bluuebunny/crossref_metadata_2025_split huggingface dataset:
OP33 Mechanistic insights on the role of ultra processed foods as a trigger/fuel for IBD
Authors: Guedelha Sabino J 
Published: January 2024

Abstract

Background
Ultra processed foods (UPFs) are a heterogeneous category of products that contain food additives and/or have undergone several industrial processes. The higher intake of UPFs seen in industrialized countries has been associated with increased incidence of inflammatory bowel diseases (IBD), mainly Crohn’s disease (CD). However, the specific mechanisms through which the UPFs can induce or maintain intestinal inflammation are still unknown. Therefore, most dietary interventions for IBD essentially exclude all UPFs from the menu, increasing the difficulty of long-term compliance of these diets. The main focus of my research is the study of which components may be detrimental in UPFs, in the hope that we can limit the number of UPFs that we need to exclude from our diets.

Methods
To understand the mechanism of action of UPFs, a translational approach is needed with complementary pre-clinical and clinical studies. We used organoid cultures from patients with CD to test the impact of food additives on the intestinal epithelium (e.g. permeability, pro-inflammatory effect). These organoid cultures are more physiologically relevant than immortalized cell lines, which lack several important aspects (e.g. genetic background, complex assembly of different cells). The results of the first tests with this platform have been submitted to ECCO (EC24-1418). Additionally, we established several protocols and collaborations to run well designed dietary intervention studies to explore the mechanisms of action of these food additives in humans. In the FOAM study, we explored the effects of 5 emulsifiers in an double blind randomized placebo controlled trial. The results of the FOAM study have also been submitted to ECCO (EC24-0858). We also explored the acceptance, feasibility, and compliance of an emulsifier free diet in healthy volunteers (EC24-1181).

Results
Our results support the need to better understand the role of food additives and UPFs in IBD, and the need for better evidence supporting the detrimental role of food additives.

Conclusion
Compliance is an important issue to consider in all dietary interventions, more than in pharmacological interventions. Strategies focusing on improving the compliance of dietary interventions can have a big impact in the applicability of these interventions in therapeutic and/or prophylactic settings. However, the current knowledge on the possible detrimental role of UPFs does not allow to pinpoint which UPFs are detrimental and which might have no effect on intestinal inflammation. Hence, there is an unmet need for pre-clinical and clinical studies focusing on the mechanisms through which these UPFs might play a role in intestinal inflammation.
DOP17 Tofacitinib versus Vedolizumab Among Bio-naïve Patients With Ulcerative Colitis: A Real-World Propensity-Weighted Comparison
Authors: Gros B , Constantine-Cooke N , Kennedy J , Elford A T , O’Hare C , Noble C , Jones G R , Arnott I D , Plevris N , Lees C W 
Published: January 2024

Abstract

Background
Over the last decade, treatment options for moderate-to-severe ulcerative colitis (UC) have expanded. However, comparative studies between these agents are limited, especially among biologic naïve patients. There are sparse data comparing biologics with small molecules for IBD. We aimed to compare the efficacy, safety and persistence of tofacitinib and vedolizumab as the first advanced treatment for patients with UC.

Methods
Patients who received tofacitinib or vedolizumab as first advanced therapy for UC in NHS Lothian were included. We capped the upper age limit at 65 years to take into account regulatory guidelines for the use of JAKi as first line therapies across IMIDs. To allow treatment effect to be assessed outside of a randomized trial, we used inverse probability of treatment weighting (IPTW). This approach takes the probability of treatment assignment into account without potentially drastically reducing the analysable cohort size. The probability of treatment assignment was calculated via logistic regression using age, gender, IBD duration, Montreal extent, CRP, concomitant corticosteroids and partial Mayo score at drug commencement. Missing data for these variables were imputed using multivariate imputation by chained equations. Confounder-adjusted survival curves were created using Kaplan-Meier estimates weighted via IPTW. The Pepe and Fleming test was used to compare survival curves from drug commencement to day 1000 of treatment.

Results
We included 158 patients of whom 81 (51.2%) received vedolizumab and 77 (48.7%) tofacitinib. Median follow-up for patients on vedolizumab was 3.1 (1.6-4.8) years and for tofacitinib 1.5 (0.34-2.3) years. Baseline demographics were comparable except for disease extent (Table 1). At drug commencement there were no differences in steroid prescription (60.5% vedolizumab versus 57.1% tofacitinib), partial Mayo score, CRP or faecal calprotectin. At week 12, steroid free clinical remission was more frequent in the vedolizumab group (69% vs 51.4%, p=0.030) Figure 1B.
Vedolizumab persistence was superior to tofacitinib (p=0.005) Figure 1A. Primary non-response and secondary loss of response were 9.9% and 17.3% for vedolizumab and 23.4% and 13% for tofacitinib respectively. There were no differences in the frequency of adverse events (11 [13.6%] vedolizumab vs 19 [24.7%] tofacitinib, p=0.629). However, adverse events resulting in temporary discontinuation of the drug occurred in 1 (1.2%) vedolizumab versus 11 (14.3%) tofacitinib, p=0.013.

Conclusion
We found that the persistence and tolerability of vedolizumab was superior to tofacitinib in bionaive UC, although the rates of clinical and biomarker remission were comparable. These data may help inform positioning of advanced therapy in UC.
DOP38 A rare KRT17+ population emerges from the epithelium in the inflamed intestinal mucosa of patients with Ulcerative Colitis
Authors: Dotti I , Melón-Ardanaz E , Sanzo Á , Gudiño V , Corraliza A M , Teubel I , Esteller M , Ricart E , Salas A 
Published: January 2024

Abstract

Background
KRT17 is an epithelial "alarmin" that contributes to the early host innate immune response to insults. We previously found that KRT17 transcription, not detectable in the healthy colon, is up-regulated in the intestinal mucosa of patients with active ulcerative colitis (UC). Here, we aimed to characterize the epithelial cells expressing KRT17 in UC mucosa and explore the contribution of the intestinal environment in promoting the emergence of this cell population.

Methods
We conducted single-cell RNAseq (scRNA-seq) on the epithelial compartment of intestinal biopsies from a cohort of non-inflammatory bowel disease (IBD) controls and patients with active UC. Analysis was performed using our own-curated pipeline in Seurat1. Spatial protein localization was analysed by immunofluorescence on fixed intestinal samples. To measure the modulation of KRT17 and associated markers, ex vivo air-liquid interface (ALI) epithelial cultures derived from human non-IBD organoids were used. The signatures of UC-derived organoids2 were mapped onto the scRNA-seq dataset.

Results
ScRNA-seq analysis identified a rare KRT17+ epithelial cell population emerging in active UC characterized by the expression of KRT17 (Fig. 1A) and other alarmins (KRT6A, KRT16, S100A8), metalloproteinases (MMP1, MMP10), and inflammatory markers (SAA1, DUOX2…). KRT17 protein, absent in non-IBD colon, was expressed in the epithelium of the inflamed UC mucosa exhibiting a patchy pattern, and marked epithelial clusters with both columnar and squamous-like morphology (Fig. 1B). The ALI culture closely recapitulated the differentiated intestinal epithelium in homeostasis by showing a columnar aspect, high expression of differentiation markers, and low or undetectable expression of stem/proliferation or KRT17+-cell markers. Exposure of the ALI culture to hypoxic stress (by re-submersion in expansion medium) induced the expression of KRT17+ cell-specific and inflammation markers (Fig. 1C), and the acquisition of a squamous morphology (Fig. 1D). IBD-related IFN-ɣ and IL-22 cytokines could not fully replicate this phenotype (Fig. 1E). Lastly, we observed that genes up-regulated in UC, compared to non-IBD organoids, were predominantly expressed within the KRT17+ population (Fig. 1F).

Conclusion
Our results suggest that a novel KRT17+ epithelial population may arise from the intestinal cells of inflamed UC mucosa under the influence of specific environmental factors. This population could contribute to the persistence of the disease over time.
References
1. Garrido A. et al, Nat Commun, 2023
2. Dotti I. et al, Gut, 2017
DOP51 Risk of kidney failure in patients with Inflammatory Bowel Disease undergoing colectomy: a nationwide cohort study
Authors: Yang Y , Ludvigsson J F , Forss A , Faucon A L , Faye A S , Olen O , Sjölander A , Carrero J J 
Published: January 2024

Abstract

Background
Inflammatory bowel disease (IBD) is frequently accompanied by kidney complications. Potential triggers or subpopulations at high-risk of kidney problems are not well elucidated. We hypothesized that surgical interventions, specifically colectomy, might in part explain this risk.

Methods
A nationwide Swedish cohort study comprising 82,052 individuals with biopsy-proven IBD diagnosed during 1965-2017, with follow-up until 2019. We investigated the association between incident colectomy (time-varying exposure) and future risk of kidney failure (diagnosis of end-stage kidney disease or death due to chronic kidney disease) using Cox proportional hazard models. We also examined the impact of partial vs. total colectomy and the presence of a stoma. Covariates included age, sex, education level, and selected comorbidities.

Results
Over a median follow-up of 14 years, 15,922 individuals underwent colectomy, and 952 kidney failure events occurred. Colectomy was associated with an increased relative risk of kidney failure (adjusted hazard ratio [aHR] 1.60; 95% CI 1.39-1.84). Compared to periods without colectomy, undergoing total colectomy (aHR 1.82; 95% CI 1.54-2.15) and colectomy with the presence of a stoma (aHR 2.40; 95% CI 1.75-3.28) showed higher risks versus partial colectomy or colectomy without a stoma, respectively. Subgroup analyses revealed higher kidney failure risk in patients with ulcerative colitis and those aged ≥40 years at IBD diagnosis. In absolute risks, at 30-year after colectomy, 8.9% of patients with IBD had kidney failure, with an absolute risk difference of 4.5% (95% CI 1.9-7.0%).

Conclusion
In people with IBD, rates of kidney failure are higher among those undergoing colectomy, particularly following total colectomy or colectomy with a stoma. This study identifies a high-risk population that may benefit from established protocols for kidney function monitoring/surveillance and referral to nephrologist care.
DOP81 Rosnilimab, a novel PD-1 agonist monoclonal antibody, reduces T cell proliferation, inflammatory cytokine secretion, and PD-1high expressing CD4 and CD8 T cells: Results from a Phase 1 healthy volunteer clinical trial
Authors: Luu K , Dahl M , Hare E , Sibley C , Lizzul P , Randazzo B 
Published: January 2024

Abstract

Background
Programmed cell death protein 1 (PD-1) is expressed on activated T cells and is a key co-inhibitory node in immune regulation. By targeting regulatory mechanisms to modulate immune cells driving disease, there is an opportunity to restore immune balance. Rosnilimab is a PD-1 agonist antibody designed to reduce T cell proliferation and inflammatory cytokine secretion and deplete PD-1high T follicular helper, T peripheral helper, and T effector cells. It is being studied for ulcerative colitis (UC), where PD-1+ T cells are prevalent in inflamed lamina propria (&gt;40%) and the periphery. The primary objective of this healthy volunteer Phase 1 study was to assess the safety and tolerability of single ascending doses (SAD) and multiple ascending doses (MAD) of rosnilimab. Findings from pharmacokinetic (PK) and pharmacodynamic (PD) assessments are summarized.

Methods
This single-centre study included 14 cohorts in SAD and 3 cohorts in MAD. Each cohort had 8 participants (6 active, 2 placebo [PBO]). Cohorts were enrolled sequentially in each phase. Intravenous (IV) and subcutaneous (SC) administration were assessed in SAD; SC route was assessed in MAD.

Results
A total of 144 participants were enrolled; 90 to active SAD cohorts, 18 to active MAD cohorts, and 30 and 6 to SAD and MAD PBO cohorts, respectively. Rosnilimab was well tolerated with no dose-limiting toxicities or deaths. Two serious adverse events were reported in SAD (deemed unrelated to treatment) and 0 in MAD. PD-1 expressing cells were reduced by ~50% in both CD4+ and CD8+ subsets, in a dose-dependent manner and in correlation with full receptor occupancy (RO) through Day 30 in SAD. PD activity was rapid with sustained reduction in PD-1+ T cells, and ex-vivo stimulation resulted in reduced T cell functional activity. This reduction was maximized on PD-1high expressing T cells: ~90% reduction vs baseline. There was no significant impact on the overall total T cell or regulatory T (Treg) cell numbers, resulting in restoration of T cell composition to a less activated state and a positive shift in the Treg:Teff ratio. An antigen-specific functional T cell assay measuring ex vivo interferon-gamma release in response to antigen challenge was inhibited up to ~90% vs baseline and the response lasted for more than 30 days following a single dose. Rosnilimab had a favourable PK profile consistent with full RO, a 2-week half-life, and dose-proportional exposure in IV and SC dosing.

Conclusion
Rosnilimab demonstrated favourable safety, PK, and PD activity. The role of PD-1 in UC pathophysiology coupled with these results and translational data, demonstrate proof of mechanism and support progression into a Phase 2 study of rosnilimab in UC. (NCT06127043)
P005 Exosome miR-132-3p derived from Adipose Stem Cells in Creeping fat Regulates RASA1/ERK1/2-dependant Lymphatic Functions and Improve Colitis and Mesenteritis
Authors: Wang X , Shu W , Wang Y 
Published: January 2024

Abstract

Background
Creeping fat (CrF) is an important pathological characteristics of Crohn’s disease (CD) and characterized by lymphangiogenesis and abnormal lymphatic functions. Adipose tissue derived stem cells (ADSCs) can regulate surrounding cells function by delivering exosomes (exo). However, whether CrF-ADSC-exo could affect lymphatic endothelium to regulate lymphatic functions, and further influence procession of mesenteritis and colitis remains elusive.

Methods
Paired CrF and uninvolved mesenteric adipose tissue (uMAT) samples were collected from CD patients during operation, and exosomes were separated by ultra-centrifugation. Human lymphatic endothelial cells (HLECs) were cultured in vitro and evaluated the abilities in proliferation, migration and tube formation. IL-10 KO mice was used for assessing the treatment of CrF-ADSC-exo in experimental colitis and mesenteritis.

Results
ADSC-derived exosomes from paired CrF and uMAT samples were confirmed to transfer to LEC by immunofluorescence microscope. In vitro, CrF-ADSC-exo effectively stimulated HLECs in proliferation, migration and tube formation. In vivo, CrF-ADSC-exo injection increased lymphangiogenesis in MAT and improved lymphatic drainage, and further alleviated colitis and mesenteritis in IL-10 KO mice. We next adopted high-throughput sequencing of paired CrF-ADSC-exo and uMAT-ADSC-exo, and validated significantly high expression of miR-132-3p in CrF-ADSC-exo. In vitro, upregulation or downregulation of miR-132-3p in HLECs stimulated or inhibited the lymphatic abilities in proliferation, migration and tube formation, respectively. Mechanically, we demonstrated that CrF-ADSC-exo regulated lymphatic function through miR-132-3p-RASA1-ERK1/2 axis by western blot. CrF-ADSC-exo miR-132-3p improved lymphatic drainage function in MAT and reduced inflammatory colon and mesentery in IL-10 KO mice. The higher level of miR-132-3p in CrF from CD patients was tightly correlated with inflammatory mediators expressions when compared with uMAT and healthy MAT.

Conclusion
Our study discovers that CrF-ADSC-exo improves lymphatic functions and alleviates colitis and mesenteritis through miR-132-3p/RASA1/ERK1/2 axis, which discloses new role of CrF involved in CD procession and provides novel insight for CD treatment.
P009 IL-17 mediates visceral hypersensitivity by sensitising colonic nociceptors
Authors: Paine L , Higham J , Barker K , Welsh F , St John Smith E , Bulmer D 
Published: January 2024

Abstract

Background
Comparison of cytokine expression in colitic tissue with respective cytokine receptor expression in pain sensing neurons highlights a likely contribution of IL-17 to the production of abdominal pain during flare.
To explore this pro-nociceptive potential of IL-17 in colitis we examined the ability of IL-17 to stimulate sensory neurons and the colonic afferent response to noxious distension.

Methods
IL-17 mediated sensory neuron activation: changes in the intracellular [Ca2+]i within thoracolumbar (T12-L5 spinal segments) dorsal root ganglia sensory neurons were examined in cells cultured overnight and loaded with Fluo-4-AM (30min) prior to imaging. Responses were measured to IL-17 (10-300 ng/mL) alone and following pre-treatment with either TRPV1 or TRPA1 inhibitors. Afterwards cells were exposed to capsaicin (1 µM) followed by 50 mM KCl, to confirm the presence of nociceptors and neurons respectively by positive response. In a separate set of experiments the effect of IL-17 was also examine on a neuron pure cell culture in which non-neuronal cells were removes by magnet assisted cell sorting.
IL-17 mediated colonic nociceptor activation: electrophysiological recordings were made of lumbar splanchnic nerve activity and the response to noxious luminal distension of the isolated colorectum (ex-vivo), perfused with carbogenated Krebs solution, examined following pre-treatment with IL-17 (50 ng/mL) alone or in the presence of respective inhibitors.
All experiments were performed using tissue from male C57BL/6J mice euthanaised by rising concentration of CO2followed by exsanguination in accordance with Schedule 1 of the UK Animals Scientific Procedures act (1986).

Results
Consistent with the ability of IL-17 to stimulate sensory neurons including those classified as nociceptors by their co-sensitivity to capsaicin, pre-treatment with IL-17 also produced a significant sensitisation of the colonic afferent response to luminal distension at noxious distending pressures. The increase in [Ca2+]i produced by IL-17 in sensory neurons was blocked by pre-treament with a TRPV1 antagonist but not a TRPA1 antagonist. Furthermore, the proportion of neurons stimulated by IL-17 was comparable between standard DRG cell cultures and neuron pure cell cultures demonstrating a direct effect of IL-17 on sensory neurons. Finally, IL-17 mediated mechanosensitisation of colonic nociceptors was unaffected by TRPV1 inhibition.

Conclusion
Our findings demonstrate that IL-17 stimulates capsaicin-sensitive nociceptors and mediates visceral hypersensitivity in colonic nociceptors consistent with a causative role for IL-17 is the generation of abdominal pain in people with colitis.
P025 Obefazimod and its active metabolites ABX-464-N-Glu act by stabilizing protein-protein interaction among key RNA biogenesis partners, CBC and ARS2
Authors: Bron P , Martin K , Sloan S , Scherrer D , Tazi J 
Published: January 2024

Abstract

Background
Obefazimod is an oral, once-daily, small molecule in phase 3 clinical trials for the treatment of patients with ulcerative colitis (UC). Obefazimod selectively enhances the expression of a single micro-RNA (miRNA), miR-124. miRNAs function by binding to specific mRNA targets and reducing their translation into their respective proteins. Enhanced expression of miR-124 results in a decrease in cytokines and immune cells, helping to reduce inflammation and potentially controlling the progression of chronic conditions like UC. Obefazimod and its main active metabolite, ABX464-N-Glu, bind the nuclear Cap Binding Complex (CBC) that directs cellular RNA biogenesis by recognizing co-transcriptionally the cap structure of RNA polymerase II transcripts. The CBC complex is made of Cbp20 and Cbp80, and interacts with a key partner involved in microRNA biogenesis, ARS2. Here, we explore the structural basis for targeting the CBC complex.

Methods
Microscale thermophoresis analyses were performed to determine the binding affinities between the two components of CBC, Cbp20 and Cbp80, in presence or absence of obefazimod or its metabolite ABX464-N-Glu, and their interaction with ARS2 also in presence or absence of the two molecules. Cryo-electron microscopy (cryo-EM) datasets of CBC-apo, CBC-obefazimod, CBC-ABX464-N-Glu, CBC-ARS2-Apo, CBC-ARS2-obefazimod, CBC-ARS2-ABX464-N-Glu were processed and after 2D classification and 3D refinement the different structures were solved. To understand and explore the conformational dynamics of the complex, 3D multibody refinement was performed on CBC-Apo, CBC-obefazimod and CBC:ABX464-N-Glu.

Results
The cryo-EM structures showed that obefazimod or ABX464-N-Glu bind the same location at the interface of CBC complex to act as orthosteric stabilizers of Cbp20 and CBp80. The conformational change induced by the binding of obefazimod or ABX464-N-Glu to the CBC complex strengthens the interaction between the two subunits of CBC, resulting in a more rigid structure of CBC complex. Thermophoresis revealed that the binding of obefazimod or ABX464-N-Glu improves the interaction of CBC with ARS2, a key partner of CBC to establish the fate of RNA in the cell. The cryo-EM structures of CBC-ARS2, obefazimod-CBC-ARS2 or ABX464-N-Glu-CBC-ARS2 show that ARS2 passes through the site where Obefazimod and ABX464-NGlu bind. We propose that the orthosteric effect of obefazimod or ABX464-N-Glu on CBC is maintained even when these molecules leave their binding site, allowing for better affinity of ARS2 for CBC.

Conclusion
Our results identify a unique interfacial stabilizing mode of action for anti-inflammatory drugs targeting the CBC complex enhancing its interaction with ARS2 to generate specific microRNA.