bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOP43 Histologic improvement, attenuation of inflammation and microbiome modulation by engineered high acetate producing Saccharomyces boulardii in DSS-induced colitis
Authors: Deleu S , Trindade de Carvalho B , Jacobs I , Vazquez Castellanos J , Verstockt S , Verstockt B , Arnauts K , Deprez L , Vissers E , Lenfant M , De Hertogh G , Huys G , Thevelein J , Raes J , Vermeire S 
Published: January 2024

Abstract

Background
The probiotic Saccharomyces cerevisiae var. boulardii (Sb) may be optimized for therapeutic use in ulcerative colitis by enhancing its acetate production, as acetate is a key factor for its probiotic efficacy and was shown to have anti-inflammatory and barrier-protective effects in vitro (Deleu, 2023). Therefore, higher acetate producing Sb strains have been engineered which were preclinically evaluated in an acute DSS mice model of colitis.

Methods
Nine-week-old female C57/Bl6 mice (N=120) were allocated to 12 treatment groups receiving drinking water or 2.75% DSS in combination with PBS (control), Baker’s yeast (non-probiotic control), SDH1 (no-acetate Sb), ENT (transient acetate strain-probiotic Enterol control), SbP (high acetate Sb) and ENT3 (extra high acetate Sb). Disease activity including weight loss, diarrhoea and the presence of occult blood were scored daily. On day 7, the DSS groups were transferred to regular drinking water and on day 14 mice were sacrificed. Colonic tissue and faeces (0, 9, 14d) were collected for resp. histology, RNA, and 16S rRNA sequencing.

Results
Disease activity in DSS subgroups (Fig.A), determined by the area under the curve, was lower for SbP compared to PBS and Baker’s yeast (both p&lt;0.05). Sb SDH1 showed higher disease activity compared to the Sb strains ENT, SbP and ENT3 (all p&lt;0.05). At sacrifice, the macroscopic damage score in DSS was lower for SbP and ENT3 (both p&lt;0.05) compared to Sb SDH1, and the colon weight/length-ratio was decreased for ENT and SbP compared to Sb SDH1 (resp. p=0.06 and p=0.08). Higher histologic inflammation was noted in the non- or transient-acetate producing strains on DSS compared to healthy PBS control (all p&lt;0.05), whereas this increase was not observed for both high-acetate producing strains SbP and ENT3 on DSS (p=NS) indicating a production dependent response. Anti-inflammatory findings were confirmed by transcriptomic analysis of differentially expressed genes e.g. decreased expression of Tnf, Il1b and S100a8/9, predominantly expressed as calprotectin, upon stimulation with the highest acetate producing strain ENT3 (all adj.p&lt;0.1; except PBS adj.p=0.16). Subsequent, microbial analysis showed a superior effect of ENT3 in maintaining a stable alpha diversity (p=0.58, Fig.E), which was not observed for the other strains.

Conclusion
Engineered high acetate producing Sb strains attenuated DSS-induced colitis, with its anti-inflammatory effects further supported by transcriptomic analysis and superiority in maintaining a stable microbiome composition. Together with our previous in vitro work in patient-derived organoids, these data indicate a role for high-acetate producing Sb- in attenuating intestinal inflammation.
DOP64 Steroid-sparing effect of risankizumab vs ustekinumab in patients with moderately to severely active Crohn’s Disease: Post hoc results from the phase 3b SEQUENCE trial
Authors: Raine T , Danese S , Schreiber S , Gao X , Hanauer S , Torres J , Kligys K , Huang X , Neimark E , Anschutz T , Crowley J , Cross R K 
Published: January 2024

Abstract

Background
Corticosteroid (CS) dependency and/or resistance occurs in approximately 50% of patients with Crohn’s disease (CD).1 In SEQUENCE, risankizumab (RZB; interleukin [IL]-23 inhibitor) demonstrated superiority over ustekinumab (UST; IL-12/IL-23 inhibitor) for the ranked secondary endpoints of CS-free clinical remission and CS-free endoscopic remission at week 48. In this post hoc analysis, we evaluate the CS-sparing effects of RZB and UST over 48 weeks in patients taking CS at baseline (BL).

Methods
SEQUENCE (NCT04524611) was an open-label, multicenter, randomised, efficacy assessment-blinded study in adults with moderately to severely active CD who previously failed ≥ 1 anti-tumor necrosis factor (TNF) therapy. Patients in the primary efficacy analysis were randomised 1:1 to receive RZB (intravenous [IV] 600 mg induction dose at weeks 0, 4, and 8, followed by a subcutaneous [SC] 360 mg maintenance dose every 8 weeks starting at week 12) or UST (single weight-based IV induction dose, followed by a SC 90 mg maintenance dose every 8 weeks starting at week 8) up to week 48. A mandatory CS taper started at week 2. CS-free outcomes (clinical remission or endoscopic remission and no CS at the assessed visit) were evaluated among patients taking CS at BL. Nominal P values were reported.

Results
The primary efficacy analysis included 520 patients (RZB, n = 255; UST, n = 265), and 24.8% (129/520) of patients were taking CS at BL. Demographics and disease characteristics were generally similar between treatment groups and between patients with and without CS use at BL. The mean (SD) daily prednisone-equivalent dose at BL was 21.4 (12.9) mg (RZB) and 19.5 (10.7) mg (UST), respectively. By week 8, more patients treated with RZB vs UST discontinued CS (75.9% vs 59.2%; nominal P &lt; .05). Although a similar proportion of patients in either treatment group discontinued CS at week 24, more patients treated with RZB vs UST discontinued CS at week 48 (86.2% vs 57.7%; nominal P &lt; .001). Of the patients taking CS at BL, RZB vs UST treatment resulted in higher rates of CS-free clinical remission (week 24: RZB, 44.8% vs UST, 33.8%; week 48: RZB, 56.9% vs UST, 31.0%) and CS-free endoscopic remission (week 24: RZB, 34.5% vs UST, 11.3%; week 48: RZB, 32.8% vs UST, 12.7%) (Table 1). Most patients who achieved CS-free outcomes at week 48 were CS-free for 90 days before week 48.

Conclusion
In patients with CD who previously failed anti-TNF therapy, RZB was more effective than UST for discontinuing CS use and achieving CS-free clinical and endoscopic remission.
References:
1. Lichtenstein G., et al. Am J Gastroenterol. 2018;113:481−517
DOP66 INSPIRE: Preliminary data from an observational post-marketing registry on the effectiveness and safety of darvadstrocel in patients with Crohn’s Disease and complex perianal fistulas
Authors: Fathallah N , Zmora O , Baumgart D C , Faubion W , Ferrante M , Gecse K , Wright E , McKay C , Ren K , Punchard M , Zhang B , Panés J 
Published: January 2024

Abstract

Background
Darvadstrocel (DVS), a suspension of expanded allogeneic adipose-derived mesenchymal stem cells, is approved for the treatment of complex Crohn’s perianal fistulas (CPF). INSPIRE (EUPAS24267) is a European observational post-approval study evaluating real-world effectiveness and safety of DVS in patients with complex CPF for up to 36 months. Here we report preliminary clinical and safety outcomes from INSPIRE.

Methods
Patients with complex CPF who had received DVS according to local standard practice were eligible to enrol. Clinical response (closure of ≥50% of external openings [EOs]) and clinical remission (closure of all EOs) of DVS-treated fistulas that were draining at baseline, were evaluated in the all-treated (AT; received ≥1 dose of DVS with an evaluation for fistula response after 6 months) and per-protocol (PP; received DVS as per label-approved guidelines) cohorts. Treatment-emergent adverse events (TEAEs), serious TEAEs and AEs of special interest were reported for the safety cohort (all patients treated with DVS).

Results
As of April 2023, 652 patients had enrolled (Table 1). Complete data to evaluate 12-month clinical response and remission were available for 134 (AT cohort) and 124 (PP cohort) patients, of whom 79.9% (AT, n = 107) and 79.8% (PP, n = 99) had a clinical response and 76.1% (AT, n = 102) and 76.6% (PP, n = 95) had clinical remission (Figure 1). From baseline to Month 12, there was a decrease in the mean (standard deviation [SD]) Perianal Disease Activity Index score (–3.5 [3.3]; n/N = 96/302 and –3.7 [3.2]; n/N = 89/249) and a decrease in the mean (SD) Harvey–Bradshaw Index for Crohn’s disease activity (-0.3 [2.8]; n/N = 102/302 and -0.4 [2.9]; n/N = 95/249) in the AT and PP cohorts, respectively. Complete safety data were available for 619 patients (median [min–max] follow-up 480 [6–1595]) days. Overall, 26% (n = 162) had ≥1 TEAE and 10% (n = 63) ≥1 serious TEAE. The most frequent TEAEs were anal abscess (6.9%), COVID-19 (1.9%) and proctalgia (1.1%). No deaths were reported. One breast cancer lymph node metastasis and one ovarian epithelial cancer were reported; both events were confounded by immunosuppressant treatment and were not considered related to DVS treatment.

Conclusion
These preliminary data are consistent with the pivotal ADMIRE-CD study and demonstrate a single dose of DVS in patients with complex CPF is associated with positive clinical outcomes in up to 80% of patients, and a favourable safety profile, both of which are maintained after 12 months. The inherent limitations of registry-based studies mean these data should be interpreted with caution. However, the ongoing INSPIRE study will provide longer follow-up data to confirm these observations with respect to any study limitations.
DOP73 Early biological use in a Belgian, prospective inception cohort of patients with Inflammatory Bowel Disease: the PANTHER cohort
Authors: Verstockt S , Glorieus E , De Wolf M , Lenfant M , Barbaraci M , Sabino J , Ferrante M , Geldof J , Verstockt B , Laukens D , Cleynen I , Vandermeulen L , Lobaton T , Vermeire S 
Published: January 2024

Abstract

Background
The growing number of advanced therapies has revolutionized the management of inflammatory bowel disease (IBD). Although early use of biological therapies is associated with better long-term outcomes, no data exist for the Belgian population. To this end, we evaluated treatment patterns in biological use and persistence in a Belgian inception cohort.

Methods
The PANTHER (Prognostic biobANk of paTients witH Early cRohn’s or colitis) cohort consists of adult IBD patients recruited in 3 Belgian IBD referral centres. Patients are included within 3 months after diagnosis and are naïve for immunosuppressives and biologicals, and without previous IBD-related surgery. Treatment use and outcomes are prospectively collected, and time trends for biological use were analysed using log-rank tests and Cox regression (R 4.3.2).

Results
Between 2015 and 2023, a total of 473 newly-diagnosed IBD patients were recruited (270 Crohn’s disease (CD) [57%]; 199 ulcerative colitis (UC) [42%]; 4 [1%] IBD type unclassified) (Table 1). During a median (IQR) follow-up of 2.6 (1.3-4.3) years, 64 patients (14%) required surgery (n=10 colectomy; n=54 ileocecal/small bowel resection); and 250 patients (53%) received biological therapy within the 1st year after diagnosis. Most patients were treated with anti-TNF (CD 67%; UC 55%) as first-line biological, followed by anti-integrins (CD 24%; UC 43%) and anti-IL12/23 (CD 9%; UC 2%). Time series analysis showed a significant increase in biological use within the 1st year after diagnosis when comparing patients diagnosed between 2015-2017 (44%) to those between 2018-2020 (57%), and to 2021-2023 (66%) (p=0.03) (Fig. 1A). Factors associated to this early biological use were younger age (HR=0.99 [95%CI: 0.98-0.99]), a diagnosis of CD (HR=2.2 [95%CI: 1.6-2.8]); and perianal disease in CD (HR=2.8 [95%CI: 1.8-12.8]). Within this early biological exposure group, 26 patients (10%) needed a resection later on. Therapy persistence over time was higher with early exposure rates in patients diagnosed in 2021-2023 (82%) and 2018-2021 (71%), as compared to 2015-2017 (63%) (p=0.08) (Fig.1B). The mode-of-action of first-line biological did not show any association with persistence (HR=1.0 [95%CI: 0.4-3.0]). Overall, only 26% of patients had to switch to a second-line, with a switch [anti-TNF &gt;anti-IL12/23] being the most frequent in CD (50%); and from [anti-TNF &gt;anti-integrins] (46%) or vice versa (40%) in UC.

Conclusion
In this Belgian inception cohort, two thirds of patients are currently initiated with biological therapy within the first year after diagnosis. This increased biological use is associated with high therapy persistence rates of &gt;80% after a median follow-up of 1.5 years, and with low rates of surgical resections.
DOP87 Characterization of pathologic fibroblast and macrophage cell populations in colonic Crohn’s Disease with spatial transcriptomics
Authors: Gudiño V , Acera M , Corraliza A M , Garrido-Trigo A , Sanzo Á , Heyn H , Mereu E , Salas A 
Published: January 2024

Abstract

Background
Single-cell transcriptomic data of the human intestine has shed new light on the cellular composition and heterogeneity present in healthy and diseased tissues. Nonetheless, little information is currently available on their spatial distribution within tissue structures and cellular neighborhoods, which is particularly relevant to infer the function of disease-specific cell types. Here, we apply spatial transcriptomics to healthy control (HC) and Crohn’s disease (CD) intestinal samples and provide a map of cell types across healthy and diseased colon.

Methods
Fresh frozen colonic sections from HC (n=1) and CD (n=3) patients were placed onto 10X Visium slides, which feature thousands of spatially barcoded spots, each capable of capturing RNA from 10-15 cells. To retrieve single-cell resolution, spots were deconvoluted according to the Cell2location approach using our previously generated human single cell RNA sequencing (scRNAseq) dataset1 as a reference. For validation and further analysis at single-cell resolution, a panel of 100 genes was measured using single molecule fluorescent in situ hybridization (Molecular Cartography) (Fig. 1A).

Results
Deconvolution analysis revealed the cellular composition of each spot across all four different tissue sections including epithelial, stromal and immune cell types. Here, we focused on studying the location and diversity of fibroblasts and macrophages given their plasticity during inflammation1,2. The most abundant fibroblast cell type in CD were the inflammation-associate (IAFs) and the GREM1+ subepithelial fibroblasts. These two subsets showed a distinct gene signature and location, suggesting different functions (Fig. 1B). Most GREM1+ fibroblasts co-expressed FGFR1 and were in proximity with endothelial cells (VWF+) expressing the VEGF receptor 2 KDR, highlighting a potential pro-angiogenic role of GREM1+ fibroblasts3 (Fig. 1C). Remarkably, GREM1 was abundantly expressed by CCL19+ fibroblastic reticular cells and TNC+ stromal cells, underlying the potential heterogeneity of GREM1+ fibroblasts. Regarding macrophages, we could identify an inflammation-specific population expressing PLA2G2D and PTGDS. These macrophages were mainly localized within granulomas surrounding M1 macrophages (Fig. 1D). While their function is unknown, their signature suggests they might be modulating inflammation through the production of anti-inflammatory lipid mediators4.

Conclusion
Using two different ST technologies, we resolved the tissue distribution of cell populations previously identified by scRNAseq and reveal their potential function based on their spatial location.
P015 iNKT cells immunomodulation and mucosal healing by microbiota-derived lactate
Authors: Strati F 
Published: January 2024

Abstract

Background
Invariant natural killer T (iNKT) cells are unconventional, CD1d-restricted, T lymphocytes playing a critical role in mucosal immune homeostasis. iNKT cells plastically adapt their functional phenotypes to the surrounding environment and are involved in IBD pathogenesis. Although iNKT cells release proinflammatory cytokines in response to the altered gut microbiota of IBD patients, exposure to microbiota-derived metabolites can promote homeostatic IL10-mediated iNKT responses resulting in better clinical outcomes in Crohn's disease (CD) patients. Thus, understanding the mechanisms leading to iNKT cells’ functional shaping by microbiota-derived metabolites is important to design novel therapeutic approaches for IBD patients. We hypothesised that iNKT cells, serving as sentinels of tissue integrity, are the primary immune cells sensing microbiota-derived metabolic signals promoting the resolution of inflammation in IBD. In particular, here we show that microbiota-derived lactate can tightly control iNKT cell functions promoting iNKT cell-mediated mucosal tolerance while preventing T cell-mediated overt inflammation and tissue injury.

Methods
We performed immunophenotyping of iNKT cells by multiparametric flow-cytometry from surgical specimens of CD patients and correlated NKT10 responses with intra-colonic levels of lactate, gut microbiome composition and tissue injury/healing. We studied the molecular pathway determining the NKT10 phenotype in a lactate-enriched microenvironment by RNA-seq and CHIP-seq. We validated the role of NKT10 responses by microbiota-derived lactate in-vivo by using experimental colitis models.

Results
Our data suggest that microbiota-derived lactate plays a role in the epigenetic control of anti-inflammatory iNKT cell functions through histone lysine lactylation, thereby protecting from intestinal inflammation.

Conclusion
On overall our data show i) how microbiota-derived lactate modulates the immunophenotype of iNKT cells, ii) the mechanisms underlying the sensing of microbiota-derived lactate by iNKT cells, iii) iNKT cells role in inflammation resolution.
This work is supported by an ECCO grant '22 to Francesco Strati
P023 Serological markers of intestinal barrier function in patients with primary sclerosing cholangitis after liver transplantation
Authors: Drastich P , Hlavaty M , Fabian O , Brezina J , Wohl P , Spicak J , Cahova M , Bajer L 
Published: January 2024

Abstract

Background
Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease associated with inflammatory bowel disease. Liver transplantation (LT) is the only curative treatment for most patients with PSC. Recurrence of PSC (rPSC) is a common long-term complication after liver transplantation in this patient group, affecting graft survival and overall patient survival. There are several lines of evidence indicating that dysregulation of the microbiome and gut barrier dysfunction are key etiologic factors in the pathogenesis of PSC. The aim of this study was to evaluate serological markers of intestinal barrier function in patients with PSC after LT and in control group, to determine potential biomarkers for rPSC.

Methods
This is a cross-sectional study of patients after LT for PSC at the Institute for Clinical and Experimental Medicine, Prague. The control group consists of patients who underwent liver transplantation for alcohol-related liver disease and/or hepatocellular carcinoma. The rPSC was assessed by MRCP and/or liver biopsy according to the Mayo criteria. IBD status was assessed by endoscopy, biopsy, and faecal calprotectin. We performed ELISA for Zonulin and Reg3a. The Kruskal-Wallis and Mann-Whitney test were used to evaluate the statistical differences.

Results
A total of 85 patients were included in the study after LT for PSC and 56 controls. rPSC was detected in 18 (21.18%) patients. IBD was diagnosed in 77 (90.5%) patients, of which 3 (3.9%) were categorised as Crohn’s disease. The remainder, 82 patients, were classified as ulcerative colitis, 41.9% with right-sided predominance and 24.3% with back-wash ileitis. The IBD treatment consisted of 5-ASA in 58 patients, azathioprine in 12 patients, vedolizumab in 5 patients, anti-TNFa in 1 patient and 9 patients were on 10 mg or more of prednisone or equivalent. MayoDAI was evaluated at the time of the visit with mean 1.74 (SD ±2.06). There was a significant difference in Reg3a levels between patients with IBD and control subjects (p&lt;0.05, Figure 1.). No significant difference in Reg3a levels was found between rPSC patients and controls (p=0.3). Interestingly, Zonulin levels were significantly higher in the control group than in PSC patients with or without IBD (p&lt;0.001). No significant difference in Reg3a and Zonulin was found between PSC and rPSC patients and between patients in remission and with active IBD.

Conclusion
Reg3a was associated with PSC-IBD in patients with PSC after LT, but its association with rPSC is unclear and should be investigated in a prospective setting. Zonulin reached higher levels in the control group.
P040 Prediction of endoscopic features of disease from single-cell RNA sequencing data in sigmoid colon of patients with ulcerative colitis
Authors: Riva A , Primas C , Wiekowski M , Badalamenti S , Reinisch W , Busslinger G 
Published: January 2024

Abstract

Background
Patients suffering from ulcerative colitis (UC) have reduced life qualities and an increased risk of developing cancer. Current treatment options are limited and have a ceiling effect with remission rates of ~35%. A possible reason is the multi-factorial aetiology, which are associated with an overactivation of the immune system and a dysbiosis of the gut microbiome. An important step towards a better understanding is the characterization of epithelial lesions. Their severity is classified by the Mayo score system based on their macroscopic appearance. While previous studies analysed cellular changes within the colon in UC patients, a detailed characterization of different UC-associated lesions are still missing, which is the aim of our study in collaboration with Sanofi Pharmaceuticals.

Methods
We recruit patients with active disease at our endoscopy unit and collect different biopsies from multiple regions within these patients to compare the reproducibility of single cell RNA sequencing (scRNAseq) results of similar appearing lesions within and between patients. For the sample preparation, we include a cellular enrichment step for immune, epithelial and stromal cells before performing 10x scRNAseq to obtain equal numbers for each cell fraction from every sampled area.

Results
Our cellular isolation strategy allows successful recovery of fibroblast, epithelial and immune cell fractions from each lesion. All expected epithelial cell types as previously described are detected in our dataset as well. Moreover, our experimental setup to obtain comparable numbers of fibroblasts, epithelial and immune cells enables us now to investigate cell-cell communication differences within different Mayo score lesions. For example, CXCL signal increased with the severity of macroscopic lesions and involves multiple cell types.

Conclusion
Our preliminary results promise exciting insights into cell-cell communications at an unprecedented depth, which identifies aberrant signalling pathway that may contribute to treatment failure in the clinics.