A13 PROTEOLYTIC BACTERIA PROMOTE INNATE IMMUNE ACTIVATION AND GLUTEN-INDUCED PATHOLOGY IN MICE.
Bibliographic record
Abstract
Celiac disease (CeD) is an immune-mediated enteropathy triggered by gluten in genetically susceptible individuals expressing the HLA-DQ2 or DQ8 genes. Only 2–4% of genetically susceptible individuals develop CeD, suggesting additional environmental triggers contribute to disease pathogenesis. Duodenal dysbiosis has been described in CeD, but no causative mechanisms been described. We have previously isolated Pseudomonas aeruginosa (Psa), an elastase-producing opportunistic pathogen, from the duodenum of active CeD patients that increases gluten peptide immunogenicity through its gluten metabolism. Here we determined whether microbial-derived elastolytic activity induces innate immune activation, a key step for enteropathy development in CeD. Altered-Schaedler flora (ASF)-colonized C57BL/6 (non-susceptible) and NOD/DQ8 (genetically susceptible) mice were supplemented with Psa prior to gliadin sensitization and challenge. Non-sensitized mice and mice supplemented with a Psa mutant lacking elastase activity (LasB) were used as controls. Small intestinal proteolytic activity, intraepithelial lymphocyte (IEL) counts and villus-to-crypt (V/C) ratios were measured following gluten challenge. ASF-colonized C57BL/6 and NOD/DQ8 mice had low proteolytic activity in small intestinal washes and were protected from gluten-induced pathology following gluten sensitization and challenge. In ASF-colonized mice supplemented with Psa (ASF-Psa), gluten exposure increased small intestinal Psa load, which paralleled increased elastase activity in small intestinal washes. ASF-Psa colonization led to increased small intestinal IELs, independent of gluten exposure, in both the non-susceptible C57BL/6 and the genetically susceptible NOD/DQ8 mice. However, reduction in small intestinal V/C ratios was only observed in ASF-Psa-colonized NOD/DQ8 mice exposed to gluten. No increase in IELs or enteropathy were observed in ASF mice supplemented with the LasB mutant. These results suggest that bacterial-derived elastase from opportunistic pathogens, such as P. aeruginosa, may directly promote IEL proliferation contributing to gluten-induced pathology in genetically susceptible hosts. Microbial-derived elastolytic activity constitutes a mechanism, in addition to its gluten metabolic activity, through which tolerance to this common dietary protein may be broken. It also opens the road to adjuvant therapies to the gluten-free diet based on protease inhibitory therapy. CIHR
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 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".