A209 ROLE OF SEROTONIN-AUTOPHAGY AXIS IN REGULATION OF EPITHELIAL CELL FUNCTION AND MICROBIOTA COMPOSITION IN GUT
Bibliographic record
Abstract
Abstract Background Serotonin (5-hydroxytryptamine; 5-HT), an enteric signalling molecule mainly produced by the enterochromaffin (EC) cells of the intestinal epithelium regulates various processes of the gut. Tryptophan hydroxylase 1 (Tph1) is the rate-limiting enzyme of 5-HT biosynthesis in EC cells. In inflammatory bowel disease (IBD) and experimental colitis, there are alterations in 5-HT content and microbiota composition in the gut. Previously we reported, Tph1-deficient (Tph1-/-) mice with reduced 5-HT in the gut exhibit reduced susceptibility to colitis. The mechanism by which 5-HT regulates colitis is unknown. Autophagy, a catabolic process regulates the function of intestinal epithelial cells (IECs), gut microbiota, and protects against intestinal inflammation. Both aberrant 5-HT signalling and autophagy is implicated in colitis. It is unclear whether they interact in regulation of production of pro-inflammatory cytokines from IECs and gut microbiota composition in relation to colitis. Our hypothesis is, an increase in 5-HT signalling inhibits autophagy in the IECs, which results in up-regulation of colitis by increasing the production of pro-inflammatory cytokines, and by selection for a more colitogenic microbiota. Aims To define the role of 5-HT-autophagy axis in the production of pro-inflammatory cytokines from IECs and gut microbiota composition in intestinal inflammation. Methods We investigated level of autophagy with or without 5% dextran sodium sulphate (DSS) in colons, mucosal scraping and IECs of Tph1-/- and their wild-type (WT) littermates. In addition, autophagy and proinflammatory cytokine production were investigated in human colonic epithelial cells (HT-29) following stimulation by 5-HT. We evaluated colitis and gut microbiota composition in WT, Tph1-/-, epithelial-specific autophagy gene Atg7 deficient (Atg7ΔIEC), and Atg7ΔIECTph1-/- (double knock out; DKO) mice. Results Tph1 -/- mice, with less 5-HT in the gut than WT mice following DSS administration exhibited an up-regulation of autophagy markers in the colon, mucosal scraping and IECs along with reduction of colitis severity. 5-HT treatment of HT-29 cells resulted in down-regulation of autophagy and upregulation of pro-inflammatory cytokine, IL-8. DKO mice exhibited increased severity of DSS-colitis, and altered microbiota composition compared to Tph1-/- mice. Conclusions These findings suggest, an increase in 5-HT in colitis inhibits autophagy in the IECs that contribute to alteration of the gut microbiota and disease severity. Blocking 5-HT signalling may promote autophagy in the IECs and alleviate the severity of colitis. Understanding the contribution of 5-HT in autophagy may identify new therapeutic target in IBD and other intestinal inflammatory conditions that exhibit dysregulated autophagy. Funding Agencies CAG, CIHR
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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".