Compromised NHE8 Expression Is Responsible for Vitamin D-Deficiency Induced Intestinal Barrier Dysfunction

• Published in: Nutrients Vol. 15; no. 22; p. 4834
• Main Authors: Guo, Yaoyu, Li, Yanni, Tang, Zeya, Geng, Chong, Xie, Xiaoxi, Song, Shuailing, Wang, Chunhui, Li, Xiao
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01-11-2023
• Subjects: Disease susceptibility; Ethylenediaminetetraacetic acid; Experiments; Feeds; Inflammatory bowel disease; intestinal barrier function; Laboratory animals; Na+/H+ exchanger isoform 8; Paricalcitol; Phosphorus; Physiology; Proteins; Ulcerative colitis; Vitamin D; vitamin D receptor; Canada; China; Beijing China; United States > US
• ISSN: 2072-6643; 2072-6643
• DOI: 10.3390/nu15224834

Objectives: Vitamin D (VitD) and Vitamin D receptor (VDR) are suggested to play protective roles in the intestinal barrier in ulcerative colitis (UC). However, the underlying mechanisms remain elusive. Evidence demonstrates that Na+/H+ exchanger isoform 8 (NHE8, SLC9A8) is essential in maintaining intestinal homeostasis, regarded as a promising target for UC therapy. Thus, this study aims to investigate the effects of VitD/VDR on NHE8 in intestinal protection. Methods: VitD-deficient mice, VDR−/− mice and NHE8−/− mice were employed in this study. Colitis mice were established by supplementing DSS-containing water. Caco-2 cells and 3D-enteroids were used for in vitro studies. VDR siRNA (siVDR), VDR over-expression plasmid (pVDR), TNF-α and NF-κb p65 inhibitor QNZ were used for mechanical studies. The expression of interested proteins was detected by multiple techniques. Results: In colitis mice, paricalcitol upregulated NHE8 expression was accompanied by restoring colonic mucosal injury. In VitD-deficient and VDR−/− colitis mice, NHE8 expression was compromised with more serious mucosal damage. Noteworthily, paricalcitol could not prevent intestinal barrier dysfunction and histological destruction in NHE8−/− mice. In Caco-2 cells and enteroids, siVDR downregulated NHE8 expression, further promoted TNF-α-induced NHE8 downregulation and stimulated TNF-α-induced NF-κb p65 phosphorylation. Conversely, QNZ blocked TNF-α-induced NHE8 downregulation in the absence or presence of siVDR. Conclusions: Our study indicates depressed NHE8 expression is responsible for VitD-deficient-induced colitis aggravation. These findings provide novel insights into the molecular mechanisms of VitD/VDR in intestine protection in UC.