Impact of L. plantarum 299v supplementation on endothelial function and inflammation in humans with type 2 diabetes

补充植物乳杆菌 299v 对 2 型糖尿病患者内皮功能和炎症的影响

• 批准号: 10132528
• 负责人: Michael E Widlansky
• 金额: $ 11.45万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-10 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10132528
• 关键词: Adipose tissue; Affect; Arterial Fatty Streak; Arteries; Atherosclerosis; Biological Assay; Biology; Biopsy; Blood Vessels; Cardiovascular system; Cells; Clinical; Clinical Trials; Coronary Arteriosclerosis; Data; Development; Diabetes Mellitus; Double-Blind Method; Endothelial Cells; Endothelium; Event; Faculty; Genetic Transcription; Goals; Human; Incidence; Individual; Inflammation; Inflammatory; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Intervention; Intestinal permeability; Investigation; K-Series Research Career Programs; Kidney Diseases; Knowledge; Laboratories; Lactobacillus plantarum; Learning; Measurement; Measures; Medicine; Mentors; Mentorship; Metabolism; Methods; Microvascular Dysfunction; Modification; Mononuclear; Myocardial Infarction; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Patients; Physicians; Physiology; Pilot Projects; Placebos; Plasma; Postdoctoral Fellow; Prevalence; Probiotics; Production; Publishing; Randomized; Reporting; Research; Research Personnel; Resistance; Retinal Diseases; Risk; Risk Factors; Scientist; Signal Transduction; Stroke; Structure; Study Subject; Supplementation; Techniques; Testing; Time; Translational Research; Ultrasonography; Ursidae Family; Vascular Diseases; Vascular Endothelium; Vasodilation; Video Microscopy; Volatile Fatty Acids; Woman; Work; acute coronary syndrome; brachial artery; cardiogenesis; cardiovascular risk factor; career; clinical translation; combat; design; glucose tolerance; glycemic control; gut microbiome; gut microbiota; human microbiota; improved; inflammatory marker; insulin sensitivity; interest; member; men; next generation; novel; patient oriented; patient oriented research; probiotic supplementation; programs; success; systemic inflammatory response; transcriptome; transcriptome sequencing; trimethylamine; trimethyloxamine; vascular endothelial dysfunction; vascular inflammation

This mid-career development award application is designed to provide critical protected time for the applicant to increase and improve his mentoring activities along with further developing his research program in clinically oriented translational research in vascular biology and endothelial function. During his 12+ years as a faculty member, the applicant has served as research mentor for 17 post-doctoral mentees, including 10 physician- scientists. Nearly 90% percent of the applicant's mentees engaged in patient-oriented research, nearly 50% percent are women, and 82% have remained in academic medicine settings. As part of this program, the applicant will create a more detailed and structured mentorship program for his trainees who are interested in careers in patient-oriented clinical/translational research in vascular biology and physiology. This K24 application is scientifically centered on determining the vascular and inflammatory impact of supplementation of humans with type 2 diabetes (T2DM) with the probiotic Lactobacillus plantarum 299v (Lp299v). This proposal represents a natural outgrowth of the applicant's current work. Despite aggressive traditional risk factor modification and glycemic control efforts with even the most recent glycemic control agents with favorable cardiovascular profiles, atherosclerotic vascular diseases and microvascular disease continue to disproportionately impact individuals with diabetes mellitus (DM). Vascular disease in T2DM begins with the development of vascular endothelial dysfunction. The applicant's group recently reported that once daily supplementation with Lp299v results in improved endothelial function and reduced systemic vascular inflammation in men with stable coronary artery disease. This was the first report of a probiotic supplement having a favorable impact on vascular endothelial function in humans. While this data supports the concept that Lp299v improves vascular endothelial function and reduces systemic inflammation, only three individuals in the pilot study had T2DM. Whether the favorable effects of Lp299v supplementation extend to humans with T2DM remains uncertain. Equipose regarding impact of Lp299v supplementation in human T2DM is further supported by the known significant differences in the composition and metabolism of the gut microbiota of humans with T2DM suggesting the interaction of T2DM gut microbiota with Lp299v may significantly differ compared to those without diabetes. The applicant's preliminary data suggest Lp299v's favorable impact on endothelium-dependent vasodilation and vascular inflammation may be magnified in individuals with T2DM. We will test the hypothesis that Lp299v supplementation improves endothelium-dependent vasodilation and microvascular function, reduces inflammation, and improves insulin sensitivity in humans with T2DM in the setting of a randomized, double-blind, placebo-controlled crossover clinical trial. The proposed studies will both advance our knowledge about a novel method for reducing vascular risk in T2DM through a gut microbiota-targeted intervention and provide an outstanding framework for mentoring the next generation of researchers in vascular-centered patient-oriented research.

该中期发展奖的申请旨在为申请人提供关键的保护时间 增加并改善他的指导活动，并进一步开发他的临床研究计划 血管生物学和内皮功能的定向转化研究。在他担任教师的12年以上 成员，申请人曾担任17名博士后指导者的研究导师，其中包括10位医生 科学家。将近90％的申请人从事以患者为导向的研究，将近50％ 百分比是女性，其中82％仍在学术医学环境中。作为该计划的一部分， 申请人将为对他的受训者创建一个更详细，结构化的指导计划 血管生物学和生理学领域的临床/转化研究职业。此K24应用程序 科学以确定补充人类的血管和炎症影响为中心 与2型糖尿病（T2DM）一起使用益生菌乳杆菌299V（LP299V）。该提案代表 申请人当前工作的自然产物。尽管有积极的传统风险因素修改和 血糖控制努力即使是具有良好心血管谱的最新血糖控制剂， 动脉粥样硬化血管疾病和微血管疾病继续对个体产生不成比例的影响 糖尿病（DM）。 T2DM中的血管疾病始于血管内皮的发展 功能障碍。申请人小组最近报告说，一旦每天补充LP299V 稳定冠状动脉的男性的内皮功能改善并减少了全身血管炎症 疾病。这是对益生菌补充剂对血管内皮产生有利影响的第一个报告 人类的功能。尽管该数据支持LP299V改善血管内皮功能和 减少了系统性炎症，试点研究中只有三个人患有T2DM。是否有利效果 LP299V的补充延伸到具有T2DM的人类，仍然不确定。关于影响 在人类T2DM中补充LP299V，进一步支持了已知的显着差异 人类肠道菌群与T2DM的组成和代谢，表明T2DM肠相互作用 与没有糖尿病的微生物群相比，具有LP299V的微生物群可能明显差异。申请人的初步 数据表明LP299V对内皮依赖性血管舒张和血管炎症的有利影响可能 在患有T2DM的个体中放大。我们将检验以下假设：补充LP299V可以改善 依赖内皮的血管舒张和微血管功能，减少炎症并改善胰岛素 在随机，双盲，安慰剂对照的跨界的情况下，具有T2DM的人类敏感性 临床试验。拟议的研究都将促进我们对减少血管的新方法的了解 通过肠道微生物群的干预措施在T2DM中冒险，并为指导提供了出色的框架 以血管为中心的患者研究中的下一代研究人员。