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

基本信息

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
项目类别：
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

项目摘要

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) 在调节生理学的众多细胞和分子机制中发挥着关键作用 NO 的消耗及其生物利用度的降低有助于多种人类疾病的病理学，包括贫血、疟疾、心力衰竭、肥胖、糖尿病和最近的报告表明，口腔微生物群通过以下作用调节 NO 稳态。一些细菌能够将营养阴离子硝酸盐还原为亚硝酸盐和一氧化氮。临床试验利用了这种硝酸盐-亚硝酸盐-NO 循环，采用口服硝酸盐来输送 NO。然而，许多人对口服硝酸盐没有反应，我们认为这是由于缺乏因此，开发益生菌等微生物调节剂来增强。和/或执行增加的硝酸盐还原和NO形成可能作为恢复的解决方案该项目的目标是测试口腔细菌在减少一氧化氮水平和生物利用度方面的作用。确定口服硝酸盐转化为血浆亚硝酸盐的程度，同时开发新的人类来源益生菌的硝酸盐-亚硝酸盐-NO 形成能力，并确定其定植和形成的粘附潜力在目标 1 中，我们将使用新颖的高通量筛选方法来识别候选者。从口腔获得并鉴定具有高效硝酸盐至亚硝酸盐转化能力的细菌菌株在目标 2 中，我们将确定硝酸盐转化为亚硝酸盐的口腔定植能力。在目标 3 中，我们将测试这些细菌菌株在确定细菌感染程度方面的作用。在小鼠模型中将口服硝酸盐转化为血浆亚硝酸盐可以成功完成这些研究。导致益生菌对抗 NO 稳态破坏引起的人类疾病。