bluuebunny/crossref_metadata_2025 huggingface dataset:
DOP84 IBD-related hospitalization and surgery rates in biologic-naïve patients with IBD treated with vedolizumab versus other biologics: Results from a long-term, prospective, observational study
Authors: Sebastian S , Siegel C , Siegmund B , Zhou J , Jones S , Adsul S , Louis E
Published: January 2023

Background

Hospitalisations and surgeries are a major driver of health resource utilisation increasing disease burden on patients (pts) with ulcerative colitis (UC) and Crohn’s disease (CD). This analysis aimed to evaluate the number of hospitalisations and surgeries among pts with UC and CD initiating vedolizumab (VDZ) or other biologic treatment, as a marker for disease modification and health resource utilisation.

Methods

Secondary outcome data from a multicentre, observational, prospective, cohort post-authorisation safety study (PASS; NCT02674308) of biologic-naïve pts with UC or CD initiating VDZ or other biologic treatment were utilised. Pts received treatment under routine standard of care with clinical decisions at the discretion of treating physicians, and so treatment could be modified or changed without the need to withdraw from the study. Inflammatory bowel disease (IBD)-related hospitalisation rate and occurrences of IBD-related surgeries were assessed in pts initiating VDZ and other biologic. Time to first hospitalisation and surgery was also assessed.

Results

In total, 1149 pts with UC (556 initiating VDZ, 593 initiating other biologics) and 1338 pts with CD (312 initiating VDZ, 1026 other biologics) were included in this analysis. Baseline characteristics are displayed in Table 1. VDZ-treated pts with UC had fewer IBD-related hospitalisations (12.9% vs 25.0%; risk ratio [RR] 0.52 [95% CI 0.40, 0.67]) and IBD-related surgeries (4.3% vs 10.1%; RR 0.43 [0.27, 0.68]) than those treated with other biologics (Table 2). With regard to surgical procedures, VDZ-treated pts with UC had fewer total colectomies (RR 0.40 [0.20, 0.80]), colectomy (RR 0.32 [0.13, 0.79]) and other IBD-related surgeries (RR 0.37 [0.17, 0.78]). Among pts with CD, those treated with VDZ had fewer IBD-related hospitalisations (19.2% vs 26.4%; RR 0.73 [0.57, 0.93]) and IBD-related surgeries (7.1% vs 13.8%; RR 0.51 [0.33, 0.78]) than those treated with other biologics (Table 2). Pts with UC treated with VDZ had a longer time to event of first IBD-related hospitalisation and primary and secondary IBD-related surgery (in pts without history of IBD-related surgery at baseline) than pts treated with other biologics (Table 3).

Conclusion

In this large multinational, observational study, fewer biologic-naïve pts with UC or CD on VDZ treatment had hospitalisations and IBD-related surgeries than pts on other biologics. These real-world data suggest VDZ as a first line biologic treatment may contribute to modifying the course of IBD over time. Further research into the role of additional factors associated with differences in biologic treatments shown here is warranted.
DOP86 Subcutaneous infliximab (CT-P13 SC) as maintenance therapy for Crohn’s disease: A phase 3, randomised, placebo-controlled study (LIBERTY-CD).
Authors: Colombel J F , Hanauer S B , Sandborn W , Sands B E , Schreiber S , Danese S , Kierkus J , Kulynych R , Klopocka M , Lahat A , Gonciarz M , Osipenko M , Borzan V , Kowalski M , Saenko D , Sardinov R , Kim S , Bae Y , Lee S , Yang S , Lee J , Lee S J , Lee S G , Park G ,   CT-P13 SC 3.8
Published: January 2023

Background

CT-P13 subcutaneous (SC) infliximab formulation showed comparable efficacy and safety with CT-P13 intravenous (IV) infliximab in inflammatory bowel disease (IBD)1 and rheumatoid arthritis2. This study aimed to demonstrate the superiority of CT-P13 SC over placebo as maintenance therapy after induction therapy of CT-P13 IV in patient with Crohn’s disease (CD).

Methods

Moderately to severely active CD patients with Crohn’s disease activity index (CDAI) score 220 to 450 and simplified endoscopic activity score for Crohn’s disease (SES-CD) of ≥6 points for ileal-colonic CD or ≥4 points including ulcer score from at least 1 segment for ileal CD or colonic CD were enrolled LIBERTY-CD study (NCT03945019) and treated with open-label CT-P13 IV 5 mg/kg at Weeks 0, 2 and 6 as induction therapy. At Week 10, patients who had a clinical response were randomised (2:1) to receive either CT-P13 SC 120 mg (CT-P13 SC) or placebo every 2 weeks up to Week 54. At Week 54, clinical remission and endoscopic response were assessed as co-primary endpoints. Clinical response, clinical remission (alternative definition), endoscopic remission, and corticosteroid-free remission were assessed at Week 54 as key secondary endpoint. Safety was evaluated up to Week 54.

Results

A total of 396 patients were enrolled and 343 patients (86.6%) were randomised (231 in CT-P13 SC arm and 112 in placebo arm) at Week 10. At Week 54, the clinical remission rate was greater in CT-P13 SC arm than placebo arm (62.3% and 32.1% respectively, with P <0.0001). The endoscopic response rate was also greater in CT-P13 arm than placebo arm (51.1% and 17.9% respectively, with P <0.0001). CT-P13 SC also had significantly greater efficacy on key secondary endpoints results compared to placebo arm (Table 1). Safety profiles were generally comparable between CT-P13 SC and placebo arms, but a single death was reported during the maintenance phase (Table 2).

Conclusion

CT-P13 SC was more effective than placebo in clinical remission, endoscopic response, clinical response, clinical remission (alternative definition), endoscopic remission, and corticosteroid-free remission at Week 54. No new safety concerns were found during treatment of CT-P13 SC. These results demonstrate that maintenance therapy with CT-P13 SC provides both a robust clinical benefit and the convenience of SC administration to moderately to severely active CD patients.

[1] Schreiber et al., 2021. Gastroenterology 2021;160:2340–23

[2] Westhovens et al., 2020. Rheumatology 2020;00:1
DOP87 The Anti-TL1A Antibody PRA023 Demonstrated Proof-of-Concept in Crohn’s Disease: Phase 2a APOLLO-CD Study Results
Authors: Feagan B G , Sands B , Siegel C A , Dubinsky M , Longman R , Sabinho J , Laurent O , Luo A , Lu J D , Nguyen D , Towfic F , DuVall A , Woyranowski M , Al Kharrat H , McGovern D P B
Published: January 2023

Background

Tumor necrosis factor-like cytokine 1A (TL1A) is an upstream regulator of pro-inflammatory cytokines and fibrosis signals. PRA023 is an anti-TL1A monoclonal antibody in development for multiple inflammatory/fibrotic diseases with a precision medicine approach. This Phase 2a multi-center, open-label study aimed to assess the efficacy and safety of PRA023 as induction treatment in adults with moderately to severely active Crohn’s Disease (CD).

Methods

Key eligibility criteria included Crohn’s disease activity index ≥220 and ≤450 with centrally read [with adjudication] Simple Endoscopic Score (SES)-CD score of ≥6 (≥4 isolated ileal disease) and a history of insufficient/loss of response and/or intolerance to conventional and/or approved biologic therapies (≤4 biologic agents from ≤3 classes). Eligible patients were treated with intravenous PRA023 1000mg on Day 1, 500mg at Weeks 2, 6, and 10. The primary endpoint was endoscopic response (reduction in SES-CD score of ≥50%) at Week 12. Study design utilized historical placebo control rate estimates as a benchmark. Exploratory endpoints include efficacy assessment in a subpopulation identified by a genetics-based companion diagnostic test (CDx).

Results

Of the 55 patients in the full analysis data set, 53 (96.4%) completed the 12-week Induction Period. The patient population was notable for the high rate of prior biologic exposure (70.9%) and a mean (SD) disease duration of 10.3 (9.3) years (Table 1). A significantly greater proportion of patients receiving PRA023 achieved endoscopic response (26% PRA023 vs. 12% historical placebo estimate, p=0.002) and clinical remission (CDAI < 150 points; 49% PRA023 vs 16% historical placebo estimate, p< 0.001). Efficacy was observed in biologic-exposed patients (33% endoscopic response and 38.5% clinical remission) while concurrent steroid or immunosuppressant use did not impact efficacy. Significant reductions from baseline in C-reactive protein and fecal calprotectin were observed at all timepoints (Figure 1). Although the pre-specified CDx algorithm provided only limited additional benefit in clinical responses, an alternative CD-specific algorithm (not based on clinical trial data) using the same genetic markers demonstrated enhanced performance across both clinical (12/21 [57%] remission) and endoscopic (9/20 [45%] response) outcomes. No serious/severe AEs were deemed as study drug-related.

Conclusion

This Phase 2a study demonstrated robust proof-of-concept for PRA023’s efficacy in moderately to severely active CD with favorable tolerability. Patient selection using prespecified genetic markers showed promising results. Placebo-controlled clinical trials will be conducted to confirm these findings.
DOP90 The association of endoscopic and histologic endpoints with faecal calprotectin and C-reactive protein in patients with moderately to severely active ulcerative colitis treated with mirikizumab
Authors: Panaccione R , Sapin C , Chan-Diehl F W , Moses R E , Siegmund B , Walsh A , Kobayashi T , Parambir D S , Travis S
Published: January 2023

Background

Mirikizumab [(miri), a p19-directed IL-23 antibody] has been shown to be effective in patients with moderately to severely active ulcerative colitis (UC) in Phase 3, randomised, double-blind, placebo-controlled trials (LUCENT-1 NCT03518086; LUCENT-2 NCT03524092).1 Given the importance of understanding treat-to-target strategies, the relationship between improved histologic and endoscopic endpoints and improvement of the inflammatory biomarkers faecal calprotectin (fCal) and C-reactive protein (CRP) was studied within miri-treated patients enrolled in the programme.

Methods

This analysis focused on miri-treated patients (n=868) from the induction study receiving intravenous (IV) every 4 weeks (Q4W) until week (W)12 and miri induction responders at week W12, who were rerandomised for the maintenance period, receiving subcutaneous miri (n=365) Q4W up to W52. The relationship between achieving histologic-endoscopic mucosal improvement (HEMI), histologic-endoscopic mucosal remission (HEMR) (definitions in Tables) and improvement of fCal (≤250µg/g) and CRP (≤6mg/L) levels at W12 and W52 was explored using Fisher’s exact tests.

Results

At W12, a significantly higher percentage of miri-treated patients achieving HEMI (n=235/868) had normalised fCal and CRP values (76.2% and 88.5%), compared to miri-treated patients who did not achieve HEMI (n=633/868) (21.8% and 72.7%, both p<0.001; Table 1). Similarly, a higher proportion of patients achieving HEMR (n=193/868) had normalised fCal and CRP values (79.3% and 89.6%), compared to those who did not achieve HEMR (n=675/868) (24.3% and 73.3%, both p<0.001; Table 1).

At W52, a significantly higher percentage of the miri induction responder patients rerandomised to miri achieving HEMI (174/365) had normalised fCal and CRP values (74.1% and 87.9%), compared to patients not achieving HEMI (191/365) (32.5% and 61.3%; both p<0.001). Similarly, at W52, a higher proportion of patients achieving HEMR (n=158/365) had normalised fCal and CRP values (76.6% and 88.0%), versus patients not achieving HEMR (n=207/365) (33.8% and 63.3%; both p<0.001, Table 2).

Conclusion

At both W12 and W52, patients treated with miri who achieved HEMI or HEMR showed statistically significant improvements in fCal and CRP levels. This suggests that CRP and fCal may be useful markers of histology and endoscopy outcomes after induction and maintenance with miri.

1.Magro et al., MP245 Efficacy of mirikizumab in resolving active histologic inflammation in Ulcerative Colitis in Lucent-1 induction and Lucent-2 maintenance trials (2022), UEG Week Moderated Posters. United European Gastroenterol J, 10: 185-472.
P014 Behaviour in mice with chronic DSS colitis mimics fatigue in IBD and is associated with neuroinflammation
Authors: Truyens M , Lernout H , Vandendriessche C , Bruggeman A , Xie J , De Vos M , Vermeirssen V , Vandenbroucke R , Laukens D
Published: January 2023

Background

Inflammatory bowel diseases (IBD) are often associated with psychological comorbidities such as fatigue. Up to 47% of patients reports fatigue despite disease remission. The aim of the current study was to assess neurobehavioural changes in a mouse model of extinguished chronic colitis and to explore associated changes along the gut-brain axis.

Methods

Repeated administration of 2% dextran sulphate sodium (DSS) was used to induce chronic colitis in C57BL/6 mice, followed by a recovery period of 3 weeks to mimic quiescent IBD (Figure 1). Behavioural testing was performed at baseline and after the recovery period and compared with control mice. RNA sequencing was performed of the distal colon and choroid plexus and weighted correlation network analysis (WGCNA) was applied. Next, quantitative polymerase chain reaction (qPCR) was used for the confirmation of the expression levels of genes identified in the WGCNA analysis. The number of microglia and their morphology were assessed by Iba1 immunofluorescence in a second experiment, also including acute colitis (aDSS), which was induced by 1 week of 2% DSS, with sampling at day 7.

Results

Chronic DSS (cDSS) treatment resulted in chronic inflammation with minimal residual intestinal symptoms (control: median disease activity index (DAI) of 0 IQR [0-0], cDSS: median DAI of 0.5 [0.5-0.88], P <0.0001) after 3 weeks of recovery, which mimics quiescent IBD. At the time of sampling, the mean weight and haematological parameters (including red and white blood cells) in cDSS were comparable to those in control mice. cDSS mice exhibited significantly reduced spontaneous activity compared with their baseline behaviour (P = 0.0084) and with the controls (P = 0.0186). WGCNA on the colon and the choroid plexus expression data revealed a consensus module of 123 co-expressed genes that differed significantly between the control and cDSS mice (P = 0.00001721). These genes were implied in pathways of neutrophil and complement activation and qPCR on different brain regions (frontal cortex, hippocampus and choroid plexus) confirmed upregulation of inflammatory genes Lcn2, TNFa, S100A8 and S100A9 (Figure 2). Acute colitis was associated with activation of microglia in the prefrontal cortex and hippocampus, persisting in the prefrontal cortex of mice that recovered from chronic colitis (Figures 3 and 4).

Conclusion

In this mouse model of chronic extinguished colitis reduced spontaneous activity was seen, indicating fatigue-like behaviour as observed in patients with IBD. Moreover, mice that recovered from colitis exhibited persisting neuroinflammation.
P015 CITE-seq analysis revealed immune cell diversity in colonic mesenteric lymph nodes from IBD patients
Authors: Wils P , Mehta H , rubio M , Sarfati M , Chapuy L
Published: January 2023

Background

Mononuclear phagocytes (MNPs), including dendritic cells (DCs), monocytes (Mo), and macrophages (Mac), are key inducers of the adaptive immune response. MNPs could circulate between blood, mucosa, and mesenteric lymph nodes (MLNs), where they interact with T cells, natural killer (NK) cells, and innate lymphoid cells (ILC), contributing to chronic inflammation. MNPs have been previously investigated at the transcriptomic level in the inflamed gut mucosa, but their molecular characterization at the single-cell level remains uncovered in inflamed MLNs of patients with inflammatory bowel diseases (IBD).

Methods

MLNs were collected from surgical colonic resections of patients with Crohn’s disease (CD; n=3) or ulcerative colitis (UC; n=3). Cell suspensions were multiplexed and then pooled for sorting CD45+CD3+CD19- T cells and CD45+CD3-CD19- non-T/non-B cells by flow cytometry. Next, sorted cells were combined and labeled with BD Abseq antibodies (antibodies conjugated to oligonucleotide tag). CITE-seq (Cellular Indexing of Transcriptomes and Epitopes by Sequencing), combining simultaneous RNA and protein expression, was performed on the BD RhapsodyTM platform.

Results

High-quality data from 3308 captured single cells (1471 from CD and 1837 from UC) identified four main immune cell populations (myeloid DCs/Mo/Mac, plasmacytoid DCs, T cells, and NK/innate lymphoid cells). We further segregated cell subsets into 16 MNP, 4 NK/ILC, and 9 T cell clusters. MNP subsets were characterized according to specific gene expression (HLA-DRA, CD1c, ITGAX, SIRPA, JCHAIN, IL3RA). They revealed transcriptionally distinct DC clusters, including one cluster of mature regulatory DC (mregDC) (LAMP3, CCR7), one cluster expressing AXL and THBD, and one cluster of CD103+ DCs expressing LTB, FLT3, and IL22RA2. Further analysis of MNP subsets also revealed 6 clusters of monocytes and macrophages, including inflammatory Mo, Inflammatory Mac, and regulatory Mac. Overall, the proportion of myeloid cells and pDC was higher in UC MLNs when compared to CD (29.6% and 21.6% versus 17.1% and 11.7%, p<0.0001) while the proportion of NK/ILC was higher in CD MLNs (11.7% versus 24.9%, p<0.0001). Comparison of differentially expressed genes (fold-change>1.5) between CD and UC samples showed that CD MLNs were enriched in NK-specific marker genes (KLRD1, IL2RB, NKG7, GZMA). In UC, the majority of upregulated genes related to myeloid gene markers (THBS1, HLA-DQA1, HLA-DRA, VCAN, IL1B, JCHAIN, and CXCL8).

Conclusion

CITE-Seq analysis of the colonic MLNs of patients with active IBD suggests differences in immune cell landscape gene expression between CD and UC.
P016 Dietary supplementation with Brazilian jaboticaba-sabará fruit (Myrciaria jaboticaba (Vell.) O. Berg) ameliorates colitis-driven colorectal cancer in mice
Authors: Nascimento R D P D , Rizzato J S , Polezi G , Moya A M T M , Silva M F , Franchi Junior G C , Borguini R G , Santiago M C P D A , Paiotti A P R , Pereira J A , Martinez C A R , Marostica Junior M R
Published: January 2023

Background

Individuals with inflammatory bowel diseases (IBD) are at a high risk of developing colorectal cancer (CRC). Recently, pre-clinical studies have demonstrated that South American crops are rich sources of bioactive compounds that can act against both IBD and CRC. Therefore, our study aimed to characterize the freeze-dried peel of jaboticaba-sabará (Myrciaria jaboticaba (Vell.) O. Berg), a native Brazilian berry, and understand its preventive effects on a mouse model of IBD-related CRC.

Methods

Jaboticaba peel powder was chemically characterized by its contents of polyphenols, carotenoids, and dietary fibers. For the animal experimentation, male BALB/c mice were given in their diets 0, 2.5, or 5% jaboticaba powder for 17 weeks. On day 28, animals received an injection of the carcinogenic azoxymethane. During days 35-42 and 49-56, a solution with dextran sodium sulfate was given as drinking water to mice to induce chronic colitis. Clinical parameters were checked frequently in order to compose the Disease Activity Index (DAI). On day 119, mice were euthanized, their organs were measured, and the colon was checked for visible tumors. Histology processing was performed to assess the incidence of adenocarcinomas and for a score analysis of inflammatory-related parameters.

Results

High-performance liquid chromatography showed that dry jaboticaba is a rich source of cyanidin-3-O-glucoside (1.45%), gallic acid (0.32%), ellagic acid (0.3%), and delphinidin-3-O-glucoside (0.1%). Other compounds were found in a lesser amount, including protocatechuic acid (0.012%), rutin (0.006%), syringic acid (0.005%), and lutein (0.002%). Additionally, the powder showed relevant contents of soluble (11.3%) and insoluble (24.9%) dietary fibers (Table 1). Animals with colitis-driven CRC had diarrhea and showed bleeding in their feces, besides an average of 11 ± 2.1 visible tumors. On the contrary, animals that received 5% jaboticaba had a significant recovery in their colon length and showed reduced signs of colitis, including less bloody diarrhea, therefore, reduced DAI. The 5% intervention decreased the number of tumors to an average of 4.2 ± 1.0 (Figure 1). Adenocarcinoma incidence went from 66.6% in the control cancer group to 37.5% in the 5% jaboticaba group, the latter in which 50% of the animals did not show any alteration (adenoma or adenocarcinoma). Finally, the 5% jaboticaba diet significantly reduced crypt distortion and the depletion of goblet cells. The 2.5% jaboticaba diet had no beneficial effects.

Conclusion

Our preliminary results indicate that anthocyanin- and fiber-rich jaboticaba could represent a potential prevention tool for IBD-related CRC. Further analyses are necessary to understand the molecular mechanisms of jaboticaba on CRC.
P021 Microbial metabolite receptors as mediators of pathogenic processes in Inflammatory Bowel Disease.
Authors: Spathakis M , Dovrolis N , Tarapatzi G , Filidou E , Kandilogiannakis L , Valatas V , Drygiannakis I , Manolopoulos V G , Kolios G , Arvanitidis K , Vradelis S
Published: January 2023

Background

Inflammatory Bowel Disease (IBD) is a chronic inflammatory condition of the alimentary tract, primarily manifested as Crohn’s disease and Ulcerative colitis. Dysbiosis of the intestinal microbial microflora is a well-established characteristic of IBD. The microbiota metabolism ends in the production of several metabolites that participate in interactions with the host and ultimately influence its physiology. Our aim is to investigate whether metabolite receptor expression differs between IBD and healthy individuals and unravel their possible interactions with inflammatory and fibrotic pathways in the intestine.

Methods

RNA-sequencing data from over 2500 intestinal biopsy samples were collected from publicly available datasets via the Sequence Read Archive. Bioinformatics analysis of metabolite receptor genes was performed using the RaNA-seq online platform which included normalization, alignment and differential expression. In addition, correlation analysis between the target receptor genes and inflammatory/fibrotic genes as well as functional analysis was performed via a R based pipeline to elucidate molecular interactions during IBD.

Results

The expression of 22 receptors responding to the major metabolite ligand classes bile acids, short chain fatty acids and indole derivatives from tryptophan metabolism was targeted. Several receptors of bile acids as well as receptors of short chain fatty acids, such as the vitamin D receptor (VDR), the peroxisome proliferator-activated receptor alpha (PPARα) and the hydroxycarboxylic acid receptor 2 (HCAR2), were found differentially expressed in intestinal biopsies of CD patients as compared to healthy individuals. Negative and positive correlation of these receptors with genes of known involvement in IBD was explored, along with their simultaneous contributions to inflammatory and fibrotic processes.

Conclusion

Our results demonstrate the interplay between the intestinal microbiota and the host on a metabolite-receptor level and identify disease related interactions with inflammation and fibrosis.
P023 Immune-metabolic profiles of creeping fat in relation to degree of severity in Crohn’s disease postsurgical recurrence.
Authors: Suau R , Pardina E , López-Tejero M D , Lorén V , Zabana Y , Llaves M , Cordobilla B , Cañete F , Guasch M , Ricart-Jané D , Mañosa M , Domènech E , Domingo J C , Manyé J
Published: January 2023

Background

Crohn’s disease (CD) is an inflammatory bowel disease (IBD) of complex etiology that normally requires bowel resection. However, many patients suffer from post-operative recurrence (POR) within one year. Here, the inflammatory and bacterial influence of the affected intestine transforms the neighboring mesenteric tissue to creeping fat (CrF). The main objective has been to characterize the immune-metabolic profile of CrF according to the POR severity and compare them with mesenteric tissues from IBD-free controls (colorectal cancer and severe obesity).

Methods

POR severity was classified using the Rutgeerts index: non-recurrents (i0+i1, n=18; NR), mild-recurrents (i2, n=14; MR) and severe-recurrents (i3+i4, n=10; SR). The CrF were gathered from intestinal resections, and IBD-free mesenteric tissues were collected from intestinal resections for colorectal cancer (n=10) and bariatric surgery for severe obese patients (n=11). The total DNA was quantified using DABA assay, 105 cytokines were semiquantified by immune blotting and the fatty acid (FA) profile was quantified by GC-MS.

Results

The DNA analyses in the CrF showed a major cellularity demonstrating the hyperplasia. When compared to the control groups and to SR, the NR patients showed an increment of infection pro-resolutive cytokines (IFN-γ, MIF, BAFF), and, specially, an increase in both Th1 and Th2 cytokines (IL-18, IL-33). Here, there was also an increase in molecules related to angiogenesis (endoglin) and cellular adhesion (ICAM-1 and VCAM-1). On the other hand, the SR showed a higher level of pro-fibrotic PAI-1 and of the leukocyte homing inducer CCL5.

Going into the FA, in comparison to the control groups, there was an increase in the saturated in front of a decrease in mono-unsaturated FA in all the CD groups. Regarding the polyunsaturated FAs, the CrF and the obese mesentery showed a general increase of the omega 6/omega 3 FA ratio when compared to colorectal cancer controls.

Finally, both obese and NR CD patients had less short-chain FAs, specifically acetate and propionate, than the colorectal controls. Unexpectedly, the butyrate levels were very low in all the mesenteric tissues.

Conclusion

The CrF from NR CD patients show an infection resolutive profile regarding the controls and the SR. Instead, these lasts showed signs of chronic inflammation and a fibrotic profile. In general, CrF FA proportions suggests changes in cell signaling due to loss of cell membrane fluidity. In addition, the greater presence of omega-6 than omega-3 FA in the CrF and mesentery of obese patients could be related to the generation of potent proinflammatory lipid mediators. In contrast, the propionate and acetate decrease detected in NR CD patients could be protective against POR.
P024 Effects of anti-TNF and anti-interleukins 12 and 23 drugs on circulating dendritic cells migratory capacity in inflammatory bowel disease
Authors: Soleto I , Ramirez C , Gómez C , Montse B , García S , Orejudo M , Mecado J , Chaparro M , Gisbert J P
Published: January 2023

Background

Inflammatory bowel disease (IBD) is an idiopathic and chronic disorder that includes ulcerative colitis (UC) and Crohn’s disease (CD). Both diseases are different but show an uncontrolled intestinal immune response that generates tissue inflammation. Dendritic cells (DC) are phagocytic professional antigen presenting cells that link the innate and adaptive immune systems. Indeed, they are the only cell type able to stimulate naïve T cells generating an antigen-specific immune response. In humans, DC can be divided into plasmacytoid (pDC) and c conventional type 1 and 2 (cDC1, cDC2). Although cDC migration towards the GI mucosa is enhanced in IBD, the mechanisms underlying these migrations and whether biological drugs can modulate them are currently unknown. This study aimed to analyze DC migratory capacity towards the GI mucosa, and whether biological drugs with different mechanisms of action can modulate this process in health and IBD.

Methods

This is a cross-sectional observational postmarketing study where the modulatory effect of different biological treatments on samples from patients with an endoscopic diagnosis of IBD and healthy controls was studied ex vivo. Peripheral blood mononuclear cells (PBMC) were obtained from 15 patients per group and were cultured in presence of golimumab or ustekinumab. Following culture, surface markers expression was determined, assessing the differential effect of biological drugs (if any) over the DC subsets in the different groups. After that, the migratory capacity of circulating DC towards CCL2, CCL25, and MadCam1 from the different study groups was determined. Finally, we evaluated the DC migratory capacities in presence of biological drugs or with culture media alone.

Results

The cCD2 subset showed higher expression levels of β7 and CCR5 compared to cCD1 (Figure 1). Golimumab and ustekinumab did not modify the expression of the homing markers in any studied subset (Figure 2). Even though no conclusive results were obtained for the biological drugs used in the study on the expression of homing markers, ustekinumab decreased the migratory capacity of cDC2 from CD patients towards a medium supplemented with CCL25 (Figure 3).

Conclusion

cDC2 showed more migratory profile markers than other DC populations. Golimumab and ustekinumab did not modify the expression of the homing markers in any DC subset in any group. Nevertheless, ustekinumab decreased the migratory capacity of cDC2 from CD patients. This fact indicates that the behavior of this population is different in CD and UC and that the migration capacity of this subset is not dependent on homing markers.
P025 Colonic rather than ileal expression of ITGA4/ITGB7 correlates with local intestinal inflammation in IBD
Authors: Csomor E , Gehrmann U , Monkley S , Tian S , Cairns J , Angermann B , Khan E , Nys J , Marks D
Published: January 2023

Background

Lymphocyte trafficking to the inflamed gut is one of the hallmarks of Inflammatory Bowel Disease (IBD) pathology. Integrin a4b7 and its ligand MADCAM1 play an important role in targeting immune cells in the bloodstream to mucosal tissues and blocking this pathway using the anti-a4b7 monoclonal antibody Vedolizumab (VDZ) proved to be an effective treatment in IBD. However, VDZ is most efficient in treatment of Ulcerative Colitis (UC) and of colonic rather than ileal Crohn’s Disease (CD), for which the reasons have not been completely understood. Here we sought to compare the expression of ITGA4, ITGB7 and MADCAM1 in gut tissue biopsies from small and large bowel with respect to the underlying severity of tissue inflammation.

Methods

Differential gene expression analysis was conducted using bulk RNA Sequencing data generated from gut tissue biopsies of the large and small intestine of 611 CD and 315 UC patients enrolled in a multicentred longitudinal Study of a Prospective Adult Research Cohort with IBD (SPARC IBD) obtained from the IBD Plexus program of the Crohn’s and Colitis Foundation. Gene expression levels of ITGA4, ITGB7 and MADCAM1 were compared across ileal, colonic and rectal segments of the intestine and data were then linked to available measures of local inflammation.

Results

ITGA4, ITGB7 and MADCAM1 were expressed at comparable levels in large vs small bowel biopsies. Expression of MADCAM1 was significantly increased in both ileal and colonic biopsies from patients with moderate to severe CD based on segmental or composite endoscopy score (SES-CD) across all bowel segments. Expression of both ITGA4 and ITGB7 was similarly increased in colonic biopsies of moderate/severe CD patients, whereas only minor changes were observed for both genes in ileal biopsies. Similar findings were obtained from UC patients, where expression of MADCAM1 was significantly increased in inflamed or ulcerated biopsies from both sigmoid colon and cecum as compared to normal appearing biopsies. Expression of ITGA4 and ITGB7 was only increased in inflamed/ulcerated biopsies of the sigmoid colon but not the cecum and correlated with the modified Mayo endoscopic score (MMES).

Conclusion

Our analysis suggests that influx of leukocytes to inflamed tissue via ITGA4/ITGB7 and MADCAM1 interactions is more common in the distal colon compared to proximal colon or ileum. This provides a possible mechanistic explanation as to why VDZ is most effective in patients with colonic IBD. Further work is needed to understand the differential regulation of cell trafficking to different regions of the gut.
P035 Anti-inflammatory Effect and Mechanism of Action of BMC333, a Rationally-Designed Live Bacterial Consortium Based on Microbiome Functional Genomic Analysis for Treating IBD
Authors: Tirosh O , Meshner S , Eshar S , Kruger Ben-Shabat S , Polonski O , Haber E , Liu B , Herzog J , Sartor R B , Ringel Y
Published: January 2023

Background

The mechanisms by which the intestinal microbiome drives inflammation and disease activity in IBD is not clear. Most of the current efforts in developing treatments targeting the intestinal microbiome in IBD are focused on microbial taxa and very few treatments are developed based on microbiome functions in this condition. Using high-resolution functional microbiome analysis we have designed a live bacterial consortium consisting of four bacterial strains with anti-inflammatory functions (BMC333); and demonstrated the significant anti-inflammatory effects of this consortium in a mouse model of DSS-induced colitis by improving disease activity index, colon length, histologic score and fecal lipocalin (presented at DDW 2022).

Aim

To validate the anti-inflammatory effects and mechanisms of action of BMC333 using IL10-reporter mouse model.

Methods

Germ free mice bearing the IL10-GFP reporter gene (B6. IL10-GFP) were orally gavaged with BMC333 at 109 CFU/strain or vehicle/placebo (n=6 in each group) at experimental days 1 and 4. The induction period was followed by 10 days without intervention and the animals were sacrificed at day 14. Immunologic effects was assessed in mouse splenocytes and lamina propria by I. quantitating lamina propria immune-suppressive cells using flow cytometry. II. Comparing the effect of stimulation with each of BMC333 bacterial strains’ lysates on IL10- and IFNγ production by splenocytes from BMC333 or vehicle-treated mice.

Results

Treatment with BMC333 resulted in:

I. Higher levels of immune-suppressive cells (IL10-expressing CD4 T cells and B cells, and regulatory T-cells) in the lamina propria of mice treated with BMC333 compared with vehicle-treated mice.

II. Higher numbers of IL10-expressing splenic immunocytes stimulated with lysates compared to non-stimulated cells. Additionally, splenocytes stimulated by each of the BMC333 bacterial strains secreted higher IL10 levels, whereas the strain lysates did not induce secretion of the pro-inflammatory cytokine IFNγ, as measured by ELISA.

Conclusion

These results validate the anti-inflammatory effects of BMC333 and indicate that this beneficial effect is, at least partially, mediated by increasing IL-10 anti-inflammatory activity as demonstrated by the increased numbers of IL-10-producing lamina propria T and B cells after in vivo colonization, and higher IL-10 producing cells and secretion by BMC333 lysate-stimulated splenocytes. BMC333 stimulates increased immuno-suppressive cell populations in the lamina propria, but no increased production of the pro-inflammatory cytokine IFNγ. These findings are consistent with our previously reported in vivo studies and provide a strong rationale for further development of BMC333 as an effective treatment for IBD.
P045 Local administration of extracellular vesicles from adipose-derived stromal cells promote healing in a rat model of radiation colitis – a pilot study
Authors: Sebbagh A , Mathieu N , Demarquay C , Geiger M , Sémont A , Simon C , Branchu J , Milliat F , Gazeau F , Wilhelm C , Silva Brun A , Rahmi G
Published: January 2023

Background

The estimated increase in prevalence of radiation enteropathy associated with a current scarcity of effective treatment options underline the need for the development of new therapies. Extracellular vesicles (EV), which are membrane-bound particles secreted by cells containing proteins, lipids and nucleic acids, have yielded promising preclinical results in various applications in regenerative medicine. Here, we aimed to investigate whether EV from adipose-derived stromal cells (ADSC) may present a therapeutic potential in the context of radiation colitis.

Methods

EV were produced from primary rat ADSC by exposure to a turbulent flow. Radiation colitis was induced by fractionated irradiation at a dose of 3x10Gy on a colorectal window (3x2cm) in male Sprague-Dawley rats (311-386g) at days 0, 2 and 4; following a pre-established protocol. Treatment was administered at days 11 and 15 through submucosal endoscopic injections of rat ADSC (n=9 rats, 2x106cells per dose), EV (n=9 rats, 1.06x1011 particles per dose), or an equivalent volume of saline (n=10 rats). The rats were sacrificed at day 17. Our primary endpoint was the extent of colonic epithelial injury at histological analysis (Table 1). Secondary endpoints included an endoscopic assessment of the severity of lesions at day 15 (Table 2) and an evaluation of macrophage infiltration in the colonic mucosa by CD68 immunohistochemistry. Comparisons of proportions were performed by the Chi-squared test followed by Fisher’s exact test.

Results

In the ADSC group, 1 rat died from anaesthesia complications. No other adverse effects were observed. No differences in total body weight evolution were observed between the groups. At day 15, a statistically significant decrease of the proportion of animals with moderate to severe lesions was evidenced by endoscopy in the EV group compared to the saline group (p=0.0031; Figure 1). No differences were observed between the other groups. Histological analysis of the colonic epithelial injury score evidenced a non-significant tendency towards a decreased length of high-grade lesions in the EV group (mean±standard deviation: 9180±3684µm; Figure 2) compared with the saline (11536±2711µm) and ADSC (11636±2815) groups. Similarly, CD68+ macrophage infiltration at the site of colonic mucosal lesions tended to be lower in the EV and ADSC groups compared to the saline group.

Conclusion

This proof-of-concept study seemed to demonstrate a beneficial effect of locally administered extracellular vesicles for the treatment of radiation colitis in the acute setting. A confirmation study in a larger animal cohort is underway, and further investigations focusing on dose effects or long-term effects on fibrosis are required to complete these preliminary results.
P046 Crohn Disease (CD) untargeted fecal metabolome shows strong correlation with specific salivary associated microbial taxa, and with disease activity
Authors: Levhar N , Hadar R , Braun T , Efroni G , Abramovich I , Gottlieb E , Granot M , Neuman S , Selinger L , Picard O , Yavzori M , Lahat A , Eliakim R , Weiss B , Kopylov U , Ben-Horin S , Amir A , Haberman Ziv Y
Published: January 2023

Background

The fecal metabolome is comprised from derivatives of the gut microbiome, the host, the environment, and the diet. Thus, it is a central output and effector that is linked with Crohn disease (CD). We aimed to characterize metabolomics profiles that are associated with CD and link metabolites with gut microbial diversity and composition.

Methods

Fecal metabolomics was performed using liquid chromatography coupled Mass Spectrometer (LC/MS). Microbiome was defined by 16Sseq. Multivariate analyses in MaAsLin2 identified differentially abundant metabolites and these were used for pathways enrichment analyses using Metacyc (PMID: 31586394). Hierarchical All-against-All association (HAllA; PMID: 35758795) was used to identify significant relationships between fecal metabolites and microbial amplicon sequence variants (ASVs).

Results

The cohort included 294 samples from 85 subjects (mean age 36, 51% males). 250 samples were from CD patients (n=59) and 44 samples were from controls (n=26). 545 metabolites were included in our predefined library and were subsequently analyzed. Multivariate analyses identified 86 increased and 18 decreased metabolites in CD, after controlling for age and gender (FDR<0.25). These included reduction in 9 long-chain fatty acids and increase of standard and post-translational modified amino-acids. Enriched pathways in CD included amino-acids biosynthesis and degradation, electron carrier biosynthesis, guanine and guanosine salvage, and indole-3-acetate inactivation (FDR<0.1). Within the CD comparison, 29 metabolites were higher in active and 97 in quiescent CD. Acetylated amino-acids, dopamine, glucuronolactone and decanoic acid were all reduced in active CD. These metabolites and others were also significantly correlated with fecal calprotectin, microbial alpha diversity (Faith’s PD) and CD dysbiosis index (PMID: 24629344) (FDR<0.25; Fig. 1). To correlate fecal metabolomics with the gut microbial dataset, we applied the HAllA analysis (n= 231) that indicated 7,184 significant associations (FDR<0.05; Fig. 2). An interesting positive correlation was noted between a group of bacteria enriched with saliva bacteria (s_parvula, g_Actinomyces, g_Streptococcus, etc.) and metabolites like fructose, stachyose, glucose, raffinose etc., that are involved in stachyose metabolism (cluster 16).

Conclusion

CD patients have distinct fecal metabolic signature which is also correlated with disease activity. Furthermore, we identified significant interactions between specific fecal metabolites and gut microbial ASVs enriched with saliva bacteria that were previously linked with CD. More research is needed to elucidate the factors governing this newly discovered link.
P055 Exosomal miR-103a-3p from Crohn’s creeping fat-derived ASCs contributes to intestinal fibrosis by targeting TGFBR3 and activating fibroblasts
Authors: Qian W , Li Y , Zhu W
Published: January 2023

Background

Mesenteric adipose tissue hypertrophy is a hallmark of Crohn’s disease (CD), and creeping fat (CF) is unique to CD. Adipose-derived stem cells (ASCs) from inflammatory status exhibited altered biological functions. The role of ASCs isolated from CF in intestinal fibrosis and the potential mechanism remains unclear.

Methods

ASCs were isolated from CF (CF-ASCs) and disease unaffected mesenteric adipose tissue (Ctrl-ASCs) of patients with CD. A series of in vitro and in vivo experiments were conducted to study the effects of exosomes from CF-ASCs (CF-Exos) on intestinal fibrosis and fibroblast activation. A miRNA microarray analysis was performed. Western blot, luciferase assay, and immunofluorescence were performed to further detect the underlying mechanisms.

Results

Our results indicated that CF-Exos promoted intestinal fibrosis by activating fibroblasts in a dose-dependent manner. They continuously promoted progression of intestinal fibrosis even after dextran sulfate sodium withdrawal. Further analysis showed that exosomal miR-103a-3p was enriched in CF-Exos and participated in exosome-mediated fibroblast activation. TGFBR3 was identified as a target gene of miR-103a-3p. Mechanistically, CF-ASCs released exosomal miR-103a-3p and promoted fibroblast activation by targeting TGFBR3 and promoting Smad2/3 phosphorylation. We also found that the expression of miR-103a-3p in diseased intestine was positively associated with degree of CF and fibrosis score.

Conclusion

Our findings showed that exosomal miR-103a-3p from CF-ASCs promotes intestinal fibrosis by activating fibroblasts via TGFBR3 targeting, suggesting that CF-ASCs are potential therapeutic targets for intestinal fibrosis in CD.
P058 Immunological effects of hepatitis B virus vaccination in inflammatory bowel disease patients
Authors: Soleto I , Marin A C , Mora I , Villagrasa J R , Baldan-Martin M , Ramírez C , Bernardo D , Chaparro M , Gisbert J P
Published: January 2023

Background

The response rate to hepatitis B virus (HBV) vaccination in the general population is about 90%. However, the response rate to the vaccine in patients with inflammatory bowel disease (IBD) is significantly lower. IBD is a multifactorial disease so, it is important to study which cell subsets are involved in the failure of the HBV vaccine. Therefore, our main objective was to study the differences between the circulating immune system of responders and not responders to the vaccine.

Methods

Observational clinical practice study on the factors associated with the immunogenicity of the HBV vaccine in patients with IBD. Per clinical practice, 19 IBD patients vaccinated for the first time against HBV were included. Patients were divided according to their vaccination response after three doses of the vaccine at 0, 1, and 6 months as responders (≥ 100 anti-HBV) and non-responders (< 100 anti-HBV). Blood was collected before and after vaccination to characterize the different immune subsets by flow cytometry. Data were analyzed manually and by high dimensional data analysis (UMAP and FlowSOM).

Results

Non-responders displayed a lower percentage of naïve T cells compared with those who responded while responders had a lower percentage of Th2 and CD4 central memory subsets before vaccination. According to the high dimensional data analysis, 22 different T-cell metaclusters were identified (Fig. 1). Indeed, the percentage of type 2 conventional dendritic cells was increased following vaccination in both responders and non-responders, allowing us to identify 11 submetacluster (Fig. 2). Finally, The percentage of IgG class switch and IgG plasmablasts were increased following vaccination in the responders group, while the percentage of IgM plasmablast was increased in non-responders. Using the high dimensional data analysis 26 different subpopulations, were identified (Fig. 3).

Conclusion

The proportion of circulating T cell subsets can be used as predictor markers of the response to the HBV vaccine in IBD patients: while non-responders showed a lower percentage of naïve T cells, responders presented a lower percentage of Th2 T cells compared with their counterparts. The analysis of the data reveals that high-resolution and high-dimensional data, show several clusters containing events that evade the canonical definition.
P059 Klebicin as a novel therapy for Klebsiella infection management
Authors: Karaliute I , Tilinde D , Ramonaite R , Kupcinskas J , Misiunas A , Denkovskiene E , Gleba Y , Razanskiene A , Skieceviciene J
Published: January 2023

Background

Common infections are becoming almost untreatable, all because of the emergence and spread of drug-resistant pathogens. The highest risk is carried by rapidly spreading multi and pan-resistant bacteria that cause infections untreatable with existing antibiotics. Nowadays the biggest concern is Klebsiella bacteria which reportedly has resistance percentages of 25% or higher for third-generation antimicrobial medicine (WHO, 2022). Orally delivered recombinant bacteriocins, like klebicins, could be employed as oral antimicrobials to eradicate multidrug-resistant Klebsiella from the intestinal tract before hospitalization.

Methods

This study aimed to investigate the antimicrobial efficacy of orally delivered Eudragit - coated klebicin (KvarM) in a murine gastrointestinal tract model of K. pneumoniae infection. Biomodels were used (5 animals/group) to test the antimicrobial efficacy of orally delivered klebicin KvarM: vehicle-only control group (K. pneumoniae, Eudragit coating) and experimental group with K. pneumoniae and KvarM coated to be released in small and large intestines. Faecal samples were used for the analysis of Klebsiella haemolysin gene (khe), which is highly specific for Klebsiella species, using RT-PCR.

Results

The gastrointestinal model of K. pneumoniae infection in mice was achieved per os without any antibiotic pretreatment following the introduction of coated klebicin KvarM therapy once per day for four days. In the first experimental group, the amounts of K. pneumoniae changed from 6,15 x 106 CFU/50 mg after K. pneumoniae administration to 4,68 x 106 CFU/50 mg after the last dose of therapy (23,9 percent efficacy) in the experimental group. Nonetheless, there was a significant difference between the vehicle-control group and the first group after klebicin administration (p=0,023).

Conclusion

Our study shows that the K. pneumoniae infection in the intestinal tract of mice was reduced by 23,9 percent and can be significantly lowered in bacterial counts using orally delivered klebicin.