Cellular and Environmental Regulation of Protein Absorption and Utilization in the Early Intestine

新生儿肠道在管腔内消化蛋白质的能力较低，而是依赖肠细胞对摄入的蛋白质进行摄取和细胞内加工。这种营养机制在包括斑马鱼在内的脊椎动物中是保守的，它是由一群具有高内吞活性的富含溶酶体的特殊肠细胞（LREs）在中肠中执行的。最近的研究已经开始揭示控制LRE发育和功能的遗传因素。然而，由于缺乏特定的分子工具和哺乳动物模型的有限实验可及性，我们对LRE生理学及其受宿主-微生物相互作用调控的分子机制的理解受到阻碍。利用斑马鱼，我们最近发现了一种保守的分子机制，它介导LREs对蛋白质的有效受体依赖和液相摄取。此外，我们发现LRE功能是斑马鱼在营养限制期间生存所必需的，并且在没有微生物群的情况下饲养的斑马鱼表现出降低的LRE活性。利用斑马鱼和小鼠模型，我们提出的研究将验证LREs在早期脊椎动物肠道功能中起重要和保守作用的中心假设。具体来说，LREs介导：1-通过受体介导和液相内吞作用有效摄取膳食蛋白质；2-营养限制下蛋白质利用与动物生长存活；宿主-微生物相互作用控制营养吸收和细菌产物的跨细胞运输。对这些控制LRE功能的保守分子机制的进一步了解，将为改善肠道生理带来新的方法，以促进包括人类在内的脊椎动物的最佳营养、免疫耐受和正常肠道发育。

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.