bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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, &lt;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

Abstract

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 &lt; 0.1 and C-Index scores &gt; 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

Abstract

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

Abstract

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 &lt; 2.0 and GHS ≥ or &lt;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 &lt;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 &lt;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

Abstract

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&lt;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

Abstract

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&lt;0.001), and Hg (63% vs 37.2%, p&lt;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 &lt;0.0002, &lt;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&lt;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

Abstract

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 &gt; 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

Abstract

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