Mutual regulation between butyrate and hypoxia-inducible factor-1α in epithelial cell promotes expression of tight junction proteins

Inflammatory bowel disease is a kind of multi-aetiological chronic disease that is driven by multidimensional factors. Hypoxia-inducible factor-1 alpha (HIF-1 alpha) plays an important role in anti-inflammatory and cellular responses to hypoxia. Previous studies have found that B or T-cell-specific HIF-1 alpha knock out mice exhibit severe colonic inflammation. However, we know very little about other functions of HIF-1 alpha in intestinal epithelial cells (IECs). In our study, HIF-1 alpha(Delta IEC) mice were used to study the function of HIF-1 alpha in IECs. HIF-1 alpha was knocked down in Caco-2 cells by transfection with a small interfering (si) RNA. Immunohistochemical staining and western blotting were used to detect the expression of zonula occluden-1 (ZO-1) and Occludin. The content of colon was harvested for high-performance liquid chromatography analysis to examine the levels of butyrate in the gut. Our research found that HIF-1 alpha played a protective role in dextran sulphate sodium-induced colitis, which was partly due to its regulation of tight junction (TJ) protein expression. Further study revealed that HIF-1 alpha mediated TJ proteins levels by moderating the content of butyrate. Moreover, we found that butyrate regulated TJ protein expression, which is dependent on HIF-1 alpha. These results indicated that there is a mutual regulatory mechanism between butyrate and HIF-1 alpha, which has an important role in the maintenance of barrier function of the gastrointestinal tract.