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

Area of Science:

• Gastroenterology
• Molecular Biology
• Immunology

Background:

• Ulcerative colitis (UC) involves intestinal barrier dysfunction.
• Vitamin D (VitD) and its receptor (VDR) are implicated in intestinal health.
• Na+/H+ exchanger isoform 8 (NHE8) is vital for intestinal homeostasis and a potential UC therapeutic target.

Purpose of the Study:

• To investigate the role of VitD/VDR in regulating NHE8 expression for intestinal protection.
• To elucidate the molecular mechanisms underlying VitD/VDR-mediated intestinal protection in UC.

Main Methods:

• Utilized VitD-deficient, VDR knockout (VDR-/-), and NHE8 knockout (NHE8-/-) mouse models of DSS-induced colitis.
• Employed Caco-2 cells and 3D enteroids for in vitro mechanistic studies.
• Investigated the effects of VDR modulation (siRNA, overexpression) and TNF-α/NF-κb signaling inhibition (QNZ) on NHE8 expression.

Main Results:

• Paricalcitol (a VitD analog) upregulated NHE8 and restored colonic mucosa in colitis mice.
• VitD deficiency or VDR knockout compromised NHE8 expression and worsened colitis.
• NHE8 deficiency rendered mice unresponsive to paricalcitol's protective effects.
• VDR knockdown exacerbated TNF-α-induced NHE8 downregulation and NF-κb activation, which was blocked by QNZ.

Conclusions:

• Depressed NHE8 expression contributes to the aggravation of VitD-deficient-induced colitis.
• VitD/VDR signaling protects the intestinal barrier, at least partly, through the regulation of NHE8.
• NHE8 represents a novel molecular target for therapeutic strategies in UC.