ER stress antagonizes metabolic stress‐induced loss of epithelial barrier function to commensal bacteria via xenophagy
Bibliographic record
Abstract
Background Patients with IBD commonly present deregulated barrier function of the intestinal epithelium. We have shown that treatment with dinitrophenol (DNP: uncouples oxidative phosphorylation) dramatically impairs the barrier function of cultured epithelial monolayers, particularly internalization of non‐invasive commensal E. coli . Mitochondria do not function in isolation and are linked to the endoplasmic reticulum (ER). We hypothesized that interaction of mitochondrial dysfunction and ER stress is a key determinant of epithelial‐bacterial interaction, specifically the fate of commensal bacteria that gain access to the intracellular compartment as a consequence of metabolic stress. Methods Human colonic biopsies were mounted in Ussing chambers and human colon‐derived epithelial cell lines were cultured on transwell filters or on plasticware. Bacteria were added to the luminal buffer and the cells treated with DNP ± the ER stressor, tunicamycin (TM), and bacterial internalization and translocation assessed. Mechanistic studies involved measuring ATP production, assessment of autophagy (i.e. LC3 activation) and gene knock‐down (KD) by siRNA and CRISPR/cas9. Results DNP promoted the translocation and internalization of E. coli in colon tissue and epithelial monolayers: TM reduced this barrier defect, but did not prevent the DNP‐evoked drop in ATP or the rate of epithelial update of inert beads. E. coli , DNP + TM‐treated cells had increased autophagy. The TM antagonist of the DNP effect was lost in cells lacking the autophagy protein, ATG16L1, suggesting that the ER‐stress promoted killing of the internalized bacteria. Of the 3 major arms of the ER stress response, only KD of ATF6 ablated the TM antagonism of the DNP‐evoked barrier effect; the increase in autophagy evoked by TM was absent in ATF6 KD epithelia. Conclusion An effective ER stress response, via mobilization of xenophagic response, can ameliorate epithelial barrier function in terms of enhanced killing of bacteria that gain access to the cell as a consequence of mitochondrial dysfunction. We suggest that target induction of ATF6 activity could be beneficial in treating disease characterized by bacterial ‘invasion’ of epithelial cells. Support or Funding Information CIHR AIHS HPI NSERC
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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".