Inducible intestinal epithelial cell‐specific NHE3 knockout causes diarrhea and more alkaline luminal content

Abstract

The Na+/H+ exchanger isoform 3 (NHE3) has an important role in intestinal and renal Na+ uptake, acid‐base regulation, and composition of the gut microbiota. Reduced intestinal NHE3 activity and/or expression were found in congenital Na+ diarrhea and inflammatory bowel disease. Previously, no viable intestinal epithelial cell‐specific NHE3 knockout model has been generated; whole body NHE3 knockout mice show 70% mortality and non‐inducible intestinal epithelial cell‐specific NHE3 knockout mice show 100% postnatal mortality. Therefore, we generated a tamoxifen‐inducible intestinal epithelial‐specific NHE3 knockout mouse (NHE3IEC‐Ko; see abstract #1519). Two weeks after tamoxifen administration, NHE3IEC‐Ko mice show ~2‐fold increase in intestinal permeability, 4 hours after oral gavage of FITC‐Dextran, compared to control mice (P<0.05). The small intestine, cecum, and colon were markedly dilated in NHE3IEC‐Ko versus control mice, which was associated with a more than 2‐fold increase in total intestinal wet weight (4.9±0.5 vs 2.2±0.1 g, P<0.05, n=4 and 8, respectively) and ~1.5‐fold increase in fecal water content (55±2 vs 81±4 %, P<0.05). Small intestinal and colonic flush pH were 0.5 pH and 0.8 pH units more alkaline, respectively, in NHE3IEC‐Ko compared to control mice (both P<0.05). Small intestinal length was not different between genotypes (36±3 vs 39±1 cm, NS), but colon length was increased in NHE3IEC‐Ko compared to control mice (8.8±0.3 vs 7.1±0.2 cm, P<0.05). Although there was not an increase in intestinal length, the proximal small intestine of NHE3IEC‐Ko mice had longer villi (493±4 vs 392±19 μm, P<0.05) but similar crypt depths compared to control mice (89±4 vs 79±3 μm, NS). No differences in villus length (159±11 vs 139±7 μm, NS) or crypt depth (58±2 vs 58±2 μm, NS) were observed in the distal small intestine between genotypes. In conclusion, this novel intestinal epithelial cell‐specific NHE3 knockout model is a useful tool for studying inflammatory bowel disease, and the role of intestinal pH on the microbiome as well as intestinal proliferation and apoptosis.Support or Funding InformationNIH 1R01DK110621, APS STRIDE Undergraduate Summer Research Fellowship 1R25HL115473‐01.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.