A35 MICROBIAL PROTEOLYTIC SIGNATURE IN ULCERATIVE COLITIS INDUCES AN INFLAMMATORY SIGNATURE IN MICROBIOTA-HUMANIZED MICE
Notice bibliographique
Résumé
Abstract Background Altered gut microbiota composition has been associated with inflammatory bowel diseases (IBD) including ulcerative colitis (UC), but causality and bacterially-driven mechanisms, are unclear. Proteases within the gastrointestinal tract play a critical role in maintaining homeostasis and are tightly regulated by anti-proteases. Host-derived proteolytic imbalances have been described in IBD, including UC, however, the role of intestinal microbiota as a source of proteases and anti-proteases has largely been ignored. Aims To study microbial proteolytic activity and intestinal microbiota profiles in a cohort of individuals at-risk for IBD, and in those individuals that develop UC at follow-up. Methods Fecal samples were collected from healthy individuals at-risk for IBD and who went on to develop UC (pre-UC; n=14) and again after UC diagnosis (post-UC, n=10). Fecal samples from matched at-risk individuals that did not develop UC were used as healthy controls (n=52). Overall fecal proteolytic and elastolytic activity was measured. We performed metagenomics sequencing in 4 UC subjects (pre and post) and 4 matched HC using Illumina Hi-Seq from stool DNA. To investigate bacterial origin and functional significance, pregnant germ-free (GF) mice were colonized with a fecal sample from a selected UC subject (pre and post) and a matched HC. Naturally colonized litters were followed for 12 weeks, after which proteolytic activities and signs of inflammation were measured. Results Fecal proteolytic and elastase activity was increased in pre- and post-UC samples compared to HCs. Metagenomics revealed over 20k genes were significantly different between HC and pre-UC samples, and of these, 440 related to proteases and peptidases. Increased fecal proteolytic activity, higher lipocalin levels, and increased colonic polymorphonuclear cells in colonic H&E sections was observed in pre- and post-UC colonized mice compared to HC colonized mice. Mice colonized with pre-UC microbiota showed increased mRNA expression of genes linked to immunological disease, antimicrobial and inflammatory responses (ie. Tlr2, Tlr5, Nod2, and Il1b) as compared to HC colonized mice. Conclusions These results suggest increased fecal proteolytic activity is observed prior to the onset and clinical diagnosis of UC in patients at-risk for IBD, and upon transfer to mice born from colonized GF dams, low-grade inflammation develops. These pathways could be developed as novel non-invasive biomarkers to monitor at-risk populations. Submitted on behalf of the CCC-GEM Project consortium. Supported by CCC GIA to EF Verdu Funding Agencies CCC
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,001 |
| Intégrité de la recherche | 0,001 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,001 |
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 source (Gemma direct ou Codex distillé), 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 ».