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.