A172 GENETIC AND DIET-ASSOCIATED MUCUS IMPAIRMENTS INCREASE SUSCEPTIBILITY TO ULCERATIVE COLITIS PATHOBIONT-DRIVEN COLITIS.
Bibliographic record
Abstract
Abstract Background The Inflammatory Bowel Diseases (IBD), Crohn’s Disease (CD) and ulcerative colitis (UC) affect > 320,000 Canadians and are increasing in incidence. Ileal CD has been linked to the overgrowth of mucosal adherent-invasive Escherichia coli. Recent studies have also implicated the adherence of E. coli pathobionts to the colonic mucosa of UC patients. Using the representative UC E. coli pathobiont p19A, we recently demonstrated it aggravated chemical-induced colitis in susceptible mice, through the actions of the toxin alpha-hemolysin, and by adhering to the inflamed colonic mucosa via the adhesin FimH. It is less clear what host factors control susceptibility to UC pathobionts. I hypothesize that a key susceptibility factor is the glycosylated mucin Muc2, which forms the protective mucus layer that covers the colonic epithelium and is often impaired in UC patients. Aims To define the role of colonic mucus structure and function in determining susceptibility to the p19A pathobiont, and its ability to cause colitis in mice. Methods Susceptibility to p19A was tested in two mouse models of colonic mucus impairment. The first is a mouse strain deficient in core 1 derived O-glycans in their intestinal epithelial cells (IEC C1galt1-/-), resulting in reduced mucin glycosylation, and thus a thin and impaired mucus barrier. The second model involves feeding wildtype (WT) C57BL/6J mice a fiber-free (FF) diet, resulting in a significantly thinner colonic mucus layer. The mice were subsequently orally gavaged with p19A and their susceptibility determined by assaying p19A burdens, intestinal histopathology, inflammatory cytokine production. Results Following oral gavage of WT mice fed a normal diet, immunostaining identified p19A localizing within the colonic mucus layer, but it did not reach the epithelium or cause disease. In contrast, p19A regularly reached the colonic epithelial surface of mucus-impaired IEC C1galt1-/- mice (as compared to IEC C1galt1flox/flox mice) and in WT mice fed a fiber-free diet. This epithelial adherence was associated with increased p19A burdens, histopathology and production of inflammatory markers such as TNF-a and lipocalin 2. Notably, fiber-free diet-fed mice showed reduced SCFA levels in their feces and thinner mucus layer in their colon at baseline. Conclusions Our results indicate that UC E. coli pathobionts are able to reach the colonic epithelial surface and induce colitis in hosts suffering genetic or diet-based mucus dysfunction. This susceptibility highlights the important role played by intestinal mucus in protecting against IBD. Funding Agencies CCC, CIHR
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.007 | 0.001 |
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".