A119 THE MICROBIAL METABOLITE SENSOR PREGNANE X RECEPTOR (PXR) RESTRAINS FIBROBLASTS FROM PROMOTING INTESTINAL INFLAMMATION AND FIBROSIS IN MICE
Bibliographic record
Abstract
Fibrosis contributes to intestinal stricture and obstruction in 30–50% of Crohn’s disease patients. The pathogenesis of fibrosis is incompletely understood and has virtually no effective treatments. The pregnane X receptor (PXR), a xenobiotic receptor involved in detoxification responses, has been identified as a modulator of fibrosis in hepatic stellate cells. Of the number of foreign ligands for the PXR, the tryptophan metabolite indole-3-propionic acid (IPA) produced by the intestinal commensal Clostridium sporogenes can bind to the PXR to mediate signalling events that protect intestinal barrier function. The role of the PXR in intestinal fibrosis and if microbial metabolite sensing can affect intestinal fibrotic responses is unknown. To examine the role of the PXR and its ability to sense microbial metabolites in the modulation of intestinal fibrosis. Intestinal inflammation was induced using DSS (3.5%) for 5 days followed by healing for 25 days. Fibrosis was assessed using Masson’s trichrome and Sirius Red staining of colonic sections. Mouse primary colonic fibroblasts were grown from wild type (WT) and PXR-/- mice and stimulated with cytomix (TNFα, IL1β, and IFNγ) for 24 hours to assess cytokine production by Luminex. Fibroblasts were also stimulated with cytomix in the presence of the PXR agonists PCN or IPA and assessed for gene expression via qPCR. NFkB activity was assessed by Western blot for phos-p65. To examine the microbiota’s role in fibrosis, after the 5-day course of DSS the microbiota was depleted for 25 days with an antibiotic cocktail (vancomycin, neomycin, metronidazole, ampicillin). C. sporogenes DNA was detected in feces using qPCR. Following a 25-day recovery after DSS, WT mice demonstrated clear intestinal fibrosis. When compared to WT mice, PXR-/- mice demonstrated significantly greater levels of fibrosis. Mouse primary fibroblasts were found to express the PXR. Following stimulation with cytomix, PXR-/- fibroblasts produced dramatically higher levels of inflammatory cytokines including eotaxin, CXCL2, G-CSF, GM-CSF, IL-9, and IL-15. Importantly, PCN and the microbial metabolite IPA suppressed the expression of these cytokines. These effects in PXR-/- fibroblasts may be linked to the increased activity of NFkB that was observed both basally and after stimulation with cytomix compared to WT fibroblasts. Depletion of the microbiota supressed levels of C. sporogenes DNA in feces and exacerbated intestinal fibrosis. PXR signaling in intestinal fibroblast appears to be required to restrain inflammation and fibrosis. Luminal sensing of bacterial derived indoles (i.e. IPA) via PXR may be involved in this process, highlighting a xenobiotic-microbiota axis that could be targeted to prevent the intestinal fibrosis observed in Crohn’s disease. CCCBeverley Phillips Rising Stars Program, The Dr. Lloyd Sutherland Investigator in IBD/GI Research, Canadian Foundation for Innovation, Canada Research Chairs Program, U.S. Department of Defense
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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) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.006 | 0.002 |
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".