bluuebunny/crossref_metadata_2025_split huggingface dataset:
P003 MicroRNAs as biomarkers in Inflammatory Bowel Disease unclassified (IBDU) patient samples may predict the development from IBDU to Crohn’s Disease or Ulcerative Colitis
Authors: Pallikkunnath James J , Riis L B , Malham M , Høgdall E , Langholz E , Nielsen B S 
Published: January 2023

Abstract

Background
Differential diagnosis in Inflammatory Bowel Disease (IBD) is challenging; typically, discriminating Crohn’s Disease (CD) from Ulcerative Colitis (UC) among IBD unclassified (IBDU) patients is a diagnostic encounter in cases where the inflammatory lesions are restricted to the colon. MicroRNAs are found to be involved in the pathogenesis and are also evaluated as diagnostic biomarkers and therapeutic targets in IBD.

Methods
We obtained formalin fixed paraffin embedded (FFPE) colonic mucosal biopsies of 35 IBDU patients (including adults and children), and 8 IBD (4 CD and 4 UC) patients who were classified into CD or UC collected from the diagnostic endoscopy. Based on the patient charts, The IBDU samples were reclassified into CDs or UC or remained as IBDU after minimum 3 years clinical follow up, ie. 12 IBDU patients were reclassified as CD (IBDU-CD) and 15 IBDU patients as UC (IBDU-UC). Eight IBDU patients remained as IBDU. MicroRNA profiling was performed on all samples using Affymatrix GeneChip miRNA Arrays. Arrays were processed using pd.mirna.4.0 and oligo packages in R and were analysed using LIMMA package.

Results
We found that miR-3176 and miR-182-5p were upregulated in IBDU-CD and miR-671-5p, miR-668-5p, miR-4793-3p, and mir-6776 were upregulated in IBDU-UC with p values of less than 0.05 and 1&lt; log [fold change] &lt;-1 for all 6 microRNAs. Higher mucosal expression levels of miR-3176 and miR-182-5p in IBDU-CD samples compared to IBDU-UC samples, resulted in an area under the curve (AUC) of 0.87 (95% confidence interval (CI), 0.71 – 1.00) and 0.81 (CI, 0.63 – 1.00), respectively, in discriminating IBDU-CD from IBDU-UC. On the other hand, miR-3176 and miR-182-5p had AUCs of 0.69 (CI, 0.25-1.00) and 0.69 (CI, 0.21-1.00), respectively, in discriminating CD and UC. MicroRNA miR-671-5p had a higher AUC of 0.81 (CI, 0.48 - 1.00) for discriminating CDs and UCs, whereas in discriminating IBDU-CD and IBDU-UC, the AUC was only 0.64 (CI, 0.42 – 0.87).

Conclusion
We conclude that differential microRNA expression among IBDU patients can predict the development of IBDU to CD and IBDU to UC, and that the microRNA expression profile of IBDU patients differ from patients classified as CD or UC at time of diagnosis. Our findings suggest that IBDUs may have different pathogenic mechanisms for IBDU-CDs and IBDU-UCs.
P007 Paradoxical effects of high and low emulsifier diets on intestinal permeability in unstressed and stressed states in healthy human adults: a pilot randomised controlled feeding trial.
Authors: Fitzpatrick J , Gibson P R , Taylor K M , Halmos E P 
Published: January 2023

Abstract

Background
In preclinical models, high doses of specific emulsifiers induce intestinal inflammation. How these findings translate to Crohn’s disease (CD) is unclear, but the effects of dietary emulsifiers in the context of our food supply are needed before safe evaluation in a CD population.

Aims
To develop novel trial healthy diets matched for all dietary components, except emulsifiers; and to evaluate their suitability for study in patients with CD by defining, in healthy subjects, tolerance, blinding and adherence to the diets and their impact on intestinal permeability with and without stress.

Methods
In a pilot single-blinded, cross-over, randomised study, healthy subjects were fed for 4 weeks with ≥3-week washout between diets. Acute stress was induced via 100 mg intravenous corticotrophin-releasing hormone (CRH) on day 28 of each diet. Intestinal permeability was analysed directly with urinary lactulose to rhamnose ratio (LRR) before and at 2 weeks; fasting serum biomarkers reflecting barrier function (intestinal fatty acid binding protein, lipopolysaccharide binding protein [LBP], soluble CD14 and syndecan-1) were measured before and during each diet. All markers were also measured 2 h post CRH. Tolerance was assessed by gastrointestinal symptoms daily using a 100-mm visual analogue scale. Success of blinding was assessed by direct questioning and adherence (defined &gt;95% consumption of only food provided) with food diaries.

Results
18 of 20 participants enrolled [median age: 34 IQR 23-46 y; 75% female] finished both diets. The diets were well tolerated with minimal overall symptoms (low: mean 9.9 (SD 8.3) vs high: 9.5 [5.5] mm). Adherence was excellent (&gt;95%). Blinding was reasonable with 30% of participants either not knowing or choosing a high emulsifier diet as the therapeutic diet. In the unstressed state (Fig 1), LRR reduced on the HIGH diet compared to baseline (p=0.016), but no difference between diets was seen. LPB concentrations were lower in the HIGH than LOW diet (p=0.039). Under acute stress (Fig 2), LRR increased by 49% during the HIGH diet (p=0.034), but fell by 41% during the LOW diet (p=0.027). The paired CRH-induced LRR was reduced on LOW vs HIGH diet in acute stress (p=0.043). No difference in concentrations of other biomarkers were seen between diets.

Conclusion
Novel low and high emulsifier trial diets were well tolerated, achieved good adherence and reasonable blinding. Paradoxically, intestinal permeability reduced with the HIGH diet in the unstressed state, but the LOW diet protected from stress-induced increase in permeability. These diets are suitable to evaluate the effects of emulsifiers on intestinal permeability and inflammation in patients with CD.
P013 Role of IL-36RA mutations in Crohn’s disease
Authors: Hecker J , Saurenbach J , Letizia M , Löscher B S , Franke A , Kühl A A , Atreya R , Koop K , Neufert C , Trajanoski Z , Schütz A , Siegmund B , Weidinger C 
Published: January 2023

Abstract

Background
The interleukin 36 (IL-36) family consists of three agonists (IL-36α, IL-36β, IL-36γ), that activate the NF-κB pathway and lead to the production of pro-inflammatory cytokines and the natural antagonist (IL-36RA), which inhibits IL-36 signaling. While it is known that IL-36 signaling is important in the skin, it has been only recently reported that IL-36 might play an important role in maintaining gut homeostasis and in the development of fibrosis (Scheibe et al., 2019).
Here, we aim to understand how IL-36RA mutations contribute to development and maintenance of intestinal inflammation in Crohn’s disease.

Methods
By whole-exome sequencing (WES) and subsequently targeted Sanger sequencing we identified a Crohn’s disease (CD) patient with a heterozygous missense mutation in IL-36RA (p.Ser113Leu). To understand how the mutation affects immune cells composition and function, we characterized peripheral blood mononuclear cells (PBMCs) of the patient by mass cytometry and measured cytokine levels in the serum by ELISA.
In an available WES dataset of 177 CD patients, 47 ulcerative colitis (UC) patients and 34 healthy donors (HD), we searched for additional patients with IL-36RA mutations.
Finally, we overexpressed the identified IL-36RA mutations in HEK cells and produced mutated recombinant proteins to study the effect of the mutations on protein expression and function.

Results
Our IL-36RA mutation-carrying patient presented with a severe course of Crohn’s disease and consecutive of fibrosis, which was resistant to all commonly used treatment options. In the patient, we detected increased levels of IL-36RA, IL-18 and IL-23 in the serum and an increased frequency of TH17 cells in the blood. These findings could hint towards an over-activation of the IL-36 signaling pathway in the IL-36RA mutated patient.
In the available WES data, we identified two more CD patients with IL-36RA mutations (p.Leu133Ile, p.Pro76Leu), indicating that IL-36RA mutations are enriched in CD patients.
By overexpressing the three identified mutations in HEK cells, we could demonstrate that two mutations (p.Ser113Leu and p.Pro76Leu) lead to a reduced protein expression. Also, our current data shows that the p.Ser113Leu mutant has a reduced capacity to antagonize IL-36 stimulation. However, further testing is required for the two other IL-36RA mutants.

Conclusion
Our data suggests that IL-36RA mutations are enriched in Crohn’s disease patients and should be considered as a possible cause for therapy-refractory and fibrotic Crohn’s disease.
P020 Characterisation of mucus in patients with Crohn’s disease
Authors: Kramer C , Ziegler J , Alzain N , Schroeter S , Almalla A , Elomaa L , Addante A , Kuppe A , Fentker K , Nazat Martinez Medina J , Jarquin-Diaz V H , Rulff H , Gradzielski M , Forslund S , Mertins P , Mall M , Weinhart M , Glauben R , Siegmund B 
Published: January 2023

Abstract

Background
Crohn’s disease (CD) is a chronic inflammatory condition that can affect all parts of the intestine. Commonly, there is inflammation in the terminal ileum. An intestinal barrier consisting of epithelial cells covered by a mucus layer is on the one hand preventing pathogen invasion while on the other hand allowing the uptake of nutrients. However, despite the significance of the terminal ileum in CD, little is known about the mucus composition and viscoelastic properties in the terminal ileum.
In our study, we wanted to do a comprehensive analysis of the mucus in the terminal ileum of CD patients compared to healthy controls. Thus, we aspire to gain a better understanding of the role of mucus and biophysical and biochemical triggers contained in the mucus layer during the course of ileal inflammation.

Methods
During colonoscopy, native mucus and saline washes containing mucus as well as biopsies from the terminal ileum of 33 CD patients and 25 healthy controls were collected. The disease course and dietary habits of all patients and healthy controls were recorded. Samples were treated according to protocol for different types of analysis such as rheology, proteomics, metabolomics, and microbiome. Furthermore, human intestinal organoids were generated from the biopsies. Additionally, we analysed bulk RNA sequencing data from intestinal mucosal biopsies of a cohort of 128 patients, consisting of non-IBD individuals and CD patients.

Results
We here present preliminary data for the different types of analyses. Regarding the viscoelastic properties, preliminary rheology data suggests that there is no major difference between CD patients and healthy controls. As for proteomics, the first cohort is currently being analysed. Concerning the microbiome, we could show that saline washes containing mucus are more suitable than biopsies for analysing bacterial as well as host DNA. Although not statistically significant, healthy controls showed a tendency for higher alpha- diversity in microbiota. Also there were some differences in the taxonomy. Intestinal organoids were grown as cultures. In the end, the results of the analyses mentioned above will be interpreted together with the clinical data. Concerning the gene expression, we found that 12 mucin and mucin-like genes were expressed both in colon and ileum tissue. Interestingly, a subset of CD patients showed a de-novo expression of MUC5AC, MUC6, MUCL1 and MUCL3 in the ileum.

Conclusion
All in all, in our multidisciplinary study we hope to achieve a thorough analysis of the mucus layer in the terminal ileum, thus gaining new insight into the pathogenetic mechanisms in intestinal inflammation that could prospectively be used for therapeutic means.
P022 A correlation of serum Fibroblast Growth Factor 21 level with inflammatory markers and indicators of nutritional status in patients with Inflammatory Bowel Disease
Authors: Łukawska A , Mulak A 
Published: January 2023

Abstract

Background
Fibroblast Growth Factor 21 (FGF21) is an endocrine hormone produced mostly in the liver, adipose tissue, and the pancreas. Main inducers of the FGF21 secretion include fasting state, overfeeding, inflammation, and physical activity. FGF21 is involved in the metabolism of lipids, carbohydrates, and proteins. It also participates in body weight regulation. Previous studies have shown that serum FGF21 level is increased in animal model of colitis and patients with Inflammatory Bowel Disease (IBD) (Liu et al. Gastroenterol Res Pract 2017). The aim of this study was to assess the correlation between serum FGF21 level and inflammatory markers as well as indicators of nutritional status in IBD patients.

Methods
Fasting serum FGF21 level was measured using ELISA test in 67 patients with IBD (38 patients with Crohn’s disease and 29 patients with ulcerative colitis) and 10 control subjects. Among IBD patients, 24 subjects were in remission and 43 in acute phase of the disease. Fecal calprotectin, serum CRP, albumin and cholesterol levels were tested in all patients. BMI was also assessed. The Spearman rank correlation coefficient (R) was calculated to evaluate associations between the variables.

Results
No significant differences were found in serum FGF21 level between four studied groups: all IBD patients, IBD patients with remission, IBD patients with exacerbation and healthy controls. However, a positive correlation was observed in IBD patients between serum FGF21 and fecal calprotectin levels (R= 0.39, p= 0.003). There was also a trend toward a positive correlation between FGF21 and CRP levels (R= 0.24, p= 0.053). Moreover, an inverse correlation was found in IBD patients between FGF21 level and nutritional status indicators: BMI (R= –0.36, p= 0.003), albumin level (R= –0.38, p= 0.001), and cholesterol level (R= –0.30, p= 0.014).

Conclusion
The intensity of intestinal inflammation is related to FGF21 level, which correlates negatively with nutritional status indicators in the course of IBD. The disturbances in FGF21 secretion may contribute to the multifactorial pathogenesis of malnutrition and weight loss in IBD patients.
P028 Transitioning patients from intravenous to subcutaneous infliximab and vedolizumab for inflammatory bowel disease – what is the opportunity cost of improving access to health care?
Authors: Hilley P , Wong D , Ma R , Peterson A , De Cruz P 
Published: January 2023

Abstract

Background
Biologic drugs are highly effective for inflammatory bowel disease (IBD) management but are key drivers of costs of care especially when administered intravenously (IV). Availability of subcutaneous (SC) formulations has increased convenience for patients and improved access to care but at the cost of revenue to health services.
The aim of this study was to evaluate the economic impact of transitioning a tertiary centre IBD cohort from IV to SC biologic administration and assess the implications for key stakeholders.

Methods
A retrospective analysis of all patients that received IV infliximab or vedolizumab in the outpatient infusion centre of a tertiary, IBD centre between July 2019 and June 2021 was undertaken. Data were extracted from electronic medical records, pharmacy dispensing systems and the hospital business intelligence unit. An economic analysis and theoretical financial/capacity impact analysis of a transition to a SC model was estimated under two theoretical scenarios, using a random 10% and 30% of the patient cohort.

Results
Transitioning our IBD cohort from IV to SC administration would result in a loss of $2,732,123.75, comprised of $1,463,003.75 in Weighted Inlier Equivalent Separation (WIES) and $1,269,120 in drug procurement revenue. However, it would ease capacity in the infusion centre by up to 5256 hours.

Conclusion
Transitioning patients to SC administration results in improved access to infusion centres and substantial savings to state governments; however, switching results in a loss of IV-biologic generated WIES to health services. Alternative funding models are required to achieve sustainability in IBD care and reduce reliance on IV biologic generated income.
P030 Assessing dietetic interventions in inflammatory bowel disease patients
Authors: Norman E , Hoque S 
Published: January 2023

Abstract

Background
Nutrition can play a role in the management of inflammatory bowel disease (IBD) as well as general nutritional status, however there are many types of dietetic interventions depending on the circumstances. We decided to survey some of the nutrition interventions that IBD patients may be provided with to obtain a general picture of how helpful this is to patients, as well as the effectiveness of having a specific IBD dietetic post.

Methods
The inclusion criteria were patients with a diagnosis of IBD, reviewed by the IBD dietitian and patients had to be under the IBD team at Whipps Cross Hospital. Patients were asked if they consented to providing their email address for the anonymous survey link to be sent to. The survey was then emailed to 50 IBD patients. Nine questions were asked on the survey and an internet survey provider was used.

Results
The total response rate was 32% to the survey. The mean age was about 40 years old. 40% of patients were male with the remainder being female. 58% of the patients had Crohn’s disease with the remainder having UC. 100% of patients felt the dietitian involved them in decision making. The results of the following dietetic interventions are only where applicable to patients: 100% of patients rated nutrition support care (including exclusive enteral nutrition for Crohn’s disease) as excellent or good. 100% of patients rated specific IBD dietary advice as excellent or good. 100% of patients rated functional symptoms or irritable bowel syndrome advice as excellent or good. 100% of patients rated artificial nutrition advice as good. 81% of patients felt advice improved symptoms and nutritional state with 13% being unsure. 81% of patients felt advice improved quality of life with 13% being unsure. 81% of patients felt cultural, lifestyle and language needs were considered with 13% being unsure. 100% of patients felt having access to a dietitian was helpful.

Conclusion
All patients felt that the specific types of dietary care provided were excellent or good, with the majority of patients responding that advice improved symptoms, improved quality of life and that cultural and lifestyle needs were taken into account. All patients found it supportive to have a dietitian as part of the IBD multidisciplinary team. It would be useful in the future to further assess these types of dietetic care, such as exclusive enteral nutrition for Crohn’s disease. These findings support the best practice guidelines for having a dietetic post as part of the IBD team.
P031 CKD-506, a new histone deacetylase 6 inhibitor, suppresses immune cells and restores intestinal epithelial function
Authors: Lee J Y , Ma H W , Kim J H , Park I S , Son M , Ryu K H , Shin J , Kim W H , Kim S W , Cheon J H 
Published: January 2023

Abstract

Background
Inflammatory bowel disease (IBD) represents a group of chronic immune-mediated diseases of the gastrointestinal tract, characterized by recurrent inflammation and consequential damage of the gastrointestinal tract. Histone deacetylases (HDACs) are a family of mostly ubiquitous enzymes that remove acetyl groups from lysines on histone proteins to regulate gene transcription. HDAC6, which is localized to the cytoplasm, appears to be a promising candidate in IBD treatment. The purpose of the current study was to examine the anti-inflammatory effects of CKD-506, a novel histone deacetylase 6 (HDAC6) inhibitor, on human peripheral blood mononuclear cells (PBMCs) and CD4+ T cells and to explore the relationship between CKD-506 and gut epithelial barrier function.

Methods
Lipopolysaccharide (LPS)-stimulated human PBMCs from inflammatory bowel disease (IBD) patients were treated with CKD-506, and tumor necrosis factor-alpha (TNF-α) expression was measured using enzyme-linked immunosorbent assay. The proliferation of CD4+ T cells from IBD patients was evaluated using flow cytometric analysis. The effects of CKD-506 on gut barrier function in a cell line and colon organoids, with examinations of mRNA production, goblet cell differentiation, and E-cadherin recovery, were investigated using quantitative reverse transcription PCR, immunofluorescence, and FITC-dextran permeability assay.

Results
TNF-α secretion, a pivotal pro-inflammatory mediator in IBD, of LPS-triggered PBMCs was markedly decreased by CKD-506 treatment in a dose-dependent manner and to a greater extent than by tofacitinib or tubastatin A treatment. E-cadherin mRNA expression and goblet cell differentiation increased significantly and dose-dependently in HT-29 cells in response to CKD-506, and inhibition of E-cadherin loss after TNF-α stimulation was significantly reduced both in HT-29 cells and gut organoids. Caco-2 cells treated with CKD-506 showed a significant reduction of barrier permeability in a dose-dependent manner.

Conclusion
The present study demonstrated that CKD-506 has anti-inflammatory effects on PBMCs and CD4+ T cells and improved gut barrier function, indicating its potential as a promising and competent candidate for small-molecule medicine for IBD treatment.
P032 Distinct immune cell trigger responses in Ulcerative Colitis – Results from an in vivo human intestinal injury model
Authors: Bronze M , Vilstrup Johansen J , Attauabi M , Tveiten Bjerrum J , Ramírez Galera M , Woetmann A , Benedict Seidelin J 
Published: January 2023

Abstract

Background
Ulcerative colitis (UC) is characterized by alternated periods of active inflammation and quiescent disease. The mechanisms behind flare-up reactions are elusive, but it is hypothesized that normally unharmful factors can initiate flares in genetically susceptible individuals with a dysfunctional mucosal barrier and hyper-responsive immune system, leading to sustained inflammation. We aimed to describe the early cellular responses to injury in the normal intestine and in UC patients in remission.

Methods
Experimental injuries were performed in six UC patients in remission (endoscopic Mayo sub-score 0 and total Mayo score below 3) and in six control subjects1. During the initial sigmoidoscopy, six experimental wounds were made. After 24 and 48 hours, the subjects were re-endoscoped and new biopsies were taken across the experimental injury by angling the biopsy forceps 90° (Figure 1), thus including the mucosa of the injury edge and the wound bed. Biopsies from each time point were sequenced (bulk RNA-sequencing) and the frequencies of different cell types were inferred using deconvolution (Cellanneal)2

Results
Type 1-conventional dendritic cells (cDC) and macrophages decreased in both UC and controls after injury (p&lt;0.05). Inflammatory monocytes increased in controls only at 48h post-injury, while in UC, these cells increased at 24h and decreased at 48h post-injury. There were no significant changes in natural killer cells or T and B cells frequencies between UC and controls both pre- and post-injury. The frequency of ILCs, mast cells, and type 2-cDC continuously increased in UC patients from pre-injury to 48h post-injury, in contrast to controls, where they decreased (Figure 2). ILC marker CD117 (expressed by ILC3 and ILC2) was overexpressed in UC pre-injury, however both CRTH2 (expressed only by ILC2) and CD127 were similar pre- and post-injury. Finally, the cytokines required for ILC3 stimulation (interleukin (IL)-1β, IL-1α and IL-23) and IL-17A, produced by ILC3 during inflammation, were increased.

Conclusion
UC patients in complete remission show an increased innate inflammatory response to mucosal injuries compared to healthy individuals, highlighted by the early engagement of inflammatory monocytes, mast cells, and ILCs, particularly ILC3s. Our data show a UC-specific innate cellular hyper-response that may explain the initial mechanisms of flares and could be targeted in future anti-flare therapies.
References
1. Seidelin JB et al. Acute Experimental Barrier Injury Triggers Ulcerative Colitis-Specific Innate Hyperresponsiveness and Ulcerative Colitis-Type Microbiome Changes in Humans. Cell Mol Gastroenterol Hepatol 2021;12:1281-1296.
2. Buchauer L, Itzkovitz S. cellanneal: A User-Friendly Deconvolution Software for Omics Data, 2021.