Elucidating the Nexus Between Urinary Tract Infection and Diabetes

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。UTI是抗生素使用的首要原因，这进一步加剧了抗生素耐药性的危机。 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体。 糖尿病是一种代谢性疾病，可显著增加UTI发展的倾向， UTI的危险并发症在美国，10人中有4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（尿糖 据推测，糖尿病患者中的尿排泄物（例如尿蛋白排泄物）会增加UTI的发病率。然而，葡萄糖燃料的作用 尿路中的细菌生长，UTI期间宿主对细菌病原体反应的变化，以及 在糖尿病患者的泌尿道代谢物景观仍然知之甚少。 了解糖尿病如何增加UTI风险的机制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 尿路细菌负荷，以及UPEC的菌血症和全身感染水平较高， 在格列净诱导糖尿的非糖尿病小鼠中观察到UTI。格列净是一种很有前途的工具， 糖尿在泌尿系病原体与糖尿病宿主相互作用中的作用。具体而言，该提案将 研究糖尿病患者和健康人的糖尿和其他尿代谢产物对UTI结局的影响 （控制）主机。长期研究目标是确定健康的细胞和分子决定因素， 泌尿系统疾病。这项研究的中心假设是糖尿是糖尿病的主要决定因素。 糖尿病患者泌尿道中的细菌定植，以及糖尿病引起的尿代谢物变化 促进细菌性UTI。该假设将在实验性UTI和T2 DM的小鼠模型中进行测试， 以下目的：1）在以下类型的小鼠模型中确定糖尿对细菌UTI结果的影响： 2型糖尿病;和2）定义糖尿病尿代谢组，及其在促进UTI中的作用。本研究预计 阐明葡萄糖和其他代谢产物如何影响UTI期间的细菌毒力和宿主反应， 糖尿病宿主这项研究的实质性积极影响将阐明UTI和 糖尿病拟议的研究是重要的，因为这些发现预计将提供机制 深入了解导致糖尿病期间UTI风险增加的因素。建议的方法是创新的 因为它将格列净诱导的糖尿与T2 DM小鼠模型相结合，并通过代谢组学分析， 解决UTI和糖尿病之间的关系。总之，拟议的研究预计将提供一个重要的 UTI是一种非常常见的感染性疾病，通常会导致严重的 糖尿病并发症和长期后遗症。

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.