A49 LACTOBACILLI DEGRADE WHEAT AMYLASE TRYPSIN INHIBITORS (ATI) TO AMELIORATE GUT DYSFUNCTION INDUCED BY IMMUNOGENIC WHEAT PROTEINS
Notice bibliographique
Résumé
Wheat-related disorders involve a wide spectrum of conditions, triggered by the ingestion of gluten-containing cereals. The induction of gluten-specific immune responses in celiac disease is well established. However, the contribution of gluten and/or non-gluten proteins in the generation of symptoms in other wheat-related disorders is controversial. Amylase trypsin inhibitors (ATIs) are pest-resistant molecules in modern wheat with TLR4-activating capacities. We investigated the role of ATIs in the generation of gut barrier dysfunction and dysmotility in wild-type mice as well as in the severity of gluten-induced immunopathology in genetically predisposed mice. We also determined the metabolic capacity of core microbial groups to degrade ATIs, and examined how this impacts ATIs or gluten-induced gut dysfunction. To determine if ATIs could induce gut dysfunction in non-genetically susceptible mice, C57BL/6 or Myd88-/- mice were placed on a wheat free diet (WFD) or ATI diet for 1 week. To study the adjuvant effect of ATIs, NOD/DQ8 mice sensitized with cholera toxin and gliadin received a diet containing: 1) ATIs with no gluten (ATIs), 2) gluten depleted of ATIs (G-ATIs), or 3) depleted gluten supplemented with ATIs (G+ATIs), for 2 weeks. Non-sensitized NOD/DQ8 (controls) received a WFD for 2 weeks. To study the metabolic capacity of microbes to degrade ATIs in vivo, Lactobacillus strains isolated from the human intestine and with different hydrolytic capacity against ATI were pooled and supplemented to mice by oral gavage daily during dietary intervention. CD3+ intraepithelial lymphocytes (IELs) were measured by immunohistochemistry, intestinal permeability by Ussing chambers, gene expression by Nanostring Technology and 16S rRNA profiling of cecal microbial content via Illumina MiSeq. We show that ATIs not only induce innate immune responses through the TLR4-MD2-CD14 pathway, but also barrier dysfunction in C57BL/6 mice in the absence of overt mucosal damage. When combined with gluten in mice with a permissive celiac genetic background (NOD-DQ8 transgenic), ATI exacerbate gluten-induced immunopathology increasing intestinal permeability, IEL proliferation and upregulation of pro-inflammatory genes. We also demonstrate that ATIs can be degraded by certain commensal bacteria such as Lactobacillus, thereby reducing their immune-stimulatory capacity in mouse models. ATIs may play a role in wheat-related disorders. Microbiome-modulating strategies based on the use of strains with specific ATIs-degrading capacity may be effective in patients with wheat-sensitive disorders. CAG, CIHR
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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 | 0,000 | 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 ».