Stallhofer Johannes, Reichl Felix, Lauseker Michael, Waldenmaier Lisa, Török Helga Paula, Mayerle Julia, Olszak Torsten, Schnitzler Fabian, Frasheri Iris, Breiteneicher Simone, Brand Stephan, Stallmach Andreas, Diegelmann Julia, Beigel Florian
Department of Internal Medicine IV, Jena University Hospital, Am Klinikum 1, 07747, Jena, Germany.
Department of Medicine II, University Hospital, LMU Munich, Munich, Germany.
Sci Rep. 2025 Jun 20;15(1):20145. doi: 10.1038/s41598-025-05094-x.
Intestinal epithelial overexpression of the Th17 cell chemoattractant CCL20 is implicated in inflammatory bowel disease and influenced by NOD2 mutations in Crohn's disease. Vitamin D metabolites have been shown to ameliorate inflammatory bowel disease. Considering NOD2 mutations in Crohn's disease, we investigated whether Vitamin D deficiency (serum 25-hydroxyvitamin D concentration < 20 ng/mL) increases circulating CCL20 levels in inflammatory bowel disease patients and healthy controls and whether active 1,25-dihydroxyvitamin D (calcitriol) downregulates systemic and intestinal CCL20 expression. In a cross-sectional study, serum concentrations of CCL20, 25-hydroxyvitamin D, and calcitriol were measured in 170 NOD2-genotyped Crohn's disease patients, 80 ulcerative colitis patients, and 60 healthy controls. Additionally, the effect of calcitriol on experimentally induced CCL20 expression was examined using human intestinal epithelial HT-29 cells. Multivariable linear regression analyses revealed that both the diagnosis of inflammatory bowel disease and vitamin D deficiency were independently associated with elevated CCL20 levels. Compared to healthy controls, Crohn's disease patients and ulcerative colitis patients exhibited significantly higher circulating CCL20 levels. Unlike in Crohn's disease patients, vitamin D deficiency was associated with higher CCL20 levels in healthy controls and ulcerative colitis patients, whereas the calcitriol/25-hydroxyvitamin D activation ratios were negatively correlated with serum CCL20 levels in healthy controls and ulcerative colitis patients with sufficient serum 25-hydroxyvitamin D status. Furthermore, calcitriol markedly inhibited intestinal epithelial induction of CCL20. In Crohn's disease patients, cholecalciferol supplementation was associated with lower serum CCL20 levels, which were unaffected by NOD2 mutations. These findings suggest that although vitamin D metabolites may downregulate CCL20 expression in healthy controls and ulcerative colitis patients, this regulatory effect appears to be impaired in Crohn's disease patients.
Th17细胞趋化因子CCL20在肠道上皮中的过表达与炎症性肠病有关，并受克罗恩病中NOD2突变的影响。维生素D代谢物已被证明可改善炎症性肠病。考虑到克罗恩病中的NOD2突变，我们研究了维生素D缺乏（血清25-羟基维生素D浓度<20 ng/mL）是否会增加炎症性肠病患者和健康对照者循环CCL20水平，以及活性1,25-二羟基维生素D（骨化三醇）是否会下调全身和肠道CCL20表达。在一项横断面研究中，测量了170例进行NOD2基因分型的克罗恩病患者、80例溃疡性结肠炎患者和60例健康对照者的血清CCL20、25-羟基维生素D和骨化三醇浓度。此外，使用人肠道上皮HT-29细胞研究了骨化三醇对实验诱导的CCL20表达的影响。多变量线性回归分析显示，炎症性肠病的诊断和维生素D缺乏均与CCL20水平升高独立相关。与健康对照者相比，克罗恩病患者和溃疡性结肠炎患者的循环CCL20水平显著更高。与克罗恩病患者不同，维生素D缺乏与健康对照者和溃疡性结肠炎患者较高的CCL20水平相关，而在血清25-羟基维生素D水平充足的健康对照者和溃疡性结肠炎患者中，骨化三醇/25-羟基维生素D激活率与血清CCL20水平呈负相关。此外，骨化三醇显著抑制肠道上皮细胞诱导的CCL20。在克罗恩病患者中，补充胆钙化醇与较低的血清CCL20水平相关，而不受NOD2突变的影响。这些发现表明，尽管维生素D代谢物可能下调健康对照者和溃疡性结肠炎患者的CCL20表达，但在克罗恩病患者中这种调节作用似乎受损。
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