Analyzing the impact of the microbiome on esophageal carcinogenesis

分析微生物组对食管癌发生的影响

• 批准号: 461355398
• 负责人: Professor Dr. Michael Quante
• 金额: --
• 依托单位: Klinik für Innere Medizin II - Gastroenterologie, Hepatologie, Endokrinologie und Infektiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/461355398?language=en
• 关键词: Analyzing; impact; microbiome; esophageal; carcinogenesis

Over the last half century the incidence rate of esophageal adenocarcinoma (EAC) has risen almost 10-fold, still the reason is not well understood. Numerous theories have been proposed to account for the increase in EAC, including diet and obesity. Additionally, in Barrett’s esophagus (BE) patients significant changes in the esophageal microbiome have been found. Moreover, unhealthy or high fat diets are likely associated with different colonization of the gut microbiome. Taken together, these observations suggest the hypothesis that changes in the gastrointestinal microbiome triggered by environmental factors could play a critical role in the pathogenesis of EAC. We developed a mouse model of BE/EAC (L2-IL-1b mice) through overexpression of the proinflammatory cytokine IL-1b in the squamous esophagus, which led to chronic esophagitis, metaplasia, dysplasia and cancer. In our established L2-IL-1b mouse model of BE, we recently described microbiome alterations that occur with progression from BE to EAC. Moreover, we have a clinical registry of more than 650 BE patients (BarrettNET) in clinical follow up for progression to EAC. We observed similar differences in the microbiomes from patients with BE that progressed to EAC vs patients with BE that did not develop cancer. However, the species and clones involved in promotion of EAC and their associated mechanisms of action are unknown.The Microbiome may summarize several changes occurring on the organism and promoting cancer, representing thus a comprehensive factor as potential biomarker or even therapeutic target. If microbes have a causative role in BE progression, they would represent an easily modifiable, and non-toxic avenue toward improved cancer prevention. Here we aim analyze if microbes drive progression from BE to EAC, in part through influencing a distinct inflammatory microenvironment and driving expansion of genetically altered clones in BE that predispose the tissue to further somatic evolution and progression. In two aims we will approach this question in the mouse model and in human tissue as well as human BE organoids and will test for an association between the microbiome composition of the BE epithelium and neoplastic progression.

在过去的半个世纪中，食管腺癌（EAC）的发病率几乎上升了10倍，但其原因尚不清楚。已经提出了许多理论来解释EAC的增加，包括饮食和肥胖。此外，在巴雷特食管（BE）患者中，已经发现食管微生物组的显著变化。此外，不健康或高脂肪饮食可能与肠道微生物组的不同定植有关。总之，这些观察结果表明，由环境因素引发的胃肠道微生物组的变化可能在EAC的发病机制中发挥关键作用。我们通过在鳞状食管中过度表达促炎细胞因子IL-1b，从而导致慢性食管炎、化生、异型增生和癌症，开发了BE/EAC小鼠模型（L2-IL-1b小鼠）。在我们建立的L2-IL-1b BE小鼠模型中，我们最近描述了从BE进展到EAC时发生的微生物组改变。此外，我们对超过650例BE患者（BarrettNET）进行了临床登记，以进行进展为EAC的临床随访。我们观察到进展为EAC的BE患者与未发生癌症的BE患者的微生物组存在类似差异。然而，参与EAC促进的物种和克隆及其相关的作用机制尚不清楚。微生物组可能总结了生物体上发生的促进癌症的几种变化，因此代表了作为潜在生物标志物甚至治疗靶点的综合因素。如果微生物在BE进展中起着致病作用，那么它们将代表一种易于改变的无毒途径，以改善癌症预防。在这里，我们的目的是分析微生物是否驱动从BE到EAC的进展，部分是通过影响独特的炎症微环境和驱动BE中基因改变的克隆的扩增，这些克隆使组织倾向于进一步的体细胞进化和进展。在两个目标中，我们将在小鼠模型和人类组织以及人类BE类器官中探讨这个问题，并将测试BE上皮的微生物组组成与肿瘤进展之间的关联。