3D bioprinted human-scale intestine models for physiological and microbial insights through fluid-driven heterogeneity

The small intestine's intricate structure enables vital functions such as nutrient absorption, microbial defense, and barrier protection, yet replicating its complexity in vitro remains a substantial challenge. We engineered a three-dimensional bioprinted intestinal model featuring biomimetic circular folds and zonated shear stress distribution to recapitulate native physiology. A filament-resolved embedded bioprinting approach enabled high-fidelity fabrication of thin-walled, continuous structures that shaped physiologically relevant flow microenvironments essential for epithelial development. These shear stress patterns regulated tight junctions, secretory activity, and transporter expression, driving region-specific epithelial specialization into barrier or absorptive phenotypes. Coculture with probiotic <i>Lactobacillus plantarum</i> activated localized immune responses and modulated epithelial function through spatially distinct colonization. Regional flow differences governed the transport of nutrient and drug probes via transcellular and paracellular pathways. Quantitative assessment of drug absorption demonstrated strong in vitro-in vivo correlation, validating physiological relevance. By unifying structural, mechanical, and functional complexity, this platform advances intestinal models for studying physiology, host-microbe interactions, and drug transport.