A238 ALTERED GUT MICROBIOME COMPOSITION AND FUNCTION ARE ASSOCIATED WITH GUT BARRIER DYSFUNCTION IN HEALTHY RELATIVES OF CROHN’S DISEASE PATIENTS
Bibliographic record
Abstract
Abstract Background The gut microbiome may play a role in gut barrier homeostasis including epithelial barrier function, but data are scarce and limited to animal studies Aims To assess if alterations in gut microbiome are associated with gut barrier function Methods We utilized the Genetic Environmental Microbial (CCC GEM) cohort of healthy first-degree relatives (FDRs) of Crohn’s disease (CD) patients. Gut barrier function was assessed using the ratio of urinary fractional excretion of lactulose to mannitol (LMR). Stool bacterial DNA was extracted and sequenced for the V4 hypervariable region of the 16S rRNA gene using MiSeq and processed using QIIME2. Microbial functions were imputed using PICRUSt2. The cohort was divided into a North American discovery cohort (n=2,472) and non-North American external validation cohort (n=655). LMR>0.025 was defined as abnormal. LMR-microbiome associations were assessed using multivariable regression model and Random Forest (RF) classifier algorithm. q<0.05 was considered significant when multiple tests were performed Results The median age of the entire cohort was 17.0 years [IQR 12.0; 24.0], 52.6% were females and 25.4% had LMR>0.025. In the discovery cohort, subjects with LMR>0.025 had markedly reduced alpha diversity (Chao1 index, estimate= -0.0037, p=4.0e-04) and altered beta diversity (Bray-Curtis dissimilarity index, PERMANOVA: pseudo-F statistic = 2.99, p=1.0e-03). We identified eight bacterial genera and 52 microbial pathways associated with LMR>0.025 (q<0.05). Four genera (decreased Adlercreutzia [odds ratio(OR)=0.74, 95% confidence interval (CI) 0.6–0.91], Clostridia-UCG-014 [OR=0.71, 95%CI 0.59–0.86], and Clostridium-sensu-stricto-1 [OR=0.75, 95%CI 0.61–0.92] and increased Colidextribacter [OR=1.65, 95%CI 1.2–2.26]) and eight pathways (including decreased biosynthesis of glutamate [OR=0.4, 95%CI 0.21–0.74], tryptophan [OR=0.06, 95%CI 0.01–0.27] and threonine [OR=0.038, 95%CI 0.003–0.41]) were replicated. Bacterial community composition was associated with gut barrier homeostasis as defined by the RF analysis (p= 1.4e-6) Conclusions Gut microbiome community and pathways are associated with gut barrier function. These findings may identify potential microbial targets to modulate barrier function Submitted on behalf of the CCC-GEM Consortium Funding Agencies CCC, CIHRCrohn’s and Colitis Canada Genetics Environment Microbial (CCC-GEM) III; The Leona M. and Harry B. Helmsley Charitable Trust; Kenneth Croitoru is the recipient of the Canada Research Chair in Inflammatory Bowel Diseases
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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 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.004 | 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".