Osmotic diarrhea and abdominal pain in humans are oftentimes associated with carbohydrate malabsorption in the small intestine due to loss of function of microvillar disaccharidases. Disaccharidases are crucial for the digestion and the subsequent absorption of carbohydrates. This review focuses on sucrase-isomaltase as the most abundant intestinal disaccharidase and the primary or induced pathological conditions that affect its physiological function. Congenital defects are primary factors which directly influence the transport and function of sucrase-isomaltase in a healthy epithelium. Based on the mutation type and the pattern of inheritance, a mutation in the sucrase-isomaltase gene may exert a variety of symptoms ranging from mild to severe. However, structure and function of wild type sucrase-isomaltase can be also affected by secondary factors which influence its structure and function either specifically via certain inhibitors and therapeutic agents or generally as a part of intestinal pathogenesis, for example in the inflammatory responses. Diagnosis of sucrase-isomaltase deficiency and discriminating it from other gastrointestinal intolerances can be latent in the patients because of common symptoms observed in all of these cases.Here, we summarize the disorders that implicate the digestive function of sucrase-isomaltase as well as the diagnostic and therapeutic strategies utilized to restore normal intestinal function.

This novel concept and the existence of mild consequences in a number of SI mutants strongly propose that CSID is an underdiagnosed and a more common intestinal disease than currently known.

Lactase-phlorizin hydrolase (LPH) is a membrane glycoprotein and the only β-galactosidase of the brush border membrane of the intestinal epithelium. Besides active transcription, expression of the active LPH requires different maturation steps of the polypeptide through the secretory pathway, including N- and O-glycosylation, dimerization and proteolytic cleavage steps. The inability to digest lactose due to insufficient lactase activity results in gastrointestinal symptoms known as lactose intolerance. In this review, we will concentrate on the structural and functional features of LPH protein and summarize the cellular and molecular mechanism required for its maturation and trafficking. Then, different types of lactose intolerance are discussed, and the molecular aspects of lactase persistence/non-persistence phenotypes are investigated. Finally, we will review the literature focusing on the lactase persistence/non-persistence populations as a comparative model in order to determine the protective or adverse effects of milk and dairy foods on the incidence of colorectal, ovarian and prostate cancers.

Miglustat is an oral medication that has approved indication for type I Gaucher disease and Niemann pick disease type C. Usually treatment with Miglustat is associated with occurrence of gastrointestinal side effects similar to carbohydrate maldigestion symptoms. Here, we studied the direct influence of Miglustat on the enzymatic function of the major disaccharidases of the intestinal epithelium. Our findings show that an immediate effect of Miglustat is its interference with carbohydrate digestion in the intestinal lumen via reversible inhibition of disaccharidases that cleave α-glycosidically linked carbohydrates. Higher non physiological concentrations of Miglustat can partly affect lactase activity. We further show that the inhibition of the disaccharidases function by Miglustat is mainly competitive and does not occur via alteration of the enzyme folding.

Intestinal NaCl, HCO3- and fluid absorption are strongly dependent on apical Na+/H+ exchange. The intestine expresses three presumably apical NHE isoforms, NHE2, NHE3 and NHE8. We addressed the role of NHE8 (SLC9A8) and its interplay with NHE2 (SLC9A2) in luminal proton extrusion during acute and chronic enterocyte acidosis, and studied the differential effects of NHE8 and NHE2 on enterocyte proliferation. In contrast to NHE3, which was upregulated in differentiated vs. undifferentiated colonoids, the expression of NHE2 and NHE8 remained constant during differentiation of colonoids and Caco2Bbe cells. Heterogeneously expressed Flag-tagged rat (r)Nhe8 and human (h)NHE8 translocated to the apical membrane of Caco2Bbe cells. rNhe8 and hNHE8, when expressed in NHE-deficient PS120 fibroblasts showed higher sensitivity to HOE642 compared to NHE2. Lentiviral shRNA knockdown of endogenous NHE2 in Caco2Bbe cells (C2Bbe/shNHE2) resulted in a decreased steady-state pHi, an increased NHE8 mRNA expression, and augmented NHE8-mediated apical NHE activity. Lentiviral shRNA knockdown of endogenous NHE8 in Caco2Bbe cells (C2Bbe/shNHE8) resulted in a decreased steady-state pHi as well, accompanied by decreased NHE2 mRNA expression and activity, which together contributed to reduced apical NHE activity in the NHE8-knockdown cells. Chronic acidosis increased NHE8 but not NHE2 mRNA expression. Alterations in NHE2 and NHE8 expression/activity affected proliferation, with C2Bbe/shNHE2 cells having lower and C2Bbe/shNHE8 having higher proliferative capacity, accompanied by amplified ERK1/2 signaling pathway and increased EGFR expression in the latter cell line. Thus, both Na+/H+ exchangers have distinct functions during cellular homeostasis by triggering different signaling pathways to regulate cellular proliferation and pHi-control.