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http://hdl.handle.net/11375/27620
Title: | Role of Serotonin-Autophagy Axis in Intestinal Inflammation |
Authors: | Haq, Sabah |
Advisor: | Khan, Waliul |
Department: | Medical Sciences |
Keywords: | 5-HT;Autophagy;Inflammation;Intestine |
Publication Date: | 2022 |
Abstract: | Autophagy, an intracellular degradation, and recycling process is essential in maintaining cellular homeostasis. Dysregulated autophagy is linked to the pathogenesis of various diseases, including inflammatory bowel disease (IBD) which consists of Crohn’s disease and ulcerative colitis. In IBD, enterochromaffin cell numbers and one of its main product serotonin (5-hydroxytryptamine; 5-HT) levels are elevated. Previously, we had shown that tryptophan hydroxylase 1 deficient (Tph1-/-) mice, with reduced gut 5-HT had decreased severity of colitis. Here, we showed that gut 5-HT plays a vital role in modulating autophagy and thus regulating gut microbial composition and susceptibility to intestinal inflammation. Tph1-/- mice, had upregulated colonic autophagy via the mammalian target of rapamycin pathway (mTOR), and decreased colitis severity. Tph1-/- mice after 5-HT replenishment, and serotonin reuptake transporter deficient (SERT-/-) mice, which have increased 5-HT levels, showed converse results. Deletion of intestinal epithelial cell-specific autophagy gene, Atg7, in Tph1-/- mice (DKO mice) abolished the protective effect of Tph1 deficiency in colitis, decreased the production of antimicrobial peptide, β-defensin 1 and promoted colitogenic microbiota. Furthermore, using cecal microbial transplantation, we found that the colitic microbiota of the DKO mice contributed to the increased severity of colitis. Supporting this pathway's translational importance, we uncovered that 5-HT treatment of peripheral blood mononuclear cells from both healthy volunteers and patients with Crohn’s disease inhibited autophagy via the mTOR pathway. Our results in this thesis emphasize the role of 5-HT-autophagymicrobiota axis in intestinal inflammation. Moreover, these findings suggest 5-HT as a novel therapeutic target in intestinal inflammatory disorders such as IBD that exhibit dysregulated autophagy. |
URI: | http://hdl.handle.net/11375/27620 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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Haq_Sabah_finalsubmission2022June_PhD.pdf | 63.7 MB | Adobe PDF | View/Open |
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