bluuebunny/crossref_metadata_2025_split huggingface dataset:
P1275 Understanding the burden of severe ulcerative colitis: outcomes and treatment use in a large U.S. cohort
Authors: Raine T , Lewis J , Chen Y , Parkes G , Huisingh C , Wegrzyn L 
Published: January 2025

Abstract

Background
Severe ulcerative colitis (UC) hospitalizations, including those with acute severe UC, result in colectomy and substantial life changes for up to 20% of patients. As the treatment landscape evolves, more knowledge on patient characteristics, treatment patterns, and outcomes in real-world settings is needed to understand the burden of severe UC hospitalizations.

Methods
This large retrospective cohort study utilized electronic health record (EHR) data from integrated delivery networks in the U.S. with linked insurance claims. As a proxy for ASUC, patients hospitalized for UC (primary position) and requiring intravenous (IV) steroid use (N=9,716) from Jan 1, 2014 – Dec 31, 2022 were included. Eligible patients were ≥18 years and had &gt;180 days of prior EHR activity. A nested cohort (n=4,383) of patients discharged from the hospital without undergoing colectomy who had &gt;1 year of post-hospitalization EHR activity and &gt;1 health care encounter during the 1 year after the hospitalization were used to describe treatments and procedures during follow-up. Results were stratified by patient subgroups: 1) no prior IBD diagnosis, 2) prior IBD diagnosis, no prior advanced therapy, and 3) prior IBD diagnosis with prior advanced therapy.

Results
Of the 9,716 patients, the mean age was 46.3 years and 52.7% being female. Most had a previous IBD diagnosis (83.3%), and 23.8% had prior advanced therapy use. During the hospitalization, 13.5% received advanced therapy, primarily TNFi (11.3%), in addition to IV steroids, and in 8.2%, 13.2%, and 18.0% in subgroups 1, 2, and 3, respectively (p&lt;0.0001). Colectomy was performed in 12.2% overall and in 12.6%, 9.2%, and 19.6% in subgroups 1, 2, and 3, respectively (p&lt;0.0001). Among those discharged without colectomy, 33.3% received advanced therapy within 90 days, with subgroup 3 (55.5%) having higher use of these treatments compared to subgroup 2 (27.8%) and subgroup 1 (21.5%) (p&lt;0.0001). Within 1-year post-index, 38.4% experienced a UC-related hospitalization. Cumulative risk of colectomy within 1 year post-index was 20.4% overall and 18.5%, 16.1%, and 32.7% in subgroups 1, 2, and 3, respectively (p&lt;0.0001).

Conclusion
This study provides better understanding of the burden and outcomes for a contemporary cohort of patients with severe UC hospitalizations, especially those who received advanced therapy before hospitalization. These findings highlight the need for effective therapies and strategies for severe UC patients during and after hospitalization.
P1276 Persistent Insomnia Ignites the Flames of Crohn's Disease by Elevating Systemic Inflammation
Authors: Cao X , Zhao J , Zhang M , Lou S , Cao Q 
Published: January 2025

Abstract

Background
The association between insomnia and the risk of inflammatory bowel disease (IBD) remains inconclusive. We aim to investigate the association between insomnia and the risk of IBD, Crohn's disease (CD) and ulcerative colitis (UC), while further considering genetic vulnerability and inflammatory mediation.

Methods
This cohort study included 480,252 participants without IBD at baseline in the UK Biobank. The mean age of the population was 56.53 years old and 54.3% were female. Cox regression models examined the associations between insomnia and the incident of IBD, CD and UC. Polygenic risk score (PRS) for IBD, UC and CD was calculated. Subgroup and mediation analyses were conducted.

Results
A total of 480,252 participants were included. The mean age of the population was 56.53 years old and 54.3% were female. During a mean follow-up of 13.20 years, 3,219 incident IBD (1,005 CD and 2,207 UC) cases were documented. Compared to non-insomniacs, there was a significant increasing trend in the frequency of insomnia and the risk of incident IBD (P for trend=0.040) and CD (P for trend=0.003). Among individuals who usually have insomnia, the risk of CD incidence increased by 31% compared to those free of insomnia (hazard ratio [HR] 1.31; 95% confidence interval [CI]: 1.09-1.57; P=0.004), but no significant association was found between usually having insomnia and the risk of IBD (HR 1.10; 95% CI: 1.00-1.22; P=0.051) and UC (HR 1.03; 95% CI 0.91-1.16; P=0.678). Consistent results were observed in subgroup and sensitivity analyses. The connection between insomnia and CD was especially significant for participants with intermediate genetic susceptibility. High genetic risk individuals with usual insomnia were associated with a 2.51-fold increased risk of CD. The association between usually having insomnia and the risk of CD was partially mediated low-grade inflammation (INFLA) score by 6.36% (natural indirect effect [NIE] 1.018; 95% CI 1.013-1.023).

Conclusion
Insomnia exposure was associated with increased risk of CD but not UC. Further study is warranted to determine if modifying insomnia could mitigate CD risk.
P1281 Active perianal fistulising Crohn’s Disease is associated with a higher burden of psychological distress, depression, anxiety, stress and opioid use
Authors: Gu B , Su W K , Nano D , Wilson W , Iliescu S , Lynch K , Andrews J M , Connor S J , Ghaly S 
Published: January 2025

Abstract

Background
Perianal fistulising Crohn’s disease (PFCD) is an aggressive phenotype of Crohn’s disease (CD) which can cause pain, sepsis and faecal incontinence with relevant impairment in quality of life (QOL). We aimed to describe the effect of PFCD on QOL as measured by mental health indicators, opioid use and days out of role (DooR) due to inflammatory bowel disease (IBD) symptoms.

Methods
Crohn’s Colitis Care (CCCare) is a cloud-based clinical management system which has been used in routine clinical care in Australia and New Zealand since 2018. The CCCare Clinical Registry was interrogated in September 2024. Adults with CD across 25 IBD centres with an outpatient encounter between September 2023 and September 2024 were included. Mental health was assessed using the Kessler Psychological Distress Scale (K10) and the Depression Anxiety and Stress Scale (DASS-21).

Results
A total of 8317 people were identified with CD, of whom 2.7% (n = 222) had active PFCD, defined as a fistula on the most recent physical examination, imaging or endoscopy. Another 4.6% (n = 379) had previously documented PFCD and 92.8% (n = 7716) never had documented PFCD. The median age of the cohort was 42.0 years (IQR 30.0 – 57.0) with an even gender distribution (50.1% female). Most of the cohort resided in Australia (63.1%, n = 5249) and the remaining 36.9% in New Zealand (n = 3068).
People with active PFCD were more likely to be currently using opioid analgesia for their IBD (2.7% vs 0.5% vs 0.2%; p &lt; 0.01) and to have at least one DooR since their last clinical assessment (12.7 vs 6.9 vs 6.0%; p &lt; 0.01) compared to those with previous or never PFCD. People with active or previous PFCD were more likely to actively smoke than those without PFCD ever (14.4 vs 14.2 vs 7.3%; p &lt; 0.01).
303 people had a completed DASS-21 and 141 a K10 within the study period. People with active PFCD had numerically higher median scores across all mental health indices but there was no statistically significant difference. A numerically higher percentage of people with active PFCD were experiencing psychological distress or reported at least mild anxiety, depression or stress compared to those with previous or have never had PFCD (table 1).

Conclusion
People with active PFCD have higher rates of opioid use, more time out of role, and higher scores in K10 and DASS-21 compared to those with previous PFCD or never had PFCD. This highlights the psychosocial burden on PFCD, and therefore the need to optimise management of PFCD as well as address psychiatric comorbidities. People with active PFCD were more likely to be active smokers, emphasising the importance of addressing smoking cessation in the multidisciplinary management approach.
P1288 The Association of Long-term Night Shift Work and Related Circulating Proteins with Inflammatory Bowel Disease: A Prospective Cohort and Multi-omics Study
Authors: Zhao J , Xue E , Yu G , Ye J , Li X 
Published: January 2025

Abstract

Background
The association between night shift work and the risk of inflammatory bowel disease (IBD) remains unclear. We aim to investigate the association between night shift work and the risk of IBD, ulcerative colitis (UC), and Crohn’s disease (CD), while further investigating the roles of genetic susceptibility and circulating proteins.

Methods
This cohort study included 149,014 UK Biobank participants without IBD at baseline, with 28,772 undergoing proteomic detection. Cox regression assessed associations between night shift work, circulating proteins, and IBD risk, while multinomial logistic regression identified proteins linked to night shift work. Bulk RNA-seq (1,030 blood, 453 intestinal tissue, and 176 Ustekinumab-treated intestinal samples) and single-cell transcriptomics (51 samples, 163,336 cells) were integrated to explore the roles of night shift-related proteins in IBD development and progression.

Results
During a mean follow-up of 13.66 years, 818 incident IBD (556 UC and 262 CD) cases were documented. Compared to day workers, there was a significant increasing trend in the frequency of current shift work and the risk of incident IBD (Ptrend=0.018). Among individuals with usual or permanent night shifts work, the risk of IBD incidence increased by 56% compared to those with no shift work, with a hazard ratio (HR) of 1.56 (95% CI: 1.15-2.13), especially for in those with intermediate genetic susceptibility to IBD. Additionally, there was a significant increasing trend in the frequency of current shift work and the risk of incident UC (Ptrend=0.037). High genetic risk individuals with usual or permanent night shifts work were respectively associated with a 3.60-fold increase in the risk of IBD, a 3.13-fold increase in the risk of CD, and a 2.77-fold increase in the risk of UC. Compared with shift workers never working nights, participants with an average frequency of more than 8 nights per month of night shift work exposure possessed higher IBD risk (HR 1.54, 95%Cl: 1.07-2.23). Six circulating proteins (IL18R1, GDNF, SOD1, TNFRSF6B, MMP12, and CCL7) related to night shift work were associated with the risk of incident IBD. Multi-omics evidence indicated that MMP12 increased UC risk through macrophage function and reduces the efficacy of Ustekinumab, while CCL7+ monocytes, possibly in conjunction with ACKR1, may facilitate the initiation of inflammation in CD.

Conclusion
Night shift work has been associated with an increased risk of IBD, CD, and UC, with MMP12 and CCL7 identified as potential drivers of this association. Further research is needed to assess whether reducing night shift frequency and duration, combined with targeted protein interventions, could mitigate IBD risk and improve prognosis.
P1291 Transcriptional heterogeneity of granzyme K CD8 T Cells in Crohn’s Disease: Implications for tissue inflammation
Authors: Lee Y , Baek J , Kim Y , Hwang S W , Lee J L , Park S H , Kim J , Yang S K , Han B , Kweon M N , Song K , Yoon Y S , Ye B D , Lee H S 
Published: January 2025

Abstract

Background
Crohn’s disease (CD) pathogenesis involves complex interactions between immune cells and intestinal tissues. We investigated the heterogeneity of CD8 effector T cells (Teff) and their role in CD inflammation at the single-cell level.

Methods
T cells were isolated from blood, inflamed, and uninflamed intestinal tissues of 15 patients with CD. Various combinations of single-cell RNA sequencing, TCR sequencing, and spatial transcriptomics were performed on subsets of these samples to comprehensively analyze the cellular landscape.

Results
Analysis of 41,699 CD8 T cells revealed two main CD8 Teff subsets: granzyme B (GZMB+) Teff cells, predominantly in blood with high cytotoxic potential, and granzyme K (GZMK+) Teff cells, enriched in intestinal tissue with lower cytotoxic potential. In the intestine, GZMK+ and GZMB+ Teff cells exhibited distinct transcriptional profiles. GZMB+ Teff cells showed higher expression of KLF2 and its target genes, including tissue egress markers S1PR1 and S1PR5, suggesting circulation propensity. In contrast, GZMK+ Teff cells displayed a tissue residency signature, with reduced egress-related gene expression and increased AP-1 transcription factors (FOS, FOSB, JUN). TCR clonotype analysis revealed substantial clonal expansion of GZMK+ Teff cells and high clonal overlap with CD8+ tissue-resident memory T (Trm) cells. Cell-cell communication analysis demonstrated GZMK+ Teff cell interactions with myeloid cells through the CXCR3/CXCL9,-10 axis, which was confirmed by spatial transcriptomics. Delving deeper into the heterogeneity of GZMK+ Teff cells, we identified three distinct subpopulations, each characterized by unique functional attributes: cytotoxic GZMK+ cells expressing high levels of PRF1, GNLY, and GZMB; stem-like GZMK+ cells expressing TCF7, a key regulator of T cell stemness; and Trm-like GZMK+ cells with high CXCR6 expression, indicative of long-term tissue residence. Notably, the Trm-like GZMK+ T cells displayed elevated levels of pro-inflammatory cytokines (IFNG, TNF), suggesting their potential role in tissue inflammation.

Conclusion
Our study reveals the transcriptional heterogeneity of CD8 Teff cells in blood and intestinal tissues of patients with CD. We identified intestinal GZMK+ CD8 Teff cells that may contribute to local inflammation through myeloid cell interactions. These findings provide new insights into CD pathogenesis and may guide the development of targeted therapies modulating tissue-specific immune responses.
P1293 Novel mutations in SASH3 cause very early onset IBD by impairing the NF-kB and mTORC1 pathways
Authors: Tang W , Piao L , Zhong H , Mao J , Jiang Z , Huang T , Huang Y 
Published: January 2025

Abstract

Background
Human SAM and SH3 domain-containing 3 (SASH3) variants globally affect TCR signaling including its downstream mTORC1 and NF-kB signaling. These 3 pathys play great roles in the pathogenesis of very early-onset inflammatory bowel diseases (VEO-IBD). Here, we report a now 4-year-old patient (P1) who was ultimately diagnosed with SASH3 deficiency in the nuclear localization signal 1(NLS1) of the protein presenting with VEO-IBD along with his adult uncle clinically asymptomatic (P2) who carries the identical variant.

Methods
a 3.2-year-old boy suspected VEO-IBD was evaluated in our clinic. Tissues were obtained by endoscopy. Genomic DNA, extracted from the peripheral blood mononuclear cells of the child and parents, were subjected to whole-exome sequencing(WES) and sanger sequencing. After mutations in the SASH3 were identified, sanger sequencing were performed for their relatives,the immunological features of our patients were analyzed including the cell proliferation assay by flow cytometry. Western blot(WB) was performed to study the protein level of SASH3 and the NF-kB and mTORC1 pathways in patients.

Results
P1 was diagnosed with Crohn’s disease according the images of endoscopy and biopsies (Figure A). WES and sanger sequencing identical a variant at exon1 in SASH3 (c.10 C&gt;T/p.R4C ) in P1, his mother was a heterozygous carrier (Figure B). Sanger sequencing confirmed that P2 who was clinically asymptomatic to date, carries the identical variant at exon1 in SASH3 (c.10 C&gt;T/p.R4C ) which inherited from P1’ grandmother(Figure C,D). The SASH3 variants identified in them is located in the NLS1 of the protein(Figure E), it caused the protein is exclusively located in the cytoplasm and no protein was found inside the nucleus which were proved by WB( Figure F). The immune phenotype were not seriously damaged in our 2 patients at homeostatic conditions, but upon stimulation with anti-CD3 and anti-CD28, both CD4+ and CD8+ T cells from P1, demonstrated impaired expression of CD71 and GLUT1 (FigureG, H), indicating defective cell proliferation and activation. The WB demonstrated that both the level of p-NFkB-p65 and p-S6 was markedly reduced in P1 (Figure I). We used Infliximab to treat P1, one year later the endoscopy showed mucosal healing and the pathology showed improved in inflammation and absent in granulation tissue. (Figure J)

Conclusion
We identified a novel mutations in SASH3 located in the NLS1 of the protein which cause VEO-IBD by impairing the NF-kB and mTORC1 pathways.
P1300 HLA-C*06 Genotype and Ustekinumab Therapy Persistence in Inflammatory Bowel Disease
Authors: Corcoran R , Ryan A , Doherty J , Quinn E , Conroy J , Conroy J , O’Hara F , Cullen G , Sheridan J , Bailey Y , Dunne C , Hartery K , McNamara D , Doherty G , Kevans D 
Published: January 2025

Abstract

Background
Ustekinumab (UST) is an anti-IL12/23 monoclonal antibody approved for use in psoriasis and inflammatory bowel disease (IBD). HLA-C*06 allele carriage has been associated with higher rates of response to UST in psoriasis patient populations.1 The association between HLA-C*06 carriage and UST response in IBD has not been previously evaluated.
We aimed to further explore HLA-C*06 carriage as a pharmacogenetic marker as a response to UST therapy in IBD patients.

Methods
A multi-centre retrospective study of IBD patients treated with UST in Ireland was performed. Baseline demographics of the cohort were collected. HLA-C*06 genotypes were generated by imputation from whole genome sequence using HIBAG. UST therapy persistence, was considered a proxy for treatment response, and was expressed as time to discontinuation of UST therapy. The primary endpoint was UST therapy persistence segregated by HLA-C*06 allele genotype. Statistical analysis was performed using survival analysis and multivariate cox logistic regression with effect of covariates on outcome expressed as odds ratios (OR).

Results
143 IBD patients were identified and included in the study population. In this population, 32 patients (22%) carried at least one HLA-C*06 allele. There was no significant difference in median time to UST therapy discontinuation comparing HLA-C*06 carriers to non-carriers at 700-days follow-up, p=0.32 [Figure 1]. In a multivariate regression neither HLA-C*06 allele carriage (OR 1.2, p=0.5), male gender (OR 1.2, p=0.6), CD phenotype (OR 1.6, p=0.44), nor concomitant immunomodulator use (OR 1.1, p=0.8) were independently associated with time to UST therapy discontinuation.

Conclusion
HLA-C*06 allele carriage is not associated with increased UST therapy persistence in IBD. Larger studies of UST therapy outcome in IBD patients with characterised HLA-C*06 genotype are required to confirm this finding.

References
1.Talamonti M, Galluzzo M, Chimenti S, Costanzo A. HLA-C*06 and response to ustekinumab in Caucasian patients with psoriasis: Outcome and long-term follow-up. J Am Acad Dermatol. 2016;74(2):374-5.
P1301 Bile acid composition and immunological effect in mouse model and IBD patients
Authors: Leistl S , Hu K , Rauh M , Neurath M , Günther C 
Published: January 2025

Abstract

Background
Bile acids (BAs) were suggested to have immunomodulatory properties that could influence inflammatory pathways in Inflammatory Bowel Disease (IBD). Dysregulated BA metabolism has been observed in IBD patients, further presented in our study by an analysis of IBD patients BA profiles with association to gene expression and targeted treatment of organoid models to elucidate the specific mechanisms by which BAs may affect intestinal inflammation in IBD.

Methods
Small intestinal organoids were grown from WT mice and an IBD mouse model with caspase-8 KO in intestinal epithelial cells (IEC). Organoids treated with primary (1°) and secondary (2°) BAs (CDCA, LCA, DCA) and BA + JAK-inhibitor (CDCA + inhibitor) were analysed thoroughly by bulk-RNA sequencing to investigate effects of BA and possible strategies to ameliorate negative effects.
BA composition of serum samples from healthy controls (HC) (n=25) and IBD patients (n= 85) was quantified using LC-MS/MS and compared to bulk-RNA sequencing results of the same individuals in order to identify correlations of BA abundancy and gene expression.

Results
In WT organoids, CDCA treatment induced a significant upregulation of numerous genes associated with key cellular processes such as immunological, cell death but also mitochondrial. In contrast, in genetically-predisposed IBD organoids predominantly displayed gene downregulation in response to CDCA, indicating a divergent transcriptional response between WT and KO genotypes. In IBD organoids, JAK inhibition in conjunction with CDCA significantly altered the expression profile, reversing the expression of several genes that were downregulated by CDCA alone. This reversal was gene-specific and suggests a compensatory or modulatory effect of JAK inhibition on CDCA signalling in a caspase-8 deficient background. Notably, this combinatorial effect was not observed in WT organoids, where CDCA + JAK inhibitor treatment did not substantially alter gene expression compared to CDCA alone.
Targeted metabolomic analysis of patient serum samples revealed two distinct bile acid profiles within the IBD cohort. In one subgroup, serum was characterized by elevated levels of the 1°BA CDCA coupled with lower concentrations of both primary and conjugated 2°BAs. In contrast, a second subgroup displayed lower CDCA levels alongside increased concentrations of secondary bile acids. These bile acid composition patterns suggest differing metabolic states within the patient cohort.

Conclusion
Our findings reveal significant links between BA composition, gene expression, and JAK pathway modulation, offering new insights into BA–driven gene regulatory mechanisms in both murine organoids and an IBD patient cohort.

References
TRR241 IBDome Consortium, TRR 241 Research Initiative, Berlin-Erlangen, Germany