A116 ABERRANT IMMUNE RESPONSE AGAINST INVADING BACTERIA INCREASES MORTALITY IN MUC2 MUCIN DEFICIENT MICE IN LPS INDUCED SEPSIS
Bibliographic record
Abstract
A physical barrier in the gut, formed mainly by the mucus bilayer, keeps gut microbiota and/or components away from translocating into host tissues. Perturbation of the mucus layer, as in inflammatory bowel diseases (IBD), leads microbial penetrants to initiate local and systemic inflammation. Unregulated inflammation can aggravate into sepsis, causing mortality due to multiple organ failure. IBD patients are at high risk for developing sepsis due to their defective gut barrier function, yet is poorly understood. Muc2-/- mice without a mucus barrier have low-grade inflammation with bacterial penetrants and is an excellent model to study chronic colitis and ideal for IBD related studies. To assess immune response in Muc2-/- mice in lipopolysaccharide (LPS) induced sepsis. LPS was administered in Muc2-/- and WT littermates intra-peritoneally (i.p.) as 5mg/kg body weight (BW) and monitored for BW loss and mortality. Mice were euthanized at 24 or 48 h. Spleen and intestinal tissue were harvested for immunophenotyping and histology. Single cell suspension of splenocytes were prepared and stained with anti CD3, CD4, CD8, CD19 and CD49b antibodies for T-cells, B-cells and NK cells. Apoptotic and dead cells were determined by Annexin V and 7-AAD staining. Immunophenotyping was done using FACS Canto and data was analyzed by FlowJo software. Bacterial penetrance into distal ileum, cecum and colonic tissue was determined using fluorescence in situ hybridization (FISH) and real time RT-PCR. Muc2-/- mice basally exhibited significantly larger numbers of splenic B-cells, CD8+ cells and NK cells than WT littermates suggesting ongoing elevated systemic inflammation. CD4+ cells were unchanged. Notably, Muc2-/- mice exhibited increased apoptosis of splenic B-cells at baseline indicating systemic inflammation and immunosuppression. Following LPS induced sepsis, we observed increased bacterial penetrance through the distal ileum, cecum and colonic walls of Muc2-/- mice at 24 and 48 h as compared to WT littermates. In WT littermates, LPS treatment led to massive accumulation and secretion of mucus (mucus plug) in the lumen that impaired bacterial translocation. Moreover, splenocytes in LPS induced sepsis showed significantly increased apoptosis of B-cells, decreased apoptosis of CD4+ and CD8+ cells in Muc2-/- as compared to WT littermates. The aberrant immune response in Muc2-/- mice was correlated with significantly increased bacterial burden in the liver and spleen resulting in rapid BW loss and mortality. Our research suggests that during chronic IBD, host immune cells may become exhausted with continual exposure to microbial penetrants leaking through the altered and/or depleted intestinal mucus barrier. This can result in aberrant immune response against invading pathogens and increased susceptibility to sepsis. 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 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.003 |
| Insufficient payload (model declined to judge) | 0.007 | 0.002 |
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".