OP19 Corticosteroid response rectal gene signature and associated microbial variation in treatment naïve ulcerative colitis
Bibliographic record
Abstract
Molecular mechanisms driving disease course and response to initial therapy in ulcerative colitis (UC) are poorly understood. In the full PROTECT cohort, the strongest predictor of corticosteroids (CS)-free remission by Weeks 12 or 52 was Week 4 (WK4) remission. We used pre-treatment rectal biopsies in new-onset UC, and defined key pathways linked to WK4 response to standardised induction with CS in the largest prospective paediatric UC cohort to date. PROTECT enrolled 428 newly diagnosed paediatric UC patients at 29 North American sites. mRNA-Seq and 16S rRNA defined pre-treatment rectal gene expression and microbial communities in 206 participants. Independent group of 50 participants were used to validate the CS response gene signature. WK4 remission was defined as PUCAI < 10 without additional therapy/colectomy. Moderate–severe UC patients (152/206) from the discovery cohort and all 50 from the validation cohort received standardised induction therapy with CS. WK4 remission was achieved in 75/152 (49%) and 21/50 (42%) of the discovery and validation groups respectively. 115 genes were differentially expressed (FDR<0.05 and FC ≥1.5) between moderate–severe UC patients who did or did not achieve WK4 remission in the discovery cohort. The corticosteroid response gene signature is highly associated with CXCR chemokines (p < 7.12E−12), innate myeloid immune signatures (p < 1.62E−15), and response to bacteria (p < 2.16E−13). Principle component analyses (PCA) PC1 that summarise the variation of the CS response signature, was significantly different between those that achieved WK4 clinical remission (p < 0.001) and mucosal healing (p = 0.002) defined as faecal calprotectin < 250 μg/g in the discovery cohort. This was replicated in the independent validation cohort, and was also associated with response to anti-TNFα and anti-α4β7 integrin induction in adults. The response gene signature was associated with shifts in microbes previously implicated in mucosal homeostasis; positive association with taxa such as Campylobacter, Veillonella, and Enterococcus implicated in mucosal inflammation, and a negative association with taxa from the Clostridiales order that are considered beneficial. Finally, the addition of the pre-treatment rectal gene signature PC1 [OR = 0.4 (0.2–0.8 95% CI)] improved WK4 clinical prediction model of remission with CS [AUC = 77.7 (70.0–85.4 95% CI)]. We identified a gene signature linked to WK4 CS response, which was validated in independent UC patients, and showed associations with response to anti-TNFα and anti-α4β7 integrin in adults, and with specific microbial taxa. Our data may prioritise future therapies for non-responders to current approaches.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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 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".