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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE306982 | GEO | 2025/09/30

REPOSITORIES: GEO

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Project description: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.

Project description:Background Understanding how obesity impacts human mammary adipose tissue (MAT) biology is crucial for deciphering its role in mammary epithelium during both physiological and pathophysiological processes, including breast cancer. Hypertrophic mammary adipocytes and Crown-like Structures are present in MAT of obese patients but whether these changes initiate a fibro-inflammatory response at the tissue level remains insufficiently explored. Objective We aimed to investigate the markers of adipose tissue dysfunction (immune cell infiltration, secretion pattern and fibrosis) in tumor-free MAT of obese versus lean patients Methods Tumor-free MAT were obtained from 61 lean and obese women who underwent mastectomy for breast cancer risk reduction or treatment. Immune and non-immune cell infiltration was determined using flow cytometry. Bulk transcriptomic was used to characterize the phenotype of CD206+ macrophages whose infiltration is increased in obese. Conditioned-medium were prepared from MAT to characterize their secretome and dose adipokines and cytokines by ELISA assay. The extra-cellular matrix (ECM) deposition was evaluated by Masson trichrome staining on cross-stained sections and 3D imaging of red picrosirius-stained tissues. Results We observed an increase in CD206+/HLA-DR+ macrophages in the stromal vascular fraction of MAT from obese patients compared to lean ones. Other immune cell infiltration and endothelial or adipose progenitor cell numbers were similar between groups. Bulk transcriptomics on CD206+ macrophages revealed a significant decrease in ECM component secretion and processing in obese samples. Additionally, no heightened secretion of pro-inflammatory cytokines or MCP-1 was noted in obese samples. ECM characterization indicated an absence of fibrosis, with obese MAT showing reduced collagen secretion and deposition compared to lean counterparts. Conclusions Obesity does not associate with inflammation or fibrosis in MAT, underscoring its unique behavior.

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

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