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

项目摘要 研究表明，患有2型糖尿病（T2 D）的顺性别女性复发的风险更大。 泌尿生殖道感染，包括尿路感染和外阴阴道念珠菌病（VVC），但尚不清楚 T2 D患者是否具有不成比例的更高的细菌性阴道病（BV）率。BV是常见的 一种阴道炎，在北美女性中的患病率为30%。BV的特点是 缺乏乳酸杆菌的阴道微生物群与性传播疾病风险增加有关 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（SGLT 2）抑制剂是一种良好的口服降糖药物， 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 与VVC发生率增加相关，但SGLT 2抑制剂对泌尿生殖系统的影响 微生物群尚未用分子方法研究。在F31中，我提出了一种分子流行病学 该项目评估了与T2 D相关的阴道微生物群以及SGLT 2抑制剂使用后的阴道微生物群。我 假设T2 D和SGLT 2抑制剂与分子BV和阴道微环境相关 乳酸含量低乳酸杆菌产生乳酸是一个重要的功能，因为它提供了 通过酸化阴道微环境（至pH <4.5）进行保护。具体目标是：1）评估 与种族/人种匹配个体相比，T2 D非妊娠个体的阴道微环境 没有T2 D。年龄在45岁及以上的顺性别女性将被招募到一项横断面研究中， 马里兰州大学糖尿病和内分泌中心和巴尔的摩的一家普通健康诊所 市中心校园。将使用16 S rRNA评估自行采集的阴道样本的细菌组成 基因扩增子测序、泛细菌定量PCR和乳酸异构体测定。问卷将 收集重要的协变量信息。2)为了比较女性在治疗前后的泌尿生殖道微生物群， 使用SGLT 2抑制剂治疗，利用从正在进行的研究中收集的尿液样本库， 旧秩序阿米什人（R 01-DK 118942，PI：Taylor，共同申办者）。单交叉研究设计允许 评估SGLT 2抑制剂给药后泌尿生殖道微生物群的变化并消除混杂因素 时间无关的因素，因为它允许每个参与者作为自己的控制。目标2基于 储存尿液样本，使其高度可行;最近发表的研究表明，尿液样本 与阴道微生物群高度一致。本F31中提出的研究将提供第一个 在T2 D背景下表征阴道微生物群，并评估SGLT 2抑制剂对 泌尿生殖道微生物这些发现将有助于BV筛查指南和妇科护理， T2 D患者和使用SGLT 2抑制剂的患者。F31将提供独特的分子训练， 人类微生物组流行病学以及糖尿病和慢性病流行病学研究。

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.