bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOP34 Human MD2 deficiency - an inborn error of immunity predisposing to early onset Inflammatory Bowel Disease
Authors: Li Y , Yu Z , Schenk M , Lagovsky I , Illig D , Walz C , Rohlfs M , Conca R , Muise A , Snapper S , Uhlig H , Garty B , Klein C , Kotlarz D 
Published: January 2023

Abstract

Background
Pattern recognition receptors (PRRs) serve as a hub of immune responses to microbes in the gut and play a critical role in maintaining intestinal homeostasis. Toll-like receptor 4 (TLR4) represents an important PRR that can recognize the gram-negative bacterial cell wall component lipopolysaccharide (LPS). Upon binding to LPS, TLR4 forms a multimeric complex with the indispensable co-receptor myeloid differentiation protein 2 (MD2) facilitating selection of TLR4 as cargo for endocytosis and TLR4-mediated activation of downstream signalling. Despite the critical role of TLR4 in innate immunity, no patients with TLR4 or MD2 deficiency have yet been reported.

Methods
To investigate potential genetic causes for two related patients presenting with very early onset Inflammatory Bowel Disease (VEO-IBD) and/or pneumonia, we have performed whole exome sequencing (WES). To assess the functional consequences of the identified LY96 (encoding for MD2) variant, we generated a CRISPR/Cas9-mediated knockout (KO) of MD2 or knockin (KI) of the patient mutation in induced pluripotent stem cells (iPSCs) and studied TLR4-mediated signalling, cytokine responses, and bacterial handling in iPSC-derived macrophages.

Results
Genetic analysis identified a 3 bp homozygous in-frame deletion in the LY96 gene (NM_015364.5, c.347_349delCAA; p.Thr116del) in our index patients following an autosomal recessive inheritance pattern. Immunoblotting revealed an altered protein expression of overexpressed Flag-tagged mutant MD2 protein due to impaired N-linked glycosylation. Correspondingly, iPSC-derived MD2-deficient macrophages showed an impaired LPS-induced TLR4 endocytosis. As a functional consequence, we could detect reduced NF-κB and MAPK signalling (phosphorylation of NF-κB p65 subunit, ERK1/2, and p38 MAPK) and dysregulated inflammasome activation (IL-1b production and secretion) upon challenge with LPS. Gentamycin protection assays and live cell imaging suggested that MD2-deficient macrophages exhibit an impaired phagocytosis of microbial pathogens. In addition, macrophages with mutant MD2 showed decreased cytokine expression (e.g., IFNB, IL6, IL10, and TNF) in response to LPS or gram-negative bacteria (E. coli and Salmonella typhimurium) but not gram-positive bacteria (Listeria monocytogenes).

Conclusion
Human MD2 deficiency is an inborn error of immunity that may predispose to VEO-IBD associated with altered TLR4-mediated signalling, cytokine responses, and bacterial handling. The first description of patients with MD2 deficiency provides critical insights on human TLR4/MD2 biology and warrants caution on therapeutics strategies targeting TLR4 signalling.
DOP42 Efficacy of etrasimod on symptomatic relief in patients with ulcerative colitis: an analysis of the phase 3 ELEVATE UC 52 and ELEVATE UC 12 trials
Authors: Chaparro M , Armuzzi A , Irving P M , Allez M , Dubinsky M C , Sands B E , Goetsch M , Wang W , Shan K , Woolcott J , Bartolome L , Wosik K , Panaccione R 
Published: January 2023

Abstract

Background
Patient-reported outcomes such as stool frequency (SF) and rectal bleeding (RB) are important measures of ulcerative colitis (UC) activity and treatment effect. Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 (S1P1,4,5) modulator in development for the treatment of moderately to severely active UC. We evaluated RB and SF subscores to assess symptomatic relief in the ELEVATE UC phase 3 programme.

Methods
In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), patients (16-80 years) with moderately to severely active UC were randomised 2:1 to once-daily etrasimod 2 mg or placebo (PBO). ELEVATE UC 52 utilized a treat-through design comprising a 12-week induction period followed by a 40-week maintenance period. ELEVATE UC 12 comprised a 12-week induction period. A key secondary endpoint was the proportion of patients with symptomatic remission (SF =0 [or =1 with a ≥1-point decrease from baseline] and RB =0) at week 12 and at week 52. RB and SF subscores, achievement of symptomatic remission, complete symptomatic remission (SF =0 and RB =0), and symptomatic response (≥30% decrease from baseline in composite RB/SF subscores) were assessed at each visit. Achievement of symptomatic remission was also summarized by subgroups in patients with prior biologic/Janus kinase inhibitor (bio/JAKi) use (yes [1, &gt;1], no) and baseline corticosteroid use (yes, no).

Results
More etrasimod- vs PBO-treated patients achieved symptomatic remission by week 2 in ELEVATE UC 52 (15.3% vs 8.9%; P=0.049) and week 4 in ELEVATE UC 12 (27.5% vs 16.1%; P=0.007). Symptomatic remission increased in etrasimod- vs PBO-treated patients at each time point through week 12 in both ELEVATE UC 52 (46.0% vs 21.5%; P&lt;0.001) and ELEVATE UC 12 (46.8% vs 29.5%; P=0.001) and was maintained through week 52 in ELEVATE UC 52 (43.4% vs 18.5%; P&lt;0.001) (Figure 1A). Achievement of symptomatic response (Figure 1B), and significant improvements in RB and SF subscores, began as early as week 2 or week 4 for etrasimod vs PBO in ELEVATE UC 12 and ELEVATE UC 52, respectively. A significant difference in complete symptomatic remission was achieved at week 4 in both studies (Figure 1C). Subgroup analyses of symptomatic remission suggested a trend towards greater benefit in patients who were bio/JAKi naïve and patients with 1 prior bio/JAKi (vs &gt;1) (Figures 2A-C).

Conclusion
In this analysis, symptomatic relief was achieved by a greater proportion of patients treated with etrasimod vs PBO as early as week 2 and was sustained through week 52. At week 2, symptomatic response and improvements in RB and SF subscores were observed. The greatest benefits were seen in patients who had no prior exposure to bio/JAKi or 1 prior bio/JAKi therapy.
DOP47 Gut microbiome contributes to the development of immune checkpoint inhibitor-related colitis
Authors: Liu X , Tang H , Zhou Q , Zeng Y , Lu B , Chen M , Xu Y , Wang M , Li Y , Tan B , Qian J 
Published: January 2023

Abstract

Background
The gut microbiota is implicated in shaping immune checkpoint inhibitors (ICIs) efficacy, but relatively little is known about how the microbiota influences immune-related adverse events (irAEs). Our study aimed to explore the association and causal relationship between gut microbiome and immune checkpoint inhibitor-related colitis.

Methods
We collected faecal samples from 32 patients with advanced malignant tumor patients developing irAE after anti-PD-1 therapy from May 2020 to Aug 2021. Faecal samples were analyzed by 16s rDNA amplicon sequencing method on Illumina MiSeq (PE300) sequencing platform. We also performed faecal microbiota transplantation (FMT) for antibiotic-treated mice with samples from patients with colitic irAE and without irAE.

Results
We compared the microbiota between 8 colitic irAE and 24 non-colitic irAE patients. Principal coordinates analysis (PCoA) plot showed significant difference of microbiota composition by Adonis analysis (P=0.003) (Fig. 1A). LEfSe analysis detected a lower abundance of Bacteroidota and a higher abundance of Proteobacteria at the phylum level and a lower abundance of Bacteroides and Bifidobacterium and higher abundance of Enterococcus at the genus level in colitic irAE (Fig. 1B). The total abundance of major butyrate-producing bacteria was lower in colitic irAE compared with non-colitic irAE patients (P=0.018) (Fig. 1C). Functional prediction analyses revealed different abundances of environmental information processing, genetic information processing, and metabolic pathways between colitic and non-colitic irAE patients (Fig. 1D). By FMT experiments in mice, we sought to explore the causal relationship between microbiota immune-related colitis. After injection of anti-PD-1 and anti-CTLA-4, three of nine colitic-irAE-FMT mice developed fatal severe colitis, while all nine non-irAE-FMT mice survived without colitis (P=0.052). The three colitic mice showed more rapid weight loss and higher disease activity index (DAI) scores compared with other mice (Fig. 2A and B). The histological colitis score in the irAE-FMT-Sac. mouse (14 points) was higher than those in the non-irAE-FMT mice (3.89 ± 1.17 points) and colitic-irAE-FMT-survival mice (3.67 ± 1.03 points) (Fig. 2C). The mean IHC scores of irAE-FMT-Sac. mouse from high to low were CD8 3.8 ± 1.3 points, CD4 2.0 ± 1.9 points, and CD20 1.1 ± 1.3 points (Fig. 2D), which also supported the occurrence of immune-related colitis.

Figure 1. The gut microbiotas of patients with colitic and non-colitic type irAEs.

Figure 2. Comparison of colitis in colitic-irAE-FMT and non-irAE-FMT mice.

Conclusion
Gut microbiota might play important role in the development of immune-related colitis, possibly by modulating metabolic pathways.
DOP51 Mucosa-associated microbial signatures associate with objective response prior to the start of anti-TNFα but not vedolizumab or ustekinumab in Crohn’s disease patients
Authors: Hageman I , Joustra V , Zafeiropoulou K , Davids M , Hakvoort T , Probert F , Satsangi J , D’Haens G , De Jonge W 
Published: January 2023

Abstract

Background
Crohn’s disease (CD) is a complex immune-mediated disease of the gastrointestinal tract where the gut microbiome plays an important role. Current biological treatment options in CD include the anti-TNFα agents adalimumab (ADA) and infliximab (IFX), vedolizumab (VDZ), and ustekinumab (USTE). Finding biomarkers to predict therapy response is still a clinical unmet need, as the majority of CD patients fail to reach endoscopic remission within 1 year of treatment. While the majority of studies focus on fecal samples, mucosa-adherent bacterial signature could bring forth stable biomarkers. In this study, we sought to identify signatures of the adherent microbiome in intestinal biopsies aimed at differentiating responders (R) from non-responders (NR), prior to the start of biological treatment.

Methods
We prospectively collected paired ileal and colonic biopsies (stored snapfrozen in -80 ºC) from adult CD patients scheduled to start anti-TNFα (IFX and ADA), VDZ and USTE treatment during baseline endoscopies. After 6-12 months of follow-up, patients were classified as either R or NR based on endoscopic response (≥50% reduction in SES-CD score) in combination with steroid-free clinical response (≥3 point drop in HBI or HBI ≤4) and/or biochemical response (≥50% reduction in C-reactive protein (CRP) and fecal calprotectin or a basal CRP ≤5 g/mL and fecal calprotectin ≤250 µg/g). Microbiome composition of the biopsies was determined using 16S RNA gene V3V4 amplicon sequencing.

Results
For the anti-TNFα cohort, we included in total 36 CD patients (21R and 18 NR), for VDZ cohort a total of 44 patients (28 R and 16 NR) and for USTE cohort a total of 40 patients (20R and 20 NR).When comparing α-diversity and β-diversity between R and NR, we did not find significant differences in ileal and colonic samples at baseline for the VDZ and USTE cohorts. Notable, for the anti-TNFα cohort (table 1), we obtained significant differences when comparing α-diversity (p=0.028) and β-diversity between R and NR. We demonstrated differences between colonic R and NR in taxa abundance for ASVs associated with the phyla Bacteroidetes, Firmicutes, Fusobacteria, Proteobacteria (figure 1). Furthermore, ASVs associated with Firmicutes, Bacteroidetes, Actinobacteria are different in abundance between ileal R and NR (figure 2).

Figure 1: Differential taxa abundance colonic R vs NR anti-TNFα

Figure 2: Differential taxa abundance ileal R vs NR anti-TNFα

Figure 3: graphical summary

Conclusion
Here, we investigated the microbial signature of R and NR before the start of treatment of three separate cohorts and we demonstrated that the mucosa-associated microbiome differentiates R and NR to anti-TNFα therapy. Further analyses as part of the EPIC Pioneer study, are ongoing.
DOP52 The faecal bacterial and fungal microbiome of newly-diagnosed, treatment naïve children with Crohn’s disease and the modifying effects of exclusive enteral nutrition and re-introduction of habitual diet
Authors: Gerasimidis K , Nichols B , Papadopoulou R , Ijaz U , Rajendran R , Quince C , Russell R K , Hansen R , Ramage G 
Published: January 2023

Abstract

Background
The fungal community (mycobiome) and immunological responses to specific fungi have been implicated in Crohn’s disease (CD) pathogenesis and its phenotype. There is limited data on profiling the mycobiome in paediatric CD and how it changes during treatment

Methods
Fungal (ITS2) and bacterial (16S rRNA) microbiome analysis in faecal samples (n=124) from n=34 CD children before, during (30 and 60 days) and after exclusive enteral nutrition (EEN) at food reintroduction (within 60 days of EEN completion), and from 31 healthy controls were profiled. IgA and IgG anti-Saccharomyces cerevisiae antibodies (ASCA) analysis by enzyme-linked immunosorbent assay, in blood, was also carried out for CD patients prior to EEN initiation.

Results
The global mycobiome composition (β diversity) was different between CD and healthy children (R2=0.050; p=0.007) and presented lower Chao1 richness (mean 24.3 vs 33.0; p=0.005) for the CD cases; 13 fungal operational taxonomic units (OTUs) differed between the two groups. Similar signals were observed for the bacterial microbiome but the difference in global community structure (β diversity) was more profound than the fungal community (R2=0.094; p&lt;0.001). Treatment with EEN induced drastic changes in mycobiome composition (β diversity), which were more profound and more variable than the effects observed for the bacterial community. Of the OTUs with abundance significantly lower in CD than healthy controls prior to EEN, one, belonging to S. cerevisiae, significantly decreased during EEN (compared with baseline; p&lt;0.001 and p=0.086 at 30 and 60 days on EEN). Patients whose faecal calprotectin was low (&lt;250 mg/kg) during food reintroduction had a lower mycobiome richness than those whose FC was raised (&gt;250 mg/kg). 29 fungal OTUs were significantly different between these two groups in samples taken during food reintroduction, following EEN. Patients who were ASCA positive had a higher abundance of three OTUs of S. cerevisiae. In co-occurrence network analysis, Simplicillium chinense, presented significant more interactions with members of the bacterial community, particularly OTUs which changed during EEN. After participants had returned to their regular diets these microbial effects reversed and community structure moved towards that observed prior to EEN.

Conclusion
The mycobiome of children with CD present features of dysbiosis similar to the bacterial microbiome and improvement in disease condition during EEN is strongly associated with changes in its composition.
DOP59 What is the relationship between fatigue, pain and urgency in people with inflammatory bowel disease? Results of the IBD-BOOST survey in 8486 participants
Authors: Hart A , Miller L , Hamborg T , Stagg I , McGuinness S , Wileman V , Tzorovili E , Mihaylova B , Roukas C , Aziz Q , Czuber-Dochan W , Dibley L , Moss-Morris R , Pollok R , Saxena S , Winsor G , Norton C 
Published: January 2023

Abstract

Background
Fatigue, pain and faecal incontinence are common in people with IBD. However, little is known about co-existence of these multiple symptoms, how they inter-relate and whether people want help for these symptoms. In qualitative interviews, patients have reported that these symptoms are often ignored in clinical consultations, where the focus is on inflammation, but that they are very bothered by these symptoms, even when disease is apparently in remission. The aim of this study was to determine the presence and relationship between fatigue, pain and incontinence in people with inflammatory bowel disease, and desire for intervention for these symptoms.

Methods
A purpose-designed survey (online or postal), incorporating validated tools and demographic details, was sent to unselected UK clinic and UK IBD-BioResource adult patients. When the covid-19 pandemic halted clinic recruitment, additional self-selected UK recruits were solicited via social media. Using the validated PROMIS tools, the following definitions were used for presence of symptoms: fatigue: PROMIS fatigue T-score of 60 or more; pain: PROMIS pain intensity T-score of 60 or more; PROMIS bowel incontinence: raw score of 50 or more. Participants also reported disease activity using the relevant PRO-2 score, IBD-Control, anxiety (GAD-7), depression (PHQ-9) and quality of life (EQ-5D-5L) which will all be reported elsewhere.

Results
A total of 8486 useable responses were received (7716 online, 770 postal). 4176 reported Crohn’s disease, 4255 had ulcerative colitis or other form of IBD. There were 3281 men and 4883 women. Median age was 51 years (range 18 - 92). 2550 (30%) reported fatigue, 1766 (21%) pain and 4565 (54%) faecal incontinence according to the above definitions; 925 (10.9%) reported having all three symptoms. Demographics by symptom are shown in Table 1. Table 2 reports those participants indicating the presence of each symptom and each combination of symptoms. Table 3 shows a summary of self-defined severity and impact of symptoms (scoring scale 0-10 for both severity and impact of each symptom). Participants scored severity and impact a mean between 3.3 and 4.8, with a wide variation. 56% of all respondents (not just those with symptoms) “definitely” wanted help for fatigue; 42% wanted help for pain; 53% wanted help for incontinence. 29% reported “definitely” wanting help for all three symptoms (Table 4).

Conclusion
This study confirms that fatigue, pain and urgency are common in IBD and for the first time reports the co-existence and unmet need for help with these symptoms.
DOP61 Ethnic disparities in the management of Inflammatory Bowel Disease in Israel and impact on outcomes
Authors: Boaz E , Ledder O , Dagan A , Lujan R , Koslowsky B , Friss C , Greenfeld S , Kariv R , Loewenberg Weisband Y , Lederman N , Matz E , Dotan I , Yellinek S , Turner D 
Published: January 2023

Abstract

Background
In this nationwide study, we aimed to explore health services utilization, medical management, and disease outcomes of inflammatory bowel diseases (IBD) between Jews and Arabs, the two major ethnic groups in Israel.

Methods
We utilized a cohort including all patients diagnosed with IBD in Israel since 2005. The primary outcome was steroid-dependency, with secondary outcomes including use of biologics, time to surgery, and IBD-related admissions. Outcomes were controlled for possible inherent differences in disease course and phenotype.

Results
Of the 32,491 included patients, 18,252 (56%) had Crohn’s disease (CD) and 14,239 (44%) had ulcerative colitis (UC); 10% were Arabs and 90% were Jews. Jewish ethnicity was associated with lower rates of steroid-dependency compared to Arab ethnicity in both CD )HR=0.7 [95%CI 0.6-0.8]) and UC (HR=0.7 [95%CI 0.6-0.8]). In addition, Jewish ethnicity was associated with increased use of biologics during the first year from diagnosis in patients with CD (HR=1.3 [95%CI 1.1-1.6]) but not with UC. The risk of IBD-related surgery in CD at 3 and 5 years was higher in the Arab group at all time points (13% vs 10%, 16% vs 14%, respectively, p=0.005). Arabs had higher number of IBD-related hospitalizations than Jews (19% vs. 28% with two or more IBD-related hospitalizations at 5 years, p&lt;0.001).

Conclusion
Arab ethnicity is associated with higher rate of hospitalizations, steroid-dependency and surgeries on one hand, and lower utilization of biologics on the other. The results should be considered by policy makers to improve access to medical care across all populations.
DOP63 Time Trends of Environmental and Socio-economical Factors in Patients with Inflammatory Bowel Disease over 40-year of Different Therapeutic Eras; results from a Population-based Cohort from Western Hungarian between 1977-2020, The Hygiene hypothesis revisited.
Authors: Wetwittayakhlang P , Gonczi L , Lakatos L , Golovics P , Pandur T , David G , Erdelyi Z , Szita I , Lakatos P L 
Published: January 2023

Abstract

Background
Data from population-based studies investigating the time trends in environmental and socio-economical factors associated with IBD is lacking. We aimed to assess time trends in environmental and socio-economical factors over 40 years of different therapeutic eras in patients with IBD from a prospective population-based inception cohort from Veszprem County, Western Hungary.

Methods
Patients from the incident IBD cohort were included between January 1,1977 and December 31,2020. Environmental and socio-economical factors, including an area of living, educational and type of employment, smoking status, appendectomy, and contraceptive drug use, were evaluated in three eras based on the different therapeutic strategies in IBD:cohort-A, 1977-1995 (pre-biologic/pre-immunomodulators era); cohort-B,1996-2008 (immunomodulator era); and cohort-C,2009-2020 (biological era).

Results
A total of 2,240 incident patients diagnosed with IBD were included [UC 61.2%, male 51.2%, the median age at diagnosis: 35 years (IQR 29-49)]. There was a significant increase in IBD incidence over time in both CD and UC1-2. A higher proportion of patients with active smoking in CD compared to UC, and the rates of smoking significantly decreased over time in CD; 60.2%, 49.9%, and 38.6% in cohorts A, B and C (p&lt;0.001). In UC patients, the rates were lower and stable; 15.4%, 15.4%, and 14.5% in cohort A,B and C, respectively (p=0.981). The use of the contraceptive drug was more common in CD than UC, and the rates were stable; 23.7%,26.6%, and 23.7% in cohorts A, B and C (p=0.950). In UC patients, the appendectomy rates before diagnosis decreased over time; 6.4%, 5.5%, and 2.3% in cohorts A, B and C (p=0.013). No significant changes in the distribution of IBD population between geographic areas [municipal area: UC; 59.8%/64.8%/62.5% (p=0.309) vs. CD; 62.5%/62.0%/59.0% (p=0.636), in cohort A/B/C]. However, fewer percentages of IBD patients who achieved primary school as maximal education level (32.2%,21.9% and 11.7% in cohorts A,B, and C, p &lt;0.001) as well as less physical work employment (53.4%,51.3%, and 42.3% in cohorts A,B and C, p=0.001) were observed in both UC and CD. (Reference 1.Gonczi L et al. Colitis. 2022 Sep 10:jjac132 Ref 2. Kurti Z et al. Crohns Colitis. 2022 Sep 19:jjac142)

Conclusion
This is one of the first long-term, prospective population-based cohorts investigating the time trends of socio-economical and environmental factors associated with IBD over 4 decades, including less primary school as maximal education level and less physical work employment. Results from this study highlight that the association between time trends of known environmental/socio-economic factors and IBD incidence is complex.