bluuebunny/crossref_metadata_2025_split huggingface dataset:
P0090 Synergistic reduction of inflammatory cytokines with obefazimod and etrasimod in combination treatment vs. either monotherapy in a mouse model of inflammatory bowel disease
Authors: Garcel A , Cataldi F , Scherrer D 
Published: January 2025

Abstract

Background
Obefazimod (Obe) is an investigational, oral, once-daily small molecule that enhances expression of microRNA-124 and has shown both efficacy and safety in Phase 2 studies in patients with moderately to severely active ulcerative colitis (UC) [1, 2]. Due to a therapeutic ceiling of 10-20% placebo adjusted remission rates among available monotherapy strategies, combination therapies are gaining interest as a treatment strategy [3]. We present early preclinical data on the combination of Obe and the sphingosine-1-phosphate receptor modulator etrasimod (Etra) in a mouse model of inflammatory bowel disease.

Methods
The efficacy of Obe and Etra, as monotherapies and in combination, in preventing colitis was assessed using the mouse T-cell adoptive transfer (TCT) model. CD4+CD45high T-cells from immunocompetent C57BI/6J mice were transferred into RAG2 knockout mice.
Treatments were administered daily (10 ml/kg, p.o.) from Day 0 (1h before cell transfer) until Day 55: vehicle (0.5% methylcellulose), Obe (40 or 100 mg/kg, Obe40, Obe100), Etra (3 mg/kg), Obe40 + Etra, Obe100 + Etra.
Body weight (BW), disease activity index (DAI, based on BW loss, fecal consistency, and fecal blood), and levels of inflammatory cytokines in the colon and blood were measured to assess disease severity and inflammation.

Results
Obe40 alone did not protect against BW loss and colitis (as measured by DAI), while Etra alone prevented BW loss but did not fully prevent colitis. Instead, the combination Obe40 + Etra improved BW and the response on DAI. Obe100 alone protected against BW loss and colitis. The combination Obe100 + Etra did not improve BW and DAI compared to Obe100 alone.
At day 55, in the colon tissue, Obe100 induced a statistically significant decrease in TNFα, IL-17 and IFNγ, while Etra did not. The combination of Obe100 + Etra increased the reduction of these cytokines in the colon.
At day 55, in the blood, Obe100 induced a statistically significant reduction in IL-17 levels, while Etra induced a significant decrease in TNFα levels. The combination therapy induced a synergistic reduction of TNFα, IL-17, IL-6 and IFNγ.
Conclusion: In the mouse TCT model, the combination of Obe and Etra improved BW and DAI and reduced CD4+ cell numbers and inflammatory cytokines in both colon and blood, showing a synergistic reduction of cytokine levels in the blood. These promising findings suggest that this combination could provide enhanced therapeutic potential for treating inflammatory conditions like UC.

References
1. Vermeire S, et al. J Crohns Colitis 2023
2. Vermeire S, et al. The Lancet Gastroenterol & Hepatol 2022
3. Solitano V, et al. Gastroenterol & Hepatol 2023.
P0096 Impaired fatty acid oxidation is a hallmark of Ulcerative Colitis: evidence from multi-cohort transcriptomics analysis
Authors: Piernik M , Eder P 
Published: January 2025

Abstract

Background
Ulcerative colitis (UC) is characterized by persistent colonic mucosal inflammation. Despite available treatments, most patients experience only temporary remission. The lack of universally effective treatments results from our incomplete understanding of UC pathophysiology. While many gene expression studies have provided valuable insights into UC mechanisms, the growing availability of transcriptomics datasets offers a unique opportunity for large-scale, cross-validating analyses. Here, we used multiple independent datasets to identify the most consistently dysregulated pathways in UC mucosal biopsies.

Methods
We performed an integrative analysis of 10 open transcriptomics datasets from human UC and healthy mucosal biopsies (n=710 samples after selection). Each dataset underwent a separate differential expression analysis followed by gene set enrichment. We used 6 different gene set databases to make the analysis as broad as possible (9962 pathways). The results were aggregated across all datasets to identify consistently altered genes and pathways. Since each dataset has a different number of samples and a different sample distribution between the groups, the aggregation was done purely on the ranking level. The complete workflow of the experiment is in Figure 1.

Results
Mitochondrial fatty acid oxidation emerged as the most significantly dysregulated pathway with a mean rank 4 (median 2.5) across 6 datasets. The analysis revealed a coordinated pattern of metabolic rewiring: systematic downregulation of the entire mitochondrial transport machinery (CPT1A, SLC25A20, CPT2) and the carnitine transporter SLC22A5, accompanied by decreased expression of β-oxidation enzymes (ACADS, ACADM, ACADVL, HADHA, HADHB, HADH, EHHADH) and consistent downregulation of the medium-chain fatty acid activating enzyme ACSF2. In contrast, ACSL4, which specifically activates polyunsaturated fatty acids, showed consistent upregulation. This metabolic disruption was coupled with coordinated changes in membrane remodeling enzymes, with upregulation of LPCAT1 and downregulation of LPCAT3, suggesting systematic alterations in membrane phospholipid composition.

Conclusion
Our multi-cohort analysis reveals a specific pattern of metabolic disruption in UC that extends beyond pathway inhibition. The coordinated upregulation of the ferroptosis mediator ACSL4 together with systematic changes in membrane remodeling enzymes suggests active metabolic rewiring that could promote ferroptotic cell death through altered membrane phospholipid composition and increased susceptibility to lipid peroxidation. These findings highlight potential new therapeutic targets in UC focused on specific aspects of lipid metabolism and ferroptosis regulation.
P0099 Histone H4 lysine 12 lactylation in CD4+ T cells promotes the progression of Ulcerative Colitis through PKM2/glycolysis loop and PKM2/STAT3 signaling pathway
Authors: Xu S , Ye L , Wu J , Tao H , Li L , Lu H , Wang F 
Published: January 2025

Abstract

Background
Immune dysfunction- the imbalance of Th17/Treg ratio is the main pathogenic factor of ulcerative colitis (UC). Histone lactylation is a new protein modification and could regulate immune function. However, the roles of histone lactylation in the naïve CD4+ T cell differentiation and UC progression remain unclear.

Methods
We employed a mouse model to elucidate the mechanism by which lactic acid facilitates the progression of ulcerative colitis through the inhibition of PKM2 and targeted knockout of Pkm2 in CD4+ T cells.

Results
Our study shows a high level of H4K12la in CD4+ T cells at the intestinal inflammatory sites in UC, which is specifically enriched at the promoters of glycolytic genes including pyruvate kinase 2 (PKM2). Then PKM2 can activate the transcriptional activation protein 3 (STAT3) signaling pathway, thereby inducing the differentiation of naïve CD4+ T cells into Th17 cells and inhibiting Treg cell differentiation, and cause sustained release of pro-inflammatory cytokines, which finally exacerbates intestinal inflammation. In addition, as a key glycolysis enzyme, the upregulation of PKM2 expression could accelerate more lactate production in a positive feedback way. Both pharmacologic inhibition of PKM2 and CD4+ T cell-specific ablation of Pkm2 could block lactate production and then downregulate the ratio of Th17/Treg to alleviate colitis.

Conclusion
The study demonstrate the pro-inflammatory role of H4K12la in CD4+ T cells, and PKM2 may be a potential target for the treatment of UC.
P0100 Intestinal adaptation in a mouse model of Crohn’s- like ileitis under short bowel conditions
Authors: Jadzewski E , Reiner J , Lamprecht G , Witte M , Berlin P 
Published: January 2025

Abstract

Background
Short bowel syndrome (SBS) is a rare and complex condition that can occur after ileo caecal resection (ICR), which is often performed in Crohn’s disease (CD) patients. The disease outcome depends on the postsurgical anatomy as well as individual risk factors that may impede intestinal adaptation. The objective of this study was to investigate intestinal adaptation following ICR in a CD mouse model.

Methods
SAMP1/YitFc (SAMP1, n=37) mice with histologically manifest ileitis and parental controls (AKR, n=34) of both sexes were subjected to 40% ICR or transection (sham) at the age of 14-20 weeks. Intestinal continuity was established by end-to-end jejunocolic anastomosis. Clinical data and stool samples were collected for either 7 or 14 days. Histomorphological adaptation and intestinal inflammation were examined by histological evaluation of residual jejunal and colonic sections as well as by analysis of blood parameters and cytokine mRNA expression in mesenteric lymph nodes (MLN).

Results
This study was the first to examine adaptation in a CD mouse model. At the age of 14 weeks SAMP1 mice exhibited spontaneous ileitis, with characteristics similar to CD (hypertrophy of muscularis, dysplasia of paneth cells, transmural infiltration, villus blunting). Following surgery, SAMP1 mice showed higher mortality after surgery in ICR and sham groups (both 33%) compared to AKR (21% ICR, 0% sham). ICR resulted in the manifestation of SBS, displayed by body weight loss and diarrhea in both strains. SAMP1 mice exhibited a higher food intake and demonstrated less weight loss than AKR mice. However, the level of wellbeing was significantly lower in comparison to AKR after ICR (p&lt;0.0001 d7, d14). Histomorphological adaptation of the remnant jejunum was worse in SAMP1 mice (villus height SAMP1 229 µm vs. AKR 376 µm, p&lt;0.01). Following ICR, SAMP1 mice exhibited normalization of preoperatively increased inflammatory values in the blood (neutropenia, lymphocytosis) and a reduction of Il4 and Infγ mRNA expression in MLN after ICR (p&lt;0.05 SAMP1 vs. AKR).

Conclusion
The SAMP1/YitFc mouse is a suitable model for investigating the mechanisms of intestinal adaptation under the influence of experimental chronic ileitis. Subsequent research will focus on the alteration of the inflammatory environment and mucus barrier of the remaining bowel following resection in this model.
P0105 Evaluation of Stimuli Driving Oncostatin M Expression in Bone Marrow-Derived Macrophages
Authors: Velasco Blázquez L , Cancino C , Luo Y , Konopka A , Hegazy A N 
Published: January 2025

Abstract

Background
Oncostatin M (OSM) is a cytokine linked to inflammatory diseases, including inflammatory bowel disease (IBD), where it contributes to inflammation, tissue remodeling, and fibrosis. Despite its established role, the specific signals driving OSM expression in colitis remain unclear.

Methods
Bone marrow-derived macrophages (BMDMs) were differentiated using M-CSF and stimulated for 36 hours with a range of Toll-like receptor (TLR) agonists, damage-associated molecular patterns (DAMPs), cytokines, and bacterial lysates. OSM secretion was quantified using enzyme-linked immunosorbent assays (ELISA). To dissect key signaling pathways, we applied chemical inhibitors and utilized macrophages derived from gene-deficient mice.

Results
Myd88-dependent stimuli, including TLR1/2 (Pam3CSK4), TLR4 (LPS), TLR2/6 (FSL-1), TLR7/8 (R848), IL-1α, and IL-33, significantly increased OSM expression in BMDMs. Gram-negative (E. coli, C. rodentium) and Gram-positive (S. aureus) bacterial lysates also enhanced OSM secretion. Pro-inflammatory cytokine IFN-γ further boosted OSM levels, consistent with in vivo findings of OSM upregulation in inflammatory monocytes. Additionally, IL-4, which induces a tissue repair phenotype in macrophages, markedly increased OSM secretion.

Conclusion
OSM expression in BMDMs is driven by multiple signaling pathways, indicating a synergistic effect of diverse stimuli. Identifying key stimulatory and inhibitory molecules, alongside macrophage-specific knockout analyses, will help clarify the upstream regulators of OSM. Understanding these drivers may uncover new therapeutic targets in IBD and offer insights into the onset of fibrotic processes.
P0109 SEMA3B is related to anti-TNF therapy response in Ulcerative Colitis patients but shows no relevant outcomes in modulating intestinal inflammation in vivo
Authors: Arosa García L , Malvar-Fernández B , García S , Conde-Aranda J ,   Molecular and Cellular Gastroenterology Group
Published: January 2025

Abstract

Background
Semaphorins are a large family of proteins originally linked to the development of the nervous system. Recently, class 3 semaphorins (SEMA3A-3G) have been identified as potential regulators of various biological processes underlying inflammation, including the modulation of immune cell activation and migration. However, the relationship between SEMA3B and Ulcerative Colitis (UC), as well as its contribution to intestinal inflammation, remains poorly understood. To address these knowledge gaps, we conducted a comprehensive transcriptomic analysis using publicly available datasets containing expression profiles of colonic tissue, complemented by in vivo experiments.

Methods
We analysed publicly available microarray and RNAseq datasets of colon biopsies [GSE38713, GSE59071, GSE12251, GSE16879, GSE73661 (Gene Expression Omnibus), and E-MTAB-7875 (European Bioinformatics Institute)]. Furthermore, ten to twelve-week-old female C57BL/6 mice (n=18) were subjected to DSS-induced acute colitis by administering 1.5% DSS in the drinking water for 7 days. Mice were treated daily with either IgG2A (50 µg/day/mouse) or SEMA3B (50 µg/day/mouse). After euthanization, we performed histology studies and analysed the inflammatory cell infiltrate using flow cytometry. Also, colonic gene expression was measured by RT-qPCR, and the integrity of the epithelial barrier was assessed by western blot.

Results
Transcriptomic analyses revealed that SEMA3B expression was downregulated in UC patients compared to healthy controls. Several receptors related to SEMA3B also exhibited dysregulated expression between UC and non-IBD controls. In the same way, UC patients who did not respond to infliximab showed reduced baseline transcript levels of that class-3 semaphorin. These patient-derived data suggest that SEMA3B could be an interesting biomarker in the context of intestinal inflammation. However, we also decided to study whether SEMA3B had a functional impact on the onset of colitis. Contrary to the human data, administering recombinant SEMA3B to mice subjected to DSS-induced acute colitis did not modify the course of the disease, epithelial barrier integrity or the expression of inflammatory markers. We only found a significant reduction in neutrophil abundance in the colonic lamina propria after recombinant SEMA3B administration.

Conclusion
Overall, our findings demonstrate that SEMA3B expression is altered in the inflamed colonic mucosa of patients with UC and may serve as a biomarker for response to anti-TNF therapy. However, the direct impact of this class-3 semaphorin on disease progression in vivo appears to be limited.
P0110 Effect of Tofacitinib on Hemostasis in Patients with Ulcerative Colitis: a Comparative Ex Vivo Study
Authors: Baldan-Martin M , Sanchez Sanchez C , Suarez Trujillo F , Ramírez C , Soleto I , Mercado J , Orejudo M , Martínez P J , Rubio Collado C , Orts M , Rubio Franco M J , Planas A , Acedo N , Butta N , Chaparro M , Gisbert J P ,   *Authors share co-senior authorship
Published: January 2025

Abstract

Background
Tofacitinib, a small-molecule Janus kinase inhibitor (JAKi), has been shown to be effective in the treatment of ulcerative colitis (UC). Despite its benefits, a higher incidence of thromboembolic events has been reported in patients treated with tofacitinib. It has been suggested that this effect might be a class effect and could affect other JAKi. Consequently, the regulatory agencies warned about its risks and restricted its conditions of use. Therefore, it would be highly relevant to understand the pathophysiological mechanism involved in this potential increase in thromboembolic events to determine the consequences in clinical practice.

Methods
In this study, we analyzed the effect of tofacitinib on platelet function and global hemostasis in 10 patients with active UC (aUC), 10 patients with quiescent UC (qUC), and 10 healthy controls (HC), under experimental conditions that minimized inter-individual variability as a result of the treatment. To know the specific effect of tofacitinib, we included an anti-TNF drug as a comparator. We performed platelet aggregometry, platelet activation assays, and rotational thromboelastometry (ROTEM).

Results
ROTEM results did not reveal significant differences between the tofacitinib and anti-TNF groups across different study groups of patients (Table 1). Platelet aggregation analysis showed no statistically significant differences between platetel-rich plasma samples incubated with tofacitinib, anti-TNF or sterile water (control group) in aUC, qUC and HC groups (Figure 1). Flow cytometry analysis of platelet activation demonstrated increased expression of activation markers CD62P and CD63 and of the binding of PAC-1 in platelets from both aUC and qUC patients incubated with tofacitinib and anti-TNF, compared to the control group. There were no differences in these parameters between the two drugs. Additionally, an increase in CD63 expression was also observed in the HC group (Figure 2).

Conclusion
The results of this study suggest that tofacitinib does not significantly alter platelet function in platelet-rich plasma or affect global coagulation in whole blood. However, future in vivo studies are necessary to corroborate these findings in patients treated with tofacitinib and to assess the long-term effects of tofacitinib on hemostasis.
P0111 Patient reported outcome measures (PROM) in patients scheduled to undergo bowel resection for Crohn’s disease
Authors: Schmitz A , Bercher M , Iesalnieks I , Hinrichs N 
Published: January 2025

Abstract

Background
Indication for surgery in Crohn’s disease patients is a matter of ongoing debate. Increasing number of available medical treatments can lead to significant postponement of surgery in many patients. Later first abdominal surgery for Crohn’s disease is commonly seen as significant achievement of modern biological treatment. However, later surgery is not necessarily a success since it might only prolong unnecessary suffering. Thus, it is of a paramount importance to understand whether patients are “losing” or “winning” time by avoiding abdominal surgery. Patient reported outcome measurement – various indices, scores and Quality-of-Life measurement tools – are used to assess the degree of suffering and to calculate the treatment success. In present prospective study, we assessed the value of commonly used PROM tools to characterize disease severity in patients scheduled for bowel resection for Crohn’s disease.

Methods
Consecutive patients scheduled for bowel resection were assessed preoperatively using CDAI (Crohn’s disease activity index), IBD-DI (IBD Disability index) and the IBDQ (IBD questionnaire to assess quality of life). Also, patients were asked to rate their global health (GH) from 1 (unbearable) to 10 (perfectly good).
Worse scoring was expected to be found in patients with disease complications which are frequent in surgical population: severe anemia (HB &lt;10g/dl) weight loss of &gt;10%, penetrating disease, intraabdominal abscess and emergency hospitalization before surgery.

Results
109 patients were assessed.

Conclusion
PROM’s alone are not sufficient to guide the decision toward or against the potential surgery since “good” scores still miss some significant disease complications. Also, PROM’s are dynamic tools with scores differing significantly over time. Indication for surgery should be rather guided by expected risks and prognosis than by mere “disease activity”.
Table 1 illustrates preoperative results of PROM’s assessment. An incongruence of all scores can be observed. While 34% of patients have a quiescent disease according to the CDAI, only 13.5 % according to IBD-Q.

Table 2 demonstrates great inconsistency between the tools regarding their ability to predict severe disease (as illustrated by emergency hospitalization, significant weight loss, presence of intraabdominal abscess and penetrating disease). Only severe anemia led to significant worsening in all calculated tools.
P0115 Selective immune responses to Lachnospiraceae flagellins discriminate therapy-naive pediatric Crohn’s disease patients with distinct host-microbial interaction
Authors: Barendregt D , Joosse M E , Hulleman-van Haaften D H , Costes L M M , Gacesa R , Plomp N , Duck L W , Klomberg R C W , Vuijk S A , Doukas M , Escher J C , Harmsen H J M , Elson C O , de Ridder L , Samsom J N 
Published: January 2025

Abstract

Background
Pathogenic CD4+ T-cell responses to commensal microbial antigens drive intestinal inflammation in Crohn’s disease (CD). Both hypo- or hyperactive anti-microbial innate immunity could underlie these aberrant T-cell responses. CD patients have increased IgG and T cell responses against commensal Lachnospiraceae-derived flagellins, which associate with disease complications. We investigated whether CD patients with high anti-Lachnospiraceae flagellin responses at diagnosis have underlying innate hypo- or hyperresponsiveness and high IgG responses to other dysbiotic commensals.

Methods
IgG reactivity to 19 recombinant flagellins from Lachnospiraceae species colonizing mouse and human gut, was measured in plasma of therapy-naïve pediatric CD patients (n=49) and controls (n=29). In addition, we measured plasma IgG responses to 1 recombinant flagellin and 71 microbial lysates of dysbiotic commensal species in therapy-naive pediatric CD patients (n=103) and controls (n=61). IgG responses were related to immunological and clinicopathological parameters.

Results
CD patients had significantly higher IgG responses to 12/19 Lachnospiraceae-derived flagellins compared to controls. Multi-reactivity to more than 10 flagellins was common in CD (41%) and associated with increased circulating flagellin-specific memory CD4+ T-cell frequencies. Multi-reactivity, and even single-reactivity to recombinant flagellin, correlated with reduced immune cell infiltration and epithelial damage, and fewer calprotectin-positive neutrophils in colonic lesional tissue, based on histological severity scoring and immune histochemistry, respectively. As these data may argue that high anti-flagellin IgG reactivity relates to innate hyporesponsiveness, we next assessed whether patients had a generalized high IgG response to lysates of dysbiotic intestinal bacteria. Hierarchical clustering identified subgroups of CD patients with different patterns of significantly increased anti-commensal IgG responses. Patients with high anti-Lachnospiraceae flagellin IgG also had high IgG responses against lysate of Roseburia inulinivorans, a Lachnospiraceae species. Of these anti-flagellin high responders, two-thirds responded to many commensals while one-third did not, arguing against a generalized high anti-commensal IgG response.

Conclusion
In conclusion, high IgG responses to Lachnospiraceae-derived flagellins identify a subgroup of pediatric therapy-naive CD patients with features of innate hyporesponsiveness. These patients do not have uniformly high IgG responses to other dysbiotic commensals, arguing that disturbed host-microbiota responses in CD are highly personalized and do not stem from an overall failure in microbiota-host crosstalk.