A119 THE MICROBIAL METABOLITE SENSOR PREGNANE X RECEPTOR (PXR) RESTRAINS FIBROBLASTS FROM PROMOTING INTESTINAL INFLAMMATION AND FIBROSIS IN MICE
Notice bibliographique
Résumé
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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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».