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High fat diet accelerates Barrett esophageal carcinogenesis by inducing a distinct IL-8 dependent immune reaction through alteration of the microbiome

ABSTRACT: Barrett Esophagus (BE) is a risk factor for the development of esophageal adenocarcinoma (EAC). As endemic obesity emerges as a risk factor for increasing numbers of EAC we utilized our IL-1b mouse model of BE to understand the impact of a high fat diet (HFD) on disease progression. Indeed, increased dysplasia development in HFD treated IL-1b mice correlated with an accelerated cytokine response with specific upregulation of IL-8 in esophageal tissue, which could be confirmed by specific overexpression of IL-8 in the BE mouse model. Consequently we observed an influx of immature myeloid cells and neutrophils resulting in a decrease of regulatory NK T cells. HFD led to a specific shift in the gut microbiome, similar to that in human BE patients, being responsible for a specific inflammatory phenotype with elevated IL-1b and IL-8 which could be eliminated under germ free conditions and lead to an increased influx of cardia (Lgr5) stem cells into the esophagus giving rise to dysplasia.

ORGANISM(S): Mus musculus

PROVIDER: GSE103616 | GEO | 2019/04/30

REPOSITORIES: GEO

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Project description:Esophageal adenocarcinoma (EAC) has become a major concern in Western countries due to rapid rises in incidence coupled with very poor survival rates. One of the key risk factors for the development of this cancer is the presence of Barrett’s esophagus (BE), which is believed to form in response to repeated gastro-esophageal reflux. In this study we performed comparative, genome-wide expression profiling (using Illumina whole-genome Beadarray) on total RNA extracted from esophageal biopsy tissues from individuals with EAC, BE (in the absence of EAC) and those with normal squamous epithelium. We combined these data with publically accessible raw data from three similar studies to investigate key gene and ontology differences between these three tissue states. The results support the deduction that BE is a tissue with enhanced glycoprotein synthesis machinery (DPP4, ATP2A3, AGR2) designed to provide strong mucosal defenses aimed at resisting gastro-esophageal reflux. EAC exhibits the enhanced extracellular matrix remodeling (collagens, IGFBP7, PLAU) effects expected in an aggressive form of cancer, as well as evidence of reduced expression of genes associated with mucosal (MUC6, CA2, TFF1) and xenobiotic (AKR1C2, AKR1B10) defenses. When our results are compared to previous whole-genome expression profiling studies keratin, mucin, annexin and trefoil factor gene families are the most frequently represented gene families. Eleven genes identified here are also represented in at least 3 other profiling studies. We used these genes to discriminate squamous, BE and EAC within the two largest cohorts using a support vector machine leave one out cross validation analysis. While this method was satisfactory for discriminating squamous and BE, it demonstrates the need for more detailed investigations into profiling changes within BE leading to the progression towards EAC. A comparison of three esophageal biopsy groups from separate individuals: normal squamous (n=9), Barrett's esophagus without dysplasia (n=22) & adenocarcinoma (n=23). Adenocarcinoma samples overlap with members of DNA copy number analysis GEO series GSE10506 such that, in each case genomic DNA and total RNA were extracted from the same biopsy. The matching copy number data GEO samples IDs are noted in characteristics: Matching CN Sample ID

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High fat diet accelerates Barrett esophageal carcinogenesis by inducing a distinct IL-8 dependent immune reaction through alteration of the microbiome

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