A BASELINE GENE EXPRESSION-BASED PROGNOSTIC FOR ANTI-TNFα THERAPY RESPONSE IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE

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.

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

Inflammatory Bowel Diseases ◽

10.1097/00054725-200401000-00001 ◽

2004 ◽

Vol 10 (1) ◽

pp. 1-14 ◽

Cited By ~ 49

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

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Characterization of mucosal gene expression in inflammatory bowel disease by direct hybridization to massively parallel oligonucleotide arrays

Gastroenterology ◽

10.1016/s0016-5085(98)83928-0 ◽

1998 ◽

Vol 114 ◽

pp. A964-A965 ◽

Cited By ~ 1

Author(s):

B. Dieckgraefe ◽

W. Stenson ◽

P. Swanson ◽

C. Harrington ◽

M. Mamadeu

Keyword(s):

Gene Expression ◽

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Massively Parallel ◽

Oligonucleotide Arrays ◽

Inflammatory Bowel ◽

Direct Hybridization

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HEALING THROUGH CYTOKINE REGULATION IN DNBS INDUCED INFLAMMATORY BOWEL DISEASE IN RATS BY HOLARRHENA ANTIDYSENTERICA

INDIAN DRUGS ◽

10.53879/id.53.08.10577 ◽

2016 ◽

Vol 53 (08) ◽

pp. 57-64

Author(s):

S. Johari ◽

◽

C. Joshi ◽

T. Gandhi

Keyword(s):

Gene Expression ◽

Inflammatory Bowel Disease ◽

Body Weight ◽

Bowel Disease ◽

Stool Consistency ◽

Cytokine Gene ◽

Group Iii ◽

Group I ◽

Holarrhena Antidysenterica ◽

Inflammatory Bowel

The objective of the study was to ascertain antioxidant, anti-inflammatory and cytokine gene regulation activity of Holarrhena antidysenterica (HA) in dinitrobenzene sulfonic acid (DNBS) induced inflammatory bowel disease (IBD) in rats. Sprague Dawley rats were divided into 6 groups, Group I (normal), Group II (50% ethanol intracolonically on 11th day), Group III (Model). Group IV to VI were given standard drug 5-amino salicylic acid (5-ASA) (100mg/kg) and hydromethanolic extract of Holarrhena antidysenterica (MEHA) 450 mg/kg and MEHA 600 mg/kg respectively for 18 days once p.o. Colitis was induced with DNBS (180mg/kg in 50% ethanol) intracolonically in animals of Group III-VI on 11th day. Body weight, food & water intake and stool consistency of each group was noted. On 18th day, blood was collected for cortisol estimation. Colon length and weight was measured. Cytokine gene expression studies of colon in group I, II, III, IV and VI was done using Real Time RT-PCR. Colon histopathology, Disease Activity Index (DAI) and Colon Mucosal Disease index (CMDI) parameters were studied. Nitric oxide (NO), malondialdehyde (MDA), myeloperoxidase (MPO) and superoxide dismutase (SOD) were estimated in colon homogenate. DNBS model control showed significant reduction in body weight, water and food intake, SOD, colon length and significant increase in stool consistency, colon weight, MDA, MPO, NO, CMDI, DAI, cortisol, IL-4, IL-6, IL-12 and IFN-gamma cytokines gene expression. Pretreatment with 5-ASA (100mg/kg) and MEHA (450 and 600 mg/kg) significantly reversed the above. MEHA reduced severity of IBD induced by DNBS through its anti-inflammatory, antioxidant and gene modulatory activity.

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

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.032 ◽

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.

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Multiple outcome meta-analysis of gene-expression data in inflammatory bowel disease

Genomics ◽

10.1016/j.ygeno.2019.09.019 ◽

2020 ◽

Vol 112 (2) ◽

pp. 1761-1767 ◽

Cited By ~ 1

Author(s):

Konstantina E. Vennou ◽

Daniele Piovani ◽

Panagiota I. Kontou ◽

Stefanos Bonovas ◽

Pantelis G. Bagos

Keyword(s):

Gene Expression ◽

Inflammatory Bowel Disease ◽

Gene Expression Data ◽

Bowel Disease ◽

Meta Analysis ◽

Expression Data ◽

Multiple Outcome ◽

Inflammatory Bowel

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A Pilot Integrative Analysis of Colonic Gene Expression, Gut Microbiota, and Immune Infiltration in Primary Sclerosing Cholangitis-Inflammatory Bowel Disease: Association of Disease With Bile Acid Pathways

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjaa021 ◽

2020 ◽

Vol 14 (7) ◽

pp. 935-947 ◽

Cited By ~ 7

Author(s):

Mohammed Nabil Quraishi ◽

Animesh Acharjee ◽

Andrew D Beggs ◽

Richard Horniblow ◽

Chris Tselepis ◽

...

Keyword(s):

Gene Expression ◽

Inflammatory Bowel Disease ◽

Bile Acid ◽

Gut Microbiota ◽

Primary Sclerosing Cholangitis ◽

Bowel Disease ◽

Sclerosing Cholangitis ◽

16S Rrna Analysis ◽

Immune Infiltration ◽

Inflammatory Bowel

Abstract Background Although a majority of patients with PSC have colitis [PSC-IBD; primary sclerosing cholangitis-inflammatory bowel disease], this is phenotypically different from ulcerative colitis [UC]. We sought to define further the pathophysiological differences between PSC-IBD and UC, by applying a comparative and integrative approach to colonic gene expression, gut microbiota and immune infiltration data. Methods Colonic biopsies were collected from patients with PSC-IBD [n = 10], UC [n = 10], and healthy controls [HC; n = 10]. Shotgun RNA-sequencing for differentially expressed colonic mucosal genes [DEGs], 16S rRNA analysis for microbial profiling, and immunophenotyping were performed followed by multi-omic integration. Results The colonic transcriptome differed significantly between groups [p = 0.01]. Colonic transcriptomes from HC were different from both UC [1343 DEGs] and PSC-IBD [4312 DEGs]. Of these genes, only 939 had shared differential gene expression in both UC and PSC-IBD compared with HC. Imputed pathways were predominantly associated with upregulation of immune response and microbial defense in both disease cohorts compared with HC. There were 1692 DEGs between PSC-IBD and UC. Bile acid signalling pathways were upregulated in PSC-IBD compared with UC [p = 0.02]. Microbiota profiles were different between the three groups [p = 0.01]; with inferred function in PSC-IBD also being consistent with dysregulation of bile acid metabolism. Th17 cells and IL17-producing CD4 cells were increased in both PSC-IBD and UC when compared with HC [p < 0.05]. Multi-omic integration revealed networks involved in bile acid homeostasis and cancer regulation in PSC-IBD. Conclusions Colonic transcriptomic and microbiota analysis in PSC-IBD point toward dysregulation of colonic bile acid homeostasis compared with UC. This highlights important mechanisms and suggests the possibility of novel approaches in treating PSC-IBD.

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V617F‐independent upregulation of JAK2 gene expression in patients with inflammatory bowel disease

Journal of Cellular Biochemistry ◽

10.1002/jcb.28844 ◽

2019 ◽

Vol 120 (9) ◽

pp. 15746-15755 ◽

Cited By ~ 3

Author(s):

Hamid Asadzadeh‐Aghdaei ◽

Kazem Mashayekhi ◽

Khadijeh Koushki ◽

Pedram Azimzadeh ◽

Mohammad Rostami‐Nejad ◽

...

Keyword(s):

Gene Expression ◽

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Inflammatory Bowel

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Characterizing Clinical Features and Creating a Gene Expression Profile Associated With Pain Burden in Children With Inflammatory Bowel Disease

Inflammatory Bowel Diseases ◽

10.1093/ibd/izz240 ◽

2019 ◽

Vol 26 (8) ◽

pp. 1283-1290 ◽

Cited By ~ 2

Author(s):

Victoria Grossi ◽

Jeffrey S Hyams ◽

Nicole C Glidden ◽

Brittany E Knight ◽

Erin E Young

Keyword(s):

Gene Expression ◽

Inflammatory Bowel Disease ◽

Abdominal Pain ◽

Bowel Disease ◽

Newly Diagnosed ◽

Pain Experience ◽

Factors Affecting ◽

Cq Method ◽

Inflammatory Bowel ◽

Rectal Biopsies

Abstract Background There is often dissociation between inflammatory activity and abdominal pain in children with inflammatory bowel disease (IBD), suggesting other factors may play a role in the pain experience. Methods Patients (8 to 17 years) newly diagnosed with IBD were enrolled in the ALLAY Study: Assessing Risk Factors for Abdominal Pain in Children with Inflammatory Bowel Disease (NCT02984059). At diagnostic colonoscopy, 3 rectal biopsies were collected, and gene expression analysis was performed using Qiagen RT2 Profiler Neuropathic and Inflammatory Pain PCR Array. Relative fold difference in gene expression for 84 pain-associated genes was calculated using the 2-ΔΔ Cq method compared with pain-free controls. Factors affecting pain burden (Pain Burden Interview; PBI) were analyzed, including age, sex, rectal inflammation, and gene expression. Data were analyzed using multiple stepwise linear regression and 2-tailed t tests (P ≤ 0.05). Results Thirty-nine newly diagnosed IBD patients were included (65% male, mean age 12.75 years [SD 2.63], 23 Crohn’s disease, 16 ulcerative colitis), along with 3 controls. Mean PBI score was 7.73 (SD 6.4, range 0 to 23) for all patients. Age and sex were not predictive of pain burden, but disease activity score was (P = 0.03). Expression of TRPV3, OPRM1, P2X3, SCN9A, PTGS2, and MAPK14 were associated with PBI score. Subsequent 2-tailed t tests comparing patients with no pain (PBI score ≦ 2, N = 11) to those with pain (PBI > 2, N = 28) confirmed differential expression of TRPV3, PTGS2, and MAPK14 was in patients with pain (all P < 0.05). Conclusion Pain burden in newly diagnosed IBD patients may be linked to TRPV3, PTGS2, and MAPK14 expression, suggesting potential therapeutic targets for managing pain in IBD.

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