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Publications // 2025

Olivera PA, Martinez-Lozano H, Leibovitzh H, Xue M, Neustaeter A, Espin-Garcia O, Xu W, Madsen KL, Guttman DS, Bernstein CN, Yerushalmi B, Hyams JS, Abreu MT, Marshall JK, Wrobel I, Mack DR, Jacobson K, Bitton A, Aumais G, Panacionne R, Dieleman LA, Silverberg MS, Steinhart AH, Moayyedi P, Turner D, Griffiths AM, Turpin W, Lee SH, Croitoru K; Crohn’s and Colitis Canada (CCC) Genetic, Environmental, Microbial (GEM) Project Research Consortium. Healthy first-degree relatives from multiplex families versus simplex families have a higher subclinical intestinal inflammation, a distinct fecal microbial signature, and harbor a higher risk of developing Crohn's disease. Gastroenterology 2025; 168 (1):99-110. 

 

Background: Unaffected first-degree relatives from families with at least 2 affected first-degree relatives with Crohn's disease (multiplex families) have a high risk of developing Crohn’s disease, although the underlying mechanisms driving this risk are poorly understood. We aimed to identify differences in biomarkers between first-degree relatives from multiplex vs simplex families and investigate the risk of future Crohn’s disease onset accounting for potential confounders.

Methods: We assessed the Crohn's and Colitis Canada Genetic Environmental Microbial cohort of healthy first-degree relatives of patients with Crohn’s disease. Genome-wide Crohn’s disease-polygenic risk scores, urinary fractional excretion of lactulose-to-mannitol ratio, fecal calprotectin, and fecal 16S ribosomal RNA microbiome were measured at recruitment. Associations between Crohn’s disease multiplex status and baseline biomarkers were determined using generalized estimating equations models. Cox models were used to assess the risk of future Crohn’s disease onset.

Results: There were 4051 participants from simplex families and 334 from Crohn’s disease multiplex families. Crohn’s disease multiplex status was significantly associated with higher baseline fecal calprotectin (P = .026) but not with baseline Crohn’s disease-polygenic risk scores or the lactulose-to-mannitol ratio. Three bacterial genera were found to be differentially abundant between both groups. Crohn’s disease multiplex status at recruitment was independently associated with a 3-4-fold increased risk of developing Crohn’s disease (adjusted hazard ratio, 3.65; 95% confidence interval, 2.18-6.11, P<.001).

Conclusion: Within first-degree relatives of patients with Crohn’s disease, participants from multiplex families had a 3-4-fold increased risk of Crohn’s disease onset, a higher fecal calprotectin, and an altered bacterial composition, but not genetic burden or altered gut permeability. These results suggest that putative environmental factors might be enriched in first-degree relatives from multiplex families.

 

 

Bernstein CN, Panaccione R, Nugent Z, Marshall DA, Kaplan GG, Vanner S, Dieleman LA, Graff LA, Otley A, Jones J, Buresi M, Murthy S, Borgaonkar M, Bressler B, Bitton A, Croitoru K, Sidani S, Fernandes A, Moayyedi P. Crohn's Disease Phenotypes and Associations With Comorbidities, Surgery Risk, Medications and Nonmedication Approaches: The MAGIC in IMAGINE Study.  Inflammatory Bowel Diseases 2024; in press.

 

Background: We aimed to establish a cohort of persons with Crohn's disease enrolled from 14 Canadian centers to describe the contemporary presentation of Crohn's disease in Canada.

Methods: All enrollees were at least 18 years old and underwent chart review for phenotype documentation by Montreal Classification at time of enrollment, comorbidities, IBD and other surgeries, and use IBD and other therapies.

Results: Of 2112 adults, 59% were female, and the mean age was 44.1 (+/-14.9SD) years. The phenotype distribution was B1 (inflammatory)= 50.4%, B2 (fibrostenotic)= 22.4%, B3 (penetrating)= 17.3%, and missing information = 9.9%. Perineal disease was present in 14.2%. Pertaining to disease location, 35.2% of patients had disease in L1 (ileal only), 16.8% in L2 (colonic only), 48% in L3 (ileocolonic), and 0.4% in L4 (upper gastrointestinal). There was no difference in phenotype by gender, anxiety score, depression score. Disease duration was significantly different depending on disease behavior type (B1 = 12.2 ± 10.1; B2 = 19.4 ± 12.9; B3 = 18.9 ± 11.8, P < .0001). Isolated colonic disease was much less likely to be fibrostenotic or penetrating than inflammatory disease. Penetrating disease was more likely to be associated with ileocolonic location than other locations. Perineal disease was most commonly seen in persons with B3 disease behavior (24%) than other behaviors (11% B1; 20% B2 disease, P < .0001) and more likely to be seen in ileocolonic disease (L3;19%) vs L2 (17%) and L1 (11%; P < .0001). Surgery related to IBD occurred across each behavior types at the following rates: B1 = 23%, B2 = 64%, and B3 = 74%. Inflammatory bowel disease-related surgery rates by location of disease were L1 = 48%, L2 = 21%, and L3 = 51%.

Conclusions: In exploring this large contemporary Crohn’s disease cohort we have determined that inflammatory disease is the main Crohn’s disease phenotype in Canada and that Crohn’s disease-related surgery remains very common.

 

 

Bernstein CN, Fisk JD, Walld R, Bolton JM, Sareen J, Patten SB, Singer A, Lix LM, Hitchon CA, El-Gabalawy R, Katz A, Graff LA, Marrie RA. Psychiatric comorbidity does not enhance prescription opioid use in inflammatory bowel disease as it does in the general population. Inflammatory Bowel Disease 2024; in press.

Background: Little is known about patterns of opioid prescribing in IBD, but pain is common in persons with IBD. We estimated the incidence (new prescriptions) and prevalence of opioid use in adults with IBD and an unaffected reference cohort and assessed factors that modified opioid use.

Methods: Using population-based health administrative data from Manitoba, Canada, we identified 5233 persons with incident IBD and 26150 persons without IBD matched 5:1 on sex, birth year, and region from 1997 to 2016. New and prevalent opioid prescription dispensations were quantified, and patterns related to duration of use were identified. Generalized linear models were used to test the association between IBD, psychiatric comorbidity, and opioid use adjusting for sociodemographic characteristics, physical comorbidities, and healthcare use.

Results: Opioids were dispensed to 27% of persons with IBD and to 12.9% of the unaffected reference cohort. The unadjusted crude incidence per 1000 person-years of opioid use was nearly twice as high for the IBD cohort (88.63; 95% CI, 82.73-91.99) vs the reference cohort (45.02; 95% CI, 43.49-45.82; relative risk 1.97; 95% CI, 1.86-2.08). The incidence rate per 1000 person-years was highest in those 18-44 years at diagnosis (98.01; 95% CI, 91.45-104.57). The relative increase in opioid use by persons with IBD compared to reference cohort was lower among persons with psychiatric comorbidity relative to the increased opioid use among persons with IBD and reference cohort without psychiatric comorbidity.

Discussion: The use of opioids is more common in people with IBD than in people without IBD. This does not appear to be driven by psychiatric comorbidity.

 

 

Venner JM, Bernstein CN. Current Endoscopic Scoring Systems in Inflammatory Bowel Disease: Strengths and Limitations. Gastrointestinal Endoscopy Clinics North America 2025 Jan;35(1):19-39.

 

There are several available endoscopic scoring systems that are designed to assess disease activity in inflammatory bowel disease. The most widely known is the Mayo endoscopic subscore for ulcerative colitis. These schemas are not routinely used in clinical practice, largely due to their complexity or lack of granularity, although they are standard for outcomes measurement in large clinical trials. While some schemas have been validated using independent cohorts, there is high inherent interobserver variation. Furthermore, derivation of these scoring systems has been subject to selection bias and limited challenge bias. In this article we review endoscopic scoring systems used in IBD, their strengths and weaknesses.

 

Hesampour F, Tshikudi D, Veysel Özden A, Bernstein CN, Ghia JE. Exploring the Efficacy of Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) in Modulating Local and Systemic Inflammation in Experimental Models of Colitis. Bioelectronic Medicine 2025; in press.

Background: Current IBD treatments often fail to achieve lasting remission and have adverse effects. Vagus nerve stimulation offers a promising therapy due to its anti-inflammatory effects. Its invasive nature, however, has led to the development of non-invasive methods like transcutaneous auricular vagus nerve stimulation. In an animal model of colitis this study assesses the impact of transcutaneous auricular vagus nerve stimulation on acute colitis progression, inflammatory, anti-inflammatory, and apoptosis-related markers.

Methods: Male C57BL/6 mice (11-12 weeks) were used for dextran sulfate sodium (DSS)- and dinitrobenzene sulfonic acid (DNBS)-induced colitis studies. The administration of transcutaneous auricular vagus nerve stimulation or no stimulation (anesthesia without stimulation) for 10 min per mouse began one day before colitis induction and continued daily until sacrifice. Ulcerative colitis-like colitis was induced by administering 5% DSS in drinking water for 5 days, after which the mice were sacrificed. Crohn's disease-like colitis was induced through a single intrarectal injection of DNBS/ethanol, with the mice sacrificed after 3 days. Disease activity index, macroscopic evaluations, and histological damage were assessed. Colon, spleen, and blood samples were analyzed via qRT-PCR and ELISA. One-way or two-way ANOVA with Bonferroni and Šídák tests were applied.

Results: Transcutaneous auricular vagus nerve stimulation improved the disease activity index, macroscopic, and histological scores in DSS colitis mice, but only partially mitigated weight loss and the disease activity index in DNBS colitis mice. In DSS colitis. Transcutaneous auricular vagus nerve stimulation locally decreased colonic inflammation by downregulating pro-inflammatory markers (IL-1β, TNF-α, Mip1β, MMP 9, MMP 2, and Nos2) at the mRNA level and upregulating anti-inflammatory TGF-β in non-colitic conditions at both mRNA and protein levels and IL-10 mRNA levels in both non-colitic and colitic conditions. Systemically, transcutaneous auricular vagus nerve stimulation decreased splenic TNF-α in non-colitic mice and increased serum levels of TGF-β in colitic mice and splenic levels in non-colitic and colitic mice. Effects were absent in DNBS-induced colitis. Additionally, transcutaneous auricular vagus nerve stimulation decreased pro-apoptotic markers (Bax, Bak1, and caspase 8) in non-colitic and colitic conditions and increased the pro-survival molecule Bad in non-colitic mice.

Conclusions: This study demonstrates that transcutaneous auricular vagus nerve stimulation has model-dependent local and systemic effects, reducing inflammation and apoptosis in UC-like colitis while offering protective benefits in non-colitic conditions. These findings encourage further research into underlying mechanisms and developing adjunct therapies for ulcerative colitis.

 

Tshikudi DM, Bernstein CN, Mishra S, Ghia JE, Armstrong HK. Influence of sex in inflammatory bowel diseases. Nature Reviews Gastroenterology and Hepatology 2025; in press.

 

The incidence rate of IBD has risen in the past decades and has emerged as a global health issue. IBD is characterized by chronic inflammation of the gastrointestinal tract. There is compelling evidence for the role of biological sex in IBD epidemiology, pathophysiology, disease progression, symptoms and extraintestinal diseases. IBD disease course, management and therapies differ between men and women, yet there is a paucity of analysis of sex as a factor. This review discusses the known influence of sex-linked genetic factors, hormones, and hormone receptors in IBD incidence, prevalence, disease burden, and clinical manifestation. Furthermore, we review the mechanisms underlying these sex-dependent effects on the dysregulation of gastrointestinal mucosal immunity (immune, epithelial barrier, and microbiota) in IBD. To support the progressive inclusion of sex in the study of IBD, we summarize the current standard research methodology that should be implemented to investigate sex as a biological variable in IBD studies. Enhanced comprehension of the influence of sex in IBD pathophysiology will advance the development of targeted therapies and improve patient care.

 

Marrie RA, Bolton JM, Ling V, Bernstein CN, Krysko K, Li P, McKay L, Pequeno P, Razaz N, Rotstein D, Deakin-Harb K, Maxwell C. Comparing Peripartum Mental Illness Rates in Mothers with Multiple Sclerosis and Other Chronic Diseases in Ontario, Canada. Neurology 2025; in press.

 

Background: Peripartum mood and anxiety disorders constitute the most frequent form of maternal morbidity in the general population but little is known about peripartum mental illness in mothers with multiple sclerosis. We compared the incidence and prevalence of peripartum mental illness among mothers with multiple sclerosis, epilepsy, IBD, diabetes, and women without these conditions.

Methods: We used population-based administrative health data from Ontario, Canada to identify mothers with multiple sclerosis, epilepsy, IBD, diabetes, and without these diseases (controls) with index dates between 2003 and 2018. Using validated definitions, we estimated the incidence (new diagnoses) and prevalence of mental illness (any, depression, anxiety, bipolar disorder, psychosis, substance use, suicide attempt) during the prenatal period, and for three years post-partum. We compared incidence and prevalence estimates between groups using incidence ratios and prevalence ratios with 95% confidence intervals (95%CI). We also compared incidence between groups using Poisson models adjusting for potential confounders. 

Results: We included 894,852 mothers (1,745 multiple sclerosis; 5,954 epilepsy; 4,924 IBD; 13,002 diabetes; 869,227 controls).  At conception, mean (SD) maternal age was 28.6 (5.7) years. One-third of mothers gave birth from 2014 to 2019, and 98.1% of births were singleton births. Any incident mental illness affected 8.4% of mothers with multiple sclerosis prenatally and 14.2% during the first post-partum year; depression and anxiety were the most common incident disorders, and the first post-partum year was a higher risk period than the prenatal period. On multivariable regression mothers with multiple sclerosis had an increased incidence of all disorders except suicide attempt during the prenatal (RR 1.26-4.31) and post-partum periods (RR 1.24-2.92 in first year) compared to control mothers. Any prevalent mental illness affected 42% of mothers with multiple sclerosis prenatally, and 50.3% in the first post-partum year. Mothers with epilepsy, IBD and diabetes also had an increased incidence and prevalence of mental illness compared to control mothers.

Conclusions: Mothers with chronic illnesses, including multiple sclerosis, have an elevated incidence and prevalence of peripartum mental illness compared to controls. Given the adverse effects of peripartum mental illness, these findings emphasize the need for preventive interventions and early treatment of mental illness.

 

Keunzig EA, Walters TD, Mack DR, Griffiths AM, Duchen R, Bernstein CN, Kaplan GG Kaplan, Otley AR, El Matary W, Yu W, Wang X, Guan J, Crowley E, Sherlock M, Carman N, Fung SG, Benchimol EI. High healthcare costs in childhood inflammatory bowel disease: Development of a prediction model using linked clinical and health administrative data. Inflammatory Bowel Disease 2025 in press.

 

Background: The incidence of pediatric-onset inflammatory bowel disease (IBD) and the costs of caring for individuals with IBD are both increasing. We calculated the direct healthcare costs of pediatric IBD in the first year after diagnosis and developed a model to predict children who would have high costs (top 25th percentile).

Methods: Using data from the Canadian Children IBD Network inception cohort (16 years of age or younger, diagnosed between 2013 and 2019) deterministically linked to health administrative data from Ontario, Canada, we estimated direct healthcare and medication costs accrued between 31 and 365 days after diagnosis. Candidate predictors included age at diagnosis, sex, rural/urban residence location, distance to pediatric center, neighborhood income quintile, IBD type, initial therapy, disease activity, diagnostic delay, health services utilization or surgery around diagnosis, regular primary care provider, and receipt of mental health care. Logistic regression with stepwise elimination was used for model building; 5-fold nested cross-validation optimized and improved model accuracy while limiting overfitting.

Results: The mean cost among 487 children with IBD was CA$15168 ± 15305. Initial treatment (anti-tumor necrosis factor therapy, aminosalicylates, or systemic steroids), having a mental health care encounter, undergoing surgery, emergency department visit at diagnosis, sex, and age were predictors of increased costs, while having a regular primary care provider was a predictor of decreased costs. The C-statistic for our model was 0.71.

Conclusions: The cost of caring for children with IBD in the first year after diagnosis is immense and can be predicted based on characteristics at diagnosis. Efforts that mitigate rising costs without compromising quality of care are needed.

 

Mok N, Knox N, Zhu F, Arnold DL, Bar-Or A, Bernstein CN, Bonner C, Forbes JD, Graham M, Marrie RA, O’Mahony J, Yeh EA, Zhao Y, Van Domselaar G, Banwell B, Waubant E, Tremlett H. The Fungal Gut Microbiota in Pediatric-Onset Multiple Sclerosis. Frontiers in Microbiology 2025; in press.

 

Background: Evidence suggests that the gut microbiome may play a role in multiple sclerosis. However, most studies have focused on gut bacterial communities; none have examined the fungal microbiota (mycobiota) in persons with pediatric-onset multiple sclerosis.

Methods: We examined the gut mycobiota in persons with and without pediatric-onset multiple sclerosis through a cross-sectional examination of the gut mycobiota from 46 participants’ stool samples (three groups: 18 pediatric-onset multiple sclerosis, 13 acquired monophasic demyelinating syndromes, and 15 unaffected controls). Using metataxonomic sequencing of the fungal internal transcribed spacer region 2, the fungal profiles were compared between participants using visualizations, statistical tests, and predictive analysis.

Results: While the mycobiome alpha (Shannon, inverse Simpson) and beta diversity differed across the three groups (ANOVA p < 0.05), further post-hoc analysis of the beta-diversity identified a difference between monophasic demyelinating syndromes versus pediatric-onset multiple sclerosis participants (p = 0.005 [adjusted]). At the genus level of taxonomy, 7/10 of the most abundant genera were similar between all three groups, with Saccharomyces spp. and Candida spp. being in the highest abundance. The Agaricus genus was especially high in pediatric-onset multiple sclerosis.  participants, dominated primarily due to the species A. bisporus (widely consumed as white button mushrooms). The commonality of high abundance fungi found in our cohort suggests a possible connection to diet. Predictive modeling of differential abundance associated C. albicans, Cyberlindera jadinii, and Fusarium poae most strongly with the pediatric-onset multiple sclerosis participants.

Conclusions: Our study provides novel insight into the fungal gut mycobiota in pediatric-onset multiple sclerosis. While findings indicate that the gut mycobiome of participants with pediatric-onset multiple sclerosis may largely comprise fungi considered transient from the diet, the differential predictive analysis suggested rare or under-detected fungal markers being of potential importance, warranting consideration in future mycobiome-multiple sclerosis related studies.

 

 

Shaffer S, Nugent Z, Schaeffer D, Chu J, Bernstein CN. Medication Withdrawal with Normal or Near-Normal Histology in Ulcerative Colitis is Associated with Clinical Relapse. Journal of Clinical Gastroenterology 2025; in press.

 

Introduction: Histologic inflammation has been shown to be a predictor of worse clinical outcomes in persons with ulcerative colitis. Some people with ulcerative colitis can develop completely normal colon biopsies without acute or even chronic changes. It is felt that achieving normal, or near-normal histology in ulcerative colitis, is associated with improved clinical outcomes along with a likely decreased risk of dysplasia. We sought to understand the clinical course and risk of dysplasia in persons with ulcerative colitis who achieve near or complete normalization of histology.
Methods: We performed a retrospective chart review in a single centre in Winnipeg, Canada. We identified patients in complete endoscopic remission with a normal pathology report (no changes of acute or chronic inflammation). Slides were sent to a gastroenterology-expert pathologist to score the slides and report them using the Geboes score, evaluating the right and left colon separately. The primary outcome was rate of clinical relapse from the index colonoscopy until the date of last follow-up. Secondary outcomes included events of low- or high-grade dysplasia, colon cancer, and colectomy. Continuous variables were analyzed using means and T-test, Fisher’s Exact test was used for 2x2 tables. Survival analysis was performed using proportional hazards regression model.

Results: There were 78 persons included in the study. Approximately one-fifth of persons had clinical relapse in follow-up. Only 2 people in this cohort had completely normal pathology in both the right and left colon after reassessment by a gastroenterologist-expert pathologist. Mean time to clinical relapse was 4.7 years (standard deviation 3.1 years). All persons with clinical relapse had chronic inactive disease in the left colon. There were no predictors of clinical relapse regarding right colon pathology. Persons who withdrew off therapy were nearly 5 times more likely to clinically relapse than those who remained on IBD-therapy (HR 4.89, 95%CI 1.32-18.08). There were zero episodes of dysplasia or colon cancer in follow-up. There were two episodes of colectomy due to medically-refractory disease both who had normal right sided pathology and chronic inactive disease in the left colon.

Conclusion: We found that histologic near-normalization as defined by Geboes score, is associated with no risk for dysplasia over a mean of 7.3 years. Hence surveillance colonoscopy intervals can be lengthened in persons with such histology. Persons with ulcerative colitis who achieve normal or near-normal histology have moderate rates of clinical relapse, and physicians should be cautious when considering withdrawing their therapy.

 

Anand R, George AT, Rubin DT, Spiegel BMR, Bernstein CN. The Role of Virtual Reality in Managing Inflammatory Bowel Disease: A Novel Approach to Bridging Mental and Physical Health. Journal of Canadian Association of Gastroenterology 2025; in press.

IBD encompassing Crohn’s disease and ulcerative colitis, is characterized by symptoms such as fatigue, abdominal pain, and diarrhea, which may persist even when inflammation is controlled. These symptoms are further exacerbated by psychological stress, which may complicate disease management that involves the gut-brain axis—a bidirectional communication pathway linking the gastrointestinal system and the central nervous system. While stress, anxiety, and depression are prevalent among patients with IBD, access to comprehensive mental health care is often limited, particularly in rural and underserved areas. Virtual reality has emerged as a promising tool in managing psychological comorbidities and enhancing the overall care of patients with IBD.

This review explores the potential of virtual reality interventions for pain and anxiety management in patients with IBD. Virtual reality also shows promise in patient education and as a tool for mental health interventions, providing immersive environments for relaxation and mindfulness. The integration of virtual reality in IBD care offers a novel, accessible approach to addressing both physical and mental health challenges, potentially improving quality of life and clinical outcomes for IBD patients. Further research is warranted to evaluate the long-term benefits and broader applicability of virtual reality-based interventions in diverse patient populations.

 

 

Lee SH, Turpin W, Espin-Garcia O, Xu W, Croitoru K; Crohn's and Colitis Canada-Genetic, Environmental, Microbial (CCC-GEM) Project Research Consortium. Development and Validation of an Integrative Risk Score for Future Risk of Crohn's Disease in Healthy First-Degree Relatives: A Multicenter Prospective Cohort Study. Gastroenterology 2025 Jan;168(1):150-153.

Background: Although the cause of Crohn’s disease is unknown, recent studies have identified a number of biomarkers associated with the risk of developing Crohn’s disease in healthy at-risk individuals. Establishing a combined prediction model that accurately stratifies healthy at-risk individuals’ future risk of Crohn’s disease is the first step towards disease prevention and will advance our understanding of pathogenesis.

Methods: We recruited healthy first-degree relatives of patients with Crohn’s disease from 2008-2017 as part of the global multicenter Crohn’s and Colitis Canada Genetic Environmental Microbial (CCC-GEM) Project. After collecting demographic information, blood, urine, and stool samples at recruitment, participants were followed prospectively for the development of Crohn’s disease. A GEM-integrative risk score (GEM-IRS), using random survival forest modeling that combined the baseline variables (demographics, measures of gut inflammation, intestinal barrier function, and fecal microbiome composition) to estimate time-to- Crohn’s disease onset, was derived and subsequently validated in two independently ascertained testing cohorts.

Findings: Of 2,619 first-degree relatives followed for a median of 6.8 years, 61 (2.3%) developed Crohn’s disease. The GEM-IRS, developed on the training cohort, had a predictive performance (concordance index) of 0.789 and a hazard ratio of 2.69 per SD increase (95% CI 2.06-3.53) for development of Crohn’s disease in the pooled-testing cohorts. Furthermore, the GEM-IRS predicted Crohn’s disease in pre-specified subgroups of first-degree relatives with minimal subclinical inflammation or normal barrier function measures, and up to 7 years before diagnosis in the pooled-testing cohorts.

Interpretation: The GEM-IRS, includes biomarkers of gut inflammation, intestinal barrier function, and the gut microbiome, is a valid risk stratification tool for predicting future development of CD in healthy FDR population. The score may be used to guide preventative care for the healthy FDR population.

 

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