The Oral Microbiome for the Detection of Barretts Esophagus

项目摘要 食管腺癌（EAC）的发病率在过去的半个世纪中上升了10倍，并且仍在继续 预后很差Barrett食管（BE）是EAC的前驱病变， 对BE患者进行早期肿瘤监测和内镜治疗。然而，超过90%的EAC 患者事先从未被诊断为BE，广泛的上消化道内窥镜检查可识别BE患者 昂贵且价值可疑。因此，迫切需要开发微创方法， BE筛查可以在初级保健环境中轻松进行，以实现高效和成本效益 降低EAC死亡率。食管微生物组受到以下物质迁移的严重影响： 通过吞咽的分泌物从口腔中排出细菌。胃食管中的食管微生物组发生改变 反流和BE，因此这些变化可能反映了口腔微生物组的变化， 取样地点事实上，我们已经证明，患者的口腔微生物组有明显的改变， 与BE，和基于特定分类的模型可以区分BE患者具有高灵敏度和特异性。我们 假设唾液微生物组分析可以高准确性地识别患有BE的患者，因此 代表了一种新的、非侵入性的筛查试验，以识别有EAC风险的患者。在目前的提案中，我们 旨在验证我们在一个大型内镜队列中的初步发现。我们建议利用已完成的研究 的患者进行第一次上消化道内窥镜检查与相关的唾液样本，以及患者疑似 早期瘤形成（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是否 识别BE患者。我们假设，基于包含相对生物量的模型的微生物组评分 劳氏菌、链球菌和肠杆菌科的丰度鉴定了患有和不患有BE的患者， 精度高。在Subaim 1a中，我们将确定口腔微生物组是否与临床 预测模型（Michigan Barrett食管预测工具; M-BERET）识别Barrett食管患者 食道作为口腔微生物组特征的外部验证，我们将使用以下方法进行病例对照研究： 作为全国范围内基于初级保健的BE筛查研究的一部分收集的唾液（Subaim 1b）。在目标2中，我们 评估口腔微生物组特征是否可以识别BE和早期肿瘤患者。在目标3中，我们 对250名有或没有BE的患者进行前瞻性队列研究，并收集系列唾液样本， 确定口腔微生物组的重复采样是否改善了BE患者的识别。我们将 还评估用于诊断BE的口腔微生物组特征的时间稳定性。我们要写一部小说， 基于生物学的非内窥镜方法，以改变EAC预防的范例。我们希望这将 导致开发基于实验室的测试策略，该策略对于患者来说是高度可接受的，是成本有效的， 并且可以很容易地转化为初级保健环境。

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.