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. / Thesis / Doctor of Philosophy (PhD) / Approximately 0.7% of Canadians are currently affected with inflammatory bowel
disease (IBD). The gut hormone serotonin, which regulates many normal functions, is
elevated in gut inflammation. Reduced serotonin levels decrease the severity of
inflammation. IBD pathology has been linked to a unique cell self-eating process called
autophagy. Using cell lines, mice, and samples from IBD patients, we assessed the
interactions between serotonin signaling and autophagy during gut inflammation. I found
that an increase in serotonin levels enhances the severity of gut inflammation by
inhibiting autophagy. We also established the connection between serotonin and
autophagy in the intestinal epithelial cells, and how this modulates epithelial cell function.
Furthermore, we demonstrated the establishment of an altered gut microbiota upon
disruption of the serotonin-autophagy axis in the epithelial cells, which subsequently
influenced gut inflammation severity. Thus, we identified one of the key triggers related
to the pathogenesis and severity of IBD.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/27620 |
| Date | January 2022 |
| Creators | Haq, Sabah |
| Contributors | Khan, Waliul, Medical Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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