ATG16L1 deficiency exacerbates acute small intestinal epithelial damage.
Bibliographic record
Abstract
Abstract Polymorphisms of the autophagy-related gene ATG16L1 are known to contribute to the genetic risk for developing Crohn’s Disease (CD), an inflammatory bowel disease that can affect the entire gastrointestinal tract. Previous studies have shown a role for autophagy in the intestinal epithelium both in Paneth cell function and in protection from intestinal damage, but no spontaneous disease at baseline. Here, we challenged mice specifically deleted for Atg16l1 in intestinal epithelial cells (Atg16l1ΔIEC) with the anti-CD3 mediated model of acute small intestinal injury. Rapid T cell activation by anti-CD3 injection results in small intestinal damage within 24 hours of injection, this typically self-resolves in wild-type mice 5 days post treatment. We found that autophagy sufficiency was protective in anti-CD3 induced injury. Atg16l1ΔIEC mice had higher mortality and worsened pathology in comparison to their wild-type littermates. We found indications of increased intestinal barrier permeability and crypt cell apoptosis in Atg16l1ΔIEC mice. In addition, expression of interferon gamma (IFNγ) and tumour necrosis factor (TNF) was significantly increased in Atg16l1ΔIEC mice, cytokines that have been implicated in driving intestinal injury in autophagy-deficient mice. Antibody-mediated blockade of either TNF or IFNγ rescued survival of Atg16l1ΔIEC mice. Interestingly, anti-IFNγ abolished both the crypt cell apoptosis and Paneth cell death at 24 hours, whereas anti-TNF did not decrease the crypt cell apoptosis or Paneth cell death, suggesting IFNγ is the primary contributor to pathology in this model. Overall, this work implicates intestinal epithelial autophagy in the protective response to acute intestinal injury.
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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) | 0.001 | 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) | 0.003 | 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".