Trust Your Gut: Diversity and Regulation of Innate Immune Responses in Intestinal Epithelial Cells
Bibliographic record
Abstract
Chronic inflammatory diseases of the gastrointestinal tract, such as Crohn’s disease and ulcerative colitis, are increasingly common in Western countries. The intestinal epithelium forms a protective barrier against pathogens while tolerating commensal microbes. This layer consists of specialized cell types, including enterocytes, goblet cells, Paneth cells, and enteroendocrine cells, which are continuously renewed from intestinal stem cells (ISCs) located in crypts. Stem cell maintenance and differentiation are regulated by key signaling pathways, notably WNT signaling, which maintains stemness in the crypts, and BMP signaling, which promotes differentiation as cells migrate toward the villi. Understanding how each epithelial cell type responds to bacterial and viral stimuli is crucial for developing new treatments for inflammatory bowel diseases (IBD). Using human intestinal organoids derived from donor stem cells, we studied cell type-specific immune responses. By directing organoids to maintain stemness or differentiate into enterocytes, we observed that bacterial exposure elicits strong responses in stem cells but minimal responses in enterocytes. This difference is driven by WNT/β-catenin signaling, and reactivation of WNT in enterocytes restores their bacterial responsiveness. Post-transcriptional regulation further modulates these responses. In contrast, viral stimuli, mimicked by synthetic double-stranded RNA (poly(I:C)), trigger strong immune responses in enterocytes, while stem cells respond only weakly. Activation of WNT/β-catenin in enterocytes suppresses antiviral responses, highlighting that cell identity determines not only the magnitude but also the type of immune pathway activated. Prolonged bacterial exposure induces a transient state of tolerance in stem cells, reducing both proliferation and immune responsiveness, which is reversed after several days without stimuli. This tolerance appears to involve negative feedback and a distinct different gene expression, potentially contributing to chronic inflammation when dysregulated. Finally, environmental triggers were investigated using nickel exposure. Organoids responded with molecular signatures resembling IBD and allergic reactions, suggesting that non-infectious factors can provoke intestinal inflammation. Overall, this thesis demonstrates that intestinal epithelial cells mount highly cell type-specific immune responses to bacterial, viral, and environmental stimuli. WNT signaling and cellular identity critically shape these responses, while mechanisms of tolerance and adaptation influence long-term epithelial immunity. Intestinal organoids combined with modern analytical techniques provide a powerful platform to study these processes, offering insights relevant for understanding IBD pathogenesis and developing targeted therapies.
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.002 | 0.002 |
| Open science | 0.000 | 0.002 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.007 | 0.003 |
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".