Non-TGFβ profibrotic signaling in ulcerative colitis after in vivo experimental intestinal injury in humans.

IF 3.9 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY American journal of physiology. Gastrointestinal and liver physiology Pub Date : 2024-07-01 Epub Date: 2024-05-07 DOI:10.1152/ajpgi.00074.2024
Jakob B Seidelin, Mariana Bronze, Anja Poulsen, Mohamed Attauabi, Anders Woetmann, Benjamin E Mead, Jeffrey M Karp, Lene B Riis, Jacob T Bjerrum
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Abstract

Although impaired regeneration is important in many gastrointestinal diseases including ulcerative colitis (UC), the dynamics of mucosal regeneration in humans are poorly investigated. We have developed a model to study these processes in vivo in humans. Epithelial restitution (ER) and extracellular matrix (ECM) regulation after an experimental injury of the sigmoid colonic mucosa was assessed by repeated high-resolution endoscopic imaging, histological assessment, RNA sequencing, deconvolution analysis, and 16S rDNA sequencing of the injury niche microbiome of 19 patients with UC in remission and 20 control subjects. Human ER had a 48-h lag before induction of regenerative epithelial cells [wound-associated epithelial (WAE) and transit amplifying (TA) cells] along with the increase of fibroblast-derived stem cell growth factor gremlin 1 mRNA (GREM1). However, UC deconvolution data showed rapid induction of inflammatory fibroblasts and upregulation of major structural ECM collagen mRNAs along with tissue inhibitor of metalloproteinase 1 (TIMP1), suggesting increased profibrotic ECM deposition. No change was seen in transforming growth factor β (TGFβ) mRNA, whereas the profibrotic cytokines interleukin 13 (IL13) and IL11 were upregulated in UC, suggesting that human postinjury responses could be TGFβ-independent. In conclusion, we found distinct regulatory layers of regeneration in the normal human colon and a potential targetable profibrotic dysregulation in UC that could lead to long-term end-organ failure, i.e., intestinal damage.NEW & NOTEWORTHY The study reveals the regulatory dynamics of epithelial regeneration and extracellular matrix remodeling after experimental injury of the human colon in vivo and shows that human intestinal regeneration is different from data obtained from animals. A lag phase in epithelial restitution is associated with induction of stromal cell-derived epithelial growth factors. Postinjury regeneration is transforming growth factor β-independent, and we find a profibrotic response in patients with ulcerative colitis despite being in remission.

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人体实验肠道损伤后溃疡性结肠炎中的非 TGFβ 坏死信号传导。
尽管再生障碍在包括溃疡性结肠炎(UC)在内的许多胃肠道疾病中都很重要,但对人体粘膜再生的动态研究却很少。我们开发了一种模型来研究人类体内的这些过程。通过反复进行高分辨率内窥镜成像、组织学评估、RNA 测序、解卷积分析以及对 19 名缓解期 UC 患者和 20 名对照组的损伤龛微生物组进行 16S rDNA 测序,对乙状结肠粘膜实验性损伤后的上皮恢复(ER)和细胞外基质(ECM)调控进行了评估。人类ER在诱导再生上皮细胞(WAE和TA细胞)以及成纤维干细胞生长因子Gremlin 1 mRNA(GREM1)增加之前有48小时的滞后期。然而,在 UC 中,解旋数据显示炎性成纤维细胞的快速诱导、主要结构 ECM 胶原 mRNA 的上调以及金属蛋白酶组织抑制剂 1 (TIMP1) 的上调,这表明畸形 ECM 沉积增加。在 UC 中,转化生长因子 β(TGFβ)mRNA 没有变化,而白细胞介素 13(IL13)和 IL11 上调,这表明人体损伤后反应可能与 TGFβ 无关。总之,我们在正常人的结肠中发现了不同的再生调节层,而在 UC 中发现了潜在的可靶向的凋亡失调,这可能导致长期的终末器官衰竭--即肠道损伤。
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来源期刊
CiteScore
9.40
自引率
2.20%
发文量
104
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Gastrointestinal and Liver Physiology publishes original articles pertaining to all aspects of research involving normal or abnormal function of the gastrointestinal tract, hepatobiliary system, and pancreas. Authors are encouraged to submit manuscripts dealing with growth and development, digestion, secretion, absorption, metabolism, and motility relative to these organs, as well as research reports dealing with immune and inflammatory processes and with neural, endocrine, and circulatory control mechanisms that affect these organs.
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