Cathelicidin Mediates a Protective Role of Vitamin D in Ulcerative Colitis and Human Colonic Epithelial Cells

Abstract

Background Vitamin D plays a protective role in ulcerative colitis (UC) patients through unclear mechanisms. Cathelicidin is an antimicrobial peptide induced by 1,25(OH)D2. Our goal was to evaluate the link between cathelicidin and vitamin D–associated clinical outcomes in UC patients, explore vitamin D induction of cathelicidin in human colon cells, and evaluate the effects of intrarectal human cathelicidin on a murine model of colitis. Methods Serum and colonic cathelicidin levels were measured in UC patients and correlated with clinical and histologic outcomes. Human colon cells were treated with 1,25(OH)2D and production of cathelicidin and cytokines were quantified. Antimicrobial activity against Escherichia coli from cell culture supernatants was measured. Mice were treated with intrarectal cathelicidin, and its effects on DSS colitis and intestinal microbiota were evaluated. Results In UC patients, serum 25(OH)D positively correlated with serum and colonic cathelicidin. Higher serum cathelicidin is associated with decreased risk of histologic inflammation and clinical relapse but not independent of 25(OH)D or baseline inflammation. The 1,25(OH)2D treatment of colon cells induced cathelicidin and IL-10, repressed TNF-α, and suppressed Escherichia coli growth. This antimicrobial effect was attenuated with siRNA-cathelicidin transfection. Intrarectal cathelicidin reduced the severity of DSS colitis but did not mitigate the impact of colitis on microbial composition. Conclusions Cathelicidin plays a protective role in 25(OH)D-associated UC histologic outcomes and murine colitis. Cathelicidin is induced by vitamin D in human colonic epithelial cells and promotes antimicrobial activity against E. coli. Our study provides insights into the vitamin D–cathelicidin pathway as a potential therapeutic target.

The Role of Micronutrients in Support of the Immune Response against Viral Infections

“…This effect was the first to be discovered, studying the causes of rickets and osteomalacia, but now it is thought that vitamin D has physiological effects much broader that its role in mineral homeostasis and bone function [ 78 ], including regulation of immunity, fetal development [ 79 ], and pulmonary function [ 80 ]. In addition, vitamin D can also induce cathelicidin in gastrointestinal epithelium [ 81 ] and plays a role in controlling gastrointestinal infections [ 82 ].…”

“…For the purpose of this review, we focused on the effects of vitamin D in modulating the immune system. Several mechanisms have been described [ 83 ]: firstly, vitamin D was found to induce the production of antimicrobial peptides such as cathelicidin and human beta-defensin from immune system cells such as neutrophils and macrophages and from epithelial respiratory cells [ 81 , 82 , 83 , 84 , 85 , 86 , 87 ]. Vitamin D also enhances the antimicrobial activity of macrophages by increasing TLR and CD14 expression [ 88 ], autophagy [ 89 , 90 ], and the activity of NADPH-dependent oxidase [ 91 ]; it also promotes the migration of dendritic cells to lymphoid organs where they can present antigens to T cells [ 92 ].…”

Vitamin D Modulates Intestinal Microbiota in Inflammatory Bowel Diseases

“…Furthermore, higher levels of vitamin D are related to increased serum cathelicidin and reduced inflammation in UC patients. In the meantime, vitamin D may improve the cathelicidin antimicrobial activity against E. coli in vitro while showed a protective effect to induced colitis in vivo [ 93 ].…”

Cathelicidin – A Novel Potential Marker of Pediatric Inflammatory Bowel Disease

“…In a recent study, Gubatan et al presented a positive correlation between levels of 25(OH)D in serum and cathelicidin in serum and colon of patients with ulcerative colitis in clinical remission. 36 Moreover, higher serum cathelicidin was associated with decreased histologic inflammation and risk of clinical relapse. 36 Thus the results of Gubatan et al imply a beneficial role of increased serum cathelicidin levels in ulcerative colitis.…”

“… 36 Moreover, higher serum cathelicidin was associated with decreased histologic inflammation and risk of clinical relapse. 36 Thus the results of Gubatan et al imply a beneficial role of increased serum cathelicidin levels in ulcerative colitis. 36 …”