The neonatal intestine has a low capacity for digesting proteins in the lumen, and instead relies on the enterocytes for uptake and intracellular processing of ingested proteins. This nutritional mechanism is conserved among vertebrates including zebrafish, and is performed by a population of specialized lysosome-rich enterocytes (LREs) in the mid-intestine that exhibit high endocytic activity. Recent studies have begun to uncover genetic factors controlling LRE development and function. However, our understanding of the molecular mechanisms underlying LRE physiology and its regulation by host-microbe interactions has been hindered by the lack of specific molecular tools and the limited experimental accessibility of mammalian models. Using zebrafish, we recently uncovered a conserved molecular machinery that mediates efficient receptor-dependent and fluid phase uptake of proteins by LREs. Moreover, we found that LRE function is required for survival during nutrient restriction in zebrafish, and that zebrafish reared in the absence of microbiota display reduced LRE activity. Using zebrafish and mouse models, our proposed studies will test the central hypothesis that that LREs play essential and conserved roles in early vertebrate intestinal function. Specifically, that LREs mediate: 1- efficient uptake of dietary protein via receptor mediated and fluid phase endocytosis; 2- protein utilization and animal growth and survival under nutritional restriction; 3- host-microbe interactions controlling nutrient uptake and transcellular transport of bacterial products. Improved understanding of these conserved molecular mechanisms governing LRE function will lead to new approaches for modifying intestinal physiology to promote optimal nutrition, immune tolerance, and normal intestinal development in vertebrates including humans.