Regional organization of nutrient absorption across the small intestine.

The small-intestinal epithelium must simultaneously enable functions that are spatially compartmentalized along the length of the organ: nutrient absorption and protection against environmental insults. Although regional differences within the intestine have been recognized for centuries, only now has a comprehensive framework emerged to define this organization at molecular, cellular and functional levels. In this Review, we highlight the epigenetic and transcriptional features of small-intestinal zonation across longitudinal and apical-basal axes, and we examine the molecular mechanisms that establish regional gene expression profiles in epithelial cells during development and that maintain these distinctions into adulthood. We integrate these molecular insights with physiological data to present a refined model of the functional landscape of nutrient absorption. Finally, we discuss gastrointestinal diseases that target specific intestinal regions, underscoring the importance of understanding local tissue environments within this highly regionalized organ.