Fig. 2: PYY restores normal glucose absorption in EEC-deficient human and mouse small intestine.

a Schematic depicting how the PYY-VIP paracrine axis might regulate ion, water, and nutrient transport in the small intestine. b In the absence of EECs, ion, water, and nutrient transport are dysregulated due to loss of one arm of the PYY-VIP axis. In EEC-deficient small intestine, loss of PYY results in increased chloride transport and increased water and sodium accumulation in the intestinal lumen. Reduced NHE3 transport activity would cause accumulation of cytosolic H⁺ and a decrease in pH. Subsequently, nutrient absorption would be dysregulated, with diminished di-/tri-peptide absorption due to increased intracellular proton accumulation and increased uptake of glucose due to an exaggerated Na⁺ gradient across the apical membrane. c Na⁺-coupled glucose transport is deranged in EEC-deficient human and mouse small intestine. Wild-type and EEC-deficient human and mouse intestinal tissues were treated with VIP prior to 25 mM D-glucose. EEC-deficient intestine had an elevated initial response to glucose (mouse, n = 28 wild-type, n = 9 mutant, **P = 0.001; HIO, n = 6 wild-type, n = 4 mutant, **P = 0.002) that was returned to wild-type levels by pre-treatment with 10 nM exogenous PYY (mouse, n = 7, *P = 0.04; HIO, n = 3). Inhibition of NPY1R in wild-type tissues using BIBO3304 caused an abnormal initial response to glucose that mimicked EEC-deficient tissues (mouse, n = 12, **P = 0.005; HIO, n = 6). Bar graphs represent the slope of the curve depicted within the boxed area. Statistics calculated by one-way ANOVA with Tukey’s multiple comparisons test. d The subcellular distribution of glucose transporters SGLT1 and GLUT2 is normal in human intestinal tissue lacking EECs. Representative images from eight independent organoids are shown. Scale bars = 50 μm. All error bars are + SEM.