Foregut microbiome in development of esophageal adenocarcinoma

项目摘要 食管腺癌(EA)，一种与胃食道反流引起的胃灼热有关的癌症 疾病(GERD)，在过去的30年里增加了6倍，这不能用通常的 环境或宿主因素。EA是一系列GERD相关疾病的最终结果，在此之前 反流性食管炎(RE)和Barrett‘s食道(BE)。我们对老年男性退伍军人的初步研究发现 食道中有两种类型的微生物。携带II型微生物区系的患者患此病的可能性是15倍。 食管炎和BE比那些携带I型微生物群的人要好。在一项小规模的研究中，我们还发现， 3例EA中含有II型生物群。这些发现开辟了一种新的方法来理解 最近，EA的发病率激增。我们的长期目标是确定GERD序列的原因。这个 有待检验的假设是，前肠微生物组的变化与EA及其前体有关， Re和Be在GERD序列中。我们将研究在老年男性受试者中的发现是否也适用于 既有年轻的也有女性的受试者。我们将进行一项病例对照研究，以证明微生物群- GERD序列各阶段的疾病关联以及分析GERD序列的变化趋势 微生物组沿着疾病向EA发展，有两个特定的目标。目标1是进行全面的 前肠微生物组的种群调查及其与GERD序列的关联。 此外，食道微生物区系与上游(口)和下游的空间关系 (胃)前肠微生物以及微生物组-疾病关联的时间稳定性也将是 检查过了。目标2是定义远端食道后基因组并证明其与GERD的关系 序列。详细的分析将包括途径-疾病和基因-疾病关联。古生菌、真菌 而病毒，如果被发现，也将与这些疾病相关。前景与未来之间的重大关联 微生物组和GERD序列，如果得到证实，将是最终测试 异常的微生物群是向EA的表型变化序列的发展所必需的。如果是EA 它的前体代表了一种微生态疾病，治疗GERD的原因可能成为可能， 例如，通过使用抗生素、益生菌或益生菌使微生物区系正常化。使役 GERD的治疗可以阻止其进展，扭转目前EA发病率上升的趋势。

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.