Protective Actions of 5-HT4 Receptors in the Colonic Epithelium
Bibliographic record
Abstract
5-HT4 receptors are expressed in colonic epithelium, and activation with 5-HT4 receptor agonists causes a number of responses, including mucus secretion from goblet cells, chloride secretion from enterocytes, and 5-HT release from enterochromaffin cells. We tested whether this receptor could serve a protective role in models of colitis and under basal conditions. Male CD-1 mice (Charles River, Canada) were administered dextran sodium sulfate (DSS; 4% w/v in tap water, MW: 40,000) or trinitrobenzene sulfonic acid (TNBS; 7.5mg/mL in 50% ethanol by enema) on day 0. Treatment with the 5-HT4 receptor agonist, tegaserod (1 mg/Kg), or agonist plus the antagonist, GR113808 (1 mg/Kg), began either 24 hours after colitis induction and continued daily for 6 days (prevention paradigm), or 5 days after colitis was induced and continued for 10 days (recovery paradigm). To test for an action of 5-HT4 receptors under basal conditions, the antagonist, GR113808 was administered to normal mice by daily enema for 10 days. Colitis was evaluated using disease activity index (DAI) and histological damage scores (HDS). Possible protective mechanisms such as improved epithelial barrier function were evaluated by cell proliferation by Ki-67 immunostaining, whereas cell migration and resistance to oxidative stress were explored in CaCo-2 cells. We also tested the effects of tegaserod and/or GR113808 on colonic motility in guinea pigs, a well described model of colonic function. Treatment with tegaserod by enema in both DSS and TNBS-inflamed animals significantly attenuated the development of colitis, and accelerated recovery from established colitis, and these effects were blocked by 5-HT4 antagonist treatment. This effect was not seen when tegaserod was administered by intraperitoneal injection. TNBS-induced dysmotility in guinea pigs was significantly reversed by 5-HT4 receptor agonist treatment, but dysmotility persisted in animals treated with the agonist plus antagonist. We observed significant increases in the proportion of epithelial cells that were Ki-67 positive in DSS-inflamed mice treated with the agonist, and this effect was blocked by the antagonist. In CaCo-2 cells, 5-HT4 receptor activation accelerated cell migration into scratches on cell cultures, and increased resistance to oxidative stress-induced apoptosis, and these effects were blocked by the antagonist. Furthermore, treatment with the antagonist alone resulted in significant increases in disease activity index, histological damage scores and bacterial translocation in mice, and led to disrupted motility patterns in guinea pig distal colon. 5-HT4 receptor stimulation reduced the development of, and accelerated the recovery from, inflammation. These effects likely involved improved wound healing and resistance to oxidative stress. Interestingly, inhibition of 5-HT4 activity in normal animals resulted in inflammation, decreased epithelial proliferation and disrupted motility. Taken together, these data suggest that activation of mucosal 5-HT4 receptors has a protective effect in the normal and the inflamed colon.
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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) | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".