bluuebunny/crossref_metadata_2025_split huggingface dataset:
P076 Abdominal pain severity for IBD in remission correlates with genetic clustering and enzymatic activity of faeces-derived Candida albicans strains
Authors: Van Thiel I , Maasland T , van Wassenaer E , Hoekman D , Spooren C , Hakvoort T , Admiraal I , Theelen B , Levin E , Benninga M , Jonkers D , D’Haens G , Rosendahl S , Boekhout T , Hagen F , de Jonge W , van den Wijngaard R 
Published: January 2023

Abstract

Background
Abdominal pain is a common occurrence for approximately 39% of patients with inflammatory bowel diseases in remission (quiescent IBD; qIBD). There is increasing evidence for a contributing role of the gastrointestinal fungal community (i.e., mycobiome) in relation to intestinal inflammation and irritable bowel syndrome (IBS). As such, abundance of Candida spp. and sub-species variation of Candida albicans were previously associated with IBD severity. In the current study, we aim to investigate mycobiome of patients with qIBD and qIBD with abdominal pain (qIBD–AP).

Methods
Patients with qIBD (defined as faecal calprotectin (FCP) ≤250 μg/g) with (n=91) or without (n=58) abdominal pain provided faecal samples. Abdominal pain was scored based on either the Irritable Bowel Syndrome Symptom Severity Scale (IBS–SSS) or Gastrointestinal Symptom Rating Score (GSRS) questionnaire. Faecal fungal communities were determined based on Internal Transcribed Spacer 1 (ITS1) sequencing. Cultivable yeasts from faecal samples were identified using Matrix Assisted Laser Deionization Time–of–Flight Mass Spectrometry. C. albicans strains (n=137 from 29 patients) were genotyped by ITS Sanger sequencing analysis and typing of seven microsatellite loci. Release of virulence-related enzymes (proteinase, phospholipase, lipase, esterase) by C. albicans was assessed through determination of precipitation zones on solid agar mediums containing enzyme-specific substrates.

Results
Descriptive mycobiota analysis revealed limited differences between compositions of qIBD and qIBD–AP patients, but a discriminative signature for abdominal pain was extracted using machine-based learning models. While ITS Sanger sequencing of faeces-derived C. albicans was insufficient to elucidate genetic variability, analysis of microsatellite loci revealed extensive variability and clustering into six clone clusters and a likely distinction between qIBD and qIBD-AP patients (Fig. 1). Phospholipase enzymatic activity of C. albicans strains correlated with GSRS–Abdominal Pain sub-score, as did proteinase activity with severity of abdominal pain according to the IBS–SSS (Fig. 2). Additionally, lipase activity inversely correlated with faecal calprotectin (Fig. 2).

Conclusion
The faecal gut mycobiome is associated with self–reported abdominal pain in patients with IBD in remission. This notion is based on both compositional and culture-dependent methods and specified clones of C. albicans may selectively contribute to abdominal pain for qIBD patients. This study opens further possibilities to investigate the role of faecal gut fungi in light of abdominal pain for qIBD-AP patients.
P078 Physiological hypoxia improves growth and functional differentiation of human intestinal epithelial organoids
Authors: Walaas G A , Gopalakrishnan S , Bakke I , Skovdahl H K , Flatberg A , Østvik A E , Sandvik A K , Bruland T 
Published: January 2023

Abstract

Background
The epithelium in the colonic mucosa is implicated in the pathophysiology of various diseases, including inflammatory bowel diseases and colorectal cancer. Intestinal epithelial organoids from the colon (colonoids) can be used for disease modelling and personalized drug screening. Colonoids are usually cultured at 18-21% oxygen without accounting for the physiological hypoxia in the colonic epithelium (3% to &lt;1% oxygen). We hypothesize that recapitulating the in vivophysiological oxygen environment (i.e., physioxia) will enhance the translational value of colonoids as pre-clinical models. Here we evaluate whether human colonoids can be established and cultured in physioxia for the entire in vitro culture period and compare growth, differentiation, and immunological responses at 2% and 20% oxygen.

Methods
Growth from single cells to differentiated colonoids was monitored by brightfield images and evaluated with a linear mixed model. Cell composition was identified by immunofluorescence staining of cell markers and single-cell RNA-sequencing (scRNA-seq). Enrichment analysis was used to identify transcriptomic differences within cell populations. Pro-inflammatory stimuli induced chemokines and Neutrophil gelatinase-associated lipocalin (NGAL) release were analysed by Multiplex profiling and ELISA. Direct response to a lower oxygen level was analysed by enrichment analysis of bulk RNA sequencing data.

Results
Colonoids established in a 2% oxygen environment acquired a significantly larger cell mass compared to a 20% oxygen environment. No differences in expression of cell markers for cells with proliferation potential (KI67 positive), goblet cells (MUC2 positive), absorptive cells (MUC2 negative, CK20 positive) and enteroendocrine cells (CGA positive) were found between colonoids cultured in 2% and 20% oxygen. However, the scRNA-seq analysis identified differences in the transcriptome within stem-, progenitor- and differentiated cell clusters. Both colonoids grown at 2% and 20% oxygen secreted CX3CL1, CXCL2, CXCL5, CXCL6, CXCL10, CXCL12, CCL20, CCL25, and NGAL upon TNF + poly(I:C) treatment, but there appeared to be a lower pro-inflammatory response in 2% oxygen. Reducing the oxygen environment from 20% to 2% in differentiated colonoids altered the expression of genes related to differentiation, metabolism, mucus lining, and immune networks.

Conclusion
Our results suggest that colonoids studies can and should be performed in physioxia when the resemblance to in vivo conditions is important.
P084 Response to appendectomy in refractory Ulcerative Colitis appears based on two distinct inflammatory phenotypes
Authors: Becker drs. M , Heuthorst L , van Roest M , van der Bilt J , Buskens C , Wildenberg M 
Published: January 2023

Abstract

Background
Appendectomy has been suggested to decrease the risk of disease flares in UC, but we recently showed that even in therapy refractory patients, appendectomy may improve symptoms in a subset of patients. Despite several hypotheses, the effector mechanism of this phenomenon remains unclear. In this study we characterized gene expression profiles of appendices from therapy refractory UC patients either responding or non-responding to appendectomy, with the aim to identify pathways involved in response as well as guide selection of patients who are optimal candidates for appendectomy.

Methods
Appendix specimen from responders (N=10) and non-responders (N=10) to appendectomy for therapy refractory UC were included (COSTA-study NCT03912714 or off-label appendectomy). Endoscopic response was defined as steroid-free remission at 12 months without intensified medical treatment. The control group consisted of patients with acute appendicitis(N=2). Post-operative biopsies were taken from the appendix and the coecal base and snap frozen. RNA was isolated and expression profiling was performed using RNAseq.

Results
Unsupervised clustering indicated two separate clusters, one containing a more stromal phenotype expressing ADH1B, IGFBP5, Desmin and FLNA and the other expressing a more intestinal/B cell phenotype (OLMF4, PIGR, CEACAM5 and IHGA2). Stainings for the presence of collagen (stromal) versus pancytokeratin (epithelial) confirmed this analysis on protein level. Both clusters contained subclusters of responders and non-responders. In both the ‘responder’ subclusters, markers of immune activation were increased, but the type of response differed between ‘stromal responders’ and ‘epithelial responders’. In ‘stromal responders’ increased expression of acute phase genes was present (FABP4, ADIPOQ, SAA1 and CXCL8). In the ‘epithelial responders’, immune activity was more characterized by increased mitochondrial activation/oxidative phosphorylation. In both subclusters, non-responders lacked these immune activation markers. We also evaluated the expression of the differentiating genes in biopsies of the coecal bottom. Indeed, the coecal samples also largerly clustered according to response based on the gene expression profile of the matching appendices.

Conclusion
Patients responding to appendectomy showed two distinct gene expression patterns, suggesting two separate mechanisms of action. Although in both cases it clearly identified the requirement of active immune responses for response, the identifying markers differed between the two groups. This finding has consequences for both further functional studies into the effector mechanism of appendectomy in UC, but also in future efforts to identify patients suitable for this surgery.
P092 Punica Granatum affects gut biofilm-forming bacteria and promotes intestinal mucosal healing regulating the crosstalk between epithelial cells and intestinal fibroblasts
Authors: Rizzo G , Pineda Chavez S E , Vandenkoornhuyse E , Cardenas C , Cento V , Meanti L , Roda G , Loy L , Dal Buono A , Gabbiadini R , Lovisa S , Rusconi R , Repici A , Armuzzi A , Vetrano S 
Published: January 2023

Abstract

Background
Punica Granatum (PG), is a bioactive compound of Pomegranate exerting anti-inflammatory activities. Clinical studies have demonstrated an improvement of clinical response in inflammatory bowel diseases (IBD) patients when PG was taken as a complement to standard medications. However, the molecular mechanisms underlying its beneficial effects are still scarcely investigated. In this study, we assessed the effects of PG on bacterial biofilm formation, and we investigated the properties of the PG to promote mucosal wound healing.

Methods
Bacterial biofilm formation was assessed using microfluidic devices for 24 or 48 hours. Acute colitis model was induced in C57BL/6N mice by 3% dextran sodium sulfate administration in their drinking water for 5 days. During the recovery phase of colitis, mice received saline or PG (200 mg/kg body weight) oral gavage for 11 days. . Colitis was scored daily evaluating the body weight loss, bleeding and consistency of stool. In vivo intestinal permeability was performed by fluorescein isothiocyanate-conjugated dextran assay, bacterial translocation by Fluorescence in situ hybridization on tissues, whereas epithelial and mucus integrity by immunostaining for JAM-A and MUC-2 markers. Primary fibroblasts, isolated from healthy and inflamed area of 6 IBD patients, and Caco-2 cells were stimulated with or without PG (15 ug/ml). Inflammatory mediators were measured at mRNA and protein levels by RT-PCR, WB or by Bio-plex multiplex immunoassay respectively.

Results
Microfluidic experiments revealed beneficial effects of PG to inhibit biofilm formation of GRAM- bacteria and to promote the expansion of some intestinal commensal Gram+ bacteria. In vivo, PG boosted the recovery phase of colitis promoting a complete restoration of intestinal barrier with the regeneration of the mucus layer compared to saline group as also demonstrated by no traces of bacteria spread into the mucosa. The PG enriched crypt-associated fibroblasts. In vitro, inflamed fibroblasts responded to PG by down-regulating the release of metalloproteinases, IL-6, IL-8 and up-regulating the levels of HGF. Caco-2 cells cultured in medium supplemented with PG increased the expression of Sox-9 and CD44, whereas in the presence of HGF or when plated with fibroblast-conditioned medium displayed a decrease expression of Sox-9 and CD44 and increase of AXIN2, a negative regulator of Wnt signaling.

Conclusion
These data provide new insight of the multiple effects of PG on promoting mucosal homeostasis in IBD by affecting biofilm formation of pathogens, promoting expansion of commensals and favoring the regeneration of intestinal barrier by regulating the crosstalk between epithelial cells and stromal cells.
P121 Clinicomic profiles new feature patterns based on a simplified location classification for Crohn’s disease
Authors: Hu W , Liang X , Luo J , Li P , Shen K , Li J , Li S , Xin J , Jiang J , Shi D , Wang X , Xu D , Yu Q , Zhang H , Zhang X , Song X , Guo H , Ge Q , Chen Y , Chen X , Chen Y , Li J 
Published: January 2023

Abstract

Background
Crohn’s disease (CD) is a heterogeneous and complicated condition that often has delayed diagnoses and poor outcomes. Disease location and site-specific mechanisms have received increasing attention in recent studies. Suboptimal classification adds complexity to clinical management for CD and the interpretation of its characteristics. This study aims to clarify the clinicopathological characteristics of CD patients through a prospective cohort.

Methods
The clinical data from 1173 patients with definite CD diagnoses and a simplified location classification based on anatomical traits (G1: esophagus+stomach+duodenum; G2: jejunum+ileum; G3: ileocecum; G4: colon+rectum) were used to clarify the feature patterns (Figure 1).

Results
Of the enrolled patients, 437 were newly diagnosed, and 736 were prevalent patients. A higher proportion of L4 involvement (45.8%) and a lower proportion of L2 (6.8%) patients were observed under the Montreal location classification. Single G2 (17.8%), G2+G3 (22.2%), G3+G4 (12.5%) and G2+G3+G4 (27.8%) were the four major types in the simplified location classification (Figure 2A-2B). The patients with G4 presented with higher C-reactive protein, G2 patients had more stricturing/penetrating behavior, and single G2 patients had the oldest age at diagnosis (Table 1). A clinicomic study with machine learning methods including principal component analysis, cluster analysis and partial least squares discriminant analysis, identified hemoglobin, platelet count and C-reactive protein as the three key indicators. A decision tree based on the three indicators and disease behavior stratified all patients into six feature patterns (simply/complicatedly active, simply/complicatedly anemia and simply/complicatedly stable), which formed a two-twisted-cycle model for natural disease history (Figure 2C). Most patients started their cycles at the active phase, and the “simply” cycle was mainly advanced by medications, while most patients in the “complicatedly” cycle needed multidisciplinary care. Comparisons among the six subgroups showed that age at diagnosis had the same rise-and-fall pattern as the G2+G4- proportion, while the G2-G4+ proportion showed the opposite trend (Table 2, Figure 2D-2E). An external validation group (n=301) confirmed the above results. The role of disease location could be interpreted as an important factor determining its start point and site-specific trajectory in the two-twisted-cycle model.

Conclusion
Site-specific clinical characteristics clarified by the simplified location classification, the new feature patterns profiled by the clinicomic study may provide new insights into CD phenotyping, risk stratification and precision treatment.
P130 Intestinal ultrasound combined to fecal calprotectin is effective to predict endoscopic mucosal healing in ulcerative colitis: a cross-sectional study
Authors: Yzet C , Meudjo E , Moreau C , Brazier F , Hautefeuille V , Decrombecque C , Sarba R , Pichois R , Meynier J , Fumery M 
Published: January 2023

Abstract

Background
In the “treat-to-target” era, the development of non-invasive markers to assess endoscopic healing in ulcerative colitis (UC) is essential. Fecal calprotectin (FC) and intestinal ultrasound (IUS) are alternatives to colonoscopy to assess UC activity. The objective of this study was to evaluate the performance of IUS and FC to assess endoscopic mucosal healing in UC patient.

Methods
All consecutive patients between January 2021 and August 2022 with UC who underwent (1) a complete colonoscopy (2) an intestinal ultrasound and/or (3) a fecal calprotectin (4) within 4 weeks were included in a prospective cohort. Bowel wall thickness (BWT) and color doppler signal (CDS) were assessed on each segment. Endoscopic mucosal healing was defined by a MAYO score of 0-1.

Results
A total of 57 patients were included, 57.9% had endoscopic healing (22/57 MAYO 0 and 11/57 MAYO 1). Thirty-two (56.1%) were female, the median age and disease duration were respectively 43 years (IQR, 30-58) and 29 years (IQR, 18-39). Respectively 16 (16/57, 28.1%) and 41 (41/57, 71.9%) patients had BWT &lt; 3 mm and an absence of Doppler signal. The sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) of BWT &lt; 3 mm to predict endoscopic mucosal healing were 37%, 77%, 72% and 44%. The association of the absence of CDS with normal BWT did not modify these performances. The same values for fecal calprotectin &lt; 150 µg/g were respectively 81%, 78%, 84% and 74%. The association of a fecal calprotectin &lt; 150 µg/g, with a BWT &lt; 3mm and the absence of Doppler signal increased the specificity and the PPV (Se 33%, Sp 94%, PPV 89%, VPN 48%). The same values were found for patients classified as MAYO 0 or MAYO 0-1 (Table 1).

Conclusion
The combination of intestinal ultrasound and fecal calprotectin is effective to identify endoscopic mucosal healing in UC.
P132 Prognosis and molecular characteristics of IBD-associated colorectal cancer: experience from a French tertiary-care center
Authors: Hammoudi N , Lehmann-Che J , Lambert J , Amoyel M , Maggiori L , Salfati D , Tran Minh M L , Baudry C , Asesio N , Poirot B , Lourenco N , Corte H , Allez M , Aparicio T , Gornet J M 
Published: January 2023

Abstract

Background
Little is known about the prognosis of colorectal cancer associated with inflammatory bowel disease (CRC-IBD) in a real-world cohort in France.

Methods
We conducted a retrospective observational study including all patients presenting CRC-IBD in a tertiary French center between 1990 and 2021. Clinical and molecular data were collected. We analyzed overall survival (OS), progression free survival (PFS) and factors associated with prognosis. Outcome probabilities were analyzed using the Kaplan-Meier method.

Results
Among 6510 patients, the incidence rate of CRC was 0.8% (N =49) with a median delay of 19.5 years after IBD diagnosis. The median age was 46 years, the main IBD was ulcerative colitis (59%), the primary tumor was rectal in 49% and localized at diagnosis in 69%. There was a previous exposure to immunosuppressants (IS) in 57% and anti-TNF in 29% of the cases. The most frequent mutation was TP53 (56%). A RAS mutation was observed in 37% of the whole population and 13% of metastatic patients. OS of the whole cohort was 45 months OS and PFS of synchronous metastatic patients was 20.4 months and 8.5 months respectively. Among the patients with localized tumor those previously exposed to IS had a better progression-free survival (39 months vs 23 months; p =0.05) and a better OS (74 vs 44 months; p =0.03). Only 2 patients (4%) experienced IBD relapse during follow-up despite IS and biologics discontinuation in all exposed patients. Chemotherapy exposure was 53% and 93% in the adjuvant and metastatic setting respectively. No unexpected side-effect was observed, the only reason for discontinuation was oxaliplatin-sensitive neuropathy.

Conclusion
Incidence of CRC is elevated in IBD patients with a poor OS in metastatic patients although IBD is not associated with under-exposure or increased toxicity to chemotherapy. Previous IS exposure may be associated with a better prognosis.
P133 Risk Factors for the Occurrence and Severity of Vertebral Fractures in Inflammatory Bowel Disease Patients: A Nationwide Population-Based Cohort Study
Authors: Jung S H , Kim T O , Kang S B , Kim J 
Published: January 2023

Abstract

Background
The risk of vertebral fractures is increased in inflammatory bowel disease (IBD) patients. However, whether the severity of vertebral fractures differs between IBD patients and the general population, or between patients with Crohn’s disease and ulcerative colitis, is unknown.

Methods
We investigated risk factors associated with the occurrence and severity of vertebral fractures in IBD patients using The National Healthcare Insurance Service (NHIS) database.

Results
From 2008 to 2018, there were 33,778 patients with IBD (24,370 UC patients and 9408 CD patients) and 101,265 patients in the reference population. The incidence rate ratio of vertebral fractures in IBD patients was 1.27 per 1000 person-years (95% CI 1.26–1.27). The risk of vertebral fracture was higher in CD and UC patients than in the matched reference group (HR 1.593; 95% CI 1.317–1.927; p &lt; 0.001 and HR 1.269; 95% CI 1.141–1.412; p &lt; 0.01 respectively). The occurrence of vertebral fracture was associated with Crohn’s disease, older age, female sex, high Charlson Comorbidity Index (CCI) score, and long-term steroid use. The severity of vertebral fractures was associated with IBD and older age.

Conclusion
Vertebral fractures occur frequently and more severely in IBD patients, particularly those with CD. Therefore, we suggest monitoring of bone density, regular vitamin D supply, and reducing the use of corticosteroids to prevent vertebral fractures in IBD patients who are older, female, or have comorbidities.
P135 Atopic dermatitis is associated with the clinical course of inflammatory bowel disease
Authors: Kim K W , Koh S J , Kang H W , Park H , Ha H , Park J , Kim K , Jun Y , Lee H J , Yoon H , Im J P , Park Y S , Kim J W , Kim J S ,   Seoul National University Inflammatory Bowel Disease Research Network (SIRN)
Published: January 2023

Abstract

Background
There are a few studies about the relationship between inflammatory bowel disease (IBD) and atopic dermatitis (AD). It implies that both diseases have common pathophysiologic mechanisms and can affect each other. However, little information is available on the effect of AD on the clinical course of patients with IBD.

Methods
This is a multicenter, retrospective, observational study. Patients with concurrent IBD and AD were defined as case group. AD was defined as chronic eczematoid dermatosis diagnosed by dermatologists. Age-, gender-, and IBD subtype-matched patients without AD were included as reference group. The ratio of the case and reference group is 1:2.

Results
The numbers of patients in the case and reference group were 61 and 122, respectively. There was a significantly shorter biologics-free survival in the case group than that in the reference one after the multivariable adjusted Cox regression analysis with the onset age, disease duration, smoking status, use of steroid, use of immunomodulator, presence of other allergic diseases and initial disease severity [hazard ratio (HR) 1.743, 95% confidence interval (CI) 1.048-2.901, p = 0.032]. The trend was shown consistently in the subgroup analysis with ulcerative colitis (HR 4.769, 95% CI 1.625-13.995, p = 0.004), but not with Crohn’s disease (HR 1.393, 95% CI 0.736-2.636, p = 0.308).

Conclusion
AD showed a significant effect on the biologics-free survival of patients with IBD, especially UC. Further mechanistic research is required to elucidate the pathogenesis of AD on the clinical course of IBD.