A273 THE CROHN’S DISEASE-ASSOCIATED PATHOBIONT ADHERENT-INVASIVE E. COLI (AIEC) INDUCES MITOCHONDRIAL FISSION IN EPITHELIAL CELLS IN ADVANCE OF APOPTOSIS
Bibliographic record
Abstract
Adherent-invasive E. coli are a putative etiological agent in a cohort of patients with Crohn’s disease. Mitochondrial dysfunction has been described in inflammatory bowel disease. Mitochondria are not distinct organelles; they exist as a dynamic network that constantly remodels via the processes of fission and fusion to meet the cells energy demands and allow recycling of damaged mitochondria. This is emerging as an area of interest in host-bacterial interaction but it is unknown if (and then how) infection with AIEC affects mitochondrial dynamics in epithelia and the consequences of this for the cell. Hypothesis: AIEC induce mitochondrial fragmentation in intestinal epithelial cells in an invasion-dependent manner that requires ROS, resulting in apoptosis and decreased epithelial barrier function. To explore the relationship between mitochondrial dynamics and epithelial function in vitro and determine if, then how, infection with AIEC affects mitochondrial dynamics and any consequence for epithelial barrier function. Human colon-derived epithelial lines were cultured with a non-invasive E. coli, AIEC (104–108 cfu; 4-16h), fixed (dead) AIEC, or spent medium from bacterial cultures. Epithelia were examined: (a) ATP levels; (b) live-cell imaging of mitochondria morphology and membrane potential with confocal microscopy; (c) immunoblotting of whole cell protein extracts for the mitochondrial fusion protein Optic Atrophy Factor 1 (OPA1) and Dynamin-Related Protein 1 (Drp1); (d) ROS neutralized by the antioxidants; and, (f) measurement of barrier function and apoptosis. AIEC infection resulted in reduced mitochondrial membrane potential and ATP, and dramatic mitochondrial fragmentation accompanied by OPA1 cleavage and recruitment of Drp1 to the mitochondria in gut epithelia in a time- and dose-dependent manner. The mitochondrial fragmentation was not reproduced by exposure to AIEC conditioned medium or fixed bacteria cells, and was not abrogated by treatment with a general (vitamin C) or a mitochondrial-specific (mitoTEMPO) anti-oxidant co-treatment. AIEC induced epithelial barrier loses, however preliminary trials with inhibitors of fission, Mdivi1 and P110, did not prevent the AIEC-induced drop in transepithelial resistance. Mitochondrial fragmentation preceded apoptosis in AIEC-infected epithelial cells. As a putative cause or contributor to Crohn’s disease, AIEC drive massive mitochondrial fragmentation in model gut epithelia independent of ROS generation or AIEC soluble factors. Epithelial cell apoptosis is a feature of AIEC infection, which may be a consequence of excessive mitochondrial fission, that would be predicted to compromise epithelial barrier function, potentiating or reactivating inflammatory disease. CCC, CIHRNSERC, University of Calgary Eyes High Funding
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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) | 0.005 | 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".