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：

---

高血糖对原代自我更新的人结肠上皮细胞的改变最小，而 TNFα 会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。导致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症经常伴有 TNFα 分泌，而这些损伤对肠上皮细胞的综合影响却知之甚少。本研究利用一个简单而优雅的肠道上皮模型，由原代人类肠道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显示出粘蛋白 2 (MUC2) 降低，以及碱性磷酸酶 (ALP) 活性降低。60 mM 葡萄糖的条件增强了细胞因子 IL-8 的分泌，这表明高血糖期间的细胞因子分泌可能是组织炎症的来源。TNFα 显着增加了 IL-8 和 IL-1β 的分泌，这在 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，肠道通透性和细胞旁转运也没有改变。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 高血糖症和 ≤30 mM 葡萄糖结合使用时，MUC2 和 ALP 活性与单独使用 TNFα 的活性相似，尽管在 60 mM 葡萄糖下观察到协同效应。开发了一个自动图像分析管道来分析 zonula occludens-1 (ZO-1) 划定的细胞边界的特性变化。虽然单独的高血糖对细胞形状和大小几乎没有影响，但细胞形态学特性对可溶性 TNFα 异常敏感。这些结果表明，相对于葡萄糖，TNFα作为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。