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Hyperglycemia minimally alters primary self-renewing human colonic epithelial cells while TNFα-promotes severe intestinal epithelial dysfunction
Integrative Biology ( IF 1.5 ) Pub Date : 2021-05-15 , DOI: 10.1093/intbio/zyab008
Johanna S Dutton 1 , Samuel S Hinman 2 , Raehyun Kim 2 , Peter J Attayek 1 , Mallory Maurer 1 , Christopher S Sims 2 , Nancy L Allbritton 2
Affiliation  

Hyperglycemia is thought to increase production of inflammatory cytokines and permeability of the large intestine. Resulting intestinal inflammation is then often characterized by excess secretion of tumor necrosis factor alpha (TNFα). Thus, hyperglycemia in hospitalized patients suffering from severe trauma or disease is frequently accompanied by TNFα secretion, and the combined impact of these insults on the intestinal epithelium is poorly understood. This study utilized a simple yet elegant model of the intestinal epithelium, comprised of primary human intestinal stem cells and their differentiated progeny, to investigate the impact of hyperglycemia and inflammatory factors on the colonic epithelium. When compared to epithelium cultured under conditions of physiologic glucose, cells under hyperglycemic conditions displayed decreased mucin-2 (MUC2), as well as diminished alkaline phosphatase (ALP) activity. Conditions of 60 mM glucose potentiated secretion of the cytokine IL-8 suggesting that cytokine secretion during hyperglycemia may be a source of tissue inflammation. TNFα measurably increased secretion of IL-8 and IL-1β, which was enhanced at 60 mM glucose. Surprisingly, intestinal permeability and paracellular transport were not altered by even extreme levels of hyperglycemia. The presence of TNFα increased MUC2 presence, decreased ALP activity, and negatively impacted monolayer barrier function. When TNFα hyperglycemia and ≤30 mM glucose and were combined, MUC2 and ALP activity remained similar to that of TNFα alone, although synergistic effects were seen at 60 mM glucose. An automated image analysis pipeline was developed to assay changes in properties of the zonula occludens-1 (ZO-1)-demarcated cell boundaries. While hyperglycemia alone had little impact on cell shape and size, cell morphologic properties were extraordinarily sensitive to soluble TNFα. These results suggest that TNFα acted as the dominant modulator of the epithelium relative to glucose, and that control of inflammation rather than glucose may be key to maintaining intestinal homeostasis.

中文翻译:


高血糖对初级自我更新人结肠上皮细胞的改变微乎其微,而TNFα则促进严重的肠上皮功能障碍



高血糖被认为会增加炎症细胞因子的产生和大肠的通透性。由此产生的肠道炎症通常以肿瘤坏死因子 α (TNFα) 的过量分泌为特征。因此,患有严重创伤或疾病的住院患者的高血糖常常伴随着TNFα的分泌,而这些损伤对肠上皮的综合影响却知之甚少。这项研究利用简单而优雅的肠上皮模型(由原代人肠干细胞及其分化后代组成)来研究高血糖和炎症因子对结肠上皮的影响。与在生理葡萄糖条件下培养的上皮细胞相比,高血糖条件下的细胞表现出粘蛋白-2 (MUC2) 降低,以及碱性磷酸酶 (ALP) 活性降低。 60 mM 葡萄糖条件增强了细胞因子 IL-8 的分泌,表明高血糖期间细胞因子的分泌可能是组织炎症的根源。 TNFα 可显着增加 IL-8 和 IL-1β 的分泌,这种分泌在 60 mM 葡萄糖时增强。令人惊讶的是,即使是极端水平的高血糖也不会改变肠道通透性和细胞旁转运。 TNFα 的存在增加了 MUC2 的存在,降低了 ALP 活性,并对单层屏障功能产生负面影响。当 TNFα 高血糖和≤30 mM 葡萄糖组合时,MUC2 和 ALP 活性仍与单独使用 TNFα 相似,尽管在 60 mM 葡萄糖下观察到协同效应。开发了自动图像分析管道来分析 zonula occlusionns-1 (ZO-1) 划定的细胞边界的特性变化。 虽然高血糖本身对细胞形状和大小影响不大,但细胞形态特性对可溶性 TNFα 异常敏感。这些结果表明,相对于葡萄糖,TNFα 是上皮细胞的主要调节剂,控制炎症而不是葡萄糖可能是维持肠道稳态的关键。
更新日期:2021-06-17
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