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Kayali S, Fantasia S, Gaiani F, Cavallaro LG, de’Angelis GL, Laghi L. NOD2 and Crohn's Disease Clinical Practice: From Epidemiology to Diagnosis and Therapy, Rewired. Inflamm Bowel Dis 2025; 31:552-562. [PMID: 38582044 PMCID: PMC11808579 DOI: 10.1093/ibd/izae075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Indexed: 04/08/2024]
Abstract
Crohn's disease (CD) is a chronic inflammatory bowel disease with a multifactorial pathogenesis involving environmental and genetic factors. Since the late 20th century, the discovery of the first susceptibility gene (NOD2, previously referred to as CARD15) for CD has paved the way for further investigations into the correlations between clinical features and genetics, and its potential impact on clinical practice has fueled the research in the last 2 decades. Recent therapeutic advancements involving novel biologic drugs and small molecules have shifted inflammatory bowel disease management from a disease-centered to a patient-centric approach. To date, the role of NOD2 has not been fully understood yet. Recent data suggest that its clinical impact may be greater than currently recognized. This review overviews the most common NOD2 variants' role in real-life clinical practice. These genetic variants increase the risk of developing the disease and can aid in tailoring diagnosis and treatment. They are associated with the stricturing phenotype and ileal involvement and increase the risk of steroid refractoriness. In the meantime, limited and inconclusive evidence exists regarding their predictive role in response to azathioprine, biologic drugs, and small molecules. Eventually, their role in increasing the risk for surgery is evident, especially in those with the L1007fs variant. If further trials will support the initial evidence reported so far, NOD2 genetic variants will emerge as possible candidates for developing precision medicine in CD.
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Affiliation(s)
- Stefano Kayali
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Stefano Fantasia
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Federica Gaiani
- Department of Medicine and Surgery, University of Parma, Parma, Italy
- Gastroenterology and Endoscopy Unit, University Hospital of Parma, Parma, Italy
| | | | | | - Luigi Laghi
- Department of Medicine and Surgery, University of Parma, Parma, Italy
- Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research Centre, Rozzano, Italy
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2
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Venkateswaran N, Sultan K. Racial and ethnic disparities in clinical presentation, management, and outcomes of patients with inflammatory bowel disease: a narrative review. Transl Gastroenterol Hepatol 2024; 9:28. [PMID: 38716206 PMCID: PMC11074478 DOI: 10.21037/tgh-23-43] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 03/11/2024] [Indexed: 02/05/2025] Open
Abstract
BACKGROUND AND OBJECTIVE Inflammatory bowel disease (IBD) is a chronic condition that has been increasing in prevalence and incidence worldwide. Although, most cases are described in Caucasian populations, there has been a rise in IBD diagnosis among other populations. In this article, we will discuss the disparities in the presentation, management, medical and surgical outcomes of IBD patients among different racial and ethnic groups. METHODS A literature search was conducted in PubMed, Medline, and Google Scholar. The search strategy included targeted keywords to identify specific studies that provided the current literature on disparities in IBD presentation and management. Articles for presentation were selected by the authors, in accordance with a narrative review format, favoring population-based studies, systematic reviews and meta-analysis over single or multicenter reports. KEY CONTENT AND FINDINGS Epidemiological data has shown that there is an increasing incidence in IBD diagnosis among Black, Asian, and Hispanic populations over the past decade. Differences in genetic predispositions have been observed, however it is difficult to ascertain if the minor differences in presentation and medical/surgical management reported are due to innate differences or due to confounding factors such as access to health care. CONCLUSIONS Differences in genetic predisposition, and clinical presentation have been observed to exist among IBD non-Caucasian populations. There were also differences observed in both surgical and medical management, but it is difficult to ascertain if these were innate differences or due to societal factors.
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Affiliation(s)
- Niranjani Venkateswaran
- Inflammatory Bowel Disease Center, Department of Gastroenterology, Northshore/Hofstra Zucker School of Medicine, Manhasset, NY, USA
| | - Keith Sultan
- Inflammatory Bowel Disease Center, Department of Gastroenterology, Northshore/Hofstra Zucker School of Medicine, Manhasset, NY, USA
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Salvador-Martín S, Rubbini G, Vellosillo P, Zapata-Cobo P, Velasco M, Palomino LM, Clemente S, Segarra O, Moreno-Álvarez A, Fernández-Lorenzo A, Pérez-Moneo B, Montraveta M, Sánchez C, Tolín M, Loverdos I, Fobelo MJ, Navas-López VM, Magallares L, García-Romero R, Torres-Peral R, Rodríguez A, Bossacoma F, Merino-Bohórquez V, Salcedo E, Álvarez R, Dopazo A, Sanjurjo-Sáez M, López-Fernández LA. Blood gene expression biomarkers of response to anti-TNF drugs in pediatric inflammatory bowel diseases before initiation of treatment. Biomed Pharmacother 2024; 173:116299. [PMID: 38401525 DOI: 10.1016/j.biopha.2024.116299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 02/06/2024] [Accepted: 02/17/2024] [Indexed: 02/26/2024] Open
Abstract
BACKGROUND/AIMS Changes in gene expression profiles among individuals with inflammatory bowel diseases (IBDs) could potentially influence the responsiveness to anti-TNF treatment. The aim of this study was to identify genes that could serve as predictors of early response to anti-TNF therapies in pediatric IBD patients prior to the initiation of treatment. METHODS We conducted a prospective, longitudinal, and multicenter study, enrolling 24 pediatric IBD patients aged less than 18 years who were initiating treatment with either infliximab or adalimumab. RNA-seq from blood samples was analyzed using the DESeq2 library by comparing responders and non-responders to anti-TNF drugs. RESULTS Bioinformatic analyses unveiled 102 differentially expressed genes, with 99 genes exhibiting higher expression in responders compared to non-responders prior to the initiation of anti-TNF therapy. Functional enrichment analyses highlighted defense response to Gram-negative bacteria (FDR = 2.3 ×10-7) as the most significant biological processes, and hemoglobin binding (FDR = 0.002), as the most significant molecular function. Gene Set Enrichment Analysis (GSEA) revealed notable enrichment in transcriptional misregulation in cancer (FDR = 0.016). Notably, 13 genes (CEACAM8, CEACAM6, CILP2, COL17A1, OLFM4, INHBA, LCN2, LTF, MMP8, DEFA4, PRTN3, AZU1, and ELANE) were selected for validation, and a consistent trend of increased expression in responders prior to drug administration was observed for most of these genes, with findings for 4 of them being statistically significant (CEACAM8, LCN2, LTF2, and PRTN3). CONCLUSIONS We identified 102 differentially expressed genes involved in the response to anti-TNF drugs in children with IBDs and validated CEACAM8, LCN2, LTF2, and PRTN3. Genes participating in defense response to Gram-negative bacterium, serine-type endopeptidase activity, and transcriptional misregulation in cancer are good candidates for anticipating the response to anti-TNF drugs in children with IBDs.
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Affiliation(s)
- Sara Salvador-Martín
- Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
| | - Gianluca Rubbini
- Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
| | - Perceval Vellosillo
- Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, Madrid, Spain; Unidad de Investigación Materno Infantil Fundación Familia Alonso (UDIMIFFA), Spain.
| | - Paula Zapata-Cobo
- Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
| | - Marta Velasco
- Hospital Universitario Infantil Niño Jesús, Madrid, Spain.
| | | | | | | | | | | | | | | | - Cesar Sánchez
- Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
| | - Mar Tolín
- Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
| | | | - María José Fobelo
- Hospital Universitario Virgen de Valme, Universidad de Sevilla, Sevilla, Spain.
| | | | | | | | | | | | - Ferrán Bossacoma
- Servicio de Gastroenterología, Hepatología y Nutrición Pediátrica, Hospital Sant Joan de Dèu, Barcelona, Spain.
| | | | | | - Rebeca Álvarez
- Genomics Unit, Spanish National Center for Cardiovascular Disease (CNIC), Madrid 28029, Spain.
| | - Ana Dopazo
- Genomics Unit, Spanish National Center for Cardiovascular Disease (CNIC), Madrid 28029, Spain.
| | - María Sanjurjo-Sáez
- Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
| | - Luis A López-Fernández
- Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
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Jiang P, Zhai Z, Zhao L, Zhang K, Duan L. α-Lipoic acid alleviates dextran sulfate sodium salt-induced ulcerative colitis via modulating the Keap1-Nrf2 signaling pathway and inhibiting ferroptosis. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2024; 104:1679-1690. [PMID: 37850313 DOI: 10.1002/jsfa.13053] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 10/08/2023] [Accepted: 10/14/2023] [Indexed: 10/19/2023]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a chronically relapsing inflammatory disease with severe diarrhea, fatigue and weight loss. α-Lipoic acid (LA), a well-known antioxidant, is able to scavenge reactive oxygen species (ROS) and maintain a healthy cellular redox state. However, the role of LA in protecting IBD is still unclear. Hence the aim of this research was to investigate the protective effect of LA on dextran sulfate sodium salt-induced ulcerative colitis (UC) and its underlying mechanism. RESULTS Here, our findings showed that LA significantly alleviated UC symptoms and the overproduction of pro-inflammatory cytokines in UC mice. In addition, LA treatment inhibited intestinal cell apoptosis by regulating the expression levels of p53/caspase-3 pathway-related protein in UC mice. Meanwhile, the inhibitory effects of LA on colonic oxidative stress and ferroptosis were revealed. Our study further demonstrated that LA treatment could regulate the Kelch-like ECH-associating protein 1 (Keap1)-nuclear factor E2-related factor 2 (Nrf2) signaling pathway. Interestingly, we confirmed that LA inhibited ferroptosis by attenuating endoplasmic reticulum stress and suppressing apoptosis in erastin-induced ferroptosis model in vitro. CONCLUSION Taken together, this study's findings suggest that LA could be considered as a therapeutic agent protecting against IBD. © 2023 Society of Chemical Industry.
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Affiliation(s)
- Peng Jiang
- Department of Gastroenterology and Digestive Endoscopy Center, The Second Hospital of Jilin University, Changchun, China
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research of the Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Zongzhen Zhai
- Department of Gastroenterology and Digestive Endoscopy Center, The Second Hospital of Jilin University, Changchun, China
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research of the Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Linxian Zhao
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Kai Zhang
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Liwei Duan
- Department of Gastroenterology and Digestive Endoscopy Center, The Second Hospital of Jilin University, Changchun, China
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research of the Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China
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Wang XY, Zhang D. Identifying Key Genes to the Early Diagnosis of Inflammatory Bowel Disease by Integrating Analysis at the Blood and Tissue Levels. Gastroenterology Res 2023; 16:318-333. [PMID: 38186585 PMCID: PMC10769606 DOI: 10.14740/gr1683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 12/09/2023] [Indexed: 01/09/2024] Open
Abstract
Background Inflammatory bowel disease (IBD) encompasses Crohn's disease (CD) and ulcerative colitis (UC), is challenging to diagnose, and frequently relapses, significantly affecting patients' quality of life. Despite extensive efforts, the pathogenesis of IBD remains unclear. Methods In this study, we integrated bioinformatics analysis and animal disease model to investigate IBD from two dimensions to identify potential diagnostic biomarkers and explore the pathogenesis of distinct conditions at tissue-specific levels. Results Firstly, we identified dysferlin (DYSF) and C-X-C motif chemokine ligand 2 (CXCL2) as crucial biomarkers for IBD, with 11 and 13 putative biomarkers for CD and UC, respectively, identified by peripheral blood testing only. CXCL8 and S100 calcium-binding protein A8 (S100A8) were determined to be critical hub genes and validated by real-time polymerase chain reaction (RT-PCR). Secondly, in CD, the differentially expressed genes (DEGs) were mainly associated with immunity based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, while the metabolism of multiple substances and substance transport activity were dominant in UC. Thirdly, essential genes in the pathological progression of CD and UC were identified through protein-protein interaction networks and molecular complex detection (MCODE) analysis. Finally, pathological examination and quantitative analysis of IBD models confirmed the above results. Conclusions Our findings could contribute to understanding the molecular mechanism of IBD, hold clinical significance for early diagnosis and prevention, and provide effective targets for treating IBD.
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Affiliation(s)
- Xin Yu Wang
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, China
| | - Dan Zhang
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, China
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Janker L, Schuster D, Bortel P, Hagn G, Meier-Menches SM, Mohr T, Mader JC, Slany A, Bileck A, Brunmair J, Madl C, Unger L, Hennlich B, Weitmayr B, Del Favero G, Pils D, Pukrop T, Pfisterer N, Feichtenschlager T, Gerner C. Multiomics-empowered Deep Phenotyping of Ulcerative Colitis Identifies Biomarker Signatures Reporting Functional Remission States. J Crohns Colitis 2023; 17:1514-1527. [PMID: 36961872 PMCID: PMC10588787 DOI: 10.1093/ecco-jcc/jjad052] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Indexed: 03/25/2023]
Abstract
INTRODUCTION Ulcerative colitis [UC] is a chronic disease with rising incidence and unclear aetiology. Deep molecular phenotyping by multiomics analyses may provide novel insights into disease processes and characteristic features of remission states. METHODS UC pathomechanisms were assessed by proteome profiling of human tissue specimens, obtained from five distinct colon locations for each of the 12 patients included in the study. Systemic disease-associated alterations were evaluated thanks to a cross-sectional setting of mass spectrometry-based multiomics analyses comprising proteins, metabolites, and eicosanoids of plasma obtained from UC patients during acute episodes and upon remission, in comparison with healthy controls. RESULTS Tissue proteome profiling indicated colitis-associated activation of neutrophils, macrophages, B and T cells, fibroblasts, endothelial cells and platelets, and hypoxic stress, and suggested a general downregulation of mitochondrial proteins accompanying the establishment of apparent wound healing-promoting activities including scar formation. Whereas pro-inflammatory proteins were apparently upregulated by immune cells, the colitis-associated epithelial cells, fibroblasts, endothelial cells, and platelets seemed to predominantly contribute anti-inflammatory and wound healing-promoting proteins. Blood plasma proteomics indicated chronic inflammation and platelet activation, whereas plasma metabolomics identified disease-associated deregulations of gut and gut microbiome-derived metabolites. Upon remission several, but not all, molecular candidate biomarker levels recovered back to normal. CONCLUSION The findings may indicate that microvascular damage and platelet deregulation hardly resolve upon remission, but apparently persist as disease-associated molecular signatures. This study presents local and systemic molecular alterations integrated in a model for UC pathomechanisms, potentially supporting the assessment of disease and remission states in UC patients.
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Affiliation(s)
- Lukas Janker
- Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria
| | - Dina Schuster
- Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria
| | - Patricia Bortel
- Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria
| | - Gerhard Hagn
- Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria
| | - Samuel M Meier-Menches
- Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria
- Joint Metabolome Facility, University of Vienna, Vienna, Austria
| | - Thomas Mohr
- Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria
- Joint Metabolome Facility, University of Vienna, Vienna, Austria
| | - Johanna C Mader
- Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria
| | - Astrid Slany
- Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria
| | - Andrea Bileck
- Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria
- Joint Metabolome Facility, University of Vienna, Vienna, Austria
| | - Julia Brunmair
- Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria
| | - Christian Madl
- Institute of Pathology and Microbiology, Krankenanstalt Rudolfstiftung, Vienna, Austria
| | - Lukas Unger
- Division of General Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Barbara Hennlich
- Institute of Pathology and Microbiology, Krankenanstalt Rudolfstiftung, Vienna, Austria
| | - Barbara Weitmayr
- Institute of Pathology and Microbiology, Krankenanstalt Rudolfstiftung, Vienna, Austria
| | - Giorgia Del Favero
- Core Facility Multimodal Imaging, Faculty of Chemistry, University of Vienna, Vienna, Austria
| | - Dietmar Pils
- Department of Obstetrics and Gynaecology, Medical University of Vienna, Vienna, Austria
| | - Tobias Pukrop
- Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany
| | - Nikolaus Pfisterer
- Institute of Pathology and Microbiology, Krankenanstalt Rudolfstiftung, Vienna, Austria
| | | | - Christopher Gerner
- Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria
- Joint Metabolome Facility, University of Vienna, Vienna, Austria
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Jang KK, Heaney T, London M, Ding Y, Putzel G, Yeung F, Ercelen D, Chen YH, Axelrad J, Gurunathan S, Zhou C, Podkowik M, Arguelles N, Srivastava A, Shopsin B, Torres VJ, Keestra-Gounder AM, Pironti A, Griffin ME, Hang HC, Cadwell K. Antimicrobial overproduction sustains intestinal inflammation by inhibiting Enterococcus colonization. Cell Host Microbe 2023; 31:1450-1468.e8. [PMID: 37652008 PMCID: PMC10502928 DOI: 10.1016/j.chom.2023.08.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 07/02/2023] [Accepted: 08/07/2023] [Indexed: 09/02/2023]
Abstract
Loss of antimicrobial proteins such as REG3 family members compromises the integrity of the intestinal barrier. Here, we demonstrate that overproduction of REG3 proteins can also be detrimental by reducing a protective species in the microbiota. Patients with inflammatory bowel disease (IBD) experiencing flares displayed heightened levels of secreted REG3 proteins that mediated depletion of Enterococcus faecium (Efm) from the gut microbiota. Efm inoculation of mice ameliorated intestinal inflammation through activation of the innate immune receptor NOD2, which was associated with the bacterial DL-endopeptidase SagA that generates NOD2-stimulating muropeptides. NOD2 activation in myeloid cells induced interleukin-1β (IL-1β) secretion to increase the proportion of IL-22-producing CD4+ T helper cells and innate lymphoid cells that promote tissue repair. Finally, Efm was unable to protect mice carrying a NOD2 gene variant commonly found in IBD patients. Our findings demonstrate that inflammation self-perpetuates by causing aberrant antimicrobial activity that disrupts symbiotic relationships with gut microbes.
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Affiliation(s)
- Kyung Ku Jang
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Thomas Heaney
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Mariya London
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Yi Ding
- Department of Laboratory Medicine, Geisinger Health, Danville, PA 17822, USA
| | - Gregory Putzel
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA; Antimicrobial-Resistant Pathogens Program, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Frank Yeung
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Defne Ercelen
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Ying-Han Chen
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Jordan Axelrad
- Division of Gastroenterology and Hepatology, Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Sakteesh Gurunathan
- Division of Gastroenterology and Hepatology, Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Chaoting Zhou
- Cell and Molecular Biology Graduate Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Magdalena Podkowik
- Antimicrobial-Resistant Pathogens Program, New York University Grossman School of Medicine, New York, NY 10016, USA; Division of Infectious Diseases and Immunology, Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Natalia Arguelles
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA; Antimicrobial-Resistant Pathogens Program, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Anusha Srivastava
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA; Antimicrobial-Resistant Pathogens Program, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Bo Shopsin
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA; Antimicrobial-Resistant Pathogens Program, New York University Grossman School of Medicine, New York, NY 10016, USA; Division of Infectious Diseases and Immunology, Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Victor J Torres
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA; Antimicrobial-Resistant Pathogens Program, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - A Marijke Keestra-Gounder
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Alejandro Pironti
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA; Antimicrobial-Resistant Pathogens Program, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Matthew E Griffin
- Department of Immunology and Microbiology, Scripps Research, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Howard C Hang
- Department of Immunology and Microbiology, Scripps Research, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA; Department of Chemistry, Scripps Research, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Ken Cadwell
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
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Alfonso Perez G, Castillo R. Gene Identification in Inflammatory Bowel Disease via a Machine Learning Approach. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1218. [PMID: 37512030 PMCID: PMC10383667 DOI: 10.3390/medicina59071218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 06/24/2023] [Accepted: 06/26/2023] [Indexed: 07/30/2023]
Abstract
Inflammatory bowel disease (IBD) is an illness with increasing prevalence, particularly in emerging countries, which can have a substantial impact on the quality of life of the patient. The illness is rather heterogeneous with different evolution among patients. A machine learning approach is followed in this paper to identify potential genes that are related to IBD. This is done by following a Monte Carlo simulation approach. In total, 23 different machine learning techniques were tested (in addition to a base level obtained using artificial neural networks). The best model identified 74 genes selected by the algorithm as being potentially involved in IBD. IBD seems to be a polygenic illness, in which environmental factors might play an important role. Following a machine learning approach, it was possible to obtain a classification accuracy of 84.2% differentiating between patients with IBD and control cases in a large cohort of 2490 total cases. The sensitivity and specificity of the model were 82.6% and 84.4%, respectively. It was also possible to distinguish between the two main types of IBD: (1) Crohn's disease and (2) ulcerative colitis.
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Affiliation(s)
- Gerardo Alfonso Perez
- Biocomp Group, Institute of Advanced Materials (INAM), Universitat Jaume I, 12071 Castello, Spain
| | - Raquel Castillo
- Biocomp Group, Institute of Advanced Materials (INAM), Universitat Jaume I, 12071 Castello, Spain
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9
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Livanos AE, Dunn A, Fischer J, Ungaro RC, Turpin W, Lee SH, Rui S, Del Valle DM, Jougon JJ, Martinez-Delgado G, Riddle MS, Murray JA, Laird RM, Torres J, Agrawal M, Magee JS, Dervieux T, Gnjatic S, Sheppard D, Sands BE, Porter CK, Croitoru K, Petralia F, Colombel JF, Mehandru S. Anti-Integrin αvβ6 Autoantibodies Are a Novel Biomarker That Antedate Ulcerative Colitis. Gastroenterology 2023; 164:619-629. [PMID: 36634824 PMCID: PMC10284061 DOI: 10.1053/j.gastro.2022.12.042] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 12/27/2022] [Accepted: 12/28/2022] [Indexed: 01/14/2023]
Abstract
BACKGROUND & AIMS Better biomarkers for prediction of ulcerative colitis (UC) development and prognostication are needed. Anti-integrin αvβ6 (anti-αvβ6) autoantibodies have been described in patients with UC. We tested for the presence of anti-αvβ6 antibodies in the preclinical phase of UC and studied their association with disease-related outcomes after diagnosis. METHODS Anti-αvβ6 autoantibodies were measured in 4 longitudinal serum samples collected from 82 subjects who later developed UC and 82 matched controls from a Department of Defense preclinical cohort (PREDICTS [Proteomic Evaluation and Discovery in an IBD Cohort of Tri-service Subjects]). In a distinct, external validation cohort (Crohn's and Colitis Canada Genetic Environmental Microbial project cohort), we tested 12 pre-UC subjects and 49 matched controls. Furthermore, anti-αvβ6 autoantibodies were measured in 2 incident UC cohorts (COMPASS [Comprehensive Care for the Recently Diagnosed IBD Patients], n = 55 and OSCCAR [Ocean State Crohn's and Colitis Area Registry], n = 104) and associations between anti-αvβ6 autoantibodies and UC-related outcomes were defined using Cox proportional hazards model. RESULTS Anti-αvβ6 autoantibodies were significantly higher among individuals who developed UC compared with controls up to 10 years before diagnosis in PREDICTS. The anti-αvβ6 autoantibody seropositivity was 12.2% 10 years before diagnosis and increased to 52.4% at the time of diagnosis in subjects who developed UC compared with 2.7% in controls across the 4 time points. Anti-αvβ6 autoantibodies predicted UC development with an area under the curve of at least 0.8 up to 10 years before diagnosis. The presence of anti-αvβ6 autoantibodies in preclinical UC samples was validated in the GEM cohort. Finally, high anti-αvβ6 autoantibodies was associated with a composite of adverse UC outcomes, including hospitalization, disease extension, colectomy, systemic steroid use, and/or escalation to biologic therapy in recently diagnosed UC. CONCLUSIONS Anti-integrin αvβ6 autoantibodies precede the clinical diagnosis of UC by up to 10 years and are associated with adverse UC-related outcomes.
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Affiliation(s)
- Alexandra E Livanos
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Alexandra Dunn
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Jeremy Fischer
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Ryan C Ungaro
- Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Williams Turpin
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada; Division of Gastroenterology and Hepatology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Sun-Ho Lee
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada; Division of Gastroenterology and Hepatology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Shumin Rui
- Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Diane Marie Del Valle
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Human Immune Monitoring Center, Precision Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Julia J Jougon
- Hepato-Gastroenterology Department, Claude Huriez Hospital, University of Lille, Lille, France
| | | | - Mark S Riddle
- University of Nevada, Reno School of Medicine, Reno, Nevada; Veterans Affairs Sierra Nevada Health Care System, Reno, Nevada
| | - Joseph A Murray
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Renee M Laird
- Enteric Diseases Department, Naval Medical Research Center, Silver Spring, Maryland; Henry M. Jackson Foundation for Military Medicine, Bethesda, Maryland
| | - Joana Torres
- Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; Gastroenterology Division, Hospital Beatriz Ângelo, Loures, Portugal; Gastroenterology Division, Hospital da Luz, Lisbon, Portugal; Faculdade de Medicina, Universidade de Lisboa, Portugal
| | - Manasi Agrawal
- Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Jared S Magee
- Gastroenterology, Walter Reed National Military Medical Center, Bethesda, Maryland
| | | | - Sacha Gnjatic
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Human Immune Monitoring Center, Precision Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Dean Sheppard
- Division of Pulmonary, Critical Care, Allergy and Sleep, Department of Medicine, University of California, San Francisco, San Francisco, California
| | - Bruce E Sands
- Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Chad K Porter
- Enteric Diseases Department, Naval Medical Research Center, Silver Spring, Maryland
| | - Kenneth Croitoru
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada; Division of Gastroenterology and Hepatology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Francesca Petralia
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Jean-Frederic Colombel
- Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
| | - Saurabh Mehandru
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
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Jang KK, Heaney T, London M, Ding Y, Yeung F, Ercelen D, Chen YH, Axelrad J, Gurunathan S, Marijke Keestra-Gounder A, Griffin ME, Hang HC, Cadwell K. Antimicrobial overproduction sustains intestinal inflammation by inhibiting Enterococcus colonization. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.29.526128. [PMID: 36778381 PMCID: PMC9915521 DOI: 10.1101/2023.01.29.526128] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
Loss of antimicrobial proteins such as REG3 family members compromises the integrity of the intestinal barrier. Here, we demonstrate that overproduction of REG3 proteins can also be detrimental by reducing a protective species in the microbiota. Patients with inflammatory bowel disease (IBD) experiencing flares displayed heightened levels of secreted REG3 proteins that mediated depletion of Enterococcus faecium ( Efm ) from the gut microbiota. Efm inoculation of mice ameliorated intestinal inflammation through activation of the innate immune receptor NOD2, which was associated with the bacterial DL-endopeptidase SagA. Microbiota sensing by NOD2 in myeloid cells mediated IL-1β secretion and increased the proportion of IL-22-producing CD4 + T helper cells and innate lymphoid cells. Finally, Efm was unable to protect mice carrying a NOD2 gene variant commonly found in IBD patients. Our findings demonstrate that inflammation self-perpetuates by causing aberrant antimicrobial activity that disrupts symbiotic relationships with gut microbes.
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11
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Johnson TO, Akinsanmi AO, Ejembi SA, Adeyemi OE, Oche JR, Johnson GI, Adegboyega AE. Modern drug discovery for inflammatory bowel disease: The role of computational methods. World J Gastroenterol 2023; 29:310-331. [PMID: 36687123 PMCID: PMC9846937 DOI: 10.3748/wjg.v29.i2.310] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 11/02/2022] [Accepted: 12/21/2022] [Indexed: 01/06/2023] Open
Abstract
Inflammatory bowel diseases (IBDs) comprising ulcerative colitis, Crohn’s disease and microscopic colitis are characterized by chronic inflammation of the gastrointestinal tract. IBD has spread around the world and is becoming more prevalent at an alarming rate in developing countries whose societies have become more westernized. Cell therapy, intestinal microecology, apheresis therapy, exosome therapy and small molecules are emerging therapeutic options for IBD. Currently, it is thought that low-molecular-mass substances with good oral bio-availability and the ability to permeate the cell membrane to regulate the action of elements of the inflammatory signaling pathway are effective therapeutic options for the treatment of IBD. Several small molecule inhibitors are being developed as a promising alternative for IBD therapy. The use of highly efficient and time-saving techniques, such as computational methods, is still a viable option for the development of these small molecule drugs. The computer-aided (in silico) discovery approach is one drug development technique that has mostly proven efficacy. Computational approaches when combined with traditional drug development methodology dramatically boost the likelihood of drug discovery in a sustainable and cost-effective manner. This review focuses on the modern drug discovery approaches for the design of novel IBD drugs with an emphasis on the role of computational methods. Some computational approaches to IBD genomic studies, target identification, and virtual screening for the discovery of new drugs and in the repurposing of existing drugs are discussed.
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Affiliation(s)
| | | | | | | | - Jane-Rose Oche
- Department of Biochemistry, University of Jos, Jos 930222, Plateau, Nigeria
| | - Grace Inioluwa Johnson
- Faculty of Clinical Sciences, College of Health Sciences, University of Jos, Jos 930222, Plateau, Nigeria
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12
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Wang L, Choi H, Su Y, Lee B, Choi J, Jang SH, Jang YS, Seo JW. Protective effect of 17S‑epoxy‑docosapentaenoic acid against dextran sulfate sodium induced ulcerative colitis in BALB/c mice. Mol Med Rep 2022; 26:278. [PMID: 35856414 PMCID: PMC9364144 DOI: 10.3892/mmr.2022.12794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 06/09/2022] [Indexed: 11/24/2022] Open
Abstract
Ulcerative colitis (UC) is difficult to eradicate as it leads to chronic inflammation in the digestive tract due to immune system malfunction. The present study demonstrated the protective effect of 7S,15R-dihydroxy-16S,17S-epoxy-docosapentaenoic acid (diHEP-DPA), which had been previously synthesized, on a dextran sulfate sodium (DSS)-induced BALB/c mouse model of UC. UC was induced with 4% DSS drinking water for 7 days. Initially, the anti-inflammatory effect of diHEP-DPA was confirmed by demonstrating that lipopolysaccharide-stimulated THP1 cells treated with diHEP-DPA decreased IL-6, TNF-α and nitrite levels by fluorescence-activated cell sorting (FACS) and Griess reagent kit. The results indicated that the administration of diHEP-DPA at 20 µg/kg significantly reduced the severity of colitis, as determined by hematoxylin and eosin staining. The levels of TNF-α, IL-6 and IL-1β in the colon tissue and serum were significantly reduced in the diHEP-DPA + DSS-treated group compared with in the control group, as determined by FACS and ELISA kit. It was also observed that diHEP-DPA decreased myeloperoxidase (MPO) and nitrite levels in the colon tissues of diHEP-DPA + DSS-treated mice, as indicated using commercial MPO and nitric oxide kits. The diHEP-DPA+DSS-treated mice also exhibited decreased expression levels of phosporylated (p)-inhibitor κB protein, p-p65 and inducible nitric oxide synthase in the colon tissue by inhibiting inflammation, which were measured by reverse transcription-quantitative PCR and weatern blot analysis. Overall, the present study demonstrated the protective effect of diHEP-DPA against a severe colitis condition in vivo.
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Affiliation(s)
- Lifang Wang
- Korea Research Institute of Bioscience and Biotechnology, Microbial Biotechnology Research Center, Jeongeup, Jeollabuk‑do 56212, Republic of Korea
| | - Hack Choi
- College of Applied Life Sciences, Jeju National University, Jeju 63243, Republic of Korea
| | - Yan Su
- Korea Research Institute of Bioscience and Biotechnology, Microbial Biotechnology Research Center, Jeongeup, Jeollabuk‑do 56212, Republic of Korea
| | - Binna Lee
- Korea Research Institute of Bioscience and Biotechnology, Microbial Biotechnology Research Center, Jeongeup, Jeollabuk‑do 56212, Republic of Korea
| | - Jong Choi
- Korea Research Institute of Bioscience and Biotechnology, Microbial Biotechnology Research Center, Jeongeup, Jeollabuk‑do 56212, Republic of Korea
| | - Sun-Hee Jang
- Department of Bioactive Material Sciences, The Institute for Molecular Biology and Genetics, Jeonbuk National University, Jeonju, Jeollabuk‑do 54896, Republic of Korea
| | - Yong-Suk Jang
- Department of Bioactive Material Sciences, The Institute for Molecular Biology and Genetics, Jeonbuk National University, Jeonju, Jeollabuk‑do 54896, Republic of Korea
| | - Jeong-Woo Seo
- Korea Research Institute of Bioscience and Biotechnology, Microbial Biotechnology Research Center, Jeongeup, Jeollabuk‑do 56212, Republic of Korea
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13
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Inflammatory auto-immune diseases of the intestine and their management by natural bioactive compounds. Biomed Pharmacother 2022; 151:113158. [PMID: 35644116 DOI: 10.1016/j.biopha.2022.113158] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 05/08/2022] [Accepted: 05/16/2022] [Indexed: 11/20/2022] Open
Abstract
Autoimmune diseases are caused by the overactivity of the immune system towards self-constituents. Risk factors of autoimmune diseases are multiple and include genetic, epigenetic, environmental, and psychological. Autoimmune chronic inflammatory bowel diseases, including celiac and inflammatory diseases (Crohn's disease and ulcerative colitis), constitute a significant health problem worldwide. Besides the complexity of the symptoms of these diseases, their treatments have only been palliative. Numerous investigations showed that natural phytochemicals could be promising strategies to fight against these autoimmune diseases. In this respect, plant-derived natural compounds such as flavonoids, phenolic acids, and terpenoids exhibited significant effects against three autoimmune diseases affecting the intestine, particularly bowel diseases. This review focuses on the role of natural compounds obtained from medicinal plants in modulating inflammatory auto-immune diseases of the intestine. It covers the most recent literature related to the effect of these natural compounds in the treatment and prevention of auto-immune diseases of the intestine.
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14
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Kopper JJ, Iennarella-Servantez C, Jergens AE, Sahoo DK, Guillot E, Bourgois-Mochel A, Martinez MN, Allenspach K, Mochel JP. Harnessing the Biology of Canine Intestinal Organoids to Heighten Understanding of Inflammatory Bowel Disease Pathogenesis and Accelerate Drug Discovery: A One Health Approach. FRONTIERS IN TOXICOLOGY 2022; 3:773953. [PMID: 35295115 PMCID: PMC8915821 DOI: 10.3389/ftox.2021.773953] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 10/07/2021] [Indexed: 12/13/2022] Open
Abstract
In a recent issue of the Lancet, the prevalence of Inflammatory Bowel Disease (IBD) was estimated at 7 million worldwide. Overall, the burden of IBD is rising globally, with direct and indirect healthcare costs ranging between $14.6 and $31.6 billion in the U.S. alone in 2014. There is currently no cure for IBD, and up to 40% of patients do not respond to medical therapy. Although the exact determinants of the disease pathophysiology remain unknown, the prevailing hypothesis involves complex interplay among host genetics, the intestinal microenvironment (primarily bacteria and dietary constituents), and the mucosal immune system. Importantly, multiple chronic diseases leading to high morbidity and mortality in modern western societies, including type II diabetes, IBD and colorectal cancer, have epidemiologically been linked to the consumption of high-calorie, low-fiber, high monosaccharide, and high-fat diets (HFD). More specifically, data from our laboratory and others have shown that repeated consumption of HFD triggers dysbiotic changes of the gut microbiome concomitant with a state of chronic intestinal inflammation and increased intestinal permeability. However, progress in our understanding of the effect of dietary interventions on IBD pathogenesis has been hampered by a lack of relevant animal models. Additionally, current in vitro cell culture systems are unable to emulate the in vivo interplay between the gut microbiome and the intestinal epithelium in a realistic and translatable way. There remains, therefore, a critical need to develop translatable in vitro and in vivo models that faithfully recapitulate human gut-specific physiological functions to facilitate detailed mechanistic studies on the impact of dietary interventions on gut homeostasis. While the study of murine models has been pivotal in advancing genetic and cellular discoveries, these animal systems often lack key clinical signs and temporal pathological changes representative of IBD. Specifically, some limitations of the mouse model are associated with the use of genetic knockouts to induce immune deficiency and disease. This is vastly different from the natural course of IBD developing in immunologically competent hosts, as is the case in humans and dogs. Noteworthily, abundant literature suggests that canine and human IBD share common clinical and molecular features, such that preclinical studies in dogs with naturally occurring IBD present an opportunity to further our understanding on disease pathogenesis and streamline the development of new therapeutic strategies. Using a stepwise approach, in vitro mechanistic studies investigating the contribution of dietary interventions to chronic intestinal inflammation and "gut leakiness" could be performed in intestinal organoids and organoid derived monolayers. The biologic potential of organoids stems from the method's ability to harness hard-wired cellular programming such that the complexity of the disease background can be reflected more accurately. Likewise, the effect of therapeutic drug candidates could be evaluated in organoids prior to longitudinal studies in dog and human patients with IBD. In this review, we will discuss the value (and limitations) of intestinal organoids derived from a spontaneous animal disease model of IBD (i.e., the dog), and how it can heighten understanding of the interplay between dietary interventions, the gut microbiota and intestinal inflammation. We will also review how intestinal organoids could be used to streamline the preclinical development of therapeutic drug candidates for IBD patients and their best four-legged friends.
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Affiliation(s)
- Jamie J Kopper
- Veterinary Clinical Sciences, Iowa State University College of Veterinary Medicine, Ames, IA, United States.,SMART Translational Medicine, Biomedical Sciences, Iowa State University College of Veterinary Medicine, Ames, IA, United States
| | - Chelsea Iennarella-Servantez
- SMART Pharmacology, Biomedical Sciences, Iowa State University College of Veterinary Medicine, Ames, IA, United States.,SMART Translational Medicine, Biomedical Sciences, Iowa State University College of Veterinary Medicine, Ames, IA, United States
| | - Albert E Jergens
- Veterinary Clinical Sciences, Iowa State University College of Veterinary Medicine, Ames, IA, United States
| | - Dipak K Sahoo
- Veterinary Clinical Sciences, Iowa State University College of Veterinary Medicine, Ames, IA, United States.,SMART Translational Medicine, Biomedical Sciences, Iowa State University College of Veterinary Medicine, Ames, IA, United States
| | - Emilie Guillot
- 3D Health Solutions, Inc., ISU Research Park, Ames, IA, United States
| | - Agnes Bourgois-Mochel
- Veterinary Clinical Sciences, Iowa State University College of Veterinary Medicine, Ames, IA, United States
| | - Marilyn N Martinez
- Office of New Animal Drug Evaluation, Center for Veterinary Medicine, Food and Drug Administration, Rockville, MD, United States
| | - Karin Allenspach
- Veterinary Clinical Sciences, Iowa State University College of Veterinary Medicine, Ames, IA, United States.,SMART Translational Medicine, Biomedical Sciences, Iowa State University College of Veterinary Medicine, Ames, IA, United States.,3D Health Solutions, Inc., ISU Research Park, Ames, IA, United States
| | - Jonathan P Mochel
- SMART Pharmacology, Biomedical Sciences, Iowa State University College of Veterinary Medicine, Ames, IA, United States.,SMART Translational Medicine, Biomedical Sciences, Iowa State University College of Veterinary Medicine, Ames, IA, United States.,3D Health Solutions, Inc., ISU Research Park, Ames, IA, United States
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15
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Knyazev OV, Kagramanova AV, Parfenov AI. Ulcerative colitis. To the 180th anniversary of the description by Karl Rokytansky. TERAPEVT ARKH 2022; 93:1564-1568. [DOI: 10.26442/00403660.2021.12.201219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Accepted: 01/16/2022] [Indexed: 11/22/2022]
Abstract
The article describes the main historical milestones in the description and study of ulcerative colitis from the time of Hippocrates to the present day. The first description of the morphological picture of non-specific ulcerative colitis (NUC) was presented by the Viennese pathologist Karl Rokitansky in 1842. The term "ulcerative colitis" was coined by S. Wilks in 1859. A detailed description of the disease was presented in 1875 by S. Wilks and W. Maxon. In an independent nosological form, NUC was isolated in 1888 by the English doctor White. Boas in 1903. For the first time, he presented the differential diagnosis of NUC and chronic dysentery. The term "non-specific ulcerative colitis" in Russia was first introduced by A.S. Kazachenko in a report at the XIII Congress of Russian Surgeons in 1913.
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de Cuevillas B, Milagro FI, Tur JA, Gil-Campos M, de Miguel-Etayo P, Martínez JA, Navas-Carretero S. Fecal microbiota relationships with childhood obesity: A scoping comprehensive review. Obes Rev 2022; 23 Suppl 1:e13394. [PMID: 34913242 DOI: 10.1111/obr.13394] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 10/28/2021] [Indexed: 12/18/2022]
Abstract
Childhood obesity is a costly burden in most regions with relevant and adverse long-term health consequences in adult life. Several studies have associated excessive body weight with a specific profile of gut microbiota. Different factors related to fecal microorganism abundance seem to contribute to childhood obesity, such as gestational weight gain, perinatal diet, antibiotic administration to the mother and/or child, birth delivery, and feeding patterns, among others. This review reports and discusses diverse factors that affect the infant intestinal microbiota with putative or possible implications on the increase of the obesity childhood rates as well as microbiota shifts associated with excessive body weight in children.
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Affiliation(s)
- Begoña de Cuevillas
- Center for Nutrition Research, Department of Nutrition, Food Sciences and Physiology. School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain
| | - Fermín I Milagro
- Center for Nutrition Research, Department of Nutrition, Food Sciences and Physiology. School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
- IdiSNA, Health Research Institute of Navarra, Pamplona, Spain
| | - Josep A Tur
- Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
- Research Group on Community Nutrition and Oxidative Stress, University of Balearic Islands-IUNICS & IDISBA, Palma de Mallorca, Spain
| | - Mercedes Gil-Campos
- Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
- Metabolism and Investigation Unit, Reina Sofia University Hospital, Maimónides Institute of Biomedicine Research of Córdoba (IMIBIC), University of Córdoba, Córdoba, Spain
| | - Pilar de Miguel-Etayo
- Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
- Growth, Exercise, Nutrition and Development (GENUD) Research Group, Instituto Agroalimentario de Aragón (IA2), Universidad de Zaragoza. Instituto de Investigación Sanitaria de Aragón (IIS Aragón), Zaragoza, Spain
| | - J Alfredo Martínez
- Center for Nutrition Research, Department of Nutrition, Food Sciences and Physiology. School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
- IdiSNA, Health Research Institute of Navarra, Pamplona, Spain
- Precision Nutrition Program, Research Institute on Food and Health Sciences IMDEA Food. CSIC-UAM, Madrid, Spain
| | - Santiago Navas-Carretero
- Center for Nutrition Research, Department of Nutrition, Food Sciences and Physiology. School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
- IdiSNA, Health Research Institute of Navarra, Pamplona, Spain
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Lorenzo-Pouso AI, Castelo-Baz P, Rodriguez-Zorrilla S, Pérez-Sayáns M, Vega P. Association between periodontal disease and inflammatory bowel disease: a systematic review and meta-analysis. Acta Odontol Scand 2021; 79:344-353. [PMID: 33370548 DOI: 10.1080/00016357.2020.1859132] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
OBJECTIVE The aim of this systematic review was to investigate the association between periodontal disease (PD) and inflammatory bowel disease (IBD), and its two major forms Crohn's disease (CD) and ulcerative colitis (UC). MATERIALS AND METHODS We searched articles in PubMed/MEDLINE, Web of Science, and LILACS published until March 2020. Observational studies evaluating the coexistence of PD in IBD and reported values of clinical periodontal parameters, or radiographic bone loss; and IBD diagnosis established by clinical, radiological, endoscopic and histological criteria were deemed eligible. RESULTS A total of 9 studies were included (33,216 individuals). Only one study reported longitudinal data on IBDs onset in patients with PD. Several case-control studies reported coexistence. Meta-analysis showed that the presence of PD was associated with IBD (2.78 [95%CI 1.36-5.69]). PD was strongly associated both with CD (3.41 [95%CI 1.36-8.56]) and UC (3.98 [95%CI 2.02-7.87]). CONCLUSION This review presents clear evidence for an association between PD and IBDs. Future studies should avoid non-longitudinal designs and focus on addressing direction. PD screening may be included in the multidisciplinary management of IBD patients. The mere theoretical possibility that PD may predispose to IBDs may be of key significance due to the rising incidence of diseases.
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Affiliation(s)
- Alejandro I. Lorenzo-Pouso
- Faculty of Medicine and Odontology, Oral Medicine, Oral Surgery and Implantology Unit, University of Santiago de Compostela, Santiago de Compostela, Spain
- MedOralRes Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - Pablo Castelo-Baz
- Department of Endodontics, Faculty of Medicine and Odontology, University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Samuel Rodriguez-Zorrilla
- Faculty of Medicine and Odontology, Oral Medicine, Oral Surgery and Implantology Unit, University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Mario Pérez-Sayáns
- Faculty of Medicine and Odontology, Oral Medicine, Oral Surgery and Implantology Unit, University of Santiago de Compostela, Santiago de Compostela, Spain
- MedOralRes Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - Pablo Vega
- Gastroenterology Department, Complexo Hospitalario Universitario de Ourense, Ourense, Spain
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Shinar Y, Ceccherini I, Rowczenio D, Aksentijevich I, Arostegui J, Ben-Chétrit E, Boursier G, Gattorno M, Hayrapetyan H, Ida H, Kanazawa N, Lachmann HJ, Mensa-Vilaro A, Nishikomori R, Oberkanins C, Obici L, Ohara O, Ozen S, Sarkisian T, Sheils K, Wolstenholme N, Zonneveld-Huijssoon E, van Gijn ME, Touitou I. ISSAID/EMQN Best Practice Guidelines for the Genetic Diagnosis of Monogenic Autoinflammatory Diseases in the Next-Generation Sequencing Era. Clin Chem 2020; 66:525-536. [PMID: 32176780 DOI: 10.1093/clinchem/hvaa024] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Accepted: 01/08/2020] [Indexed: 12/22/2022]
Abstract
BACKGROUND Monogenic autoinflammatory diseases are caused by pathogenic variants in genes that regulate innate immune responses, and are characterized by sterile systemic inflammatory episodes. Since symptoms can overlap within this rapidly expanding disease category, accurate genetic diagnosis is of the utmost importance to initiate early inflammation-targeted treatment and prevent clinically significant or life-threatening complications. Initial recommendations for the genetic diagnosis of autoinflammatory diseases were limited to a gene-by-gene diagnosis strategy based on the Sanger method, and restricted to the 4 prototypic recurrent fevers (MEFV, MVK, TNFRSF1A, and NLRP3 genes). The development of best practices guidelines integrating critical recent discoveries has become essential. METHODS The preparatory steps included 2 online surveys and pathogenicity annotation of newly recommended genes. The current guidelines were drafted by European Molecular Genetics Quality Network members, then discussed by a panel of experts of the International Society for Systemic Autoinflammatory Diseases during a consensus meeting. RESULTS In these guidelines, we combine the diagnostic strength of next-generation sequencing and recommendations to 4 more recently identified genes (ADA2, NOD2, PSTPIP1, and TNFAIP3), nonclassical pathogenic genetic alterations, and atypical phenotypes. We present a referral-based decision tree for test scope and method (Sanger versus next-generation sequencing) and recommend on complementary explorations for mosaicism, copy-number variants, and gene dose. A genotype table based on the 5-category variant pathogenicity classification provides the clinical significance of prototypic genotypes per gene and disease. CONCLUSIONS These guidelines will orient and assist geneticists and health practitioners in providing up-to-date and appropriate diagnosis to their patients.
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Affiliation(s)
- Yael Shinar
- Laboratory of FMF, Amyloidosis and Rare Autoinflammatory Diseases, Heller Institute, Sheba Medical Center, Tel Hashomer, Israel
| | | | | | | | - Juan Arostegui
- Department of Immunology, Hospital Clínic, Barcelona, Spain.,Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Eldad Ben-Chétrit
- Rheumatology Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Guilaine Boursier
- Department of Medical Genetics, Rare Diseases and Personalized Medicine, Reference Center CEREMAIA, CHU Montpellier, University of Montpellier, Montpellier, France
| | - Marco Gattorno
- Center for Autoinflammatory Diseases and Immunodeficiency, IRCCS Giannina Gaslini, Genova
| | | | - Hiroaki Ida
- Department of Medicine, Division of Respirology, Neurology and Rheumatology, Kurume University School of Medicine, Kurume, Japan
| | - Nobuo Kanazawa
- Department of Dermatology, Wakayama Medical University, Wakayama, Japan
| | | | | | - Ryuta Nishikomori
- Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan
| | | | - Laura Obici
- Amyloidosis Research and Treatment Centre, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Osamu Ohara
- Department of Applied Genomics, Kazusa DNA Research Institute, Kisarazu, Japan
| | - Seza Ozen
- Department of Pediatrics, Hacettepe University, Ankara, Turkey
| | - Tamara Sarkisian
- Center of Medical Genetics and Primary Health Care, Yerevan, Armenia
| | - Katie Sheils
- European Molecular Genetics Quality Network (EMQN), Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester, UK
| | - Nicola Wolstenholme
- European Molecular Genetics Quality Network (EMQN), Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester, UK
| | - Evelien Zonneveld-Huijssoon
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Marielle E van Gijn
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Isabelle Touitou
- Department of Medical Genetics, Rare Diseases and Personalized Medicine, Reference Center CEREMAIA, CHU Montpellier, University of Montpellier, Montpellier, France.,Stem Cells, Cellular Plasticity, Regenerative Medicine and Immunotherapies, INSERM, Montpellier, France
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19
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Mari A, Khoury T, Ahamad HS, Bragazzi NL, Sbeit W, Mahamid A, Mahamid L, Nesseir W, Baker FA, Pellicano R, Amital H, Watad A, Mahamid M. Autoimmune diseases in first- and second-degree relatives of patients with inflammatory bowel diseases: a case-control survey in Israel. Minerva Med 2020; 111:107-114. [PMID: 31828987 DOI: 10.23736/s0026-4806.19.06389-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/29/2023]
Abstract
BACKGROUND Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are chronic, relapsing, inflammatory diseases of the gastrointestinal tract with unknown etiology. IBD are complex, multi-factorial disorders, in which genetic factors play a major role, the so-called phenomenon of familial aggregation or clustering of IBD. A positive family history of IBD is often reported among CD and UC probands, with percentages depending on the geographic context in which the studies are carried out. Israel is a complex and pluralistic society comprising of two major ethno-national groups (Arabs and Jewish) and, as such, represents a unique living laboratory in which to test the role of genetic factors in the development of IBD as well as of associated autoimmune disorders (ADs). While some studies have found a lower prevalence of ADs among Arabs when compared to Jews, few studies directly compared the two ethnicities. METHODS The present case-control study was designed to compare the rate of ADs in first- and second-degree relatives of IBD patients, stratified according to Jewish or Arabic ethnicity. RESULTS We found that first-degree relatives of Jews patients had a higher risk of developing ADs (OR=1.89, P=0.0086). Classifying ADs into systemic and local (endocrinological, gastrointestinal, dermatological, and neurological) types, first-degree relatives of Jews patients had a higher OR of developing local ADs (OR=2.12, P=0.0056). CONCLUSIONS Israeli Jewish IBD patients had more first-degree relatives with local ADs as compared to Arab patients.
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Affiliation(s)
- Amir Mari
- Unit of Gastroenterology and Endoscopy, EMMS Nazareth Hospital, Nazareth, Israel -
- Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel -
| | - Tawfik Khoury
- Unit of Gastroenterology and Endoscopy, EMMS Nazareth Hospital, Nazareth, Israel
- Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
- Department of Gastroenterology, Galilee Medical Center, Nahariya, Israel
- Faculty of Medicine in Galilee, Bar-Ilan University, Safed, Israel
| | - Helal S Ahamad
- Unit of Gastroenterology and Endoscopy, EMMS Nazareth Hospital, Nazareth, Israel
- Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Nicola L Bragazzi
- Postgraduate School of Public Health, Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy
| | - Wisam Sbeit
- Department of Gastroenterology, Galilee Medical Center, Nahariya, Israel
- Faculty of Medicine in Galilee, Bar-Ilan University, Safed, Israel
| | - Ahmad Mahamid
- Department of General Surgery, Rambam Medical Center, Ruth Rappaport Faculty of Medicine, Haifa, Israel
| | - Lames Mahamid
- Department of Internal Medicine, Meir Medical Center, Kefar Saba, Israel
| | - William Nesseir
- Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
- Department of Internal Medicine, EMMS Nazareth Hospital, Nazareth, Israel
| | - Fadi A Baker
- Department of Gastroenterology, Hilel Yaffe Medical Center, Hadera, Israel
| | | | - Howard Amital
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel
| | - Abdulla Watad
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Mahmud Mahamid
- Unit of Gastroenterology and Endoscopy, EMMS Nazareth Hospital, Nazareth, Israel
- Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
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20
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MicroRNA binding site polymorphism in inflammatory genes associated with colorectal cancer: literature review and bioinformatics analysis. Cancer Gene Ther 2020; 27:739-753. [PMID: 32203060 DOI: 10.1038/s41417-020-0172-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 02/21/2020] [Accepted: 03/10/2020] [Indexed: 02/06/2023]
Abstract
Inflammation, among environmental risk factors, is one of the most important contributors to colorectal cancer (CRC) development. In this way, studies revealed that the incidence of CRC in inflammatory bowel disease patients is up to 60% higher than the general population. MicroRNAs (miRNAs), small noncoding RNA molecules, have attracted excessive attention due to their fundamental role in various aspects of cellular biology, such as inflammation by binding to the 3'-untranslated regions (3'-UTR) of pro and anti-inflammatory genes. Based on multiple previous studies, SNPs at 3'-UTR can affect miRNA recognition elements by changing the thermodynamic features and secondary structure. This effect can be categorized, based on the number of changes, into four groups, including break, decrease, create, and enhance. In this paper, we will focus on functional variants in miRNA binding sites in inflammatory genes, which can modulate the risk of CRC by both investigating previous studies, regarding miRSNPs in inflammatory genes associated with CRC and recruiting in silico prediction algorithms to report putative miRSNPs in 176 inflammatory genes. In our analysis, we achieved 110 miRSNPs in 3'-UTR of 67 genes that seem good targets for future researches.
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21
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Inflammatory bowel disease - one entity with many molecular faces. GASTROENTEROLOGY REVIEW 2019; 14:228-232. [PMID: 31988668 PMCID: PMC6983764 DOI: 10.5114/pg.2019.90249] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 02/14/2019] [Indexed: 01/06/2023]
Abstract
Inflammatory bowel disease (IBD) is a heterogenous group of chronic inflammations in the gastrointestinal tract, which traditionally consists of two types: Crohn’s disease and ulcerative colitis. They differ when it comes to clinical, endoscopic, and histopathological changes. The exact aetiology of IBD has not been fully comprehended, but what is known so far is that the aetiopathogenesis of the disease is compound. Many articles have been written on the cellular/molecular background of IBD. Based on various molecular pathways, new forms of the disease have been discovered, including very early-onset IBD (VEO-IBD) or IBD coexisting with primary sclerosing cholangitis. The aim of this article is to present the molecular mechanisms leading to IBD, focusing on new forms of this disorder.
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22
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Yao Q, Li E, Shen B. Autoinflammatory disease with focus on NOD2-associated disease in the era of genomic medicine. Autoimmunity 2019; 52:48-56. [PMID: 31084224 DOI: 10.1080/08916934.2019.1613382] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Systemic autoinflammatory diseases (SAIDs) represent a spectrum of genetically heterogeneous inflammatory disorders. Some SAID-associated genes are located in chromosome 16, including familial Mediterranean fever gene (MEFV) and nucleotide-binding oligomerization domain 2 [NOD2] gene that are linked to Crohn's disease, Blau syndrome, and Yao syndrome. These disorders share overlapping clinical phenotypes, and genotyping is diagnostically helpful and distinctive. Using next generation sequencing in SAIDs, digenic variants or combinations of more genetic variants in different genes can be detected, and they may be related to the MEFV and NOD2 genes. These variants may contribute to heterogeneous phenotypes in an individual, complicating the diagnosis and therapy. An awareness of the clinical significance of the digenic or combined gene variants is important in the era of genomic medicine.
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Affiliation(s)
- Qingping Yao
- a Division of Rheumatology, Allergy and Immunology , Stony Brook University , Stony Brook , NY , USA
| | - Ellen Li
- b Division of Gastroenterology , Stony Brook University , Stony Brook , NY , USA
| | - Bo Shen
- c Center for Inflammatory Bowel Disease , Digestive Disease and Surgery Institute, the Cleveland Clinic Foundation , Cleveland , OH , USA
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23
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Kadiyska T, Tourtourikov I, Popmihaylova AM, Kadian H, Chavoushian A. Role of TNFSF15 in the intestinal inflammatory response. World J Gastrointest Pathophysiol 2018; 9:73-78. [PMID: 30809418 PMCID: PMC6384511 DOI: 10.4291/wjgp.v9.i4.73] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 10/11/2018] [Accepted: 10/18/2018] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal diseases, specifically Crohn’s disease, ulcerative colitis, diverticular disease, and primary biliary cirrhosis are all characterized by complicated inflammation of the digestive tract. Their pathology is multifactorial, and risk factors encompass both genetic and environmental factors. Recent advances in the genetic component of inflammatory bowel diseases (IBDs) have revealed that the tumor necrosis factor superfamily member 15 (TNFSF15) contains a number of risk alleles associated not only with IBD but also with other diseases such as diverticular disease and primary biliary cirrhosis. These risk alleles in TNFSF15 and the altered expression of its gene product can serve as the common ground between these disorders by explaining at least some of the underlying processes that lead to a dysregulated immune response and subsequent chronic inflammation. Here, we aim to outline how the TNFSF15 gene is involved in the proliferation and cell fate of different populations of T cells and subsequently in the control of both pro- and anti-inflammatory cytokines. Furthermore, we summarize what is currently known of TNFSF15 control region variants, how they are associated with each mentioned disease, and how these variants can explain the autoimmune pathology of said diseases through altered TNFSF15 expression.
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Affiliation(s)
- Tanya Kadiyska
- Department of Medical Chemistry and Biochemistry, Sofia Medical University, Sofia 1431, Bulgaria
- Genetic Medico-Diagnostic Laboratory Genica, Sofia 1612, Bulgaria
| | | | | | - Hilda Kadian
- Bulgarian Association for Inflammatory Bowel Diseases, Sofia 1527, Bulgaria
| | - Ani Chavoushian
- Department of Gastroenterology, Acibadem City Clinic Oncology Center, Sofia 1784, Bulgaria
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24
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Khan S, Imran A, Malik A, Chaudhary AA, Rub A, Jan AT, Syed JB, Rolfo C. Bacterial imbalance and gut pathologies: Association and contribution of E. coli in inflammatory bowel disease. Crit Rev Clin Lab Sci 2018; 56:1-17. [DOI: 10.1080/10408363.2018.1517144] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Shahanavaj Khan
- Nanomedicine Research Unit, Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
- Department of Bioscience, Shri Ram Group of College (SRGC), Muzaffarnagar, India
| | - Ahamad Imran
- King Abdullah Institute for Nanotechnology, King Saud University, Riyadh, Saudi Arabia
| | - Abdul Malik
- Department of Clinical Laboratory Science, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Anis Ahmad Chaudhary
- Department of Pharmacology, College of Medicine, Al-Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Abdur Rub
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al Majmaah, Saudi Arabia
| | - Arif Tasleem Jan
- School of Biotechnology, Yeungnam University, Gyeongsan, Republic of Korea
| | - Jakeera Begum Syed
- King Abdullah Institute for Nanotechnology, King Saud University, Riyadh, Saudi Arabia
- College of Medicine and Dentistry, Dar Al Uloom University, Riyadh, Saudi Arabia
| | - Christian Rolfo
- Phase I-Early Clinical Trials Unit, Oncology Department and Multidisciplinary Oncology Center Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium
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25
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Li J, Glover SC. Innate Lymphoid Cells in Inflammatory Bowel Disease. Arch Immunol Ther Exp (Warsz) 2018; 66:415-421. [PMID: 30155762 DOI: 10.1007/s00005-018-0519-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Accepted: 05/18/2018] [Indexed: 12/25/2022]
Abstract
Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a complex chronic inflammatory condition of the human gut of unknown causes. Traditionally, dysregulated adaptive immune responses are thought to play a major role; however, accumulating evidence suggests that innate immunity also contributes to this process. Innate lymphoid cells (ILCs) are recently identified important components of innate immunity. They have critical roles in immunity, tissue development and remodeling. Numerous researchers have linked ILCs to the pathogenesis of IBD. In this review, we describe recent progress in our understanding about the phenotype and function alterations of ILCs as well as its interactions with other key mucosal cells in the gut of IBD patients. A better delineation of the ILCs' behavior in the human intestine will contribute to our understanding of ILCs biology and provide valuable insights for potential therapeutic target selection for IBD patients.
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Affiliation(s)
- Jian Li
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Florida, 1600 SW Archer Rd, PO Box 100214, Gainesville, FL, 32610, USA
| | - Sarah C Glover
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Florida, 1600 SW Archer Rd, PO Box 100214, Gainesville, FL, 32610, USA.
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26
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Kroschwald S, Chiu CY, Heydeck D, Rohwer N, Gehring T, Seifert U, Lux A, Rothe M, Weylandt KH, Kuhn H. Female mice carrying a defective Alox15 gene are protected from experimental colitis via sustained maintenance of the intestinal epithelial barrier function. Biochim Biophys Acta Mol Cell Biol Lipids 2018; 1863:866-880. [PMID: 29702245 DOI: 10.1016/j.bbalip.2018.04.019] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Revised: 04/17/2018] [Accepted: 04/21/2018] [Indexed: 12/19/2022]
Abstract
Lipoxygenases (ALOXs) are involved in the regulation of cellular redox homeostasis. They also have been implicated in the biosynthesis of pro- and anti-inflammatory lipid mediators and play a role in the pathogenesis of inflammatory diseases, which constitute a major health challenge owing to increasing incidence and prevalence in all industrialized countries around the world. To explore the pathophysiological role of Alox15 (leukocyte-type 12-LOX) in mouse experimental colitis we tested the impact of systemic inactivation of the Alox15 gene on the extent of dextrane sulfate sodium (DSS) colitis. We found that in wildtype mice expression of the Alox15 gene was augmented during DSS-colitis while expression of other Alox genes (Alox5, Alox15b) was hardly altered. Systemic Alox15 (leukocyte-type 12-LOX) deficiency induced less severe colitis symptoms and suppressed in vivo formation of 12-hydroxyeicosatetraenoic acid (12-HETE), the major Alox15 (leukocyte-type 12-LOX) product in mice. These alterations were paralleled by reduced expression of pro-inflammatory gene products, by sustained expression of the zonula occludens protein 1 (ZO-1) and by a less impaired intestinal epithelial barrier function. These results are consistent with in vitro incubations of colon epithelial cells, in which addition of 12S-HETE compromised enantioselectively transepithelial electric resistance. Consistent with these data transgenic overexpression of human ALOX15 intensified the inflammatory symptoms. In summary, our results indicate that systemic Alox15 (leukocyte-type 12-LOX) deficiency protects mice from DSS-colitis. Since exogenous 12-HETE compromises the expression of the tight junction protein ZO-1 the protective effect has been related to a less pronounced impairment of the intestinal epithelial barrier function.
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Affiliation(s)
- Saskia Kroschwald
- Institute of Biochemistry, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Chariteplatz 1, D-10117 Berlin, Germany; Institute for Molecular and Clinical Immunology, Medical Faculty of the Otto-von-Guericke-University, Leipziger Str. 44, 39120 Magdeburg, Germany
| | - Cheng-Ying Chiu
- Division of Medicine, Department of Hepatology, Gastroenterology and Metabolism, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Dagmar Heydeck
- Institute of Biochemistry, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Chariteplatz 1, D-10117 Berlin, Germany
| | - Nadine Rohwer
- Division of Medicine, Department of Hepatology, Gastroenterology and Metabolism, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Tatjana Gehring
- Institute of Biochemistry, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Chariteplatz 1, D-10117 Berlin, Germany
| | - Ulrike Seifert
- Institute for Molecular and Clinical Immunology, Medical Faculty of the Otto-von-Guericke-University, Leipziger Str. 44, 39120 Magdeburg, Germany
| | - Anke Lux
- Institute for Molecular and Clinical Immunology, Medical Faculty of the Otto-von-Guericke-University, Leipziger Str. 44, 39120 Magdeburg, Germany
| | - Michael Rothe
- Lipidomix GmbH, Robert-Rössle-Str. 10, 13125 Berlin, Germany
| | - Karsten-Henrich Weylandt
- Division of Medicine, Department of Hepatology, Gastroenterology and Metabolism, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13353 Berlin, Germany; Division of Medicine, Department of Gastroenterology and Oncology, Ruppiner Kliniken, Brandenburg Medical School, 16816 Neuruppin, Germany.
| | - Hartmut Kuhn
- Institute of Biochemistry, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Chariteplatz 1, D-10117 Berlin, Germany.
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27
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Mehta M, Ahmed S, Dryden G. Immunopathophysiology of inflammatory bowel disease: how genetics link barrier dysfunction and innate immunity to inflammation. Innate Immun 2018; 23:497-505. [PMID: 28770665 DOI: 10.1177/1753425917722206] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Inflammatory bowel diseases (IBD) comprise a distinct set of clinical symptoms resulting from chronic or relapsing immune activation and corresponding inflammation within the gastrointestinal (GI) tract. Diverse genetic mutations, encoding important aspects of innate immunity and mucosal homeostasis, combine with environmental triggers to create inappropriate, sustained inflammatory responses. Recently, significant advances have been made in understanding the interplay of the intestinal epithelium, mucosal immune system, and commensal bacteria as a foundation of the pathogenesis of inflammatory bowel disease. Complex interactions between specialized intestinal epithelial cells and mucosal immune cells determine different outcomes based on the environmental input: the development of tolerance in the presence of commensal bacterial or the promotion of inflammation upon recognition of pathogenic organisms. This article reviews key genetic abnormalities involved in inflammatory and homeostatic pathways that enhance susceptibility to immune dysregulation and combine with environmental triggers to trigger the development of chronic intestinal inflammation and IBD.
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Affiliation(s)
- Minesh Mehta
- 1 Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville, Louisville, KY, USA
| | - Shifat Ahmed
- 2 Department of Internal Medicine, University of Louisville, Louisville, KY, USA
| | - Gerald Dryden
- 1 Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville, Louisville, KY, USA
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28
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Kamm F, Strauch U, Degenhardt F, Lopez R, Kunst C, Rogler G, Franke A, Klebl F, Rieders F. Serum anti-glycan-antibodies in relatives of patients with inflammatory bowel disease. PLoS One 2018; 13:e0194222. [PMID: 29596443 PMCID: PMC5875751 DOI: 10.1371/journal.pone.0194222] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2017] [Accepted: 02/27/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Serum anti-glycan antibodies are a promising tool for differential diagnosis, disease stratification and prediction of Crohn's disease (CD). To investigate possible heritability of the markers we assessed the presence of serum anti-glycan antibodies in affected and unaffected relatives of patients with CD. METHODS Serum samples of 169 IBD patients of the German inflammatory bowel disease (IBD) network (140 CD & 29 Ulcerative colitis (UC)), 349 relatives of CD patients, 63 relatives of UC patients and 46 healthy controls were tested for the presence of anti-glycan antibodies by ELISA in a blinded fashion. Clinical data of the IBD patients and controls were available. RESULTS A higher proportion of non-affected CD relatives was positive for anti-glycan antibodies compared to healthy subjects. No inheritance of a specific pattern of anti-glycan antibodies could be detected. No difference in marker expression depending on the degree of relationship in the non-affected relatives was noted and the presence of family history did not lead to a difference in marker levels in the affected CD subjects. CONCLUSIONS Non-affected CD relatives had a higher frequency of anti-glycan antibodies compared to healthy subjects. This difference was mild and was found to be true for the overall reactivity to glycan antigens, but not for specific patterns. This may indicate an inherited mechanism resulting in a non-specific increased reactivity to microbial antigens in IBD.
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Affiliation(s)
- Florian Kamm
- Department of Internal Medicine I, University of Regensburg, Regensburg, Germany
| | - Ulrike Strauch
- Department of Internal Medicine I, University of Regensburg, Regensburg, Germany
| | - Frauke Degenhardt
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Rocio Lopez
- Department of Quantitative Health Sciences, Cleveland Clinic Foundation, Cleveland, United States of America
| | - Claudia Kunst
- Department of Internal Medicine I, University of Regensburg, Regensburg, Germany
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
- Zurich Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland
| | - Andre Franke
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Frank Klebl
- Department of Internal Medicine I, University of Regensburg, Regensburg, Germany
| | - Florian Rieders
- Department of Internal Medicine I, University of Regensburg, Regensburg, Germany
- Department of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, United States of America
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29
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Nakamura H, Lim T, Puri P. Inflammatory bowel disease in patients with Hirschsprung's disease: a systematic review and meta-analysis. Pediatr Surg Int 2018; 34:149-154. [PMID: 28983688 DOI: 10.1007/s00383-017-4182-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/21/2017] [Indexed: 12/21/2022]
Abstract
AIM AND OBJECTIVES Hirschsprung-associated enterocolitis (HAEC) continues to be an important cause of morbidity in patients with Hirschsprung's disease (HSCR). HAEC can occur at any time during the course of the disease. The reported incidence of HAEC before surgery ranges from 6 to 50%, and after surgery, it ranges from 2 to 35%. HAEC and inflammatory bowel disease (IBD) have similar clinical presentation including diarrhea, hematochezia, and abdominal pain. In recent years, isolated cases of IBD have been reported in patients who had surgical treatment for HSCR. The exact pathogenesis of HAEC or IBD is not known. However, both conditions are characterized by an abnormal intestinal mucosal barrier function, which may be a common pathway. The purpose of this meta-analysis was to determine the clinical presentation and outcome in patients with HSCR who developed IBD after pull-through operation. MATERIALS AND METHODS A systematic literature search for relevant articles was performed in four databases using the combinations of the following terms "inflammatory bowel disease", "Crohn/Crohn's disease", "ulcerative colitis", and "Hirschsprung disease/Hirschsprung's disease" for studies published between 1990 and 2017. The relevant cohorts of HSCR associated with IBD were systematically searched for clinical presentation and outcomes. RESULTS 14 studies met defined inclusion criteria, reporting a total of 66 patients who had HSCR associated with IBD. Mean age at first operation for HSCR was 5.8 months, mean age at diagnosis of IBD was 7.7 years, and the majority of patients were male (73%). The extent of aganglionosis was total colonic aganglionosis in 41% of patients, long segment in 45%, and rectosigmoid in 14%. The majority of patients underwent a Duhamel procedure (84%) for HSCR. The distribution of IBD was Crohn's disease in 72.3% of patients, ulcerative colitis in 16.9%, and others in 10.8%. Eight articles (47 patients) reported about HAEC, and 22 patients (47%) had experienced HAEC after surgery for HSCR. CONCLUSION Male patients with extensive colonic aganglionosis who continue to suffer from postoperative HAEC after a Duhamel procedure are more susceptible to develop IBD. Recognition of IBD may be important in the long-term follow-up of HSCR patients who have had postoperative HAEC.
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Affiliation(s)
- H Nakamura
- National Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland
| | - T Lim
- Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ, USA
| | - P Puri
- National Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland. .,School of Medicine and Medical Science and Conway Institute of Biomolecular and Biomedical Research University College Dublin, Dublin, Ireland.
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Santos MPC, Gomes C, Torres J. Familial and ethnic risk in inflammatory bowel disease. Ann Gastroenterol 2017; 31:14-23. [PMID: 29333063 PMCID: PMC5759609 DOI: 10.20524/aog.2017.0208] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 09/21/2017] [Indexed: 02/07/2023] Open
Abstract
Familial aggregation in inflammatory bowel disease (IBD) has been established for several decades, reflecting shared genetic and environmental susceptibility. A positive family history remains the strongest recognizable risk factor for the development of IBD and is reported in around 8-12% of IBD patients. Crohn’s disease shows a more frequent familial pattern than ulcerative colitis. The risk of developing IBD in first-degree relatives of an affected proband is increased 4- to 8-fold. The risk for twins and children born from couples who both have IBD is also substantially higher; a cumulative effect of the number of family members affected has been described, with the highest incidence being described for families with three or more affected members. Herein, we review the available evidence regarding familial IBD, and briefly discuss the variation of IBD across different races and ethnicities, hoping to provide a useful update and a practical guide that can serve clinicians as a guide for counseling.
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Affiliation(s)
- Maria Pia Costa Santos
- Gastroenterology Division, Surgical Department, Hospital Beatriz Ângelo, Loures, Portugal
| | - Catarina Gomes
- Gastroenterology Division, Surgical Department, Hospital Beatriz Ângelo, Loures, Portugal
| | - Joana Torres
- Gastroenterology Division, Surgical Department, Hospital Beatriz Ângelo, Loures, Portugal
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31
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Moini M, Saadat M, Saadat H, Esmailnejad A, Safarpour A. Association Study of Glutathione S-transferases Gene Polymorphisms (GSTM1 and GSTT1) with Ulcerative Colitis and Crohn's Disease in the South of Iran. Adv Biomed Res 2017. [PMID: 28626742 PMCID: PMC5468788 DOI: 10.4103/2277-9175.190981] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Background: Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn's disease (CD), are chronic inflammatory disorders of the gastrointestinal tract. A combination of environmental factors and interactions with a genetic predisposition are suggested to play an important role in the etiology and pathogenesis of the IBD. Glutathione S-transferases (GSTs) are multifunctional enzymes involved in the cellular oxidative stress handling. Possible associations between GSTs gene polymorphisms and susceptibility to UC and CD have been reported in different population. The relationship between GSTM1 and GSTT1 deletion polymorphisms and susceptibility to UC and CD were investigated in the Iranian population. Materials and Methods: The study was performed in 106 IBD patients and 243 age- and sex-matched healthy Iranian controls consulting the IBD registry center of the Motahari Clinic, Shiraz University of Medical Sciences, Shiraz, Iran, between 2011 and 2013. GSTM1 and GSTT1 genotyping were performed using multiplex polymerase chain reaction and differences in the distribution of gene polymorphisms were analyzed statistically between the studied groups. Results: Statistically significant higher frequency of GSTM1 null genotype was observed in IBD patients (P = 0.01) and in the subgroup of patients with UC (P = 0.04) compared to healthy controls, whereas this was not true for CD patients. No significant association was found between GSTT1 gene polymorphism and UC or CD. Conclusions: Absence of GSTT1 functional gene does not play an important role in the pathophysiology and development of IBD, UC, and CD in Iranian population whereas GSTM1 null genotype could be considered as a possible genetic predisposing factor for more susceptibility to IBD and UC.
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Affiliation(s)
- Maryam Moini
- Department of Internal Medicine, Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mostafa Saadat
- Department of Biology, College of Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
| | - Hooshang Saadat
- Department of Internal Medicine, Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Atefeh Esmailnejad
- Department of Pathobiology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
| | - Alireza Safarpour
- Department of Internal Medicine, Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Bijanzadeh M. The recurrence risk of genetic complex diseases. JOURNAL OF RESEARCH IN MEDICAL SCIENCES 2017; 22:32. [PMID: 28461818 PMCID: PMC5390543 DOI: 10.4103/1735-1995.202143] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Revised: 10/30/2016] [Accepted: 12/18/2016] [Indexed: 12/19/2022]
Abstract
Complex inherited diseases affected by an interaction between collective effects of the genotype at one or multiple loci either to increase or to lower susceptibility to disease, combined with a variety of environmental exposures that may trigger, accelerate, exacerbate, or protect against the disease process. The new aspects of genetic techniques have been opened for diagnosis and analysis of inherited disorders. While appropriate Mendelian laws is applied to estimate the recurrence risk of single gene diseases, using empirical recurrence risks are the most important and available method to evaluate pedigree of complex (multifactorial), chromosomal, and unknown etiology disorders. Although, generally, empirical recurrent risks are not accurate, either because of the difference of gene frequencies and environmental factors among populations or heterogeneity of disease; using results of plenty family population studies, computerized estimating programs, genotyping technologies, and Genome-wide association studies (GWASs) of single nucleotide polymorphisms (SNPs), can make it possible nowadays to estimate these risks. The specific family situation and importance recurrence risks of some common complex genetic diseases will be presented in this review and some important multifactorial disorders’ recurrence risks will be summarized to help genetic counselors for supporting families and representing better view of genetic disorders.
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Affiliation(s)
- Mahdi Bijanzadeh
- Health Research Institute, Thalassemia and Hemoglobinopathy Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Department of Medical Genetics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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Inflammatory bowel disease: exploring gut pathophysiology for novel therapeutic targets. Transl Res 2016; 176:38-68. [PMID: 27220087 DOI: 10.1016/j.trsl.2016.04.009] [Citation(s) in RCA: 133] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2015] [Revised: 03/17/2016] [Accepted: 04/28/2016] [Indexed: 12/14/2022]
Abstract
Ulcerative colitis and Crohn's disease are the 2 major phenotypes of inflammatory bowel disease (IBD), which are influenced by a complex interplay of immunological and genetic elements, though the precise etiology still remains unknown. With IBD developing into a globally prevailing disease, there is a need to explore new targets and a thorough understanding of the pathophysiological differences between the healthy and diseased gut could unearth new therapeutic opportunities. In this review, we provide an overview of the major aspects of IBD pathogenesis and thereafter present a comprehensive analysis of the gut pathophysiology leading to a discussion on some of the most promising targets and biologic therapies currently being explored. These include various gut proteins (CXCL-10, GATA-3, NKG2D, CD98, microRNAs), immune cells recruited to the gut (mast cells, eosinophils, toll-like receptors 2, 4), dysregulated proinflammatory cytokines (interleukin-6, -13, -18, -21), and commensal microbiota (probiotics and fecal microbiota transplantation). We also evaluate some of the emerging nonconventional therapies being explored in IBD treatment focusing on the latest developments in stem cell research, oral targeting of the gut-associated lymphoid tissue, novel anti-inflammatory signaling pathway targeting, adenosine deaminase inhibition, and the beneficial effects of antioxidant and nutraceutical therapies. In addition, we highlight the growth of biologics and their targets in IBD by providing information on the preclinical and clinical development of over 60 biopharmaceuticals representing the state of the art in ulcerative colitis and Crohn's disease drug development.
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Racial and Ethnic Minorities with Inflammatory Bowel Disease in the United States: A Systematic Review of Disease Characteristics and Differences. Inflamm Bowel Dis 2016; 22:2023-40. [PMID: 27379446 DOI: 10.1097/mib.0000000000000835] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) has predominantly affected whites, particularly Ashkenazi Jews. Over the last 2 decades, IBD has "emerged" in minorities. Differences in natural history and disease characteristics have been suggested. The objective of this systematic review is to summarize these differences in studies from the United States. METHODS A structured search was performed within the Medline database through PubMed, EMBASE, and Cochrane databases. Published studies of genetics, pathogenesis, prevalence or incidence, disease location and behavior, extraintestinal manifestations, disparities and access to care in patients with IBD who are of African American, Asian, and Hispanic descent living in the United States were eligible. RESULTS A total of 47 studies were included for African Americans (n = 20,054), Hispanics (n = 10,762), and Asians (n = 2668). The incidence and prevalence of IBD is increasing among minorities. There is less of a genetic influence in the pathogenesis of IBD among African Americans; however, novel variants have been identified. There is a predilection for pancolonic ulcerative colitis among Hispanics and Asians. Crohn's disease-related hospitalizations are increasing in Asians, whereas African Americans are more likely to use the emergency department. No major differences are seen in disease location and behavior, upper gastrointestinal tract, and perianal involvement and extraintestinal manifestations among races and ethnic groups. Medication utilization seems to be similar. Differences in surgery are likely explained by health insurance status. CONCLUSIONS Future prospective studies are needed to fully characterize disease characteristics and treatment response among minorities. With novel IBD therapies in the pipeline, enrollment in clinical trials should emphasize increased representation of all races and ethnic groups.
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Zanello G, Goethel A, Rouquier S, Prescott D, Robertson SJ, Maisonneuve C, Streutker C, Philpott DJ, Croitoru K. The Cytosolic Microbial Receptor Nod2 Regulates Small Intestinal Crypt Damage and Epithelial Regeneration following T Cell-Induced Enteropathy. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2016; 197:345-55. [PMID: 27206769 DOI: 10.4049/jimmunol.1600185] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 04/21/2016] [Indexed: 12/21/2022]
Abstract
Loss of function in the NOD2 gene is associated with a higher risk of developing Crohn's disease (CD). CD is characterized by activation of T cells and activated T cells are involved in mucosal inflammation and mucosal damage. We found that acute T cell activation with anti-CD3 mAb induced stronger small intestinal mucosal damage in NOD2(-/-) mice compared with wild-type mice. This enhanced mucosal damage was characterized by loss of crypt architecture, increased epithelial cell apoptosis, delayed epithelial regeneration and an accumulation of inflammatory cytokines and Th17 cells in the small intestine. Partial microbiota depletion with antibiotics did not decrease mucosal damage 1 d after anti-CD3 mAb injection, but it significantly reduced crypt damage and inflammatory cytokine secretion in NOD2(-/-) mice 3 d after anti-CD3 mAb injection, indicating that microbial sensing by Nod2 was important to control mucosal damage and epithelial regeneration after anti-CD3 mAb injection. To determine which cells play a key role in microbial sensing and regulation of mucosal damage, we engineered mice carrying a cell-specific deletion of Nod2 in villin and Lyz2-expressing cells. T cell activation did not worsen crypt damage in mice carrying either cell-specific deletion of Nod2 compared with wild-type mice. However, increased numbers of apoptotic epithelial cells and higher expression of TNF-α and IL-22 were observed in mice carrying a deletion of Nod2 in Lyz2-expressing cells. Taken together, our results demonstrate that microbial sensing by Nod2 is an important mechanism to regulate small intestinal mucosal damage following acute T cell activation.
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Affiliation(s)
- Galliano Zanello
- Department of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Ashleigh Goethel
- Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Sandrine Rouquier
- Department of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - David Prescott
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Susan J Robertson
- Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Charles Maisonneuve
- Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Catherine Streutker
- Department of Pathology and Laboratory Medicine, St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada
| | - Dana J Philpott
- Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Kenneth Croitoru
- Department of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Zane Cohen Centre for Digestive Diseases, The Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario M5G 1X5, Canada; and Division of Gastroenterology, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada
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Gutiérrez A, Zapater P, Juanola O, Sempere L, García M, Laveda R, Martínez A, Scharl M, González-Navajas JM, Such J, Wiest R, Rogler G, Francés R. Gut Bacterial DNA Translocation is an Independent Risk Factor of Flare at Short Term in Patients With Crohn's Disease. Am J Gastroenterol 2016; 111:529-40. [PMID: 26902226 DOI: 10.1038/ajg.2016.8] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2015] [Accepted: 12/03/2015] [Indexed: 02/08/2023]
Abstract
OBJECTIVES We aimed at evaluating bacterial DNA (bactDNA) presence in blood of Crohn's disease (CD) patients in remission as an independent risk factor of flare at 6 months. METHODS This is a prospective, multicenter study on CD patients with Crohn's disease activity index (CDAI)<150. The primary end point was time-to-relapse as evaluated by CDAI>150 in the following 6 months. BactDNA in blood, the nucleotide-binding oligomerization domain containing 2 (NOD2) genotype, and serum cytokine levels were determined at baseline. RESULTS A total of 288 patients were included. BactDNA was detected in 98 patients (34.0%). A variant-NOD2 genotype was identified in 114 patients (39.6%). Forty patients (14%) relapsed during follow-up. Multivariate survival analysis identified bactDNA as an independent risk factor of flare (hazard ratio (HR) 8.75 (4.02-19.06) 95% confidence interval (CI)). Hospitalization, surgery, switch of treatment, initiation and escalation of anti-tumor necrosis factor (TNF) therapy, steroids initiation, and increased fecal calprotectin levels at 6 months were associated with bactDNA at baseline. A logistic regression analysis showed bactDNA as an independent and significant predictive factor of hospitalization (odds ratio (OR) 11.9 (3.4-42.3); P<0.001), steroids startup (OR 8.5 (2.7-27.1); P<0.001), and switch of treatment (OR 3.5 (1.6-7.7); P=0.002) at 6 months. No relationship was observed between bactDNA and mucosal lesions in patients with colonoscopy at admission. Serum pro-inflammatory cytokines were significantly increased in patients with bactDNA or a variant-NOD2 genotype. The combination of both factors induced decreased anti-TNF-α levels and a higher percentage of patients on intensified anti-TNF therapy. CONCLUSIONS BactDNA is an independent risk factor of relapse at 6 months in CD patients. BactDNA is also independently associated with an increased risk of hospitalization, switch of treatment, and steroids initiation.
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Affiliation(s)
- Ana Gutiérrez
- Servicio de Medicina Digestiva, Hospital General Universitario de Alicante, Alicante, Spain.,CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Pedro Zapater
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Oriol Juanola
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Laura Sempere
- Servicio de Medicina Digestiva, Hospital General Universitario de Alicante, Alicante, Spain
| | - Marifé García
- Servicio Digestivo, Hospital Universitario de Elche, Alicante, Spain
| | - Raquel Laveda
- Hospital Clínico Universitario de San Juan, Alicante, Spain
| | | | - Michael Scharl
- Division of Gastroenterology and Hepatology, University Hospital Zìrich, Zìrich, Switzerland
| | | | - José Such
- Digestive Disease Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, UAE
| | - Reiner Wiest
- Department of Gastroenterology, University Clinic for Visceral Medicine, Inselspital, Bern, Switzerland
| | - Gerhard Rogler
- Division of Gastroenterology and Hepatology, University Hospital Zìrich, Zìrich, Switzerland
| | - Rubén Francés
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.,Departamento Medicina Clínica, Universidad Miguel Hernández, San Juan de Alicante, Spain
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Timms VJ, Daskalopoulos G, Mitchell HM, Neilan BA. The Association of Mycobacterium avium subsp. paratuberculosis with Inflammatory Bowel Disease. PLoS One 2016; 11:e0148731. [PMID: 26849125 PMCID: PMC4746060 DOI: 10.1371/journal.pone.0148731] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Accepted: 12/09/2015] [Indexed: 12/14/2022] Open
Abstract
The association of Mycobacterium avium subspecies paratuberculosis (M. paratuberculosis) with Crohn’s disease is a controversial issue. M. paratuberculosis is detected by amplifying the IS900 gene, as microbial culture is unreliable from humans. We determined the presence of M. paratuberculosis in patients with Crohn’s disease (CD) (n = 22), ulcerative colitis (UC) (n = 20), aphthous ulcers (n = 21) and controls (n = 42) using PCR assays validated on bovine tissue. Culture from human tissue was also performed. M. paratuberculosis prevalence in the CD and UC groups was compared to the prevalence in age and sex matched non-inflammatory bowel disease controls. Patients and controls were determined to be M. paratuberculosis positive if all three PCR assays were positive. A significant association was found between M. paratuberculosis and Crohn’s disease (p = 0.02) that was not related to age, gender, place of birth, smoking or alcohol intake. No significant association was detected between M. paratuberculosis and UC or aphthous ulcers; however, one M. paratuberculosis isolate was successfully cultured from a patient with UC. We report the resistance of this isolate to ethambutol, rifampin, clofazamine and streptomycin. Interestingly this isolate could not only survive but could grow slowly at 5°C. We demonstrate a significant association between M. paratuberculosis and CD using multiple pre-validated PCR assays and that M. paratuberculosis can be isolated from patients with UC.
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Affiliation(s)
- Verlaine J. Timms
- School of Biotechnology and Biomolecular Sciences, Level 3, Biosciences Building, University of New South Wales, Sydney, Australia
| | - George Daskalopoulos
- Inner West Endoscopy Centre, Endoscopy Services Pty. Ltd., Marrickville, Sydney, Australia
| | - Hazel M. Mitchell
- School of Biotechnology and Biomolecular Sciences, Level 3, Biosciences Building, University of New South Wales, Sydney, Australia
| | - Brett A. Neilan
- School of Biotechnology and Biomolecular Sciences, Level 3, Biosciences Building, University of New South Wales, Sydney, Australia
- * E-mail:
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Abstract
Genetic factors play a significant role in determining inflammatory bowel disease (IBD) susceptibility. Epidemiologic data support genetic contribution to the pathogenesis of IBD, which include familial aggregation, twin studies, and racial and ethnic differences in disease prevalence. Recently, several new genes have been identified to be involved in the genetic susceptibility to IBD. The characterization of novel genes potentially will lead to the identification of therapeutic agents and clinical assessment of phenotype and prognosis in patients with IBD. The development of genetic markers associated with clinical outcomes in patients with IBD will be very important in the future. The progress of molecular biology tools (microarrays, proteomics, and epigenetics) have progressed the field of the genetic markers discovery. The advances in bioinformatics coupled with cross-disciplinary collaborations have greatly enhanced our ability to retrieve, characterize, and analyze large amounts of data generated by the technological advances. The techniques available for markers development are genomics (single nucleotide polymorphism genotyping, pharmacogenetics, and gene expression analyses) and proteomics. This could be a potential great benefit in predicting the course of disease in individual patients and in guiding appropriate medical therapy.
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Salkic NN, Adler G, Zawada I, Alibegovic E, Karakiewicz B, Kozlowska-Wiechowska A, Wasilewicz M, Sulzyc-Bielicka V, Bielicki D. NOD2/CARD15 mutations in Polish and Bosnian populations with and without Crohn's disease: prevalence and genotype-phenotype analysis. Bosn J Basic Med Sci 2015; 15:67-72. [PMID: 26042516 PMCID: PMC4469939 DOI: 10.17305/bjbms.2015.348] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2015] [Revised: 02/23/2015] [Accepted: 02/23/2015] [Indexed: 12/22/2022] Open
Abstract
Data on prevalence and phenotypic consequences of nucleotide-binding oligomerisation domain 2/caspase recruitment domains 15 (NOD2/CARD15) variants in Crohn's disease (CD) population in Poland and Bosnia and Herzegovina (B&H) are nonexistent. We aimed to determine the prevalence of NOD2/CARD15 mutations and their association with disease phenotype in Polish and Bosnian patients with CD and in healthy controls. We prospectively recruited 86 CD patients and 83 controls in Poland and 30 CD patients and 30 controls in B&H, 229 in total. We determined the prevalence of NOD2/CARD15 mutations and their association with the disease phenotype according to Montreal classification. Participants were genotyped for Leu1007fsinsC and Gly908Arg mutations. At least one CD-associated allele was found in 29/86 (33.7%) of Polish CD patients and in 9/83 (10.8%) of healthy controls (p<0.001). In both CD patients and controls in Bosnian sample, at least one NOD2 mutation was found in equal number of patients (3/30; 10%) with all of the NOD2 mutation positive CD patients being homozygous, while controls being heterozygous. In Polish sample, perianal disease was less frequent in CD patients with any NOD2 mutation (1/21; 4.8%) compared to those without (11/41; 26.8%; p=0.046). Higher percentage of patients with NOD2 mutations had history of CD related surgery when compared with those without mutations (66.7% vs. 43.3%; p=0.05). The risk for CD is increased in patients with NOD2 mutations (Poland) and especially in the presence of homozygous NOD2 mutations (Poland and Bosnia). The presence of variant NOD2 alleles is associated with increased need for surgery and reduced occurrence of perianal disease.
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Affiliation(s)
- Nermin N Salkic
- Department of Gastroenterology and Hepatology University Clinical Center Tuzla.
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40
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Bach H. What Role Does Mycobacterium avium subsp. paratuberculosis Play in Crohn's Disease? Curr Infect Dis Rep 2015; 17:463. [PMID: 25754452 DOI: 10.1007/s11908-015-0463-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Crohn's disease (CD) is a chronic, debilitating inflammatory bowel disease with no etiological agent yet identified. Studies have demonstrated that the bacterium Mycobacterium avium subsp. paratuberculosis (MAP) is present in a high percentage of CD patients. Although MAP has been isolated from human specimens, current techniques fail to show the presence of MAP in 100 % of tissues or biopsies obtained from CD patient lesions, and thus MAP cannot meet Koch's postulate as the etiological agent of CD. In this report, the effect of genetic and immune factors as well as the presence of MAP as a potential environmental factor is analyzed.
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Affiliation(s)
- Horacio Bach
- Division of Infectious Diseases, Department of Medicine, University of British Columbia, 410-2660 Oak Street, Vancouver, BC, V6H 3Z6, Canada,
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41
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Abstract
BACKGROUND There is increasing recognition of Crohn's disease (CD) in non-white populations. However, reports of racial disparities in the phenotype of CD are still inconsistent. AIM : The aim of this study was to test the hypothesis that African American (AA) patients have higher incidence of severe fistulizing perianal Crohn's disease (FPD) compared with white patients. METHODS Cross-sectional analysis of 333 adult CD patients treated at The Mount Sinai Hospital with infliximab between May 2011 and December 2011 was conducted. Self-reported race/ethnicity was recorded and proportions of each group with FPD were compared across the population. RESULTS Among all 333 evaluable CD patients on infliximab, 73.6% were white, 11.4% AA, 13.2% Hispanic, and 1.8% Asian. Of these 333 patients, 88 had FPD: only 48 of these (54.5%) were white, whereas fully 18 (20.5%) were AA, 20 (22.7%) were Hispanic, and 2 (2.3%) were Asian. Thus, patients receiving infliximab for FPD were significantly more likely to be AA or Hispanic than white (AA vs. whites: risk ratio=2.63; 95% confidence interval, 1.74-3.96; P=<0.0001; Hispanics vs. whites: risk ratio=2.32; 95% confidence interval, 1.54-3.50; P=0.0001). There was no statistically significant difference between AA and Hispanics. CONCLUSION CD patients at our medical center with FPD requiring infliximab therapy were significantly more likely to be AA or Hispanic.
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Branković I, van Ess EF, Noz MP, Wiericx WAJ, Spaargaren J, Morré SA, Ouburg S. NOD1 in contrast to NOD2 functional polymorphism influence Chlamydia trachomatis infection and the risk of tubal factor infertility. Pathog Dis 2015; 73:1-9. [PMID: 25854006 DOI: 10.1093/femspd/ftu028] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/15/2014] [Indexed: 01/01/2023] Open
Abstract
Intracellular pattern-recognition receptors NOD1 and NOD2 are capable of sensing common structural units of bacterial walls. Recognition triggers specific immune signalling pathways and leads to pro-inflammatory cytokine upregulation and adequate immune response. We investigated whether two functional polymorphisms in NOD1 and NOD2 exert an effect on susceptibility to (STD patients) and severity of (female patients visiting the fertility clinic) Chlamydia trachomatis infection in 807 Dutch Caucasian women. A significant association of the NOD1 +32656 GG insertion variant with protection against infection with C. trachomatis has been detected [p: 0.0057; OR: 0.52]. When comparing C. trachomatis-positive women without symptoms to C. trachomatis-positive women with symptoms, and to C. trachomatis-positive women with TFI, we observed an increasing trend in carriage of the GG allele [Ptrend: 0.0003]. NOD2 1007fs failed to reveal an association. We hypothesize that the underlying mechanism might be a functional effect of the GG insertion on IFN-beta-dependent regulation of immune response in the genital tract. The research is part of an ongoing effort of identifying key polymorphisms that determine the risk of TFI and effectively translating them into the clinical setting for the purpose of optimizing diagnostic management of women at risk for developing TFI.
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Affiliation(s)
- Ivan Branković
- Laboratory of Immunogenetics, Department of Medical Microbiology and Infection Control, VU University Medical Center, 1081 HV Amsterdam, The Netherlands Institute for Public Health Genomics, Department of Genetics and Cell Biology, School for Oncology and Developmental Biology (GROW), Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200 MD Maastricht, The Netherlands
| | - Eleanne F van Ess
- Laboratory of Immunogenetics, Department of Medical Microbiology and Infection Control, VU University Medical Center, 1081 HV Amsterdam, The Netherlands
| | - Marlies P Noz
- Laboratory of Immunogenetics, Department of Medical Microbiology and Infection Control, VU University Medical Center, 1081 HV Amsterdam, The Netherlands
| | - Wilhelmina Anke J Wiericx
- Laboratory of Immunogenetics, Department of Medical Microbiology and Infection Control, VU University Medical Center, 1081 HV Amsterdam, The Netherlands
| | - Joke Spaargaren
- Laboratory of Immunogenetics, Department of Medical Microbiology and Infection Control, VU University Medical Center, 1081 HV Amsterdam, The Netherlands
| | - Servaas A Morré
- Laboratory of Immunogenetics, Department of Medical Microbiology and Infection Control, VU University Medical Center, 1081 HV Amsterdam, The Netherlands Institute for Public Health Genomics, Department of Genetics and Cell Biology, School for Oncology and Developmental Biology (GROW), Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200 MD Maastricht, The Netherlands Dutch Chlamydia trachomatis Reference Laboratory, Department of Medical Microbiology and Infection Control, VU University Medical Center, 1081 HV Amsterdam, The Netherlands
| | - Sander Ouburg
- Laboratory of Immunogenetics, Department of Medical Microbiology and Infection Control, VU University Medical Center, 1081 HV Amsterdam, The Netherlands
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Abstract
: Inflammasomes are multiprotein complexes that process procytokines into mature forms of interleukin 1β and interleukin 18 and induce pyroptotic cell death. Evidence linking NLRP3, NLRC4, and NLRP6 inflammasomes to intestinal inflammation is reviewed to provide a basis to understand how the innate immune system discriminates pathogenic bacteria from commensal bacteria and shapes microbial ecology. Inflammasomes have a direct and important role limiting colitis by directing effective immune responses against pathogenic bacterial infections in the intestine. Chronic granulomatous disease is presented to reveal a contrasting proinflammatory effect of inflammasomes. This pathogenic effect is unmasked in a state of immunodeficiency where bacterial growth is poorly controlled increasing inflammasome activity. The role of inflammasomes in inflammation associated with Crohn's disease and ulcerative colitis is discussed. Finally, mechanistic studies linking genetic polymorphisms in ATG16L and NOD2 to inflammasome activation provide a basis for new hypotheses to explain how genetic polymorphism associated with Crohn's disease modulate intestinal inflammation. A deeper understanding of the role of inflammasomes in intestinal inflammation is expected to identify new ways of treating inflammatory bowel disease.
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Muro M, López-Hernández R, Mrowiec A. Immunogenetic biomarkers in inflammatory bowel diseases: Role of the IBD3 region. World J Gastroenterol 2014; 20:15037-15048. [PMID: 25386052 PMCID: PMC4223237 DOI: 10.3748/wjg.v20.i41.15037] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Revised: 12/19/2013] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
Many studies have demonstrated the linkage between the IBD3 region (6p21.1-23), an area which encompasses the famous human leukocyte antigen (HLA) complex, and Crohn’s disease (CD) or ulcerative colitis (UC). IBD3 is the only region that meets genome-wide significance, and provides stronger evidence of the linkage than 16p13.1-16q12.2 (IBD1), the locus that contains the susceptibility gene CARD15. However, despite these findings, IBD3 susceptibility genes remain elusive and unclear due to the strong linkage disequilibrium, extensive polymorphism, and high gene density that characterize this area and also due to varying allele frequencies in populations around the world. This area presents an extremely high abundance of genes, including the classical and non-classical major histocompatibility complex (MHC) class I and II genes, and other genes, namely MHC class III genes tumor necrosis factor (TNF)-α and -β, and Hsp, whose proteins play key functions in immunological processes. To date, it is not clear which genes within the MHC family contribute to the IBD pathogenesis, although certain HLA alleles have been associated with IBD. Recent insights into the biological function of other genes encoded within the IBD3 region, such as the MHC class I chain-related (MIC) genes, have led investigators to a more comprehensive exploration of this region. MHC class I chain-related molecule A (MICA) is highly polymorphic and interacts with NKG2D, its receptor on the surface of NK, Tγδ and T CD8+ cells. Increased expression of MICA in intestinal epithelial cells and increased expression of NKG2D in CD4+ T cells (lamina propria) in patients with CD have also been reported. MICA alleles have also been associated with IBD, and a variation at amino acid position 129 of the α2-heavy chain domain seems to categorize MICA alleles into strong and weak binders of NKG2D receptor, thereby influencing the effector cells’ function. In this regard, a relevant role of MICA-129-Val/Met single nucleotide polymorphism has recently been implicated in the pathogenesis of IBD. TNF-α and -β also play an important role in inflammatory response. In fact, IBD is commonly treated with TNF-α inhibitors. Additionally, polymorphisms of TNF-α gene are known to affect the gene expression level and particular TNF-α genotypes may influence the response of IBD patients treated with TNF-α inhibitors.
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Association between nucleotide oligomerisation domain two (Nod2) gene polymorphisms and canine inflammatory bowel disease. Vet Immunol Immunopathol 2014; 161:32-41. [DOI: 10.1016/j.vetimm.2014.06.003] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2014] [Revised: 06/06/2014] [Accepted: 06/19/2014] [Indexed: 02/07/2023]
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Li Y, Tian Y, Zhu W, Gong J, Gu L, Zhang W, Guo Z, Li N, Li J. Cesarean delivery and risk of inflammatory bowel disease: a systematic review and meta-analysis. Scand J Gastroenterol 2014; 49:834-844. [PMID: 24940636 DOI: 10.3109/00365521.2014.910834] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE It has been considered that cesarean delivery is a risk factor for the two subtypes of inflammatory bowel diseases (IBDs): Crohn's disease (CD) and ulcerative colitis (UC). The aim of this meta-analysis was to examine the relationship between cesarean delivery and the development of IBD. MATERIAL AND METHODS We searched the articles retrieved by PubMed, MEDLINE and EMBASE databases to identify observational studies regarding the relationship between cesarean section and the development of CD and/or UC. Pooled odds ratios were calculated for each relationship. RESULTS Nine studies evaluated the potential association between cesarean delivery and the development of IBD and met all of our inclusion criteria. The pooled data from six included studies indicated cesarean delivery was a risk factor for CD (95% confidence interval [CI]: 1.12-1.70; p = 0.003). Likewise, we observed a positive association between cesarean delivery and pediatric CD (95% CI: 1.06-1.35; p = 0.005). However, results from the four included studies for UC indicated the rate of cesarean section in UC patients was not higher than that of control subjects (95% CI: 0.87-1.32; p = 0.54). Overall, we did not observe a positive relationship between cesarean delivery and IBD (95% CI: 0.99-1.30; p = 0.08). CONCLUSION Results of this meta-analysis support the hypothesis that cesarean delivery was associated with the risk of CD but not of UC. The total rate of cesarean delivery of IBD patients was similar with that of control subjects.
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Affiliation(s)
- Yi Li
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University , No. 305 East Zhongshan Road, Nanjing , PR China
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Song M, Park HJ. Anti-inflammatory effect of Phellinus linteus grown on germinated brown rice on dextran sodium sulfate-induced acute colitis in mice and LPS-activated macrophages. JOURNAL OF ETHNOPHARMACOLOGY 2014; 154:311-318. [PMID: 24495471 DOI: 10.1016/j.jep.2013.12.059] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2013] [Revised: 12/07/2013] [Accepted: 12/31/2013] [Indexed: 06/03/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE AND AIM OF THE STUDY Phellinus linteus is a herb used in traditional Asian medicine to treat stomachache, inflammation, and tumors. Recent studies show that the extract of Phellinus linteus has anti-inflammatory and antitumor activities. However, Phellinus linteus extract has limitation of high cost and limited availability because of supply shortage. Here, we grew Phellinus linteus on germinated brown rice to address the issue of supply shortage and investigated anti-inflammatory effect in vivo as well as in vitro. MATERIALS AND METHODS Phellinus linteus grown on germinated brown rice (PBR) were extracted using filtration steps, which included γ-aminobutyric acid (GABA). The PBR (200, 500mg/kg/day) was applied into the mouse model of dextran sodium sulfate (DSS)-induced colitis and lipopolysaccharide (LPS)-stimulated mouse macrophage RAW264.7 cells. We used sulfasalazine as a reference drug. In addition, mechanism related to anti-inflammatory was investigated by Western blotting. RESULTS In the mouse model of DSS-induced colitis, PBR ameliorated the pathological characteristics of colitis such as shortening of colon length and improved the disease activity index score. In addition, we showed that PBR reduced the expression of nuclear factor-kappa B (NF-κB) in colitis. Western blotting showed that PBR decreased the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (Cox-2) proteins. Further, PBR treatment reduced the expression of mitogen-activated protein kinases (MAPKs) (e.g., extracellular signal-regulated protein kinase (ERK) and p38) in the mouse model of DSS-induced colitis. CONCLUSIONS Treatment of RAW 264.7 macrophages with a combination of PBR and LPS showed a significant concentration-dependent inhibition of nitric oxide (NO) and prostaglandin E2 (PGE2) production. In addition, we determined the ability of PBR to reduce the iNOS and tumor necrosis factor (TNF)-α expression. PBR inhibited the expression of iNOS, NF-κB, and Cox-2 proteins in LPS-stimulated RAW264.7 macrophages. This study presents the potential use of PBR as a drug candidate against colitis.
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Affiliation(s)
- Minjung Song
- Department of Bioscience and Biotechnology, Konkuk University, Gwangjin-Gu, Achasan-rho 263, Seoul, South Korea
| | - Hye-Jin Park
- Department of Food science and Biotechnology, College of BioNano technology, Gachon University, Sungnam 461-701, South Korea.
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Strisciuglio C, Auricchio R, Martinelli M, Staiano A, Giugliano FP, Andreozzi M, De Rosa M, Giannetti E, Gianfrani C, Izzo P, Troncone R, Miele E. Autophagy genes variants and paediatric Crohn's disease phenotype: a single-centre experience. Dig Liver Dis 2014; 46:512-517. [PMID: 24656308 DOI: 10.1016/j.dld.2014.02.016] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2013] [Revised: 02/10/2014] [Accepted: 02/18/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Little evidence demonstrating the correlation between several single nucleotide polymorphisms and a specific phenotype of Crohn's disease has been reported in children. We investigated the relationship between autophagy genes variants and clinical features in our children with Crohn's disease. METHODS Genotyping for ATG16L1, NOD2/CARD15, and IRGM1 was performed in 80 consecutive patients with Crohn's disease (median age: 11 years; range: 0.7-17.9 years). Crohn's disease location and behaviour were classified using the Paris classification. Additional data were collected from clinical records on patients' demographics, age at symptom onset and diagnosis, extraintestinal manifestations, therapy, clinical relapses, and need of surgical intervention. RESULTS Patients homozygous for the risk allele ATG16L1 (T300A) showed a trend towards switching to a stricturing phenotype during the course of disease compared to children either homozygous for the wild-type allele or heterozygous for the ATG16L1 single nucleotide polymorphism (p=0.01). Homozygosity for the ATG16L1 risk allele was associated with a major recurrence of clinical relapses and earlier introduction of immunosuppressants (p=0.006 and p=0.04, respectively). Heterozygosity for the NOD2 rs2066847 allele was associated with major ileal involvement (p=0.01). CONCLUSION In patients carrying the T300A variant, Crohn's disease follows a more aggressive clinical course.
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Affiliation(s)
- Caterina Strisciuglio
- Department of Translational Medical Sciences, Section of Pediatrics, University of Naples "Federico II", Italy
| | - Renata Auricchio
- Department of Translational Medical Sciences, Section of Pediatrics, University of Naples "Federico II", Italy
| | - Massimo Martinelli
- Department of Translational Medical Sciences, Section of Pediatrics, University of Naples "Federico II", Italy
| | - Annamaria Staiano
- Department of Translational Medical Sciences, Section of Pediatrics, University of Naples "Federico II", Italy.
| | - Francesca Paola Giugliano
- Department of Translational Medical Sciences, Section of Pediatrics, University of Naples "Federico II", Italy
| | - Marialuisa Andreozzi
- Department of Translational Medical Sciences, Section of Pediatrics, University of Naples "Federico II", Italy
| | - Marina De Rosa
- Department of Molecular Medicine and Medical Biotechnology and CEINGE, University of Naples "Federico II", Italy
| | - Eleonora Giannetti
- Department of Translational Medical Sciences, Section of Pediatrics, University of Naples "Federico II", Italy
| | - Carmela Gianfrani
- Department of Translational Medical Sciences, Section of Pediatrics, University of Naples "Federico II", Italy; Institute of Protein Biochemistry-CNR, Naples, Italy
| | - Paola Izzo
- Department of Molecular Medicine and Medical Biotechnology and CEINGE, University of Naples "Federico II", Italy
| | - Riccardo Troncone
- Department of Translational Medical Sciences, Section of Pediatrics, University of Naples "Federico II", Italy
| | - Erasmo Miele
- Department of Translational Medical Sciences, Section of Pediatrics, University of Naples "Federico II", Italy
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Bhullar M, Macrae F, Brown G, Smith M, Sharpe K. Prediction of Crohn’s disease aggression through NOD2/ CARD15 gene sequencing in an Australian cohort. World J Gastroenterol 2014; 20:5008-5016. [PMID: 24803813 PMCID: PMC4009534 DOI: 10.3748/wjg.v20.i17.5008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2013] [Revised: 08/04/2013] [Accepted: 09/17/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the association between mutations in oligomerisation domain 2/caspase recruitment domains 15 (NOD2/CARD15) and the natural history of Crohn’s disease (CD) to identify patients who would benefit from early aggressive medical intervention.
METHODS: We recruited thirty consecutive unrelated CD patients with a history of ileo-caecal or small bowel resection during the period 1980-2000; Fifteen patients of these had post-operative relapse that required further surgery and fifteen did not. Full sequencing of the NOD2/CARD15 gene using dHPLC for exons 3, 5, 7, 10 and 12 and direct sequencing for exons 2, 4, 6, 8, 9 and 11 was conducted. CD patients categorized as carrying variants were anyone with at least 1 variant of the NOD2/CARD15 gene.
RESULTS: About 13.3% of the cohort (four patients) carried at least one mutant allele of 3020insC of the NOD2/CARD15 gene. There were 20 males and 10 females with a mean age of 43.3 years (range 25-69 years). The mean follow up was 199.6 mo and a median of 189.5 mo. Sixteen sequence variations within the NOD2/CARD15 gene were identified, with 9 of them occurring with an allele frequency of greater than 10 %. In this study, there was a trend to suggest that patients with the 3020insC mutation have a higher frequency of operations compared to those without the mutation. Patients with the 3020insC mutation had a significantly shorter time between the diagnosis of CD and initial surgery. This study included Australian patients of ethnically heterogenous background unlike previous studies conducted in different countries.
CONCLUSION: These findings suggest that patients carrying NOD2/CARD15 mutations follow a rapid and more aggressive form of Crohn’s disease showing a trend for multiple surgical interventions and significantly shorter time to early surgery.
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Aljebreen AM, Alharbi OR, Azzam NA, Almalki AS, Alswat KA, Almadi MA. Clinical epidemiology and phenotypic characteristics of Crohn's disease in the central region of Saudi Arabia. Saudi J Gastroenterol 2014; 20:162-9. [PMID: 24976279 PMCID: PMC4067912 DOI: 10.4103/1319-3767.132993] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND/AIMS Despite the remarkable increase in the incidence of Crohn's disease among Saudis in recent years, data about Crohn's disease in Saudi Arabia are scarce. The aim of this study was to determine the clinical epidemiology and phenotypic characteristics of Crohn's disease in the central region of Saudi Arabia. PATIENTS AND METHODS A data registry, Inflammatory Bowel Disease Information System (IBDIS), was used to register Crohn's disease patients who presented to the gastroenterology clinics in four tertiary care centers in Riyadh, Saudi Arabia between September 2009 and February 2013. Patients' characteristics, disease location, behavior, age at diagnosis according to the Montreal classification, course of the disease, and extraintestinal manifestation were recorded. RESULTS Among 497 patients with Crohn's disease, 59% were males with a mean age at diagnosis of 25 years [95% Confidence Interval (CI): 24-26, range 5-75 years]. The mean duration from the time of complaint to the day of the diagnosis was 11 months, and the mean duration of the disease from diagnosis to the day of entry to the registry was 40 months. Seventy-seven percent of our patients were aged 17-40 years at diagnosis, 16.8% were ≤16 years of age, and 6.6% were >40 years of age. According to the Montreal classification of disease location, 48.8% of patients had ileocolonic involvement, 43.5% had limited disease to the terminal ileum or cecum, 7.7% had isolated colonic involvement, and 16% had an upper gastrointestinal involvement. Forty-two percent of our patients had a non-stricturing, non-penetrating behavior, while 32.8% had stricturing disease and 25.4% had penetrating disease. CONCLUSION Crohn's disease is frequently encountered in Saudi Arabia. The majority of patients are young people with a predilection for males, while its behavior resembled that of western societies in terms of age of onset, location, and behavior.
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Affiliation(s)
- Abdulrahman M. Aljebreen
- Gastroenterology Division, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
- Address for correspondence: Dr. Abdulrahman M. Aljebreen, PO Box 2925, Internal Medicine Department, King Khalid University Hospital, Riyadh - 11461, Saudi Arabia. E-mail:
| | - Othman R. Alharbi
- Gastroenterology Division, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
| | - Nahla A. Azzam
- Gastroenterology Division, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
| | | | - Khalid A. Alswat
- Gastroenterology Division, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
| | - Majid A. Almadi
- Gastroenterology Division, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
- The McGill University Health Center, Montreal General Hospital, McGill University, Montreal, Canada
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