The Oral Microbiome for the Detection of Barretts Esophagus

项目总结 食管腺癌(EAC)的发病率在过去的半个世纪里上升了10倍，而且还在继续 有一个悲观的预后。Barrett‘s食道(BE)是EAC的前驱病变，患者诊断为 对早期肿瘤进行监测和内窥镜治疗。然而，超过90%的EAC 患者事先从未被诊断为BE，而广泛使用上消化道内窥镜检查来确定患者是否患有BE 是昂贵的，而且价值值得怀疑。因此，迫切需要开发微创的治疗方法。 可以在初级保健环境中轻松进行的筛查，以实现高效和成本效益 旨在降低EAC死亡率的干预措施。食道微生物组受细菌迁移的影响很大。 通过吞咽分泌物从口腔中排出的细菌。胃食道中的食道微生物群发生改变 反流和BE，这些变化可能因此反映了口腔微生物群的变化，这是一种容易获得的 采样点。事实上，我们已经证明，患者的口腔微生物群有明显的变化。 与BE相比，基于特定分类群的模型可以区分BE患者，具有较高的敏感性和特异性。我们 假设唾液微生物组分析可以高精度地识别BE患者，因此 代表了一种新的、非侵入性的筛查测试，以识别有EAC风险的患者。在目前的提案中，我们 目的在一个大型内窥镜队列中验证我们的初步发现。我们建议利用一项已完成的研究 接受第一次上消化道内窥镜检查并采集相关唾液样本的患者以及疑似 早期肿瘤(高度异型增生或早期EAC)。在目标1中，我们将确定口腔微生物组 确定患者患有BE。我们假设微生物群得分基于包含相对的模型 大量的月桂花、链球菌和肠杆菌科细菌可以区分患有和不患有BE的患者 精确度高。在Subaim 1a中，我们将确定口腔微生物组是否结合临床 预测模型(密歇根巴雷特食道预测工具；M-beret)识别巴雷特患者 食管。作为口腔微生物组签名的外部验证，我们将进行一项病例对照研究，使用 作为基于初级保健的全国性BE筛查研究的一部分收集的唾液(Subaim 1b)。在目标2中，我们将 评估口腔微生物组特征是否可以识别BE和早期肿瘤的患者。在《目标3》中，我们将 对250名患有和不患有BE的患者进行前瞻性队列研究，并收集系列唾液样本以 确定口腔微生物组的重复采样是否能提高BE患者的识别能力。我们会 同时评估用于诊断BE的口腔微生物组特征的时间稳定性。我们提出了一部小说， 以生物为基础的非内窥镜方法，以改变预防EAC的范例。我们希望这将是 导致以实验室为基础的检测策略的发展，该策略为患者高度接受，成本效益高， 并且可以容易地转换到初级护理环境中。

PROJECT SUMMARY The incidence of esophageal adenocarcinoma (EAC) has risen 10-fold over the past half century and continues to have a dismal prognosis. Barrett’s esophagus (BE) is the precursor lesion to EAC, and patients diagnosed with BE undergo surveillance and endoscopic therapy for early neoplasia. However, more than 90% of EAC patients are never diagnosed with BE beforehand, and widespread upper endoscopy to identify patients with BE is expensive and of questionable value. Thus, there is an urgent need to develop minimally-invasive methods of BE screening that can be easily performed in the primary care setting to allow for efficient and cost-effective interventions to decrease EAC mortality. The esophageal microbiome is heavily influenced by migration of bacteria from the mouth via swallowed secretions. The esophageal microbiome is altered in gastroesophageal reflux and BE, and these changes may therefore reflect changes in the oral microbiome, an easily accessible sampling site. In fact, we have demonstrated that there are marked alterations to the oral microbiome in patients with BE, and a model based on specific taxa can distinguish BE patients with high sensitivity and specificity. We hypothesize that microbiome analysis of saliva can identify patients with BE with high accuracy, thus representing a novel, non-invasive screening test to identify patients at risk for EAC. In the current proposal we aim to validate our preliminary findings in a large endoscopic cohort. We propose to leverage a completed study of patients undergoing a first upper endoscopy with associated saliva samples, as well as patients with suspected early neoplasia (high grade dysplasia or early EAC). In Aim 1, we will determine whether the oral microbiome identifies patients with BE. We hypothesize that a microbiome score based on a model containing relative abundance of Lautropia, Streptococcus, and Enterobacteriaceae identifies patients with and without BE with high accuracy. In Subaim 1a, we will determine whether the oral microbiome in combination with a clinical prediction model (Michigan Barrett’s Esophagus pREdiction Tool; M-BERET) identifies patients with Barrett’s esophagus. As external validation of an oral microbiome signature, we will perform a case-control study using saliva collected as part of a nationwide, primary care-based BE screening study (Subaim 1b). In Aim 2, we will assess whether an oral microbiome signature can identify patients with BE and early neoplasia. In Aim 3, we will conduct a prospective cohort study of 250 patients with and without BE, and collect serial saliva samples to determine whether repeated sampling of the oral microbiome improves identification of patients with BE. We will also assess temporal stability of an oral microbiome signature for the diagnosis of BE. We propose a novel, biologically-based non-endoscopic approach to change the paradigm for EAC prevention. We hope that this will lead to development of a laboratory-based testing strategy that is highly acceptable to patients, is cost-effective, and can be easily translated to the primary care setting.