scholarly journals OP33 Multi-omics analysis reveals specific bio-geographical and functional characteristics in inflammatory bowel disease intestinal mucosa

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S031-S034
Author(s):  
N Maimon ◽  
S Gerassy-Vainberg ◽  
H Bar-Yosef ◽  
A Alpert ◽  
E Starosvetsky ◽  
...  
Keyword(s):  
Gene Expression ◽  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Immune Cell ◽  
Response To Therapy ◽  
Anatomical Location ◽  
Specific Cell ◽  
Cell Composition ◽  
Dominant Feature ◽  
Inflammatory Bowel

Abstract Background Anatomical location and extent of disease are main factors that affect inflammatory bowel disease (IBD) course and prognosis. No explanation is available for segmental intestinal involvement in either Crohn’s disease (CD) or ulcerative colitis (UC), or for selective segmental response to therapy or disease complications. Therefore, studying the cellular composition of different intestinal segments may provide pathophysiological insights into these phenomena. Methods We compared location-specific cell composition and function by Cytometry Time-of-Flight (CyTOF), gene expression and single-cell (sc) RNAseq data obtained from 3 independent cohorts of healthy donors and IBD patients during remission and flare-ups. Using CyTOF data (n = 38 biopsies), we built a high-resolution screening of immune cell behaviour along the intestine. We validated the findings with gene expression data of 370 samples, and expanded screening resolution by computational methodologies. We then tested a specific pathway in scRNAseq data (n = 10 paired biopsies from 5 patients) and validated its significance by cell-specific Significance Analysis of Microarrays (csSAM). Results We found a location along the intestine to be a dominant feature determining immune and non-immune cell composition. We observed that inflammation reduced anatomic segregation beyond cell infiltration, and decreased the ability to cope with oxidative stress. An upregulated IL-6 pathway in T regulatory cells in UC patients was recognised as sigmoid-specific compared with known inflammatory IL-6 roles in macrophages, as seen in the right colon. This observation may be linked to colonic perforations associated with anti-IL-6R treatment. Suppressor of cytokine signalling 3 (SOCS3) may control IL-6 location-specific action. Conclusion Our study displays a unique and comprehensive cell map of IBD in a location-specific context, providing potential explanations to unexplained clinical phenomena. These observations may allow to tailor therapies to affected areas with improved therapeutic index and efficacy.

scholarly journals Inflammation status modulates the effect of host genetic variation on intestinal gene expression in inflammatory bowel disease

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Shixian Hu ◽  
Werna T. Uniken Venema ◽  
Harm-Jan Westra ◽  
Arnau Vich Vila ◽  
Ruggero Barbieri ◽  
...  
Keyword(s):  
Gene Expression ◽  
Inflammatory Bowel Disease ◽  
Genetic Variation ◽  
Bowel Disease ◽  
Immune Cell ◽  
Interaction Analysis ◽  
Cell Types ◽  
Inflammatory Conditions ◽  
Host Genetic ◽  
Inflammatory Bowel

AbstractMore than 240 genetic risk loci have been associated with inflammatory bowel disease (IBD), but little is known about how they contribute to disease development in involved tissue. Here, we hypothesized that host genetic variation affects gene expression in an inflammation-dependent way, and investigated 299 snap-frozen intestinal biopsies from inflamed and non-inflamed mucosa from 171 IBD patients. RNA-sequencing was performed, and genotypes were determined using whole exome sequencing and genome wide genotyping. In total, 28,746 genes and 6,894,979 SNPs were included. Linear mixed models identified 8,881 independent intestinal cis-expression quantitative trait loci (cis-eQTLs) (FDR < 0.05) and interaction analysis revealed 190 inflammation-dependent intestinal cis-eQTLs (FDR < 0.05), including known IBD-risk genes and genes encoding immune-cell receptors and antibodies. The inflammation-dependent cis-eQTL SNPs (eSNPs) mainly interact with prevalence of immune cell types. Inflammation-dependent intestinal cis-eQTLs reveal genetic susceptibility under inflammatory conditions that can help identify the cell types involved in and the pathways underlying inflammation, knowledge that may guide future drug development and profile patients for precision medicine in IBD.

37 Monitoring the evolution of inflammatory bowel disease (IBD) in pediatric and adult cohorts of patients to identify biomarkers to predict cancer risk

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A38-A38
Author(s):  
Shilpa Ravindran ◽  
Heba Sidahmed ◽  
Harshitha Manjunath ◽  
Rebecca Mathew ◽  
Tanwir Habib ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Colorectal Cancer ◽  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Mesenchymal Transition ◽  
Increased Risk ◽  
Hamad Medical Corporation ◽  
Inflammatory Bowel ◽  
Left And Right

BackgroundPatients with inflammatory bowel disease (IBD) have increased risk of developing colorectal cancer (CRC), depending on the duration and severity of the disease. The evolutionary process in IBD is driven by chronic inflammation leading to epithelial-to-mesenchymal transition (EMT) events in colonic fibrotic areas. EMT plays a determinant role in tumor formation and progression, through the acquisition of ‘stemness’ properties and the generation of neoplastic cells. The aim of this study is to monitor EMT/cancer initiating tracts in IBD in association with the deep characterization of inflammation in order to assess the mechanisms of IBD severity and progression towards malignancy.Methods10 pediatric and 20 adult IBD patients, admitted at Sidra Medicine (SM) and Hamad Medical Corporation (HMC) respectively, have been enrolled in this study, from whom gut tissue biopsies (from both left and right side) were collected. Retrospectively collected tissues (N=10) from patients with malignancy and history of IBD were included in the study. DNA and RNA were extracted from fresh small size (2–4 mm in diameter) gut tissues using the BioMasher II (Kimble) and All Prep DNA/RNA kits (Qiagen). MicroRNA (miRNA; N=700) and gene expression (N=800) profiling have been performed (cCounter platform; Nanostring) as well as the methylation profiling microarray (Infinium Methylation Epic Bead Chip kit, Illumina) to interrogate up to 850,000 methylation sites across the genome.ResultsDifferential miRNA profile (N=27 miRNA; p<0.05) was found by the comparison of tissues from pediatric and adult patients. These miRNAs regulate: i. oxidative stress damage (e.g., miR 99b), ii. hypoxia induced autophagy; iii. genes associated with the susceptibility to IBD (ATG16L1, NOD2, IRGM), iv. immune responses, such as TH17 T cell subset (miR 29). N=6 miRNAs (miR135b, 10a196b, 125b, let7c, 375) linked with the regulation of Wnt/b-catenin, EM-transaction, autophagy, oxidative stress and play role also in cell proliferation and mobilization and colorectal cancer development were differentially expressed (p<0.05) in tissues from left and right sides of gut. Gene expression signature, including genes associated with inflammation, stemness and fibrosis, has also been performed for the IBD tissues mentioned above. Methylation sites at single nucleotide resolution have been analyzed.ConclusionsAlthough the results warrant further investigation, differential genomic profiling suggestive of altered pathways involved in oxidative stress, EMT, and of the possible stemness signature was found. The integration of data from multiple platforms will provide insights of the overall molecular determinants in IBD patients along with the evolution of the disease.Ethics ApprovalThis study was approved by Sidra Medicine and Hamad Medical Corporation Ethics Boards; approval number 180402817 and MRC-02-18-096, respectively.

Regulation of Gene Expression in Inflammatory Bowel Disease and Correlation with IBD Drugs

2004 ◽  
Vol 10 (1) ◽  
pp. 1-14 ◽  
Author(s):  
Thomas P. Dooley ◽  
Ernest V. Curto ◽  
Shanker P. Reddy ◽  
Richard L. Davis ◽  
Glenna W. Lambert ◽  
...  
Keyword(s):  
Gene Expression ◽  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Regulation Of Gene Expression ◽  
Inflammatory Bowel

scholarly journals Hyperactive chemotaxis contributes to anti-TNFα treatment resistance in inflammatory bowel disease

2021 ◽  
Author(s):  
Tung On Yau ◽  
Jayakumar Vadakekolathu ◽  
Gemma Ann Foulds ◽  
Guodong Du ◽  
Christos Polytarchou ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Immune Cell ◽  
Treatment Resistance ◽  
Enrichment Analysis ◽  
Cell Populations ◽  
Treated Animal ◽  
Necrosis Factor Alpha ◽  
Potential Biomarker ◽  
Inflammatory Bowel

Background & Aims Anti-tumour necrosis factor-alpha (anti-TNFα) agents have been used for inflammatory bowel disease (IBD), however, it has up to 30% non-response rate. Identifying molecular pathways and finding reliable diagnostic biomarkers for patient response to anti-TNFα treatment are clearly needed. Methods Publicly available transcriptomic data from IBD patients receiving anti-TNFα therapy was systemically collected and integrated. In silico flow cytometry approaches and MetaScape were applied to evaluate immune cell populations and to perform gene enrichment analysis, respectively. Genes identified within enrichment pathways validated in neutrophils were tracked in an anti TNFα-treated animal model (with lipopolysaccharide (LPS)-induced inflammation). The receiver operating characteristic (ROC) curve was applied to all genes to identify the best prediction biomarkers. Results A total of 449 samples were retrieved from control, baseline and after primary anti-TNFα therapy or placebo. No statistically significant differences were observed between anti-TNFα treatment responders and non-responders at baseline in immune microenvironment scores. Neutrophils, endothelial and B cell populations were higher in baseline non-responders and chemotaxis pathways may contribute to the treatment resistance. Genes related to chemotaxis pathways were significantly up-regulated in LPS-induced neutrophils but no statistically significant changes were observed in neutrophils treated with anti-TNFα. Interleukin 13 receptor subunit alpha 2 (IL13RA2) is the best predictor (ROC: 80.7%, 95% CI: 73.8% - 87.5%) with a sensitivity of 68.13% and specificity of 84.93%, and significantly higher in non-responders compared to responders (p < 0.0001). Conclusions Hyperactive chemotaxis influences responses to anti TNFα treatment and IL13RA2 is a potential biomarker to predict anti-TNFα treatment response.

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