维生素 D 受体信号传导和维生素 D 对溃疡性结肠炎结肠上皮细胞命运决定的影响。

Lauge Kellermann, Stine Lind Hansen, Grzegorz Maciag, Agnete Marie Granau, Jens Vilstrup Johansen, Joji Marie Teves, Raul Bardini Bressan, Marianne Terndrup Pedersen, Christoffer Soendergaard, Astrid Moeller Baattrup, Alexander Hammerhøj, Lene Buhl Riis, John Gubatan, Kim Bak Jensen, Ole Haagen Nielsen
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引用次数: 0

摘要

背景和目的:流行病学研究表明,维生素 D(25(OH)D)水平低于正常与溃疡性结肠炎(UC)临床病程加重有关。尽管人们越来越关注维生素 D 和维生素 D 受体(VDR)信号传导的治疗重要性,但维生素 D-VDR 轴对 UC 的影响机制仍然难以捉摸。因此,我们旨在研究在人体器官组织中暴露于活性维生素 D(1,25(OH)2D3)/VDR 信号是否会影响结肠上皮的维持:方法:通过免疫组化、RNA表达阵列和单细胞RNA测序研究了UC患者和健康人结肠活检标本的肠道VDR表达。为了描述1,25(OH)2D3的功能和转录效应,我们使用了源自患者的结肠器官组织。结果表明,1,25(OH)2D3对结肠的功能和转录作用具有重要影响:我们的研究结果表明,1,25(OH)2D3/VDR刺激支持结肠上皮的分化,而1,25(OH)2D3/VDR信号传导受损可能会损害肠上皮屏障的结构,从而导致UC复发。此外,主要在结肠隐窝顶部完全分化的细胞中观察到了对VDR活性的转录反应,这种反应在UC发作时会减弱:我们发现了维生素 D 信号在支持人类结肠上皮分化细胞状态中的重要作用,从而维护了肠道屏障的完整性。这使得维生素 D-VDR 信号轴成为一个有趣的治疗目标,以实现并维持 UC 患者的病情缓解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Influence of Vitamin D Receptor Signalling and Vitamin D on Colonic Epithelial Cell Fate Decisions in Ulcerative Colitis.

Background and aims: Epidemiological studies have shown that subnormal levels of vitamin D (25[OH]D) are associated with a more aggravated clinical course of ulcerative colitis [UC]. Despite an increased focus on the therapeutic importance of vitamin D and vitamin D receptor [VDR] signalling, the mechanisms underlying the effects of the vitamin D-VDR axis on UC remain elusive. Therefore, we aimed to investigate whether exposure to active vitamin D (1,25[OH]2D3/VDR) signalling in human organoids could influence the maintenance of the colonic epithelium.

Methods: Intestinal VDR expression was studied by immunohistochemistry, RNA expression arrays, and single-cell RNA sequencing of colonic biopsy specimens obtained from patients with UC and healthy individuals. To characterise the functional and transcriptional effects of 1,25[OH]2D3, we used patient-derived colonic organoids. The dependency of VDR was assessed by knocking out the receptor with CRISPR/Cas9.

Results: Our results suggest that 1,25[OH]2D3/VDR stimulation supports differentiation of the colonic epithelium and that impaired 1,25[OH]2D3/VDR signalling thereby may compromise the structure of the intestinal epithelial barrier, leading to flares of UC. Furthermore, a transcriptional response to VDR activity was observed primarily in fully differentiated cells at the top of the colonic crypt, and this response was reduced during flares of UC.

Conclusions: We identified an important role of vitamin D signalling in supporting differentiated cell states in the human colonic epithelium, and thereby maintenance of the intestinal barrier integrity. This makes the vitamin D-VDR signalling axis an interesting target for therapeutic efforts to achieve and maintain remission in patients with UC.

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