Type 2 diabetes, sodium glucose, cotransporter-2 (SGLT2) inhibitors and the vaginal microbiota

项目总结 研究表明，患有2型糖尿病(T2D)的顺性女性有更大的复发风险 泌尿生殖系统感染，包括尿路感染和外阴阴道念珠菌病(VVC)，但尚不清楚 T2D患者是否有不成比例的细菌性阴道病(BV)发生率。BV是一种常见的 一种阴道炎，在北美妇女中的流行率为30%。BV的特征是 乳杆菌缺乏的阴道微生物区系与性传播风险增加有关 感染，包括艾滋病毒，以及严重影响生活质量的外阴阴道症状。钠 葡萄糖协同转运蛋白-2(SGLT2)抑制剂是一种很受欢迎的口服降糖药物，通过抑制 肾脏对葡萄糖的重吸收，导致尿液中葡萄糖排泄增加。这一机制具有 与VVC发病率增加有关，但SGLT2抑制剂对泌尿生殖系统的影响 微生物区系还没有用分子方法进行研究。在这份F31中，我提出了一种分子流行病学 该项目评估与T2D相关的阴道微生物区系以及使用SGLT2抑制剂后的阴道微生物区系。我 假设T2D和SGLT2抑制剂与分子BV和阴道微环境有关 乳酸含量低。乳酸菌生产乳酸是一项重要的功能，因为它提供了 通过酸化阴道微环境进行保护(pH和lt；4.5)。具体目标是：1)评估 非妊娠T2D患者与种族/种族匹配患者的阴道微环境比较 没有T2D。45岁及以上的顺性女性将被招募到一项横断面研究中 马里兰大学糖尿病和内分泌学中心和巴尔的摩的一家普通健康诊所 市中心的校园。将使用16S rRNA对自己采集的阴道样本进行细菌组成评估 基因扩增序列测定、全细菌定量聚合酶链式反应和乳酸异构体分析。调查问卷将 收集重要的协变量信息。2)比较治疗前后女性的泌尿生殖道微生物区系 使用SGLT2抑制剂治疗，利用从正在进行的研究中收集的尿样储存库 旧秩序阿米什(R01-DK118942，PI：泰勒，共同发起人)。单交叉研究设计允许 评估SGLT2抑制剂治疗后泌尿生殖道微生物区系的变化并消除混淆 关于时间无关的因素，因为它允许每个参与者充当自己的控制力。《目标2》基于 储存尿样，使其高度可行；最近发表的研究表明，尿样 显示出与阴道微生物区系高度一致。本F31中提议的研究将提供第一个 T2D环境下阴道微生物区系的特征和评估SGLT2抑制剂对 泌尿生殖道微生物区系。这些发现将有助于BV筛查指南和妇科护理 T2D患者和服用SGLT2抑制剂的患者。F31将在分子方面提供独特的培训 人类微生物群的流行病学以及糖尿病和慢性病流行病学的研究。

PROJECT SUMMARY Studies have shown that cisgender women with type 2 diabetes (T2D) are at greater risk for recurrent urogenital infections, including urinary tract infections and vulvovaginal candidiasis (VVC), but it is unknown whether individuals with T2D have disproportionately higher rates of bacterial vaginosis (BV). BV is a common form of vaginitis with a 30% prevalence among North American women. BV is characterized by a Lactobacillus-deficient vaginal microbiota and is associated with increased risk for sexually transmitted infections, including HIV, as well as vulvovaginal symptoms that significantly affect quality of life. Sodium glucose cotransporter-2 (SGLT2) inhibitors, a favorable oral antidiabetic medication, function by inhibiting reabsorption of glucose in the kidneys, causing increased excretion of glucose in urine. This mechanism has been associated with increased incidence of VVC, but the influence of SGLT2 inhibitors on the genitourinary microbiota has not been investigated with molecular methods. In this F31, I propose a molecular epidemiologic project which assesses the vaginal microbiota associated with T2D and after SGLT2 inhibitor use. I hypothesize that T2D and SGLT2 inhibitors are associated with molecular-BV and a vaginal microenvironment low in lactic acid. The production of lactic acid by lactobacilli is an important function because it provides protection by acidifying the vaginal microenvironment (to pH <4.5). The specific aims are: 1) To assess the vaginal microenvironment in non-pregnant individuals with T2D compared to ethnicity/race-matched individuals without T2D. Cisgender women aged 45 years and greater will be recruited to a cross-sectional study at the University of Maryland Center for Diabetes and Endocrinology and a general health clinic at the Baltimore Midtown campus. Self-collected vaginal samples will be assessed for bacterial composition utilizing 16S rRNA gene amplicon sequencing, pan-bacterial quantitative PCR and lactic acid isomer assays. Questionnaires will collect important covariate information. 2) To compare the genitourinary microbiota of women before and after treatment with SGLT2 inhibitors, utilizing a repository of urine samples collected from an ongoing study in the Old Order Amish (R01-DK118942, PI: Taylor, co-sponsor). The single cross-over study design allows for assessment of changes in the genitourinary microbiota following SGLT2 inhibitors and eliminates confounding on time-independent factors because it allows each participant to serve as their own control. Aim 2 is based on repository urine samples, making it highly feasible; recently published studies suggest urine samples demonstrate high concordance with vaginal microbiota. The studies proposed in this F31 will provide the first characterization of the vaginal microbiota in the setting of T2D and assess the impact of SGLT2 inhibitors on the genitourinary microbiota. These findings will contribute to BV screening guidelines and gynecologic care for patients with T2D and those taking SGLT2 inhibitors. The F31 will provide unique training in the molecular epidemiology of the human microbiome and studies of diabetes and chronic disease epidemiology.