Activation Of The Constitutive Androstane Receptor Enhances Wound Healing – A New Link Between Xenobiotic Sensing And Intestinal Mucosal Homeostasis?
Bibliographic record
Abstract
Background Compounds released from the intestinal microbiota may play a role in maintaining mucosal homeostasis, but little is known about the receptors that sense and respond to these compounds. Recently a cytosolic xenobiotic sensor, called the pregnane X receptor (PXR), was identified as a receptor for microbial metabolites, and shown to play a key role in regulating intestinal epithelial barrier and wound healing following injury. In the current study, we sought to determine whether the constitutive androstane receptor (CAR), which shares structural, functional and pharmacological features with the PXR, plays a role in regulating wound healing and mucosal repair. Methods Caco‐2 intestinal epithelial cells were used to model wound healing. Wounds formed using Ibidi culture inserts were treated with CITCO, a selective human CAR agonist, and imaged for 24 hours. Wound closure was quantified and cell migration tracks assessed. To interrogate the intracellular events involved in the CITCO‐induced responses, we assessed the role of p38 MAPK and ERK1/2 signaling in our assays, along with proliferation and migration (xCELLigence impedance‐based migration assay). To determine the role of the CAR in vivo , we assessed recovery from dextran sulphate sodium (DSS)‐induced colitis (2.5% W/V in drinking water; 5 days exposure, followed by 9 days of recovery) in CAR‐deficient mice and WT mice treated with TCPOBOP (3 mg/kg; IP; daily during recovery phase), a selective rodent CAR agonist. Results Activation of the CAR enhanced wound closure in Caco‐2 monolayers, which was associated with increased cell migration, but not proliferation. The enhancement of cell migration was dependent on p38 MAPK signaling. Treating WT mice with a CAR agonist accelerated their recovery from DSS‐induced colitis. In contrast, CAR‐deficient mice exhibited delayed recovery. Conclusions Our data suggest that the CAR regulates the cellular events that contribute to wound healing and mucosal restitution following injury. While the microbe‐derived compounds that activate the CAR have yet to be identified, its close relative, the PXR, has been shown to respond to such ligands. Taken together, we posit that xenobiotic receptors play a key role in regulating the response to injury and may provide new therapeutic targets to enhance mucosal repair. Support or Funding Information Crohn's & Colitis Canada; Canadian Foundation for Innovation; The Dr. Lloyd Sutherland Investigatorship in IBD/GI Research
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 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 teacher head, 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".