A19 BACTERIAL PROTEASES INCREASE SENSITIVITY TO DIETARY ANTIGEN THROUGH PAR-2 SIGNALING
Bibliographic record
Abstract
Microbial-dietary-host interactions are generally homeostatic but when dysfunctional, can incite food sensitivities such as celiac disease in genetically predisposed people. However, the specific pathways involved and sequence of events remain poorly understood. We have previously shown that bacterial metabolism of the common dietary antigen, gluten, affects its immunogenicity. Here we tested whether microbial proteases able to degrade gluten also activate innate immune mechanisms important for the development of food sensitivity. Clean SPF (Altered Schaedler flora colonized) C57BL/6 and NOD-DQ8 mice were colonized with wild-type (WT) Pseudomonas aeruginosa strain PA14 or its lasB mutant derivative (lacking elastase activity) and then sensitized and challenged with gluten. In order to study bacterial-host specific interactions, germ-free mice were also colonized with both P. aeruginosa strains (WT and lasB) and placed on a gluten-free diet. Finally, SPF protease-resistant PAR2 mutant mice were colonized with WT and lasB. Small intestinal microbial composition, proteolytic activity, intraepithelial lymphocyte (IEL) counts, expression of specific innate genes, bacterial infiltration in the mucus layer and villus-to-crypt (V/C) ratios were measured in all mice. P. aeruginosa expressing elastase, previously shown to participate in the intestinal metabolism of gluten peptides, produced a PAR-2 pro-inflammatory response associated with increases in IELs in clean-SPF and GF C57BL/6 mice, independently of gluten treatment. This response was characterized by an increased expression of certain genes related to IEL induction and cytotoxicity, barrier function, and autoimmunity including Ifnγ, Tnfα, Tgfβ, Il6, IL17, IL22 and Fasl in the IEL compartment. Moreover, the presence of P. aeruginosa expressing elastase also led to shifts in the microbiota composition and bacterial encroachment to the mucosa. In NOD-DQ8 mice, a mouse model of gluten sensitivity, P. aeruginosa expressing elastase enhanced gluten immunopathology characterized by a reduction in V/C ratios. Bacterial protease, previously shown to degrade gluten peptides, can directly impact the host immune response through activation of PAR-2 and contribute to small intestinal pathology. This pathway could be targeted therapeutically in genetically susceptible individuals to prevent celiac disease. CAG, CIHRFarncombe Institute Postdoctoral Fellowship
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".