Dysregulated Intestinal Nutrient Absorption in Obesity Is Associated with Altered Chromatin Accessibility.

Area of Science:

• Gastroenterology
• Metabolic Diseases
• Epigenetics

Background:

• Obesity is a widespread epidemic with diverse health consequences.
• Individual obese phenotypes and their therapeutic responses are poorly understood.
• Epigenetic alterations in obesity are observed across multiple tissues, but intestinal epithelial features remain unclear.

Purpose of the Study:

• To investigate the transcriptional and epigenomic characteristics of intestinal organoids from non-obese, obese, and obese hyperabsorptive individuals.
• To identify molecular features associated with the obese hyperabsorption phenotype in the gut.

Main Methods:

• Human intestinal organoids were established from donors classified by BMI and glucose transport assays.
• Transcriptomic analysis (gene expression) and chromatin accessibility assays were performed.
• Transcription factor binding and quantitative RT-PCR were used to validate findings.

Main Results:

• Obese hyperabsorptive organoids exhibited upregulated nutrient absorption transcripts and downregulated type I interferon targets.
• Chromatin accessibility suggested enhanced HNF4G binding may drive the hyperabsorption phenotype.
• Expression of CUBN, GIP, SLC5A11, and SLC2A5 in intestinal epithelia strongly correlated with hyperabsorption.

Conclusions:

• The obese hyperabsorption phenotype is characterized by transcriptional shifts promoting increased intestinal nutrient uptake.
• Differential chromatin accessibility may underlie these transcriptional changes.
• Identifying distinct intestinal phenotypes in obesity offers novel therapeutic strategies.