炎性因子促进肠嗜铬细胞增生和5-HT合成在肠易激综合征中的作用及机制研究

Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disease with unclear pathophysiologic mechanisms and no effective radical treatment. One important cause of IBS is the dysfunction of the brain-gut axis. The neurotransmitter 5-hydroxytryptamine (5-HT), one signaling molecule of the brain-gut axis, is majorly synthesized by enterochromaffin cells (ECs) and significantly increases in partial IBS, but the reason for the increase is still unknown. Here, through analyzing the microarray data from intestinal mucous of patients with IBS in the GEO database, we found that IBS is highly correlated with inflammation, while inflammation is reported associated with 5-HT synthesis in some cases. Further, we stimulated the cultured intestinal organoid with TNF-α and IL-6, and found the number of ECs and the protein level of tryptophan hydroxylase 1 (TPH1), which is the rate-limiting enzyme in the synthesis of 5-HT, were increased. Next, we intend to further verify the effects of inflammatory factors on intestinal ECs proliferation and 5-HT synthesis, and elucidate the regulatory mechanisms. Our work will not only contribute to the understanding of IBS’s pathogenesis, but also may provide new targets for IBS therapy.

肠易激综合征（Irritable Bowel Syndrome，IBS）是一种常见的慢性功能性胃肠疾病，发病机制不明，目前缺乏根治手段。脑-肠轴功能紊乱是IBS发生发展的重要原因，其中肠嗜铬细胞合成的神经递质5-HT水平升高是部分IBS的致病因素，但目前尚不清楚是何原因导致5-HT增加。我们前期通过分析GEO数据库中IBS患者肠黏膜芯片数据，发现IBS发病与炎症高度相关，而炎症在某些情况下与5-HT合成相关。我们通过体外培养小肠类器官，给予炎性因子（TNF-α和IL-6）刺激后检测，发现小肠类器官中肠嗜铬细胞数目增加，同时5-HT合成的限速酶TPH1的表达也升高。在此基础上，我们拟进一步阐明炎性因子对肠嗜铬细胞增生和5-HT合成的影响及具体的调控机制。我们的研究将不仅有助于深入认识IBS的发病机制，并可能为IBS治疗提供新的靶标。

肠易激综合征（Irritable Bowel Syndrome，IBS）是一种常见的慢性功能性胃肠疾病，发病机制不明，目前缺乏根治手段。脑-肠轴功能紊乱是IBS发生发展的重要原因，其中肠嗜铬细胞合成的神经递质5-HT水平升高是部分IBS的致病因素，但目前尚不清楚是何原因导致5-HT增加。我们通过分析GEO数据库中IBS患者肠黏膜芯片数据，发现IBS发病与炎症高度相关。通过体外培养小肠类器官，给予炎性因子（TNF α和IL-6）刺激后检测，发现小肠类器官中肠嗜铬细胞数目增加，同时5-HT合成的限速酶TPH1的表达也升高。我们进一步构建了缓解型肠炎小鼠模型（DSS小鼠），发现其在体重、DAI评分和肠道外观方面较健康对照小鼠无明显差异，但肠粘膜下存在明显的炎症灶，IL-6和TNF-α相关炎症因子的表达上调，行为学检测发现这些小鼠与神经递质5-HT高度相关的焦虑和抑郁样行为存在改变。进一步通过生信分析和分子生物学实验验证表明IL-6和TNF-α促5-HT合成作用主要通过TNF-P38-C/EBP-β信号通路实现。我们的这一研究可能为阐明IBS的发生机制和开发新的治疗方法奠定基础。