PDF(Pubmed)
Abstract：
The impact of antidepressants on Inflammatory bowel diseases (IBD) has been extensively studied. However, the biological effects and molecular mechanisms of antidepressants in alleviating colitis remain unclear.
We systematically assessed how antidepressants (fluoxetine, fluvoxamine and venlafaxine) affected IBD and chose fluoxetine, the most effective one, for mechanism studies. We treated the C56BL/6 mice of the IBD model with fluoxetine and their controls. We initially assessed the severity of intestinal inflammation in mice by body weight loss, disease Activity Index scores and the length of the colon. The H&E staining and immunohistochemical staining of MUC2 of colon sections were performed to observe the pathological changes. RT-qPCR and western blot were conducted to assess the expression level of the barrier and inflammation-associated genes. Then, single-cell RNA sequencing was performed on mouse intestinal mucosa. Seurat was used to visualize the data. Uniform Manifold Approximation and Projection (UMAP) was used to perform the dimensionality reduction. Cell Chat package was used to perform cell-cell communication analysis. Monocle was used to conduct developmental pseudotime analysis. Last, RT-qPCR, western blot and immunofluorescence staining were conducted to test the phenomenon discovered by single-cell RNA sequencing in vitro.
We found that fluoxetine treatment significantly alleviated colon inflammation. Notably, single-cell RNA sequencing analysis revealed that fluoxetine affected the distribution of different cell clusters, cell-cell communication and KEGG pathway enrichment. Under the treatment of fluoxetine, enterocytes, Goblet cells and stem cells became the dominating cells. The pseudotime analysis showed that there was a trend for M1 macrophages to differentiate into M2 macrophages. Lastly, we tested this phenomenon in vitro, which exhibited anti-inflammatory effects on enterocytes.
Fluoxetine exhibited anti-inflammatory effects on intestinal mucosa via remodeling of the intestinal cells and macrophages, which reveals that fluoxetine is a promising therapeutic drug for the treatment of IBD and psychiatric comorbidities.
We systematically assessed how antidepressants (fluoxetine, fluvoxamine and venlafaxine) affected IBD and chose fluoxetine, the most effective one, for mechanism studies. We treated the C56BL/6 mice of the IBD model with fluoxetine and their controls. We initially assessed the severity of intestinal inflammation in mice by body weight loss, disease Activity Index scores and the length of the colon. The H&E staining and immunohistochemical staining of MUC2 of colon sections were performed to observe the pathological changes. RT-qPCR and western blot were conducted to assess the expression level of the barrier and inflammation-associated genes. Then, single-cell RNA sequencing was performed on mouse intestinal mucosa. Seurat was used to visualize the data. Uniform Manifold Approximation and Projection (UMAP) was used to perform the dimensionality reduction. Cell Chat package was used to perform cell-cell communication analysis. Monocle was used to conduct developmental pseudotime analysis. Last, RT-qPCR, western blot and immunofluorescence staining were conducted to test the phenomenon discovered by single-cell RNA sequencing in vitro.
We found that fluoxetine treatment significantly alleviated colon inflammation. Notably, single-cell RNA sequencing analysis revealed that fluoxetine affected the distribution of different cell clusters, cell-cell communication and KEGG pathway enrichment. Under the treatment of fluoxetine, enterocytes, Goblet cells and stem cells became the dominating cells. The pseudotime analysis showed that there was a trend for M1 macrophages to differentiate into M2 macrophages. Lastly, we tested this phenomenon in vitro, which exhibited anti-inflammatory effects on enterocytes.
Fluoxetine exhibited anti-inflammatory effects on intestinal mucosa via remodeling of the intestinal cells and macrophages, which reveals that fluoxetine is a promising therapeutic drug for the treatment of IBD and psychiatric comorbidities.
摘要：
背景：已经广泛研究了抗抑郁药对炎症性肠病（IBD）的影响。然而,抗抑郁药缓解结肠炎的生物学效应和分子机制尚不清楚.
方法：我们系统地评估了抗抑郁药（氟西汀，氟伏沙明和文拉法辛）影响IBD，并选择氟西汀，最有效的,机制研究。我们用氟西汀治疗IBD模型的C56BL/6小鼠及其对照。我们最初通过体重减轻来评估小鼠肠道炎症的严重程度，疾病活动指数评分和结肠长度。行结肠切片MUC2的H&E染色和免疫组化染色观察病理改变。进行RT-qPCR和蛋白质印迹以评估屏障和炎症相关基因的表达水平。然后，对小鼠肠粘膜进行单细胞RNA测序.使用Seurat可视化数据。使用均匀流形近似和投影（UMAP）来执行降维。使用细胞聊天包进行细胞-细胞通信分析。使用Monocle进行发育假时间分析。最后,RT-qPCR,采用westernblot和免疫荧光染色检测单细胞RNA测序发现的现象。
结果：我们发现氟西汀治疗可显著缓解结肠炎症。值得注意的是,单细胞RNA测序分析显示氟西汀影响不同细胞簇的分布,细胞间通讯和KEGG途径富集。在氟西汀的治疗下，肠细胞,杯状细胞和干细胞成为主要细胞。假时间分析表明M1巨噬细胞有向M2巨噬细胞分化的趋势。最后,我们在体外测试了这种现象，对肠上皮细胞表现出抗炎作用。
结论：氟西汀通过重塑肠细胞和巨噬细胞对肠粘膜具有抗炎作用，这表明氟西汀是治疗IBD和精神病合并症的一种有前途的治疗药物。
方法：我们系统地评估了抗抑郁药（氟西汀，氟伏沙明和文拉法辛）影响IBD，并选择氟西汀，最有效的,机制研究。我们用氟西汀治疗IBD模型的C56BL/6小鼠及其对照。我们最初通过体重减轻来评估小鼠肠道炎症的严重程度，疾病活动指数评分和结肠长度。行结肠切片MUC2的H&E染色和免疫组化染色观察病理改变。进行RT-qPCR和蛋白质印迹以评估屏障和炎症相关基因的表达水平。然后，对小鼠肠粘膜进行单细胞RNA测序.使用Seurat可视化数据。使用均匀流形近似和投影（UMAP）来执行降维。使用细胞聊天包进行细胞-细胞通信分析。使用Monocle进行发育假时间分析。最后,RT-qPCR,采用westernblot和免疫荧光染色检测单细胞RNA测序发现的现象。
结果：我们发现氟西汀治疗可显著缓解结肠炎症。值得注意的是,单细胞RNA测序分析显示氟西汀影响不同细胞簇的分布,细胞间通讯和KEGG途径富集。在氟西汀的治疗下，肠细胞,杯状细胞和干细胞成为主要细胞。假时间分析表明M1巨噬细胞有向M2巨噬细胞分化的趋势。最后,我们在体外测试了这种现象，对肠上皮细胞表现出抗炎作用。
结论：氟西汀通过重塑肠细胞和巨噬细胞对肠粘膜具有抗炎作用，这表明氟西汀是治疗IBD和精神病合并症的一种有前途的治疗药物。
