A289 THE CROHN’S DISEASE-ASSOCIATED ADHERENT-INVASIVE E. COLIINDUCES MITOCHONDRIAL FRAGMENTATION IN ENTERIC EPITHELIUM THAT IS NOT DEPENDENT ON BACTERIAL SOLUBLE PRODUCTS OR MITOCHONDRIAL REACTIVE OXYGEN SPECIES
Bibliographic record
Abstract
Despite the popular depiction, mitochondria are not distinct organelles; they exist as a dynamic network that is constantly remodelling via the balanced processes of fission and fusion to meet the energy demands of the cell and allow recycling of damaged mitochondria. Mitochondrial dysfunction has been described in IBD and pharmacologically-induced mitochondrial dysfunction leads to increased epithelial permeability. The Crohn’s disease-associated pathobiont, adherent-invasive E. coli (AIEC) can stimulate reactive oxygen species (ROS) production from epithelial cells and be apoptotic. Little is known of microbial regulation of enterocytic mitochondrial dynamics and nothing of the potential of AIEC to perturb the critical metabolic function that mitochondria fulfill for the cell. AIEC induce mitochondrial fission in intestinal epithelial cells in an invasion-dependent manner that requires ROS. 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 AIEC or a non-invasive E. coli and the following readouts assessed: (a) visualization of mitochondria morphology and membrane potential with confocal microscopy; (b) immunoblotting of whole cell protein extracts for the mitochondrial fusion protein Optic Atrophy Factor 1 (OPA1); (c) ROS neutralized by the antioxidants; and, (e) measurement of mitochondrial fragmentation and OPA1 protein expression following treatment with spent medium from bacterial cultures. AIEC infection resulted in reduced ATP levels, reduced mitochondrial membrane potential and dramatic mitochondrial fission (fragmented mitochondria and OPA1 cleavage) in gut epithelia in a time- and dose-dependent manner. The mitochondrial fragmentation was not reproduced by exposure to AIEC conditioned medium and was not abrogated by treatment with a general (vitamin C) or a mitochondrial-specific (mitoTEMPO) anti-oxidant co-treatment. Invasion of epithelial cells by AIEC was unaffected by use of pharmacological inhibitor of mitochondria fission, P110. As a putative cause or contributor to the pathophysiology of Crohn’s disease, AIEC are shown to drive massive mitochondrial fission in epithelial cells independent of ROS generation or AIEC soluble factors. We speculate this perturbation of mitochondrial dynamics would disrupt the epithelial barrier function and lead to apoptosis which could perpetuate inflammation. CIHRUniversity of Calgary Eyes High Program
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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) | 0.003 | 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".