SGLT‐1‐mediated glucose uptake protects intestinal epithelial cells against LPS‐induced apoptosis and barrier defects: a novel cellular rescue mechanism?

Abstract

Excessive apoptosis induced by enteric microbes leads to epithelial barrier defects. This mechanism has been implicated in the pathogenesis of inflammatory bowel diseases (IBD) and bacterial enteritis. The sodium-dependent glucose cotransporter (SGLT-1) is responsible for active glucose uptake in enterocytes. The aim was to investigate the effects of SGLT-1 glucose uptake on enterocyte apoptosis and barrier defects induced by bacterial lipopolysaccharide (LPS). SGLT-1-transfected Caco-2 cells were treated with LPS (50 mug/mL) in low (5 mM) or high (25 mM) glucose media. LPS in low glucose induced caspase-3 cleavage, DNA fragmentation, and increased paracellular permeability to dextran in epithelial cells. These phenomena were significantly attenuated in high glucose. LPS increased SGLT-1 activity in high, but not low glucose media. Addition of phloridzin, which competitively binds to SGLT-1, inhibited the cytoprotection mediated by high glucose. Western blot showed that LPS in high glucose increased the levels of anti-apoptotic Bcl-2 and Bcl-X(L,) and did not change proapoptotic Bax. Differential extraction of membranous vs. cytosolic cell components demonstrated that high glucose inhibits mitochondrial cytochrome c translocation to cytosol. Collectively, SGLT-1-mediated glucose uptake increases anti-apoptotic proteins, and protects enterocytes from LPS-induced apoptosis and barrier defects. The understanding of this novel glucose-mediated rescue mechanism may lead to therapeutic interventions for various enteric diseases.