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Saadah OI, AlAmeel T, Al Sarkhy A, Hasosah M, Al-Hussaini A, Almadi MA, Al-Bawardy B, Altuwaijri TA, AlEdreesi M, Bakkari SA, Alharbi OR, Azzam NA, Almutairdi A, Alenzi KA, Al-Omari BA, Almudaiheem HY, Al-Jedai AH, Mosli MH. Saudi consensus guidance for the diagnosis and management of inflammatory bowel disease in children and adolescents. Saudi J Gastroenterol 2025; 31:107-136. [PMID: 39215473 DOI: 10.4103/sjg.sjg_171_24] [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: 05/13/2024] [Accepted: 07/20/2024] [Indexed: 09/04/2024] Open
Abstract
ABSTRACT The management of inflammatory bowel disease (IBD) in children and adolescents is challenging. Clear evidence-based guidelines are required for this population. This article provides recommendations for managing IBD in Saudi children and adolescents aged 6-19 years, developed by the Saudi Ministry of Health in collaboration with the Saudi Society of Clinical Pharmacy and the Saudi Gastroenterology Association. All 57 guideline statements are based on the most up-to-date information for the diagnosis and management of pediatric IBD.
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Affiliation(s)
- Omar I Saadah
- Department of Pediatrics, Faculty of Medicine, King Abdulaziz University, Inflammatory Bowel Disease Unit, King Abdulaziz University Hospital, Jeddah, Saudi Arabia
| | - Turki AlAmeel
- Department of Medicine, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Ahmed Al Sarkhy
- Gastroenterology Unit, Pediatrics Department, King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia
| | - Mohammed Hasosah
- Department of Pediatrics, Gastroenterology Unit, King Abdulaziz Medical City, National Guard Hospital, Jeddah, Saudi Arabia
- Department of Pediatric Gastroenterology, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- Department of Pediatric Gastroenterology, King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
| | - Abdulrahman Al-Hussaini
- Children's Specialized Hospital, King Fahad Medical City, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Majid A Almadi
- Division of Gastroenterology, Department of Medicine, College of Medicine, King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia
| | - Badr Al-Bawardy
- Department of Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia, Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA
| | - Talal A Altuwaijri
- Department of Surgery, Division of Vascular Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Mohammed AlEdreesi
- Gastroenterology Unit, Pediatric Department, Al Habib Medical Group, Khobar, Saudi Arabia
| | - Shakir A Bakkari
- Department of Gastroenterology, King Saud Medical City, Riyadh, Saudi Arabia
| | - Othman R Alharbi
- Division of Gastroenterology, Department of Medicine, College of Medicine, King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia
| | - Nahla A Azzam
- Division of Gastroenterology, Department of Medicine, College of Medicine, King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia
| | - Abdulelah Almutairdi
- Department of Medicine, King Faisal Specialist Hospital and Research Center, Alfaisal University, Riyadh, Saudi Arabia
| | - Khalidah A Alenzi
- Executive Management of Transformation, Planning, and Business Development, Tabuk Health Cluster, Tabuk, Saudi Arabia
| | - Bedor A Al-Omari
- Department of Pharmaceutical Care Services, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | | | - Ahmed H Al-Jedai
- Deputyship of Therapeutic Affairs, Ministry of Health, Riyadh, Saudi Arabia
- Colleges of Medicine and Pharmacy, Alfaisal University, Riyadh, Saudi Arabia
| | - Mahmoud H Mosli
- Department of Internal Medicine, King Abdulaziz University, Inflammatory Bowel Disease Unit, King Abdulaziz University Hospital, Jeddah, Saudi Arabia
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Friedman S, Garvik OS, Nielsen J, Jølving LR, Andersen ML, Nørgård BM. The Consequences of Preterm Birth in the Children of Mothers with Inflammatory Bowel Disease: A Nationwide Cohort Study. Inflamm Bowel Dis 2025:izaf010. [PMID: 39899387 DOI: 10.1093/ibd/izaf010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Indexed: 02/05/2025]
Abstract
INTRODUCTION Mothers with inflammatory bowel disease (IBD) are at increased risk of delivering their infants preterm. In the general population, chronic diseases in adulthood as well as increased morbidity and mortality are associated with being born preterm. We aimed to examine whether this was true for preterm versus full-term infants born to mothers with IBD. METHODS This is an observational cohort study based on the Danish Health Registries. The study population comprised all live-born singleton children, born to mothers with IBD, during the study period of 1995 through 2016. We estimated the risk of selected chronic diseases in offspring born preterm to mothers with IBD. These included epilepsy, chronic lung disease and asthma, depression and bipolar affective disorder, autism spectrum disorders, schizophrenia/psychosis, attention-deficit hyperactivity disorder, and mental retardation/intellectual disabilities. We adjusted for relevant confounders. RESULTS In all, 736 children were born preterm, and 9655 were born full-term to mothers with IBD. The median, 25th, and 75th percentiles of the follow-up time of the children were 11.1 (6.4, 16.3) years and 11.4 (7.3, 16.3) years for the full-term and preterm cohorts, respectively. There was a statistically significant increased risk of mental retardation/intellectual disabilities in preterm versus full-term children (aHR 2.15; 95% CI 1.07-4.36). We also found a non-significantly increased risk of epilepsy (1.11; 0.51-2.42), chronic lung disease and asthma (1.10; 0.76-1.60), schizophrenia/psychosis (1.17; 0.50-2.73), and attention-deficit/hyperactivity disorder 1.15 (0.83-1.60). CONCLUSION Our study indicates the possibility of chronic health consequences in children born preterm to mothers with IBD.
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Affiliation(s)
- Sonia Friedman
- Gastroenterology Division, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA
- Center for Clinical Epidemiology, Odense University Hospital, Odense, Denmark
- Research Unit of Clinical Epidemiology, Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Olav Sivertsen Garvik
- Center for Clinical Epidemiology, Odense University Hospital, Odense, Denmark
- Research Unit of Clinical Epidemiology, Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Jan Nielsen
- Center for Clinical Epidemiology, Odense University Hospital, Odense, Denmark
- Research Unit of Clinical Epidemiology, Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Line Riis Jølving
- Center for Clinical Epidemiology, Odense University Hospital, Odense, Denmark
- Research Unit of Clinical Epidemiology, Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Mette Louise Andersen
- Center for Clinical Epidemiology, Odense University Hospital, Odense, Denmark
- Research Unit of Clinical Epidemiology, Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Bente Mertz Nørgård
- Gastroenterology Division, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA
- Center for Clinical Epidemiology, Odense University Hospital, Odense, Denmark
- Research Unit of Clinical Epidemiology, Department of Clinical Research, University of Southern Denmark, Odense, Denmark
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Onwuka S, Bravo-Merodio L, Gkoutos GV, Acharjee A. Explainable AI-prioritized plasma and fecal metabolites in inflammatory bowel disease and their dietary associations. iScience 2024; 27:110298. [PMID: 39040076 PMCID: PMC11261406 DOI: 10.1016/j.isci.2024.110298] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 04/29/2024] [Accepted: 06/14/2024] [Indexed: 07/24/2024] Open
Abstract
Fecal metabolites effectively discriminate inflammatory bowel disease (IBD) and show differential associations with diet. Metabolomics and AI-based models, including explainable AI (XAI), play crucial roles in understanding IBD. Using datasets from the UK Biobank and the Human Microbiome Project Phase II IBD Multi'omics Database (HMP2 IBDMDB), this study uses multiple machine learning (ML) classifiers and Shapley additive explanations (SHAP)-based XAI to prioritize plasma and fecal metabolites and analyze their diet correlations. Key findings include the identification of discriminative metabolites like glycoprotein acetyl and albumin in plasma, as well as nicotinic acid metabolites andurobilin in feces. Fecal metabolites provided a more robust disease predictor model (AUC [95%]: 0.93 [0.87-0.99]) compared to plasma metabolites (AUC [95%]: 0.74 [0.69-0.79]), with stronger and more group-differential diet-metabolite associations in feces. The study validates known metabolite associations and highlights the impact of IBD on the interplay between gut microbial metabolites and diet.
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Affiliation(s)
- Serena Onwuka
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Laura Bravo-Merodio
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
- Centre for Health Data Research, University of Birmingham, Birmingham, UK
- Institute of Translational Medicine, University of Birmingham, Birmingham, UK
| | - Georgios V. Gkoutos
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
- Centre for Health Data Research, University of Birmingham, Birmingham, UK
- Institute of Translational Medicine, University of Birmingham, Birmingham, UK
| | - Animesh Acharjee
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
- Centre for Health Data Research, University of Birmingham, Birmingham, UK
- Institute of Translational Medicine, University of Birmingham, Birmingham, UK
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Fasano A, Matera M. Probiotics to Prevent Celiac Disease and Inflammatory Bowel Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1449:95-111. [PMID: 39060733 DOI: 10.1007/978-3-031-58572-2_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/28/2024]
Abstract
The incidence of chronic inflammatory diseases (CIDs) is dramatically increasing in the developed world, resulting in an increased burden of disease in childhood. Currently, there are limited effective strategies for treating or preventing these conditions. To date, myriads of cross-sectional studies have described alterations in the composition of the gut microbiota in a variety of disease states, after the disease has already occurred. We suggest that to mechanically link these microbiome changes with disease pathogenesis, a prospective cohort design is needed to capture changes that precede or coincide with disease onset and symptoms. In addition, these prospective studies must integrate microbiological, metagenomic, meta transcriptomic and metabolomic data with minimal and standardized clinical and environmental metadata that allow to correctly compare and interpret the results of the analysis of the human microbiota in order to build a system-level model of the interactions between the host and the development of the disease. The creation of new biological computational models thus constructed will allow us to finally move from the detection of simple elements of "association" to the identification of elements of real "causality" allowing to provide a mechanistic approach to the exploration of the development of CIDs.This can only be done when these diseases are studied as complex biological networks. In this chapter we discuss the current knowledge regarding the contribution of the microbiome to CID in childhood, focusing on celiac disease and inflammatory bowel disease, with the overall aim of identifying pathways to shift research from descriptive to mechanistic approaches. We then examine how some components of the microbiota, through epigenetic reprogramming, can start the march from genetic predisposition to clinical expression of CIDs, thus opening up new possibilities for intervention, through microbiota therapy targeting the manipulation of the composition and function of the microbiota, for future applications of precision medicine and primary prevention.
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Affiliation(s)
- Alessio Fasano
- Research Centre for Immunology and Mucosal Biology and Division of Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital for Children - Harvard Medical School, Boston, USA, MA.
- Mucosal Immunology and Biology Research Center and Division of Pediatric Gastroenterology and Nutrition, Mass General for Children - Harvard Medical School, Boston, MA, USA.
| | - Mariarosaria Matera
- Neonatologist, Neurodevelopmental Clinics and Pediatric Clinical Microbiomic - Misericordia Hospital, Grosseto, Italy
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Sosna B, Aebisher D, Myśliwiec A, Dynarowicz K, Bartusik-Aebisher D, Oleś P, Cieślar G, Kawczyk-Krupka A. Selected Cytokines and Metalloproteinases in Inflammatory Bowel Disease. Int J Mol Sci 2023; 25:202. [PMID: 38203373 PMCID: PMC10779120 DOI: 10.3390/ijms25010202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 12/19/2023] [Accepted: 12/20/2023] [Indexed: 01/12/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a collective term for two diseases: ulcerative colitis (UC) and Crohn's disease (CD). There are many factors, e.g., genetic, environmental and immunological, that increase the likelihood of these diseases. Indicators of IBDs include extracellular matrix metalloproteinases (MMPs). The aim of this review is to present data on the role of selected cytokines and metalloproteinases in IBD. In recent years, more and more transcriptomic studies are emerging. These studies are improving the characterization of the cytokine microenvironment inside inflamed tissue. It is observed that the levels of several cytokines are consistently increased in inflamed tissue in IBD, both in UC and CD. This review shows that MMPs play a major role in the pathology of inflammatory processes, cancer, and IBD. IBD-associated inflammation is associated with increased expression of MMPs and reduced ability of tissue inhibitors of metalloproteinases (TIMPs) to inhibit their action. In IBD patients in tissues that are inflamed, MMPs are produced in excess and TIMP activity is not sufficient to block MMPs. This review is based on our personal selection of the literature that was retrieved by a selective search in PubMed using the terms "Inflammatory bowel disease" and "pathogenesis of Inflammatory bowel diseases" that includes systematic reviews, meta-analyses, and clinical trials. The involvement of the immune system in the pathophysiology of IBD is reviewed in terms of the role of the cytokines and metalloproteinases involved.
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Affiliation(s)
- Barbara Sosna
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
| | - David Aebisher
- Department of Photomedicine and Physical Chemistry, Medical College, University of Rzeszów, 35-959 Rzeszów, Poland;
| | - Angelika Myśliwiec
- Center for Innovative Research in Medical and Natural Sciences, Medical College, University of Rzeszów, 35-310 Rzeszów, Poland; (A.M.); (K.D.)
| | - Klaudia Dynarowicz
- Center for Innovative Research in Medical and Natural Sciences, Medical College, University of Rzeszów, 35-310 Rzeszów, Poland; (A.M.); (K.D.)
| | - Dorota Bartusik-Aebisher
- Department of Biochemistry and General Chemistry, Medical College, University of Rzeszów, 35-959 Rzeszów, Poland;
| | - Piotr Oleś
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
| | - Grzegorz Cieślar
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
| | - Aleksandra Kawczyk-Krupka
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
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Hu M, Caldarelli G, Gili T. Inflammatory bowel disease biomarkers revealed by the human gut microbiome network. Sci Rep 2023; 13:19428. [PMID: 37940667 PMCID: PMC10632483 DOI: 10.1038/s41598-023-46184-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 10/29/2023] [Indexed: 11/10/2023] Open
Abstract
Inflammatory bowel diseases (IBDs) are complex medical conditions in which the gut microbiota is attacked by the immune system of genetically predisposed subjects when exposed to yet unclear environmental factors. The complexity of this class of diseases makes them suitable to be represented and studied with network science. In this paper, the metagenomic data of control, Crohn's disease, and ulcerative colitis subjects' gut microbiota were investigated by representing this data as correlation networks and co-expression networks. We obtained correlation networks by calculating Pearson's correlation between gene expression across subjects. A percolation-based procedure was used to threshold and binarize the adjacency matrices. In contrast, co-expression networks involved the construction of the bipartite subjects-genes networks and the monopartite genes-genes projection after binarization of the biadjacency matrix. Centrality measures and community detection were used on the so-built networks to mine data complexity and highlight possible biomarkers of the diseases. The main results were about the modules of Bacteroides, which were connected in the control subjects' correlation network, Faecalibacterium prausnitzii, where co-enzyme A became central in IBD correlation networks and Escherichia coli, whose module has different patterns of integration within the whole network in the different diagnoses.
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Affiliation(s)
- Mirko Hu
- Department of Medicine and Surgery, University of Parma, 43121, Parma, Italy
| | - Guido Caldarelli
- Department of Molecular Science and Nanosystems, Ca' Foscari University of Venice, 30123, Venice, Italy.
- Institute of Complex Systems, National Research Council (ISC-CNR), 00185, Rome, Italy.
- Fondazione per il Futuro delle Città, FFC, 50133, Firenze, Italy.
- European Centre for Living Technology, (ECLT), 30123, Venice, Italy.
| | - Tommaso Gili
- Networks Unit, IMT School for Advanced Studies Lucca, 55100, Lucca, Italy
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Alfonso Perez G, Castillo R. Gene Identification in Inflammatory Bowel Disease via a Machine Learning Approach. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1218. [PMID: 37512030 PMCID: PMC10383667 DOI: 10.3390/medicina59071218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 06/24/2023] [Accepted: 06/26/2023] [Indexed: 07/30/2023]
Abstract
Inflammatory bowel disease (IBD) is an illness with increasing prevalence, particularly in emerging countries, which can have a substantial impact on the quality of life of the patient. The illness is rather heterogeneous with different evolution among patients. A machine learning approach is followed in this paper to identify potential genes that are related to IBD. This is done by following a Monte Carlo simulation approach. In total, 23 different machine learning techniques were tested (in addition to a base level obtained using artificial neural networks). The best model identified 74 genes selected by the algorithm as being potentially involved in IBD. IBD seems to be a polygenic illness, in which environmental factors might play an important role. Following a machine learning approach, it was possible to obtain a classification accuracy of 84.2% differentiating between patients with IBD and control cases in a large cohort of 2490 total cases. The sensitivity and specificity of the model were 82.6% and 84.4%, respectively. It was also possible to distinguish between the two main types of IBD: (1) Crohn's disease and (2) ulcerative colitis.
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Affiliation(s)
- Gerardo Alfonso Perez
- Biocomp Group, Institute of Advanced Materials (INAM), Universitat Jaume I, 12071 Castello, Spain
| | - Raquel Castillo
- Biocomp Group, Institute of Advanced Materials (INAM), Universitat Jaume I, 12071 Castello, Spain
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Akbulut S. An assessment of serum vitamin B12 and folate in patients with Crohn's disease. Medicine (Baltimore) 2022; 101:e31892. [PMID: 36550821 PMCID: PMC9771213 DOI: 10.1097/md.0000000000031892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Crohn's disease is a chronic inflammatory condition that can involve any area in the gastrointestinal tract often involving the distal ileum where vitamin B12 is specifically absorbed. The aim of this study was to ascertain serum vitamin B12 and folate levels in order to investigate the correlation among these vitamin levels and disease activation, localization, duration and age at the onset of the disease. Study population included 103 patients with Crohn's disease and a healthy control group of 114 individuals. C-reactive protein, vitamin B12, folate levels were studied along with hemogram analyses. The results were evaluated in statistical comparisons. While serum vitamin B12 levels and serum folate levels were 161.9 ± 63.2(73-496) pg/mL and 4.9 ± 1.4(1.2-9.4) ng/mL in the Crohn's patient group respectively, they were 321.7 ± 126.3(85-680) pg/mL and 7.6 ± 3.8(3-25.1) ng/mL in the control group respectively. Vitamin B12 and folate levels were distinctly lower in patients with Chron's disease than those of the control group (P < .001). The intragroup analysis of the patient group revealed that low vitamin B12 levels were significantly lower in the moderate group classified according to the Crohn's Disease Activity Index (P < .001), along with those in the L1 group with terminal/distal ileal involvement (P < .001). Vitamin B12 and folate deficiencies are quite prevalent in patients with Crohn's disease while this condition can lead to various complications and they prove to be important risk factors associated especially with thrombosis and its complications. Patients must be regularly followed-up for vitamin B12 and folate levels to supplement them where needed.
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Affiliation(s)
- Sabiye Akbulut
- Department of Gastroenterology, University of Health Sciences, Kartal Koşuyolu High Specialty Training and Research Hospital, Istanbul, Turkey
- * Correspondence: Sabiye Akbulut, Department of Gastroenterology, University of Health Sciences, Kartal Koşuyolu High Specialty Training and Research Hospital, Istanbul 34865, Turkey (e-mail: )
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Bakshi H, Nagpal M, Singh M, Dhingra GA, Aggarwal G. Treatment of Psoriasis: A Comprehensive Review of Entire Therapies. Curr Drug Saf 2020; 15:82-104. [DOI: 10.2174/1574886315666200128095958] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 12/03/2019] [Accepted: 12/05/2019] [Indexed: 12/19/2022]
Abstract
Background:
Psoriasis is an autoimmune disease that ingeminates itself with the repeated
proliferation of keratinocytes. It globally strikes a 2-5 % population on an average. Management
of psoriasis remains a daunting task with various challenges influencing treatment, such as patient
conformity and adherence to therapy, delicate patient profiles, psychological aspects, and skin as a
barrier to topical delivery. The first part reviewed pathophysiology, triggering factors, and clinical
classification. The second part reviewed all the therapies, such as topical, oral, biological, parenteral
therapy, phototherapy, and the phyto-pharmaceuticals.
Methods:
The research data related to the existing and upcoming therapies for psoriasis treatment,
several nanocarriers, existing marketed formulations, and detailed description of phytopharmaceuticals
with their mechanism.
Results:
Topical therapy is the mainstay treatment option with limited adverse effects. Biological therapy
has reformed conventional psoriasis treatment by being more efficacious and has increased patient
acceptance due to decreased adverse events. Nanoformulations present an edge over conventional
therapy due to improved anti-psoriatic effect and decreased side effects. Phyto-pharmaceuticals act as
a complementary and alternative therapy for diminishing psoriasis symptoms.
Conclusion:
A rationalized cost-effective patient compliant therapy is required for effective management
and complete cure of psoriasis.
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Affiliation(s)
- Harman Bakshi
- Chitkara College of Pharmacy, Chitkara University, Chandigarh-Patiala, NH 7, 64, Tehsil, Rajpura, Punjab, India
| | - Manju Nagpal
- Chitkara College of Pharmacy, Chitkara University, Chandigarh-Patiala, NH 7, 64, Tehsil, Rajpura, Punjab, India
| | - Manjinder Singh
- Chitkara College of Pharmacy, Chitkara University, Chandigarh-Patiala, NH 7, 64, Tehsil, Rajpura, Punjab, India
| | | | - Geeta Aggarwal
- Delhi Pharmaceutical Sciences and Research University, New Delhi-110017, India
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Abstract
BACKGROUND Ileocolectomy is the most common surgery performed for Crohn's disease, and postoperative complications occur frequently. There has been minimal evaluation of complications after ileocolectomy as a function of both clinical and genetic factors. OBJECTIVE The purpose of this study was to evaluate both genetic and clinical factors associated with complications after Crohn's ileocolectomy. DESIGN This was a retrospective clinical and genetic cohort study. SETTINGS This study was conducted at a high-volume tertiary care center. PATIENTS We identified 269 patients with Crohn's disease who had undergone 287 ileocolectomies at our institution between July 2008 and October 2018. MAIN OUTCOME MEASURES We measured the association of complications with a combination of clinical factors and 6 Crohn's-associated single nucleotide polymorphisms in NOD2 (rs2076756, rs2066844, and rs2066845), IRGM (rs4958847 and rs13361189), and ATG16L1 (rs2241880). RESULTS There were 86 ileocolectomies of 287 (30%) with complications requiring intervention. The single nucleotide polymorphism rs13361189 in the gene IRGM was significantly associated with complications on univariate and multivariate analysis. There were 61 patients with a variant at the rs13361189 single nucleotide polymorphism and 26 of them had complications, although only 55 of the 208 wild-type patients had complications (43% vs 26%; OR = 2.1; p = 0.02). Other significant factors associated with complication after ileocolectomy were open surgery, placement of a proximal ileostomy, and a greater perioperative decrease in hematocrit. LIMITATIONS This study was limited by its retrospective design and inherent selection bias. CONCLUSIONS In addition to clinical risk factors, the rs13361189 single nucleotide polymorphism in the IRGM gene was independently associated with complications after ileocolectomy for Crohn's disease. The use of such genetic determinants may identify patients at increased risk for surgical complications after ileocolectomy. See Video Abstract at http://links.lww.com/DCR/B124. FACTORES CLÍNICOS Y GENÉTICOS ASOCIADOS CON COMPLICACIONES DESPUÉS DE LA ILEOCOLECTOMÍA DE CROHN: La ileocolectomía es la cirugía más común realizada para la enfermedad de Crohn y con frecuencia ocurren complicaciones postoperatorias. Ha habido una evaluación mínima de complicaciones después de la ileocolectomía, en función de factores clínicos y genéticos.Evaluar factores genéticos y clínicos asociados con complicaciones, después de la ileocolectomía por Crohn.Estudio retrospectivo de cohorte clínico y genético.Este estudio se realizó en un centro de atención terciaria de alto volumen.Identificamos a 269 pacientes con enfermedad de Crohn, sometidos a 287 ileocolectomías en nuestra institución, entre julio de 2008 y octubre de 2018.La asociación de complicaciones con una combinación de factores clínicos y seis polimorfismos de un solo nucleótido asociados a Crohn en NOD2 (rs2076756, rs2066844 y rs2066845), IRGM (rs4958847 y rs13361189) y ATG16L1 (rs2241880).Hubieron 86 ileocolectomías en 287 (30%) pacientes con complicaciones que requirieron intervención. El polimorfismo de un solo nucleótido rs13361189 en el gen IRGM se asoció significativamente con complicaciones en el análisis univariado y multivariado. Hubieron 61 pacientes con una variante en el polimorfismo de un solo nucleótido rs13361189 y 26 de ellos tuvieron complicaciones, mientras que solo 55 de los 208 pacientes de tipo salvaje (WT) tuvieron complicaciones (43% vs 26%, OR 2.1, p = 0.02). Otros factores significativos asociados con las complicaciones después de la ileocolectomía fueron, la cirugía abierta, la colocación de una ileostomía proximal y una mayor disminución perioperatoria del hematocrito.Este estudio estuvo limitado por su diseño retrospectivo y sesgo de selección inherente.Además de los factores de riesgo clínicos, el polimorfismo de un solo nucleótido rs13361189 en el gen IRGM se asoció independientemente con complicaciones después de la ileocolectomía, para la enfermedad de Crohn. El uso de tales determinantes genéticos puede identificar a los pacientes con mayor riesgo de complicaciones quirúrgicas, después de la ileocolectomía. Consulte Video Resumen en http://links.lww.com/DCR/B124.
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Nørgård BM, Jølving LR, Larsen MD, Friedman S. Parental IBD and Long-term Health Outcomes in the Offspring. Inflamm Bowel Dis 2019; 25:1339-1348. [PMID: 30624631 DOI: 10.1093/ibd/izy396] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Indexed: 12/15/2022]
Abstract
For decades, the research on reproductive consequences in women with inflammatory bowel disease (IBD) has focused on short-term outcomes, including adverse pregnancy outcomes (eg, abruptio placenta, placenta previa, preeclampsia/eclampsia) and adverse birth outcomes (eg, small for gestational age, preterm birth, and congenital malformations). The long-term health outcomes of the children of parents with IBD have been studied to a much lesser extent, and there is a critical research gap in understanding the influence of parental IBD on long-term outcomes. In this review, we propose the reasons for this lack of evidence and highlight the weakest areas of the research on the impact of parental IBD on offspring health. We will focus on health outcomes in children of parents with IBD from an age of 1 year through childhood, adolescence, and adulthood.
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Affiliation(s)
- Bente Mertz Nørgård
- Center for Clinical Epidemiology, Odense University Hospital and Research Unit of Clinical Epidemiology, Odense Denmark.,Department of Clinical Research, University of Southern Denmark, Odense Denmark.,Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Line Riis Jølving
- Center for Clinical Epidemiology, Odense University Hospital and Research Unit of Clinical Epidemiology, Odense Denmark
| | - Michael Due Larsen
- Center for Clinical Epidemiology, Odense University Hospital and Research Unit of Clinical Epidemiology, Odense Denmark
| | - Sonia Friedman
- Center for Clinical Epidemiology, Odense University Hospital and Research Unit of Clinical Epidemiology, Odense Denmark.,Department of Clinical Research, University of Southern Denmark, Odense Denmark.,Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
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12
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Laing BB, Lim AG, Ferguson LR. A Personalised Dietary Approach-A Way Forward to Manage Nutrient Deficiency, Effects of the Western Diet, and Food Intolerances in Inflammatory Bowel Disease. Nutrients 2019; 11:nu11071532. [PMID: 31284450 PMCID: PMC6683058 DOI: 10.3390/nu11071532] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 06/29/2019] [Accepted: 07/02/2019] [Indexed: 12/12/2022] Open
Abstract
This review discusses the personalised dietary approach with respect to inflammatory bowel disease (IBD). It identifies gene–nutrient interactions associated with the nutritional deficiencies that people with IBD commonly experience, and the role of the Western diet in influencing these. It also discusses food intolerances and how particular genotypes can affect these. It is well established that with respect to food there is no “one size fits all” diet for those with IBD. Gene–nutrient interactions may help explain this variability in response to food that is associated with IBD. Nutrigenomic research, which examines the effects of food and its constituents on gene expression, shows that—like a number of pharmaceutical products—food can have beneficial effects or have adverse (side) effects depending on a person’s genotype. Pharmacogenetic research is identifying gene variants with adverse reactions to drugs, and this is modifying clinical practice and allowing individualised treatment. Nutrigenomic research could enable individualised treatment in persons with IBD and enable more accurate tailoring of food intake, to avoid exacerbating malnutrition and to counter some of the adverse effects of the Western diet. It may also help to establish the dietary pattern that is most protective against IBD.
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Affiliation(s)
- Bobbi B Laing
- Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand
- Nutrition Society of New Zealand, Palmerston North 4444, New Zealand
| | - Anecita Gigi Lim
- Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand
| | - Lynnette R Ferguson
- Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand.
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13
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Hong J, Yang HR, Moon JS, Chang JY, Ko JS. Association of IL23R Variants With Crohn's Disease in Korean Children. Front Pediatr 2019; 7:472. [PMID: 31799225 PMCID: PMC6878822 DOI: 10.3389/fped.2019.00472] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Accepted: 10/28/2019] [Indexed: 12/23/2022] Open
Abstract
Background: The interleukin 23 receptor gene (IL23R) is strongly associated with Crohn's disease (CD). It is unknown whether genetic variations in IL23R determine susceptibility for pediatric CD in Asian populations. Here, we investigated the association between IL23R variants and CD in Korean children. Methods: Four single nucleotide polymorphisms (SNPs) of IL23R [rs76418789 (G149R), rs1004819, rs7517847, and rs1495965] were genotyped in 141 children with CD and 150 controls using DNA direct sequencing. The risk allele and genotype frequencies were compared between patients and controls. The association between clinical phenotypes and genotypes of patients was also analyzed. Results: Two IL23R SNPs, rs76418789 (G149R), and rs1495965, were associated with CD in Korean pediatric patients as defense and risk loci, respectively. The odds ratio (OR) for rs76418789 (G149R) and rs1495965 was 0.409 (95% confidence interval [CI], 0.177-0.944; p = 0.031) and 1.484 (95% CI, 1.070-2.059; p = 0.018), respectively. Patients with the homozygous G allele of rs1495965 showed higher CD risk than those with other genotypes (GG vs. AA: OR, 2.256; 95% CI, 1.136-4.478; p = 0.019; GG vs. GA+AA: OR, 2.000; 95% CI, 1.175-3.404; p = 0.010). Additionally, they were more likely to have relatively invasive disease behavior of stenosis and/or penetration than simple inflammation (OR, 2.297; 95% CI, 1.065-4.950; p = 0.032). Conclusions: This is the first study reporting IL23R variants in Asian pediatric patients with CD. IL23R was significantly associated with Korean pediatric CD, and the rs1495965 may influence the clinical features of CD in Korean children.
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Affiliation(s)
- Jeana Hong
- Department of Pediatrics, Kangwon National University School of Medicine, Chuncheon, South Korea.,Department of Pediatrics, Seoul National University College of Medicine, Seoul, South Korea
| | - Hye Ran Yang
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, South Korea.,Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam-si, South Korea
| | - Jin Soo Moon
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, South Korea
| | - Ju Young Chang
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, South Korea.,Department of Pediatrics, SMG-SNU Boramae Medical Center, Seoul, South Korea
| | - Jae Sung Ko
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, South Korea
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14
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Yu Y, Chen KC, Chen J. Exclusive enteral nutrition versus corticosteroids for treatment of pediatric Crohn's disease: a meta-analysis. World J Pediatr 2019; 15:26-36. [PMID: 30666565 PMCID: PMC6394648 DOI: 10.1007/s12519-018-0204-0] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Accepted: 10/19/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND Many studies have examined the effects of exclusive enteral nutrition (EEN) in children with Crohn's disease (CD), but corticosteroids are considered a superior therapy and are frequently used in China. This meta-analysis aims to compare the efficacy of EEN with corticosteroids in treating pediatric CD. METHODS A comprehensive retrieval from medical databases, including PubMed, EMBASE, MEDLINE, Web of Science, Wanfang data, VIP and CNKI, was performed using the search terms "diet therapy", "exclusive enteral nutrition", "Crohn's disease", "inflammatory bowel diseases", "child" and "pediatrics" from January 1990 to April 2017. RESULTS We included 18 studies from 1329 identified sources in this meta-analysis. EEN was as effective as corticosteroids in inducing remission rate of children suffering from CD (OR = 1.35; 95% CI 0.90, 2.10; P = 0.14). Nevertheless, patients who received EEN were more likely to achieve both endoscopic mucosal healing (OR = 5.24; 95% CI 2.06, 13.37; P = 0.0005) and histological mucosal healing (OR = 4.78; 95% CI 1.89, 12.08; P = 0.0009) than those who received corticosteroids; the Pediatric Crohn's Disease Activity Index was lower [mean difference (MD) = - 3.67; 95% CI - 4.91, - 2.43] and weight gain was higher (MD = 1.92; 95% CI 0.02, 3.83; P = 0.05) in those patients who received EEN than in those who received corticosteroids. No difference was found in relapse rate (OR = 0.57; 95% CI 0.25, 1.29; P = 0.18), height for age or body mass index between the patients treated with EEN and corticosteroids at the 1-year end point. CONCLUSIONS This meta-analysis reveals that there is no significant difference between EEN and corticosteroids in the efficacy of inducing remission rate of CD in a pediatric population, but EEN is superior to corticosteroids in improving short-term mucosal inflammation and reducing the PCDAI index.
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Affiliation(s)
- Yu Yu
- 0000 0004 1759 700Xgrid.13402.34Department of Gastroenterology, Children’s Hospital, Zhejiang University School of Medicine, 3333 Binsheng Road, Binjiang District, Hangzhou, 310051 China
| | - Kang-Chen Chen
- 0000 0004 1759 700Xgrid.13402.34First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Shangcheng District, Hangzhou, 310002 China
| | - Jie Chen
- Department of Gastroenterology, Children's Hospital, Zhejiang University School of Medicine, 3333 Binsheng Road, Binjiang District, Hangzhou, 310051, China.
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15
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Pink A, Anzengruber F, Navarini A. Acne and hidradenitis suppurativa. Br J Dermatol 2018; 178:619-631. [DOI: 10.1111/bjd.16231] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/26/2017] [Indexed: 02/06/2023]
Affiliation(s)
- A. Pink
- St John's Institute of Dermatology; Division of Genetics and Molecular Medicine; Guy's Hospital; King's College; London SE1 9RT U.K
| | - F. Anzengruber
- Department of Dermatology; University Hospital Zurich; Zurich 8091 Switzerland
| | - A.A. Navarini
- Department of Dermatology; University Hospital Zurich; Zurich 8091 Switzerland
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16
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Serena G, Fasano A. Use of Probiotics to Prevent Celiac Disease and IBD in Pediatrics. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1125:69-81. [PMID: 30565165 DOI: 10.1007/5584_2018_317] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The incidence of chronic inflammatory diseases (CIDs) is increasing worldwide. Their dramatic rise associated with limited effective strategies to slow down these epidemics calls for a better understanding of their pathophysiology in order to decrease the burdens on childhood. Several cross-sectional studies have demonstrated the association between intestinal dysbiosis and active diseases. Although informative, these studies do not mechanistically link alterations of the microflora with disease pathogenesis and, therefore, with potential therapeutic targets. More prospective studies are needed to determine whether intestinal dysbiosis plays a causative role in the onset and development of CIDs. Furthermore, given the complexity of the microflora interaction with the host, it is necessary to design a systems-level model of interactions between the host and the development of disease by integrating microbiome, metagenomics, metatranscriptomics, and metabolomics with either clinical either environmental data.In this chapter we will discuss the current knowledge regarding the microbiome's contribution to celiac disease and inflammatory bowel disease with a particular focus on how probiotics may be used as potential preventive therapy for CIDs.
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Affiliation(s)
- Gloria Serena
- Mucosal Immunology and Biology Research Center and Division of Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital for Children - Harvard Medical School, Boston, MA, USA.
| | - Alessio Fasano
- Mucosal Immunology and Biology Research Center and Division of Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital for Children - Harvard Medical School, Boston, MA, USA
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17
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Lightner AL, Pemberton JH, Dozois EJ, Larson DW, Cima RR, Mathis KL, Pardi DS, Andrew RE, Koltun WA, Sagar P, Hahnloser D. The surgical management of inflammatory bowel disease. Curr Probl Surg 2017; 54:172-250. [PMID: 28576304 DOI: 10.1067/j.cpsurg.2017.02.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Amy L Lightner
- Division of Colon and Rectal Surgery, Mayo Clinic, Rochester, MN.
| | - John H Pemberton
- Division of Colon and Rectal Surgery, Mayo Clinic, Rochester, MN
| | - Eric J Dozois
- Division of Colon and Rectal Surgery, Mayo Clinic, Rochester, MN
| | - David W Larson
- Division of Colon and Rectal Surgery, Mayo Clinic, Rochester, MN
| | - Robert R Cima
- Division of Colon and Rectal Surgery, Mayo Clinic, Rochester, MN
| | - Kellie L Mathis
- Division of Colon and Rectal Surgery, Mayo Clinic, Rochester, MN
| | - Darrell S Pardi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Rachel E Andrew
- Division of Colorectal Surgery, Penn State Health Milton S. Hershey Medical Center, Penn State College of Medicine, Hershey, PA
| | - Walter A Koltun
- Division of Colorectal Surgery, Penn State Health Milton S. Hershey Medical Center, Penn State College of Medicine, Hershey, PA
| | - Peter Sagar
- Division of Colorecal surgery, St. James University Hospital, Leeds, England
| | - Dieter Hahnloser
- Division of Colorecal surgery, Lausanne University Hospital, Lausanne, Switzerland
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18
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Fecteau ME, Pitta DW, Vecchiarelli B, Indugu N, Kumar S, Gallagher SC, Fyock TL, Sweeney RW. Dysbiosis of the Fecal Microbiota in Cattle Infected with Mycobacterium avium subsp. paratuberculosis. PLoS One 2016; 11:e0160353. [PMID: 27494144 PMCID: PMC4975387 DOI: 10.1371/journal.pone.0160353] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Accepted: 07/18/2016] [Indexed: 02/06/2023] Open
Abstract
Johne's disease (JD) is a chronic, intestinal infection of cattle, caused by Mycobacterium avium subsp. paratuberculosis (MAP). It results in granulomatous inflammation of the intestinal lining, leading to malabsorption, diarrhea, and weight loss. Crohn’s disease (CD), a chronic, inflammatory gastrointestinal disease of humans, has many clinical and pathologic similarities to JD. Dysbiosis of the enteric microbiota has been demonstrated in CD patients. It is speculated that this dysbiosis may contribute to the intestinal inflammation observed in those patients. The purpose of this study was to investigate the diversity patterns of fecal bacterial populations in cattle infected with MAP, compared to those of uninfected control cattle, using phylogenomic analysis. Fecal samples were selected to include samples from 20 MAP-positive cows; 25 MAP-negative herdmates; and 25 MAP-negative cows from a MAP-free herd. The genomic DNA was extracted; PCR amplified sequenced on a 454 Roche platform, and analyzed using QIIME. Approximately 199,077 reads were analyzed from 70 bacterial communities (average of 2,843 reads/sample). The composition of bacterial communities differed between the 3 treatment groups (P < 0.001; Permanova test). Taxonomic assignment of the operational taxonomic units (OTUs) identified 17 bacterial phyla across all samples. Bacteroidetes and Firmicutes constituted more than 95% of the bacterial population in the negative and exposed groups. In the positive group, lineages of Actinobacteria and Proteobacteria increased and those of Bacteroidetes and Firmicutes decreased (P < 0.001). Actinobacteria was highly abundant (30% of the total bacteria) in the positive group compared to exposed and negative groups (0.1–0.2%). Notably, the genus Arthrobacter was found to predominate Actinobacteria in the positive group. This study indicates that MAP-infected cattle have a different composition of their fecal microbiota than MAP-negative cattle.
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Affiliation(s)
- Marie-Eve Fecteau
- Department of Clinical Studies-New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, Pennsylvania, United States of America
- * E-mail:
| | - Dipti W. Pitta
- Department of Clinical Studies-New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, Pennsylvania, United States of America
| | - Bonnie Vecchiarelli
- Department of Clinical Studies-New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, Pennsylvania, United States of America
| | - Nagaraju Indugu
- Department of Clinical Studies-New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, Pennsylvania, United States of America
| | - Sanjay Kumar
- Department of Clinical Studies-New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, Pennsylvania, United States of America
| | - Susan C. Gallagher
- Department of Clinical Studies-New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, Pennsylvania, United States of America
| | - Terry L. Fyock
- Department of Clinical Studies-New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, Pennsylvania, United States of America
| | - Raymond W. Sweeney
- Department of Clinical Studies-New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, Pennsylvania, United States of America
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19
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Kamada N, Rogler G. The Innate Immune System: A Trigger for Many Chronic Inflammatory Intestinal Diseases. Inflamm Intest Dis 2016; 1:70-77. [PMID: 29922660 DOI: 10.1159/000445261] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2016] [Accepted: 03/08/2016] [Indexed: 12/31/2022] Open
Abstract
Background Mononuclear phagocytes, such as monocytes, macrophages, and dendritic cells, are important cellular components of the innate immune system that contribute to the pathogenesis of many intestinal inflammatory diseases. Summary While mononuclear phagocytes play a key role in the induction of inflammation in many different tissues through production of pro-inflammatory cytokines and chemokines (such as IL-1, TNF, IL-6, IL-8 and MCP-1), free oxygen radicals (also termed 'oxidative burst'), proteases (such as cathepsins) and tissue-degrading enzymes (such as metalloproteinases), resident macrophages as well as dendritic cells in the intestine display an anergic and 'tolerogenic' phenotype mediating tolerance to commensal bacteria. In recent years many single nucleotide polymorphisms (SNPs) in genes mainly expressed in the above-mentioned cell types have been identified to convey an increased risk of autoimmune diseases. SNPs in the NOD2, ATG16L1 and TNFSF15 genes, which are involved in the function of the innate immune cells, are identified as risk factors for Crohn's disease (CD). Of note, these genes are involved in the different functions in the innate immune cells. For example, while NOD2 is required for intracellular recognition of microbial components, ATG16L1 is involved in autophagy responses against intracellular microbes. Likewise, TNFSF15 contributes to the induction of inflammatory responses by innate immune cells. Furthermore, the frequency of mutations in these genes differs by ethnicity. Genetic variations in the NOD2 and ATG16L1 genes are associated with CD in Caucasians but much less in Eastern Asian populations, whereas SNPs in TNFSF15 are dominated in Asian populations. Thus, different genetic risks may eventually lead to similar impairments in innate immune cells, thereby developing the same disease in Western and Asian patients with CD. Key Messages Despite differences in risk genes, similar mechanisms associated with the innate immune system may trigger autoimmune and chronic inflammatory intestinal diseases in East and West.
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Affiliation(s)
- Nobuhiko Kamada
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Mich., USA
| | - Gerhard Rogler
- Division of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland
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20
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DeCoster E, Alves de Medeiros A, Bostoen J, Stockman A, van Geel N, Lapeere H, Lambert J. A multileveled approach in psoriasis assessment and follow-up: A proposal for a tailored guide for the dermatological practice. J DERMATOL TREAT 2015; 27:298-310. [PMID: 26671313 DOI: 10.3109/09546634.2015.1117566] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND Psoriasis is a complex and heterogeneous disease resulting from interactions between genetic, immunological, and environmental factors. To make the most optimal treatment decision, the dermatologist must therefore have a detailed overview of the patient's history and lifestyle. OBJECTIVES We sought to offer an overview of the various relevant aspects in clinical dermatological assessment of psoriasis patients, emphasizing the importance of a multidisciplinary and integrated clinical approach. METHODS We gathered information on psoriasis management and developed a tailored checklist covering all health-related aspects associated with psoriasis. RESULTS Demographics, personal and family history were elaborately described as well as drug history to discuss how they affect psoriasis management. Relevant patient information such as the vaccination status or cardiovascular profile were included in the checklist as well and treatment recommendations were adapted and updated in accordance with evidence-based literature. This checklist also emphasizes the importance of drug surveillance, proper follow-up and specialist referral, and why the dermatologist needs to address these health-related aspects when assessing psoriasis patients, going beyond optimal skin care. CONCLUSIONS Our comprehensive overview can be used as a consultation checklist for good clinical practice in psoriasis patient management and aid in treatment decision.
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Affiliation(s)
- Eveline DeCoster
- a Department of Dermatology , Ghent University Hospital , Ghent , Belgium and
| | | | - Jessica Bostoen
- a Department of Dermatology , Ghent University Hospital , Ghent , Belgium and
| | - Annelies Stockman
- b Department of Dermatology , AZ Sint Rembert Hospital , Torhout , Belgium
| | - Nanja van Geel
- a Department of Dermatology , Ghent University Hospital , Ghent , Belgium and
| | - Hilde Lapeere
- a Department of Dermatology , Ghent University Hospital , Ghent , Belgium and
| | - Jo Lambert
- a Department of Dermatology , Ghent University Hospital , Ghent , Belgium and
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21
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Iskandar I, Ashcroft D, Warren R, Yiu Z, McElhone K, Lunt M, Barker J, Burden A, Ormerod A, Reynolds N, Smith C, Griffiths C. Demographics and disease characteristics of patients with psoriasis enrolled in the
B
ritish
A
ssociation of
D
ermatologists
B
iologic
I
nterventions
R
egister. Br J Dermatol 2015; 173:510-8. [DOI: 10.1111/bjd.13908] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/12/2015] [Indexed: 12/24/2022]
Affiliation(s)
- I.Y.K. Iskandar
- Centre for Pharmacoepidemiology and Drug Safety Manchester Pharmacy School The University of Manchester Manchester U.K
| | - D.M. Ashcroft
- Centre for Pharmacoepidemiology and Drug Safety Manchester Pharmacy School The University of Manchester Manchester U.K
| | - R.B. Warren
- Dermatology Centre Salford Royal NHS Foundation Trust Manchester Academic Health Science Centre The University of Manchester Barnes BuildingManchester M6 8HDU.K
| | - Z.Z.N. Yiu
- Dermatology Centre Salford Royal NHS Foundation Trust Manchester Academic Health Science Centre The University of Manchester Barnes BuildingManchester M6 8HDU.K
| | - K. McElhone
- Dermatology Centre Salford Royal NHS Foundation Trust Manchester Academic Health Science Centre The University of Manchester Barnes BuildingManchester M6 8HDU.K
| | - M. Lunt
- Arthritis Research U.K. Epidemiology Unit The University of Manchester Manchester U.K
| | - J.N.W.N. Barker
- St John's Institute of Dermatology Guy's and St Thomas’ NHS Foundation Trust London U.K
| | - A.D. Burden
- Department of Dermatology Western Infirmary Glasgow U.K
| | - A.D. Ormerod
- Division of Applied Medicine University of Aberdeen Foresterhill Aberdeen U.K
| | - N.J. Reynolds
- Dermatological Sciences Institute of Cellular Medicine Medical School Royal Victoria Infirmary Newcastle University Newcastle upon Tyne U.K
| | - C.H. Smith
- St John's Institute of Dermatology Guy's and St Thomas’ NHS Foundation Trust London U.K
| | - C.E.M. Griffiths
- Dermatology Centre Salford Royal NHS Foundation Trust Manchester Academic Health Science Centre The University of Manchester Barnes BuildingManchester M6 8HDU.K
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22
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Biedermann L, Rogler G. The intestinal microbiota: its role in health and disease. Eur J Pediatr 2015; 174:151-67. [PMID: 25563215 DOI: 10.1007/s00431-014-2476-2] [Citation(s) in RCA: 130] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Revised: 12/08/2014] [Accepted: 12/10/2014] [Indexed: 12/13/2022]
Abstract
UNLABELLED The intestinal microbiota (previously referred to as "intestinal flora") has entered the focus of research interest not only in microbiology but also in medicine. Huge progress has been made with respect to the analysis of composition and functions of the human microbiota. An "imbalance" of the microbiota, frequently also called a "dysbiosis," has been associated with different diseases in recent years. Crohn's disease and ulcerative colitis as two major forms of inflammatory bowel disease, irritable bowel syndrome (IBS) and some infectious intestinal diseases such as Clostridium difficile colitis feature a dysbiosis of the intestinal flora. Whereas this is somehow expected or less surprising, an imbalance of the microbiota or an enrichment of specific bacterial strains in the flora has been associated with an increasing number of other diseases such as diabetes, metabolic syndrome, non-alcoholic fatty liver disease or steatohepatitis and even psychiatric disorders such as depression or multiple sclerosis. It is important to understand the different aspects of potential contributions of the microbiota to pathophysiology of the mentioned diseases. CONCLUSION With the present manuscript, we aim to summarize the current knowledge and provide an overview of the different concepts on how bacteria contribute to health and disease in animal models and-more importantly-humans. In addition, it has to be borne in mind that we are only at the very beginning to understand the complex mechanisms of host-microbial interactions.
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Affiliation(s)
- Luc Biedermann
- Division of Gastroenterology and Hepatology, University Hospital Zürich, Rämistrasse 100, 8091, Zürich, Switzerland,
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23
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Regeling A, Somasundaram R, de Haar C, van der Woude CJ, Braat H, Peppelenbosch MP. Role of defective autophagia and the intestinal flora in Crohn disease. SELF NONSELF 2014; 1:323-327. [PMID: 21487507 DOI: 10.4161/self.1.4.13990] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The precise mechanisms underlying the development of Crohn disease (CD) remain controversial, but sufficient data have been collected to suggest that an uncontrolled immune response within the intestinal mucosa leads to inflammation in a genetically susceptible host. Although lack of mucosal regulatory T cells causes colitis in humans and experimental rodents, patients with CD have more rather than less regulatory activity in the intestine, apparently excluding defects in tolerance as the cause of CD. Genome-wide association studies have identified many gene variants that confer susceptibility and which seem associated to diminished functioning of especially innate immunity. In apparent agreement, CD patients are impaired with respect to innate immune responses and controlling bacterial flora in the intestine. Furthermore, severe genetic deficiencies in innate immunity, like e.g., lack of NADP oxidase activity or diminished function of the Wiskott Aldrich syndrome protein are associated with colitis in mice and men, and are often mistakenly diagnosed as CD. Thus we favor the view that the primary defect in CD is a lack in innate immunity, causing second tier immunological defenses to combat otherwise easily controlled bacterial breaches of the mucosal barrier.
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Affiliation(s)
- Anouk Regeling
- Diseases University Medical Center Groningen Hanzeplein 1 9713 GZ Groningen, The Netherlands
| | - Rajesh Somasundaram
- Department of Gastroenterology and Hepatology; Erasmus MC; University Medical Center Rotterdam; Rotterdam, The Netherlands
| | - Colin de Haar
- Department of Gastroenterology and Hepatology; Erasmus MC; University Medical Center Rotterdam; Rotterdam, The Netherlands
| | - C Janneke van der Woude
- Department of Gastroenterology and Hepatology; Erasmus MC; University Medical Center Rotterdam; Rotterdam, The Netherlands
| | - Henri Braat
- Department of Gastroenterology and Hepatology; Erasmus MC; University Medical Center Rotterdam; Rotterdam, The Netherlands
| | - Maikel P Peppelenbosch
- Department of Gastroenterology and Hepatology; Erasmus MC; University Medical Center Rotterdam; Rotterdam, The Netherlands
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Prevention and Control of Diseases by Use of Pro- and Prebiotics (Synbiotics). FOOD REVIEWS INTERNATIONAL 2014. [DOI: 10.1080/87559129.2014.929142] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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The complex role of inflammasomes in the pathogenesis of Inflammatory Bowel Diseases - lessons learned from experimental models. Cytokine Growth Factor Rev 2014; 25:715-30. [PMID: 24803013 DOI: 10.1016/j.cytogfr.2014.04.003] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2014] [Accepted: 04/04/2014] [Indexed: 02/08/2023]
Abstract
Inflammasomes are a large family of multiprotein complexes recognizing pathogen-associated molecular pattern molecules (PAMPs) and damage-associated molecular patterns (DAMPs). This leads to caspase-1 activation, promoting the secretion of mature IL-1β, IL-18 and under certain conditions even induce pyroptosis. Inflammatory Bowel Diseases (IBD) is associated with alterations in microbiota composition, inappropriate immune responses and genetic predisposition associated to bacterial sensing and autophagy. Besides their acknowledged role in mounting microbial induced host responses, a crucial role in maintenance of intestinal homeostasis was revealed in inflammasome deficient mice. Further, abnormal activation of these functions appears to contribute to the pathology of intestinal inflammation including IBD and colitis-associated cancer. Herein, the current literature implicating the inflammasomes, microbiota and IBD is comprehensively reviewed.
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Wang Y, Tong J, Chang B, Wang BF, Zhang D, Wang BY. Genetic polymorphisms in the IL-18 gene and ulcerative colitis risk: a meta-analysis. DNA Cell Biol 2014; 33:438-47. [PMID: 24621393 DOI: 10.1089/dna.2013.2310] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
This meta-analysis was performed to evaluate the relationships between genetic polymorphisms in the IL-18 gene and ulcerative colitis (UC) risk. The PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library, and CBM databases were searched for relevant articles published before November 1st, 2013 without any language restrictions. Meta-analysis was conducted using the STATA 12.0 software. Crude odds ratios (ORs) with their 95% confidence intervals (95% CI) were calculated. Eight case-control studies with a total of 1000 UC cases and 1392 healthy subjects met the inclusion criteria. Six common polymorphisms in the IL-18 gene were evaluated, including rs1946518 A>C, rs187238 G>C, rs917997 G>A, Codon35, rs1946519 C>A, and rs360718 A>C. The results of our meta-analysis suggest that the IL-18 rs1946518 (allele model: OR=1.22, 95% CI: 1.01-1.48, p=0.039; dominant model: OR=1.44, 95% CI: 1.01-2.06, p=0.045; respectively), rs187238 (allele model: OR=1.38, 95% CI: 1.19-1.61, p<0.001; dominant model: OR=1.50, 95% CI: 1.03-2.19, p=0.034; respectively), and rs360718 (allele model: OR=2.18, 95% CI: 1.22-3.90, p=0.008) polymorphisms might be strongly correlated with an increased risk of UC. A subgroup analysis was conducted to investigate the effect of ethnicity on an individual's risk of UC. Our results revealed positive significant correlations between IL-18 genetic polymorphisms and an increased risk of UC among Asians (allele model: OR=1.36, 95% CI: 1.16-1.60, p<0.001; dominant model: OR=1.50, 95% CI: 1.14-1.98, p=0.004; respectively) and Africans (allele model: OR=1.45, 95% CI: 1.03-2.05, p=0.034), but not among Caucasians (all p>0.05). Our findings provide convincing evidence that IL-18 genetic polymorphisms may contribute to susceptibility to UC, especially the rs1946518, rs187238, and rs360718 polymorphisms among Asians and Africans.
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Affiliation(s)
- Ying Wang
- Department of Gastroenterology, The First Hospital of China Medical University , Shenyang, People's Republic of China
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Freeman HJ. Natural history and long-term clinical course of Crohn’s disease. World J Gastroenterol 2014; 20:31-36. [PMID: 24415855 PMCID: PMC3886024 DOI: 10.3748/wjg.v20.i1.31] [Citation(s) in RCA: 117] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2012] [Revised: 11/20/2012] [Accepted: 04/10/2013] [Indexed: 02/06/2023] Open
Abstract
Crohn’s disease is a chronic inflammatory disease process involving different sites in the gastrointestinal tract. Occasionally, so-called metastatic disease occurs in extra-intestinal sites. Granulomatous inflammation may be detected in endoscopic biopsies or resected tissues. Genetic, epigenetic and environmental factors appear to play a role. Multiple susceptibility genes have been described in both familial and non-familial forms while the disease is phenotypically heterogeneous with a female predominance. The disorder occurs over a broad age spectrum, from early childhood to late adulthood. More than 80% are diagnosed before age 40 years usually with terminal ileal and colonic involvement. Pediatric-onset disease is more severe and more extensive, usually with a higher chance of upper gastrointestinal tract disease, compared to adult-onset disease. Long-term studies have shown that the disorder may evolve with time into more complex disease with stricture formation and penetrating disease complications (i.e., fistula, abscess). Although prolonged remission may occur, discrete periods of symptomatic disease may re-appear over many decades suggesting recurrence or re-activation of this inflammatory process. Eventual development of a cure will likely depend on identification of an etiologic cause and a fundamental understanding of its pathogenesis. Until now, treatment has focused on removing risk factors, particularly cigarette smoking, and improving symptoms. In clinical trials, clinical remission is largely defined as improved numerical and endoscopic indices for “mucosal healing”. “Deep remission” is a conceptual, more “extended” goal that may or may not alter the long-term natural history of the disease in selected patients, albeit at a significant risk for treatment complications, including serious and unusual opportunistic infections.
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Laing B, Han DY, Ferguson LR. Candidate genes involved in beneficial or adverse responses to commonly eaten brassica vegetables in a New Zealand Crohn's disease cohort. Nutrients 2013; 5:5046-64. [PMID: 24352087 PMCID: PMC3875924 DOI: 10.3390/nu5125046] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2013] [Revised: 11/22/2013] [Accepted: 11/29/2013] [Indexed: 12/20/2022] Open
Abstract
Crohn’s disease (CD) is one of the two manifestations of inflammatory bowel disease. Particular foods are thought with CD to exacerbate their illness. Vegetables, especially Brassicaceae, are often shunned by people with CD because of the negative effects they are alleged to have on their symptoms. Brassicaceae supply key nutrients which are necessary to meet recommended daily intakes. We sought to identify the candidate genes involved in the beneficial or adverse effects of Brassicaceae most commonly eaten, as reported by the New Zealand adults from the “Genes and Diet in Inflammatory Bowel disease Study” based in Auckland. An analysis of associations between the single nucleotide polymorphisms (SNPs) and the beneficial or adverse effects of the ten most commonly eaten Brassicaceae was carried out. A total of 37 SNPs were significantly associated with beneficial effects (p = 0.00097 to 0.0497) and 64 SNPs were identified with adverse effects (p = 0.0000751 to 0.049). After correcting for multiple testing, rs7515322 (DIO1) and rs9469220 (HLA) remained significant. Our findings show that the tolerance of some varieties of Brassicaceae may be shown by analysis of a person’s genotype.
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Affiliation(s)
- Bobbi Laing
- Discipline of Nutrition, School of Medical Sciences, Auckland University, 85 Park Road, Grafton Campus, Auckland 1142, New Zealand.
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Moon CM, Shin DJ, Son NH, Shin ES, Hong SP, Kim TI, Kim WH, Cheon JH. Genetic variants in the IL12B gene are associated with inflammatory bowel diseases in the Korean population. J Gastroenterol Hepatol 2013; 28:1588-94. [PMID: 23573954 DOI: 10.1111/jgh.12214] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/01/2013] [Indexed: 12/29/2022]
Abstract
BACKGROUND AND AIM Recent genomic studies have identified genetic variants in the IL12B gene, which encodes the p40 subunit shared by interleukin 12 and interleukin 23, as susceptibility loci for inflammatory bowel disease (IBD). The study aimed to identify additional novel genetic variants in IL12B and investigated whether variants confer susceptibility to the development of Crohn's disease (CD) or ulcerative colitis (UC) in the Korean population. METHODS To detect single nucleotide polymorphisms (SNPs) in IL12B, direct sequencing of all coding exons, exon-intron boundaries, promoter region, and 5' untranslated region was performed in 24 randomly selected samples. Selected haplotype-tagging SNPs were subsequently genotyped in 493 IBD patients (245 patients with CD and 248 with UC) and 504 healthy controls. RESULTS Two haplotype-tagging SNPs (rs2288831 and rs919766) were selected through direct sequencing and were genotyped. Of them, SNP rs2288831 in the IL12B gene was significantly associated with CD susceptibility in allelic association analysis (odds ratio = 1.30; 95% confidence interval 1.04-1.62; P = 0.019). This significant association with CD was also observed for a haplotype consisting of SNP rs919766 and rs2288831 (odds ratio = 1.29; 95% confidence interval 1.03-1.60; P = 0.025). However, none of IL12B SNPs were associated with UC susceptibility. Finally, no specific associations between genetic variants and disease phenotype of CD were identified. CONCLUSIONS This study is first to identify SNP rs2288831 in the IL12B gene as a susceptible variation for CD. Further studies in other ethnic groups are warranted to validate the association of this genetic variant with IBD.
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Affiliation(s)
- Chang Mo Moon
- Department of Internal Medicine, Graduate School, Yonsei University College of Medicine, Seoul, Korea; Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
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Delgado MG, Vega J, Santamarta E, Caminal L. Complex partial status epilepticus in a patient with Crohn's disease. BMJ Case Rep 2013; 2013:bcr-2013-200503. [PMID: 24014561 DOI: 10.1136/bcr-2013-200503] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Few cases of Crohn's disease complicated with meningitis and epidural abscess have been described in literature. We present a case of a 42-year-old former smoker female patient diagnosed with Crohn's disease in September 1995 (with severe nutritional problems). On 20 February 2012, she was admitted due to a probable sepsis (without any previous treatment). After several days she developed a confusion syndrome (probable Wernicke's disease). On 5 March 2012, the patient presented with a febrile episode of 39 ° C. Two days later, the patient presented aphasia and paraparesis, and 3 days later she presented a complex partial status epilepticus. A lumbar puncture was performed and showed 131 leucocytes (63% granulocytes) and proteins 296.3. The abdominopelvic CT scan revealed a presacral collection that seem to extend cranially towards the lumbosacral spine. The lumbar MRI confirmed the lumbar epidural abscess secondary to the fistulisation of the presacral abscess.
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Zhang H, Ma L, Dong LQ, Shu C, Xu JL. Association of the macrophage migration inhibitory factor gene--173G/C polymorphism with inflammatory bowel disease: a meta-analysis of 4296 subjects. Gene 2013; 526:228-31. [PMID: 23707797 DOI: 10.1016/j.gene.2013.05.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2012] [Revised: 05/01/2013] [Accepted: 05/06/2013] [Indexed: 12/26/2022]
Abstract
A variety of epidemiologic studies have focused on the association between macrophage migration inhibitory factor (MIF) gene--173G/C polymorphism and inflammatory bowel disease (IBD). However, results in different studies have been inconsistent. In order to derive a more precise estimation of the associations, we performed this meta-analysis and systematic searches of electronic databases PubMed and Web of Science (up to April 30, 2013). Based on our search criteria, a total of seven eligible studies concerning the MIF--173G/C polymorphism and IBD risk were included in the final meta-analysis, comprising 2162 IBD cases and 2134 controls. Significant association was found between MIF--173G/C polymorphism and the risk of IBD when all studies were pooled into the meta-analysis (for C allele vs. G allele: OR=1.25, 95% CI=1.12-1.41, p=0.000; for C/C vs. G/G: OR=1.71, 95% CI=1.23-2.39, p=0.002; for C/C+G/C vs. G/G: OR=1.24, 95% CI=1.09-1.42, p=0.002; for C/C vs. G/C+G/G: OR=1.67, 95% CI=1.20-2.33, p=0.002). Heterogeneity and publication bias did not exist in the overall comparisons. The present meta-analysis suggests an association between the MIF--173G/C polymorphism and IBD risk. However, due to few studies and the selection bias existed in some studies, the results should be interpreted with caution.
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Affiliation(s)
- Hui Zhang
- Department of Neurosurgery, Air Force General Hospital of the Chinese PLA, 30 Fucheng Road, Haidian District, Beijing 100142, China
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Combined serological, genetic, and inflammatory markers differentiate non-IBD, Crohn's disease, and ulcerative colitis patients. Inflamm Bowel Dis 2013; 19:1139-48. [PMID: 23518807 PMCID: PMC3792797 DOI: 10.1097/mib.0b013e318280b19e] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Previous studies have demonstrated that serological markers can assist in diagnosing inflammatory bowel disease (IBD). In this study, we aim to build a diagnostic tool incorporating serological markers, genetic variants, and markers of inflammation into a computational algorithm to examine patterns of combinations of markers to (1) identify patients with IBD and (2) differentiate patients with Crohn's disease (CD) from ulcerative colitis (UC). METHODS In this cross-sectional study, patient blood samples from 572 CD, 328 UC, 437 non-IBD controls, and 183 healthy controls from academic and community centers were analyzed for 17 markers: 8 serological markers (ASCA-IgA, ASCA-IgG, ANCA, pANCA, OmpC, CBir1, A4-Fla2, and FlaX), 4 genetic markers (ATG16L1, NKX2-3, ECM1, and STAT3), and 5 inflammatory markers (CRP, SAA, ICAM-1, VCAM-1, and VEGF). A diagnostic Random Forest algorithm was constructed to classify IBD, CD, and UC. RESULTS Receiver operating characteristic analysis compared the diagnostic accuracy of using a panel of serological markers only (ASCA-IgA, ASCA-IgG, ANCA, pANCA, OmpC, and CBir1) versus using a marker panel that in addition to the serological markers mentioned above also included gene variants, inflammatory markers, and 2 additional serological markers (A4-Fla2 and FlaX). The extended marker panel increased the IBD versus non-IBD discrimination area under the curve from 0.80 (95% confidence interval [CI], ±0.05) to 0.87 (95% CI, ±0.04; P < 0.001). The CD versus UC discrimination increased from 0.78 (95% CI, ±0.06) to 0.93 (95% CI, ±0.04; P < 0.001). CONCLUSIONS Incorporating a combination of serological, genetic, and inflammation markers into a diagnostic algorithm improved the accuracy of identifying IBD and differentiating CD from UC versus using serological markers alone.
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Baik SH, Park KJ, Lee KY, Cho YB, Choi GS, Lee KY, Yoon SN, Yu CS. Characteristic phenotypes in Korean Crohn's disease patients who underwent intestinal surgery for the treatment. J Korean Med Sci 2013; 28:575-9. [PMID: 23579265 PMCID: PMC3617311 DOI: 10.3346/jkms.2013.28.4.575] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2012] [Accepted: 01/30/2013] [Indexed: 01/03/2023] Open
Abstract
There are no previous large scale studies which have evaluated the phenotypes and clinical characteristics of Korean Crohn's disease patients who underwent intestinal resection. The purpose of this multicenter retrospective cohort study was to evaluate the clinical characteristics of Korean Crohn's disease patients who underwent intestinal resection during the study period. A total of 686 patients were enrolled in this study. The study period was over a 20-yr period (1990-2009). The patients were divided into the first-10-yr group and the second-10-yr group. The phenotypes and clinical characteristics were compared between the groups. The most common site of the disease was the ileal area (37.8%) and stricturing behavior was observed in 38.3% patients. The most common type of surgery was segmental resection of the small bowel (30.6%). These phenotypes showed a similar pattern in both the first and second study period groups and did not show any significant differences between the groups. The number of registered patients increased continuously. The phenotypes of Korean Crohn's disease patients who underwent intestinal resection are different compared with previously reported clinical characteristics of general Crohn's disease patients.
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Affiliation(s)
- Seung Hyuk Baik
- Section of Colon and Rectal Surgery, Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
- IBD Study Group, Korean Society of Coloproctology, Korea
| | - Kyu Joo Park
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
- IBD Study Group, Korean Society of Coloproctology, Korea
| | - Kang Young Lee
- Section of Colon and Rectal Surgery, Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
- IBD Study Group, Korean Society of Coloproctology, Korea
| | - Yong Beom Cho
- Department of Surgery, Sungkyunkwan University School of Medicine, Seoul, Korea
- IBD Study Group, Korean Society of Coloproctology, Korea
| | - Gyu-Seog Choi
- Department of Surgery, Kyungpook National University School of Medicine, Daegu, Korea
- IBD Study Group, Korean Society of Coloproctology, Korea
| | - Kil Yeon Lee
- Department of Surgery, Kyung Hee University School of Medicine, Seoul, Korea
- IBD Study Group, Korean Society of Coloproctology, Korea
| | - Sang Nam Yoon
- Department of Surgery, Hansol Hospital, Seoul, Korea
- IBD Study Group, Korean Society of Coloproctology, Korea
| | - Chang Sik Yu
- Section of Colon and Rectal Surgery, Department of Surgery, University of Ulsan, College of Medicine and Asan Medical Center, Seoul, Korea
- IBD Study Group, Korean Society of Coloproctology, Korea
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Immunogenetic study in Chinese population with ankylosing spondylitis: are there specific genes recently disclosed? Clin Dev Immunol 2013; 2013:419357. [PMID: 23401698 PMCID: PMC3562651 DOI: 10.1155/2013/419357] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2012] [Revised: 12/24/2012] [Accepted: 12/27/2012] [Indexed: 12/17/2022]
Abstract
Purpose. Ankylosing spondylitis (AS) is a systemic, autoimmune disease resulting in the destruction of the affected joints. Over the past 5 years, several new genes or genetic regions associated with AS have been identified in the Chinese population. This paper aims to discuss the major findings and related potential mechanisms of these studies in our population. Recent Findings. In recent years, due to the rapid advances in computational genetics and technology, there has been an increasing list of well-validated genes or genetic regions associated with AS susceptibility. So far, several genes or genetic regions have now been reported in the Han ethnic Chinese population, containing the major histocompatibility complex (MHC), ERAP1, IL-23R, 12q12, 2p15, 5q14.3, and so on. Different hypotheses for disease mechanisms have been investigated on the basis of the functional studies of these genes or genetic regions. Summary. This paper tries to summarize the association of several candidate genes with risk for AS in the Han ethnic Chinese population and aims to identify the novel inflammatory pathways and provide potential strategies for better therapies.
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Baik SH, Kim WH. A comprehensive review of inflammatory bowel disease focusing on surgical management. JOURNAL OF THE KOREAN SOCIETY OF COLOPROCTOLOGY 2012; 28:121-31. [PMID: 22816055 PMCID: PMC3398107 DOI: 10.3393/jksc.2012.28.3.121] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/04/2012] [Accepted: 06/10/2012] [Indexed: 12/15/2022]
Abstract
The two main diseases of inflammatory bowel disease are Crohn's disease and ulcerative colitis. The pathogenesis of inflammatory disease is that abnormal intestinal inflammations occur in genetically susceptible individuals according to various environmental factors. The consequent process results in inflammatory bowel disease. Medical treatment consists of the induction of remission in the acute phase of the disease and the maintenance of remission. Patients with Crohn's disease finally need surgical treatment in 70% of the cases. The main surgical options for Crohn's disease are divided into two surgical procedures. The first is strictureplasty, which can prevent short bowel syndrome. The second is resection of the involved intestinal segment. Simultaneous medico-surgical treatment can be a good treatment strategy. Ulcerative colitis is a diffuse nonspecific inflammatory disease that involves the colon and the rectum. Patients with ulcerative colitis need surgical treatment in 30% of the cases despite proper medical treatment. The reasons for surgical treatment are various, from life-threatening complications to growth retardation. The total proctocolectomy (TPC) with an ileal pouch anal anastomosis (IPAA) is the most common procedure for the surgical treatment of ulcerative colitis. Medical treatment for ulcerative colitis after a TPC with an IPAA is usually not necessary.
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Affiliation(s)
- Seung Hyuk Baik
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
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Chiodini RJ, Chamberlin WM, Sarosiek J, McCallum RW. Crohn's disease and the mycobacterioses: a quarter century later. Causation or simple association? Crit Rev Microbiol 2012; 38:52-93. [PMID: 22242906 DOI: 10.3109/1040841x.2011.638273] [Citation(s) in RCA: 108] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
It has been more than 25 years since Mycobacterium paratuberculosis was first proposed as an etiologic agent in Crohn's disease based on the isolation of this organism from several patients. Since that time, a great deal of information has been accumulated that clearly establishes an association between M. paratuberculosis and Crohn's disease. However, data are conflicting and difficult to interpret and the field has become divided into committed advocates and confirmed skeptics. This review is an attempt to provide a thorough and objective summary of current knowledge from both basic and clinical research from the views and interpretations of both the antagonists and proponents. The reader is left to draw his or her own conclusions related to the validity of the issues and claims made by the opposing views and data interpretations. Whether M. paratuberculosis is a causative agent in some cases or simply represents an incidental association remains a controversial topic, but current evidence suggests that the notion should not be so readily dismissed. Remaining questions that need to be addressed in defining the role of M. paratuberculosis in Crohn's disease and future implications are discussed.
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Affiliation(s)
- Rodrick J Chiodini
- Divisions of Infectious Diseases, Department of Internal Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, USA.
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Systems analysis of inflammatory bowel disease based on comprehensive gene information. BMC MEDICAL GENETICS 2012; 13:25. [PMID: 22480395 PMCID: PMC3368714 DOI: 10.1186/1471-2350-13-25] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/19/2011] [Accepted: 04/05/2012] [Indexed: 12/19/2022]
Abstract
Background The rise of systems biology and availability of highly curated gene and molecular information resources has promoted a comprehensive approach to study disease as the cumulative deleterious function of a collection of individual genes and networks of molecules acting in concert. These "human disease networks" (HDN) have revealed novel candidate genes and pharmaceutical targets for many diseases and identified fundamental HDN features conserved across diseases. A network-based analysis is particularly vital for a study on polygenic diseases where many interactions between molecules should be simultaneously examined and elucidated. We employ a new knowledge driven HDN gene and molecular database systems approach to analyze Inflammatory Bowel Disease (IBD), whose pathogenesis remains largely unknown. Methods and Results Based on drug indications for IBD, we determined sibling diseases of mild and severe states of IBD. Approximately 1,000 genes associated with the sibling diseases were retrieved from four databases. After ranking the genes by the frequency of records in the databases, we obtained 250 and 253 genes highly associated with the mild and severe IBD states, respectively. We then calculated functional similarities of these genes with known drug targets and examined and presented their interactions as PPI networks. Conclusions The results demonstrate that this knowledge-based systems approach, predicated on functionally similar genes important to sibling diseases is an effective method to identify important components of the IBD human disease network. Our approach elucidates a previously unknown biological distinction between mild and severe IBD states.
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Clinical and genetic risk factors for perianal Crohn's disease in a population-based cohort. Am J Gastroenterol 2012; 107:589-96. [PMID: 22158027 DOI: 10.1038/ajg.2011.437] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Perianal Crohn's disease (CD) affects around one-quarter of CD patients and represents a distinct disease phenotype. The objective of this study was to investigate a large population-based cohort of inflammatory bowel disease (IBD) patients to identify clinical and genetic risk factors for perianal CD. METHODS Data were collected in the Canterbury IBD database, estimated to include 91% of all patients with IBD in Canterbury, New Zealand. Genotyping was performed for selected loci previously demonstrated to be associated with CD. Patients with perianal disease were then compared with both CD patients without perianal disease and healthy controls to assess the presence of potential phenotypic, environmental, and genetic risk factors. RESULTS Of the 715 CD patients in the database, 190 (26.5%) had perianal disease. In all, 507 patients with genotype data available were analyzed. Perianal disease was associated with younger age at diagnosis (P < 0.0001), complicated intestinal disease (P < 0.0001), and ileal disease location (P = 0.002). There was no association with gender, ethnicity, smoking, or breast feeding. Genotype analysis revealed an association with the neutrophil cytosolic factor 4 (NCF4) gene compared with both non-perianal CD patients (odds ratio (OR): 1.47; 95% confidence interval (CI): 1.08-1.99) and healthy controls (OR: 1.47; 95% CI: 1.10-1.95). There was no association identified with other genes, including IBD5 (OR: 0.91; 95% CI: 0.69-1.20), tumor necrosis factor α (OR: 1.04; 95% CI: 0.56-1.85), and IRGM (immunity-related guanosine triphosphatase protein type M) (OR: 1.21; 95% CI: 0.80-1.82). CONCLUSIONS This study suggests that younger age at diagnosis, complicated disease behavior, and ileal disease location are risk factors for perianal CD. In addition, this paper represents the first report of an association of the NCF4 gene with perianal disease.
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Malmborg P, Bahmanyar S, Grahnquist L, Hildebrand H, Montgomery S. Cesarean section and the risk of pediatric Crohn's disease. Inflamm Bowel Dis 2012; 18:703-8. [PMID: 21538718 DOI: 10.1002/ibd.21741] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2011] [Accepted: 03/23/2011] [Indexed: 12/09/2022]
Abstract
BACKGROUND Crohn's disease (CD) could involve an inappropriate immune response against normal bowel flora. Disrupted or atypical patterns of microbial bowel colonization may impair development of homeostasis between gut flora and the immune system. Perinatal microbial exposures may be particularly important in stimulating intestinal immune recognition. As birth by cesarean section is thought to represent an atypical pattern of early bowel colonization, we examined its association with pediatric CD. METHODS Some 1536 patients diagnosed with pediatric CD and 15,439 controls matched by delivery unit, week of birth, sex, and born between 1973 and 2006 were identified through Swedish registers. The association of birth by cesarean section with pediatric CD was examined using conditional logistic regression, with stratification by sex and adjustment for parental socioeconomic index and maternal infections during pregnancy. RESULTS Birth by cesarean section is associated with a modestly increased risk for pediatric CD among boys (odds ratio [OR] = 1.25, 95% confidence interval [CI] 1.01-1.54) but not girls, (OR = 0.99, 95% CI 0.76-1.29) and elective cesarean section is associated with a modest increased risk for the entire population (OR = 1.36, 95% CI 1.02-1.80). CONCLUSIONS This study does not suggest that the delivery procedure should be altered, but the findings may be of etiological significance in CD, indicating a potential role for perinatal exposures associated with delivery mode. Although the sex difference may have arisen by chance, the modestly increased CD risk for boys delivered by cesarean section is consistent with sex-specific differences in susceptibility to some exposures.
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Affiliation(s)
- Petter Malmborg
- Department of Women and Child Health, Karolinska Institutet, Stockholm, Sweden.
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Sehgal R, Berg A, Polinski JI, Hegarty JP, Lin Z, McKenna KJ, Stewart DB, Poritz LS, Koltun WA. Mutations in IRGM are associated with more frequent need for surgery in patients with ileocolonic Crohn's disease. Dis Colon Rectum 2012; 55:115-21. [PMID: 22228152 DOI: 10.1097/dcr.0b013e31823ccea8] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND There are no clear criteria for judging the severity of disease in patients with Crohn's disease. Yet classification of patients into low- and high-risk severity groups would benefit both medical and surgical management. At the time of this study, approximately 80 single-nucleotide polymorphisms within 55 genes had been associated with IBD. OBJECTIVE The aim of this study was to identify genetic determinants (single-nucleotide polymorphisms) that could be markers of Crohn's disease severity by the use of frequency of ileocolic surgery as a surrogate for disease severity. DESIGN Sixty-six patients (30 male) with ileocolonic Crohn's disease who previously underwent ileocolectomy were retrospectively studied. The severity of Crohn's disease was quantified by dividing the total number of ileocolectomy procedures by the time between IBD diagnosis and the patient's last clinic visit, the rationale being that more severe disease would be associated with a more frequent need for surgery. Genotyping for the 83 single-nucleotide polymorphisms associated with IBD was done on a customized Illumina Veracode genotyping platform. Three genetic models (general, additive, and dominant) were used to statistically quantify the genetic association of the studied single-nucleotide polymorphisms to the frequency of surgery after adjusting for covariates (age, smoking, family history, disease location, and disease behavior). RESULTS For the entire group the average number of ileocolectomies per patient was 1.7 (range, 1-5) with an average duration of disease of 14.7 years. Single-nucleotide polymorphism rs4958847 in the IRGM gene (immunity-related GTPase family, M) was the most significant single-nucleotide polymorphism in all 3 models tested (p = 0.007) as being associated with ileocolectomy, and it remained significant even after a Benjamini-Hochberg false-discovery correction for multiple observations. Patients carrying the "at-risk" allele for this single-nucleotide polymorphism (n = 20) had an average of 1 surgery every 6.87 ± 1.33 years in comparison with patients carrying the wild-type genotype (n = 46) who averaged 1 surgery in 11.43 ± 1.21 years (p = 0.007, Mann-Whitney U test). CONCLUSIONS : Single-nucleotide polymorphism rs4958847 in the IRGM gene correlated very significantly with frequency of surgery in patients with ileocolonic Crohn's disease. IRGM is a mediator of innate immune responses and is involved in autophagy. The presence of this IRGM SNP may be a marker for disease severity and/or early recurrence after ileocolectomy and may assist in surgical and medical decision making.
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Affiliation(s)
- Rishabh Sehgal
- Division of Colon and Rectal Surgery, Penn State Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033, USA.
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Tsianos EV, Katsanos KH, Tsianos VE. Role of genetics in the diagnosis and prognosis of Crohn's disease. World J Gastroenterol 2012; 18:105-18. [PMID: 22253516 PMCID: PMC3257437 DOI: 10.3748/wjg.v18.i2.105] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2011] [Revised: 04/25/2011] [Accepted: 05/02/2011] [Indexed: 02/06/2023] Open
Abstract
Considering epidemiological, genetic and immunological data, we can conclude that the inflammatory bowel diseases are heterogeneous disorders of multifactorial etiology in which hereditability and environment interact to produce the disease. It is probable that patients have a genetic predisposition for the development of the disease coupled with disturbances in immunoregulation. Several genes have been so far related to the diagnosis of Crohn's disease. Those genes are related to innate pattern recognition receptors, to epithelial barrier homeostasis and maintenance of epithelial barrier integrity, to autophagy and to lymphocyte differentiation. So far, the most strong and replicated associations with Crohn's disease have been done with NOD2, IL23R and ATG16L1 genes. Many genes have so far been implicated in prognosis of Crohn's disease and many attempts have been made to classify genetic profiles in Crohn's disease. CARD15 seems not only a susceptibility gene, but also a disease-modifier gene for Crohn's disease. Enriching our understanding on Crohn's disease genetics is important but when combining genetic data with functional data the outcome could be of major importance to clinicians.
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Tsianos EV, Katsanos KH, Tsianos VE. Role of genetics in the diagnosis and prognosis of Crohn's disease. World J Gastroenterol 2011; 17:5246-59. [PMID: 22219593 PMCID: PMC3247688 DOI: 10.3748/wjg.v17.i48.5246] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2011] [Revised: 06/15/2011] [Accepted: 06/22/2011] [Indexed: 02/06/2023] Open
Abstract
Considering the epidemiological, genetic and immunological data, we can conclude that the inflammatory bowel diseases are heterogeneous disorders of multifactorial etiology in which hereditability and environment interact to produce the disease. It is probable that patients have a genetic predisposition for the development of the disease coupled with disturbances in immunoregulation. Several genes have so far been related to the diagnosis of Crohn's disease. These genes are related to innate pattern recognition receptors, to epithelial barrier homeostasis and maintenance of epithelial barrier integrity, to autophagy and to lymphocyte differentiation. So far, the strongest and most replicated associations with Crohn's disease have been demonstrated with NOD2, IL23R and ATG16L1 genes. Many genes have so far been implicated in the prognosis of Crohn's disease and many attempts have been made for classification of genetic profiles in Crohn's disease. CARD15 seems to be not only a susceptibility gene, but also a disease-modifier gene for Crohn's disease. Enriching our understanding of Crohn's disease genetics is of value, but when combining genetic data with functional data the outcome could be of major importance to clinicians.
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Alpha-defensin DEFA1A3 gene copy number elevation in Danish Crohn's disease patients. Dig Dis Sci 2011; 56:3517-24. [PMID: 21701837 DOI: 10.1007/s10620-011-1794-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2010] [Accepted: 03/25/2011] [Indexed: 01/13/2023]
Abstract
BACKGROUND AND PURPOSE OF STUDY Extensive copy number variation is observed for the DEFA1A3 gene encoding alpha-defensins 1-3. The objective of this study was to determine the involvement of alpha-defensins in colonic tissue from Crohn's disease (CD) patients and the possible genetic association of DEFA1A3 with CD. METHODS Two-hundred and forty ethnic Danish CD patients were included in the study. Reverse transcriptase PCR assays determined DEFA1A3 expression in colonic tissue from a subset of patients. Immunohistochemical analysis identified alpha-defensin peptides in colonic tissue. Copy number of DEFA1A3 and individual alleles, DEFA1 and DEFA3, were compared with those for controls, by use of combined real-time quantitative PCR and pyrosequencing, and correlated with disease location. RESULTS Inflammatory-dependent mRNA expression of DEFA1A3 (P < 0.001), and the presence of alpha-defensin peptides, were observed in colonic tissue samples. Higher DEFA1A3 gene copy number (CD: mean copy number, 7.2 vs. controls 6.7; P < 0.001) and individual DEFA1 alleles (CD mean copy number 5.6 vs. controls 5.1; P < 0.01) were associated with CD, with strong association with colonic location (P < 0.001). CONCLUSIONS Alpha-defensins are involved in the inflammation of CD, with local mRNA and peptide expression. In combination with the findings that a high DEFA1A3 copy number is significantly linked to CD, these results suggest that a high DEFA1A3 copy number might be important in hindering the normal inflammatory response in CD, particularly colonic CD.
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Abstract
Twin studies have demonstrated the importance of environmental factors in the pathogenesis of inflammatory bowel disease, but progress has been relatively slow in identifying these, with the exception of smoking, which is positively associated with Crohn's disease and negatively associated with ulcerative colitis. Genetic studies have identified risk alleles which are involved in host-bacterial interactions and the mucosal barrier, and evidence is building for a likely pathogenic role for changes in the gut microbiome, with respect to both faecal and mucosa-associated microbiota. Some of these changes may be secondary to inflammation, nevertheless promising new therapeutic targets are beginning to emerge.
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Van Hauwermeiren F, Vandenbroucke RE, Libert C. Treatment of TNF mediated diseases by selective inhibition of soluble TNF or TNFR1. Cytokine Growth Factor Rev 2011; 22:311-9. [PMID: 21962830 DOI: 10.1016/j.cytogfr.2011.09.004] [Citation(s) in RCA: 116] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The TNF signaling pathway is a valuable target in the therapy of autoimmune diseases, and anti-TNF drugs are successfully used to treat diseases such as rheumatoid arthritis, Crohn's disease and psoriasis. By their ability to interfere with inflammatory processes at multiple levels, these TNF blockers have become invaluable tools to inhibit the inflammation induced damage and allow recovery of the affected tissues. Unfortunately this therapy has some drawbacks, including increased risk of infection and malignancy, and remarkably, the onset of new auto-immune diseases. Some of these effects are caused by the unwanted abrogation of beneficial TNF signaling. More specific targeting of the pathological TNF-induced signaling might lead to broader applicability and improved safety. Specificity might be increased by inhibiting the soluble TNF/TNFR1 axis while leaving the often beneficial transmembrane TNF/TNFR2 signaling untouched. This approach looks promising because it inhibits the pathological effects of TNF and reduces the side effects, and it opens the way for the treatment of other diseases in which TNFR2 inhibition is detrimental. In this review we give an overview of in vivo mouse studies of TNF mediated pathologies demonstrating that the blockade or genetic deletion of sTNF or TNFR1 is preferable over total TNF blockade.
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Nimmo ER, Stevens C, Phillips AM, Smith A, Drummond HE, Noble CL, Quail M, Davies G, Aldhous MC, Wilson DC, Satsangi J. TLE1 modifies the effects of NOD2 in the pathogenesis of Crohn's disease. Gastroenterology 2011; 141:972-981.e1-2. [PMID: 21699783 DOI: 10.1053/j.gastro.2011.05.043] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2010] [Revised: 05/16/2011] [Accepted: 05/20/2011] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS The mechanisms by which specific mutations in NOD2/CARD15 increase the risk for Crohn's disease (CD) are unclear. We identified proteins that interact with NOD2 and investigated them by expression, genetic, and functional analyses. METHODS By using a yeast 2-hybrid screen of an intestinal epithelial library, we identified proteins that interact with NOD2 and confirmed the interactions in mammalian cells using co-immunoprecipitation. We used microarray analysis to analyze gene expression patterns in 302 intestinal biopsy samples (129 from patients with ulcerative colitis [UC], 106 with CD, and 67 controls). Eighty single-nucleotide polymorphisms within the genes that encoded 6 interacting proteins were genotyped in a discovery cohort (869 cases of inflammatory bowel disease [IBD], 885 controls) and a replication cohort (504 patients with IBD, 713 controls). We investigated interaction between transducin-like enhancer of split 1 (TLE1) and NOD2 in HEK293 cells. RESULTS We identified 6 NOD2-interacting proteins (TLE1, UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 2 [GALNT2], HIV-1 Tat interactive protein [HTATIP], Vimentin, fission 1 (mitochondrial outer membrane) homolog [FIS1], and protein phosphatase 2, regulatory subunit B', epsilon isoform [PPP2R5E]). Of these, expression of GALNT2 (CD, P = .004) and vimentin (CD, P = .006; UC, P = .0025) was altered in patients with IBD compared with controls. Single-nucleotide polymorphisms within TLE1 were associated with susceptibility to CD, specifically with ileal disease (rs6559629, P = 3.1 × 10⁻⁵; odds ratio, 1.45). The TLE1 risk allele is required for susceptibility to CD in carriers of NOD2 mutations. In cells, TLE1 and NOD2 co-localized around the nuclear membrane and TLE1 inhibited activation of nuclear factor-κB by NOD2. CONCLUSIONS Epistatic and biological interactions between TLE1 and NOD2 are involved in IBD pathogenesis. NOD2 might be involved in a series of pathways such as epigenetic regulation of expression (via TLE1 and HTATIP), biosynthesis of mucin (via GALNT2), apoptosis (via PPP2R5E and FIS1), and integrity of the intracellular cytoskeleton (vimentin).
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Affiliation(s)
- Elaine R Nimmo
- Gastrointestinal Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Molecular Medicine Centre, Western General Hospital, Edinburgh, UK.
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John G, Hegarty JP, Yu W, Berg A, Pastor DM, Kelly AA, Wang Y, Poritz LS, Schreiber S, Koltun WA, Lin Z. NKX2-3 variant rs11190140 is associated with IBD and alters binding of NFAT. Mol Genet Metab 2011; 104:174-9. [PMID: 21803625 DOI: 10.1016/j.ymgme.2011.06.023] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2011] [Accepted: 06/29/2011] [Indexed: 12/31/2022]
Abstract
NKX2-3 SNP rs11190140 is associated with inflammatory bowel disease (IBD). The T allele is over-transmitted in IBD and the C allele represents a potential CpG methylation site. We hypothesize that genetic variation and/or methylation of SNP rs11190140 may play a role in NKX2-3 gene expression by affecting transcription factor binding. We studied 233 IBD cases and 250 unrelated healthy individuals from an IBD population from central Pennsylvania and performed genotype analyses of the genetic variation and methylation status analysis using PCR-based RFLP. For transcription factor binding, nuclear extracts from human B cells were incubated with biotin-labeled oligonucleotide sequences of the NKX2-3 promoter region containing the genetic variation of T, non-methylated C or methylated C at rs11190140, followed by biotin pull-down and Western blot analysis for transcription factors SP1, NFAT1, NF-κB, and ETS-1. In case-control analysis, the genetic variation was significantly associated with IBD (OR=0.503, 95% CI=0.330-0.764, p<0.001). Methylation status analyses revealed that the C allele is subject to modification by DNA methylation. transcription factor binding assay indicated distinct differential binding of NFAT1 to the NKX2-3 promoter sequence, with higher binding to those with non-methylated and methylated C than to T. The binding of NFAT1 to the NKX2-3 promoter region with rs1190140 was confirmed by ChIP assay. We speculate that the rs11190140 may regulate NKX2-3 expression and have a role in IBD pathogenesis.
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Affiliation(s)
- Gerrit John
- Department of Surgery, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA
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Waterman M, Xu W, Stempak JM, Milgrom R, Bernstein CN, Griffiths AM, Greenberg GR, Steinhart AH, Silverberg MS. Distinct and overlapping genetic loci in Crohn's disease and ulcerative colitis: correlations with pathogenesis. Inflamm Bowel Dis 2011; 17:1936-42. [PMID: 21830272 PMCID: PMC3164287 DOI: 10.1002/ibd.21579] [Citation(s) in RCA: 100] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2010] [Accepted: 10/18/2010] [Indexed: 12/17/2022]
Abstract
BACKGROUND A common genotypic basis for ulcerative colitis (UC) and Crohn's disease (CD) is implied by overlapping clinical characteristics, epidemiological studies, and association of genes with both UC and CD. We evaluated the overlap between CD and UC genetic loci stratified by pathogenetic pathways and by disease location. METHODS The allele frequencies of six UC-associated and 34 CD-associated single nucleotide polymorphisms (SNPs) were determined in a Canadian IBD cohort (n = 2374). Differences between CD, UC, colon-only CD, ileal CD, and controls were analyzed controlling for ethnicity, age of diagnosis, and gender. RESULTS In all, 21 of 34 CD-associated SNPs had similar allele frequencies in UC (n = 1230) and CD (n = 1144). Three of six UC-associated SNPs had significantly different frequencies in CD (n = 1144). Most of the divergence in allele frequency among CD and UC was noted in NOD2/autophagy pathway SNPs, while most SNPs with similar frequencies were in IL-22/23 Th17, adaptive immunity, and barrier pathways. Colon-only CD (n = 228) was compared with healthy controls: three of six UC SNPs (in MST1, HLA-DRA, and IL-23R) and 11 of 34 CD SNPs: in IRGM, NOD2 (rs2066845), CCNY, MST1, IL23R, PTPN22, C11orf30, ZNF365, PTPN2, PSMG1, and rs1456893 were significantly associated. In all, 29 of 34 CD SNPs had similar allele frequencies in colonic CD compared with ileal CD (n = 366). All UC SNPs had similar frequencies in UC and colonic CD. CONCLUSIONS Our results suggest that CD and UC share common genetic associations related to impaired adaptive immunity and diverge in pathways of foreign antigen processing. Colon-only CD overlaps extensively with UC and considerably with ileal CD.
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Affiliation(s)
- Matti Waterman
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital IBD Group, Toronto, ON
| | - Wei Xu
- Dalla Lana School of Public Health, University of Toronto, ON
| | - Joanne M. Stempak
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital IBD Group, Toronto, ON
| | - Raquel Milgrom
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital IBD Group, Toronto, ON
| | | | - Anne M. Griffiths
- Faculty of Medicine, University of Toronto, Toronto ON,Division of Gastroenterology, Hospital for Sick Children, Toronto ON, Canada
| | - Gordon R. Greenberg
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital IBD Group, Toronto, ON,Faculty of Medicine, University of Toronto, Toronto ON
| | - A. Hillary Steinhart
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital IBD Group, Toronto, ON,Faculty of Medicine, University of Toronto, Toronto ON
| | - Mark S. Silverberg
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital IBD Group, Toronto, ON,Faculty of Medicine, University of Toronto, Toronto ON
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Lin Z, John G, Hegarty JP, Berg A, Yu W, Wang Y, Kelly AA, Peterson BZ, Poritz LS, Floros J, Koltun WA. Genetic variants and monoallelic expression of surfactant protein-D in inflammatory bowel disease. Ann Hum Genet 2011; 75:559-68. [PMID: 21790524 DOI: 10.1111/j.1469-1809.2011.00662.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Surfactant protein-D (SP-D) is expressed on mucosal surfaces and functions in the innate immune response to microorganisms. We studied the genetic association of the two nonsynonymous SP-D single nucleotide polymorphisms (SNPs) rs721917 and rs2243639 in 256 inflammatory bowel disease (IBD) cases (123 CD and 133 UC) and 376 unrelated healthy individuals from an IBD population from Central Pennsylvania. Case-control analysis revealed a significant association of rs2243639 with susceptibility to Crohn's disease (CD) (p= 0.0036), but not ulcerative colitis (UC) (p= 0.883), and no association of rs721917 with CD (p= 0.328) or UC (p= 0.218). Using intestinal tissues from 19 individuals heterozygous for each SNP, we compared allelic expression of these two SNPs between diseased and matched normal tissues. rs2243639 exhibited balanced biallelic (BB) expression; while rs721917 exhibited differential allelic expression (BB 37%, imbalanced biallelic [IB] 45%, and dominant monoallelic [DM] 18%). Comparison of allelic expression pattern between diseased and matched normal tissues, 13 of 19 individuals (14 UC, 5 CD) showed a similar pattern. The six patients exhibiting a different pattern were all UC patients. The results suggest that differential allelic expression may affect penetrance of the SNP rs721917 disease-susceptibility allele in IBD. The potential impact of SP-D monoallelic expression on incomplete penetrance is discussed.
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Affiliation(s)
- Zhenwu Lin
- Department of Surgery, Pennsylvania State University College of Medicine, Hershey, USA.
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Andersen V, Nimmo E, Krarup HB, Drummond H, Christensen J, Ho GT, Ostergaard M, Ernst A, Lees C, Jacobsen BA, Satsangi J, Vogel U. Cyclooxygenase-2 (COX-2) polymorphisms and risk of inflammatory bowel disease in a Scottish and Danish case-control study. Inflamm Bowel Dis 2011; 17:937-46. [PMID: 20803508 DOI: 10.1002/ibd.21440] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2010] [Accepted: 06/29/2010] [Indexed: 12/19/2022]
Abstract
BACKGROUND Inflammatory bowel diseases (IBDs) are a result of interactions between luminal pathogens and the intestinal immune response. Cyclooxygenase-2 (COX-2) plays a key role in the regulation of the inflammatory response upon stimulation by luminal pathogens via Toll-like receptors. METHODS Genotypes of the COX-2/PTGS2/PGHS2 A-1195G (rs689466), G-765C (rs20417), and T8473C (rs5275) polymorphisms were assessed in a Scottish and Danish case-control study including 732 Crohn's disease (CD) cases, 973 ulcerative colitis (UC) cases, and 1157 healthy controls using logistic regression. RESULTS Carriers of the COX-2 A-1195G variant allele had increased risk of UC (odds ratio [OR], 95% confidence interval [CI] = 1.25 [1.02-1.54], P = 0.03) and of both UC and IBD among never smokers (OR [95% CI] = 1.47 [1.11-1.96], P = 0.01 and OR [95% CI] = 1.37 [1.06-1.77], P = 0.02, respectively). Furthermore, this variant genotype was associated with increased risk of diagnosis of UC before age 40 years and with extensive UC (OR [95% CI] = 1.34 [1.11-1.62], P = 0.002 and OR [95% CI] = 1.32 [1.03-1.69], P = 0.03, respectively). CONCLUSIONS COX-2 A-1195G polymorphism was associated with the risk of UC, especially among never-smokers, suggesting that low activity of COX-2 may predispose to UC. Our results suggest that inclusion of smoking status may be essential for the evaluation of the role of genetic predisposition to IBD.
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Affiliation(s)
- Vibeke Andersen
- Medical Department, Viborg Regional Hospital, Viborg, Denmark.
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