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Published on: January 5, 2017
Antidepressant fluoxetine alleviates colitis by reshaping intestinal microenvironment
Shuo Teng1,2, Yi Yang1, Wanru Zhang1
1Department 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.
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
Insights
Fluoxetine effectively reduces colon inflammation in Inflammatory bowel diseases (IBD) by remodeling intestinal cells and macrophages. This antidepressant shows promise for treating IBD and associated psychiatric conditions.
Area of Science:
- Gastroenterology
- Immunology
- Pharmacology
Background:
- Antidepressants' impact on Inflammatory Bowel Diseases (IBD) is studied, but molecular mechanisms for alleviating colitis are unclear.
- Existing research highlights the need to understand how specific antidepressants influence IBD pathogenesis.
Purpose of the Study:
- To systematically assess the effects of fluoxetine, fluvoxamine, and venlafaxine on IBD.
- To elucidate the molecular mechanisms by which fluoxetine alleviates colitis in a mouse model.
Main Methods:
- Assessed fluoxetine efficacy in a C56BL/6 mouse IBD model using clinical and histological markers.
- Employed single-cell RNA sequencing to analyze changes in intestinal mucosa cell distribution, communication, and pathways.
- Validated findings in vitro using RT-qPCR, western blot, and immunofluorescence staining.
Main Results:
- Fluoxetine significantly alleviated colon inflammation, improving disease activity and colon length.
- Single-cell RNA sequencing revealed fluoxetine's impact on cell clusters, cell-cell communication, and KEGG pathways.
- Fluoxetine treatment promoted enterocytes, Goblet cells, and stem cells, and suggested M1 macrophage to M2 macrophage differentiation.
Conclusions:
- Fluoxetine demonstrates anti-inflammatory effects on intestinal mucosa by remodeling intestinal cells and macrophages.
- Fluoxetine is a potential therapeutic agent for Inflammatory Bowel Diseases and comorbid psychiatric conditions.
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