Adaptation of region-specific gene expression in the small intestine in response to acute and chronic dietary perturbations - phenomenological association and mechanistic insights

The mammalian small intestine plays a central role in systemic physiology by mediating nutrient absorption, coordinating neuroendocrine signaling, maintaining commensal microbiota and supporting metabolic homeostasis. Despite these critical functions, the upstream molecular mechanisms that enable the small intestine to dynamically adapt to dietary inputs remain poorly understood. Using multiple paradigms and multi-omic approaches, we have demonstrated basal transcriptional differences across the duodenum, jejunum and ileum, and further investigated how this region-specific gene expression is altered in response to acute and chronic dietary perturbations.
Comparison between peak fed and starved states, and time-restricted feeding in mice revealed the ability of duodenum, jejunum and ileum to exhibit dynamic reversal of gene expression and metabolic sensing between feeding and fasting states. The magnitude and nature of feed-fast driven changes varied substantially along the intestinal axis, indicating an integrated influence of anatomical position and feeding–fasting cues. Reversing the time of feeding led to region-specific dampening or inversion of the rhythmicity of gene expression and metabolic sensing, further underscoring the importance of time of feeding/fasting and anatomical position in shaping intestinal gene expression. A chronic dietary perturbation of 10% sucrose in water for 3 months in mice also demonstrated the region-specificity of gene-expression perturbation in response to the same dietary input. This intervention induced extensive molecular rewiring in the duodenum and jejunum, characterized by upregulation of carbohydrate transport machinery alongside downregulation of transporter genes for lipids, amino acids and peptides, and dysregulation of metabolic sensing. In contrast, the ileum was largely resistant to these changes.
Studies including ours have shown how perturbation of intestinal gene expression and metabolic sensing is sufficient to drive physiological deficits such as hyperglycemia, insulin resistance, etc. We propose investigating region-specific interplay between metabolic sensing and gene expression in the small intestine to elucidate its physiological plasticity and design dietary interventions against metabolic disorders.