A140 AN ATYPICAL NON-CELL AUTONOMOUS REGULATION OF GUT HOMEOSTASIS: THE CONTRIBUTION OF ENTEROCYTES-RELATED AUTOPHAGY
Bibliographic record
Abstract
Inflammatory bowel diseases (IBD) are multifactorial diseases associated with environmental and microbial factors as well as with specific genetic variants. Over the past years, GWAS identified various autophagy-related genes (ATG16L1, LRRK2, VAMP3) as susceptibility variants in IBD. Autophagy is an essential process, defined as the degradation and recycling of cytoplasmic components by the lysosomal machinery. Interestingly, defect in the autophagy process have been revealed in patients suffering from IBD. Although the contribution of autophagy to IBD is well established in Paneth cells, it is still unclear how enterocytes-related autophagy participate in such pathologies. Enterocytes (Ec) define the main intestinal cell population in direct contact with the lumen, thus representing an ideal target for IBD treatments. Our goal is to characterize the effect of autophagy inhibition in Ec on gut homeostasis and its contribution in IBD initiation and development. Drosophila is a well characterized organism with powerful genetic tool, representing an excellent model to investigate intestinal biology, as it is highly conserved with humans. Drosophila gut is composed of intestinal stem cells (ISC) that differentiate into progenitor cells that yield differentiated enteroendocrines (Ee) and Ec cells. Taking advantage of the cell specific inducible GAL4/UAS system available in drosophila, we independently depleted in Ec autophagy-related genes. In such context, various aspects of gut homeostasis were analyzed. Intestinal morphology and functional integrity were evaluated using nucleus staining (DAPI) and permeability assay. Additionally, Ec apoptosis and ISC proliferation were monitored. Furthermore, differentiated cell populations were assessed using Prospero (Ee) and Pdm1 (Ec) immunostaining. Finally, assessment of life survival effect was monitored by establishing lifespan curve. Our results show that silencing of the autophagy-related genes ATG16, VAMP3, ATG5, SYX17 and VAMP8 in drosophila Ec affects different facet of the intestinal epithelium, although it does not perturb either intestinal integrity or lifespan. Indeed, autophagy-related genes inhibition lead to an increase in cell density, which correlate with a gain in the rate of proliferative cells. Furthermore, we observe an increase in the rate of Ee. Such results strongly suggest a non-cell autonomous effect of Ec-related autophagy in regulating ISC proliferation and favoring Ee specification and/or differentiation, thus contributing to maintenance of gut homeostasis. Our data indicate that basal autophagy plays an important role in Ec to regulate intestinal homeostasis through regulation of ISC proliferation and Ee fate. Therefore, as Ec represent the major cell type of the gut, upregulating autophagy in such cells could improve IBD treatments. FRQS and CRMUS
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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 | 0.000 |
| 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 | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 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".