Analyzing the impact of the microbiome on esophageal carcinogenesis

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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.