A33 ROLE OF SEROTONIN-AUTOPHAGY AXIS IN INTESTINAL INFLAMMATION
Bibliographic record
Abstract
Serotonin (5-hydroxytryptamine; 5-HT) is an important enteric signalling molecule that regulates physiological and pathological processes of the gut. Enterochromaffin (EC) cells are the main producer of 5-HT in gut, and tryptophan hydroxylase 1 (Tph1) is the rate-limiting enzyme of 5-HT biosynthesis in EC cells. Changes in EC cell number and 5-HT content are detected in inflammatory bowel disease (IBD) and in experimental colitis. Tph1-/- mice with significantly reduced 5-HT in their gut exhibit reduced susceptibility to colitis. It is also shown that serotonin transporter deficient (SERT-/-) mice with elevated 5-HT in their gut exhibit enhanced colitis. The mechanism by which 5-HT regulates colitis is unknown. Autophagy, a catabolic process modulates intestinal homeostasis by regulating anti-microbial defense, epithelial barrier integrity and immune response. Genome wide association studies found links between several autophagy gene variants and IBD. Though both aberrant 5-HT signalling and autophagy have been implicated in colitis, it remains unclear whether they interact in relation to colitis. Our hypothesis is that an increase in 5-HT signalling enhances the severity of gut inflammation by inhibiting autophagy. To define the role of 5-HT-autophagy axis in intestinal inflammation. We investigated autophagy and inflammatory markers with or without 5% dextran sodium sulphate (DSS) in colons of Tph1-/-, SERT-/- and their wild-type littermates. We assessed autophagy in Tph1-/-mice after restoration of 5-HT levels by administration of 5-hydroxytryptophan (5-HTP; immediate precursor of 5-HT) with or without treatment with rapamycin (mTOR inhibitor; autophagy enhancer). We investigated autophagy and proinflammatory cytokine production in colonic epithelial cells (HT-29 cells) following stimulation by 5-HT. Tph1-/- mice, with reduced levels of DSS-colitis compared to Tph1+/+ mice, had upregulated autophagy markers. SERT-/- mice with increased colitis had reduced levels of autophagy. Administration of 5-HTP to Tph1-/- mice receiving DSS replenished the 5-HT levels in the gut, increased severity of colitis and decreased levels of autophagy. These findings in Tph1-/- mice following administration of 5-HTP were reversed by treatment with rapamycin. 5-HT treatment of HT-29 cells resulted in down-regulation of autophagy and upregulation of proinflammatory cytokine, IL-8. These findings suggest that an increase in 5-HT in colitis inhibits autophagy that contribute to disease severity. Blocking 5-HT signalling can promote autophagy and alleviate the severity of colitis. Understanding the contribution of 5-HT in autophagy may ultimately identify new therapeutic target in intestinal inflammatory conditions such as IBD that exhibit dysregulated autophagy. Ontario Graduate Scholarship
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".