Kevan Jacobson

Background: Siblings of individuals with Crohn’s disease (CD) are at increased risk for developing CD but the underlying mechanisms remain unclear. Objective: We hypothesised that childhood (vs adult) exposure to a sibling with CD drives microbial perturbations, increasing CD susceptibility. Design: We used the prospective Genetic Environmental Microbial (GEM) Project and the nationwide South Korean database to assess the association between childhood exposure to affected siblings and CD onset. The association between childhood exposure and gut microbiome was evaluated in the GEM cohort. A T-cell transfer model of colitis in germ-free mice was conducted to investigate the effects of stool from childhood-exposed versus adult-exposed siblings. Finally, an integrative risk model combining faecal calprotectin (FCP) and microbial enterotypes was trained and internally validated within the GEM cohort. Results: In the GEM cohort, childhood exposure to an affected sibling was associated with a fourfold higher risk of developing CD compared with adult exposure (adjusted HR (aHR) (95% CI) 4.00 (1.83 to 8.75); p=5.3×10 ⁻⁴ ), which was validated in the South Korean dataset (aHR (95%CI) 2.54 (1.70 to 3.81; p=6.0×10 ⁻⁶ )). Childhood exposure was associated with reduced abundances of Lachnospira , Roseburia and Colidextribacter , reductions that mediation analysis identified as partially mediating CD risk. In vivo, transplantation of childhood exposure-associated microbiota into germ-free recipient mice exacerbated colitis and elevated mucosal interleukin-22 expression, supporting a potential mechanistic role. Our model identified siblings with elevated FCP and Blautia -enriched or Prevotella -enriched enterotypes as highest risk, with a 10-year cumulative incidence of 22.5%. Conclusion: Childhood exposure to siblings with CD is an independent risk factor of CD onset, potentially mediated by early-life microbial perturbation.

Background: Older adults (≥60 years) are one of the fastest-growing age groups, with a rising prevalence of chronic conditions such as inflammatory bowel disease (IBD). Mental health conditions are common among people living with IBD; however, the burden of depression, anxiety, and stress/psychological distress, specifically among older adults with IBD, remains poorly characterized. Most available evidence comes from younger or mixed-age cohorts, underscoring the need to synthesize evidence explicitly focused on older adults to address this gap. Methods/design: We will conduct a systematic review and, where applicable, a meta-analysis following PRISMA-P guidance. The protocol is registered in PROSPERO (ID: (CRD420251157744)). We will include quantitative observational studies (cross-sectional, cohort, and case-control) published in English-language journals from January 2014 to the present. Eligible studies must report extractable data for older adults (≥60 years, or ≥65 years where used) with IBD (Crohn’s disease, ulcerative colitis, or IBD-unclassified) and at least one eligible mental health outcome (depression, anxiety, and/or stress/psychological distress). Searches will be conducted in MEDLINE, EMBASE, PsycINFO, and CINAHL, and supplemented with reference-list screening, forward citation searching, and targeted grey literature searches using a pre-specified approach. Two reviewers will independently screen records, extract data, and assess risk of bias using design-appropriate tools. Pooled prevalence will be estimated using random-effects meta-analyses, with an appropriate transformation for proportions. Heterogeneity will be explored using I² and pre-specified subgroup/sensitivity analyses. Where pooling is not appropriate due to substantial heterogeneity, findings will be summarized using structured narrative synthesis. Where eligible longitudinal or comparative observational studies are available, association estimates (e.g., OR/RR/HR) will be synthesized and reported separately from prevalence outcomes. Discussion: This review may provide a consolidated synthesis of international evidence on the prevalence and pooled prevalence of depression, anxiety, and stress/psychological distress among older adults with IBD. Where data allow, it may also summarize association evidence as a separate stream. Findings may inform integrated care pathways for older adults with IBD, helping to identify key sources of heterogeneity and evidence gaps that can inform future research and care planning.

Background: We aimed to build a serum proteomics-based model to predict primary nonresponse (PNR) to infliximab (IFX) in pediatric colonic inflammatory bowel disease, with early proactive therapeutic drug monitoring. Methods: Children in the prospective Canadian Children IBD Network with ulcerative colitis (UC), inflammatory bowel disease unclassified (IBD-U), or colonic Crohn’s disease (CD) with serum pre-IFX were eligible. We defined PNR as IFX cessation plus surgery/drug switch within 6 months. We compared clinical features between groups (Mann Whitney U, chi-square test). We measured serum proteins with Olink Inflammation/Immune Response panels. We built a regularized regression (generalized linear model [GLM]) machine learning model and compared its performance with other models with 10-fold cross-validation repeated 10 times (receiver-operating characteristic/precision-recall curves, predictive score separation). We ranked proteomic features by SHAP (SHapley Additive exPlanations) analysis. We hypothesized that treatment-naïve serum would be more informative than treatment-exposed serum. Results: We included 96 patients: 71 UC/IBD-U (23 nonresponders), 42 treatment-naïve (12 nonresponders); and 25 CD, 19 treatment-naïve. Pre–third and pre–fourth dose serum infliximab levels were similar and robust (>10 µg/mL) in primary nonresponders and responders. Predictive performance was superior for diagnostic, treatment-naïve samples; the GLM showed good ability to separate primary nonresponders and responders. The GLM model on treatment-naïve serum (area under the curve ∼0.75) had better specificity to predict responders and included 21 proteins, with CSF1 and ITM2A top ranked. UC/IBD-U responders more often were steroid refractory and received infliximab as first maintenance. Conclusions: A serum proteomics linear model on treatment-naïve serum best predicted PNR. Findings require external validation but suggest that the diagnostic/pretreatment window may be key to understanding biology central to effective drug sequencing.

Background: The inflammatory bowel disease (IBD) ulcerative colitis (UC) is characterized by colonic mucosal inflammation and barrier dysfunction. We hypothesized that UC causes persistent defects in mucosal homeostasis, evident even in the absence of active inflammation, contributing to disease chronicity. Methods: To test our hypothesis, we grew patient biopsy-derived sigmoid colonoids into air-liquid interface (ALI) monolayers, characterizing them through microscopy, proteomics, bulk RNA Sequencing (RNAseq), and their susceptibility to UC patient-isolated Escherichia coli pathobiont p19A. Results: Non-IBD ALI monolayers formed uniform crypt-like structures and a thick mucus layer containing all epithelial-derived proteins previously identified in human colonic mucus. In contrast, ALI monolayers from UC patients displayed a range of impairments, with classification ranging from a mild phenotype with distorted architecture and a thinner, more permeable mucus layer to a severe phenotype with defects in cellular differentiation and an inability to produce a mucus layer. With the use of transcriptome analysis, we identified activated pathways associated with extracellular matrix formation and cell signaling, including numerous cancer-associated genes in UC ALI monolayers, which also proved significantly more susceptible to E. coli p19A. Conclusions: Taken together, the culturing of patient biopsies into ALI colonoid monolayers provides a powerful model to assess human colonic mucosal development, healing, homeostasis, and mucus barrier function, revealing that UC-derived colonoid monolayers display a range of developmental and functional defects that persist in the absence of inflammation.

BACKGROUND The diagnosis of inflammatory bowel disease (IBD) involves clinical, endoscopic, and radiologic evaluation. Endoscopic procedures, particularly in pediatrics, require general anesthesia and carry potential risks. AIM To investigate whether serum biomarkers can differentiate between pediatric patients with and without IBD. Secondary objectives included identifying biomarkers that distinguish Crohn’s disease (CD) from ulcerative colitis (UC) and assessing their predictive value for progression to biologic therapy. METHODS Pediatric patients undergoing diagnostic colonoscopy at British Columbia Children’s Hospital between December 2017 and June 2022 were enrolled. Blood samples were collected at colonoscopy, and demographic clinical data, laboratory, and histopathologic evaluation were obtained. An exploratory screen of 50 biomarkers was undertaken in a subset of patients (54 IBD, 41 controls) using LegendplexTM flow cytometry kits to identify candidates. A refined panel of 12 serum biomarkers was subsequently selected and a supervised learning model was developed to classify patients. RESULTS The study included 246 pediatric patients, who had a median age of 13.03 years and were 37.4% female (103 CD, 52 UC, 91 controls). In univariate analyses, C-X-C motif chemokine ligand 9 (CXCL9) was the only biomarker significantly elevated in IBD vs controls (P < 0.001). A multivariable model achieved an area under the receiver operating characteristic of 0.861 for distinguishing IBD from controls. Interleukin 8 (IL-8) emerged as a key biomarker alongside CXCL9 and IL-22 in the model. The random forest model identified CXCL9 with the greatest diagnostic accuracy (area under the curve [AUC] = 0.81), followed by IL8 and IL22 (AUC = 0.737 and 0.68, respectively). CXCL9 and IL-18 showed higher levels in CD (P = 0.016), whereas CXCL1 levels predicted progression to biologic therapy within 1 year (P = 0.039). However, the model did not effectively predict disease subclassification or progression to biologic therapy. CONCLUSION Serum biomarkers, particularly CXCL9, IL-8, and IL-22, can aid in the diagnosis of pediatric IBD. CXCL9 and IL18 were found to be significant predictors of CD, and CXCL1 differed between patients requiring biologic therapy vs those who did not.

Background: The PIONIR (Preventing IBD ONset in Individuals at Risk) trial evaluates whether the Tasty&Healthy diet can reduce risk of Crohn’s disease (CD) development in first-degree relatives (FDRs). The optimal preclinical stage of CD for enrolling subjects to prevention trials is unknown. Objectives: We aimed to propose a framework for identifying high-risk participants for prevention trials by reporting the outcomes of the pre-PIONIR screening stage. Design: Faecal calprotectin was measured in asymptomatic FDRs aged 6–38 years; those with persistent elevation, defined as >70 µg/g in at least two separate tests, were offered panenteric video capsule-endoscopy or ileocolonoscopy. Results: Of 950 FDRs approached, 331 (35%) agreed to be screened: 63 (19%) had persistently elevated calprotectin, of whom 42 underwent further evaluation. Nine (2.7%) had endoscopic appearance compatible with presymptomatic CD, 22 (6.6%) had non-specific macroscopic mucosal changes and 11 (3.3%) had normal mucosa despite elevated calprotectin, suggesting probable histological inflammation. The 33 participants in the two latter groups were defined as ‘potential pre-CD’ (17.9% of all screened after adjusting for missing values). Calprotectin >225 µg/g predicted presymptomatic CD (area under the receiver operating characteristic curve 0.97 (95% CI 0.94 to 1.0; p<0.001; sensitivity 89%, specificity 94%). Of those with a single elevated calprotectin value, 22% normalised on repeat testing with significant variability (intraclass correlation coefficient 0.72 (95% CI 0.57 to 0.82)). Conclusion: Approximately one in five asymptomatic FDRs had persistently elevated calprotectin, which was able to differentiate those with presymptomatic CD. The findings highlight calprotectin’s utility in identifying at-risk individuals during the potential pre-CD stage for enrolment in prevention trials.

Host - microbiome interactions are central to Crohn'sdisease (CD) pathogenesis; yet the early metabolic alterations that precededisease onset remain poorly defined. To explore preclinical metabolicsignatures of CD, we analyzed baseline serum metabolomic profiles in a nestedcase-control study within the Crohn's and Colitis Canada - Genetics, Environment, Microbiome (CCC-GEM) Project, a prospective cohort of 5,122 healthyfirst-degree relatives (FDRs) of CD patients. We included 78 individuals wholater developed CD and 311 matched FDRs who remained disease-free. In an untargetedassessment of metabolomic data, we identified 63 metabolites significantlyassociated with future CD risk. Integrative analyses further identifiedmultiple associations between CD-related metabolites and proteomic markers, gutmicrobiome composition, antimicrobial antibody, fecal calprotectin andC-reactive protein. Quinolinate, a tryptophan catabolite, was elevated inindividuals who later developed CD and showed strong positive correlations withC-reactive protein, fecal calprotectin, and C-X-C motif chemokine ligand 9 (CXCL9).In contrast, higher levels of ascorbate and isocitrate were associated withreduced CD risk and were negatively correlated with C-reactive protein and CD-associated proteins.These findings identify several distinct molecular pathways that contribute toCD pathogenesis.

The gut microbiome has been linked to the pathogenesis of type 1 diabetes (T1D), identifying it as a promising therapeutic target. Nutritional interventions, which are an effective way to modulate the gut microbiome, thus show potential to be applied as complementary therapies for T1D. One particular dietary intervention, prolonged therapeutic fasting, has been shown to ameliorate symptoms of several autoimmune diseases, while also modifying the gut microbiota composition of healthy populations. It is unclear, however, how the gut microbiota of patients suffering from diseases of autoimmunity will respond to fasting. In this pilot study, we investigate the effects of prolonged fasting on the gut microbiome of T1D patients: Fasting substantially changed the composition and structure of the T1D gut microbiome so that it converged with that of non-diabetic controls immediately post fasting. Moreover, a comparison with a population of patients suffering from Multiple Sclerosis revealed substantial overlap in post-fasted microbiome changes and a remarkable consistency with published data of non-autoimmune populations, indicating that fasting leads to signature microbiome changes that are independent of host health status and disease type. A correlation analysis between fasting-mediated microbiota modifications and changes in clinical parameters revealed several significant associations between the Oscillospiraceae and Lachnospiraceae families and cholesterol and blood pressure changes in the T1D cohort, corroborating previous studies reporting on these associations in non-diabetic subjects. In conclusion, the observed fasting-mediated microbiome signature suggests that nutrient availability is a major disease-independent factor in shaping gut microbiome composition, likely driven by the need for metabolic diversification of microbial nutrient acquisition. The corresponding clinical associations highlight the need to investigate if these fasting-driven changes in the reported taxa are causally linked to the recorded clinical benefits of therapeutic fasting and what importance fasting as an additional therapeutic intervention might have to improve long term conditions in people with T1D.