TAS2R46 activation protects intestinal barrier from chronic high glucose

Bitter Taste Receptor member 46 (TAS2R46) has a high gene abundance in enteric epithelial cells; however, the biological functions of TAS2R46 are unclear. Intestinal barrier damage caused by diabetes is widely known, but the molecular mechanism remains to be elucidated. So, our study aimed to verify that TAS2R46 signaling exerts a vital role in improving intestinal barrier injury derived from diabetes, and clarified the underlying molecular mechanisms. In the present study, we found that the TAS2R46 agonist quinine ameliorated intestinal barrier dysfunction, as evidenced by increases in the protein expression of Zonula occluden 1, occludin, and E-cadherin, as well as reduction of glycogen deposition and morphological improvement of enteric cells using PAS and H&E staining, respectively, in the colon of diabetic mice. Meanwhile, quinine activated TAS2R46 signaling, as revealed by elevations in protein expression of TAS2R46 and its key downstream element Phospholipase C β2 in colon. Furthermore, the TAS2R46 agonist strychnine and hydrocortisone attenuated enteric epithelial barrier injury, activated TAS2R46 signaling, and suppressed pro-inflammatory NF-κB signaling in the high glucose-cultured Caco-2 cells, a human enteric epithelium cell line, whereas the effects were abolished after TAS2R46 blockage or knockdown. Further, results from RNA Sequencing showed that up-regulation of serine/threonine protein kinase SGK3 and transport protein SNX16 might mediate the effects of TAS2R46 activation. In summary, activation of TAS2R46 signaling contributed to alleviation of intestinal barrier injury in diabetes, which was accomplished by activation of SGK3/NF-κB pathway and enhancement of SNX16/E-cadherin axis in the gut.

Bitter taste receptor TAS2R46; High glucose; Inflammation; Intestinal barrier damage; SGK3; SNX16.