A6 INVESTIGATING THE RELATIONSHIP BETWEEN MUCOSAL INFLAMMATION AND PROTEOLYTIC ACTIVITY IN CROHN’S DISEASE
Bibliographic record
Abstract
Abstract Background Dysregulated proteolytic activity (PA) has been detected in intestinal biopsy samples of individuals with inflammatory bowel disease (IBD) compared to healthy controls. It is known that increased microbial fecal PA precedes ulcerative colitis (UC) diagnosis in an at-risk population. Intestinal inflammation in UC is characterized by continuous ulceration, inflammation in Crohn’s disease (CD) is patchy in nature. Sites of inflammation in CD has been associated with altered mucosa-associated microbes and higher permeability, suggesting these could be localized sites of increased microbial PA. Aims To investigate whether inflamed mucosal areas in CD are associated with proteolytic microbiota and increased permeability. Methods CD patients in flare (n=23) were recruited at McMaster University Medical Centre and matched (or paired) biopsies were collected at colonoscopy from inflamed and adjacent (within 5 cm) non-inflamed sites. Biopsy mucosal-to-serosal 51Cr-EDTA flux rate and tissue conductance were measured with Ussing chambers. Total proteolytic (trypsin), elastase-like (FITC-elastin), and mucolytic (0.05% mucin plates) activities were also assessed in biopsies from both sites and in situ zymography was used to measure and localize elastase-like activity in biopsy samples. Mucosal brushing samples from the same participants were also collected and total RNA purified for metatranscriptomic analysis to characterize active microbial pathways with a focus on identifying highly expressed microbial proteases. Results Paracellular permeability and tissue conductance were greater in biopsies from inflamed areas than in biopsies from matched non-inflamed areas (p<0.001). Elastase-like and mucolytic activities were higher in inflamed areas compared to matched non-inflamed areas (p<0.05 and p=0.04, respectively), no significance was detected in total proteolytic activity. In situ zymography revealed greater elastase-like activity in inflamed areas compared to non-inflamed areas (p=0.04), localized to both the epithelial and submucosa layers in inflamed tissues but only to the epithelial layer in matched non-inflamed tissue. Preliminary analysis of the metatranscriptomics results suggests that specific microbial proteases may be increased at inflamed sites in CD. Conclusions Our results suggest that localised variations in tissue inflammation, PA and mucosal permeability in CD may be causally linked, providing a rationale for the patchy distribution of mucosal injury. We, therefore, hypothesize that microbial elastase-like activity promotes mucosal inflammation through barrier disruption. This mechanism could be targeted locally to prevent or modulate microbially associated PA with the aim of enhancing mucosal healing in IBD. Funding Agencies:
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
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".