiome; microbiome composition; monolayer; mouse model; novel; oral bacteria; oral microbial community; oral microbiome; screening; translational applications; virulence gene

Nitric oxide (NO) plays critical roles in a myriad of cellular and molecular mechanisms regulating physiology and function of various organs and systems. Depletion of NO and its reduced bioavailability contributes to the pathology of several human diseases including anemia, malaria, heart failure, obesity, diabetes and neurodegeneration. Recent reports suggest that oral microbiota regulate NO homeostasis through the action of some bacteria that have the ability to perform reduction of the nutrient anion nitrate to nitrite and NO. Several clinical trials have taken advantage of this nitrate-nitrite-NO cycle employing oral nitrate to deliver NO. However, many individuals do not respond to oral nitrate, and we hypothesize that this is due to a deficiency in nitrate to nitrite converting bacteria. Hence, developing microbiome modulators like probiotics to enhance and/or perform increased nitrate reduction and NO formation can potentially serve as a solution to recover diminished NO levels and bioavailability. The goal of this project is to test the role of oral bacteria in determining the extent of conversion of oral nitrate to plasma nitrite while developing novel human-origin probiotics of nitrate-nitrite-NO formation abilities and determine their adherence potential to colonize and form biofilms in epithelia. In Aim 1 we will use novel, high throughput screening assays to identify candidate bacterial strains with efficient nitrate to nitrite conversion abilities obtained from the oral cavity and characterize these strains. In Aim 2 we will determine the oral cavity colonizing capabilities of the nitrate to nitrite converting bacterial strains. In Aim 3, we will test the role of these bacterial strains’ in determining the extent of conversion of oral nitrate to plasma nitrite in a murine model. Successful completion of these studies could lead to probiotics against human diseases caused by NO homeostasis abrogation.

一氧化氮（NO）在调节生理的无数细胞和分子机制中起着关键作用 以及各种器官和系统的功能。NO的消耗及其降低的生物利用度有助于 包括贫血、疟疾、心力衰竭、肥胖症、糖尿病和 神经变性最近的报道表明，口腔微生物群通过以下作用调节NO稳态： 一些细菌具有将营养阴离子硝酸盐还原为亚硝酸盐和NO的能力。 临床试验利用了这种硝酸盐-亚硝酸盐-NO循环，使用口服硝酸盐来递送NO。 然而，许多人对口服硝酸盐没有反应，我们假设这是由于缺乏 将硝酸盐转化为亚硝酸盐的细菌。因此，开发微生物组调节剂，如益生菌， 和/或进行增加的硝酸盐还原和NO形成可以潜在地用作回收的解决方案 降低NO水平和生物利用度。该项目的目标是测试口腔细菌在 确定口服硝酸盐转化为血浆亚硝酸盐的程度，同时开发新的人源性 益生菌的硝酸盐-亚硝酸盐-NO形成能力，并确定其粘附的潜力， 上皮中的生物膜。在目标1中，我们将使用新的高通量筛选方法来鉴定候选药物。 从口腔中获得的具有有效的硝酸盐至亚硝酸盐转化能力的细菌菌株， 这些菌株。在目标2中，我们将确定硝酸盐转化为亚硝酸盐的口腔定殖能力 细菌菌株在目标3中，我们将测试这些细菌菌株的作用，以确定程度， 在小鼠模型中口服硝酸盐转化为血浆亚硝酸盐。成功完成这些研究可以 导致益生菌对抗由NO稳态破坏引起的人类疾病。