Enhancement of gut barrier function by microbial metabolite, urolithin A via AhR-Nrf2 dependent pathways in IBD
Bibliographic record
Abstract
Abstract Inflammatory bowel diseases (IBD) consisting of Crohn’s and ulcerative colitis are resultant of dysregulation of the immune system leading to intestinal inflammation and microbial dysbiosis. Numerous studies in recent years highlighted the pivotal role of gut microbiota and their metabolites in host physiological processes including in IBD. Urolithin A (UroA) is a microbial metabolite derived from polyphenolics (e.g., ellagitannins/ellagic acid) of pomegranate and berries. We also synthesized a potent structural analogue of UroA (UAS03) and tested their efficacies in preventing and treating colitis in pre-clinical models. Our studies showed that UroA/UAS03 significantly enhance gut barrier function in addition to blocking unwarranted inflammation. We demonstrate that UroA and UAS03 exert their barrier functions through activation of aryl hydrocarbon receptor (AhR)- nuclear factor erythroid 2–related factor 2 (Nrf2)-dependent pathways to upregulate epithelial tight junction proteins. In addition, treatment with these compounds attenuated colitis in pre-clinical models by remedying barrier dysfunction and blocking increased inflammatory mediators such as IL-6, TNF-α and IL-1β. UroA/UAS03 failed to induce tight junction proteins and protect against 2,4,6-Trinitrobenzenesulfonic acid (TNBS)-induced colitis in AhR−/− and Nrf2−/− mice suggesting an obligatory requirement of AhR and Nrf2 pathways for UroA/UAS03 mediated beneficial activities. Overall, the results highlight how microbial metabolites provide two-pronged beneficial activities at gut epithelium by enhancing barrier functions and reducing systemic and local inflammation to protect from colonic diseases.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 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) | 0.000 | 0.000 |
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 teacher head, 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".