Protective Actions of 5‐HT <sub>4</sub> Receptors in the Colonic Epithelium
Bibliographic record
Abstract
5‐HT 4 receptors are expressed in colonic epithelium, and activation with 5‐HT 4 receptor agonists causes 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. CD‐1 mice were given DSS (4% w/v for 5 days in drinking water) or TNBS (7.5 mg/mL) on day 0. 5‐HT 4 receptor agonist (Tegaserod, 1mg/kg), vehicle, or antagonist (GR 113808) plus agonist was delivered by enema daily day 1–7 (prevention) or day 6–15 (recovery) to determine the effects of epithelial 5‐HT 4 receptor activation in colitis. To test the actions of 5‐HT 4 receptors under basal conditions, GR 113808 was administered to normal mice by enema for 10 days. Colitis was evaluated using disease activity index (DAI) and histological damage scores (HDS). Possible protective actions such as cell proliferation in colonic tissue and migration and resistance to oxidative stress in CaCo‐2 cell culture were also explored. To investigate function, we evaluated propulsive motility in the guinea pig distal colon. Intraluminal tegaserod treatment in both DSS and TNBS‐inflamed animals significantly attenuated the development of, and accelerated the recovery from, colitis in an antagonist‐sensitive manner. However, administration of Tegaserod (1 mg/kg) by intraperitoneal injection had no effect. TNBS‐induced dysmotility in guinea pigs was reversed by 5‐HT 4 receptor agonist treatment, and this action was blocked by the atagonist. Increased cell proliferation was detected in the form of increased Ki‐67 immunoreactivity in crypts of inflamed animals treated with Tegaserod. We also observed areas of accelerated healing of scratches and increased resistance to H 2 O 2 induced oxidative stress in CaCo‐2 cells. Interestingly, antagonist treatment alone in normal mice resulted in significant increases in DAI, HDS, and bacterial translocation in mice, as well as disrupted motility patterns in guinea pig colon. In summary, activation of 5‐HT 4 receptors on the colonic epithelium reduces the development of, and accelerates recovery from, colitis. It is likely acting through increased wound healing by increased cell migration and cell proliferation, as well as resistance to apoptosis. Additionally, 5‐HT 4 receptor activation protects colonic motility. Taken together, these data suggest that epithelial 5‐HT 4 receptors have a protective effect in the normal and inflamed colon. Support or Funding Information Funded by DK62267
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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 | 0.001 |
| 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".