A16 SENSING OF A MICROBIAL METABOLITE BY FIBROBLASTS THROUGH THE PREGNANE X RECEPTOR RESTRAINS INFLAMMATION AND FIBROSIS IN MICE
Notice bibliographique
Résumé
Fibrosis is a serious and irreversible complication of Crohn’s disease (CD) that can lead to intestinal obstruction and has no effective treatment beyond surgical resection. The pathogenesis of fibrosis is incompletely understood however, it is thought to involve an aberrant repair response following inflammation-associated tissue damage. The pregnane X receptor (PXR), a xenobiotic receptor, is recognized for its role in suppressing inflammation and has been show to influence fibrogenesis in the liver. In the intestine, PXR-signaling is influenced by the tryptophan metabolite indole-3-propionic acid (IPA), which can affect intestinal inflammation, in turn influencing fibrogenesis. How microbial metabolite sensing through the PXR influences intestinal fibrotic responses has not been explored. To understand the impact PXR-signaling has on intestinal fibrosis and determine whether it can be modulated by IPA. Intestinal inflammation was induced using DSS (3.5%) for 5 days followed by healing for 25 days. Fibrosis in the colon was assessed using Masson’s trichrome and Sirius Red histological stains in wild type (WT), PXR-/-, epithelial-specific PXR-/- and fibroblast-specific PXR-/- mice. Immune cell influx was measured by flow cytometry and cytokine concentrations by Luminex. Fibroblasts isolated from WT and PXR-/- mice were stimulated with cytomix (TNF-α, IL-1β, and IFN-γ) or LPS in the presence or absence of IPA for 24 hours and assessed for gene expression. To examine the role of microbial metabolites in fibrosis, the microbiota was depleted using a cocktail of broad-spectrum antibiotics and some mice treated with IPA. Following recovery from DSS, WT mice showed clear evidence of colonic fibrosis, a response that was exacerbated in PXR-/- mice and correlated with greater neutrophil infiltration and levels of innate cytokines (e.g. CXCL2, GMCSF, GCSF,) in the colon. This phenotype was not observed when PXR deficiency was limited to the epithelial cells, but was reproducible in mice with fibroblast-specific PXR-deficiency. Mechanistically, PXR-/- fibroblasts were hyper-responsive to proinflammatory cytokines and LPS, producing increased levels of CXCL2, GM-CSF and G-CSF compared to WT cells. Importantly, the microbial metabolite IPA was able to block the expression of these cytokines. Depletion of the microbiota completely suppressed systemic levels of IPA and exacerbated intestinal fibrosis, an effect that was reversed by IPA treatment. PXR signaling in intestinal fibroblasts restrains their inflammatory responses, reducing fibrogenesis. Luminal sensing of the bacterial derived indole, IPA, via PXR may be involved in this process, highlighting a microbial metabolite-sensing pathway in fibroblasts that could be targeted to prevent intestinal fibrosis observed in CD. CAG, CCC, CIHRAbbvie/CAG/CIHR, Alberta Innovates, Canadian Foundation for Innovation, US Department of Defense
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
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 | 0,000 |
| 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 ».