UMR PNCA, AgroParisTech, INRA, Université Paris-Saclay, Paris 75005, France.
UMR MICALIS, INRA, Université Paris-Saclay, Jouy-en-Josas 78350, France.
World J Gastroenterol. 2019 Jul 21;25(27):3572-3589. doi: 10.3748/wjg.v25.i27.3572.
Mucosal healing has become a therapeutic goal to achieve stable remission in patients with inflammatory bowel diseases. To achieve this objective, overlapping actions of complex cellular processes, such as migration, proliferation, and differentiation, are required. These events are longitudinally and tightly controlled by numerous factors including a wide range of distinct regulatory proteins. However, the sequence of events associated with colon mucosal repair after colitis and the evolution of the luminal content characteristics during this process have been little studied.
To document the evolution of colon mucosal characteristics during mucosal healing using a mouse model with chemically-induced colitis.
C57BL/6 male mice were given 3.5% dextran sodium sulfate (DSS) in drinking water for 5 d. They were euthanized 2 (day 7), 5 (day 10), 8 (day 13), and 23 (day 28) d after DSS removal. The colonic luminal environment and epithelial repair processes during the inflammatory flare and colitis resolution were analyzed with reference to a non-DSS treated control group, euthanized at day 0. Epithelial repair events were assessed histo-morphologically in combination with functional permeability tests, expression of key inflammatory and repairing factors, and evaluation of colon mucosa-adherent microbiota composition by 16S rRNA sequencing.
The maximal intensity of colitis was concomitant with maximal alterations of intestinal barrier function and histological damage associated with goblet cell depletion in colon mucosa. It was recorded 2 d after termination of the DSS-treatment, followed by a progressive return to values similar to those of control mice. Although signs of colitis were severe (inflammatory cell infiltrate, crypt disarray, increased permeability) and associated with colonic luminal alterations (hyperosmolarity, dysbiosis, decrease in short-chain fatty acid content), epithelial healing processes were launched early during the inflammatory flare with increased gene expression of certain key epithelial repair modulators, including transforming growth factor-β, interleukin (Il)-15, Il-22, Il-33, and serum amyloid A. Whereas signs of inflammation progressively diminished, luminal colonic environment alterations and microscopic abnormalities of colon mucosa persisted long after colitis induction.
This study shows that colon repair can be initiated in the context of inflamed mucosa associated with alterations of the luminal environment and highlights the longitudinal involvement of key modulators.
黏膜愈合已成为炎症性肠病患者实现稳定缓解的治疗目标。为了实现这一目标，需要重叠复杂的细胞过程，如迁移、增殖和分化等多种细胞的协同作用。这些事件受到许多因素的纵向和紧密控制，包括广泛的不同调节蛋白。然而，在结肠炎后结肠黏膜修复相关的事件序列以及在这个过程中管腔内容物特征的演变，研究甚少。
使用化学诱导结肠炎的小鼠模型，记录结肠黏膜在黏膜愈合过程中的特征演变。
雄性 C57BL/6 小鼠连续 5 天饮用 3.5%葡聚糖硫酸钠（DSS）。在 DSS 去除后第 2、5、8 和 23 天（分别为第 7、10、13 和 28 天）处死小鼠。通过与未接受 DSS 处理的对照组（第 0 天处死）比较，分析在炎症发作和结肠炎缓解期间结肠腔内环境和上皮修复过程。上皮修复事件通过组织形态学结合功能通透性试验、关键炎症和修复因子的表达以及 16S rRNA 测序评估结肠黏膜黏附菌群组成来评估。
结肠炎的最大强度与肠道屏障功能的最大改变以及结肠黏膜中杯状细胞耗竭相关的组织学损伤同时发生。它在 DSS 治疗结束后 2 天记录到，随后逐渐恢复到类似于对照小鼠的值。尽管结肠炎的迹象严重（炎症细胞浸润、隐窝排列紊乱、通透性增加），并与结肠管腔改变相关（高渗性、菌群失调、短链脂肪酸含量减少），上皮愈合过程在炎症发作早期就开始了，某些关键上皮修复调节剂的基因表达增加，包括转化生长因子-β、白细胞介素（IL）-15、IL-22、IL-33 和血清淀粉样蛋白 A。尽管炎症迹象逐渐减少，但管腔结肠环境的改变和结肠炎诱导后的结肠黏膜微观异常仍然存在。
本研究表明，在与管腔环境改变相关的炎症黏膜的背景下，可以启动结肠修复，并强调了关键调节剂的纵向参与。
