Enteroendocrine cells couple nutrient sensing to nutrient absorption by regulating ion transport

Abstract

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.

Impaired Intestinal Sodium Transport in Inflammatory Bowel Disease: From the Passenger to the Driver's Seat

“…The development of gut-derived organoid culture systems has provided researchers with unapparelled opportunities to study functional aspects of biology of genes regulating sodium transport and disease pathophysiology. For example, the role of NHE3 in regulating the water/electrolyte homeostasis of the gut epithelium has been shown in mouse and human organoids [90,91]. Patientderived organoids and induced pluripotent stem cell models are resources for mechanistic studies and J o u r n a l P r e -p r o o f personalized medicine.…”

Functional human gastrointestinal organoids can be engineered from three primary germ layers derived separately from pluripotent stem cells

“…Moreover, human organoids are now being used to study human organ physiology. hPSC-derived human intestinal organoids have been used as a model of malabsorption in humans and led to discovery of a previously unknown mechanism by which enteroendocrine cells control nutrient absorption (McCauley et al, 2020).…”

Engineering functional human gastrointestinal organoid tissues using the three primary germ layers separately derived from pluripotent stem cells

“…Moreover, human organoids are now being used to study human organ physiology. For example, hPSC-derived human intestinal organoids were used as a model of malabsorption in humans and led to the discovery of a new mechanism by which enteroendocrine cells control nutrient absorption (McCauley et al ., 2020).…”