Within the gut, a complex landscape of physiological factors, cellular constituents, and molecular mechanisms coalesce to regulate systemic metabolic homeostasis. Nutrient uptake occurs in a dynamic luminal environment. Accordingly, the gut relies on the intestinal epithelium—a simple cellular monolayer with unique structural and compositional features—to serve as a multifaceted sensory, absorptive, secretory, and protective interface. Across the small intestine, these functions are distributed among a variety of distinct cell types that comprise millions of crypt-villus units, all continuously renewed by intricate signaling gradients and gene expression patterns that drive epithelial differentiation from the crypt-based intestinal stem niche. Perturbations to the intestinal epithelium, including those induced by dietary factors, can lead to the pathogenesis of metabolic disease, while treatment strategies have also leveraged the adaptability of the gut in a therapeutic manner. The mechanistic basis for how such alterations arise, however, remains unclear. To better understand intestinal epithelial contributions to metabolic health, this dissertation outlines two approaches using cutting-edge, genome-scale technology to investigate the gut at the cellular and molecular levels. First, I assembled the first single-cell transcriptomic survey of epithelial adaptations within the small intestine upon treatment of diet-induced metabolic disease by bariatric surgery. By dissecting the heterogeneity of the epithelium at single-cell resolution, I revealed alterations in gene expression within specific cell lineages throughout the crypt-villus axis. Notably, these molecular changes suggested that an obesogenic diet maladaptively alters nutrient absorption by villus enterocytes and metabolic activity within the crypt-based stem niche, whereas bariatric surgery rescues these effects. Next, I addressed an underexplored knowledge gap surrounding the post-transcriptional regulation of enteroendocrine cells (EECs), a therapeutically relevant secretory lineage. EECs are known to secrete various hormones that coordinate metabolic physiology; however, the mechanisms underlying their specification and function are ill-defined. By experimentally depleting, enriching, and purifying EEC populations across both murine and human models, I identified three conserved microRNAs as candidate post-transcriptional regulators of the enteroendocrine lineage: miR-7, miR-375, and miR-1224. Taken together, these efforts highlight an interdisciplinary lens through which we can view the precise molecular mechanisms that comprise gut function, aimed towards improving metabolic health.