Sodium-Dependent Glucose Transporter-1 as a Novel Immunological Player in the Intestinal Mucosa

Abstract

In this study, we demonstrate the protective effect of the activation of sodium-dependent glucose transporter-1 (SGLT-1) on damages induced by TLR ligands, in intestinal epithelial cells and in a murine model of septic shock. In intestinal epithelial cell lines, glucose inhibited the IL-8/keratinocyte-derived chemokine production and the activation of the TLR-related transcription factor NF-κB stimulated by LPS or CpG-oligodeoxynucleotide. Oral ingestion of glucose was found to protect 100% of mice from lethal endotoxic shock induced by i.p. LPS administration; protection was only observed when glucose was administered orally, not by i.p. route, suggesting the important role of intestinal epithelial cells in this protection. In addition, we observed that the in vivo protection depends on an increase of anti-inflammatory cytokine IL-10. The cornerstone of the observed immunomodulatory and life-saving effects resides in activation of SGLT-1; in fact, the glucose analog 3-O-methyl-d-gluco-pyranose, which induces the transporter activity, but is not metabolized, exerted the same inhibitory effects as glucose both in vitro and in vivo. Thus, we propose that activated SGLT-1, apart from its classical metabolic function, may be a promising target for inhibition of bacteria-induced inflammatory processes and life-saving treatments, assuming a novel role as an immunological player.

Sodium glucose cotransporter 1 ligand BLF501 as a novel tool for management of gastrointestinal mucositis

“…This protective effect is independent of glucose metabolism, since BLF501 is a C-glycoside and, as such, does not enter the metabolic pathways of D-glucose [21]. The protective effect of the orally-administered SGLT-1 agonist 3-O-methyl-glucose (3-OMG), a non-metabolizable analog of D-glucose that does not enter glucose metabolic pathways, and of D-glucose has been previously reported in a model of LPS-induced injury to the intestinal mucosa [19]. It is noteworthy that the dose of BLF501 necessary to protect from DXR-induced injury was much lower than doses of D-glucose or 3-OMG shown to protect from LPS-induced injury (25 μg/kg vs 2.5 g/kg).…”

“…For example, expression of SGLT-1 was shown to be necessary to preserve the integrity of plasma membranes and tight junctions in tubular renal epithelial cells after exposure to cisplatin in vitro [16,18]. Moreover, we have shown in a mouse model of septic shock that oral administration of high doses of D-glucose or the non-metabolized glucose analog 3-0-methyl-D-glucopyransoide protected the intestinal epithelium from lipopolysaccharide-induced inflammatory injury [19,20]. Based on these data, we speculated that SGLT-1-mediated signaling might be beneficial in maintaining intestinal mucosal integrity from chemotherapy-induced damage.…”

SGLT1 Deficiency Turns Listeria Infection into a Lethal Disease in Mice

“…Unlike the facilitative glucose carriers of the GLUT family [10-12], the Na + -coupled glucose carriers can transport glucose against a chemical gradient and accomplish cellular glucose accumulation even at low extracellular glucose concentrations [9]. SGLT1 is expressed in intestinal epithelial cells and SGLT1 as well as SGLT2 in renal epithelial cells thus accomplishing the concentrative cellular uptake of glucose from the intestinal or renal tubular lumen across the apical cell membrane [9, 13]. The low luminal glucose concentrations provide some protection against luminal bacterial growth and genetic or pharmacological inhibition of the carriers may favor the development of urinary tract infection [14, 15] and diarrhea [16, 17].…”

Dansyl C‐Glucoside as a Novel Agent Against Endotoxic Shock

“…Methyl a-d-glucopyranoside was reduced with triethylsilane, affording 1-deoxy-d-glucose 9. Then selective tosylation of the primary hydroxy group, treatment of the tosylate 10 with NaN 3 , reduction of the obtained azide 11 with H 2 /Pd(OH) 2 , and finally treatment of the amine 12 with dansyl chloride, afforded compound 13.…”

“…[2] This protection is mediated by the activation of the sodium-dependent glucose transporter-1 (SGLT-1). A major drawback of this treatment is that a high concentration of glucose, which impacts metabolism, must be used.…”