Muc2 Limits Pathogen Burdens and Epithelial Barrier Dysfunction During Salmonella Typhimurium Colitis
Bibliographic record
Abstract
Commensal as well as pathogenic bacteria have been implicated as possible triggers of Inflammatory Bowel Disease (IBD). The ability of pathogens to cause episodes of infectious gastroenteritis could play a role in the initiation, and/or exacerbation of IBD. In fact, an increased risk of IBD has been reported in individuals who suffer an acute episode of Salmonella gastroenteritis. For Salmonella to cause gastroenteritis, it has to directly infect the epithelial cells lining the mammalian intestine. Despite many studies exploring Salmonella interactions with epithelial cells, it is unclear how this pathogen evades and survives the array of host defenses found in the mammalian intestine. In particular it is unclear how Salmonella interacts with as well as crosses the mucus layer that protects the underlying intestinal epithelial cells from such noxious agents. Salmonella enterica serovar Typhimurium is a model organism used to test the virulence factors involved in Salmonella pathogenesis. To study Salmonella’s ability to cause intestinal inflammation, most groups use a colitis model relying on streptomycin to displace intestinal commensal microbes, resulting in heavy pathogen colonization of cecal tissues and severe inflammation. Although intestinal mucus is the first line of defense in the mouse GI tract, its role in providing host defense against Salmonella is still unclear. The mucus barrier is made up of the highly glycosylated mucin Muc2, which is secreted by goblet cells. Muc2 glycosylation occurs within the goblet cell and likely has significant implications for the function and effectiveness of the mucus barrier. Glycosylation involves the actions of several enzymes, for example, Core 3- O derived glycans are synthesized by Core 3 β1,3-N-acetylglucosaminyltransferase (C3GnT). Mice lacking these glycans still produce the Muc2 protein, but display a thinner mucus barrier, and show increased susceptibility to chemical induced colitis. We began our investigations by comparing Salmonella induced colitis and mucus dynamics in Muc2 deficient (-/-) mice, C3GnT-/- mice and wildtype C57BL/6 mice. We observed that mucus secretion increased in response to Salmonella infection in C3GnT-/- and C57BL/6, with Salmonella found within the mucus layer. In contrast, Muc2-/- mice showed dramatic susceptibility to Salmonella infection, carrying 100 fold heavier cecal pathogen burdens and developing significantly increased barrier disruption compared with C57BL/6 mice. As a result, Muc2 -/- mice displayed high rates of morbidity and mortality. We also tested the susceptibility of C3GnT -/- mice, finding they carry WT pathogen burdens but developed exaggerated barrier disruption like Muc2 -/- mice. These data suggest that the intestinal mucus layer plays a critical role in controlling Salmonella intestinal burdens, whereas core-3 glycosylation plays an important role in controlling intestinal epithelial barrier function.
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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) | 0.001 | 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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
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".