New therapeutic targets in ulcerative colitis: The importance of ion transporters in the human colon

Abstract

Background: The absorption of water and ions (especially Na+ and Cl−) is an important function of colonic epithelial cells in both physiological and pathophysiological conditions. Despite the comprehensive animal studies, there are only scarce available data on the ion transporter activities of the normal and inflamed human colon. Methods: In this study, 128 healthy controls and 69 patients suffering from ulcerative colitis (UC) were involved. We investigated the expressional and functional characteristics of the Na+/H+ exchangers (NHE) 1–3, the epithelial sodium channel (ENaC), and the SLC26A3 Cl−/HCO 3− exchanger downregulated in adenoma (DRA) in primary colonic crypts isolated from human biopsy and surgical samples using microfluorometry, patch clamp, and real‐time reverse‐transcription polymerase chain reaction (RT‐PCR) techniques. Results: Data collected from colonic crypts showed that the activities of electroneutral (via NHE3) and the electrogenic Na+ absorption (via ENaC) are in inverse ratio to each other in the proximal and distal colon. We found no significant differences in the activity of NHE2 in different segments of the colon. Surface cell Cl−/HCO 3− exchange is more active in the distal part of the colon. Importantly, both sodium and chloride absorptions are damaged in UC, whereas NHE1, which has been shown to promote immune response, is upregulated by 6‐fold. Conclusions: These results open up new therapeutic targets in UC. (Inflamm Bowel Dis 2011;)

Bile acids inhibit Na+/H+ exchanger and Cl−/HCO3 − exchanger activities via cellular energy breakdown and Ca2+ overload in human colonic crypts

“…The measurement of the ion transporter activites revealed that in the D group the activities of NHE1-3 isoforms were markedly lower, compared to the control group. This inhibitory pattern is clearly different from our previous observations in ulcerative colitis patients, where the activity of NHE1 was increased, whereas the activity of NHE3 was significantly decreased in colonic epithelial cell [9]. Moreover the activity of CBE was significantly diminished in patients in group D as well.…”

“…Mutation of this transporter results in congenital chloride-losing diarrhoea [19], moreover, similar conditions develop in SLC26A3-deficient mice [36]. The fact that impaired activities of these transporters were observed in diarrhoea-associated diseases, such as ulcerative colitis and secretory diarrhoea [8,28,50], further underlies the importance of the NHE3 and SLC26A3 in colonic electrolyte and water absorption.…”

High-fat diet modifies the PPAR-γ pathway leading to disruption of microbial and physiological ecosystem in murine small intestine

“…The intestine functions as a secretory and absorptive organ maintaining the homeostatic control of electrolytes and fluid balance that impact on mucosal defenses and the characteristics of the intestinal microbiota (16,17). Intestinal secretion mainly results from the active transport of Cl − and HCO 3 − (46).…”

“…Other elements of epithelial barrier capacity comprise tight junctions (9,10) and production/secretion of antimicrobial peptides (AMP) (11,12). The antibacterial lectin Reg3γ promotes the spatial segregation of microbiota and host in the intestine (13), the secretion and organization of the mucus layer that provides physico-chemical protection and a matrix for secreted antimicrobial molecules (14,15), and the control of electrolyte balance (16,17) contribute to this defense. The microbiota itself participates in strengthening mucosal defenses by stimulating epithelial renewal (18)(19)(20), production of AMP (21), cytoprotection against xenobiotics (22,23), immune maturation, increase of intestinal impermeability (24), and modulation of mucus quality and penetrability (25).…”

News from the End of the Gut-How the Highly Segmental Pattern of Colonic HCO3- Transport Relates to Absorptive Function and Mucosal Integrity

“…A recent study in ulcerative colitis patients reported reduced Cl Ϫ /HCO 3 Ϫ exchange activity in surface colonocytes and a decrease in DRA expression in inflamed biopsies taken from distal colonic segments. 138) These findings provide the molecular explanation for early data demonstrating reduced HCO 3 Ϫ secretion rates in subjects with ulcerative colitis. 134) Both in UC patient biopsies as well as the mouse colon, NHE3 expression was preserved, which is in agreement with another study of unaltered NHE3 expression, but changes in its regulation with respect to PDZ adapter proteins in UC patient biopsies.…”