bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOP19 High dimensional profiling of IL-23-responsive cells revealed molecular signatures that predict response to anti-IL-23 therapy in patients with Crohn’s Disease
Authors: Cao S , Colonna M , Deepak P 
Published: January 2024

Abstract

Background
The interleukin (IL)-23 signaling plays a crucial role in the pathogenesis of Crohn’s disease (CD). IL-23 activates T-helper (Th) 17 cells, IL-17-secreting CD8 T (Tc)17 cells, gd T cells, nature killer (NK) T cells, and group 3 innate lymphoid cells (ILC3) to secrete proinflammatory cytokines including IL-17, IFN-g, and TNF-a. Risankizumab is the first selective IL-23 antagonist approved for moderate-severe CD. However, there is currently no biomarker to predict response to anti-IL-23 antibodies in IBD. Here, we characterized the cell type- and cytokine-specific pathways in IL-23-responsive cells that predict response to risankizumab in CD patients.

Methods
Adult patients with a history of ileal, colonic, or ileocolonic CD were included. Active CD in terminal ileum and/or colon were confirmed by colonoscopy and/or MRI. Blood samples were collected within 3 months before and 4, 8, 12, and 52 weeks after the initiation of risankizumab. Peripheral blood mononuclear cells (PBMC) were isolated and cryopreserved for batch analysis using mass cytometry (CyTOF). Pre-treatment PBMCs were stimulated ex vivo with IL-23, and stained for lineage markers to identify Th17, Tc17, gd T, NKT cells, and ILC3, as well as intracellular cytokines including IL-17, IFN-g, TNF-a, IL-22, IL-6, and GM-CSF, using a pre-optimized and validated antibody panel. The CyTOF data were analyzed using the viSNE tool in Cytobank and FlowJo. Patients’ responses were evaluated 12-40 weeks after the initiation of risankizumab based on clinical symptoms and endoscopic/radiographic assessment.

Results
Among IL-23-responsive cells, increased frequency of NKT cells was identified in the peripheral blood of non-responders before initiation of risankizumab (Figure 1A). In non-responders, Tc17 cells, gd T cells, and ILC3 demonstrated significant elevations in TNF-a, a key pathogenic mediator in CD. gd T cells from non-responders also showed increased IL-17F before treatment. In contrast, NKT cells from non-responders expressed significantly lower GM-CSF, which was previously shown to alleviate intestinal inflammation in patients and mouse models (Figure 1B). Ongoing study is investigating the cytokine production in IL-23-responsive cells after the initiation of risankizumab, as well as before and after starting ustekinumab, an anti-IL-12/IL-23 antibody.

Conclusion
High dimensional profiling of pre-treatment PBMCs revealed molecular signatures, e.g., elevated TNF-a in multiple IL-23-responsive cells, which are associated with resistance to risankizumab in CD patients. Those findings may help identify response biomarkers for IL-23 antagonists and provide a rationale for using anti-IL-23/anti-TNF combination therapy in some patients with refractory CD.
DOP28 Yield of surveillance colonoscopy in patients with Primary Sclerosing Cholangitis
Authors: Van De Pol N , Mol B , de Jong M J , Weersma R K , Inderson A , Slooter F C , Gibbes L A , van der Meer A J , Derikx L A A P , Ponsioen C Y , de Vries A C 
Published: January 2024

Abstract

Background
Patients with primary sclerosing cholangitis (PSC) have a higher risk of developing colorectal cancer (CRC), in particular in patients with concurrent diagnosis of inflammatory bowel disease (IBD). Therefore, strict surveillance colonoscopy in patients with PSC and PSC-IBD is recommended with consideration of random biopsies. The aim of this study was to assess the method and yield of surveillance colonoscopy in patients with PSC and PSC-IBD in routine practice in the Netherlands.

Methods
An observational cohort study was performed within the EpiPSC2 cohort in The Netherlands. Patients with a confirmed PSC diagnosis were included from January 2008 onwards. Data were collected retrospectively from the date of diagnosis until inclusion, and prospectively from that date forward. Patient demographics, PSC and IBD disease characteristics were collected at study inclusion and during annual follow-up. For this study, data collection was expanded retrospectively with colonoscopy and pathology reports. Outcomes were endoscopic surveillance technique, whether random or targeted biopsies were taken, if polypectomy was performed, dysplasia detection rate and type of dysplasia.

Results
The study population included 1,203 PSC patients, of whom 82.1% had large duct PSC, and 70.6% concomitant IBD (table 1). A total of 4,099 colonoscopies were performed in 759 individual patients, with a median of 4 colonoscopies per patient (IQR 2 – 8). The median follow-up duration was 11 years (IQR 12 – 17). In total, 11.5% (n=473) of colonoscopies were performed with chromo-endoscopy. Among the conducted colonoscopies, 2,543 included biopsies, 355 involved polypectomies, and 86 comprised both biopsies and polypectomies. Dysplasia was identified in 11.4% (341 out of 2,984) of the colonoscopies, including 14.1% indefinite for dysplasia (n=48), 75.1% low grade dysplasia (n=256), 7.6% high grade dysplasia (n=26), and 5.9% adenocarcinoma (n=20). The detection of dysplasia occurred through random biopsies in 89 colonoscopies (26.1%), targeted biopsies in 114 colonoscopies (33.4%) and polypectomy in 153 colonoscopies (44.9%) (figure 1). Dysplasia was observed in 195 (26%) individual patients, of whom 80.5% had PSC-IBD.

Conclusion
Our data highlights the importance of colonoscopic surveillance in PSC and PSC-IBD patients. Dysplasia was detected in over a quarter of patients undergoing surveillance colonoscopy. Notably, 26.1% of dysplasia cases were identified through random biopsies, emphasizing the importance of incorporating random biopsies into surveillance protocols for this specific patient population.
DOP34 Deciphering immune-epithelial interactions in health and in Inflammatory Bowel Disease
Authors: Jowett G M , Read E , Pena-Cearra A , Coman D , Coales I , Kromann E , Ilangovan J , Roberts L , Gentleman E , Lord G M , Neves J F 
Published: January 2024

Abstract

Background
Intestinal homeostasis is dependent on appropriate interactions between various compartments including immune, mesenchymal, neural, epithelial and bacteria cells. Disrupt of these interactions has been associated with the development of Inflammatory Bowel Disease (IBD).
Using intestinal organoids as a starting point, we built complexity into this model by adding other cellular components to be able to study these interactions in health and disease.
One of the key immune players in the intestine is Innate Lymphoid Cells (ILC). ILC precursors (ILCP) migrate to mucosa where they mature, promote homeostasis, and provide a potent, antigen-non-specific sources of cytokines. Deciphering what local stimuli drive the final stages of ILCP maturation in these tissues remains a pressing question, as ILC frequencies can become dysregulated in IBD.

Methods
Here, we develop and use co-cultures gut organoids with Innate Lymphoid Cells precursors (ILCP) and with mature intestinal Innate Lymphoid Cells (ILC).

Results
Harnessing these versatile models, we demonstrate that epithelial cells provide a complex niche capable of supporting the final maturation of all subsets including ILC1, ILC2, ILC3 and Natural Killer (NK) cells, Notably, organoid identity was sufficient to robustly recapitulate tissue-specific ILC imprints and frequencies, even in the absence of microbial stimuli, other cell types, or cytokine supplementation.
In addition, we show that human gut ILC1 drive intestinal and extracellular matrix remodelling through production of TGFβ. This indicates the potential impact of ILC1 accumulation in IBD patients in driving intestinal cancer and fibrosis, two sequelae of IBD.
Finally, we identify a new module of interaction between ILCs and the intestinal epithelium: goblet cells provide Notch ligands that are essential for maintenance of NC3R+ ILC3 and for their production of IL-22. In turn, ILC3 drive intestinal epithelial cells towards a secretory phenotype.

Conclusion
Taken together, our work provides unprecedented insight into in situ ILC maturation, which we show to be driven by epithelial signals, and into ILC function through deciphering new modules of ILC-epithelial interaction in health and IBD.
DOP35 Spatial transcriptomics reveals cellular niches associated with histological inflammation in postoperative Crohn’s Disease
Authors: Battat R , Sangiorgi B , Linggi B , Gui S , Torti D , Smith M I , Mehandru S , Longman R , Lukin D J , Scherl E J , Qin L , Ma C , Teft W , Vande Casteele N 
Published: January 2024

Abstract

Background
Postoperative Crohn’s disease (CD) recurs in ~70% of patients ≤1 year following ileocolonic resection (ICR), as observed endoscopically. Current understanding of molecular determinants underlying histological intestinal inflammation in patients with postoperative CD recurrence is minimal. To address this issue, we used advanced spatial transcriptomic analyses on intestinal biopsy samples with matched histological and endoscopic assessments from neoterminal ileum, anastomosis, and colon of patients with CD who had undergone colonoscopy following ICR.

Methods
Formalin-fixed paraffin-embedded (FFPE) tissue biopsies from neoterminal ileum, anastomosis, and colon were prospectively collected from a 15-patient cross-sectional cohort with CD who underwent routine endoscopic assessment following ICR. Spatial transcriptomics was performed on samples using 10X Genomics Visium CytAssist Spatial Gene Expression for FFPE V2.0. Annotation of tissue regions of histologically active inflammation and classification of histologically inactive (Robarts Histopathology Index ≤3 with subscores of 0 for neutrophils in the lamina propria and epithelium) or active disease were performed by an expert gastrointestinal pathologist. R programming language was used for data analysis (Figure).

Results
Fourteen of the 43 (32.6%) FFPE biopsies had histological evidence of inflammation. Spatial transcriptomics clustering revealed a distinct transcriptional signature by the segregation of 4 clusters ("inflamed clusters") composed mostly (≥69%) of cells from samples defined by histologically active disease. Tissue regions identified as inflamed by expert pathologist annotation contributed to &gt;46% of inflamed clusters’ composition and &lt;15% of remaining clusters. Cell type decomposition and cellular niche analysis revealed immune (e.g., myeloid, T cells, and B cells) and epithelial cells in close proximity sharing a similar microenvironment in 3 inflamed clusters while the 4th cluster was composed of &gt;90% epithelial cells. Differentially expressed genes from the inflamed clusters were similarly expressed across intestinal segments including inflamed anastomotic biopsies and were enriched for signalling pathways involving immune cells recruitment/activation, inflammatory signalling, extracellular matrix organisation, and oxidative stress response.

Conclusion
This is the first study to explore spatial transcriptomic signatures associated with histological inflammation in patients with postoperative CD recurrence. Our analysis revealed a spatial signature of cellular niches and signalling pathways arising upon histological inflammation, providing insight into therapeutic targets and biomarkers across anatomic locations and the anastomosis.
DOP37 Noninvasive assessment of gut function using transcriptional recording sentinel cells
Authors: Zimmermann J , Macpherson A 
Published: January 2024

Abstract

Background
Bacteria within the human gut continuously adapt their gene expression to environmental conditions that are associated with diet, health, and disease. Noninvasive measurements of bacterial gene expression patterns throughout the intestine are important to understand in vivo microbiota physiology and pathophysiology. Current methods do not offer sufficient information about transient or proximal events within the intestine without using indirect or invasive approaches that disturb normal physiology and are inapplicable to clinical practice.

Methods
Here we used transcriptional recording sentinel cells that through a reverse transcriptase-Cas1–Cas2 complex record their own short-lived mRNA expression into long-lived DNA-based CRISPR arrays to report on gut function. We colonized gnotobiotic mice with E. coli sentinel cells and performed Record-seq on fecal samples to reconstruct their cellular histories as they passed along the gastrointestinal tract.

Results
Upon colonization of the mouse intestine, sentinel cells reported on diet, inflammation, and microbial interactions. Through transcriptome-scale information, Record-seq elucidated E. coli’s adaptations to intraluminal conditions including pH, oxygen levels, and ion availability. Unlike RNA-seq, Record-seq performed on stool samples retained information from proximal gut sections to noninvasively report on the luminal conditions in vivo. In a mouse model of inflammatory bowel disease, Record-seq not only diagnosed the inflammation in a severity-dependent manner but also revealed pathological gut conditions such as mucus depletion and hyperoxygenation.

Conclusion
Transcriptional recording sentinel cells noninvasively report on gut function and reveal environmental cues such as diet, inflammation, and microbial interactions, even in proximal gut sections that are otherwise unamenable to unbiased diagnostic interrogation.
DOP58 Human Leukocyte Antigen drives methylation signatures in primary sclerosing cholangitis but not in IgG4-related sclerosing cholangitis
Authors: Cabras S , Adams A , Noble A , Motta R , Moron Flores B , Glapa-Nowak A , Nowak J , Geremia A , Culver E , Satsangi J 
Published: January 2024

Abstract

Background
Primary sclerosing cholangitis (PSC) and IgG4-related sclerosing cholangitis (IgG4-SC) are fibro-inflammatory hepatobiliary conditions, with genetic, environmental, and immunologic risk factors, in which epigenetic alterations may provide insights into pathophysiology and novel biomarkers.

Methods
Whole blood DNA methylation profiling and genotyping was performed in 70 PSC (57 with PSC and ulcerative colitis (PSC-UC)), 56 IgG4-SC, 66 UC, and 88 healthy controls (HC), with MethylationEPIC and Global Screening arrays (Illumina). UC patients were selected to match the clinical characteristics of UC in the PSC-UC cohort. Methylation data was processed with Minfi and limma, genotyping analysed with Plink, and meQTLs with linear models.

Results
There were 31, 13 and 8 Holm-significant methylation differences between PSC and controls, IgG4-SC and controls, and UC and controls respectively (8 probes shared). Inflammatory genes (including CEP97, IFNAR1, TXK, and SMAD2) and methylation loci associated with mitochondrial DNA copy number (C5orf36, PYY, and MTRNR2L1) were predominant. Sub-analyses of PSC-UC and PSC without IBD detected 25 and 4 differences with HC respectively (p&lt;0.05). DNA methylation age acceleration was observed in IgG4-SC, but not on PSC, PSC-IBD or UC. MeQTL analyses to identify genetic determinants of methylation revealed a strong HLA signal in PSC but not IgG4-SC, with 19/40 significant findings in 5 clusters (HLA-DRB1, HLA-DPB1, BTNL2, CSNK2B, and SFTA2). There was no overlap with the 36 meQTLs found in IgG4-SC. Using multivariate adaptive shrinkage for meQTLs in PSC, IgG4-SC, and UC yielded 5505 meQTLs with local false discovery rate &lt;0.05 in at least one condition, with 1230 unique to PSC, and 1043 to IgG4-SC.

Conclusion
We identify characteristic epigenetic alterations in PSC and IgG4-related disease, providing insights into disease pathogenesis; and highlight the potential interaction with germ-line variation.
DOP67 MB310: From Clinical FMT to a Phase 1 Study with a Defined, Orally Administered Live Bacterial Therapeutic for Mild Moderate Ulcerative Colitis
Authors: Villemin C , Schreiber F , Bakdash G , Rimington O , McCluskey S , Neville A , Robinson M , Birrell C , Wilkinson A , Carter R , Lawley T 
Published: January 2024

Abstract

Background
The composition of the gut microbiome is a key determinant in inflammatory bowel disease. Consequently, modifying the composition of the gut microbiota has the potential to transform the treatment of ulcerative colitis (UC). The clinical use of faecal microbiota transplantation (FMT) has become widespread, especially for the treatment of C. difficile associated diseases, as a method of changing the composition of the gut microbiome from a diseased to a healthy state. FMT is, by its nature, an undefined and variable therapy due to differences between donors. Microbiotica has taken a "patient-first" discovery approach to identify a defined consortium, which is being developed as a live bacterial therapeutic for treatment of mild-to-moderate UC patients in a Phase 1b clinical trial, the COMPOSER-1 study, in 2024.

Methods
A clinical trial in UC patients (Costello et al., 2019), in which patients were treated with FMT from healthy donors, showed a 32% clinical remission rate in the active treatment group, as compared to 9% in the placebo arm. Donor, pre-treatment recipient, and post-FMT recipient samples were analysed using shotgun metagenomic sequencing. All samples were analysed using Microbiotica’s precision microbiome analysis platform to identify bacteria associated with patient response. These bacteria were assessed in cellular assays using relevant human cell/cell lines including: Caco2, dendritic cells, M1 macrophages, and CD4+ T-cells.

Results
We defined a signature of therapeutic response based on bacteria that engrafted from the donor into UC patients and were associated with clinical benefit. A sub-species level analysis identified 8 bacteria, which have been developed into a defined live bacterial therapeutic, MB310. The consortium bacteria enhanced the barrier integrity of an epithelial cell monolayer, and protected the barrier from inflammatory challenge by LPS. In vitro, the bacteria also have an anti-inflammatory effect when incubated with different primary innate immune cells, dendritic cells and M1 macrophages. Specific MB310 bacteria, either directly or via metabolites, are able to regulate T-cell responses.

Conclusion
In summary, we have identified a consortium of bacteria using patient-first discovery in a successful FMT study that is being developed as a treatment for UC. The consortium of 8 bacteria is able to impact multiple disease-relevant mechanisms including epithelial barrier integrity and immunomodulation. MB310 is being advanced to a first-in-human study in 2024 to explore safety and initial signs of efficacy.
Costello, et al. (2019) Jama 321.2: 156-164.
DOP69 Longitudinal gut microbiome dynamics in relation to disease flares in Inflammatory Bowel Disease, pilot data from the IBD-Tracker study
Authors: Gacesa R , Klaassen M A Y , Collij V , Björk J R , Blankenstein A D , Jansen B H , Dijkstra G , Visschedijk M , Festen E A M , Ananthakrishnan A , Alm E , Weersma R K 
Published: January 2024

Abstract

Background
The pathogenetic mechanisms that lead to IBD flares are unknown and the absence of reliable predictive biomarkers results in a therapeutic approach focused on treating active flares rather than prevention. While IBD is known to be associated to changes in gut microbiota, the longitudinal dynamics of the microbiome in relation to disease flares and its biomarker potential remain poorly understood. We initiated the IBD -racker study which aims to include 100 patients with weekly fecal sampling along other biomaterials and clinical data. The aim is to elucidate patient-specific dynamics of the gut microbiome, including changes during IBD flares, strain replacements, and the potential for personalized prediction of flares based on microbiome. Here we present pilot microbiome data from the first 5 patients that completed the collection.

Methods
A comprehensive analysis of microbiome dynamics was conducted by collecting 52 weekly fecal samples, calprotectin measurements and clinical disease scores from five IBD patients. Metagenomic sequencing was employed on 248 samples, followed by biobakery4 tools for profiling of microbiome composition and function. Stability and dynamics of gut microbiota were evaluated through analysis of autocorrelation and stable states, while bacterial strains were profiled using markers and metagenomic assembly and binning based approaches. Finally, microbiome signatures associated with IBD flares were identified using multivariate generalized regression models correcting for patient-driven heterogeneity.

Results
The core gut microbiome of IBD patients (43 to 82 patient-specific highly prevalent species) is highly personalized and largely stable over time, regardless of flares (patient ID R2 &gt; 0.4 in ADONIS of microbiome composition and function). The bacterial strains of these core species cluster by patients, indicating flares do not perturb them. Despite this stability of the core microbome, ~60% of identified bacterial taxa were present in &lt;70% of weekly samples, indicating that a large part of the microbiome is dynamic. Differential abundance analysis revealed 32 bacterial species genomic bins (e.g. Clostridia pathobionts) and one pathway significantly associated with IBD flares (FDR &lt; 0.1). Intriguingly, several species (e.g. Faecalibacterium sp. SGB15346, Clostridium inoocum) showed switches between high and low abundance stable states correlated with flares, and certain bacteria (e.g., Blautia wexlerae) underwent strain replacement during flares, which was not reversed post flare.

Conclusion
Our results indicate that IBD flares perturb a large part of the non-core gut microbiome, implying that personalized longitudinal monitoring of microbiota has potential for prediction and monitoring of IBD flares.