Foregut microbiome in development of esophageal adenocarcinoma

项目摘要 食管腺癌（EA），与胃食管反流引起的胃灼热有关的癌症类型 在过去的30年里，胃食管反流病（GERD）的发病率增加了6倍，这是不能用通常的胃食管反流病来解释的。 环境或宿主因素。EA是一系列GERD相关疾病的最终结果， 反流性食管炎（RE）和Barrett食管（BE）。我们对老年男性退伍军人的初步研究发现， 食道中的两种微生物携带II型微生物群的患者有>15倍的可能性患有 食管炎和BE比那些携带I型微生物群。在一项小规模的研究中，我们还发现， 3例EA携带II型生物群。这一发现为理解 最近EA发病率激增。我们的长期目标是找出GERD序列的原因。的 待检验的假设是前肠微生物组的变化与EA及其前体相关， GERD序列中的RE和BE。我们将研究在老年男性受试者中的发现是否也适用于 年轻人和女性受试者。我们将进行病例对照研究来证明微生物组- GERD序列每个阶段的疾病关联，并分析 微生物群沿着疾病进展向EA，通过两个特定的目的。目标1是进行全面的 前肠微生物组的群体调查，并证明其与GERD序列的关联。 此外，食管微生物群与上游（口）和下游之间的空间关系 （胃）前肠微生物群以及微生物群-疾病关联的时间稳定性也将被评估。 考察目的2是确定远端食管宏基因组并证明其与GERD的相关性 顺序详细分析将包括路径-疾病和基因-疾病关联。真菌属 而病毒如果被发现的话，也会和疾病有关联。前肠和前肠之间的重要联系 微生物组和GERD序列，如果得到证实，将是最终测试是否有一个 异常的微生物组是向EA发展的表型变化序列所必需的。如果EA 及其前体代表一种微生态疾病，治疗GERD的病因可能成为可能， 例如通过使用抗生素、益生菌或益生元使微生物群正常化。致病 GERD的治疗可以防止其进展，并扭转目前EA发病率增加的趋势。

Project Summary Esophageal adenocarcinoma (EA), the type of cancer linked to heartburn due to gastroesophageal reflux diseases (GERD), has increased six fold in the past 30 years, which can not be explained by the usual environmental or host factors. EA is the end result of a sequence of GERD-related diseases, preceded by reflux esophagitis (RE) and Barrett's esophagus (BE). Our preliminary study in elderly male veterans found two types of microbiotas in the esophagus. Patients who carry the type II microbiota are >15 fold likely to have esophagitis and BE than those harboring the type I microbiota. In a small scale study, we also found that 3 of 3 cases of EA harbored the type II biota. The findings have opened a new approach to understanding the recent surge in the incidence of EA. Our long-term goal is to identify the cause of GERD sequence. The hypothesis to be tested is that changes in the foregut microbiome are associated with EA and its precursors, RE and BE in GERD sequence. We will examine whether the finding in elderly male subjects also applies to younger as well as female subjects. We will conduct a case control study to demonstrate the microbiome- disease association in every stage of GERD sequence as well as analyze the trend in changes in the microbiome along disease progression toward EA, by two specific aims. Aim 1 is to conduct a comprehensive population survey of the foregut microbiome and demonstrate its association with GERD sequence. Furthermore, spatial relationship between the esophageal microbiota and upstream (mouth) and downstream (stomach) foregut microbiotas as well as temporal stability of the microbiome-disease association will also be examined. Aim 2 is to define the distal esophageal metagenome and demonstrate its association with GERD sequence. Detailed analyses will include pathway-disease and gene-disease associations. Archaea, fungi and viruses, if identified, also will be correlated with the diseases. A significant association between the foregut microbiome and GERD sequence, if demonstrated, will be the first step for eventually testing whether an abnormal microbiome is required for the development of the sequence of phenotypic changes toward EA. If EA and its precursors represent a microecological disease, treating the cause of GERD might become possible, for example, by normalizing the microbiota through use of antibiotics, probiotics, or prebiotics. Causative therapy of GERD could prevent its progression and reverse the current trend of increasing incidence of EA.