Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, 100050, People's Republic of China.
Peking University Ninth School of Clinical Medicine, Beijing, 100038, China.
Cell Commun Signal. 2024 Mar 12;22(1):176. doi: 10.1186/s12964-024-01538-5.
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.
抗抑郁药对炎症性肠病（IBD）的影响已得到广泛研究。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。
我们系统地评估了抗抑郁药（氟西汀、氟伏沙明和文拉法辛）如何影响 IBD，并选择最有效的氟西汀进行机制研究。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、疾病活动指数评分和结肠长度评估小鼠肠道炎症的严重程度。对结肠切片进行 H&E 染色和 MUC2 免疫组织化学染色，观察病理变化。进行 RT-qPCR 和 Western blot 以评估屏障和炎症相关基因的表达水平。然后，对小鼠肠黏膜进行单细胞 RNA 测序。使用 Seurat 可视化数据。使用 Uniform Manifold Approximation and Projection (UMAP) 进行降维。使用 Cell Chat 包进行细胞间通讯分析。使用 Monocle 进行发育拟时分析。最后，通过 RT-qPCR、Western blot 和免疫荧光染色，在体外测试单细胞 RNA 测序发现的现象。
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群的分布、细胞间通讯和 KEGG 途径富集。在氟西汀的治疗下，肠上皮细胞、杯状细胞和干细胞成为优势细胞。拟时分析显示 M1 巨噬细胞向 M2 巨噬细胞分化的趋势。最后，我们在体外对此现象进行了测试，结果显示对肠上皮细胞具有抗炎作用。
氟西汀通过重塑肠细胞和巨噬细胞发挥对肠道黏膜的抗炎作用，表明氟西汀是治疗 IBD 和精神共病的一种有前途的治疗药物。
