bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOP103 Optimization of Ustekinumab Treatment Induction Using a Pharmacokinetic Model in Inflammatory Bowel Disease Patients
Authors: Ramos Lopez L , Del Rosario-García B , Pérez-González F , Alonso-Abreu I , Carrillo-Palau M , Reygosa C , Medina-Chico J S , Medina-Heras S , Benítez-Zafra F , Morant-Domínguez A , Vera-Santana B , Ramos-Díaz R , Gutiérrez-Nicolás F , Hernández-Guerra M 
Published: January 2025

Abstract

Background
Therapeutic drug monitoring and pharmacokinetic modeling, implemented in the treatment of patients with inflammatory bowel disease (IBD), improve drug efficacy and reduce side effects. Recently, Ustekinumab (UST) levels associated with therapeutic targets have been established, principally during induction, highlighting the need for appropriate optimization of this phase to improve response to UST treatment.

Objectives
To evaluate the effectiveness of proactive dose optimization of UST using pharmacokinetic modeling during induction (target concentration at week 8) in the treatment of IBD with UST.

Methods
A prospective comparative study was conducted on IBD patients initiating UST treatment, divided into two groups: standard induction protocol (initial intravenous UST dose adjusted to weight) or optimized induction protocol (following the initial weight-adjusted intravenous UST dose, UST levels were measured at 4 weeks and, using a pharmacokinetic model—including weight, height, and serum albumin levels—induction dosing was adjusted). UST plasma concentration was measured by FIA at 4 weeks in the optimized group and at 8 weeks from treatment initiation in all patients. Data on IBD and the clinical status of patients at UST treatment initiation were reviewed.

Results
A total of 88 patients were included: 72 in the standard protocol group (male 52.8%; Crohn's disease 59.2%; prior biologic use 95.8%; fecal calprotectin &gt;150 g/kg 61.5%) and 16 in the optimized group (male 56.3%; Crohn's disease 68.8%; prior biologic use 93.88%; fecal calprotectin &gt;150 g/kg 68.8%), with no significant differences in baseline characteristics between groups. The mean UST concentration at the end of induction (8 weeks) was significantly higher in patients with optimization via pharmacokinetic model compared to the standard protocol (15.4 [10.4-20.3] µg/ml vs 9.2 [7.7-10.7] µg/ml; p&gt;0.0018) (Fig. A). In the optimized group, 6 patients (37.5%) received additional intravenous UST doses (3 patients received 1 dose and 3 patients received 2 doses before week 8). The percentage of patients achieving a UST concentration ≥ 6.6 µg/ml (linked to biochemical remission at weeks 12 and 24) and ≥ 9 µg/ml (associated with treatment durability ≥ 12 months) was significantly higher in the optimized group compared to those on the standard protocol (Figs. B and C).

Conclusion
Optimized UST treatment, through proactive dose adjustment based on pharmacokinetic modeling, achieves a target UST concentration during induction that should ensure treatment efficacy.
DOP106 Geographic disparities in Healthcare Utilisation in people with inflammatory bowel disease, Crohn’s Colitis Cure Data Insights Program
Authors: Su W K , Wilson W , Ng W , Su H , Forbes A , Walker G , Kim A , Giles E , Lawrance I , Dutt S , Brett L , An Y K , Lynch K , Connor S J , Andrews J M 
Published: January 2025

Abstract

Background
Inflammatory bowel disease (IBD) is a lifelong illness, increasing in prevalence, with Australia (AUS) and New Zealand (NZ) amongst the highest in the world. Long-term management poses significant economic burden on people with IBD and the healthcare system. We aim to describe the healthcare utilisation (HCU) across 18 sites using Crohn’s Colitis Care (CCCare) as their IBD electronic management record (EMR).

Methods
CCCare is a cloud based EMR used in Australasia. Data feed into a de-identified clinical quality registry (CQR), which was interrogated in September 2024 to examine HCU over a 12-month period (September 2023 to 2024). People under active care, with a clinical assessment during the last 14 months were included. Descriptive statistics and a negative binomial regression model were used to examine for possible relationships amongst disease and demographic characteristics.

Results
There were 7506 eligible people, with a median age of 42 years (IQR 31 – 56). There was an even gender distribution (49.0%, n=3679, male) and more than half had Crohn’s disease (CD) (55.8%, n=4187), 41.4% (n=3107) ulcerative colitis (UC), and 2.8% (n=212) IBD-Unclassified. The median disease duration was 10.7 years (IQR 5.1 – 19.2). Most resided in AUS (73.1%, n=5487) and 26.9% (n=2019) in NZ. The majority of people resided in a metropolitan area (75.2%, n=4973), with 26.9% (n=1643) in non-metropolitan areas. Patient demographics are presented in table 1.
Ambulatory HCU is presented in table 1. Over the past 12 months, there were 10,705 helpline contacts (1.4 pp) and 11,439 (1.5 pp) clinical assessments either in-person or via telehealth. There were notably fewer endoscopic (0.2 pp) and radiology (0.3 pp) events. People with UC received endoscopies at a higher rate, but radiological events at a lower rate than those with CD (both p&lt;0.001). Helpline contacts were also less frequent from people with UC compared to those with CD (p&lt;0.01). Those residing in NZ consistently show lower HCU than in AUS in all HCU measures (p&lt;0.01). Residing in non-metropolitan area is associated with lower use rate of radiology (p&lt;0.05) and clinical assessments (p&lt;0.01), but higher rates of helpline contacts compared to those in metropolitan areas (p&lt;0.001).

Conclusion
The disparity in HCU suggests unwarranted variation in care or disparities in resource allocation creating inequities in health outcomes and access to care. The significant difference in HCU between countries and regions requires further correlation with healthcare outcomes. Identifying the most cost-effective approach to care that also improves patient outcomes will ultimately optimise health outcomes and advance value-based healthcare models for IBD management.
DOP112 Inflammation-associated monocytes express ACOD1 to curtail inflammatory behaviour in IBD and experimental colitis
Authors: Jones G R , Drury B , Hegarty L , Alegbe T , Krzak M , Raine T , Byrne A , Anderson C , Ho G T , Bain C 
Published: January 2025

Abstract

Background
ACOD1 is the ubiquitous source of the anti-inflammatory metabolite itaconate. We hypothesised monocyte ACOD1 expression is an inhibitory pathway that limits intestinal inflammation.

Methods
We performed single-cell RNA sequencing of colonoscopic biopsies from &gt;120 Crohn’s disease (CD) patients and healthy controls, with complementary analysis of DSS treated C57BL/6J (WT) mice, validated using flow cytometry in independent cohorts. Acod1–/– mice received 2% DSS in acute and recovery models, complemented by competitive bone marrow chimeric mice, anti-IFN / itaconate-derivate treatment and transgenic cell depletion models.

Results
We profile the monocyte / macrophage compartment in human IBD using single-cell RNA sequencing and identify a discrete population of intestinal CXCL9/10+ cells that accumulate in IBD, which we term inflammation associated monocytes (IAMs).
These can be identified by the expression of CD319, CD274 and CCRL2, and demonstrate specific expression of IBD susceptibility genes, including NOD2. By performing cross-species analysis in mice, we show an analogous population of IAMs accumulate during chemically induced colitis. Using transgenic fate mapping approaches, we show these cells likely derive from a discrete MDP-precursor in the bone marrow and are locally imprinted to produce heightened IL-1β and TNF in mouse and humans.
Importantly, we show that co-incident with a hyper-inflammatory phenotype, these same cells uniquely and specifically express aconitate decarboxylase (ACOD1) in response to local Toll-like receptor (TLR) and interferon (IFN) receptor signalling, to limit unrestricted cytokine production.

Conclusion
Thus, the intestinal environment after injury instructs both inflammation and recovery specifically within a transitioning population of monocytes that are absent in health. Reduced itaconate production from IAMs in CD may predispose to chronic inflammation and disease progression.
DOP114 LDN-071, the novel amino acid-based PAI-1 inhibitor, significantly reduces the severity of acute and chronic inflammation in colitis models
Authors: Jójárt B , Csákány-Papp N , Laub H , Vasas B , Barta B , Szabó V , Kajári L , Bagyánszki M , Farkas K , Mándity I , Heltovics G , Pallagi P , Maléth J ,   Epithelial Cell Signaling and Secretion Research Group
Published: January 2025

Abstract

Background
Over recent decades, significant progress has been made in the pharmacological management of Inflammatory Bowel Diseases (IBD). However, the sustained efficacy of existing anti-inflammatory therapies remains suboptimal, highlighting the urgent need for novel treatments. Recent studies have implicated the coagulation pathway, particularly Plasminogen Activator Inhibitor 1 (PAI-1), as a crucial link between epithelium and inflammation in IBD. Genetic deletion of PAI-1 has been shown to reduce experimental colitis severity in mice. Based on these findings, we aimed to develop and evaluate novel PAI-1 inhibitors for IBD treatment.

Methods
Using the A3SMO® platform, we synthesized LDN-071, an amino acid-based PAI-1 inhibitor, and assessed its inhibitory potential and cytotoxicity in vitro. Acute and chronic colitis models were induced in mice using DSS, with 10 mg/bwkg LDN-071 administered orally. Body weight, spleen weight, and colon length were monitored, while colon histology was analysed. Cytokine expression was measured via ELISA and qRT-PCR, and collagen deposition was quantified using a hydroxyproline assay. Human colon organoid (HCO) and fibroblast (FB) cultures from IBD patients were used to evaluate LDN-071’s effects. Toxicity was assessed in vivo in mice.

Results
LDN-071 effectively inhibited PAI-1 in vitro without cytotoxicity (1µM–1mM). In DSS-treated mice, 10 mg/bwkg LDN-071 prevented body weight loss, bloody diarrhea, colon shortening, and spleen enlargement. Histological analysis showed that PAI-1 inhibition significantly reduced severe inflammation, ulceration, crypt structure loss, and goblet cell depletion in acute and chronic colitis models. Additionally, PAI-1 inhibition reduced mucosal TNF-α, IL-1β, and IL-6 expression during acute inflammation. In chronic colitis, LDN-071 decreased inflammation, epithelial erosion, and fibrosis while significantly lowering collagen deposition. Importantly, no toxicity was observed at 100 mg/bwkg LDN-071 for seven days. In vitro, LDN-071 reduced pro-inflammatory cytokine expression in HCOs from IBD patients and significantly decreased fibrosis-related gene expression in patient-derived FB cultures.

Conclusion
Our results showed that LDN-071, a novel amino acid-based inhibitor of PAI-1, significantly ameliorated the severity of acute and chronic colitis in mice. However, the LDN-071 reduced the expression of inflammation- and fibrosis-related genes and proteins in vitro human models. We propose that the inhibition of PAI-1 could be a potential novel therapeutic strategy in IBD.
DOP117 Innate lymphoid cells control colitis and intestinal fibrosis via cellular stress response in mice and human
Authors: Cao S , Ma K , Deepak P 
Published: January 2025

Abstract

Background
Group 2 innate lymphoid cells (ILC2s) are increased in peripheral blood and intestinal samples from IBD patients and mice with colitis. ILC2s are major producers of type 2 cytokines including IL-5 and IL-13 and growth factor AREG that induce goblet cell hyperplasia and mitigate acute inflammation in the gut. On the other hand, prolonged or uncontrolled ILC2 activation may contribute to chronic inflammation and tissue fibrosis, although the role of ILC2s in stricturing/fibrostenotic Crohn’s disease (CD) has been unknown. In this study, we investigated the function of IRE1a-XBP1 pathway, a regulatory hub of cellular stress response, in colitis and fibrosis in mice and CD patients.

Methods
We generated conditional knockout Ire1aflo/floxIl5-Cre (Ire1aΔIl5) and Rag-/-Ire1aΔIl5 mice with Ire1a deleted in ILC2s. Dextran sodium sulfate (DSS)-induced and T-cell transfer colitis models were used. Human peripheral ILC2s were collected for flow cytometry and ex vivo stimulations.

Results
Mouse intestinal ILC2s express high level of Ire1a. The number of ILC2s increased in colon, small intestine (SI), and esophagus of Ire1aΔIl5 mice with elevated proliferation marker Ki67. Additionally, SI and colonic Ire1aΔIl5 ILC2s produced more IL-5, IL-13, and AREG after ex vivo stimulation with IL-33 or IL-25. Consistently, selective IRE1 inhibitor 4u8C enhanced production of IL-13, while selective IRE1 activator IXA4 suppressed IL-13 in sort-purified human ILC2s ex vivo (Figure 1). Bulk RNA-seq of SI Ire1aΔIl5 ILC2s showed reduced Rxrg and elevated fatty acid transport by pathway analysis, which may lead to the increased proliferation and cytokine production in Ire1aΔIl5 ILC2s. Upon DSS challenge, Ire1aΔIl5 mice exhibited milder signs of disease including weight loss, clinical scores as well as colon shortening and histology, which was accompanied by elevations in ILC2-derived cytokines and AREG as well as heightened goblet cell differentiation and mucin production. In contrast, upon adoptive T-cell transfer, Rag-/-Ire1aΔIl5 mice developed worsened chronic colitis and intestinal fibrosis, which was reversed by intraperitoneal injection of neutralizing antibody against IL-13 or AREG. Furthermore, CD patients with intestinal strictures expressed higher level of IL-13 in ILC2s in the blood (Figure 2).

Conclusion
IRE1a-XBP1 constrains cytokine production by intestinal ILC2s during inflammation. IRE1a deficiency in ILC2s protected against acute colitis with heightened type 2 cytokines and AREG; while loss of IRE1a exacerbated chronic colitis and fibrosis. The presence of CD strictures was associated with elevated IL-13 in peripheral ILC2s . We identified IRE1a and ILC2s as potential biomarkers and therapeutic targets for stricturing CD.
DOP123 Linking microbial genes to mucosal metabolites uncovers host-microbial interactions during 5-ASA therapy for ulcerative colitis
Authors: Jiang L , Guo M , Ruan G , Zhou R , Cao Y , Bai X , Yang H 
Published: January 2025

Abstract

Background
The severity of ulcerative colitis (UC) depends on the state of the colon mucosa, where achieving mucosal remission markedly improves patient prognosis and quality of life. The study aimed to characterize essential mucosal metabolites and microbial gene involved in UC remission, and to elucidate the mechanisms by which specific metabolites regulate intestinal homeostasis.

Methods
An integrated metagenomic and metabolomic analysis was conducted to elucidate the correlation between disease-associated microbes and host mucosal metabolites. Participants included non-UC controls and individuals with UC, comprising the responding group (UCR) and ineffective group (UCA) in 5-ASA treatment. The differential metabolite was further investigated using a DSS-induced colitis mouse model, followed by in vitro experiments to explore the mechanisms.

Results
The levels of mucosal secondary bile acids were found to have a significant negative association with intestinal inflammation during 5-ASA treatment. Integrated analysis of metagenomics and metabolomics revealed that host mucosal bile acid metabolites were negatively associated with the bile acid synthesis-related genes cbh in microbial genomes. Administration of the secondary bile acid mitigated mucosal inflammation in a colitis model by decreasing the proportion of Th17 and pathogenic Th17 cells. This secondary bile acid functions as an immunomodulatory metabolite, suppressing glycolysis in Th17-polarizing T cells to inhibit the Th17 cell response and modulating the gut microbiota.

Conclusion
These findings suggest that alterations in microbiome-metabolome interactions are critical for maintaining mucosal homeostasis during UC remission. The specific bile acid acts as an immunomodulatory metabolite, and may represent a potential therapeutic strategy for UC.

References
1.Lloyd-Price J, Arze C, Ananthakrishnan AN, et al. Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases. Nature 2019;569:655-662.
2.Dang EV, Barbi J, Yang HY, et al. Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell 2011;146:772-84.
3.Png CW, Linden SK, Gilshenan KS, et al. Mucolytic bacteria with increased prevalence in IBD mucosa augment in vitro utilization of mucin by other bacteria. Am J Gastroenterol 2010;105:2420-8.
DOP125 CD11b−CD27− NK subsets account for NK-cell dysfunction in patients with inflammatory bowel disease
Authors: Zhang Y , Hong G 
Published: January 2025

Abstract

Background
Natural killer (NK) cells play a crucial role in the dynamic interaction between innate and adaptive immune responses but their function is dysregulated in patients with inflammatory bowel disease (IBD)[1-4]. The mechanism that contributes to NK-cell dysregulation in IBD requires further elucidation.

Methods
Using flow cytometry staining, we precisely characterized the frequency, phenotype and function of NK subsets distinguished by CD27 and CD11b in 61 treatment-naive patients with active IBD (including 34 with Crohn’ s disease (CD) and 27 with ulcerative colitis (UC)), as compared to 30 healthy volunteers.

Results
We observed a significantly increased proportion of the peripheral CD11b-CD27- (double-negative, or DN) NK subsets in IBD patients. Notably, these relatively expanded DN NK subsets exhibited an inactive and immature phenotype. Functional analysis, conducted by stimulating and assessing the expression of CD107a and interferon-gamma (IFN-γ), revealed that the DN NK subsets had poor cytotoxic capacity and a deficient potential to produce IFN-γ. In addition, the percentages of DN NK subsets expressing CD107a and IFN-γ were positively correlated with NK degranulation and cytokine production, respectively. Interestingly, we also found that the frequency of DN NK subsets seemed to correlate with the plasma levels of IL-17A. High levels of IL-17A constrain the proliferation and maturation of NK cells in vitro. In some IBD patients who achieved clinical remission after receiving biological agent therapy, the percentage of DN NK subsets decreased accordingly.

Conclusion
The increased proportion of DN NK subsets may account for NK-cell dysfunction in IBD patients, potentially associated with elevated plasma levels of IL-17A. These alterations in NK cell subsets may contribute to defective killing and thus the secondary infections and increased risk of cancer observed in IBD patients.

References
1. Zaiatz Bittencourt V, Jones F, Tosetto M, Doherty GA, Ryan EJ. Dysregulation of Metabolic Pathways in Circulating Natural Killer Cells Isolated from Inflammatory Bowel Disease Patients. J Crohns Colitis. 2021;15(8):1316-1325.
2. Samarani S, Sagala P, Jantchou P, et al. Phenotypic and Functional Changes in Peripheral Blood Natural Killer Cells in Crohn Disease Patients. Mediators Inflamm. 2020;2020:6401969.
3. Yadav PK, Chen C, Liu Z. Potential role of NK cells in the pathogenesis of inflammatory bowel disease. J Biomed Biotechnol. 2011;2011:348530.
4. Giacomelli R, Passacantando A, Frieri G, et al. Circulating soluble factor-inhibiting natural killer (NK) activity of fresh peripheral blood mononuclear cells (PBMC) from inflammatory bowel disease (IBD) patients. Clin Exp Immunol. 1999;115(1):72-77.
DOP126 Circulating neutrophils exhibit distinct transcriptional and maturity changes in CD and UC that relate to pathogenic Th1/17 CD4+ memory T cell responses
Authors: Pascutti M F , Calado B , Smits W K , Tuk B , Hulleman-van Haaften D H , van Berkel L A , Barendregt D M H , Heredia M , Klomberg R C W , Camman A E , . Escher J C , de Ridder L , Samsom J N 
Published: January 2025

Abstract

Background
Neutrophils are key players in intestinal damage in Crohn’s disease (CD) and ulcerative colitis (UC) but their immunological role in disease heterogeneity is largely overlooked. In both diseases, mature circulating neutrophils enter the intestinal tissue to clear invading bacteria but cause irreversible tissue damage. However, neutrophil function can be altered by pathogenic Th1/17 CD4+ memory T cell (Tm) responses even before the cells enter the tissue. We hypothesize that altered neutrophil function differs between, and within, CD and UC and that interpatient differences in pathogenic Tm responses change transcriptional profiles in circulating neutrophils, impacting their function in the inflamed mucosa.

Methods
We analyzed clinically well-characterized therapy-naive pediatric CD (n=33) and UC (n=12) patients and IBD-negative controls (IBDneg; n=11) from the PIBD-SETQ cohort and performed RNAseq on purified circulating neutrophils, neutrophil flow cytometry and plasma proteomics using Proximity Extension Assay technology.

Results
Comparison of gene expression profiles at diagnosis revealed 263 differentially expressed genes (DEG) in neutrophils from CD vs IBDneg, and 421 DEG in UC vs IBDneg, with 137 genes common to both comparisons and 137 DEG in CD vs UC. CD and UC neutrophil transcriptomes were enriched for granule biology pathways (MMP8, S100A8/9), while IFN-related pathways were only present in CD neutrophils. As granule proteins are expressed in neutrophils during maturation in bone marrow but not in circulation, we assessed the maturity of circulating neutrophils by flow cytometry. Neutrophils from UC, but not CD patients had phenotypic features of immaturity (lower surface expression of CD10, CD16 and CXCR2). As predicted, neutrophil gene expression profiles showed high interpatient heterogeneity within CD and UC. Within both CD and UC, hierarchical clustering on the basis of neutrophil DEG identified two patient clusters. In UC1 patients, neutrophils had higher expression of genes for granule proteins which related to higher plasma concentrations of IL-17A, CCL20 and MMP10 compared to UC2. In CD2 patients, neutrophils had increased gene expression for IFN-signaling and extracellular matrix re-organization relating to higher plasma IFNg, CDCP1 and CXCL9 compared to CD1.

Conclusion
We demonstrate that at time of diagnosis circulating neutrophils have acquired changes in transcriptional and maturity profiles that differ between and within CD and UC. In individual patients, transcriptomic changes correlate to pathogenic Th1/17 CD4+ Tm profiles. These changes may functionally alter neutrophil-mediated bacterial clearance and tissue damage in the inflamed mucosa and help decipher disease pathogenesis in individual patients.