A144 CHRONIC DSS LEADS TO ALTERED EXPRESSION OF IRAK4/TPL2 PATHWAYS IN UC-COLONIZED MICE
Bibliographic record
Abstract
Abstract Background Ulcerative colitis (UC) is one of two forms of inflammatory bowel disease (IBD). The exact cause of IBD is unknown but altered host-microbe interactions and genetic susceptibility are involved in its pathogenesis. Many patients with IBD do not respond to biological therapies targeting single cytokines, therefore new therapies that target common immune pathways are being developed and need to be tested in relevant preclinical models. Previously we have shown that mice colonized with UC microbiota upregulated genes related to inflammation without induction of colitis compared to healthy volunteer-colonized mice. We thus investigated whether IRAK4 and TPL2-induced pathways, new therapeutic targets in development upstream of inflammatory cytokine gene activation, are upregulated in mice colonized with UC microbiota and chronic colitis. Aims Our aim was to characterize TPL2 and IRAK4 signalling pathways and T cell phenotypes in UC-colonized mice following chronic low-dose dextran sodium sulfate (DSS) colitis. Methods 10-16-week-old germ-free C57BL/6 mice were colonized with fecal microbiota from a patient with UC experiencing a flare (n=16). Mice were housed in a gnotobiotic facility during the experiment. Three weeks following colonization, colitis was induced in half of the mice by three cycles (5 d each; 2.0%, 1.5% and 1.5%, respectively) of DSS in drinking water with a 5-d wash-out period between cycles. All mice were fed a control diet (7004, Teklad). Fecal samples were collected weekly. At sacrifice, disease activity (colon length, occult blood in feces, stool consistency, and spleen weight) was measured and colon tissue was collected for histological analysis and RNA sequencing. Mesenteric lymph nodes (MLNs) were acquired for flow cytometry to analyze T cell phenotypes. Results In UC-colonized mice, chronic low-dose DSS induced softer feces (p<0.0001), shorter colon length (p<0.0001), and increased spleen weight (p<0.0001), compared with water treated mice. This was paralleled by detectable blood in stool, development of moderate colitis (DSS: 1.9+/-1.4 vs H2O: 0.5+/-0.2; p<0.02) and higher proportion of IL-17 (p=0.003) and IFN-γ-producing T cells (p=0.06) in MLNs compared with water treated mice. RNA sequencing revealed that inflammatory genes, mainly related to the IRAK4/TPL2 pathway (e.g., Gadd45b, Socs3, Il1b), were significantly increased (p≤0.05) in the colon of mice treated with DSS compared with water. Conclusions When challenged with a chronic low-dose chemical injury agent, mice colonized with UC microbiota develop clinical and histological signs of colitis and upregulation of genes involved in inflammation like Gadd45b, Socs3, and Il1b. Thus, this model represents a new valuable tool for preclinical testing of new drug candidates, such as those related to the modulation of IRAK4/TPL2 pathways. Funding Agencies CCC
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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 | 0.002 |
| 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".