Elucidating the Nexus Between Urinary Tract Infection and Diabetes

阐明尿路感染与糖尿病之间的关系

• 批准号: 10632066
• 负责人: Sargurunathan Subashchandrabose
• 金额: $ 18.94万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10632066
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; Adult; Affect; Antibiotics; Antimicrobial Resistance; Bacteremia; Bacterial Infections; Chronic; Dangerousness; Development; Diabetes Mellitus; Disease; Etiology; Excretory function; Experimental Models; Functional disorder; Genes; Gluconeogenesis; Glucose; Glycolysis; Goals; Growth; Health; Health Benefit; Human; Immune response; Incidence; Infection; Innate Immune Response; Intervention; Kidney; Klebsiella pneumoniae; Link; Metabolic Diseases; Mission; Modeling; Molecular; Monitor; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient availability; Outcome; Outcome Study; Pathogenicity; Pathologic; Persons; Prediabetes syndrome; Predisposition; Public Health; Pyelonephritis; Research; Risk; Role; Systemic infection; Testing; United States; United States National Institutes of Health; Urinary tract; Urinary tract infection; Urine; Uropathogen; Uropathogenic E. coli; Urothelium; Virulence; Work; burden of illness; design; diabetic; effective intervention; experimental study; fitness; health determinants; indexing; innovation; insight; long-term sequelae; metabolome; mouse model; mutant; non-diabetic; novel strategies; pathogen; pathogenic bacteria; pharmacologic; prevent; reuptake; tool; urinary

Urinary tract infection (UTI) is among the most common bacterial infection encountered by millions of people annually. UTI is a top reason for antibiotic use, which further compounds the crisis of antimicrobial resistance in bacterial pathogens. Uropathogenic Escherichia coli (UPEC) is the predominant etiological agent of UTI. Diabetes is a metabolic disease that significantly increases the propensity for development of UTI, and dangerous complications of UTI. In the United States, ~4 in 10 people were either diabetic or prediabetic in 2018, and type 2 diabetes mellitus (T2DM) is the most common form of diabetes. Glucosuria (urinary glucose excretion) in diabetics has been presumed to increase the incidence UTI. However, roles of glucose-fueled bacterial growth in the urinary tract, changes in the host response to bacterial pathogens during UTI, and shifts in the metabolite landscape of the urinary tract in diabetic hosts continue to remain poorly understood. Mechanistic understanding of how diabetes increases the risk for UTI is critical to design effective intervention strategies, and to develop novel approaches to monitor urinary tract health in diabetics. Significant increases in bacterial burden in the urinary tract, and higher levels of bacteremia and systemic infection with UPEC during UTI were observed in non-diabetic mice with gliflozin-induced glucosuria. Gliflozins are promising tools to probe the role of glucosuria in the interaction between uropathogens and diabetic hosts. Specifically, this proposal will investigate the effect of glucosuria and other urinary metabolites on the outcomes of UTI in diabetic and healthy (control) hosts. The long-term research goal is to define the cellular and molecular determinants of health and disease in the urinary tract. The central hypothesis for this study is that glucosuria is the primary determinant of bacterial colonization in the diabetic urinary tract, and that diabetes-induced changes in urinary metabolites promote bacterial UTI. This hypothesis will be tested in a mouse model of experimental UTI, and T2DM with the following Aims: 1) Determine the impact of glucosuria on the outcomes of bacterial UTI in a mouse model of type 2 diabetes; and 2) Define the diabetic urinary metabolome, and its role in promoting UTI. This study is expected to shed light on how glucose and other metabolites affect bacterial virulence and host response during UTI in diabetic hosts. The substantial positive impact of this study will be elucidating the causal link between UTI and diabetes. The proposed study is significant because these findings are anticipated to provide mechanistic insights into factors that contribute to increased risk for UTI during diabetes. The proposed approach is innovative because it integrates gliflozin-induced glucosuria with a mouse model of T2DM, and metabolome analysis to address the nexus between UTI and diabetes. In summary, the proposed study is expected to confer a significant public health benefit against UTI, an extremely common infectious condition that often results in severe complications and long-term sequelae in diabetics.

尿路感染(UTI)是数百万人遇到的最常见的细菌感染之一 每年一次。UTI是使用抗生素的首要原因，这进一步加剧了中国的抗菌素耐药性危机 细菌病原体。尿路致病性大肠杆菌(UPEC)是尿路感染的主要病原菌。 糖尿病是一种代谢性疾病，显著增加了发生尿路感染的倾向， 尿路感染的危险并发症。在美国，每10个人中就有4个人患有糖尿病或糖尿病前期 2018年，2型糖尿病(T2 DM)是最常见的糖尿病形式。糖尿症(尿糖 糖尿病患者的尿路感染(尿路感染)可能会增加尿路感染的发生率。然而，葡萄糖燃料的作用 尿路细菌生长、尿路感染期间宿主对细菌病原体反应的变化 糖尿病宿主的尿路代谢产物情况仍然知之甚少。 从机理上理解糖尿病如何增加尿路感染的风险，对于设计有效的干预措施至关重要 战略，并开发新的方法来监测糖尿病患者的尿路健康。显著增加了 尿路细菌负荷，以及较高水平的菌血症和UPEC系统感染 在非糖尿病小鼠中观察到了尿路感染，这些小鼠患有格列环素诱导的葡萄糖尿。优降糖是一种很有前途的探测工具 尿糖在尿路病原体与糖尿病宿主相互作用中的作用。具体地说，这项提议将 糖尿病患者和健康人尿糖及其他代谢产物对尿路感染结局的影响 (控制)主机。长期的研究目标是确定细胞和分子决定因素的健康和 尿路疾病。这项研究的中心假设是葡萄糖尿是糖尿病的主要决定因素。 糖尿病患者尿路细菌定植以及糖尿病引起的尿代谢物改变 推广细菌性尿路感染。这一假设将在实验性UTI的小鼠模型和T2 DM的小鼠模型中进行验证 目的如下：1)确定葡萄糖尿对细菌性尿路感染结局的影响。 2)糖尿病；2)定义糖尿病的尿代谢物，以及它在促进尿路感染中的作用。这项研究是预期的 阐明葡萄糖和其他代谢物在尿路感染期间如何影响细菌毒力和宿主反应 糖尿病患者。这项研究的重大积极影响将是阐明UTI和UTI之间的因果联系 糖尿病。这项拟议的研究意义重大，因为这些发现有望提供机械性的 对糖尿病期间导致尿路感染风险增加的因素的洞察。建议的方法是创新的。 因为它将格列福秦诱导的葡萄糖尿与T2 DM的小鼠模型相结合，并通过代谢组分析来 解决尿路感染和糖尿病之间的关系。总而言之，拟议的研究预计将提供一个重要的 公共卫生受益于尿路感染，这是一种非常常见的传染病，通常会导致严重的 糖尿病患者的并发症和长期后遗症。