Vitamin D3 alleviates inflammation in ulcerative colitis by activating the VDR-NLRP6 signaling pathway

Abstract

Inflammation is a key factor in the development of ulcerative colitis (UC). 1,25-dihydroxyvitamin D3 (1,25(OH)2D3, VD3), as the major active ingredient of vitamin D and an anti-inflammatory activator, is closely related to the initiation and development of UC, but its regulatory mechanism remains unclear. In this study, we carried out histological and physiological analyses in UC patients and UC mice. RNA sequencing (RNA-seq), assays for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq), chromatin immunoprecipitation (ChIP) assays and protein and mRNA expression were performed to analyze and identify the potential molecular mechanism in UC mice and lipopolysaccharide (LPS)-induced mouse intestinal epithelial cells (MIECs). Moreover, we established nucleotide-binding oligomerization domain (NOD)-like receptor protein nlrp6-/- mice and siRNA-NLRP6 MIECs to further characterize the role of NLRP6 in anti-inflammation of VD3. Our study revealed that VD3 abolished NOD-like receptor protein 6 (NLRP6) inflammasome activation, suppressing NLRP6, apoptosis-associated speck-like protein (ASC) and Caspase-1 levels via the vitamin D receptor (VDR). ChIP and ATAC-seq showed that VDR transcriptionally repressed NLRP6 by binding to vitamin D response elements (VDREs) in the promoter of NLRP6, impairing UC development. Importantly, VD3 had both preventive and therapeutic effects on the UC mouse model via inhibition of NLRP6 inflammasome activation. Our results demonstrated that VD3 substantially represses inflammation and the development of UC in vivo. These findings reveal a new mechanism by which VD3 affects inflammation in UC by regulating the expression of NLRP6 and show the potential clinical use of VD3 in autoimmune syndromes or other NLRP6 inflammasome-driven inflammatory diseases.

VDR Immunohistochemistry Expression Is Down-Regulated in Colorectal Cells of Patients with IBD and Could Rank the Patients According to Their Complications Risk

“…Gao H et al, 2023 found that vitamin D supplementation alleviates inflammation in ulcerative colitis, and provided evidence for the use of vitamin D in the clinical treatment of ulcerative colitis [28]. This is in line with our suggestions, according to the significance of our results.…”

“…Considering our results, as well as the results of previous studies, which confirm the effects of vitamin D supplementation in suppressing inflammation [28][29][30], the analysis of VD status and vitamin D supplementation during treatment of IBD is recommended.…”

Recent Advances in the Biomedical Applications of Copper Nanomaterial‐Mediated Cuproptosis

“…Copper is an indispensable trace metal element in the human body, actively participating in energy production, iron metabolism, neuropeptide activation, connective tissue synthesis, and neurotransmitter synthesis. [6] Extensive research indicates that copper, serving as a cofactor for various crucial metabolic enzymes, is a vital component of the body's defense system, driving a wide array of physiological processes. [6,7] Involving multiple copper transport proteins and their regulation, both shallow and high copper levels have been shown to lead to cell death.…”

“…[6] Extensive research indicates that copper, serving as a cofactor for various crucial metabolic enzymes, is a vital component of the body's defense system, driving a wide array of physiological processes. [6,7] Involving multiple copper transport proteins and their regulation, both shallow and high copper levels have been shown to lead to cell death. Thus, maintaining copper levels within an appropriate range is essential.…”

The Role of Vitamin D in Patients with Inflammatory Bowel Disease Treated with Vedolizumab

“…Because vitamin D plays a role in modulating the immune system [23][24][25][26], we hypothesized that patients who have a high baseline vitamin D level of ≥30 ng/mL at the initiation of vedolizumab would have the best clinical and endoscopic responses to therapy. This vitamin D level is based on the classifications of normal, insufficient, and deficient levels of vitamin D [27].…”