|
1
|
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.
Collapse
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
| |
Collapse
|
|
2
|
Wu J, Zhu N, Hu J, Zhang C, Fang Y, Wu Y, Shi Y, Liu Q, Ding H, Mei Q, Bai B, Han W. Does HLA-DQA1*05 carriage have a greater impact on the outcome of infliximab therapy for isolated small-bowel Crohn's disease? Int J Immunogenet 2024; 51:380-387. [PMID: 39387318 DOI: 10.1111/iji.12696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 08/28/2024] [Accepted: 09/22/2024] [Indexed: 10/15/2024]
Abstract
Carriage of HLA-DQA1*05 is thought to increase the formation of anti-tumour necrosis factor alpha (TNF-α) antibodies, reducing the drug efficacy in Crohn's disease (CD) patients. However, little data are currently available for small-bowel Crohn's disease (SB-CD). A specific assessment of the impact of HLA-DQA1*05 on the clinical response to treatment with infliximab (IFX), a TNF-α antagonists, in SB-CD patients is necessary. We conducted a single-center retrospective study that included 106 SB-CD patients treated with IFX. The serum samples were collected for antibodies to infliximab (ATI) testing and HLA-DQA1*05 genotyping. Double-balloon enteroscopy (DBE) was performed following the IFX treatment, with endoscopic outcomes evaluated using the partial simple endoscopic score for CD (pSES-CD), whereas the clinical response was assessed with the Crohn's disease activity index (CDAI). Multivariate logistic regression and multivariate COX regression analyses were employed to analyze the correlation of the HLA-DQA1*05 genotypes with other clinical variables. In this study, 30.2% of SB-CD patients carried the HLA-DQA1*05 allele, which significantly increased their risk of ATI generation (odds ratio [OR] = 2.337, p = .043), but it was not associated with the clinical response to IFX and drug persistence (OR = 2.356, p = .145; OR = 0.457, p = .249). The endoscopic remission rates were 40.6% (13/32) and 55.4% (41/74) in HLA-DQA1*05 carriers and non-carriers, respectively. HLA-DQA1*05 was not associated with endoscopic remission (OR = 0.684, p = .414). The HLA-DQA1*05 variant is identified as a significant risk factor of ATI formation in Chinese patients with SB-CD, but is not associated with the clinical response of IFX treatment and endoscopic remission of SB lesions.
Collapse
Affiliation(s)
- Juan Wu
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Nannan Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jing Hu
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Chenyu Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yuanyuan Fang
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yumei Wu
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yongrong Shi
- The First Clinical Medical College, Anhui Medical University, Hefei, China
| | - Qiuyuan Liu
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Hao Ding
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Qiao Mei
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Bingqing Bai
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Wei Han
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| |
Collapse
|
|
3
|
El Hadad J, Schreiner P, Vavricka SR, Greuter T. The Genetics of Inflammatory Bowel Disease. Mol Diagn Ther 2024; 28:27-35. [PMID: 37847439 PMCID: PMC10787003 DOI: 10.1007/s40291-023-00678-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/26/2023] [Indexed: 10/18/2023]
Abstract
The genetic background of inflammatory bowel disease, both Crohn's disease and ulcerative colitis, has been known for more than 2 decades. In the last 20 years, genome-wide association studies have dramatically increased our knowledge on the genetics of inflammatory bowel disease with more than 200 risk genes having been identified. Paralleling this increasing knowledge, the armamentarium of inflammatory bowel disease medications has been growing constantly. With more available therapeutic options, treatment decisions become more complex, with still many patients experiencing a debilitating disease course and a loss of response to treatment over time. With a better understanding of the disease, more effective personalized treatment strategies are looming on the horizon. Genotyping has long been considered a strategy for treatment decisions, such as the detection of thiopurine S-methyltransferase and nudix hydrolase 15 polymorphisms before the initiation of azathioprine. However, although many risk genes have been identified in inflammatory bowel disease, a substantial impact of genetic risk assessment on therapeutic strategies and disease outcome is still missing. In this review, we discuss the genetic background of inflammatory bowel disease, with a particular focus on the latest advances in the field and their potential impact on management decisions.
Collapse
Affiliation(s)
- Jasmina El Hadad
- Department of Internal Medicine, Triemli Hospital, Zurich, Switzerland
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Philipp Schreiner
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Stephan R Vavricka
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
- Center for Gastroenterology and Hepatology, Zurich, Switzerland
| | - Thomas Greuter
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
- Division of Gastroenterology and Hepatology, University Hospital Lausanne-CHUV, Lausanne, Switzerland.
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, GZO Zurich Regional Health Center, Spitalstrasse 66, 8620, Wetzikon, Switzerland.
| |
Collapse
|
|
4
|
Kamal S, Parkash N, Beattie W, Christensen B, Segal JP. Are We Ready to Reclassify Crohn's Disease Using Molecular Classification? J Clin Med 2023; 12:5786. [PMID: 37762727 PMCID: PMC10532006 DOI: 10.3390/jcm12185786] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 08/21/2023] [Accepted: 09/02/2023] [Indexed: 09/29/2023] Open
Abstract
Crohn's disease (CD) is a type of inflammatory bowel disease. The number of IBD cases worldwide was estimated to be 4.9 million in 2019. CD exhibits heterogeneity in clinical presentation, anatomical involvement, disease behaviour, clinical course and response to treatment. The classical description of CD involves transmural inflammation with skip lesions anywhere along the entire gastrointestinal tract. The complexity and heterogeneity of Crohn's disease is not currently reflected in the conventional classification system. Though the knowledge of Crohn's pathophysiology remains far from understood, the established complex interplay of the omics-genomics, transcriptomics, proteomics, epigenomics, metagenomics, metabolomics, lipidomics and immunophenomics-provides numerous targets for potential molecular markers of disease. Advancing technology has enabled identification of small molecules within these omics, which can be extrapolated to differentiate types of Crohn's disease. The multi-omic future of Crohn's disease is promising, with potential for advancements in understanding of its pathogenesis and implementation of personalised medicine.
Collapse
Affiliation(s)
- Shahed Kamal
- Department of Gastroenterology, Northern Hospital, Epping, Melbourne VIC 3076, Australia
| | - Nikita Parkash
- Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Melbourne VIC 3052, Australia
| | - William Beattie
- Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Melbourne VIC 3052, Australia
| | - Britt Christensen
- Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Melbourne VIC 3052, Australia
- Department of Gastroenterology, The University of Melbourne, Parkville, Melbourne VIC 3010, Australia
| | - Jonathan P. Segal
- Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Melbourne VIC 3052, Australia
- Department of Gastroenterology, The University of Melbourne, Parkville, Melbourne VIC 3010, Australia
| |
Collapse
|
|
5
|
Richard N, Savoye G, Leboutte M, Amamou A, Ghosh S, Marion-Letellier R. Crohn’s disease: Why the ileum? World J Gastroenterol 2023; 29:3222-3240. [PMID: 37377591 PMCID: PMC10292140 DOI: 10.3748/wjg.v29.i21.3222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/23/2023] [Accepted: 05/08/2023] [Indexed: 06/01/2023] Open
Abstract
Crohn’s disease (CD) is an inflammatory bowel disease characterized by immune-mediated flares affecting any region of the intestine alternating with remission periods. In CD, the ileum is frequently affected and about one third of patients presents with a pure ileal type. Moreover, the ileal type of CD presents epidemiological specificities like a younger age at onset and often a strong link with smoking and genetic susceptibility genes. Most of these genes are associated with Paneth cell dysfunction, a cell type found in the intestinal crypts of the ileum. Besides, a Western-type diet is associated in epidemiological studies with CD onset and increasing evidence shows that diet can modulate the composition of bile acids and gut microbiota, which in turn modulates the susceptibility of the ileum to inflammation. Thus, the interplay between environmental factors and the histological and anatomical features of the ileum is thought to explain the specific transcriptome profile observed in CD ileitis. Indeed, both immune response and cellular healing processes harbour differences between ileal and non-ileal CD. Taken together, these findings advocate for a dedicated therapeutic approach to managing ileal CD. Currently, interventional pharmacological studies have failed to clearly demonstrate distinct response profiles according to disease site. However, the high rate of stricturing disease in ileal CD requires the identification of new therapeutic targets to significantly change the natural history of this debilitating disease.
Collapse
Affiliation(s)
- Nicolas Richard
- University of Rouen Normandie, INSERM, ADEN UMR 1073, Nutrition, Inflammation and Microbiota-Gut-Brain Axis, Rouen F-76000, France
- CHU Rouen, Department of Gastroenterology, Rouen University Hospital-Charles Nicolle, Rouen F-76000, France
- Institute for Research and Innovation in Biomedicine, University of Rouen Normandie, Rouen F-76000, France
| | - Guillaume Savoye
- University of Rouen Normandie, INSERM, ADEN UMR 1073, Nutrition, Inflammation and Microbiota-Gut-Brain Axis, Rouen F-76000, France
- CHU Rouen, Department of Gastroenterology, Rouen University Hospital-Charles Nicolle, Rouen F-76000, France
- Institute for Research and Innovation in Biomedicine, University of Rouen Normandie, Rouen F-76000, France
| | - Mathilde Leboutte
- University of Rouen Normandie, INSERM, ADEN UMR 1073, Nutrition, Inflammation and Microbiota-Gut-Brain Axis, Rouen F-76000, France
- Institute for Research and Innovation in Biomedicine, University of Rouen Normandie, Rouen F-76000, France
| | - Asma Amamou
- APC Microbiome Ireland, Biosciences Building, University College Cork, Cork T12 YT20, Ireland
| | - Subrata Ghosh
- APC Microbiome Ireland, Biosciences Building, University College Cork, Cork T12 YT20, Ireland
| | - Rachel Marion-Letellier
- University of Rouen Normandie, INSERM, ADEN UMR 1073, Nutrition, Inflammation and Microbiota-Gut-Brain Axis, Rouen F-76000, France
- Institute for Research and Innovation in Biomedicine, University of Rouen Normandie, Rouen F-76000, France
| |
Collapse
|
|
6
|
Shome M, Song L, Williams S, Chung Y, Murugan V, Park JG, Faubion W, Pasha SF, Leighton JA, LaBaer J, Qiu J. Serological profiling of Crohn’s disease and ulcerative colitis patients reveals anti-microbial antibody signatures. World J Gastroenterol 2022; 28:4089-4101. [PMID: 36157118 PMCID: PMC9403437 DOI: 10.3748/wjg.v28.i30.4089] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 06/16/2022] [Accepted: 07/11/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The healthcare burden of inflammatory bowel disease (IBD) is rising globally and there are limited non-invasive biomarkers for accurate and early diagnosis.
AIM To understand the important role that intestinal microbiota play in IBD pathogenesis and identify anti-microbial antibody signatures that benefit clinical management of IBD patients.
METHODS We performed serological profiling of 100 Crohn’s disease (CD) patients, 100 ulcerative colitis (UC) patients and 100 healthy controls against 1173 bacterial and 397 viral proteins from 50 bacteria and 33 viruses on protein microarrays. The study subjects were randomly divided into discovery (n = 150) and validation (n = 150) sets. Statistical analysis was performed using R packages.
RESULTS Anti-bacterial antibody responses showed greater differential prevalence among the three subject groups than anti-viral antibody responses. We identified novel antibodies against the antigens of Bacteroidetes vulgatus (BVU_0562) and Streptococcus pneumoniae (SP_1992) showing higher prevalence in CD patients relative to healthy controls. We also identified antibodies against the antigen of Streptococcus pyogenes (SPy_2009) showing higher prevalence in healthy controls relative to UC patients. Using these novel antibodies, we built biomarker panels with area under the curve (AUC) of 0.81, 0.87, and 0.82 distinguishing CD vs control, UC vs control, and CD vs UC, respectively. Subgroup analysis revealed that penetrating CD behavior, colonic CD location, CD patients with a history of surgery, and extensive UC exhibited highest antibody prevalence among all patients. We demonstrated that autoantibodies and anti-microbial antibodies in CD patients had minimal correlation.
CONCLUSION We have identified antibody signatures for CD and UC using a comprehensive analysis of anti-microbial antibody response in IBD. These antibodies and the source microorganisms of their target antigens improve our understanding of the role of specific microorganisms in IBD pathogenesis and, after future validation, should aid early and accurate diagnosis of IBD.
Collapse
Affiliation(s)
- Mahasish Shome
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ 85281, United States
| | - Lusheng Song
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ 85281, United States
| | - Stacy Williams
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ 85281, United States
| | - Yunro Chung
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ 85281, United States
| | - Vel Murugan
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ 85281, United States
| | - Jin G Park
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ 85281, United States
| | - William Faubion
- Department of Internal Medicine, Mayo Clinic, Rochester, MN 55902, United States
| | - Shabana F Pasha
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, Scottsdale, AZ 85259, United States
| | - Jonathan A Leighton
- Division of Gastroenterology, Mayo Clinic School of Medicine, Scottsdale, AZ 85259, United States
| | - Joshua LaBaer
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ 85281, United States
| | - Ji Qiu
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ 85281, United States
| |
Collapse
|
|
7
|
Krovi SH, Kuchroo VK. Activation pathways that drive CD4 + T cells to break tolerance in autoimmune diseases . Immunol Rev 2022;307:161-190. [PMID: 35142369 PMCID: PMC9255211 DOI: 10.1111/imr.13071] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 01/22/2022] [Indexed: 12/11/2022]
Abstract
Autoimmune diseases are characterized by dysfunctional immune systems that misrecognize self as non-self and cause tissue destruction. Several cell types have been implicated in triggering and sustaining disease. Due to a strong association of major histocompatibility complex II (MHC-II) proteins with various autoimmune diseases, CD4+ T lymphocytes have been thoroughly investigated for their roles in dictating disease course. CD4+ T cell activation is a coordinated process that requires three distinct signals: Signal 1, which is mediated by antigen recognition on MHC-II molecules; Signal 2, which boosts signal 1 in a costimulatory manner; and Signal 3, which helps to differentiate the activated cells into functionally relevant subsets. These signals are disrupted during autoimmunity and prompt CD4+ T cells to break tolerance. Herein, we review our current understanding of how each of the three signals plays a role in three different autoimmune diseases and highlight the genetic polymorphisms that predispose individuals to autoimmunity. We also discuss the drawbacks of existing therapies and how they can be addressed to achieve lasting tolerance in patients.
Collapse
Affiliation(s)
- Sai Harsha Krovi
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Vijay K Kuchroo
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| |
Collapse
|
|
8
|
Verstockt B, Bressler B, Martinez-Lozano H, McGovern D, Silverberg MS. Time to Revisit Disease Classification in Inflammatory Bowel Disease: Is the Current Classification of Inflammatory Bowel Disease Good Enough for Optimal Clinical Management? Gastroenterology 2022; 162:1370-1382. [PMID: 34995534 DOI: 10.1053/j.gastro.2021.12.246] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 12/08/2021] [Accepted: 12/09/2021] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel disease (IBD), historically subdivided into Crohn's disease and ulcerative colitis, is a very heterogeneous condition. While the tendency in medicine is to try to reduce complexity, IBD is a disease that cannot justify a one-size-fits-all principle. Our current clinical classification tools are suboptimal and need further refinement to capture, at least in part, the variety of phenotypes encountered in daily clinical practice. Although these revised classification tools alone will not be sufficient and should be complemented by more detailed molecular subclassifications, optimized clinical phenotypes can contribute to improved trial designs, future translational research approaches, and better treatment outcomes. In the current review, we discuss key clinical features important in IBD disease heterogeneity, tackle limitations of the current classification systems, propose some potential improvements, and raise priorities for future research in this domain.
Collapse
Affiliation(s)
- Bram Verstockt
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Katholieke Universiteit Leuven, Leuven, Belgium; Department of Chronic Diseases and Metabolism, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Brian Bressler
- Division of Gastroenterology, Department of Medicine, St. Paul's Hopsital, University of British Columbia, Vancouver, British Columbia, Canada
| | - Helena Martinez-Lozano
- Division of Gastroenterology, Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Dermot McGovern
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Mark S Silverberg
- Division of Gastroenterology, Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
| |
Collapse
|
|
9
|
Ås J, Bertulyte I, Eriksson N, Magnusson PK, Wadelius M, Hallberg P. HLA-variants associated with azathioprine-induced pancreatitis in patients with Crohn's disease. Clin Transl Sci 2022; 15:1249-1256. [PMID: 35120281 PMCID: PMC9099136 DOI: 10.1111/cts.13244] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 01/14/2022] [Accepted: 01/20/2022] [Indexed: 11/30/2022] Open
Abstract
The immunosuppressant drug azathioprine is associated with a 4% risk of acute pancreatitis in patients with inflammatory bowel disease (IBD). Studies have demonstrated an increased risk in carriers of HLA‐DQA1*02:01 and HLA‐DRB1*07:01. We investigated whether these human leukocyte antigen (HLA) types were associated with azathioprine‐induced pancreatitis also in Swedish patients with IBD, and whether the type of disease affected the association. Nineteen individuals with IBD who developed acute pancreatitis after initiation of azathioprine were genotyped and compared with a population control cohort (n = 4891) and a control group matched for disease (n = 81). HLA‐DQA1*02:01 and HLA‐DRB1*07:01 were in full linkage disequilibrium, and were significantly associated with acute pancreatitis both when cases were compared with population controls (OR 3.97 [95% CI 1.57–9.97], p = 0.0035) and matched controls (OR 3.55 [95% CI 1.23–10.98], p = 0.0275). In a disease‐specific analysis, the correlation was positive in patients with Crohn's disease versus matched controls (OR 9.27 [95% CI 1.86–46.19], p = 0.0066), but not in those with ulcerative colitis versus matched controls (OR 0.69 [95% CI 0.07–6.74], p = 0.749). In patients with Crohn's disease, we estimated the conditional risk of carriers of HLA‐DQA1*02:01‐HLA‐DRB1*07:01 to 7.3%, and the conditional risk of a non‐carrier to 2.2%. We conclude that HLA‐DQA1*02:01‐HLA‐DRB1*07:01 is a marker for increased risk of acute pancreatitis in individuals of Swedish genetic origin, treated with azathioprine for Crohn's disease.
Collapse
Affiliation(s)
- Joel Ås
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Ilma Bertulyte
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | | | - Patrik Ke Magnusson
- Swedish Twin Registry, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Mia Wadelius
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Pär Hallberg
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| |
Collapse
|
|
10
|
Berger TD, Lee HM, Padmanaban LR, Wine E, Yerushalmy-Feler A, Hojsak I, Kazeka D, Serban DE, Yogev D, Ledder O, Lionetti P, Scarallo L, Gasparetto M, Croft NM, Miele E, Staiano A, Meredith J, Aloi M, Alvisi P, Urlep D, Weiss B, Malham M, Matar M, Navas-López VM, Romano C, Dipasquale V, Norsa L, Kolho KL, Shamir R, Shouval DS. Clinical Features and Outcomes of Paediatric Patients With Isolated Colonic Crohn Disease. J Pediatr Gastroenterol Nutr 2022; 74:258-266. [PMID: 34694270 DOI: 10.1097/mpg.0000000000003335] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Adult studies suggest that patients with isolated colonic Crohn disease (L2 CD) exhibit unique characteristics differentiating them from patients with ileo-caecal (L1) CD and ulcerative colitis (UC). We aimed to characterize clinical features and outcomes of paediatric patients with L2. METHODS Retrospective data was collected through the Porto Inflammatory Bowel Disease group of the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) on Paediatric patients with L2, L1 or UC at different time-points. Outcome measures included time to first flare, hospital admissions, initiation of anti-tumor necrosis factor-alpha (TNFα) drug, stricture and surgery. RESULTS Three hundred patients were included: 102 L1, 94 L2 and 104 UC. Rates of hematochezia at presentation were 14.7%, 44.7% and 95.2%, while rates of fever were 12.7%, 26.6% and 2.9%, for patients with L1, L2 and UC, respectively (P < 0.001 for all comparisons). Skip lesions were identified in 65% of patients with L2, and granulomas in 36%, similar to L1 patients. Rates of anti-Saccharomyces cerevisiae antibodies (ASCA) and perinuclear antineutrophil cytoplasmic (pANCA) positivity significantly differed between the three groups: 25.4% and 16.7% for patients with L2, compared with 55.2% and 2.3%, and 1.8% and 52.9% for patients with L1 and UC, respectively. Response rates to exclusive enteral nutrition were comparable between L1 and L2 (78.3-82.4%), as was the response to oral steroids (70.4-76.5%) in the three groups. While times to first flare and admission were similar between groups, patients with L1 were commenced on anti-TNFα earlier. Moreover, stricturing phenotype and need for colectomy were very rare in patients with L2. CONCLUSIONS Significant differences are observed in the clinical presentation and outcomes of Paediatric patients with L2, compared to patients with L1 and UC.
Collapse
Affiliation(s)
- Tal David Berger
- Pediatric Gastroenterology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Huey Miin Lee
- Paediatric Liver, GI & Nutrition Centre and Mowat Labs, King's College Hospital NHS Foundation Trust, London, UK
| | - Lavenya Ramasamy Padmanaban
- Paediatric Liver, GI & Nutrition Centre and Mowat Labs, King's College Hospital NHS Foundation Trust, London, UK
| | - Eytan Wine
- Edmonton Pediatric IBD Clinic, University of Alberta, Edmonton, Canada
| | - Anat Yerushalmy-Feler
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
- Pediatric Gastroenterology Unit, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Tel-Aviv, Israel
| | - Iva Hojsak
- Children's Hospital Zagreb, University of Zagreb School of Medicine, University of J. J. Strossmayer School of Medicine Osijek, Croatia
| | - Denis Kazeka
- Department of Paediatrics, University Hospital Motol, Prague, Czech Republic
| | - Daniela Elena Serban
- 2nd Clinic of Pediatrics, "Iuliu Hatieganu" University of Medicine and Pharmacy, Emergency Clinical Hospital for Children, Cluj-Napoca, Romania
| | - Dotan Yogev
- Juliet Keidan Institute of Paediatric Gastroenterology and Nutrition, Shaare Zedek Medical Center, affiliated to the Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Oren Ledder
- Juliet Keidan Institute of Paediatric Gastroenterology and Nutrition, Shaare Zedek Medical Center, affiliated to the Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Paolo Lionetti
- Department Neurofarba, University of Florence, Meyer Children Hospital, Florence, Italy
| | - Luca Scarallo
- Department Neurofarba, University of Florence, Meyer Children Hospital, Florence, Italy
| | - Marco Gasparetto
- The Royal London Children's Hospital, Barts' Health NHS Trust, London
| | - Nicholas M Croft
- The Royal London Children's Hospital, Barts' Health NHS Trust, London
- Barts and the London School of Medicine, Queen Mary University of London, London, UK
| | - Erasmo Miele
- Department of Translational Medical Science, Section of Pediatrics, University of Naples "Federico II", Naples, Italy
| | - Annamaria Staiano
- Department of Translational Medical Science, Section of Pediatrics, University of Naples "Federico II", Naples, Italy
| | - Joseph Meredith
- Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, UK
| | - Marina Aloi
- Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Rome
| | | | - Darja Urlep
- Department of Gastroenterology Hepatology and Nutrition, Children's Hospital University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Batia Weiss
- Pediatric Gastroenterology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Mikkel Malham
- The pediatric Department, Copenhagen University Hospital, Hvidovre, and The Pediatric Department, Holbaek Hospital, Denmark
| | - Manar Matar
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
- Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petach Tikva, Israel
| | | | - Claudio Romano
- Pediatric Gastroenterology and Cystic Fibrosis Unit, Department of Human Pathology in Adulthood and Childhood "G. Barresi", University of Messina, Messina, Italy
| | - Valeria Dipasquale
- Pediatric Gastroenterology and Cystic Fibrosis Unit, Department of Human Pathology in Adulthood and Childhood "G. Barresi", University of Messina, Messina, Italy
| | - Lorenzo Norsa
- Paediatric Hepatology Gastroenterology and Transplantation, Papa Giovanni XXIII Hospital, Bergamo, Italy
| | - Kaija-Leena Kolho
- Paediatric Gastroenterology of the Children's Hospital, University of Helsinki, Helsinki, Finland
| | - Raanan Shamir
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
- Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petach Tikva, Israel
| | - Dror S Shouval
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
- Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petach Tikva, Israel
| |
Collapse
|
|
11
|
Ueno A, Jijon HB, Peng R, Sparksman S, Mainoli B, Filyk A, Li Y, Wilson S, Novak K, Panaccione R, Hirota S, Dufour A, Lu C, Beck PL. Association of Circulating Fibrocytes With Fibrostenotic Small Bowel Crohn's Disease. Inflamm Bowel Dis 2022; 28:246-258. [PMID: 34428284 DOI: 10.1093/ibd/izab157] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Fibrocytes are hematopoietic cells with features of mesenchymal cells found in the circulation and inflammatory sites implicated in promoting fibrosis in many fibroinflammatory diseases. However, their role(s) in the development of intestinal fibrosis is poorly understood. Here, we investigated a potential role of fibrocytes in the development of fibrosis in Crohn's disease (CD) and sought factors that may impact their development and function. METHODS Plasma and mononuclear cells were collected from patients with and without fibrostenotic CD. Fibrocytes defined as CD11b+, CD34+, and Collagen 1+ were correlated with clinical assessments of fibrosis, including evaluation using intestinal ultrasound. We measured the levels of relevant circulating molecules via Luminex and studied the effect of patient plasma proteins on fibrocyte differentiation. RESULTS Fibrocyte numbers were increased in CD patients with stricturing Crohn's disease compared with patients with an inflammatory phenotype (P = .0013), with strong correlation between fibrocyte numbers and acoustic radiation force impulse (ARFI), a measure of bowel elasticity on intestinal ultrasound (R = .8383, P = .0127). Fibrostenotic plasma was a more potent inducer of fibrocyte differentiation in both primary human monocytes and cell line and contained increased levels of cytokines implicated in fibrocyte differentiation compared with plasma from inflammatory patients. Interestingly, increased fibrocyte numbers at time of ultrasound were associated with escalation of medical therapy and endoscopic/surgical management of small bowel strictures at 30 months follow-up. CONCLUSIONS Circulating fibrocytes strongly correlate with fibrostenotic disease in CD, and they may serve as predictors for escalation of medical +/- surgical therapy.
Collapse
Affiliation(s)
- Aito Ueno
- Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Humberto B Jijon
- Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Richard Peng
- Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Steven Sparksman
- Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Barbara Mainoli
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Alexis Filyk
- Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Yan Li
- Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Stephanie Wilson
- Department of Radiology, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Kerri Novak
- Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Remo Panaccione
- Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Simon Hirota
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Antoine Dufour
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Cathy Lu
- Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Paul L Beck
- Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Canada
| |
Collapse
|
|
12
|
Brown H, Esterházy D. Intestinal immune compartmentalization: implications of tissue specific determinants in health and disease. Mucosal Immunol 2021; 14:1259-1270. [PMID: 34211125 DOI: 10.1038/s41385-021-00420-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 05/05/2021] [Accepted: 05/24/2021] [Indexed: 02/04/2023]
Abstract
The emerging concept of tissue specific immunity has opened the gates to new inquiries into what factors drive immune cell niche adaptation and the implications on immune homeostasis, organ specific immune diseases, and therapeutic efficacy. These issues are particularly complicated at barrier sites, which are directly exposed to an ever-changing environment. In particular, the gastrointestinal (GI) tract faces even further challenges given the profound functional and structural differences along its length, raising the possibility that it may even have to be treated as multiple organs when seeking to answer these questions. In this review, we evaluate what is known about the tissue intrinsic and extrinsic factors shaping immune compartments in the intestine. We then discuss the physiological and pathological consequences of a regionally distinct immune system in a single organ, but also discuss where our insight into the role of the compartment for disease development is still very limited. Finally, we discuss the technological and therapeutic implications this compartmentalization has. While the gut is perhaps one of the most intensely studied systems, many of these aspects apply to understanding tissue specific immunity of other organs, most notably other barrier sites such as skin, lung, and the urogenital tract.
Collapse
Affiliation(s)
- Hailey Brown
- Committee on Immunology, University of Chicago, Chicago, IL, USA
| | - Daria Esterházy
- Committee on Immunology, University of Chicago, Chicago, IL, USA. .,Department of Pathology, University of Chicago, Chicago, IL, USA.
| |
Collapse
|
|
13
|
Genetic Variants of DMBT1 and SFTPD and Disease Severity in Paediatric Inflammatory Bowel Disease—A Polish Population-Based Study. CHILDREN 2021; 8:children8110946. [PMID: 34828659 PMCID: PMC8618964 DOI: 10.3390/children8110946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/08/2021] [Accepted: 10/09/2021] [Indexed: 11/16/2022]
Abstract
Deleted in malignant brain tumours 1 protein (DMBT1) and surfactant protein D (SFTPD) are antimicrobial peptides previously linked to inflammatory bowel disease (IBD) susceptibility. This study attempts to link the most potential IBD-associated polymorphisms in DMBT1 and SFTPD with the disease severity in children. A total of 406 IBD patients (Crohn’s disease (CD) n = 214 and ulcerative colitis (UC) n = 192) were genotyped using hydrolysis probe assay. Clinical expression was described by disease activity scales, albumin and C-reactive protein levels, localisation and behaviour (Paris classification), systemic steroid, immunosuppressive, biological, and surgical treatment, number of exacerbation-caused hospitalisations, relapses and nutritional status. IBD patients with the risk genotype (AA) in DMBT1 rs2981804 had more frequent biological treatment (AA: vs. AG/GG; p = 0.012), concomitant diseases (AA vs. AG vs. GG; p = 0.015) and cutaneous manifestations (AA vs. AG/GG, p = 0.008). In UC, rs2981804 genotypes might be linked with albumin concentrations at diagnosis (AA vs. AG vs. GG; p = 0.009). In CD, DMBT1 rs2981745 was significantly associated with the number of severe relapses per year of disease (p = 0.020) and time-to-immunosuppression (p = 0.045). SFTPD was seemingly found to be associated with age at first immunosuppression in IBD (CC vs. CT vs. TT; p = 0.048). In conclusion, selected polymorphisms of DMBT1 and SFTPD might be associated with some disease severity measures in children with IBD. However, the magnitude of associations and their clinical relevance might be minor.
Collapse
|
|
14
|
Zhu Y, Qian W, Huang L, Xu Y, Guo Z, Cao L, Gong J, Coffey JC, Shen B, Li Y, Zhu W. Role of Extended Mesenteric Excision in Postoperative Recurrence of Crohn's Colitis: A Single-Center Study. Clin Transl Gastroenterol 2021; 12:e00407. [PMID: 34597277 PMCID: PMC8483874 DOI: 10.14309/ctg.0000000000000407] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Accepted: 08/10/2021] [Indexed: 01/08/2023] Open
Abstract
INTRODUCTION The mesentery is involved in Crohn's disease. The impact of the extent of mesenteric resection on postoperative disease progression in Crohn's disease remains unconfirmed. This study aimed to determine the association between resection of the mesentery and postoperative outcomes in patients with Crohn's colitis (CC) undergoing colorectal surgery. METHODS Patients with CC who underwent colorectal resection between January 2000 and December 2018 were reviewed, and the data were gathered from a prospectively maintained database. Patients were divided into 2 groups according to the extent of mesenteric resection, the extensive mesenteric excision (EME) group and the limited mesenteric excision (LME) group. Outcomes including early postoperative morbidities and surgical recurrence were compared between the 2 groups. RESULTS Of the 126 patients included, 60 were in the LME group and 66 in the EME group. There was no significant difference between the 2 groups in early postsurgical outcomes except the intraoperative blood loss was increased in the LME group (P = 0.002). Patients in the EME group had a longer postoperative surgical recurrence-free survival time when compared with those in the LME group (P = 0.01). LME was an independent predictor of postoperative surgical recurrence (hazard ratio 2.67, 95% confidence interval 1.04-6.85, P = 0.04). This was further confirmed in the subgroup analysis of patients undergoing colorectal resection and anastomosis (hazard ratio 2.83, 95% confidence interval 1.01-7.96, P = 0.048). DISCUSSION In patients undergoing surgery for CC, inclusion of the mesentery is associated with similar short-term outcomes and improved long-term outcomes compared with those seen when the mesentery is retained.
Collapse
Affiliation(s)
- Yipeng Zhu
- Department of General Surgery, Jinling Hospital, Medical School of Southeast University, Nanjing, PR China;
| | - Wenwei Qian
- Department of General Surgery, Jinling Hospital, Medical School of Southeast University, Nanjing, PR China;
| | - Liangyu Huang
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China;
| | - Yihan Xu
- Department of General Surgery, Jinling Hospital, School of Nanjing Medical University, Nanjing, PR China;
| | - Zhen Guo
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China;
| | - Lei Cao
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China;
| | - Jianfeng Gong
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China;
| | - J. Calvin Coffey
- Department of Surgery, University Hospital Limerick, Limerick, Ireland
| | - Bo Shen
- Section of Inflammatory Bowel Diseases and Center for Interventional IBD, Columbia University Irving Medical Center-New York Presbyterian, New York, New York, USA
| | - Yi Li
- Department of General Surgery, Jinling Hospital, Medical School of Southeast University, Nanjing, PR China;
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China;
| | - Weiming Zhu
- Department of General Surgery, Jinling Hospital, Medical School of Southeast University, Nanjing, PR China;
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China;
| |
Collapse
|
|
15
|
Petryszyn P, Dudkowiak R, Gruca A, Jaźwińska-Tarnawska E, Ekk-Cierniakowski P, Poniewierka E, Wiela-Hojeńska A, Głowacka K. C3435T Polymorphism of the ABCB1 Gene in Polish Patients with Inflammatory Bowel Disease: A Case-Control and Meta-Analysis Study. Genes (Basel) 2021; 12:genes12091419. [PMID: 34573401 PMCID: PMC8465101 DOI: 10.3390/genes12091419] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 09/05/2021] [Accepted: 09/11/2021] [Indexed: 12/30/2022] Open
Abstract
P-glycoprotein encoded by the ABCB1 gene constitutes a molecular barrier in the small and large bowel epithelium, and its different expression may influence susceptibility to inflammatory bowel disease (IBD). We aimed to assess the contribution of the C3435T polymorphism to disease risk in the Polish population. A total of 100 patients (50 Crohn's disease (CD), 50 ulcerative colitis (UC)) and 100 healthy controls were genotyped for the single nucleotide polymorphism (SNP) C3435T by using the PCR-RFLP method. Patients were classified on the basis of disease phenotype and the specific treatment used. A meta-analysis was carried out of our results and those from previously published Polish studies. There was no significant difference in allele and genotype frequencies in IBD patients compared with controls. For CD patients, a lower frequency of TT genotype in those with colonic disease, a lower frequency of T allele, and a higher frequency of C allele in those with luminal disease were observed, whereas for UC patients, a lower frequency of CT genotype was observed in those with left-sided colitis. A meta-analysis showed a tendency towards higher prevalence of CC genotype in UC cases. These results indicate that the C3435T variants may confer a risk for UC and influence disease behaviour.
Collapse
Affiliation(s)
- Paweł Petryszyn
- Department of Clinical Pharmacology, Wroclaw Medical University, 50-571 Wroclaw, Poland; (A.G.); (E.J.-T.); (A.W.-H.); (K.G.)
- Correspondence: ; Tel.: +48-717840601
| | - Robert Dudkowiak
- Department of Gastroenterology and Hepatology, Wroclaw Medical University, 50-571 Wroclaw, Poland; (R.D.); (E.P.)
| | - Agnieszka Gruca
- Department of Clinical Pharmacology, Wroclaw Medical University, 50-571 Wroclaw, Poland; (A.G.); (E.J.-T.); (A.W.-H.); (K.G.)
| | - Ewa Jaźwińska-Tarnawska
- Department of Clinical Pharmacology, Wroclaw Medical University, 50-571 Wroclaw, Poland; (A.G.); (E.J.-T.); (A.W.-H.); (K.G.)
| | | | - Elżbieta Poniewierka
- Department of Gastroenterology and Hepatology, Wroclaw Medical University, 50-571 Wroclaw, Poland; (R.D.); (E.P.)
| | - Anna Wiela-Hojeńska
- Department of Clinical Pharmacology, Wroclaw Medical University, 50-571 Wroclaw, Poland; (A.G.); (E.J.-T.); (A.W.-H.); (K.G.)
| | - Krystyna Głowacka
- Department of Clinical Pharmacology, Wroclaw Medical University, 50-571 Wroclaw, Poland; (A.G.); (E.J.-T.); (A.W.-H.); (K.G.)
| |
Collapse
|
|
16
|
Atreya R, Siegmund B. Location is important: differentiation between ileal and colonic Crohn's disease. Nat Rev Gastroenterol Hepatol 2021; 18:544-558. [PMID: 33712743 DOI: 10.1038/s41575-021-00424-6] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/29/2021] [Indexed: 01/31/2023]
Abstract
Crohn's disease can affect any part of the gastrointestinal tract; however, current European and national guidelines worldwide do not differentiate between small-intestinal and colonic Crohn's disease for medical treatment. Data from the past decade provide evidence that ileal Crohn's disease is distinct from colonic Crohn's disease in several intestinal layers. Remarkably, colonic Crohn's disease shows an overlap with regard to disease behaviour with ulcerative colitis, underlining the fact that there is more to inflammatory bowel disease than just Crohn's disease and ulcerative colitis, and that subtypes, possibly defined by location and shared pathophysiology, are also important. This Review provides a structured overview of the differentiation between ileal and colonic Crohn's disease using data in the context of epidemiology, genetics, macroscopic differences such as creeping fat and histological findings, as well as differences in regard to the intestinal barrier including gut microbiota, mucus layer, epithelial cells and infiltrating immune cell populations. We also discuss the translation of these basic findings to the clinic, emphasizing the important role of treatment decisions. Thus, this Review provides a conceptual outlook on a new mechanism-driven classification of Crohn's disease.
Collapse
Affiliation(s)
- Raja Atreya
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Britta Siegmund
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
| |
Collapse
|
|
17
|
Dang JT, Dang TT, Wine E, Dicken B, Madsen K, Laffin M. The Genetics of Postoperative Recurrence in Crohn Disease: A Systematic Review, Meta-analysis, and Framework for Future Work. CROHN'S & COLITIS 360 2021; 3:otaa094. [PMID: 36778938 PMCID: PMC9802308 DOI: 10.1093/crocol/otaa094] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Indexed: 12/12/2022] Open
Abstract
Background Recurrence following abdominal surgery in Crohn disease is over 50%. The impact of genetics on postoperative recurrence is not well defined. Methods A literature search was conducted where inclusion required an assessment, by genotype, of postoperative recurrence. The primary endpoint was odds of surgical recurrence. Results Twenty-eight studies identified a total of 6715 patients. Thirteen loci were identified as modifying the risk of recurrence. NOD2 was identified as a risk factor for recurrence by multiple works (cumulative odds ratio: 1.64, P = 0.003). Conclusions A NOD2 risk allele is associated with recurrence following surgery in Crohn disease. Progress in this area will require standardized reporting in future works.
Collapse
Affiliation(s)
- Jerry T Dang
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
| | - ThucNhi T Dang
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Eytan Wine
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Bryan Dicken
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
| | - Karen Madsen
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Michael Laffin
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada,Address correspondence to: Michael Laffin, MD, PhD, Department of Surgery, University of Alberta, University of Alberta Hospital, 8440 112 Street NW, Edmonton, AB T6G 2B7, Canada ()
| |
Collapse
|
|
18
|
Zhou Y, He Y, Liu L, Zhou W, Wang P, Hu H, Nie Y, Chen Y. Alterations in Gut Microbial Communities Across Anatomical Locations in Inflammatory Bowel Diseases. Front Nutr 2021; 8:615064. [PMID: 33718417 PMCID: PMC7952524 DOI: 10.3389/fnut.2021.615064] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 02/05/2021] [Indexed: 12/19/2022] Open
Abstract
We previously discovered that gut microbiota can serve as universal microbial biomarkers for diagnosis, disease activity assessment, and predicting the response to infliximab treatment for inflammatory bowel diseases (IBD). Much still remains unknown about the relationship between alterations in gut microbiota and IBD affected bowel region, in particular in the case of ulcerative colitis (UC) and colonic Crohn's disease (cCD) without endoscopic and biopsy data. In the current study gut microbiota from a population in China was found to be distinct from that of the Western world [Human Microbiome Project (HMP) data]. Furthermore, both gut microbiota greatly differed from microbiota of other anatomical locations (oral, skin, airway, and vagina), with higher alpha-diversity (Chinese gut > HMP gut > oral microbiome > airway microbiome > skin microbiome > vaginal microbiome), and marked differences in microbiome composition. In patients with IBD in China, UC was characterized by the presence of Gardnerella, while cCD was characterized by the presence of Fusobacterium. Moreover, gut microbiota, such as Gardnerella and Fusobacterium, may be potential biomarkers for identifying UC from cCD. Together, this study revealed crucial differences in microbial communities across anatomical locations, and demonstrated that there was an important association between IBD affected bowel region and gut microbiota.
Collapse
Affiliation(s)
- Youlian Zhou
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Yan He
- State Key Laboratory of Organ Failure Research, Division of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Le Liu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Wanyan Zhou
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Pu Wang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Han Hu
- Shenzhen Xbiome Biotech Co. Ltd., Shenzhen, China
| | - Yuqiang Nie
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Ye Chen
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| |
Collapse
|
|
19
|
Mager R, Roda G, Shalaby MK, Vetrano S. Fibrotic Strictures in Crohn's Disease: Mechanisms and Predictive Factors. Curr Drug Targets 2021; 22:241-251. [PMID: 33081672 DOI: 10.2174/1389450121666201020160803] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 08/13/2020] [Accepted: 08/27/2020] [Indexed: 11/22/2022]
Abstract
Fibrotic strictures are one of the most severe complications of Crohn's Disease (CD). They occur in about 50% of patients at five years and in 70% at ten years of the diagnosis. The only treatment available for symptomatic fibrotic strictures is surgical resection and endoscopic dilation. Both strategies are associated with a high rate of recurrence, and with multiple surgical resections, which pose the threat of surgical morbidity and short bowel syndrome. Therefore, it is crucial to identify, early, the patients more prone to develop intestinal fibrosis to intensify follow-ups, switch to more aggressive treatments, and suggest lifestyle modifications. Scarce data are available concerning biomarkers and genetic determinants to predict which patient will develop intestinal fibrosis. Biologic or clinical markers would be useful to determine this subgroup of CD patients and to predict the onset of intestinal fibrosis and, ideally, its severity. Furthermore, the identification of environmental risk factors may suggest lifestyle changes aimed at modifying the natural course, thus decreasing the risk of complicated CD. In this review, we will critically revise clinical, environmental, genetic, and serologic factors that have been associated with a complicated CD course with a particular focus on the fibrostenosing phenotype and their possible implications as predictive factors of intestinal fibrosis.
Collapse
Affiliation(s)
- Riccardo Mager
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090, Milan, Italy
| | - Giulia Roda
- IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center-IRCCS, Rozzano, Milan, Italy
| | - Mohammad Khaled Shalaby
- IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center-IRCCS, Rozzano, Milan, Italy
| | - Stefania Vetrano
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090, Milan, Italy
| |
Collapse
|
|
20
|
Leite Dantas R, Bettenworth D, Varga G, Weinhage T, Wami HT, Dobrindt U, Roth J, Vogl T, Ludwig S, Wixler V. Spontaneous onset of TNFα-triggered colonic inflammation depends on functional T lymphocytes, S100A8/A9 alarmins, and MHC H-2 haplotype. J Pathol 2020; 251:388-399. [PMID: 32449525 DOI: 10.1002/path.5473] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 05/05/2020] [Accepted: 05/18/2020] [Indexed: 12/17/2022]
Abstract
Recently, we established a doxycycline-inducible human tumor necrosis factor alpha (TNFα)-transgenic mouse line, ihTNFtg. Non-induced young and elderly mice showed low but constitutive expression of hTNFα due to promoter leakiness. The persistently present hTNFα stimulated endogenous pro-inflammatory mouse mS100A8/A9 alarmins. Secreted mS100A8/A9 in turn induced the expression and release of mouse mTNFα. The continuous upregulation of pro-inflammatory mTNFα and mS100A8/A9 proteins, due to their mutual expression dependency, gradually led to increased levels in colon tissue and blood. This finally exceeded the threshold levels tolerated by the healthy organism, leading to the onset of intestinal inflammation. Here, recombinant hTNFα functioned as an initial trigger for the development of chronic inflammation. Crossing ihTNFtg mice with S100A9KO mice lacking active S100A8/A9 alarmins or with Rag1KO mice lacking T and B lymphocytes completely abrogated the development of colonic inflammation, despite the still leaky hTNFα promoter. Furthermore, both the intensity of the immune response and the strength of immunosuppressive Treg induction was found to depend on the major histocompatibility complex (MHC) genetic composition. In summary, the onset of intestinal inflammation in elderly mice depends on at least four factors that have to be present simultaneously: TNFα upregulation, S100A8/A9 protein expression, functional T lymphocytes and genetic composition, with the MHC haplotype being of central importance. Only joint action of these factors leads to chronic intestinal inflammation, while absence of any of these determinants abrogates the development of the autoimmune disorder. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Collapse
Affiliation(s)
- Rafael Leite Dantas
- Institute of Molecular Virology, Westfaelische Wilhelms University, Muenster, Germany
| | - Dominik Bettenworth
- Department of Medicine B, Gastroenterology and Hepatology, University Hospital Muenster, Muenster, Germany
| | - Georg Varga
- Pediatric Rheumatology and Immunology, Westfaelische Wilhelms University, Muenster, Germany
| | - Toni Weinhage
- Pediatric Rheumatology and Immunology, Westfaelische Wilhelms University, Muenster, Germany
| | | | - Ulrich Dobrindt
- Institute of Hygiene, Westfaelische Wilhelms University, Muenster, Germany
| | - Johannes Roth
- Institute of Immunology, Westfaelische Wilhelms University, Muenster, Germany
| | - Thomas Vogl
- Institute of Immunology, Westfaelische Wilhelms University, Muenster, Germany
| | - Stephan Ludwig
- Institute of Molecular Virology, Westfaelische Wilhelms University, Muenster, Germany
| | - Viktor Wixler
- Institute of Molecular Virology, Westfaelische Wilhelms University, Muenster, Germany
| |
Collapse
|
|
21
|
Inflammation-Induced Mucosal KYNU Expression Identifies Human Ileal Crohn's Disease. J Clin Med 2020; 9:jcm9051360. [PMID: 32384670 PMCID: PMC7290775 DOI: 10.3390/jcm9051360] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 04/30/2020] [Accepted: 05/05/2020] [Indexed: 12/31/2022] Open
Abstract
The widely varying therapeutic response of patients with inflammatory bowel disease (IBD) continues to raise questions regarding the unclarified heterogeneity of pathological mechanisms promoting disease progression. While biomarkers for the differentiation of Crohn’s disease (CD) versus ulcerative colitis (UC) have been suggested, specific markers for a CD subclassification in ileal CD versus colonic CD are still rare. Since an altered signature of the tryptophan metabolism is associated with chronic inflammatory disease, we sought to characterize potential biomarkers by focusing on the downstream enzymes and metabolites of kynurenine metabolism. Using immunohistochemical stainings, we analyzed and compared the mucosal tryptophan immune metabolism in bioptic samples from patients with active inflammation due to UC or CD versus healthy controls. Localization-specific quantification of immune cell infiltration, tryptophan-metabolizing enzyme expression and mucosal tryptophan downstream metabolite levels was performed. We found generally increased immune cell infiltrates in the tissue of all patients with IBD. However, in patients with CD, significant differences were found between regulatory T cell and neutrophil granulocyte infiltration in the ileum compared with the colon. Furthermore, we observed decreased kynurenine levels as well as strong kynureninase (KYNU) expression specifically in patients with ileal CD. Correspondingly, significantly elevated levels of the kynurenine metabolite 3-hydroxyanthranilic acid were detected in the ileal CD samples. Highlighting the heterogeneity of the different phenotypes of CD, we identified KYNU as a potential mucosal biomarker allowing the localization-specific differentiation of ileal CD versus colonic CD.
Collapse
|
|
22
|
Ashton JJ, Mossotto E, Stafford IS, Haggarty R, Coelho TA, Batra A, Afzal NA, Mort M, Bunyan D, Beattie RM, Ennis S. Genetic Sequencing of Pediatric Patients Identifies Mutations in Monogenic Inflammatory Bowel Disease Genes that Translate to Distinct Clinical Phenotypes. Clin Transl Gastroenterol 2020; 11:e00129. [PMID: 32463623 PMCID: PMC7145023 DOI: 10.14309/ctg.0000000000000129] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 01/03/2020] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVES Monogenic inflammatory bowel disease (IBD) comprises rare Mendelian causes of gut inflammation, often presenting in infants with severe and atypical disease. This study aimed to identify clinically relevant variants within 68 monogenic IBD genes in an unselected pediatric IBD cohort. METHODS Whole exome sequencing was performed on patients with pediatric-onset disease. Variants fulfilling the American College of Medical Genetics criteria as "pathogenic" or "likely pathogenic" were assessed against phenotype at diagnosis and follow-up. Individual patient variants were assessed and processed to generate a per-gene, per-individual, deleteriousness score. RESULTS Four hundred one patients were included, and the median age of disease-onset was 11.92 years. In total, 11.5% of patients harbored a monogenic variant. TRIM22-related disease was implicated in 5 patients. A pathogenic mutation in the Wiskott-Aldrich syndrome (WAS) gene was confirmed in 2 male children with severe pancolonic inflammation and primary sclerosing cholangitis. In total, 7.3% of patients with Crohn's disease had apparent autosomal recessive, monogenic NOD2-related disease. Compared with non-NOD2 Crohn's disease, these patients had a marked stricturing phenotype (odds ratio 11.52, significant after correction for disease location) and had undergone significantly more intestinal resections (odds ratio 10.75). Variants in ADA, FERMT1, and LRBA did not meet the criteria for monogenic disease in any patients; however, case-control analysis of mutation burden significantly implicated these genes in disease etiology. DISCUSSION Routine whole exome sequencing in pediatric patients with IBD results in a precise molecular diagnosis for a subset of patients with IBD, providing the opportunity to personalize therapy. NOD2 status informs risk of stricturing disease requiring surgery, allowing clinicians to direct prognosis and intervention.
Collapse
Affiliation(s)
- James J. Ashton
- Department of Human Genetics and Genomic Medicine, University of Southampton, Southampton, UK;
- Department of Paediatric Gastroenterology, Southampton Children's Hospital, Southampton, UK;
| | - Enrico Mossotto
- Department of Human Genetics and Genomic Medicine, University of Southampton, Southampton, UK;
- NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK;
| | - Imogen S. Stafford
- Department of Human Genetics and Genomic Medicine, University of Southampton, Southampton, UK;
| | - Rachel Haggarty
- NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK;
| | - Tracy A.F. Coelho
- Department of Paediatric Gastroenterology, Southampton Children's Hospital, Southampton, UK;
| | - Akshay Batra
- Department of Paediatric Gastroenterology, Southampton Children's Hospital, Southampton, UK;
| | - Nadeem A. Afzal
- Department of Paediatric Gastroenterology, Southampton Children's Hospital, Southampton, UK;
| | - Matthew Mort
- Human Genetic Mutation Database, Cardiff University, Cardiff, UK
| | - David Bunyan
- Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury, UK.
| | - Robert Mark Beattie
- Department of Paediatric Gastroenterology, Southampton Children's Hospital, Southampton, UK;
| | - Sarah Ennis
- Department of Human Genetics and Genomic Medicine, University of Southampton, Southampton, UK;
| |
Collapse
|
|
23
|
Ashton JJ, Latham K, Beattie RM, Ennis S. Review article: the genetics of the human leucocyte antigen region in inflammatory bowel disease. Aliment Pharmacol Ther 2019; 50:885-900. [PMID: 31518029 DOI: 10.1111/apt.15485] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 07/05/2019] [Accepted: 08/10/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND The human leucocyte antigen (HLA) complex, located at chromosome 6p21.3 is a highly polymorphic region containing the classical class I and II HLA genes. The region is highly associated with inflammatory bowel disease (IBD), largely through genome-wide association studies (GWAS). AIMS To review the role of HLA in immune function, summarise data on risk/protective HLA genotypes for IBD, discuss the role of HLA in IBD pathogenesis, treatment and examine limitations that might be addressed by future research. METHODS An organised search strategy was used to collate articles describing HLA genes in IBD, including Crohn's disease and ulcerative colitis. RESULTS All classical HLA genes with variation (including HLA-A, B, C, DRB1, DQA1, DQB1, DPA1 and DPB1) harbour IBD-associated genotypes. The most implicated gene is HLA-DRB1, with HLA-DRB1*03:01 the most associated risk allele in both Crohn's disease and ulcerative colitis. Elucidating precise disease associations is challenging due to high linkage disequilibrium between HLA genotypes. The mechanisms by which risk alleles cause disease are multifactorial, with the best evidence indicating structural and electrostatic alteration impacting antigen binding and downstream signalling. Adverse medication events have been associated with HLA genotypes including with thiopurines (pancreatitis) and anti-TNF agents (antibody formation). CONCLUSIONS The HLA complex is associated with multiple risk/protective alleles for IBD. Future research utilising long-read technology, ascertainment of zygosity and integration in disease modelling will improve the functional understanding and clinical translation of genetic findings.
Collapse
Affiliation(s)
- James J Ashton
- Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.,Department of Paediatric Gastroenterology, Southampton Children's Hospital, Southampton, UK
| | - Katy Latham
- Anthony Nolan Research Institute, University College London, London, UK
| | - Robert Mark Beattie
- Department of Paediatric Gastroenterology, Southampton Children's Hospital, Southampton, UK
| | - Sarah Ennis
- Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK
| |
Collapse
|
|
24
|
Lee HS, Cleynen I. Molecular Profiling of Inflammatory Bowel Disease: Is It Ready for Use in Clinical Decision-Making? Cells 2019; 8:E535. [PMID: 31167397 PMCID: PMC6627070 DOI: 10.3390/cells8060535] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 05/29/2019] [Accepted: 05/30/2019] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a heterogeneous disorder in terms of age at onset, clinical phenotypes, severity, disease course, and response to therapy. This underlines the need for predictive and precision medicine that can optimize diagnosis and disease management, provide more cost-effective strategies, and minimize the risk of adverse events. Ideally, we can leverage molecular profiling to predict the risk to develop IBD and disease progression. Despite substantial successes of genome-wide association studies in the identification of genetic variants affecting IBD susceptibility, molecular profiling of disease onset and progression as well as of treatment responses has lagged behind. Still, thanks to technological advances and good study designs, predicting phenotypes using genomics and transcriptomics in IBD has been rapidly evolving. In this review, we summarize the current status of prediction of disease risk, clinical course, and response to therapy based on clinical case presentations. We also discuss the potential and limitations of the currently used approaches.
Collapse
Affiliation(s)
- Ho-Su Lee
- Laboratory of Complex Genetics, Department of Human Genetics, KU Leuven, Herestraat 49 - box 610, 3000 Leuven, Belgium.
- Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul 05505, Korea.
| | - Isabelle Cleynen
- Laboratory of Complex Genetics, Department of Human Genetics, KU Leuven, Herestraat 49 - box 610, 3000 Leuven, Belgium.
| |
Collapse
|
|
25
|
Kredel LI, Jödicke LJ, Scheffold A, Gröne J, Glauben R, Erben U, Kühl AA, Siegmund B. T-cell Composition in Ileal and Colonic Creeping Fat - Separating Ileal from Colonic Crohn's Disease. J Crohns Colitis 2019; 13:79-91. [PMID: 30272118 DOI: 10.1093/ecco-jcc/jjy146] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Creeping fat [CF] is a hyperplasia of adipose tissue adjacent to inflamed intestine in Crohn's disease [CD]. Data from genome-wide association studies [GWAS] distinguished Crohn's colitis from ileal CD and ulcerative colitis [UC]. This study analysed the T-cell compartments of ileal and colonic mesenteric fat and corresponding mucosa to provide cellular proof for the suggested GWAS classification. METHODS Samples were obtained from 34 CD or UC patients. Cells were analysed by immunohistochemistry and flow cytometry, and tissue cytokine release was assessed by cytometric bead array. RESULTS Only ileal CF revealed the distinct adipocyte hyperplasia combined with dense T-cell infiltration and fibrosis; colonic fat from CD and UC patients lacked these findings. T-cell subpopulations differed between mesenteric fat in ileal CD, colonic CD and UC: ileal CF had nearly 10 times more T-cells than colonic fat. The proportions of regulatory and central memory T-cells were significantly higher in ileal CF compared with colonic fat in CD and UC. In all groups, the mucosal T-cell compartment was distinct from the mesenteric fat. Remarkably, correlation between disease activity and proportion of pro- and anti-inflammatory T-cell subpopulations was inverse, comparing ileal and colonic fat in CD. CONCLUSIONS This first in-depth analysis of the T-cell compartment in ileal and colonic mesenteric adipose tissue in CD and UC identifies a unique T-cell niche in the ileal mesenteric fat tissue in CD. From a clinical point of view, our findings underscore the novel concept of colonic and ileal CD as distinct IBD entities.
Collapse
Affiliation(s)
- Lea I Kredel
- Medical Department, Division of Gastroenterology, Infectiology and Rheumatology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Lisa J Jödicke
- Medical Department, Division of Gastroenterology, Infectiology and Rheumatology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Alexander Scheffold
- Medical Department [Rheumatology, Clinical Immunology], Department of Cellular Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Jörn Gröne
- Department of Surgery, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.,Department of Surgery, Rotes Kreuz Krankenhaus Bremen, Bremen, Germany
| | - Rainer Glauben
- Medical Department, Division of Gastroenterology, Infectiology and Rheumatology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Ulrike Erben
- Medical Department, Division of Gastroenterology, Infectiology and Rheumatology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.,iPATH, Core Unit/Research Center ImmunoSciences, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Anja A Kühl
- Medical Department, Division of Gastroenterology, Infectiology and Rheumatology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.,iPATH, Core Unit/Research Center ImmunoSciences, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Britta Siegmund
- Medical Department, Division of Gastroenterology, Infectiology and Rheumatology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| |
Collapse
|
|
26
|
Zhang H, Zeng Z, Mukherjee A, Shen B. Molecular diagnosis and classification of inflammatory bowel disease. Expert Rev Mol Diagn 2018; 18:867-886. [PMID: 30152711 DOI: 10.1080/14737159.2018.1516549] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Traditional diagnosis and classification of inflammatory bowel diseases (IBDs) have been based on clinical evaluation, laboratory testing, endoscopy, imaging, and histological examinations. With the advancement of medical technology, an increasing number of molecular surrogates are playing a key role in diagnosis, differential diagnosis, assessment of disease activity, prediction of clinical course, and therapeutic response of IBD. Areas covered: The authors review roles of both existing and emerging surrogates including genetic, serological, histologic, and fecal markers in diagnosis and classification of IBD. Comparisons in advantages and disadvantages of different markers have also been discussed. In addition, this review underscores controversial and unclear aspects which need further study. Expert commentary: IBD is characteristic of chronicity, relapse-remission and destructiveness. It is of great importance for clinicians to make an accurate diagnosis and classification. Current and new molecular markers perform well with acceptable sensitivity and specificity. The use of molecular markers in clinical practice needs to be further explored and then generalized. More work is warranted to identify novel useful markers and elucidate how to apply them together with current markers in clinical settings.
Collapse
Affiliation(s)
- Hu Zhang
- a Center for Inflammatory Bowel Disease & Department of Gastroenterology , West China Hospital, Sichuan University , Chengdu , China
| | - Zhen Zeng
- a Center for Inflammatory Bowel Disease & Department of Gastroenterology , West China Hospital, Sichuan University , Chengdu , China
| | - Arjudeb Mukherjee
- b West China School of Medicine , Sichuan University , Chengdu , China
| | - Bo Shen
- c Center for Inflammatory Bowel Disease, Digestive Disease and Surgery Institute, The Cleveland Clinic Foundation , Cleveland , Ohio , USA
| |
Collapse
|
|
27
|
Targeted Gene Sequencing in Children with Crohn's Disease and Their Parents: Implications for Missing Heritability. G3-GENES GENOMES GENETICS 2018; 8:2881-2888. [PMID: 30166421 PMCID: PMC6118318 DOI: 10.1534/g3.118.200404] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Crohn’s disease is a complex genetic trait characterized by chronic relapsing intestinal inflammation. Genome wide association studies (GWAS) have identified more than 170 loci associated with the disease, accounting for ∼14% of the disease variance. We hypothesized that rare genetic variation in GWAS positional candidates also contribute to disease pathogenesis. We performed targeted, massively-parallel sequencing of 101 genes in 205 children with Crohn’s disease, including 179 parent-child trios and 200 controls, both of European ancestry. We used the gene burden test implemented in VAAST and estimated effect sizes using logistic regression and meta-analyses. We identified three genes with nominally significant p-values: NOD2, RTKN2, and MGAT3. Only NOD2 was significant after correcting for multiple comparisons. We identified eight novel rare variants in NOD2 that are likely disease-associated. Incorporation of rare variation and compound heterozygosity nominally increased the proportion of variance explained from 0.074 to 0.089. We estimated the population attributable risk and total heritability of variation in NOD2 to be 32.9% and 3.4%, respectively, with 3.7% and 0.25% accounted for by rare putatively functional variants. Sequencing probands (as opposed to genotyping) to identify rare variants and incorporating phase by sequencing parents can recover a portion of the missing heritability of Crohn’s disease.
Collapse
|
|
28
|
Palmela C, Chevarin C, Xu Z, Torres J, Sevrin G, Hirten R, Barnich N, Ng SC, Colombel JF. Adherent-invasive Escherichia coli in inflammatory bowel disease. Gut 2018; 67:574-587. [PMID: 29141957 DOI: 10.1136/gutjnl-2017-314903] [Citation(s) in RCA: 352] [Impact Index Per Article: 50.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Revised: 09/20/2017] [Accepted: 10/28/2017] [Indexed: 02/06/2023]
Abstract
Intestinal microbiome dysbiosis has been consistently described in patients with IBD. In the last decades, Escherichia coli, and the adherent-invasive E coli (AIEC) pathotype in particular, has been implicated in the pathogenesis of IBD. Since the discovery of AIEC, two decades ago, progress has been made in unravelling these bacteria characteristics and its interaction with the gut immune system. The mechanisms of adhesion of AIEC to intestinal epithelial cells (via FimH and cell adhesion molecule 6) and its ability to escape autophagy when inside macrophages are reviewed here. We also explore the existing data on the prevalence of AIEC in patients with Crohn's disease and UC, and the association between the presence of AIEC and disease location, activity and postoperative recurrence. Finally, we highlight potential therapeutic strategies targeting AIEC colonisation of gut mucosa, including the use of phage therapy, bacteriocins and antiadhesive molecules. These strategies may open new avenues for the prevention and treatment of IBD in the future.
Collapse
Affiliation(s)
- Carolina Palmela
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.,Division of Gastroenterology, Hospital Beatriz Ângelo, Loures, Portugal
| | - Caroline Chevarin
- Université Clermont Auvergne, Inserm U1071, USC-INRA 2018, M2iSH, CRNH Auvergne, F-63000 Clermont-Ferrand, France
| | - Zhilu Xu
- Department of Medicine and Therapeutics, Institute of Digestive Diseases, LKS Institute of Health Science, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Joana Torres
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.,Division of Gastroenterology, Hospital Beatriz Ângelo, Loures, Portugal
| | - Gwladys Sevrin
- Université Clermont Auvergne, Inserm U1071, USC-INRA 2018, M2iSH, CRNH Auvergne, F-63000 Clermont-Ferrand, France
| | - Robert Hirten
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
| | - Nicolas Barnich
- Université Clermont Auvergne, Inserm U1071, USC-INRA 2018, M2iSH, CRNH Auvergne, F-63000 Clermont-Ferrand, France
| | - Siew C Ng
- Department of Medicine and Therapeutics, Institute of Digestive Diseases, LKS Institute of Health Science, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Jean-Frederic Colombel
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
| |
Collapse
|
|
29
|
de Bruyn M, Vermeire S. NOD2 and bacterial recognition as therapeutic targets for Crohn’s disease. Expert Opin Ther Targets 2017; 21:1123-1139. [DOI: 10.1080/14728222.2017.1397627] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Magali de Bruyn
- Translational Research in GastroIntestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium
| | - Séverine Vermeire
- Translational Research in GastroIntestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium
- University Hospitals Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium
| |
Collapse
|
|
30
|
Reichhardt M, Holmskov U, Meri S. SALSA—A dance on a slippery floor with changing partners. Mol Immunol 2017; 89:100-110. [DOI: 10.1016/j.molimm.2017.05.029] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Revised: 05/31/2017] [Accepted: 05/31/2017] [Indexed: 02/06/2023]
|
|
31
|
Tamzaourte M, Errabih I, Krami H, Maha F, Maria L, Benzzoubeir N, Ouazzani L, Sefiani A, Ouazzani H. [NOD2 gene mutation in Moroccan patients with Crohn's disease: prevalence, genotypic study and correlation of NOD2 gene mutation with the phenotype of Crohn's disease]. Pan Afr Med J 2017; 27:116. [PMID: 28819537 PMCID: PMC5554695 DOI: 10.11604/pamj.2017.27.116.9187] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Accepted: 05/29/2017] [Indexed: 12/16/2022] Open
Abstract
L'objectif était de déterminer la prévalence des mutations du gène NOD2/CARD15 dans un groupe de patients Marocains atteint de Maladie de Crohn et étudier sa corrélation génotype-expression phénotypique. Etude transversale cas témoin menée sur une durée de 16 mois. Ont été inclus 101 patients atteints de la maladie de Crohn, entre Janvier 2012 et Avril 2013 ainsi qu'un groupe contrôle de 107 patients. L'analyse génétique a consisté à rechercher 3 variants du gène NOD2: p.Arg702Trp, p.Gly908Arg et p.Leu1007fsins. Puis une étude de corrélation génotype-expression phénotypique a été menée. L'analyse génétique des patients atteint de maladie de crohn a mis en évidence la présence de la mutation NOD2 chez 14 patients (13,77%) contre 7 patients (6,53%) du groupe témoin. L'étude de la fréquence des différents allèles a retrouvé la mutation de p.Gly908Arg dans 6,43%, p.Leu1007fsins dans 0,99% et p.Arg702Trp dans 0,49% contre respectivement 2,80%, 0% et 0,46% dans le groupe témoin. L'étude de la corrélation génotype, expression phénotypique a démontré que la mutation CARD15 est corrélée à une localisation iléo-caecale de la maladie, à une présentation fistulisante et sténosante ainsi qu'à une évolution sévère avec recours fréquent à la chirurgie et aux immunosuppresseurs. La prévalence de la mutation NOD2/ CARD15 dans notre série est faible. Cette mutation est corrélée à une forme grave de la maladie.
Collapse
Affiliation(s)
- Mouna Tamzaourte
- Service d'Hépato-Gastroentérologie «B», Centre Hospitalier Universitaire Ibn Sina, Rabat, Maroc
| | - Ikram Errabih
- Service d'Hépato-Gastroentérologie «B», Centre Hospitalier Universitaire Ibn Sina, Rabat, Maroc
| | - Hayat Krami
- Service d'Hépato-Gastroentérologie «B», Centre Hospitalier Universitaire Ibn Sina, Rabat, Maroc
| | - Fadlouallah Maha
- Service d'Hépato-Gastroentérologie «B», Centre Hospitalier Universitaire Ibn Sina, Rabat, Maroc
| | - Lahmiri Maria
- Service d'Hépato-Gastroentérologie «B», Centre Hospitalier Universitaire Ibn Sina, Rabat, Maroc
| | - Nadia Benzzoubeir
- Service d'Hépato-Gastroentérologie «B», Centre Hospitalier Universitaire Ibn Sina, Rabat, Maroc
| | - Laaziza Ouazzani
- Service d'Hépato-Gastroentérologie «B», Centre Hospitalier Universitaire Ibn Sina, Rabat, Maroc
| | - Ahmed Sefiani
- Service de Génétique Médicale, Centre Nationale d'Hygiène, Rabat, Maroc
| | - Houria Ouazzani
- Service d'Hépato-Gastroentérologie «B», Centre Hospitalier Universitaire Ibn Sina, Rabat, Maroc
| |
Collapse
|
|
32
|
Genetic and environmental factors significant for the presentation and development of inflammatory bowel disease. Eur J Gastroenterol Hepatol 2017; 29:909-915. [PMID: 28452812 DOI: 10.1097/meg.0000000000000877] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
OBJECTIVES The aim of the study was to evaluate associations between inflammatory bowel disease (IBD) presentation and variants in NOD2, TLR4, TNF-α, IL-6, IL-1β, and IL-RN genes in order to identify possible environmental factors that may affect IBD occurrence, investigate potential predictors for surgical treatment of IBD, and correlate the presence of granulomas in biopsy specimens with clinical characteristics of Crohn's disease (CD) patients. PATIENTS AND METHODS We genotyped 167 IBD patients using PCR-based methodology and tested for disease genotype-phenotype associations. RESULTS In CD patients ileal localization of disease was more frequent in NOD2 variant carriers. Ileal CD was associated with IL-6 GC+CC genotypes, identifying C allele as a possible marker of increased risk for ileal CD. In CD patients a positive family history for IBD was related to earlier onset of disease, higher risk for CD-related surgery, and appendectomy. CD patients who are TLR4 299Gly carriers are at higher risk for surgery at onset of the disease compared with TLR4 299Asp variant carriers. The presence of granuloma in biopsy specimens was more frequent in patients in whom a diagnosis of CD was made during emergency surgery. Multivariate analysis showed that CD carriers of the 299Gly allele had a 4.6-fold higher risk for emergency surgery before CD diagnosis is established compared with noncarriers, suggesting an aggressive disease course. Granuloma in endoscopic biopsies is detected 5.4-fold more frequently in patients treated surgically at the time of diagnosis. CONCLUSION Genetic variants together with epidemiological and clinical data of IBD patients could potentially be used as predictors of the disease course.
Collapse
|
|
33
|
Gabbani T, Deiana S, Marocchi M, Annese V. Genetic risk variants as therapeutic targets for Crohn's disease. Expert Opin Ther Targets 2017; 21:381-390. [PMID: 28281904 DOI: 10.1080/14728222.2017.1296431] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION The pathogenesis of Inflammatory bowel diseases (IBD) is multifactorial, with interactions between genetic and environmental factors. Despite the existence of genetic factors being largely demonstrated by epidemiological data and several genetic studies, only a few findings have been useful in term of disease prediction, disease progression and targeting therapy. Areas covered: This review summarizes the results of genome-wide association studies in Crohn's disease, the role of epigenetics and the recent discovery by genetic studies of new pathogenetic pathways. Furthermore, it focuses on the importance of applying genetic data to clinical practice, and more specifically how to better target therapy and predict potential drug-related toxicity. Expert opinion: Some genetic markers identified in Crohn`s disease have allowed investigators to hypothesize about, and in some cases, prove the usefulness of new specific therapeutic agents. However, the heterogeneity and complexity of this disease has so far limited the daily clinical use of genetic information. Finally, the study of the implications of genetics on therapy, either to predict efficacy or avoid toxicity, is considered still to be in its infancy.
Collapse
Affiliation(s)
- Tommaso Gabbani
- a Gastroenterology UO , Azienda Unita Sanitaria Locale della Romagna , Forlì , Italy
| | - Simona Deiana
- b Division of Gastroenterology , AOU Careggi University Hospital , Florence , Italy
| | - Margherita Marocchi
- c Division of Gastroenterology , AOU Modena University Hospital , Modena , Italy
| | - Vito Annese
- d Department of Gastroenterology , Valiant Clinic , Dubai , UAE
| |
Collapse
|
|
34
|
Genetics of inflammatory bowel disease: beyond NOD2. Lancet Gastroenterol Hepatol 2017; 2:224-234. [PMID: 28404137 DOI: 10.1016/s2468-1253(16)30111-x] [Citation(s) in RCA: 113] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 09/02/2016] [Accepted: 09/02/2016] [Indexed: 01/11/2023]
Abstract
The study of the genetic underpinnings of inflammatory bowel disease has made great progress since the identification of NOD2 as a major susceptibility gene. Novel genotyping and sequencing technologies have led to the discovery of 242 common susceptibility loci, 45 of which have been fine-mapped to statistically conclusive causal variants; 50 genes associated with very-early-onset inflammatory disease have been identified. The evolving genetic architecture of inflammatory bowel disease has deepened our understanding of its pathogenesis through identification of major disease associated pathways-knowledge that has the potential to indicate novel drug targets or markers for personalised medicine. However, many causal variants have yet to be identified, and a large proportion of missing heritability still needs to be accounted for. In addition, the medical and scientific communities are probably not yet fully harnessing the power of these genetic discoveries.
Collapse
|
|
35
|
Gabbani T, Deiana S, Annese AL, Lunardi S, Annese V. The genetic burden of inflammatory bowel diseases: implications for the clinic? Expert Rev Gastroenterol Hepatol 2016; 10:1109-1117. [PMID: 27258545 DOI: 10.1080/17474124.2016.1196131] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Inflammatory bowel diseases (IBD), which include Crohn's disease (CD) and ulcerative colitis (UC), are characterized by chronic intestinal inflammation. Their etiology is multifactorial, with complex interactions between genetic and environmental factors, which are still largely unclear. Areas covered: The influence of genetics is clearly demonstrated by important epidemiological data, including familial aggregation and concordance in twins. In 2001, the first genetic susceptibility gene for IBD, the NOD2 gene, was identified. Currently, thanks to genetic wide association studies, over 200 susceptibility genetic markers are know. Expert commentary: However, clinically highly relevant gene associations are still very limited and the usefulness of these information in the current clinical strategies for treatment and surveillance of IBD is weak. Nevertheless, the recent identification of some genetic risk variants has clarified some newbiological pathways of these diseases thus paving the way for the discoveries in the near future of new targeted therapies.
Collapse
Affiliation(s)
- Tommaso Gabbani
- a Division of Gastroenterology , AOU Careggi University Hospital , Florence , Italy
| | - Simona Deiana
- a Division of Gastroenterology , AOU Careggi University Hospital , Florence , Italy
| | - Antonio Luca Annese
- a Division of Gastroenterology , AOU Careggi University Hospital , Florence , Italy
| | - Sarah Lunardi
- b Division of Internal Medicine 4 , AOU Careggi University Hospital , Florence , Italy
| | - Vito Annese
- a Division of Gastroenterology , AOU Careggi University Hospital , Florence , Italy
| |
Collapse
|
|
36
|
Ye BD, McGovern DP. Genetic variation in IBD: progress, clues to pathogenesis and possible clinical utility. Expert Rev Clin Immunol 2016; 12:1091-107. [PMID: 27156530 PMCID: PMC5083126 DOI: 10.1080/1744666x.2016.1184972] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Epidemiological and clinical studies have suggested that the pathogenesis of inflammatory bowel disease (IBD) is strongly influenced by genetic predisposition. Beyond the limitations of linkage analysis, multiple genome-wide association studies, their meta-analyses, and targeted genotyping array techniques have broadened our understanding of the genetic architecture of IBD. Currently, over 200 single nucleotide polymorphisms are known to be associated with susceptibility to IBD and through functional analysis of genes and loci, a substantial proportion of pathophysiologic mechanisms have been revealed. However, because only a modest fraction of predicted heritability can be explained by known genes/loci, additional strategies are needed including the identification of rare variants with large effect sizes to help explain the missing heritability. Considerable progress is also being made on applying outcomes of genetic research in diagnostics, classification, prognostics, and the development of new therapeutics of IBD.
Collapse
Affiliation(s)
- Byong Duk Ye
- Department of Gastroenterology and Inflammatory Bowel Disease Center, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Dermot P.B. McGovern
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| |
Collapse
|
|
37
|
Verstockt B, Cleynen I. Genetic Influences on the Development of Fibrosis in Crohn's Disease. Front Med (Lausanne) 2016; 3:24. [PMID: 27303667 PMCID: PMC4885006 DOI: 10.3389/fmed.2016.00024] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Accepted: 05/13/2016] [Indexed: 12/11/2022] Open
Abstract
Fibrostenotic strictures are an important complication in patients with Crohn’s disease (CD), very often necessitating surgery. This fibrotic process develops in a genetically susceptible individual and is influenced by an interplay with environmental, immunological, and disease-related factors. A deeper understanding of the genetic factors driving this fibrostenotic process might help to unravel the pathogenesis, and ultimately lead to development of new, anti-fibrotic therapy. Here, we review the genetic factors that have been associated with the development of fibrosis in patients with CD, as well as their potential pathophysiological mechanism(s). We also hypothesize on clinical implications, if any, and future research directions.
Collapse
Affiliation(s)
- Bram Verstockt
- Department of Medicine and Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Cambridge, UK; Translational Research in Gastrointestinal Disorders (TARGID), Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
| | - Isabelle Cleynen
- Laboratory of Complex Genetics, Department of Human Genetics, KU Leuven , Leuven , Belgium
| |
Collapse
|
|
38
|
Epistatic interaction between TLR4 and NOD2 in patients with Crohn's Disease: relation with risk and phenotype in a Spanish cohort. Immunobiology 2016; 221:927-33. [PMID: 27290609 DOI: 10.1016/j.imbio.2016.05.015] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2016] [Revised: 05/18/2016] [Accepted: 05/27/2016] [Indexed: 01/11/2023]
Abstract
Crohn's Disease is one of the two major forms of the Inflammatory Bowel Diseases and, although the etiology is not completely understood, the confluence of environmental and genetic factors has been demonstrated. The aim of this study was to determine the distribution of TLR4 variants in a Spanish cohort of Crohn's Disease patients and their relation with phenotype and common NOD2 variants. A total of 371 Crohn's Disease (CD) patients and 636 healthy controls (HC) were included. Single Nucleotide Polimorphisms (SNPs) in TLR4 (D299G and T399I) and NOD2 (R702W and G908R) detection was performed by a Taqman(®) Allelic Discrimination Assay. 1007insC NOD2 variant was analyzed using a PCR combined with fluorescent technology and the different alleles were determined depending on the PCR products size. D299G and T399I were related to CD only in patients carrying NOD2 variants (NOD2+/TLR4+ haplotype) (p=0.036; OR=1.924), increasing the risk to develop CD when 1007insC and TLR4 variants were both present (OR=4.886). We also described a strong association between mutant NOD2 and CD risk (p<0.001, OR=3.214). R702W, G908R and 1007insC were associated when they were considered separately (p<0.001; p=0.002; p<0.001, respectively). Moreover, the patients carrying any mutant D299G or T399I polymorphisms were predisposed to develop a stricturing disease (p=0.013; OR=2.391), especially in the presence of NOD2 mutation (p=0.002; OR=4.989). In this study, ileal disease was also associated with the presence of at least one NOD2 susceptibility allele (p=0.001; OR=3.838) and, the risk of ileal CD was increased if TLR4 variants were presents (p<0.050; OR=4.160). TLR4 variants were related to bowel perforation, independently of NOD2.
Collapse
|
|
39
|
Guan LF, Li WB, Hu BW, Sun L, Liu TT. Risk factors, prediction, prevention and management of postoperative recurrence of Crohn's disease. Shijie Huaren Xiaohua Zazhi 2016; 24:1993-2001. [DOI: 10.11569/wcjd.v24.i13.1993] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Due to the repeated recurrence of Crohn's disease (CD), many CD patients have to undergo operative treatment. However, postoperative CD recurrence is common. Therefore, it is important for postoperative CD patients to realize the risk factors and predictors of postoperative recurrence in order to prevent recurrence and prolong remission. The purpose of the present review is to discuss the risk factors, prediction, prevention and postoperative management of postoperative CD recurrence.
Collapse
|
|
40
|
Defining Disease Severity in Inflammatory Bowel Diseases: Current and Future Directions. Clin Gastroenterol Hepatol 2016; 14:348-354.e17. [PMID: 26071941 DOI: 10.1016/j.cgh.2015.06.001] [Citation(s) in RCA: 302] [Impact Index Per Article: 33.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Revised: 06/01/2015] [Accepted: 06/03/2015] [Indexed: 02/07/2023]
Abstract
Although most treatment algorithms in inflammatory bowel disease (IBD) begin with classifying patients according to disease severity, no formal validated or consensus definitions of mild, moderate, or severe IBD currently exist. There are 3 main domains relevant to the evaluation of disease severity in IBD: impact of the disease on the patient, disease burden, and disease course. These measures are not mutually exclusive and the correlations and interactions between them are not necessarily proportionate. A comprehensive literature search was performed regarding current definitions of disease severity in both Crohn's disease and ulcerative colitis, and the ability to categorize disease severity in a particular patient. Although numerous assessment tools for symptoms, quality of life, patient-reported outcomes, fatigue, endoscopy, cross-sectional imaging, and histology (in ulcerative colitis) were identified, few have validated thresholds for categorizing disease activity or severity. Moving forward, we propose a preliminary set of criteria that could be used to classify IBD disease severity. These are grouped by the 3 domains of disease severity: impact of the disease on the patient (clinical symptoms, quality of life, fatigue, and disability); measurable inflammatory burden (C-reactive protein, mucosal lesions, upper gastrointestinal involvement, and disease extent), and disease course (including structural damage, history/extension of intestinal resection, perianal disease, number of flares, and extraintestinal manifestations). We further suggest that a disease severity classification should be developed and validated by an international group to develop a pragmatic means of identifying patients with severe disease. This is increasingly important to guide current therapeutic strategies for IBD and to develop treatment algorithms for clinical practice.
Collapse
|
|
41
|
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: 35] [Impact Index Per Article: 3.9] [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.
Collapse
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:
| |
Collapse
|
|
42
|
Abstract
BACKGROUND The etiology of inflammatory bowel disease is believed to involve a shift in the microbiota toward more proinflammatory species. Crohn's disease (CD) usually manifests as one of three phenotypes, involving inflammation of the terminal ileum, the colon, or both. However, what determines the particular phenotype and the level of disease activity remains unknown. In this study, we aim to characterize the intestinal microbiota associated with different CD phenotypes. METHODS DNA was extracted from biopsies of 31 patients with ileal, ileocolic, or colon-restricted CD, and also from 5 non-inflammatory bowel disease control subjects, and analyzed by 16S rRNA gene amplicon pyrosequencing. Data were processed using the Quantitative Insights Into Microbial Ecology pipeline and analyzed using linear discriminant analysis with effect size estimation and PICRUSt algorithms. Two additional recently published cohorts were also analyzed in this study. RESULTS Highly significant separation was observed between bacterial composition of ileal CD compared with CD with colonic involvement (genus level Bray-Curtis P = 0.005, R = 20%). This separation was unaffected by the biopsy's location or its inflammatory state, or by the patients' condition (remission or relapse). Faecalibacterium was strongly reduced in ileal CD compared with CD with colonic involvement, whereas Enterobacteriaceae were more abundant in the former. Fusobacterium relative abundance was strongly correlated with disease activity in patients with ileal-involving, but not in colon-involving, CD. CONCLUSIONS Ileal and colon-involving CD sustain distinct microbiotas, suggesting that different mechanisms underlie the two major manifestations of CD. The potential contribution of Fusobacterium to inflammation in ileal CD should be further investigated.
Collapse
|
|
43
|
Cleynen I, Boucher G, Jostins L, Schumm LP, Zeissig S, Ahmad T, Andersen V, Andrews JM, Annese V, Brand S, Brant SR, Cho JH, Daly MJ, Dubinsky M, Duerr RH, Ferguson LR, Franke A, Gearry RB, Goyette P, Hakonarson H, Halfvarson J, Hov JR, Huang H, Kennedy NA, Kupcinskas L, Lawrance IC, Lee JC, Satsangi J, Schreiber S, Théâtre E, van der Meulen-de Jong AE, Weersma RK, Wilson DC, Parkes M, Vermeire S, Rioux JD, Mansfield J, Silverberg MS, Radford-Smith G, McGovern DPB, Barrett JC, Lees CW. Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study. Lancet 2016; 387:156-67. [PMID: 26490195 PMCID: PMC4714968 DOI: 10.1016/s0140-6736(15)00465-1] [Citation(s) in RCA: 542] [Impact Index Per Article: 60.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases. METHODS This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34,819 patients (19,713 with Crohn's disease, 14,683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype-phenotype associations across 156,154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile. FINDINGS After quality control, the primary analysis included 29,838 patients (16,902 with Crohn's disease, 12,597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with disease subphenotype (p=1·65 × 10(-78)), even after exclusion of NOD2, MHC, and 3p21 (p=9·23 × 10(-18)). Predictive models based on the genetic risk score strongly distinguished colonic from ileal Crohn's disease. Our genetic risk score could also identify a small number of patients with discrepant genetic risk profiles who were significantly more likely to have a revised diagnosis after follow-up (p=6·8 × 10(-4)). INTERPRETATION Our data support a continuum of disorders within inflammatory bowel disease, much better explained by three groups (ileal Crohn's disease, colonic Crohn's disease, and ulcerative colitis) than by Crohn's disease and ulcerative colitis as currently defined. Disease location is an intrinsic aspect of a patient's disease, in part genetically determined, and the major driver to changes in disease behaviour over time. FUNDING International Inflammatory Bowel Disease Genetics Consortium members funding sources (see Acknowledgments for full list).
Collapse
Affiliation(s)
- Isabelle Cleynen
- Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK; Department of Clinical and Experimental Medicine, TARGID, KU Leuven, Leuven, Belgium
| | - Gabrielle Boucher
- Université de Montréal and the Montreal Heart Institute, Research Center, Montréal, Québec, Canada
| | - Luke Jostins
- Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Christ Church, University of Oxford, St Aldates, UK
| | - L Philip Schumm
- Department of Public Health Sciences, University of Chicago, Chicago, IL, USA
| | - Sebastian Zeissig
- Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Germany
| | - Tariq Ahmad
- Peninsula College of Medicine and Dentistry, Exeter, UK
| | - Vibeke Andersen
- Medical Department, Viborg Regional Hospital, Viborg, Denmark; Hospital of Southern Jutland Aabenraa, Aabenraa, Denmark
| | - Jane M Andrews
- Inflammatory Bowel Disease Service, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, Australia; School of Medicine, University of Adelaide, Adelaide, Australia
| | - Vito Annese
- Unit of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza (IRCCS-CSS) Hospital, San Giovanni Rotondo, Italy; Azienda Ospedaliero Universitaria (AOU) Careggi, Unit of Gastroenterology SOD2, Florence, Italy
| | - Stephan Brand
- Department of Medicine II, University Hospital Munich-Grosshadern, Ludwig-Maximilians-University, Munich, Germany
| | - Steven R Brant
- Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA; Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | - Judy H Cho
- Department of Genetics, Yale School of Medicine, New Haven, CT, USA
| | - Mark J Daly
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Marla Dubinsky
- Department of Pediatrics, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | - Richard H Duerr
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA
| | - Lynnette R Ferguson
- School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Andre Franke
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany
| | - Richard B Gearry
- Department of Medicine, University of Otago, Christchurch, New Zealand; Department of Gastroenterology, Christchurch Hospital, Christchurch, New Zealand
| | - Philippe Goyette
- Université de Montréal and the Montreal Heart Institute, Research Center, Montréal, Québec, Canada
| | - Hakon Hakonarson
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Jonas Halfvarson
- Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Sweden; School of Health and Medical Sciences, Örebro University, Örebro, Sweden
| | - Johannes R Hov
- Norwegian PSC Research Center, Research Insitute of Internal Medicine and Department of Transplantation Medicine, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Hailang Huang
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Nicholas A Kennedy
- Gastrointestinal Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - Limas Kupcinskas
- Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Ian C Lawrance
- Centre for Inflammatory Bowel Diseases, Saint John of God Hospital, Subiaco WA and School of Medicine and Pharmacology, University of Western Australia, Harry Perkins Institute for Medical Research, Murdoch, WA, Australia
| | - James C Lee
- Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
| | - Jack Satsangi
- Gastrointestinal Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - Stephan Schreiber
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany; Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Germany
| | - Emilie Théâtre
- Unit of Animal Genomics, Groupe Interdisciplinaire de Genoproteomique Appliquee (GIGA-R) and Faculty of Veterinary Medicine, University of Liege, Liege, Belgium; Division of Gastroenterology, Centre Hospitalier Universitaire, Universite de Liege, Liege, Belgium
| | | | - Rinse K Weersma
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, Netherlands
| | - David C Wilson
- Child Life and Health, University of Edinburgh, Edinburgh, UK; Royal Hospital for Sick Children, Paediatric Gastroenterology and Nutrition, Glasgow, UK
| | - Miles Parkes
- Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
| | - Severine Vermeire
- Department of Clinical and Experimental Medicine, TARGID, KU Leuven, Leuven, Belgium; Division of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium
| | - John D Rioux
- Université de Montréal and the Montreal Heart Institute, Research Center, Montréal, Québec, Canada
| | - John Mansfield
- Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK
| | - Mark S Silverberg
- Mount Sinai Hospital Inflammatory Bowel Disease Centre, University of Toronto, Toronto, ON, Canada
| | - Graham Radford-Smith
- Inflammatory Bowel Diseases, Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Australia; Department of Gastroenterology, Royal Brisbane and Women's Hospital, and School of Medicine, University of Queensland, Brisbane, Australia
| | - Dermot P B McGovern
- F Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Jeffrey C Barrett
- Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
| | - Charlie W Lees
- Gastrointestinal Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
| |
Collapse
|
|
44
|
Pathogenic aspects and therapeutic avenues of intestinal fibrosis in Crohn's disease. Clin Sci (Lond) 2015; 129:1107-13. [PMID: 26494636 DOI: 10.1042/cs20150472] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
In Crohn's disease, one of the two major forms of inflammatory bowel diseases in human beings, persistent and chronic inflammation promotes fibrotic processes thereby facilitating formation of strictures, the most common indication for surgical intervention in this disorder. The pathogenesis of Crohn's disease-associated fibrosis is not fully understood, but variants of genes involved in the recognition of microbial components/products [e.g. CARD15 (caspase-activating recruitment domain 15) and ATG16L1 (autophagy-related 16-like 1)] are associated with this phenotype, and experimental evidence suggests that intestinal fibrosis results from an altered balance between deposition of ECM (extracellular matrix) and degradation of ECM by proteases. Studies have also contributed to identify the main phenotypic and functional alterations of cells involved in the fibrogenic process, as well as molecules that stimulate such cells to produce elevated amounts of collagen and other ECM-related proteins. In the present review, we assess the current knowledge about cellular and molecular mediators of intestinal fibrosis and describe results of recent studies aimed at testing the preventive/therapeutic effect of compounds in experimental models of intestinal fibrosis.
Collapse
|
|
45
|
Stankovic B, Dragasevic S, Popovic D, Zukic B, Kotur N, Sokic-Milutinovic A, Alempijevic T, Lukic S, Milosavljevic T, Nikcevic G, Pavlovic S. Variations in inflammatory genes as molecular markers for prediction of inflammatory bowel disease occurrence. J Dig Dis 2015; 16:723-33. [PMID: 26316104 DOI: 10.1111/1751-2980.12281] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2015] [Revised: 06/26/2015] [Accepted: 08/03/2015] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Research on inflammatory bowel disease (IBD) has highlighted genes involved in the regulation of inflammatory responses as contributors to disease pathogenesis. This study aimed to evaluate the associations between IBD and variations in NOD2, TLR4, TNF-α, IL-6, IL-1β and IL-1RN genes, and to use the genetic data obtained in predictive modeling. METHODS A total of 167 IBD patients and 101 healthy controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism. Using the genotype data attained as the input to various classification algorithms, IBD prediction models were designed. The area under the receiver operating characteristic curve (AUROC) was used to measure their performance. RESULTS Significant associations were found between Crohn's disease (CD) and minor NOD2 variants, as well as TLR4 299Gly, TNF-α G-308A, IL-6 G-174C and IL-1RN VNTR A2 variants, while ulcerative colitis (UC) was associated only with IL-1RN VNTR A2 variants. CD and UC showed highly significant difference in the allelic distribution of TNF-α G-308A, where the A allele was found to be related to CD, and the G allele to UC. A combined effect of patients' gender and TLR4 variants was observed among CD patients. When all analyzed genotype and gender data were used, prediction performance achieved a maximum AUROC of 0.690 for CD and 0.601 for UC dataset. CONCLUSION Variations in the genes involved in immune regulation are genetic factors of importance in IBD susceptibility that could potentially be used as predictors of disease development.
Collapse
Affiliation(s)
- Biljana Stankovic
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
| | - Sanja Dragasevic
- Clinic for Gastroenterology and Hepatology, Clinical Center of Serbia, Belgrade, Serbia
| | - Dragan Popovic
- School of Medicine, University of Belgrade, Belgrade, Serbia.,Clinic for Gastroenterology and Hepatology, Clinical Center of Serbia, Belgrade, Serbia
| | - Branka Zukic
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
| | - Nikola Kotur
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
| | - Aleksandra Sokic-Milutinovic
- School of Medicine, University of Belgrade, Belgrade, Serbia.,Clinic for Gastroenterology and Hepatology, Clinical Center of Serbia, Belgrade, Serbia
| | - Tamara Alempijevic
- School of Medicine, University of Belgrade, Belgrade, Serbia.,Clinic for Gastroenterology and Hepatology, Clinical Center of Serbia, Belgrade, Serbia
| | - Snezana Lukic
- School of Medicine, University of Belgrade, Belgrade, Serbia.,Clinic for Gastroenterology and Hepatology, Clinical Center of Serbia, Belgrade, Serbia
| | - Tomica Milosavljevic
- School of Medicine, University of Belgrade, Belgrade, Serbia.,Clinic for Gastroenterology and Hepatology, Clinical Center of Serbia, Belgrade, Serbia
| | - Gordana Nikcevic
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
| | - Sonja Pavlovic
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
| |
Collapse
|
|
46
|
Germain A, Guéant RM, Chamaillard M, Bresler L, Guéant JL, Peyrin-Biroulet L. CARD8 gene variant is a risk factor for recurrent surgery in patients with Crohn's disease. Dig Liver Dis 2015; 47:938-42. [PMID: 26283210 DOI: 10.1016/j.dld.2015.07.013] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Revised: 07/11/2015] [Accepted: 07/20/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Post-operative recurrence is frequent in Crohn's disease. Genetic factors associated with post-operative recurrence remain poorly understood. Identification of genetic variants associated with repeat surgery would allow risk stratification of patients who may benefit from early aggressive therapy and/or post-operative prophylactic treatment. METHODS Crohn's disease patients who had at least one bowel resection were retrospectively identified from the "Nancy IBD cohort". Covariates and potential interactions were assessed using the Cox proportional hazard model. Kaplan-Meier curves for time to surgical recurrence were developed for 200 genetic variants and analyzed with the log-rank test. RESULTS 137 patients had at least 1 resection in our cohort: 38 had a surgical recurrence (28%). In multivariate analysis, current smoker status (OR 6.97, 95% CI 1.85-26.22, p=0.004), post-operative complications after prior surgery (OR 2.72, 95% CI 1.02-7.22, p=0.044), and Caspase recruitment domain-containing protein 8 (CARD8) homozygosity for the risk allele (OR 7.56, 95% CI 1.13-50.37, p=0.036) remained significantly and independently associated with surgical recurrence. CONCLUSION Current smoker status was associated with increased risk of surgical recurrence. A novel association between CARD8 and increased risk of surgical recurrence in Crohn's disease was observed. CARD8 could be a new marker for risk stratification and prevention of recurrent surgery.
Collapse
Affiliation(s)
- Adeline Germain
- Department of Digestive Surgery, University Hospital of Nancy-Brabois, Vandoeuvre-les-Nancy, France; INSERM U954, Nutrition-Génétique et Exposition aux risques environnementaux, Faculté de Médecine, Université de Lorraine, Vandoeuvre-les-Nancy, France.
| | - Rosa-Maria Guéant
- INSERM U954, Nutrition-Génétique et Exposition aux risques environnementaux, Faculté de Médecine, Université de Lorraine, Vandoeuvre-les-Nancy, France
| | - Mathias Chamaillard
- Institut Pasteur de Lille, Center for infection and immunity of Lille, Lille, France; INSERM U1019, Team 7, Equipe FRM, Lille, France
| | - Laurent Bresler
- Department of Digestive Surgery, University Hospital of Nancy-Brabois, Vandoeuvre-les-Nancy, France
| | - Jean-Louis Guéant
- INSERM U954, Nutrition-Génétique et Exposition aux risques environnementaux, Faculté de Médecine, Université de Lorraine, Vandoeuvre-les-Nancy, France
| | - Laurent Peyrin-Biroulet
- INSERM U954, Nutrition-Génétique et Exposition aux risques environnementaux, Faculté de Médecine, Université de Lorraine, Vandoeuvre-les-Nancy, France; Department of Gastroenterology, University Hospital of Nancy-Brabois, Vandoeuvre-les-Nancy, France
| |
Collapse
|
|
47
|
Boukercha A, Mesbah-Amroun H, Bouzidi A, Saoula H, Nakkemouche M, Roy M, Hugot JP, Touil-Boukoffa C. NOD2/ CARD15 gene mutations in North Algerian patients with inflammatory bowel disease. World J Gastroenterol 2015; 21:7786-7794. [PMID: 26167078 PMCID: PMC4491965 DOI: 10.3748/wjg.v21.i25.7786] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Revised: 04/23/2015] [Accepted: 05/07/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyse allelic frequency of NOD2 gene variants and to assess their correlation with inflammatory bowel disease (IBD) in Algeria.
METHODS: We studied 132 unrelated patients diagnosed with IBD, 86 with Crohn’s disease (CD) and 46 with ulcerative colitis (UC). Data was prospectively collected between January 2011 and December 2013. The demographic and clinical characteristics were recorded for all the patients. A group of 114 healthy unrelated individuals were selected as controls. All groups studied originated from different regions of North Algeria and confirmed the Algerian origin of their parents and grandparents. Informed and written consent was obtained from each of the participants. All individuals were genotyped for the three CD-associated NOD2 variants (p.Arg702Trp, p.Gly908Arg and p.Leu1007fsinsC mutations) using the polymerase chain reaction-restriction fragment length polymorphism method. Allele and genotype frequencies in patients and control subjects were compared by χ2 test and Fisher’s exact test where appropriate. Odds ratios (OR) and 95% confidence intervals (95%CI) were also estimated. Association analyses were performed to study the influence of these variants on IBD and on clinical phenotypes.
RESULTS: The p.Arg702Trp mutation showed the highest frequency in CD patients (8%) compared to UC patients (2%) (P = 0.09, OR = 3.67, 95%CI: 0.48-4.87) and controls (5%) (P = 0.4, OR = 1.47, 95%CI: 0.65-3.31). In CD patients allelic frequencies of p.Gly908Arg and p.Leu1007fsinsC variants compared to HC were 3% vs 2% (P = 0.5, OR = 1.67, 95%CI: 0.44-6.34); 2% vs 1% (P = 0.4 OR = 2.69 95%CI: 0.48-14.87 respectively). In UC patients, allelic frequencies of p.Gly908Arg and p.Leu1007fsinsC variants compared to HC were 1% vs 2% (P = 1, OR = 1.62, 95%CI: 0.17-4.74) and 2% vs 1% (P = 0.32, OR = 0.39, 95%CI: 0.05-2.87). The total frequency of the mutated NOD2 chromosomes was higher in CD (13%), than in HC (8%) and UC (5%). In addition, NOD2 variants were linked to a particular clinical sub-phenotype in CD in this Algerian cohort. As expected, the three NOD2 variants showed a significant association with CD but did not reach statistical significance, despite the fact that the allele frequency of NOD2 variants was in the range found in most of the European populations. This might be due to the non-exposure of the NOD2 carriers to environmental factors, required for the expression of the disease.
CONCLUSION: Further analyses are necessary to study genetic and environmental factors in IBD in the Algerian population, using larger patient groups.
Collapse
|
|
48
|
Abstract
Inflammatory Bowel Disease (IBD), mainly comprising Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic condition that primarily affects the intestine and is characterized by leukocytic infiltration. Blocking the migration of leukocytes from the circulation is therefore a reasonable therapeutic goal. Recent clinical trials using this approach have shown promise, with the monoclonal antibody to α4β7 integrin, vedolizumab, and previously with the monoclonal antibody to the α4 subunit, natalizumab. Directly targeting the subset of α4β7 expressing cells that co-express CC chemokine receptor 9 (CCR9), using the orally administered antagonist, CCX282-B, also known as vercirnon, has also been evaluated in Phase II and III trials that have produced mixed results. Although CCX282-B showed efficacy in inducing response in active CD in early studies, this was not confirmed in a Phase III study. CCX282-B was also more effective than placebo in maintaining remission, and this result has yet to be confirmed in Phase III. The efficacy of blocking CCR9 in UC, where vedolizumab was effective, has not been tested. The prospect of targeting CCR9 in IBD remains attractive. Much of the local accumulation of inflammatory cells in the intestine arises from migration rather than local proliferation and genetic and pharmacological targeting of CCR9 or its ligand in preclinical models that mimic UC and CD ameliorate inflammation in some cases. Furthermore, binding of chemokine ligands to receptor is a critical step in activating integrin binding, so there is a potential for synergistic action between integrin and chemokine antagonists. CCR9 is expressed on a smaller proportion of circulating cells than α4β7 integrin, which may offer greater specificity of effect, particularly in long term use. Furthermore, while α4β7 is widely expressed on T and B cell subsets, CCR9 is mainly expressed on effector memory Th1 cells. Indications for the use of intestine-specific integrin and chemokine receptor targeting may also extend beyond IBD, to include, for example, postoperative ileus, and primary sclerosing cholangitis.
Collapse
Affiliation(s)
- Emily Wendt
- Translational Gastroenterology Unit, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK
| | - Satish Keshav
- Translational Gastroenterology Unit, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK
| |
Collapse
|
|
49
|
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is typically diagnosed at 20 to 40 years of age. However, very young versus elderly patients with IBD may have different mechanisms of disease that may affect prognosis and care. OBJECTIVES The purpose of this work was to identify single nucleotide polymorphisms associated with age of onset of Crohn's disease and ulcerative colitis. DESIGN Patients were genotyped using a custom microarray chip containing 332 IBD-associated single nucleotide polymorphisms. Age at diagnosis as a continuous variable was assessed using linear regression. Patients were then subgrouped by age at diagnosis and compared by the Fisher exact test. Bonferroni correction was used in all of the analyses. SETTINGS This study was conducted at a tertiary academic hospital. PATIENTS Sixty patients with Crohn's disease and 26 with ulcerative colitis were ≤ 16 years old, 259 patients with Crohn's disease and 248 with ulcerative colitis were 17-60 years old, and 10 patients with Crohn's disease and 20 with ulcerative colitis were >60 years old at diagnosis and included in this study. MAIN OUTCOME MEASURES Age at diagnosis and single nucleotide polymorphism correlations were measured in this study. RESULTS The NOD2 single nucleotide polymorphism rs2076756 was associated with younger age at Crohn's disease diagnosis (p = 0.0002). Patients with the AA/wild-type genotype were diagnosed at 31.9 ± 1.23 years, AG heterozygotes at 25.6 ± 0.99 years, and GG/at-risk allele homozygotes at 22.6 ± 1.32 years. Depending on age categories compared, single nucleotide polymorphisms in POU5F1, TNFSF15, and HLA DRB1*501 were associated with age of Crohn's disease diagnosis. No genetic associations were seen between ulcerative colitis and linear age at diagnosis; however, the G allele of the LAMB1 single nucleotide polymorphism rs886774 was found to be associated with ulcerative colitis diagnosed at ≤ 16 versus >17 years old (p = 0.008). LIMITATIONS This study was limited to known IBD single nucleotide polymorphisms. CONCLUSIONS This analysis reaffirms the association between NOD2, a molecule of innate immunity, and early Crohn's disease onset. This is the first report of a possible association between early Crohn's disease and the POU5F1, TNFSF15, and HLA DRB1*501 genes. The LAMB1 gene, associated with mucosal basement membrane integrity, was associated with early onset ulcerative colitis and, thus, suggests a fundamentally different mechanism of early disease pathogenesis in ulcerative colitis versus Crohn's disease.
Collapse
|
|
50
|
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.
Collapse
|