bluuebunny/crossref_metadata_2025 huggingface dataset:
A151 STRATEGIES TO ENHANCE THE CLINICAL APPLICATIONS OF A NOVEL PH SENSITIVE ANALGESIC IN A PRECLINICAL MODEL OF COLITIS
Authors: Parkar N , Jimenez Vargas N , Blazevic L , Stein C , Vanner S J
Published: February 2025

Background

Improved pain management is an identified top five priority for the treatment of patients suffering from inflammatory bowel disease. Although conventional opioids and NSAIDs can provide pain relief, their side effects pose serious health risks. We developed a unique pH-sensitive analgesic, NFEPP, that is only active at sites of injury/inflammation without affecting healthy tissues, e.g. brain and gut. Preclinical studies using parenteral routes(s.c. or i.v.) demonstrate that NFEPP exhibits potency comparable to fentanyl, but without the risks of addiction or severe side effects like respiratory depression. The duration of action of NFEPP is ~2 hrs, which would require continuous infusion or frequent applications to treat a painful disorder. To broaden the potential clinical applications, strategies are needed to increase its half-life and to understand its efficacy compared to conventional treatments.

Aims

To examine the therapeutic index(TI) of NFEPP and determine if a high index could be exploited to extend its duration of action, and to compare the analgesic efficacy of NFEPP with a standard NSAID, diclofenac.

Methods

Acute colitis was induced in C57BL/6 mice by administering 2.5% dextran sulfate sodium(DSS) in drinking water for five days. Following s.c. injections of vehicle, NFEPP, fentanyl or diclofenac, visceromotor responses (VMRs) to colorectal distension were measured using telemetric transmitters inserted in the abdominal wall muscles. To assess cardiorespiratory side effects, mice were monitored via pulse oximetry.

Results

NFEPP(0.4 mg s.c.) and fentanyl(0.4 mg s.c.) exhibited similar analgesic effects on VMR but fentanyl markedly inhibited O2 saturation (~10%; p<0.05), causing hypoxia. NFEPP at 50X’s this analgesic dose(20 mg/kg s.c.) had no effect on O2 saturation, suggesting a very high TI. We therefore examined whether the duration of action of NFEPP could be extended into the range of other oral analgesics by increasing the dose (doubling the dose increases T1/2 by ~<1, 1st order kinetics). NFEPP 0.4 mg/kg s.c. was tested at 2 hrs and 1.6 mg/kg s.c. at 6 hrs. NFEPP (1.6 mg/kg s.c.) caused a 37.8% (p<0.05) reduction in VMR responses after 6 hrs, similar to the effect of NFEPP 0.4 mg/kg at 2 hrs (36.8% reduction in VMR; p<0.01). Comparator studies of the efficacy of NFEPP(0.4 mg/kg s.c.; ~EC75 dose) and diclofenac(30 mg/kg s.c., ~EC100 dose) demonstrated a 54.2% (p<0.001) and 49.7% (p<0.01) reduction in VMR, respectively.

Conclusions

NFEPP has a very high TI compared to fentanyl, and this property could potentially be exploited to increase its half-life in oral and/or patch formulations by increasing the dose without risk of respiratory depression. NFEPP has similar or greater analgesic efficacy compared to NSAIDs and could potentially be an alternative for some clinical indications.

Funding Agencies

CIHR
A153 IL10-PRODUCING GUT-RESIDENT TR1 CELLS ARE FOUND AT HIGH FREQUENCIES IN HEALTHY HUMANS AND MICE AND MAY PROTECT AGAINST MURINE ACUTE COLITIS
Authors: Poloni C , Sze A , Lim S , Esmaeilzadeh M , Wang X , Cook L , Steiner T
Published: February 2025

Background

Inflammatory bowel disease (IBD) affects an estimated 270,000 people in Canada and is increasing in prevalence. Current treatments, such as anti-TNFα mAbs, block inflammatory pathways, but require repeated dosing and do not reverse intestinal fibrosis. Additionally, a significant subset of IBD patients have relapsing disease and do not respond to biologics. We have shown type 1 regulatory cells (Tr1s) are capable of suppressing inflammation via IL-10, promote gut-healing and barrier function via IL-22, and are long-lasting in mouse models.

Aims

We aimed to evaluate adoptive transfer of Tr1 cells as a therapy for IBD. We hypothesized that Tr1 cells can prevent inflammatory damage and fibrosis in the context of IBD.

Methods

The frequency of non-FOXP3 (Tr1) regulatory cells were analyzed from IL-10-eGFP mice and human gut samples from the Australian Donation and Transplantation Biobank to determine the major source of gut-resident T-cell-derived IL-10. Adoptive transfer experiments were performed using 9-10 week old C57BL/6 mice, where mice were briefly irradiated, injected with 1x106 FOXP3neg IL-10+ (Tr1) cells or PBS prior to administration of dextran sulfate sodium (DSS) to induce acute colitis. Weight and disease score were measured for 14 days, followed by histologic analysis of gut tissue and flow cytometric analysis of adoptively transferred (Thy1.1+) and endogenous (Thy1.2+) T cells.

Results

Tr1 cells act as the major source of intestinal CD4+ gut-resident derived IL-10, as compared to FOXP3+ T regulatory cells in mice and humans (p=0.0051, 0.0156). Further, mice receiving Tr1 adoptive transfer therapy have decreased weight loss at day 7 post DSS administration (p = 0.0163), increased colon length (p=0.0406), decreased colon thickening (p=0.0234), and decreased blinded histologic scoring (p=0.0229) at experimental endpoint. Furthermore, successfully engrafted adoptively transferred Tr1 cells have increased expression of T regulatory marker ICOS in the blood, spleen, and mesenteric lymph node of mice receiving cellular therapy, as compared to endogenous CD4+ T cells (p=0.0003, 0.003, <0.0001). Preliminary experiments suggest human CD4+ ICOS+ T cells secrete high levels of IL-10.

Conclusions

Tr1 cells are the major T cell producers of anti-inflammatory cytokine IL-10 in both human and murine intestine, producing more IL-10 than FOXP3+ regulatory T cells. Adoptive transfer of Tr1 cells into a murine model of acute colitis protects against weight loss and colon remodeling. Further, these cells are long-lived and detectable up to 8 weeks post transfer. Together, this data suggests Tr1 cellular therapy may be a promising treatment for IBD.

Funding Agencies

CIHR
A157 PREDICTING SURVIVAL TIME FOR BOWEL RESECTION IN INDIVIDUAL CROHN DISEASE PATIENTS
Authors: Suarez Suarez R G , Ahmed S , Huynh H , Shaikh A , Otley A , Jacobson K , Zachos M , Deslandres C , El-Matary W , deBruyn J , Griffiths A , Walters T , Wine E
Published: February 2025

Background

Pediatric onset Crohn disease (pCD) tends to be more complicated with a higher likelihood of requiring intestinal resection surgery. Currently there are no predictive tools for surgery in pCD; risk scores and relative survival analysis are available, but these cannot accurately calculate the probability of surgery in children with CD at an individual level.

Aims

This study aims to apply machine learning to create an individual survival time distributions (ISD) tool for accurate prediction of bowel resection over time in a novel pCD patient.

Methods

A prospectively-followed cohort of pCD patients (n= 934) was collected through the Canadian Children Inflammatory Bowel Disease Network (CIDsCaNN) inception cohort (2013-2021). 58 of the 934 pCD patients underwent surgery, while the remaining 876 either did not require surgery by the study’s end, transitioned to adult care, or were lost to follow-up. Surgeries included bowel resections for stricturing or penetrating disease.

Clinical, laboratory, and treatment data were compiled into three datasets: baseline, induction (baseline + 10 weeks follow-up data), and longitudinal (baseline + 3 equally spaced follow-up visits with all treatment data).

To develop the ISD predictor, we built a learning algorithm that includes maximum relevance minimum redundancy (mRMR) feature selection, Cox Proportional Hazards, and Random Survival Forest models. To estimate the quality of the ISD predictor, measured by the Integrated Brier Score (IBS) and Concordance Index (C-Index), we used k-fold (external) cross validation.

Results

Our resulted ISD predictors, two trained Cox Proportional Hazards models and one Random Survival Forest model, had IBS scores < 0.1 and C-Index scores > 0.83. These results indicate that our models provide a reliable ranking of survival times based on the individual probability for surgery. The results also showed that the features that are most informative for prediction of surgery were stricturing behavior, penetrating behavior, and distal bowel involvement.

Conclusions

This study suggests that it is possible to produce an ISD predictor capable of forecasting bowel resection over future times in a novel pCD patient. This novel approach can build tools to improve both the choice and timing of therapy.

Funding Agencies

CIHRWomen and Children’s Health Research Institute
A164 SINGLE-CELL RNASEQ INDICATES INCREASE IN COLONIC REGULATORY MACROPHAGES DURING CITROBACTER RODENTIUM INFECTIOUS COLITIS
Authors: Cortez S , Herik A , Hannawayya R , Wang A , McKay D , Cobo E
Published: February 2025

Background

Citrobacter rodentium (CR) is a murine attaching and effacing enteric bacterial pathogen that induces colitis and mimics enteropathogenic and enterohemorrhagic E. coli in humans. Studies of macrophages during CR infection have focused on proinflammatory functions, paying less attention to M2 or regulatory macrophages. We have shown that IL-4-treated macrophages (M(IL4)) have promising potential as a novel anti-colitic therapy using chemical-induced colitis in mice. However, any benefit of M(IL4)s in infectious colitis is unknown. This study tests the hypothesis that regulatory macrophages, specifically M(IL4)s, limit the severity of CR-infectious colitis.

Aims

i. Determine if M2 macrophages increase in the colon of CR infected mice.

ii. Assess the impact of M(IL4) treatment in CR infection severity and inflammation.

Methods

C57Bl/6 mice were orally infected with CR (5x108 CFU), and colons were collected during the colonization, expansion, and clearance phases (0, 3, 8, 21 days post-infection, DPI) for single-cell RNAseq to examine immune profiles and differentially expressed genes (DEG). The effect of M(IL4) treatment was assessed through ip. delivery of M(IL4)s (106cells) two days before CR infection followed by analysis of bacterial shedding and colonic histopathology. Inflammation was measured by neutrophil-mediated lipocalin-2 in feces by ELISA and RT-qPCR for mRNA expression of the anti-microbial peptide, REGIIIγ, and Th1 cytokine, IFN-γ.

Results

Peaking at 3 DPI, there was a significant increase in arginase1+ Relma+ Ym1+ M2 macrophages in the colon of CR-infected mice compared to proinflammatory M1 subsets. These M2-type cells showed upregulated expression of Cxcl9 and Acod1 mRNA, which possess antimicrobial activity essential in mitigating CR infection. Pretreatment with M(IL4)s did not exacerbate CR infection as bacterial shedding and histopathology scores (n=13) were similar in both groups, with all mice clearing CR by 18 DPI (n=5). Infection with CR was accompanied by increased fecal lipocalin and tissue REGIIIγ and IFNγ mRNA, independent of M(IL4) treatment (n=13).

Conclusions

This study suggests a formerly unappreciated antimicrobial role of M2 macrophages in the defense against CR. While M(IL4) treatment did not improve the outcome of infection with CR, neither did it exaggerate the severity of the infection, suggesting that the adoption of M(IL4) therapy for IBD would not increase the individual’s susceptibility to enteric infection.

Funding Agencies

NRC
A169 THE ASSOCIATION OF FAECAL CALPROTECTIN MEASUREMENTS WITH ENDO-HISTOLOGICAL REMISSION IN ULCERATIVE COLITIS: A POOLED ANALYSIS.
Authors: Dubé L , Lakatos P , Afif W , Bitton A , Wild G , Magro F , Patel A , Guardiola J , Bessissow T
Published: February 2025

Background

Endoscopic and histologic evaluation is standard practice to confirm the presence of active disease in ulcerative colitis (UC) before treatment. Fecal calprotectin (FCAL) levels show a positive correlation with endoscopic indices, relapse, and response to treatment. Meta-analyses on the diagnostic yield of FCAL for histologic remission are hampered by the different cut-offs used by existing studies.

Aims

Our study aims to select an optimal FCAL threshold to discriminate between active disease or remission in UC based on Mayo endoscopic score (MES) and Geboes histologic score (GHS).

Methods

We performed a pooled analysis of retrospective and prospective studies of patients with UC from 4 academic centres. Key inclusion criteria were adult UC patients undergoing colonoscopy, with recent FCAL measurements. Receiver operating characteristics curves and area under the curve (AUC) were computed to determine the optimal FCAL threshold for prediction of active UC based on specificity (SP) and sensitivity (SN). Active endoscopic disease was assessed using MES 0-1 vs 2-3 and MES 0 vs 1-3. Active histologic disease was assessed using GHS ≥ or < 2.0 and GHS ≥ or <3.1.

Results

A total of 741 patients with UC were included in our analysis. For MES 0 vs 1-3, the AUC was 0.730 (95% CI; 0.686-0.775) with an optimal threshold of 145.2 µg/g (SP: 0.68, SN: 0.68). For MES 0-1 vs 2-3, an AUC of 0.806 (95% CI; 0.759-0.852) was computed with an optimal FCAL threshold of 215.3 µg/g (SP: 0.71, SN: 0.71). For GHS <2.0 vs GHS ≥2.0, the AUC was 0.656 (95% CI; 0.614-0.698) with an optimal threshold of 118.0 µg/g (SP: 0.60, SN: 0.60). For GHS <3.1 vs GHS ≥3.1, the AUC was 0.752 (95% CI; 0.712-0.792) with an optimal threshold of 164.7 µg/g (SP: 0.70, SN: 0.70).

Conclusions

Our analysis suggests that FCAL has the potential to be used in the clinical setting to determine the likelihood of concurrent endoscopic and/or histological disease activity. We plan on testing and validating our thresholds in an independent dataset to assess the clinical relevance of FCAL in predicting UC remission and in guiding physicians in pursuing further tests such as endoscopy and biopsy.

Funding Agencies

None
A174 THE DIRECT HEALTHCARE COST OF INFLAMMATORY BOWEL DISEASE IN CANADA: A POPULATION-BASED ANALYSIS OF ADMINISTRATIVE DATA
Authors: Coward S , Benchimol E I , Bernstein C N , Avina-Zubieta A , Bitton A , Hoentjen F , Kuenzig E , Lu N , Leal J , Ma C , Murthy S , Novak K , Nugent Z , Otley A , Panaccione R , Peña-Sánchez J , Singh H , Targownik L , Kaplan G G
Published: February 2025

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
A176 SEROLOGICAL HEAVY METAL ASSESSMENT IN PERSONS WITH IBD
Authors: Narvey S , Dolovich C L , Bernstein C N
Published: February 2025

Background

Inflammatory Bowel Disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic conditions of aberrant gut inflammation. The increasing prevalence of IBD in parallel with increasing human exposure to heavy metals (HMs) has raised concern regarding the contribution of HMs to gut pathology. Emerging evidence has implicated HMs as influential factors in IBD pathogenesis, however, our current understanding of how HMs impact gut barrier integrity, inflammation, and dysbiosis is limited in the context of IBD and deserving of further attention.

Aims

The preliminary study aim was to establish a foundational understanding of serum levels of certain HMs in IBD. Additionally, we aimed to characterize a correlation between HM concentrations in serum and gut tissue.

Methods

Using Inductively Coupled Plasma Mass Spectrometry (ICP-MS), serum concentrations of Aluminum (Al), Chromium (Cr), Mercury (Hg), and Titanium (Ti) were measured in individuals with CD, UC, multiple sclerosis (MS), and in healthy controls (HC), where MS was used as an immune-mediated inflammatory disease control. A bivariate analysis was used to evaluate associations between HM levels and specific disease groups. Logistic regression analysis was used to assess HM outcomes predicted by disease groups and healthy controls while controlling for demographic factors.

Results

Relative to HCs, the proportion of higher serum levels of Al (79% vs. 38.6%, p<0.001), and Hg (63% vs 37.2%, p<0.001) were greater in CD. Whereas higher Ti levels were lower in CD (59%), UC (14.0%), and MS (6.1%) relative to HCs (84.1%); p-values <0.0002, <0.0001, and 0.001 respectively. In MS, the proportion of higher levels of Cr were greater compared to HCs (83.7% vs 38.0%, p<0.001) and Hg (57.1% vs 37.2%,p=0.025).When controlling for demographic factors, the odds of having higher serum Al (OR=6.41[CB1], 95%CI 3.04-13.5) and Hg (OR=2.27, 95%CI 1.13-4.57) were significantly greater in CD relative to HCs. In contrast, the odds of having elevated serum Ti were significantly lower in CD (OR=0.25, 95%CI 0.11-0.57) and UC (OR=0.02, 95%CI 0.01-0.08) relative to HCs. The odds of having increased Cr were 12 times greater for MS relative to HC [OR=12.33, 95%CI (3.83-39.7)]. In our investigation of gut biopsies, we did not find a correlation between HM levels in serum and intestinal tissue.

Conclusions

Our investigation demonstrated significant differences in serum HM levels between CD, UC, MS, and HCs. These results support the need for further exploration into the specific involvement of HMs in IBD.

Funding Agencies

None
A183 INVESTIGATING THE ROLE OF HUMAN BETARETROVIRUS (HBRV) INFECTION IN THE PATHOGENESIS OF CROHN’S DISEASE AND ULCERATIVE COLITIS
Authors: Waly D , Syed H , Oyegbami O , Sun N , Hotte N , Lerner E , Armstrong H , Wine E , Madsen K , Perry T , Mason A
Published: February 2025

Background

We have been investigating the role of viral infections in the development of inflammatory bowel disease (IBD) in genetically predisposed individuals. Using the SvEv IL10 -/- model of colitis, we found evidence of mouse mammary tumor virus (MMTV) infection and modulated the disease with combination antiretroviral therapy. Reducing MMTV RNA in the colon lowered inflammation, cytokine levels, and microbial dysbiosis. Our results showed viral superantigen (SAg) activity, which MMTV uses to replicate in lymphocytes. MMTV also exploits IL-10 to tolerize the host, and we hypothesize that IL-10 deficiency leads to colitis in this model (Armstrong et al., Microbiome, 2023).

Aims

This study investigates SAg activity in patients with IBD, focusing on Crohn’s disease (CD) and ulcerative colitis (UC) by analyzing T cell receptor variable beta region (TCR-Vβ) skewing. Additionally, we assess TCR diversity and selective enrichment of specific TCR-Vβ families by comparing IBD patients with healthy subjects and analyzing TCR profiles between active and inactive disease.

Methods

Peripheral blood samples (n > 2500) from the IBD Plexus database were analyzed to evaluate TCR-Vβ skewing as an indicator of SAg activity in patients with IBD. Comparisons of TCR-Vβ family usage were made between healthy subjects and those with CD and UC. Statistical analyses were performed in R, using unpaired t-tests and Bonferroni correction. TCR diversity was assessed using the Inverse Simpson Index (ISI) for CD, UC, and age-matched healthy controls. ISI values were also compared between active and inactive disease states.

Results

An analysis of TCR repertoires from PBMCs in CD (n=1901), UC (n=913), and healthy controls (n=725) revealed greater SAg activity in CD and UC patients than in controls. In healthy individuals, the TCR-Vβ repertoire was diverse and polyclonal, while IBD patients had skewed repertoires. TRBV-03, TRBV-09, and TRBV-24 were consistently enriched in CD and UC patients across all age groups. The inverse Simpson’s index showed increased T cell clonality in CD and UC patients. Additionally, TCR diversity was significantly lower in patients with active disease than in those with inactive disease.

Conclusions

Our study underscores the role of SAg activity in IBD, particularly in CD and UC. We observed notable TCR-Vβ skewing and TRBV subset enrichment in IBD patients, accompanied by increased T cell clonality, especially in active disease. This selective skewing of TCR-Vβ subsets suggests involvement of distinct SAgs. While bacterial SAgs are often linked to severe disease, our results indicate a contribution from non-bacterial SAgs, highlighting a potential connection between SAg activity and the onset of IBD.

Funding Agencies

CCC
A190 MICROBIAL AND MOLECULAR PROFILING OF THE APPENDIX OF PEDIATRIC PATIENTS WITH INFLAMMATORY BOWEL DISEASES
Authors: Arjomand Fard N , Githaka J M , Veniamin S , Guan L , Andrews J , Madsen K , Perry T , Wine E
Published: February 2025

Background

Inflammatory bowel diseases (IBD), including Crohn disease (CD) and ulcerative colitis (UC), are chronic inflammatory conditions influenced by genetic, environmental, and microbial factors. Emerging evidence suggests a role for the appendix in IBD with immune and microbe impacts on the colon. Peri-appendicular patch (PAP) inflammation is observed in some UC patients; appendectomy has shown protective effects, reducing relapse and colectomy rates in UC. However, the mechanisms underlying these associations remain unclear.

Aims

This study aims to explore these mechanisms by characterizing microbial species, molecular pathways, and host-microbiota interactions in the appendix of IBD patients.

Methods

Mucus from the appendix and non-inflamed colon of 10 pediatric IBD and 5 non-IBD patients undergoing elective surgical resection was collected for DNA and whole-genome sequencing. RNA and DNA from appendix tissues were used for RNA-seq and 16S rRNA sequencing, respectively. Metagenomic analysis was performed across all platforms. Fluorescence in-situ hybridization (FISH) and immunofluorescence defined localization.

Results

Proteobacteria were significantly enriched in IBD (mean = 27.23% ± 32%) compared to non-IBD mucus samples (mean = 1.6% ± 0.23%, p = 0.0052), with reduced bacterial diversity in the appendix of IBD patients. Differential abundance analysis revealed site-specific changes in MetaCyc pathways, notably in the IBD-appendix; for example, ABH and Lewis epitopes biosynthesis pathways were highly enriched in this organ. 38 of 50 MetaCyc pathways were linked to specific species, with E. coli contributing to 32 pathways. Immune and inflammatory pathways were significantly upregulated in the IBD-appendix. Strong correlations were observed between host tissue and microbial pathways in IBD mucus; for instance, Chondroitin Sulfate and Dermatan Sulfate Biosynthesis bacterial pathways were positively correlated with the upregulated host pathway Chemokine Receptors Bind Chemokines (Rho = 0.8851 and 0.88549, respectively), reflecting host-bacteria interaction in the appendix. Bacteria were observed in the mucus layer of IBD-appendix.

Conclusions

The appendix in IBD exhibits unique molecular and microbial features, offering key insights into its role in IBD pathogenesis and potential therapeutic avenues, reinforcing the efficacy of interventions such as appendectomy in UC.

Funding Agencies

CIHRWCHRI
A193 MICROBIOTA CHARACTERIZATION OF PATIENTS WITH INFLAMMATORY BOWEL DISEASE BASED ON SELF-REPORTED FOOD INTOLERANCES
Authors: Dang R , Boron D , Linton J , Marshall J , Narula N , Caminero A
Published: February 2025

Background

Approximately, 20% of the world’s population experiences adverse reactions to different food items. Patients with inflammatory bowel disease (IBD) including Crohn’s disease (CD) and ulcerative colitis (UC) commonly exhibit more food intolerances. The dietary triggers and mechanistic pathways involved in food intolerances are unknown. As IBD patients present an altered intestinal microbiota, we hypothesized that IBD-related adverse reactions are associated with defective microbial metabolism.

Aims

We aim to 1) understand dietary triggers and patterns of adverse reactions to foods in IBD and 2) characterize the intestinal microbiota of IBD patients based on food intolerance.

Methods

127 participants (85 IBD and 42 healthy controls) were recruited from the Gastroenterology clinic and recruitment posters at McMaster University between August 2021 to September 2023. Inclusion criteria for IBD included a confirmed diagnosis of CD or UC and between 18 to 75 years old. All participants completed questionnaires related to food intolerances, symptoms, demographics, and provided a stool sample for 16S rRNA Illumina sequencing to determine microbial composition.

Results

86% of IBD patients reported at least 1 food intolerance compared to 33% of controls. The mean number of food intolerances reported in patients with CD was 3.5 (SD=1.90), UC was 3.2 (SD=1.80), and controls was 1.3 (SD=0.83). Among IBD participants who reported a food intolerance, the common reactions were reported to dairy (72% CD and 73% UC), wheat (44% CD and 37% UC), and peanuts/tree nuts (28% CD and 30% UC). Regarding microbiota analysis, IBD patients had an altered fecal microbiota with lower alpha diversity (Shannon index) compared to healthy controls (p<0.0001). Alpha diversity was lower in IBD patients who reported 2 or more food intolerances compared to those who had none or 1. Also, specific adverse reactions such as dairy intolerance is associated with low alpha diversity in UC patients. IBD patients who reported a food intolerance had a higher abundance of Bacteroidota (p<0.05) compared to IBD with no food intolerance.

Conclusions

Overall, IBD patients reported a high number of intolerances to foods including dairy, wheat, peanuts/tree nuts, and caffeine. IBD patients have a lower alpha diversity measure compared to controls, which was more pronounced in patients experiencing several food intolerances. Further research to understand these offending foods in intestinal inflammation could help guide dietary interventions for IBD patients.

Funding Agencies

CCC
A195 MALNUTRITION IMPAIRS WOUND HEALING DURING DSS COLITIS AND AN IN-VITRO EPITHELIAL MIGRATION ASSAY
Authors: Littlejohn P , Yang H , Wang K , Kobor M , vallance B
Published: February 2025

Background

Malnutrition is a major public health burden. Caused by insufficient intake of food/nutrients, malnutrition often stems from poverty and lack of access to food. Malnutrition is also a common complication of many gastrointestinal diseases, including inflammatory bowel disease (IBD). Reportedly, more than half of all IBD patients suffer from micronutrient or macronutrient malnutrition, resulting from malabsorption, low nutrient intake, and excessive bleeding or diarrhea. Nutritional deficiencies can alter the course of IBD, prolong hospitalizations, alter treatment response, and delay wound healing. Notably, epithelial wound healing is critical in IBD, but efficient re-epithelization rely on nutrients such as zinc and vitamin A. I thus hypothesize that malnutrition will impair intestinal epithelial wound repair, in vivo and in vitro.

Aims

We tested how malnutrition affects wound healing following epithelial damage caused by dextran sulphate sodium (DSS)-induced colitis and in a 2D monolayer gap closure assay.

Methods

We used our previously published mouse model of multiple micronutrient deficiencies (MND) and induced colitis using dextran sodium sulfate (DSS). Weanling three-week-old male C57BL/6N mice were fed a diet deficient in (zinc, vitamin A, B12, folate and iron) or a control diet for 4 weeks. At 3 weeks, we induced colitis by administering 2.5% DSS in drinking water for 4 days, plus 3 days of water recovery. We investigated epithelial damage, wound repair and molecular responses through histological and gene expression profiling. We also generated 3D colonoids from non-colitic malnourished mice, converted them to a 2D monolayer and subjected them to a wound migration assay cultured using an established malnourished media containing standard nutrients, and 50% of normal levels.

Results

We found that while DSS induced tissue damage both in our control and MND mice, those on the MND diet exhibited impaired tissue repair with decreased re-epithelization over the wounded area compared to controls. Organoids cultured in the 50% malnourished media showed diminished growth, being smaller and less dense compared to standard media. Notably, epithelial migration towards gap closure in the 2D monolayer was delayed by 75% compared to standard media.

Conclusions

Our work demonstrates that malnutrition impairs intestinal wound repair mechanisms. We also demonstrate an effective organoid model for examining the effects of malnutrition in vitro. We propose that efforts to address underlying malnutrition may improve wound healing leading to better outcomes for patients with IBD.

Funding Agencies

CIHRTRIANGLE/Crohn’s and Colitis Canada, BC Children’s Hospital Research Foundation
A196 MATERNAL AND NEONATAL OUTCOMES IN PREGNANT WOMEN WITH IBD TREATED WITH USTEKINUMAB OR RISANKIZUMAB: A CASE SERIES
Authors: Li K , Nabavian H , Eisen S , O’Connor K , Srikanth V , Huang V
Published: February 2025

Background

Biologics are an important therapy for patients with moderate to severe IBD. These include Ustekinumab (UST) – anti-IL-12/23, and the newer biologic Risankizumab (RIS) – anti-IL23. For UST, the PIANO registry and some cohort studies found no significant difference in maternal/neonatal outcomes compared to controls. However, the EPI-MERES registry found an increase in likelihood of small for gestational age births, and one study reported a slower initial postnatal growth rate for in-utero exposed infants. RIS currently has limited evidence in pregnancy.

Aims

We present a case series of maternal and neonatal outcomes of UST and RIS treated pregnant patients with IBD.

Methods

We conducted a single-centre case series including patients treated with UST and RIS at any point during pregnancy enrolled between Jan 1, 2017 and Jul 31, 2024. Data was collected on maternal outcomes including live birth, miscarriage, delivery method, and pregnancy-related complications. Neonatal outcomes included preterm birth, small for gestational age (SGA), large for gestational age (LGA), congenital anomalies, NICU admission, APGAR scores, and neonatal infection.

Results

There were 23 UST patients – 21 (91.3%) had live births and 2 (8.7%) had miscarriages. Of the 21 that delivered, there were 12 (57.1%) vaginal deliveries, 8 (38.1%) elective c-sections, and 1 (4.8%) emergency c-section due to placental insufficiency. One patient had gestational diabetes, 1 had pre-eclampsia, but there were no preterm premature rupture of membranes or intrauterine growth restrictions (IUGR). Of the 21 neonates, 3 (14.3%) were preterm, 1 (4.8%) was SGA, 3 (14.3%) were LGA, and 1 unknown. There were no congenital anomalies. Five (23.8%) infants were admitted to the NICU after birth and 1 (4.8%) was reported to have a postnatal infection within 3 months. Of the 12 infants with known APGAR scores, 10 had scores ≥7 at 1 minute, and 2 were <7. At 5 minutes, all scores were ≥7.

Of the 2 RIS patients, 1 was exposed to RIS throughout the entire pregnancy and the other was given a dose during the 1st and 3rd trimester only. Both pregnancies resulted in live births with 1 vaginal delivery and 1 elective c-section. One neonate was LGA. One had an APGAR score of 8 at 1 minute and 9 at 5 minutes. The other infant scored 9 at 1 minute and the score at 5 minutes was not documented. There were no preterm births, congenital anomalies, or pregnancy-related complications.

Conclusions

In our case series of UST and RIS exposed pregnancies, there were no significant adverse maternal or neonatal outcomes. Further data is necessary to better characterize the safety of both medications.

Funding Agencies

None
A198 BIO-EXPERIENCED ULCERATIVE COLITIS PATIENTS REQUIRING ADMISSION HAVE A TWO-FOLD RISK OF COLECTOMY AS COMPARED TO BIO-NAÏVE PATIENTS
Authors: Panteluk A , Chappell K , Gozdzik M , Kroeker K
Published: February 2025

Background

Admission rates for patients with ulcerative colitis (UC) are decreasing, however patients admitted with a UC flare are at increased risk of colectomy. In recent years, numerous advanced therapies have emerged to treat flares and maintain remission. Many patients are now “bio-experienced”, defined as prior/current exposure to at least one advanced therapy. In flare management, colectomy is reserved for patients with severe or refractory disease, or to manage complications such as toxic megacolon or perforation. It is not known if a patient’s bio-exposure status (i.e. bio-experienced or bio-naive) affects their risk of requiring a colectomy when they are hospitalized for a UC flare. Such information is important to clinicians when choosing to initiate therapy, determining the timing of therapy escalation and allowing patients to understand their risk to make informed treatment decisions.

Aims

To assess the relative risk of 90-day colectomy in bio-experienced versus bio-naïve patients admitted to hospital with UC flare as well as secondary outcomes such as time to first advanced therapy in hospital and length of stay (LOS).

Methods

This is a single centre retrospective cohort study that included patients admitted with a diagnosis of UC flare to a major tertiary hospital in Edmonton, AB from Nov 2019 to Apr 2024. The cohort was designated as bio-naïve, having never received advanced therapies or bio-experienced, having received at least one advanced therapy prior to admission. Administrative data extraction and chart review was used to obtain the primary and secondary outcomes. Relative risk of colectomy was calculated between groups and a 95% confidence interval generated for this. The secondary outcomes were analyzed using an unpaired t-test with the significance level of p<0.05. For LOS with colectomy, given significant variance, median and IQR were reported instead.

Results

In total, there were 216 admissions; 87 patients were bio-experienced and 129 were bio-naïve at the time of admission. Twenty-six patients underwent colectomy within 90 days. Of the patients who were bio-experienced, 18.39% underwent colectomy compared to 7.75% in the bio-naïve group. The relative risk of 90-day colectomy in the bio-experienced compared to bio-naïve patients was 2.37 (1.13-4.98 95% CI).

Secondary outcomes showed similar average length of stay, however bio-experienced patients were placed on advanced therapy sooner and those requiring colectomy had shortened LOS, compared to bio-naïve patients (Figure 1). Chart review for other secondary outcomes (eg. prior therapies, disease duration) is underway.

Conclusions

In this retrospective cohort study, we demonstrated that the relative risk of colectomy for UC patients admitted with flare is 2.3 fold higher in bio-experienced compared to bio-naïve patients.

Figure 1

Funding Agencies

None
A205 IMPACT OF THE PANDEMIC ON BUDESONIDE MMX DISPENSING AND TREATMENT FAILURE IN ULCERATIVE COLITIS
Authors: Coward S , Martins K , Klarenbach S , Kroeker K , Ma C , Panaccione R , Richer L , Seow C , Targownik L , Kaplan G G
Published: February 2025

Background

Budesonide MMX is a locally acting corticosteroid with reduced side effects compared to prednisone. During the pandemic, budesonide MMX may have been preferred due to its favourable side effect profile.

Aims

To analyze rates of budesonide MMX dispensing and treatment failure before / during the pandemic.

Methods

We analyzed population-based administrative healthcare data from Alberta to identify people dispensed budesonide MMX who met three criteria: 1. incident cases of ulcerative colitis (UC) after January 1, 2018; 2. ≥18 years old; 3. not concurrently on prednisone. We defined failure of budesonide MMX as subsequent prednisone dispensing within 30 days. We calculated rates of budesonide MMX dispensing per 1000 incident UC cases. We calculated average monthly percentage change (AMPC) in dispensing and failure rates with 95% confidence intervals (CI) by Poisson or negative binomial models. An interaction term tested differences between pre-pandemic rates (prior to April 2020) and pandemic rates (April 2020 to March 2023). We used Cox proportional hazard models to compare budesonide MMX failure before vs during the pandemic, with hazard ratios (HR) and 95%CIs—a sensitivity analysis was done to extend the follow-up time to 90 days.

Results

Overall, 320 incident UC cases were dispensed budesonide MMX with 30-days follow-up. Of those, 14.06% (95%CI: 10.25, 17.87) received prednisone within 30 days. Mean time to failure was 17 days. There was a significant difference in the AMPC in dispensing rates was observed pre-pandemic vs during the pandemic (p=0.037) (Table 1). After the pandemic onset, budesonide MMX dispensing significantly decreased (AAPC: −2.43%; 95%CI: −3.77, −1.08). For the 30 days, the HR for budesonide MMX failure was 1.92 (95%CI: 0.95, 3.88). When the follow-up was extended to 90 days the HR was significant at 1.68 (95%CI: 1.05, 2.71), suggesting a significantly increased hazard of budesonide MMX failure during the pandemic compared to pre-pandemic.

Conclusions

Budesonide MMX dispensing was stable pre-pandemic but significantly decreased during. The pandemic may have been associated with an increased failure rate of budesonide MMX—particularly within 90 days—as more patients required prednisone to manage their UC.

Analysis of Rates per 1000 Individuals with Incident UC

Funding Agencies

Ferring Pharmaceuticals
A211 CLINICAL CHARACTERISTICS OF INFLAMMATORY BOWEL DISEASE IN JORDANIAN CHILDREN: A RETROSPECTIVE STUDY
Authors: Altamimi E , Alsmadi A S , Almomani H H , Alshurman M A
Published: February 2025

Background

Inflammatory Bowel Disease (IBD) is a chronic condition characterized by inflammation of the gastrointestinal tract. While IBD is increasingly recognized in pediatric populations worldwide, there is limited data on its characteristics in Jordanian children.

Aims

This study aims to describe the clinical presentation and management outcomes of IBD in children from a tertiery center in North Jordan.

Methods

A retrospective analysis was conducted on pediatric patients (aged 0-18 years) diagnosed with IBD between July 2017 and July 2024 at King Abdullah University Hospital in North Jordan. Data on demographic information, clinical symptoms, diagnostic procedures, treatment regimens, and follow-up outcomes were collected from medical records.

Results

Over the study period, 31 patients were diagnosed with IBD, with 58% being female. Among these, 51.6% were classified as Crohn’s disease, 29.0% as ulcerative colitis, and 19.4% as indeterminate colitis. The mean age at diagnosis was 8.7 years. The most common presenting symptoms were diarrhea (67.6%), abdominal pain (58.0%), weight loss (32.2%), and fatigue/malaise (32.2%).

Anemia was observed in 17 patients (54.8%). Intravenous iron therapy was required in 3 patients (9.7%), while 2 patients (6.5%) needed multiple blood transfusions. Escalation of initial therapy was necessary for 15 patients (48.4%). Biologic therapy (Anti-TNF agents) was used in 8 patients (25.8%), all of whom initially responded. However, 3 patients (37.5%) were switched to a second anti-TNF agent after secondary loss of response. Two patients (25.0%) developed psoriatic lesions, although none experienced serious infections. Notably, one patient (12.5%) required concomitant anti-tuberculosis treatment due to a latent tuberculosis diagnosis prior to initiating biologics.

One patient (3.2%) developed pancreatitis requiring hospitalization. This same patient also experienced dural venous thrombosis, necessitating prolonged anticoagulant therapy. None of the patients in this cohort underwent surgical intervention.

Conclusions

IBD in Jordanian children presents with clinical features similar to those reported in other regions, although environmental or genetic factors may lead to some variations in disease patterns, and treatments` response. Further studies are needed to optimize management protocols for pediatric IBD in Jordan.

Funding Agencies

None
A216 THE COST-EFFECTIVENESS OF FERRIC DERISOMALTOSE VERSUS FERRIC CARBOXYMALTOSE IN THE TREATMENT OF IRON DEFICIENCY ANAEMIA IN CANADA
Authors: Pollock R F , Bernstein C N , Shaffer S
Published: February 2025

Background

In Canada, approximately 0.8% of people have inflammatory bowel disease (IBD), which is estimated to rise by 2.4% annually over the next decade. Iron deficiency anaemia (IDA) is common in people with IBD, who can experience high levels of fatigue that may be alleviated by iron treatment. Intravenous (IV) iron is recommended for people who are intolerant or unresponsive to oral iron or those who require iron rapidly. Ferric carboxymaltose (FCM) and ferric derisomaltose (FDI) are high-dose, rapid-infusion iron formulations approved for treatment of IDA in people with IBD.

Aims

To evaluate the cost-utility of FDI versus FCM when treating IDA in patients with IBD in Canada.

Methods

A published model was adapted to evaluate the cost-utility of FDI versus FCM in Canada. Joint distributions of bodyweight and haemoglobin were used alongside the product monographs (PMs) to model iron need. Iron supply models for FCM and FDI were developed based on posological information in the PMs. Disease-related quality of life (QoL) was modelled using SF-36 data from the PHOSPHARE-IBD randomized trial and a diminishing marginal utility model was used to estimate the effect of iron infusions on QoL. Costs were obtained from Canadian sources aligned with a previous CDA-AMC appraisal of FDI. Price parity between FCM and FDI was assumed, and indirect costs arising from attending IV iron infusions were captured. Analyses were run over 10 years, costs were expressed in 2023 Canadian dollars ($), and future costs and effects were discounted at 1.5% per annum. Scenario analyses were performed incorporating fracture incidence based on recent data showing elevated fracture risk after administration of FCM versus FDI.

Results

Relative to FCM, FDI was associated with an additional 0.147 QALYs over 10 years, driven primarily by differences in disease-related QoL (Table). Costs were lower with FDI than FCM ($7,630 versus $9,236), corresponding to a saving of $1,606 per patient over 10 years driven by a reduced number of infusions required to correct iron need with FDI (11.13 versus 14.21 with FCM), and no requirement to monitor phosphate after FDI (Figure). FDI was therefore the dominant intervention. In the fracture scenario analysis, fracture risk was similar before and after treatment with FDI, but was higher with FCM, accompanied by additional costs of $3,086 versus FDI over 10 years ($4,285 versus $1,199).

Conclusions

In people with IBD and IDA requiring IV iron, FDI dominated FCM, reducing costs while improving QoL.

Contributors to QoL over 10 years

Direct cost drivers in the base case analysis and indirect costs in the societal analysis

Funding Agencies

Pharmacosmos A/S
A218 INFLAMMATORY PHENOTYPE AS A PREDICTOR OF TREATMENT RESPONSE IN ULCERATIVE COLITIS
Authors: AlDarwish A , Wilson A
Published: February 2025

Background

A variety of immune pathways contribute to the propagation of inflammation in ulcerative colitis (UC). Both, Th1- and Th2-associated cytokines and cells, have been implicated in the pathogenesis of the disease. Eosinophils, which are elicited by Th2 immune response, are increasingly recognized to have a pivotal role in the pathogenesis of UC, however, the exact link between eosinophils and UC disease outcomes and treatment responses over time is still incompletely defined.

Aims

We aim to evaluate the association between pre-treatment peripheral eosinophil counts and treatment response in patients with ulcerative colitis.

Methods

In this retrospective cohort study, data from 150 treatment naïve adult patients who were diagnosed with ulcerative colitis between 2005 and 2020 were reviewed. White blood count differential was collected at diagnosis and following exposure to one or more of the following treatments: corticosteroids, TNFa antagonists, or vedolizumab. Patients were stratified into two cohorts for analysis: “high-eosinophil” cohort (>=0.2x109cells/L) and “low-eosinophil” cohort (<0.2x109cells/L). The partial and endoscopic Mayo scores were evaluated at baseline and following treatment. Patients’ data were collected until their last gastroenterology follow-up or until surgical intervention. Demogoraphic data were summarized using descriptive statistics. Fisher’s Exact test was used to evaluate the association between eosinophil count and drug response as well as other outcomes.

Results

A total of 150 patients were included. 92 patients (63.3%) were included in the high-eosinophil cohort, while 58 patients (38.6%) were included in the low-eosinophil cohort. The median duration of follow-up was 78 months (IQR42.5) and 74 months (IQR45) in the high-eosinophil group and low-eosinophil group, respectively. Between the high-eosinophil group and low eosinophil group, there was no statistically significant difference in terms of steroid response (71.3%, 78.6% respectively, p=0.330), achieving steroid-free remission with TNFa antagonist (76%, 72.2% respectively, p=0.662), achieving steroid-free remission with vedolizumab (54.1%, 65.2% respectively, p=0.394), or disease refractoriness requiring more than 2 drug changes (15.4%, 8.8% respectively, p = 0.106).

Conclusions

This study did not show a correlation between baseline eosinophil count and response to therapy - corticosteroids, TNFa antagonist, and vedolizumab. Larger prospective studies are warranted to assess disease outcomes and treatment response to eosinophil-targeted therapy.

Funding Agencies

None