肠道共生菌调控3型先天淋巴细胞影响溃疡性结肠炎黏膜愈合的机制研究

Commensal-dependent innate immunity directly affects the initiation and progression of ulcerative colitis. Their effects on mucosal healing post inflammation and injury still remain unclear. One principle molecular pathway involving mucosal healing in rodent experimental colitis is IL-22/STAT3. Innate lymphoid cell 3(ILC3) is established as the major source of IL-22 in intestine after breakdown of the mucosal barrier whose activation is under delicate regulation of dendritic cells from lamina propria. We found that antibiotics targeting Gram+ bacteria can cause delayed tissue repairing as well as diminished number of tissue resident ILC3 and IL-22 level. Whether Gram+ commensal can interfere with the homeostasis of ILC3 and IL-22/STAT3 pathway hence regulating tissue repair is largely unknown. Our project sets to unveil the mechanisms of commensal dependent IL-22 expression by ILC3. Special attention would be paid on the interaction of intestinal DC and ILC3. Our investigation would help achieve mucosal healing and maintain long-term remission of ulcerative colitis as well as justify the usage of probiotics from a brand new perspective.

肠道共生菌与黏膜免疫的相互作用直接影响溃疡性结肠炎（UC）肠道炎症的发生及消退，但其对炎症后修复过程的影响尚未阐明。既往大量研究表明IL-22/STAT3信号通路在小鼠实验性肠炎的黏膜修复过程中发挥重要作用，3型先天淋巴细胞（ILC3）为肠道主要的IL-22来源，ILC3的增殖和活化主要受固有层树突细胞（DC）调控。前期工作中我们发现，针对革兰氏阳性（G+）菌的抗生素可明显降低小鼠肠道炎症恢复期ILC3数量及IL-22水平，延迟组织修复，但将共生菌与ILC3联系起来的具体分子机制尚不明确。本项目拟结合体外实验与转基因动物模型深入研究G+共生菌在小鼠实验性肠炎恢复期对ILC3细胞增殖及活化，特别是IL-22分泌的调控机制，揭示共生菌影响下肠道固有层树突细胞与ILC3的相互作用模式，以期为达到UC黏膜愈合、维持长期缓解提供新的启示，并为UC治疗中益生菌的使用提供全新的理论依据。

本研究使用不同抗生素干预肠道菌群后建立DSS肠炎模型，发现万古霉素干预组小鼠存在DSS肠炎愈合延迟的现象，进一步的研究发现ILC3的增殖与IL-22分泌能力受损可能为肠炎愈合障碍的原因，ILC3增殖及功能缺陷可能源于树突状细胞迁徙及分泌障碍，提出了革兰氏阳性共生菌-单核/吞噬细胞-ILC3通路可能是革兰氏阳性共生菌调控粘膜愈合的内在机制，为溃疡性结肠炎治疗中益生菌的使用提供了全新的理论依据。此外，本研究发现与IL-22同一家族的IL-26在炎症性肠病患者肠粘膜表达上调，尤其是疾病累及部位，然而炎症性肠病患者血清IL-26的表达明显下调。此外，LPS干预可促进THP1细胞分泌IL-26，M1型巨噬细胞IL-26的表达亦明显上调，提示IL-26在炎症性肠病疾病进展中发挥着重要的调控作用。