bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract

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&lt;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&lt;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&lt;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&lt;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

Abstract

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

Abstract

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 (&lt; 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

Abstract

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.
P065 Altered B cell expansion and maturation in Crohn’s disease
Authors: Kappel-Latif S , Kotagiri P , Schuld G , Schlager L , Walterskirchen N , Schimek V , Jobst J , Murthy S , Messner B , Lyons P A , Oehler R , Bergmann M , Stift A , Unger L 
Published: January 2023

Abstract

Background
One of the hallmarks of Crohn’s disease (CD) is mesenteric thickening, accompanied by enlarged draining lymph nodes (LNs) in the affected areas. Descriptive studies imply that lymphatic architecture is altered in affected areas. Additionally, an altered IgA and IgG response towards commensal bacteria in CD patients compared to healthy controls has been described. Thus, we set out to investigate the B cell response in draining lymph nodes of patients with CD undergoing surgery.

Methods
We prospectively collected draining lymph nodes and serum samples in patients with Crohn’s disease during intestinal resections. LNs of affected and adjacent unaffected intestinal segments were processed for phenotyping by flowcytometry (n=18) and B cell receptor (BCR) sequencing (n=24). Histological analysis was performed to investigate size and number of germinal centers in affected and unaffected areas (n=10). Serum samples were collected from patients with CD undergoing surgery (n=18), and healthy individuals (n=16). The study was approved by the local ethics committee (EK #1480/2016) and all patients prospectively gave their written informed consent to participate in the study.

Results
Affected draining LNs showed a significantly increased fraction of CD45+CD19+ B cells (p=0.0055) compared to unaffected LNs. Fractions of double negative B cells (p=0.0394) and plasmablasts (p=0.0126) were significantly increased, and memory B cells significantly decreased (p=0.0127) in affected draining lymph nodes, respectively. Histological analysis revealed no difference in the numbers of germinal centers per high power field, but a significantly increased germinal center size (p&lt;0.001). BCR sequencing demonstrated a reduction in IGHA (p&lt;0.001) and IGHE (p=0.031), and a significant increase in IGHG1/2 (p&lt;0.001) in affected LNs compared to unaffected LNs. Analysis of somatic hypermutation of BCRs and diversity analysis showed no significant increase in somatic hypermutation in IGHG1/2, and diversity analysis indicated significant diversity in specificity. Serum IgA of patients with CD recognized a significantly greater fraction of commensals in CD patients, and IgG binding towards commensals was almost universally detectable in CD patients but absent in healthy controls.

Conclusion
Our data indicate that a pathological IgG response in patients with severe disease is directed towards a broad set of antigens, most likely stemming from commensals. Additionally, expansion only at the site of inflammation may indicate a triggered immune response due to a leaky intestinal barrier. The relevance of pathological IgG antibodies on disease recurrence following surgery needs to be addressed in future studies.
P073 Let′s talk about sex: an unicentric cross-sectional study on sexual dysfunction, sexual satisfaction and body schema disorders in Inflammatory Bowel Disease
Authors: Lindenthal D , Kranzeder A , Hirning C , von Wietersheim J , Klaus J 
Published: January 2023

Abstract

Background
Patients with Inflammatory Bowel Disease (IBD) suffer from a variety of physical and psychological symptoms. Especially sexual health is an often underestimated but leading concern among patients. Despite its major impact, there has been little systematic research on this topic in the past. The aim of this study was to investigate sexual dysfunction, sexual satisfaction and body schema disorders in patients with IBD compared to a healthy control group.

Methods
A cross-sectional unicentric study was performed. 123 patients with IBD and 71 population controls were recruited for 12 months. Inclusion criteria for the patient group included a diagnosed IBD (Crohn's Disease or Ulcerative Colitis), age between 18 - 65 years and sufficient language skills to complete the questionnaires. For the control group inclusion criteria were similar but without a diagnosed IBD. Data was collected using standardised questionnaries (IBDQ, IBD-F, pMS, HBI, IIEF, BISF-W, FKKS, PHQ15, PHQ9, HADS-D). Sexual dysfunction, sexual satisfaction and body schema disorders were mainly assessed by the „Frankfurter Körperkonzeptskalen“ (FKKS) and „The Brief Index of Sexual Functioning for Women“ (BISF-W).

Results
Significant differences (p &lt; 0.05) could be found within the individual questionnaire scales. Regarding the FKKS, the control group scored higher in three of the nine scales: Health and physical condition scale (SGKB), Sexuality scale (SSEX) and Body self-acceptance scale (SSAK). A similar result was also shown in the BISF-W: population controls had higher scores in two of the seven dimension scores: "Arousal" (D2) and "Pleasure/Orgasm" (D5). Overall, when comparing the total scores of FKKS and BISF-W between patients and population controls no remarkable distinctions were identified.

Conclusion
Sexual health seems to be impaired in patients with IBD. Patients suffer from reduced sexual arousal, orgasmic sensation and physical well-being. In addition, they are also more inhibited in sexual contact with their partners and devalue their own body in terms of aesthetics and biological functionality. Overall, these results can help to understand the disease′s complexity considering not only clinical but also psychological factors regarding sexual well-being and point to new therapeutical directions.
P074 Interferon-γ promotes antigen processing and presentation pathway in the intestinal epithelium of patients with Crohn’s disease
Authors: Hong S N , Lee C , Kim J E , Kim E R , Chang D K , Kim Y H 
Published: January 2023

Abstract

Background
Interferon-γ (IFN-γ) is a major driver of excessive immune response, leading to intestinal mucosal damage and contributing the pathogenesis of Crohn’s diseases (CD). In contrast to the inflammatory cells and immune system, IFN-γ-induced cellular responses has not been well documented in the intestinal epithelium. The intestinal epithelium consists of multiple cell types and patient-derived intestinal organoid model may be appropriate to evaluate the IFN-γ-induced epithelial cellular responses in patients with CD.

Methods
To evaluate the IFN-γ-mediated epithelial cellular responses, human small intestinal organoids (enteroids) derived from the controls (n=6) and patients with Crohn’s disease (CD, n=10) were constructed. We focused on the IFN-γ-induced cell death mechanism upregulated in CD enteroids and validated them in surgically resected small intestine in patients with active CD.

Results
As the concentration of IFN-γ increased in the culture medium, the organoid-forming efficiency decreased steadily, which did not differ between control and CD enteroids. The enteroid viability measured using MTT was estimated to be 83.10 pg/ml for EC50. In control and CD enteroids treated with 100 pg/ml IFN-γ, PANoptosis was the main inflammatory cell death mechanism. Bulk and single-cell RNA sequencing revealed that IFN-γ induced the expression of MHC class II-associated genes, co-inhibitory molecule CD274 (PD-L1), and IDO1 in control and CD enteroids, which may be associated with peripheral tolerance in the absence of exogenous antigens. Gene set enrichment analysis identified an up-regulated antigen processing and presentation pathway with increased expression of MHC class I molecules in IFN-γ-treated CD enteroids compared to IFN-γ-treated control enteroids (normalized enrichment score=2.13, p=0.002, q=0.005). IFN-γ-induced MHC class I pathway could result in T cell-mediated cytotoxicity in CD enteroids. The selective JAK1 inhibitor, upadacitinib, inhibited the IFN-γ-induced PANoptosis and T cell-mediated cytotoxicity in CD enteroids. The expression of HLA-A and B was higher in the inflamed small intestine in patients with CD than those in patients with ischemic enteritis.

Conclusion
IFN-γ promotes antigen processing and presentation pathway in the intestinal epithelium. In patients with CD, increased expression of MHC class I molecules may induce T cell-mediated cytotoxicity, which could contribute to the development of CD.
P108 Development and evaluation of the i-Tracker Risankizumab and i-Tracker Anti-Risankizumab kits: rapid and innovative tests intended for monitoring patients treated with Risankizumab.
Authors: Khater G , Noguier G , Daviere S , Montaillier C , Guilbert V 
Published: January 2023

Abstract

Background
Risankizumab is a human monoclonal antibody directed against the cytokine IL-23. This drug is commonly used for the treatment of patients with chronic inflammatory diseases such as psoriasis. Risankizumab is about to get an indication in Crohn’s disease and Ulcerative Colitis. Theradiag has just developed new rapid (results in less than 40 minutes) and innovative assays allowing the quantification of Risankizumab: these tests are available on the new innovative i-Track10 chemiluminescence platform and allowing the rapid quantification of Risankizumab as well as anti-Risankizumab antibodies induced by the patient.

Methods
The analytical performance was studied using two types of samples: human serum samples spiked with Risankizumab or anti-Risankizumab antibodies, and human serum samples from patients with inflammatory diseases treated with Risankizumab. For drug assay, Risankizumab was captured using IL-23-coupled magnetic microparticles and detected using an acridinium ester-conjugated anti-Risankizumab polyclonal antibody. For the assay of anti-Risankizumab antibodies, microparticles coupled to Risankizumab were used. The anti-Risankizumab antibodies thus captured were detected by Risankizumab conjugated to the acridinium ester. Light emission from acridinium ester conjugates is directly related to the amount of Risankizumab or anti-Risankizumab antibodies present in the sample.

Results
The quantification of Risankizumab by the i-Tracker Risankizumab kit shows very good accuracy (the percentages of recovery are between 84% and 108%). The intra-test and inter-test reproducibility is very good (CV &lt;7.3% for the Risankizumab assay and CV &lt;8.0% for the anti-Risankizumab antibody assay). No interference from biological agents (bilirubin, hemoglobin, triglycerides, rheumatoid factors) was detected. The assay measurement ranges are 1 µg/mL to 80 µg/mL for Risankizumab and 10 ng/mL to 2000 ng/mL for anti-Risankizumab antibodies.

Conclusion
The i-Tracker Risankizumab and anti-Risankizumab kits are rapid tests (results obtained in less than 40 minutes) and highly accurate. Monitoring Risankizumab plasma levels could provide clinicians with relevant information to improve treatment efficacy.