BACKGROUND & AIMS:The gut microbiome is implicated in Crohn's disease (CD) development. However, human microbiome studies need experimental evidence to demonstrate whether specific microbial differences promote CD pathogenesis. This study was conducted to determine whether the gut microbiome from individuals who later developed CD promotes colitis in germ-free recipient mice. METHODS:Germ-free mice were colonized with fecal samples from 12 pairs of discordant siblings, where one sibling later developed CD (pre-CD), and the other remained a healthy matched control (HMC). After colonization, colitis was induced by T-cell transfer to assess the effect of stool on multiple measures of colitis severity. Comparative analysis with human donor metadata explored transferred pathogenic traits. RESULTS:Mice receiving pre-CD stool exhibited increased weight loss, fecal lipocalin-2, and intestinal histologic damage compared with mice receiving HMC stool. Fecal metabolomic analysis revealed differences in 40 metabolites between pre-CD and HMC colonized mice. Furthermore, 2 metabolic pathways were shared between pre-CD participants and mice. Notably, sphingolipids showed a positive correlation between humans and mice and associated with increased colitis in mice. CONCLUSIONS:This study functionally demonstrates that the stool microbiome of individuals susceptible to CD is altered years before diagnosis, exhibiting greater inflammatory potential when transferred to susceptible mice.

Background: We aimed to examine the relationship between disease symptoms and disease phenotype in a large Canadian cohort of persons with Crohn’s disease (CD). Methods: Adults (n=1515) with CD from 14 Canadian centers participated in the Mind And Gut Interactions Cohort (MAGIC) between 2018 and 2023. Disease activity was measured using the 24-item IBD Symptom Inventory-Short-Form (IBDSI-SF). We compared the symptoms commonly associated with active versus inactive disease, and explored symptoms patterns in relation to disease phenotype, based on the Montreal Classification. To assess psychological status the Generalized Anxiety Disorder-7 and Patient Health Questionnaire-9 were used. Results: The mean disease duration was 15.6±11.8 years. The 5 most common symptoms were similar for those with active disease, although at higher prevalence (89% to 98%) versus those with inactive disease (47% to 79%), and included fatigue, diarrhea, gas, bloating, and urgency. The intensity of symptoms was higher in those with active than inactive IBDSI-SF scores. The rank order and relative distribution of the symptoms and intensity of the symptoms reported were similar between those with different disease phenotypes B1, B2, and B3 and L1, L2, and L3. Persons with active IBDSI-SF had a higher prevalence of anxiety (24.6%) and depression (38.2%) versus persons with inactive IBDSI-SF (6.3% and 8%, respectively) Conclusions: Individuals with CD with active and inactive disease by IBDSI, experience similar symptoms, but the prevalence of symptoms and their intensity is greater in persons with active IBDSI. Persons with inactive IBDSI report many symptoms. There was no difference in symptom reporting by disease behavior or location.

Background and Aims: This study surveyed Canadian inflammatory bowel disease (IBD) specialists to understand their perceptions, preferences, and practices regarding image-enhancement modalities (including dye-spray chromoendoscopy [DCE], virtual chromoendoscopy [VCE], and artificial intelligence [AI]-aided endoscopy) for colorectal neoplasia (CRN) detection in IBD, to inform future studies and recommendations. Methods: Developed collaboratively by IBD experts and methodologists, the survey assessed physicians' attitudes toward colonoscopy image-enhancement modalities for CRN surveillance in IBD, evaluating 5 domains: current practices, familiarity with advanced techniques, perceptions of AI-assisted endoscopy, barriers to adoption, and research priorities. It was distributed to IBD specialists affiliated with the Canadian IBD Research Consortium and conducted per The Strengthening the Reporting of Observational Studies in Epidemiology guidelines. Results: Of 82 specialists invited, 33 responded (40.2%). Most worked in academic centers (90%); 39.4% managed large IBD practices. VCE was the most used advanced imaging modality (84.8%), followed by DCE (33.3%), high-definition white-light endoscopy (HD-WLE) plus nontargeted biopsies (33.3%), AI-assisted colonoscopy (18.2%), and HD-WLE alone (6.1%). Although 60.6% considered DCE and VCE similarly effective, drawbacks included bowel preparation (VCE: 26.6%; DCE: 24.1%) and poor visualization with inflammation (VCE: 26.6%; DCE: 12%). AI-assisted colonoscopy was seen as promising for CRN detection; 78.8% agreed randomized controlled trials are needed, and 39.4% would adopt AI if it improved CRN detection by 5% over HD-WLE. Conclusions: This survey highlights a shift toward VCE over DCE, perceived drawbacks of chromoendoscopy, limited availability and uncertainty about AI-assisted colonoscopy, and a desire for research to demonstrate AI's utility for CRN detection in IBD.

Current guidelines recommend pancolonic chromoendoscopy (pCE) over white light endoscopy (WLE) alone for colorectal neoplasia (CRN) detection in individuals with inflammatory bowel diseases (IBD). However, these techniques are poorly adopted due to technical and logistical limitations. Artificial intelligence–based computer-aided detection (CADe) is a promising new technology integrated into modern endoscopy platforms that has been shown to increase CRN detection in the non-IBD population. We aim to compare CADe-guided colonoscopy to chromoendoscopy in a randomized controlled trial (RCT) in individuals with IBD undergoing surveillance colonoscopy. This is a pragmatic, multicenter, parallel-group, open-label, non-inferiority RCT comparing CADe-guided colonoscopy (intervention) to pCE (virtual or dye spray) (standard of care). Consenting adults (≥ 18 years) with longstanding (≥ 8 years) IBD (or any duration with primary sclerosing cholangitis) involving ≥ 1/3 of the colorectum, in clinical remission and undergoing surveillance colonoscopy, will be included. Those who undergo a high-quality colonoscopy (adequate preparation, minimal inflammation, complete intubation) will be included in the primary analysis. Patients will be centrally randomized by permuted blocks, stratified by endoscopist. The anticipated CRN rate is 15

INTRODUCTION:The urban environment increases the risk of inflammatory bowel disease (IBD). Specific environmental exposures involved in IBD etiology remain unknown. We examined the association between outdoor artificial light at night (ALAN) and IBD incidence, surgery, and health services utilization (HSU). METHODS:Using population-based deterministically linked health administrative data from Ontario, Canada we conducted a birth cohort study (incidence), matched case-control study (incidence), and cohort study (surgery, HSU). Individuals with IBD were identified using previously validated algorithms. ALAN, the average digital number of lights consistently present, was a 3-level variable: <35 (reference), 35-60, > 60. We used Cox proportional hazards models (birth cohort, surgery), conditional logistic regression (matched case-control study), and Poisson regression (HSU). RESULTS:Among 3 929 374 individuals in the birth cohort, 5539 (0.1%) developed IBD; no association between ALAN at birth and IBD was observed (35-60: hazard ratio [HR] 1.03, 95% confidence interval [CI] 0.87-1.22; >60: HR 0.93, 95% CI 0.78-1.11). Among 32 176 IBD cases matched to 160 709 controls, high ALAN was associated with a lower IBD risk (>60: odds ratio [OR] 0.84, 95% CI 0.78-0.92); there was no association between IBD and the middle ALAN level. High ALAN was associated with fewer IBD-specific outpatient visits (rate ratio [RaR] 0.93, 95% CI 0.86-0.99) and hospitalizations (RaR 0.83, 95% CI 0.72-0.95) 1 year after diagnosis. ALAN was not associated with surgery or emergency department visits. DISCUSSION:The association between ALAN and IBD is heterogeneous. Additional research is needed to understand how ALAN impacts IBD and identify other environmental exposures contributing to IBD etiology.

Background Individuals with ulcerative colitis (UC) are frequently re-hospitalized for persistent or recurrent severe disease flares. Accurate prediction of the risk of early re-hospitalization at the time of discharge could promote targeted outpatient interventions to reduce this risk.Methods We conducted a retrospective study in adults with UC admitted to The Ottawa Hospital between 2009 and 2016 for an acute UC-related indication. We ascertained candidate demographic, clinical, and health services predictors through medical records and administrative health databases. We derived and bootstrap validated a multivariable logistic regression model of 90-day UC-related re-hospitalization risk. We chose a probability cut point that maximized Youden's index to differentiate high-risk from low-risk individuals and assessed model performance.Results Among 248 UC-related hospitalizations, there were 27 (10.9%) re-hospitalizations within 90 days of discharge. Our multivariable model identified gastroenterologist consultation within the prior year (adjusted odds ratio [aOR] 0.11, 95% confidence interval [CI], 0.04-0.39), male sex (aOR 3.27, 95% CI, 1.33-8.05), length of stay (OR 0.94, 95% CI, 0.88-1.01), and narcotic prescription at discharge (OR 1.96, 95% CI, 0.73-5.27) as significant predictors of 90-day re-hospitalization. The optimism-corrected c-statistic value was 0.78, and the goodness-of-fit test P-value was .09. The chosen probability cut point produced a sensitivity of 77.8%, specificity of 80.9%, positive predictive value (PPV) of 33.0%, and negative predictive value (NPV) of 96.7% in the derivation cohort.Conclusions A limited set of variables accessible at the point of hospital discharge can reasonably discriminate re-hospitalization risk among individuals with UC. Future studies are required to validate our findings. People with ulcerative colitis (UC), a condition that causes swelling in the colon, often need to go to the hospital because their disease is severe. After they leave the hospital, some patients have to be re-admitted quickly because their condition worsens or they have problems with their treatment. If doctors could predict which patients are most likely to be re-admitted, they could focus on giving them better care after they leave the hospital. In this study, we looked at the medical records of adults with UC who were hospitalized at The Ottawa Hospital between 2009 and 2016. We wanted to find out what factors might predict if someone would end up back in the hospital within 90 days. We used this information to create a mathematical model to predict the risk of re-admission and tested how accurate it was. We found that things like seeing a gastroenterologist in the past year, the patient's gender, how long they stayed in the hospital, and if they were prescribed narcotics at discharge all helped predict the risk of being re-admitted. Combining all these factors helped make the prediction even more accurate.

BACKGROUND:Novel colorectal cancer endoscopic surveillance techniques for inflammatory bowel disease (IBD) have recently been developed. AIMS:Compare the efficacy of currently available techniques for dysplasia detection in colonic IBD. METHODS:We conducted a systematic literature search from inception to March 2024 for randomized controlled trials (RCTs) or prospective cohort studies enrolling adults with IBD and having surveillance colonoscopy for dysplasia screening. Primary outcome was the number of dysplastic lesions (per-lesion analysis). Secondary outcome was the number of patients with dysplasia (per-patient analysis). We assessed endpoints using the frequentist NMA random effect model. RESULTS:We included 25 studies (22 RCTs). 4837 patients met eligibility criteria (850 total dysplastic lesions; 105 with advanced dysplasia). Nine different screening techniques were studied. In per-lesion analysis, dye-based chromoendoscopy (DCE) ranked the highest (83%) per SUCRA ranking. DCE was superior to HD-WLE (OR, 1.78; 95% CI, 1.06-3.00). There were no significant differences between NBI and DCE, HD-WLE with SR or CEM in head-to-head comparisons. In a sub-analysis confined to ulcerative colitis (UC), DCE ranked highest (98%) with per-lesion analysis, and was superior to NBI (OR, 1.69; 95% CI, 1.03-2.77). CONCLUSIONS:HD-WLE-SR, DCE and CEM demonstrated superiority over other techniques for detection of dysplasia in colonic IBD. DCE was superior for dysplasia detection in colonic IBD. DCE was superior to HD-WLE in colonic IBD. DCE was the best technique in UC. Further studies to compare HD-WLE-SR and NBI with DCE are warranted to ascertain performance equivalency and define the optimal surveillance technique.

Background The prevalence of inflammatory bowel disease (IBD) in Canada is rising rapidly, with an estimated 0.86% of the population living with IBD in 2025. With this rise in prevalence comes a rise in the direct costs to healthcare systems. Aims To assess direct healthcare costs associated with IBD in Canada. Methods We analyzed population-based administrative healthcare costing data from AB, BC, MB, and SK from fiscal year (FY) 2010/11 to 2016/17. Costs were adjusted to 2020 CAD$ using the Consumer Price Index. Average annual costs were calculated for: annual per IBD person cost (All), and medication costs (on a biologic ± other IBD-related medications, and only other IBD-related medication [eg. mesalamine] (AB,BC,MB)). Per event costs were calculated by outcome: IBD-related hospitalization or surgery (AB,MB), emergency department visit (AB, BC), and colonoscopy (AB,BC). We calculated the average annual percentage change (AAPC) with 95% confidence intervals (CI) using weighted costs in log-gamma models. Autoregressive moving average models to forecasted costs to FY2025/26 with 95% prediction intervals (PI). Results In FY 2016/17, the annual average cost per IBD person was $11186 (95%CI:11052,11320), significantly increased from FY2010/11 (5.12%;95%CI:4.75,5.48). Biologics were the largest cost, accounting for 45.11% (95%CI:44.23,45.98) of the total costs and significantly increasing (2.13%; 95%CI:1.43,2.84). Costs for other IBD medications significantly decreased (−2.00%; 95%CI:−3.47,−0.51), contributing 5.46% (95%CI:5.09,5.64) of total costs. Costs of emergency department visits and colonoscopies significantly increased, while costs for IBD-related hospitalizations and surgeries remained stable. By FY2025/26, the annual cost per IBD person is forecasted to be $15345 (95%PI:14915,15775). Conclusions The direct healthcare costs of IBD are rising, largely driven by the costs of biologics. As IBD prevalence continues to grow, the burden on healthcare systems is expected to escalate. Proactive measures are essential to address this burden and ensure individuals with IBD receive the necessary care. ¥Proportions will not add up to 100% as individuals can be captured in multiple cost categories each year (e.g., an IBD-related surgery cost is also a hospitalization). * p<0.05 Funding Agencies CCC, CIHR

Experimental studies suggest that the probiotic yeast Saccharomyces boulardii can mitigate the symptoms of inflammatory bowel disease. However, these results are equivocal and S. boulardii probiotic therapy has not gained widespread acceptance in clinical practice. To assess whether the therapeutic properties of S. boulardii might be improved upon, we engineered S. boulardii to overproduce and secrete spermidine, a pro-regenerative natural metabolite. We employed CRISPR gene deletion and integration of gene cassettes at the Ty2 locus to achieve high level polyamine synthesis and transport. We tested whether spermidine secreting S. boulardii could reduce disease symptoms in dextran sulfate sodium (DSS) and azoxymethane induced models of intestinal inflammation and cancer. We demonstrate that oral delivery of spermidine-secreting S. boulardii in mice populates the gastrointestinal tract with viable spermidine-secreting S. boulardii cells and raises free spermidine levels in the gastrointestinal tract. Strikingly, spermidine-secreting S. boulardii strains were significantly more effective than wild-type S. boulardii in reducing colitis symptoms as well as colitis-associated carcinogenesis in mice. These results suggest that in situ spermidine secretion by engineered synthetic biotic yeast strains may be an effective and low-cost therapy to mitigate inflammatory bowel disease and associated colon cancer.

Abstract Background Hospitalizations among individuals with inflammatory bowel disease (IBD) place a strain on healthcare resources. The decline in hospitalization rates during the era of anti-TNF therapies remains debated in the literature. Aims To examine temporal trends in hospitalization rates among individuals with in IBD across Canada. Methods We used population-based administrative healthcare data (2002–2014) from seven Canadian provinces (AB, BC, MB, NS, QC, ON, SK) to identify hospitalizations in prevalent IBD cases. Hospitalizations were categorized as: 1. all-cause, any hospitalization of an IBD patient; 2. IBD-related, admission for IBD or symptoms/comorbidities associated with IBD (eg. venous thromboembolism). We calculated hospitalization rates per 100 IBD persons with 95% confidence intervals (CIs) using IBD prevalence data. Hospitalization rates were forecast from 2015–2025, with 95% prediction intervals (PIs), using auto regressive integrated moving average models on log transformed data. We calculated average annual percentage change (AAPC) using Poisson models with quadratic equations applied for non-linear trends. We stratified by IBD subtype (CD, UC), age (<18, 18–64, 65+), and sex (female, male). We calculated AAPCs for counts to assess the actual number of hospitalizations. Results From 2002–2014, hospitalizations rates decreased for both all-cause and IBD-related admissions for IBD patients, and across age, sex, and IBD type (Table 1). In 2025, we forecast hospitalization rates to be 15.82 (95%CI:14.17,17.66) per 100 for all-cause and 7.87 (95%CI:6.16,9.90) per 100 for IBD-related. Hospitalization rates are falling, but AAPCs for hospitalization counts significantly increased for all-cause (2.65%; 95%CI: 2.42,2.89) and IBD-related (1.52%; 95%CI: 1.29,1.76). The disparity between decreasing rates and increasing counts is due to the faster rise in the AAPC of IBD prevalence (denominator) compared to hospital counts (numerator). Conclusions During the anti-TNF era (2002–2014), hospitalization rates for IBD steadily declined across Canada and are projected to continue decreasing through 2025. Despite this decline, the actual number of hospitalizations is increasing, likely driven by the rising prevalence of IBD. ¥ Includes IBD-Unclassified *Non-linear Funding Agencies CIHR

Background Trends in extra-digestive (ED) cancer incidence and mortality in inflammatory bowel diseases (IBD) may be changing with newer approaches to management.Aims To study temporal trends and contemporary risks of ED cancers in individuals with and without IBD.Methods Using population-level administrative data from Ontario, Canada, we studied ED cancer rates among individuals with IBD and age-sex-matched controls (1:10) without IBD between 1994 and 2020. We modelled age-sex-standardised annual cancer incidence (per 100,000 person-years) over time by first-order linear autoregression, and standardised cancer incidence and mortality rate ratios (SIR, SMR) by quasi-Poisson regression.Results The average annual percentage change (AAPC) in ED cancer incidence was stable among 110,919 people with IBD (0.108%/year; 95% CI, -0.380, 0.599) but declined among 1,109,190 matched controls (-1.39%/year; 95% CI, -1.57, -1.21). Among those with IBD, AAPC was significant for non-Hodgkin's lymphoma (1.48%/year; 95% CI, 0.161, 2.82), melanoma (1.77%/year; 95% CI, 0.781, 2.77), cervical (2.31%/year; 95% CI, 0.602, 4.10), uterine (4.41%/year; 95% CI, 0.045, 8.96) and thyroid (8.10%/year; 95% CI, 4.31, 12.0) cancers, and statistically greater than controls for cervical, ovarian, lung, and bladder cancers. During 2010-2020, ED cancer incidence was higher in those with IBD (SIR 1.20; 95% CI 1.15, 1.26), while ED cancer-related mortality was specifically higher in those with Crohn's disease (CD; SMR 1.31; 95% CI 1.14, 1.51), as compared to matched controls.Conclusions ED cancer incidence has not changed among those with IBD but has declined among matched controls. Beyond 2010, ED cancer incidence is higher among those with IBD and cancer-related mortality is higher among those with CD, relative to matched controls.

Inflammatory bowel diseases (IBD), including Crohn’s disease (CD), and ulcerative colitis (UC), are chronic immune-mediated inflammatory disorders (IMID) affecting both intestinal and extraintestinal organs. Chronic intestinal inflammation causes multifocal DNA damage, increasing the risks of intestinal cancers. While the widespread use of effective biologic and small molecule therapies and intensified immune modulating (IM) regimens in recent years may have contributed toward declining colorectal cancer risks, these treatments could have introduced unexpected cancer risks in organs not directly affected by IBD due to reduced immune surveillance. Among individuals with IBD, the use of thiopurines has been frequently associated with risks of lymphoma, non‑melanoma skin cancer (NMSC), and cervical cancer. Several large studies have also reported increased risks of lymphoma, and melanoma associated with anti-tumour necrosis factor alpha (anti‑TNF) therapies, although other studies have not shown these associations. A randomized controlled trial (RCT) in elderly individuals with rheumatoid arthritis (RA) and cardiovascular risk factors reported a slightly increased all‑cause cancer risk with the non-selective Janus kinase inhibitor (JAKi), tofacitinib. Other immunosuppressive (IS) therapies, including methotrexate, anti-interleukin (IL)‑12/23 or anti‑IL-23 therapies, anti-α4β7 integrin therapy, JAK-1-selective inhibitors (upadacitinib), and sphingosine-1-phosphate receptor agonists, have not been associated with increased cancer risks to date. However, some of these newer therapies have only been available for a few years. Given the low absolute risk of treatment‑related cancers, controlling underlying IBD with IS therapies is typically prioritized to improve quality of life and reduce IBD-related complications. However, the decision to start or continue IS therapy in individuals with current or prior malignancy is more complex, as immune surveillance may be more crucial for these patients. Clinical trials generally exclude patients with a cancer history, which limits the available evidence on cancer recurrence risks associated with specific therapies. Additionally, some cytotoxic chemotherapy regimens can control IBD for prolonged periods, suggesting that additional immunomodulation may be unnecessary, and potentially harmful, during cancer treatment. Conversely, hormonal, radiation, and immune checkpoint inhibitor therapies have been associated with increased risks of IBD flares. Therefore, a careful and collaborative approach with oncologists is essential for the optimal management of IBD patients diagnosed with cancer. Recently, the European Crohn’s and Colitis Organization (ECCO) and the American Gastroenterological Association (AGA) released practice recommendations regarding the use of IS therapies in individuals with IBD in the post‑cancer setting. This review summarizes the evidence regarding cancer risks associated with specific IBD therapies in this context and presents a management approach based on both scientific and practical considerations.

Background:Individuals with inflammatory bowel diseases (IBD) are at increased risk of repeated disease-related hospital admissions, some of which may be preventable with targeted outpatient interventions. We assessed population-level trends in the rates of IBD-specific hospital readmission within 30 and 90 days of index hospitalization among those with Crohn's disease (CD) and ulcerative colitis (UC) during a period marked by major changes to IBD management. Methods:We accessed Ontario health administrative datasets to study CD (2002-2017) and UC (2004-2020) patients hospitalized for IBD-specific indications. We compared IBD-specific 30-day and 90-day hospital readmission rates across 4 (UC) and 5 (CD) year time periods using multivariable logistic regression, controlling for age, sex, comorbidities, residential setting, household income, hospital type, and clustering of admissions within patients. Results:Among CD patients, 30-day readmission rates decreased from 9.7% to 7.4%, and 90-day rates decreased from 16.0% to 14.1% between 2002-2007 and 2012-2017 periods. There was a higher likelihood of 30-day readmission during 2002-2007 (adjusted odds ratio [aOR] 1.32; 95% CI, 1.16-1.50) and 2007-2012 (aOR 1.15; 95% CI, 1.01-1.32), and of 90-day readmission during 2002-2007 (aOR 1.14; 95% CI, 1.03-1.26), as compared to 2012-2017. Among UC patients, readmission rates remained stable across time periods. Conclusion:Inflammatory bowel disease-related early rehospitalization risk has declined over time among individuals with CD but not among individuals with UC.