Intestinal epigenomic alterations are associated with a dysregulated nutrient absorption phenotype in obesity [ATAC-Seq]

Obesity is an epidemic with myriad health effects, but little is understood regarding individual obese phenotypes and how they may respond to therapy. Epigenetic changes associated with obesity have been detected in blood, liver, pancreas, and adipose tissues. Previous work has found that dietary glucose hyperabsorption occurs in some obese subjects, but detailed transcriptional or epigenomic features of the intestine associated with this phenotype are unknown. This study evaluated differentially expressed genes and relative chromatin accessibility in intestinal organoids to characterize the obese hyperabsorptive phenotype. Methods: Intestinal organoids established from donors classified as lean, obese, or obese hyperabsorptive by body mass index and glucose transport assays were analyzed by RNA-seq, ATAC-seq, and transcription factor footprinting to characterize transcriptional and/or epigenomic features of each phenotype. Organoids from additional lean and obese hyperabsorptive donors were analyzed for specific transcripts by quantitative PCR to validate the predictive value of biomarkers associated with the hyperabsorptive phenotype. Results: Transcriptomic analysis indicated that obese hyperabsorptive subjects have significantly upregulated dietary nutrient absorption proteins and downregulated type I interferon targets. Chromatin accessibility and transcription factor footprinting suggested that enhanced binding of HNF4G promotes the obese hyperabsorption phenotype. Quantitative PCR assessment in a larger subject cohort suggested that intestinal epithelial expression of CUBN, GIP, and SLC2A5 have high correlation with hyperabsorption. Conclusions: The obese hyperabsorption phenotype is characterized by transcriptional changes that support increased nutrient uptake and appear to be driven by differentially accessible chromatin. These observations support obesogenic imprinting on intestinal stem cells (ISCs), the cell population from which organoid cultures are derived and sustained, such that absorptive, metabolic, and innate immune perturbations persist ex vivo in a controlled tissue culture environment. Recognizing that intestinal phenotypes in obesity may differ provides new perspective in considering therapeutic targets and options to manage the disease.