Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, 45229, USA.
Center for Stem Cell and Organoid Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, 45229, USA.
Nat Commun. 2020 Sep 22;11(1):4791. doi: 10.1038/s41467-020-18536-z.
The ability to absorb ingested nutrients is an essential function of all metazoans and utilizes a wide array of nutrient transporters found on the absorptive enterocytes of the small intestine. A unique population of patients has previously been identified with severe congenital malabsorptive diarrhea upon ingestion of any enteral nutrition. The intestines of these patients are macroscopically normal, but lack enteroendocrine cells (EECs), suggesting an essential role for this rare population of nutrient-sensing cells in regulating macronutrient absorption. Here, we use human and mouse models of EEC deficiency to identify an unappreciated role for the EEC hormone peptide YY in regulating ion-coupled absorption of glucose and dipeptides. We find that peptide YY is required in the small intestine to maintain normal electrophysiology in the presence of vasoactive intestinal polypeptide, a potent stimulator of ion secretion classically produced by enteric neurons. Administration of peptide YY to EEC-deficient mice restores normal electrophysiology, improves glucose and peptide absorption, diminishes diarrhea and rescues postnatal survival. These data suggest that peptide YY is a key regulator of macronutrient absorption in the small intestine and may be a viable therapeutic option to treat patients with electrolyte imbalance and nutrient malabsorption.
吸收摄入营养的能力是所有后生动物的基本功能，利用了广泛存在于小肠吸收肠细胞上的营养转运蛋白。先前已经确定了一类独特的患者，他们在摄入任何肠内营养时都会出现严重的先天性吸收不良性腹泻。这些患者的肠道在宏观上是正常的，但缺乏肠内分泌细胞（EEC），这表明这种罕见的营养感应细胞群在调节宏量营养素吸收方面具有重要作用。在这里，我们使用 EEC 缺乏的人类和小鼠模型来确定 EEC 激素肽 YY 在调节离子偶联葡萄糖和二肽吸收中的未被认识的作用。我们发现，肽 YY 在存在血管活性肠肽的情况下在小肠中是必需的，血管活性肠肽是一种经典地由肠神经元产生的离子分泌的强刺激物。肽 YY 给药可恢复 EEC 缺乏小鼠的正常电生理学，改善葡萄糖和肽吸收，减少腹泻并挽救出生后生存。这些数据表明，肽 YY 是小肠中宏量营养素吸收的关键调节剂，可能是治疗电解质失衡和营养吸收不良患者的可行治疗选择。
