A48 COLITIS FAVORS THE EXPANSION OF BACTERIA THAT ACTIVATE PAR2 AMPLIFYING INFLAMMATORY RESPONSE
Bibliographic record
Abstract
Abstract Background Proteolytic imbalance has been described in patients with inflammatory bowel disease (IBD) and in different models of experimental colitis. Although the proteases reported to be increased are mainly from the host, the role of bacterial proteases has recently emerged, as they can promote inflammation, in part, through activation of Protease-activated receptors (PARs). PAR2 deficient mice are resistant to inflammation and PAR2 activation affects multiple aspects of the tissue response to injury. However, PAR2 communicates with other receptors such as toll-like and other PARs, which are important in multiple immune signaling pathways. Thus, the direct implication of PAR2 in colitis, and specifically the activation of the external domain by microbial proteases, remains unclear. Aims To study the role of PAR2 and bacterial proteases in experimental colitis. Methods C57BL/6 and protease-resistant PAR2 (R38E-PAR2) mice, in which activation site of PAR2 is missing, were given 3.5% dextran sodium sulfate (DSS) in drinking water for 5 days followed by 2 days of water. Control C57BL/6 (wild-type) and R38E-PAR2 mice received only water. Percent weight change was evaluated along the study. Fecal microbiota (16S Ilumina), expression of proinflammatory genes (Nanostring), gut permeability (Ussing chamber), proteolytic activities (colorimetric assay) and bacterial translocation (plating) were measured in all mice at sacrifice. Inflammation was determined by analyzing stool consistency, fecal blood and by microscopic scores (Cooper score). Bacteria with proteolytic activity were isolated using agar-media with protein as main nutrient and bacterial capacity to release the external domain of PAR2 was tested in cells harbouring luciferase at the PAR2 N terminus. Results Wild-type, but not R38E-PAR2 mice, had increased expression of several pro-inflammatory genes, such as tnf, map3k and tlr, gut dysfunction and increased intestinal permeability, increased bacterial translocation into spleen and altered microbiota profiles following DSS treatment. DSS induced colitis in both mouse strains, but clinical and microscopic scores were significantly lower in R38E-PAR2 compared with wild-type mice. DSS increased the abundance of opportunistic pathogens such as Enterococcus and Staphylococcus only in wild-type mice. Proteolytic phenotype of these bacteria, and their capacity to cleave the external domain of PAR2, was confirmed. Conclusions Mice lacking the activation site of PAR2 are protected from DSS-induced colitis. DSS treatment leads to expansion of bacteria releasing active proteases, which may mediate injury through PAR2. These results suggest that intestinal injury promotes microbial proteolytic imbalance which in turn, exacerbates inflammation. Funding Agencies CAG, CCC, 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) | 0.000 | 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) | 0.006 | 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".