Challenges in IBD Research 2024: Environmental Triggers.

Environmental factors play an important role in inflammatory bowel diseases (IBD; Crohn's disease, [CD], ulcerative colitis [UC]). As part of the Crohn's & Colitis Challenges 2024 agenda, the Environmental Triggers workgroup summarized the progress made in the field of environmental impact on IBD since the last Challenges cycle in this document. The workgroup identified 4 unmet gaps in this content area pertaining to 4 broad categories: (1) Epidemiology; (2) Exposomics and environmental measurement; (3) Biologic mechanisms; and (4) Interventions and Implementation. Within epidemiology, the biggest unmet gaps were in the study of environmental factors in understudied populations including racial and ethnic minority groups and in populations witnessing rapid rise in disease incidence globally. The workgroup also identified a lack of robust knowledge of how environmental factors may impact difference stages of the disease and for different disease-related end points. Leveraging existing cohorts and targeted new prospective studies were felt to be an important need for the field. The workgroup identified the limitations of traditional questionnaire-based assessment of environmental exposure and placed high priority on the identification of measurable biomarkers that can quantify cross-sectional and longitudinal environmental exposure. This would, in turn, allow for identifying the biologic mechanisms of influence of environmental factors on IBD and understand the heterogeneity in effect of such influences. Finally, the working group emphasized the importance of generating high-quality data on effective environmental modification on an individual and societal level, and the importance of scalable and sustainable methods to deliver such changes.

Environmental factors are important in inflammatory bowel diseases. It is a high priority to identify environmental factors impacting different disease stages and in different populations, develop biomarkers for such exposures, and generate evidence for modifying them to improve outcomes.

The Impact of Migration on the Gut Metagenome of South Asian Canadians.

South Asian (SA) Canadian immigrants have a higher risk of developing certain immune-mediated inflammatory diseases compared to non-migrant SAs. We sought to investigate the effect of migration on the gut metagenome and to identify microbiological associations between migration and conditions that may influence the development of immune-mediated inflammatory diseases. Metagenomic analysis of 58 first-generation (GEN1) SA immigrants and 38 unrelated Canadian born children-of-immigrants (GEN2) determined that the time lived in Canada was associated with continued changes in gut microbial communities. Migration of GEN1 to Canada early in life results in a gut community with similarities to GEN2 SA Canadians and non-SA North Americans. Conversely, GEN1 immigrants who arrived recently to Canada exhibited pronounced differences from GEN2, while displaying microbial similarities to a non-migrating SA cohort. Multivariate analysis identified that community composition was primarily influenced by high abundance taxa. Prevotella copri dominated in GEN1 and non-migrant SAs. Clostridia and functionally related Bacteroidia spp. replaced P. copri dominance over generations in Canada. Mutually exclusive Dialister species occurred at differing relative abundances over time and generations in Canada. This shift in species composition is accompanied by a change in genes associated with carbohydrate utilization and short-chain fatty acid production. Total energy derived from carbohydrates compared to protein consumption was significantly higher for GEN1 recent immigrants, which may influence the functional requirements of the gut community. This study demonstrates the associations between migration and the gut microbiome, which may be further associated with the altered risk of immune-mediated inflammatory diseases observed for SA Canadians.

Stricturing and Fistulizing Crohn's Disease Is Associated with Anti-tumor Necrosis Factor-Induced Psoriasis in Patients with Inflammatory Bowel Disease.

BACKGROUND: Paradoxical development of psoriasis in patients on anti-TNF agents has been increasingly reported. AIM: The aim was to characterize the prevalence and clinical characteristics of anti-TNF-associated psoriasis in a large cohort of inflammatory bowel disease patients. METHODS: Medical records of patients with Crohn's disease or ulcerative colitis treated with anti-TNF therapy at a single, tertiary IBD center were identified between 2004 and 2016. Patients identified as having developed psoriasis while on anti-TNF underwent detailed retrospective review of dermatologic features and changes in IBD treatment prompted by the development of psoriasis. RESULTS: Among 676 patients treated with anti-TNF (infliximab or adalimumab), the incidence of psoriasis was 10.7% (N = 72). Female gender (OR 1.88 [95% CI 1.12-3.17], p = 0.017), stricturing or fistulizing Crohn's disease (OR 1.83 [95% CI 1.04-3.21], p = 0.036) and upper GI Crohn's disease (OR 3.03 [95% CI 1.06-8.33], p = 0.039) were associated with psoriasis development. The median time to psoriasis onset was 569 days from initiation of anti-TNF, with onset occurring earlier in patients who developed psoriasis on adalimumab versus infliximab (457 vs. 790.5 days, p = 0.008). Overall, in 15/72 (20.8%), cases, cessation of the anti-TNF was required as a result of psoriasis. Plaque psoriasis was the most common type of psoriatic lesion (75%). Topical corticosteroids were the most common treatment for psoriasis. CONCLUSION: We report a high incidence of anti-TNF-associated psoriasis that was associated with female gender, foregut disease location, and fistulizing and stricturing disease behavior. More prospective studies and genetic analyses evaluating possible pathophysiologic underpinnings of this problem are needed.

Use of Complementary and Alternative Medicine for Inflammatory Bowel Disease Is Associated with Worse Adherence to Conventional Therapy: The COMPLIANT Study.

BACKGROUND: Complementary and alternative medicine (CAM) use is highly prevalent among inflammatory bowel disease (IBD patients). We assessed whether its use, both for IBD and for general health, influenced adherence to conventional medications. METHODS: We enrolled 392 IBD subjects in a prospective cohort study and categorized them as CAM nonusers (38%) and those who used CAM for general health (CAM-GEN, 41%) and for IBD (CAM-IBD, 21%). Their self-reported adherence was measured using the 4-item Morisky Adherence Scale during a median follow-up period of 6.8 months. RESULTS: CAM-IBD users were less likely to be adherent to medical therapy than CAM nonusers and CAM-GEN users (70% vs. 84% and 81%, respectively, P < 0.05). Nearly all subjects who were nonadherent reported that it was unintentional (97%), and this did not vary use of CAM. After adjusting for confounders, the adjusted odds ratio for adherence among CAM-IBD relative to CAM nonuser was 0.47 (95% CI, 0.22-0.96). CAM-GEN demonstrated similar adherence to CAM nonusers (adjusted odds ratio, 0.85; 95% CI, 0.44-1.66). CAM-IBD was also less likely than CAM nonusers and CAM-GEN to have improvement in their adherence scores during follow-up (14% vs. 33% and 34%, respectively, P < 0.01). The adjusted odds ratio for improved adherence in CAM-IBD compared with CAM nonusers and CAM-GEN were 0.32 (95% CI, 0.15-0.69) and 0.34 (95% CI, 0.16-0.72), respectively. CONCLUSIONS: CAM-IBD, but not CAM-GEN, was associated with lower adherence to IBD medical therapy. A third of CAM nonusers and CAM-GEN improved adherence during the observation period, suggesting a Hawthorne effect.

Low Fecal Calprotectin Correlates with Histological Remission and Mucosal Healing in Ulcerative Colitis and Colonic Crohn's Disease.

BACKGROUND: Data regarding the correlation of histologic and endoscopic healing with fecal calprotectin (FC) are conflicting. We examined how FC levels correlate with histological and endoscopic remission in colonic inflammatory bowel disease. METHODS: Fifty-eight patients (23 with colonic Crohn's disease [CD] and 35 with ulcerative colitis [UC]) were included. Clinical activity was assessed by Harvey-Bradshaw index (CD) and Mayo score (UC). Inflammatory activity was assessed by ileocolonoscopy, C-reactive protein, and FC. Clinical remission was defined as Harvey-Bradshaw index ≤ 4 or Mayo score ≤ 2 and mucosal healing as Mayo endoscopic subscore = 0 (UC), and Simple Endoscopic Score-CD <3 (CD). Histologic activity was assessed in 27 patients (15 CD, 12 UC). Histological remission was defined as absence of active inflammation (Geboes score <3.1) and absence of basal plasmacytosis. RESULTS: In UC, FC correlated with clinical Mayo score (r = 0.63, P < 0.0001). This correlation was strengthened by adding the endoscopic subscore (r = 0.90, P < 0.0001). The endoscopic subscore also independently correlated with FC (r = 0.96, P < 0.0001). In Crohn's colitis, endoscopic activity correlated with FC (r = 0.61, P < 0.001). FC levels were lower overall for patients with endoscopic remission compared with active endoscopic disease (median 100 versus 1180 µg/g, P < 0.0001). FC also correlated with histological remission (Geboes score < 3.1) and absence of basal plasmacytosis in CD (r = 0.77, r = 0.80, respectively; P < 0.01). Area under the curve for FC as a predictor of histological remission (Geboes score <3.1) was 0.95 (95% CI, 0.82-1). CONCLUSIONS: Low FC correlates well with histological remission and mucosal healing in colonic inflammatory bowel disease and is thus a clinically useful surrogate for inflammatory activity.

IBD Genetic Risk Profile in Healthy First-Degree Relatives of Crohn's Disease Patients.

BACKGROUND: Family history provides important information on risk of developing inflammatory bowel disease [IBD], and genetic profiling of first-degree relatives [FDR] of Crohn's disease [CD]- affected individuals might provide additional information. We aimed to delineate the genetic contribution to the increased IBD susceptibility observed in FDR. METHODS: N = 976 Caucasian, healthy, non-related FDR; n = 4997 independent CD; and n = 5000 healthy controls [HC]; were studied. Genotyping for 158 IBD-associated single nucleotide polymorphisms [SNPs] was performed using the Illumina Immunochip. Risk allele frequency [RAF] differences between FDR and HC cohorts were correlated with those between CD and HC cohorts. CD and IBD genetic risk scores [GRS] were calculated and compared between HC, FDR, and CD cohorts. RESULTS: IBD-associated SNP RAF differences in FDR and HC cohorts were strongly correlated with those in CD and HC cohorts, correlation coefficient 0.63 (95% confidence interval [CI] 0.53 - 0.72), p = 9.90 x 10(-19). There was a significant increase in CD-GRS [mean] comparing HC, FDR, and CD cohorts: 0.0244, 0.0250, and 0.0257 respectively [p < 1.00 x 10(-7) for each comparison]. There was no significant difference in the IBD-GRS between HC and FDR cohorts [p = 0.81]; however, IBD-GRS was significantly higher in CD compared with FDR and HC cohorts [p < 1.00 x 10(-10) for each comparison]. CONCLUSION: FDR of CD-affected individuals are enriched with IBD risk alleles compared with HC. Cumulative CD-specific genetic risk is increased in FDR compared with HC. Prospective studies are required to determine if genotyping would facilitate better risk stratification of FDR.

13C urea breath test for (Helicobacter pylori): determination of the optimal cut-off point in a Canadian community population.

AIM: To determine the test characteristics and the optimal cut-off point for the (13)C urea breath test ((13)C UBT) in a Canadian community laboratory setting. METHODS: Of 2232 patients (mean age +/- SD: 51+/-21 years, 56% female) who completed a (13)C UBT, 1209 were tested to evaluate the primary diagnosis of (Helicobacter pylori) infection and 1023 were tested for confirmation of eradication following treatment. Cluster analysis was performed on the (13)C UBT data to determine the optimal cut-off point and the risk of false-positive and false-negative results. Additionally, 176 patients underwent endoscopic biopsy to allow validation of the sensitivity and specificity of the (13)C UBT against histology and microbiology using the calculated cut-off point. RESULTS: The calculated cut-off points were 3.09 delta/1000 for the whole study population (n=2232), 3.09 delta/1000 for the diagnosis group (n=1209) and 2.88 delta/1000 for the post-treatment group (n=1023). When replacing the calculated cut-off points by a practical cut-off point of 3.0 delta/1000, the risk of false-positive and false-negative results was lower than 2.3%. The (13)C UBT showed 100% sensitivity and 98.5% specificity compared with histology and microbiology (n=176) for the diagnosis of active (H pylori) infection. CONCLUSIONS: The (13)C UBT is an accurate, noninvasive test for the diagnosis of (H pylori) infection and for confirmation of cure after eradication therapy. The present study confirms the validity of a cut-off point of 3.0 delta/1000 for the (13)C UBT when used in a large Canadian community population according to a standard protocol.

Inhalation tolerance is induced selectively in thoracic lymph nodes but executed pervasively at distant mucosal and nonmucosal tissues.

Under immunogenic conditions, both the site of initial Ag exposure and consequent T cell priming in specific draining lymph nodes (LNs) imprint the ensuing immune response with lasting tissue-selective tropism. With respect to immune tolerance, whether the site of tolerance induction leads to compartmentalized or, alternatively, pervasive tolerance has not been formally investigated. Using a murine model of inhalation tolerance, we investigated whether the induction of respiratory mucosal tolerance precludes the development of de novo Th2 sensitization upon subsequent exposure to the same Ag at distant mucosal (gut) and nonmucosal (cutaneous) sites. By tracking the proliferation of CFSE-labeled OVA-TCR transgenic CD4(+) T cells upon OVA inhalation in vivo, we defined the site of tolerance induction to be restricted to the thoracic LNs. Expectedly, inhalation tolerance prevented de novo Th2 sensitization upon subsequent exposure to the same Ag at the same site. Importantly, although gut- and skin-draining LNs were not used during tolerance induction, de novo Ag-specific proliferation and Th2 differentiation in these LNs, as well as memory/effector Th2 responses in the gut (allergic diarrhea) and skin (late-phase cutaneous responses) were inhibited upon immunogenic challenge to the same Ag. Interestingly, this pervasive tolerogenic phenotype was not associated with the presence of suppressive activity throughout the lymphatics; indeed, potent suppressive activity was detected solely in the spleen. These data indicate that while inhalation tolerance is selectively induced in local thoracic LNs, its tolerogenic activity resides systemically and leads to pervasive immune tolerance in distant mucosal and nonmucosal sites.

High-level serum antibodies to bacterial antigens are associated with antibiotic-induced clinical remission in Crohn's disease: a pilot study.

In Crohn's disease, antibiotics are used with variable efficacy, suggesting that some patients are more likely to respond. The aim of this study was to determine whether Crohn's patients with predominant serum antibody reactivity toward bacterial antigens OmpC and/or I2 were more likely to achieve remission with antibiotics. Patients with ileal or ileal with right-sided colonic Crohn's disease were studied in a double-blind trial of budesonide alone or budesonide plus metronidazole and ciprofloxacin. In the budesonide plus metronidazole and ciprofloxacin group, patients with OmpC/I2 predominant profiles had the highest remission rate, whereas the group with no antibody predominant profiles had the lowest rate. In the budesonide group, patients with the OmpC/I2 predominant profile had the lowest remission rate, and the no-antibody group rate was higher. Although not statistically significant, these results support further testing to determine whether predominant serum reactivity to certain bacterial antigens may be a marker for efficacious use of antibiotics.

IL-10 modulates intestinal damage and epithelial cell apoptosis in T cell-mediated enteropathy.

In vivo T cell activation by anti-CD3 monoclonal antibody (mAb) results in intestinal damage characterized by loss of villi and epithelial cell apoptosis. The role of the increased interleukin (IL)-10 released during this process is not clear. We assessed the effects of IL-10 on T cell-induced mucosal damage in vivo using IL-10-deficient C57BL/6 [IL-10 knockout (KO)] mice. IL-10 KO and wild-type C57BL/6 mice were injected with anti-CD3 mAb and observed for diarrhea. Changes in serum cytokine levels were measured by ELISA. Histological changes and epithelial cell apoptosis were analyzed on hematoxylin- and eosin-stained tissue sections. Fas expression on intestinal epithelial cells was assessed by flow cytometry analysis of freshly isolated intestinal epithelial cells. Anti-CD3-treated IL-10 KO mice developed more severe diarrhea, a greater loss of intestinal villi, and an increase in the numbers of apoptotic cells in the crypt epithelium. This difference in IL-10 KO mice was associated with an increase in serum tumor necrosis factor-alpha and interferon-gamma levels and with an increase in Fas expression on fresh, isolated, small intestinal epithelial cells. In addition, the enhanced intestinal tissue damage induced by anti-CD3 in IL-10 KO mice was significantly diminished by treatment with recombinant murine IL-10. Therefore, the lack of IL-10 allowed for an increased T cell-induced intestinal tissue damage, and this was associated with an increase in T cell cytokine release and an increase in epithelial cell Fas expression.

The establishment of a national tissue bank for inflammatory bowel disease research in Canada.

The Crohn's and Colitis Foundation of Canada (CCFC) has established a national bank for tissue, serum and blood from patients with inflammatory bowel disease (IBD). Investigators from across the country submit material to the bank together with clinical data. Investigators may access their own patient information from the bank for their own study purposes, but the distribution of tissue is restricted to specific CCFC-funded projects. Currently, tissues are being collected from newly diagnosed, untreated IBD patients to support a recent initiative aimed at characterizing microbes in colonic and ileal biopsies from such patients. In the future, criteria for the submission of tissue will be tailored to specific research questions. This bank is believed to be the first national bank of its kind dedicated to research in Crohn's disease and ulcerative colitis