A86 EXPLORING GENE-ENVIRONMENT INTERACTIONS IN CROHN’S DISEASE: THE EFFECT OF VITAMIN D DEFICIENCY ON INTESTINAL HOMEOSTASIS IN THE CONTEXT OF SUSCEPTIBILITY GENE NOD2L1007FS
Bibliographic record
Abstract
Recent studies have implicated vitamin D deficiency in IBD susceptibility and outcomes. Although the mechanisms through which vitamin D affects IBD are not yet understood, emerging evidence from our lab and others demonstrate a role of vitamin D deficient signaling in dysregulating autophagy. In addition, vitamin D can modulate host immune responses and may play a role in regulating the stem cell niche. These effects of vitamin D have the potential to synergize with a major CD genetic risk factor, a frameshift mutation in the NOD2 gene (NOD2L1007fs or NOD2fs). NOD2fs results in a nonfunctional protein and causes dysregulation of inflammation and autophagy, pathways implicated in IBD pathogenesis. NOD2 mutations also effect the stem cell niche by causing dysregulation of Paneth cells, which represents an additional point of synergism for vitamin D deficiency and NOD2fs. We aim to determine if vitamin D deficiency in the context of the NOD2fs mutation results in alteration in intestinal homeostasis in vivo. We will also determine the effect of vitamin D on the intestinal epithelium using organoids generated from NOD2fs or wildtype mice. We hypothesize that vitamin D deficiency and the NOD2fs mutation will act synergistically to dysregulate autophagy and disrupt intestinal homeostasis, thereby promoting inflammation and driving susceptibility to CD. Mice homozygous for the NOD2fs CD susceptibility gene and wildtype littermates were fed either the vitamin D deficient (VDD) diet or matched control diet for 6 weeks. Ileum and colon sections were excised and lysates were used to assess the degree of autophagy between groups by western blotting for autophagy markers ATG16L1 and LC3II. Vitamin D ELISA of serum confirmed a significant reduction of vitamin D concentration in animals fed the VDD diet (p<0.0001). Unexpectedly, the NOD2fs mutation further reduced serum vitamin D concentration amongst animals on the control diet (p<0.0001) and animals on the VDD diet (p=0.051). The current results demonstrate reduction of ATG16L1 protein expression in ileal whole tissue lysates from animals with the NOD2fs mutation fed the VDD diet (p<0.05). This work will help to uncover gene-environment interactions involved in CD pathogenesis and will identify potential targetable pathways for development of novel therapies. The project has the potential for a translation through use of patient-derived organoids. CCCRestracomp (SickKids), Ontario Graduate Scholarship
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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) | 0.000 | 0.001 |
| 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) | 0.003 | 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".