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1
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Xu X, Gao Y, Xiao Y, Yu Y, Huang J, Su W, Li N, Xu C, Gao S, Wang X. Characteristics of the gut microbiota and the effect of Bifidobacterium in very early-onset inflammatory bowel disease patients with IL10RA mutations. Front Microbiol 2024; 15:1479779. [PMID: 39687875 PMCID: PMC11647010 DOI: 10.3389/fmicb.2024.1479779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 11/12/2024] [Indexed: 12/18/2024] Open
Abstract
Very early-onset inflammatory bowel disease (VEO-IBD) is a distinct subtype of inflammatory bowel disease (IBD) characterized by onset before the age of 6 years, and patients often exhibit more severe clinical features. Interleukin 10 receptor alpha (IL10RA) is a hotspot mutation in the Chinese population and is associated with a poor prognosis closely linked to the onset of IBD. However, limited knowledge exists regarding how the IL10RA mutation influences the host microbiota and its role in disease development. We employed 16S rRNA sequencing to conduct a comprehensive assessment of microbial changes in different types of IBD, employed database to thoroughly examine the influence of Bifidobacterium in IBD and to demonstrate a potential positive effect exerted by Bifidobacterium breve M16V (M16V) through a mouse model. The study demonstrated a significant reduction in the abundance and diversity of the gut microbiota among children with IL10RA mutations compared to those with late-onset pediatric IBD and nonmutated VEO-IBD. Furthermore, the analysis identified genera capable of distinguishing between various types of IBD, with the genus Bifidobacterium emerging as a potential standalone diagnostic indicator and Bifidobacterium may also be involved in related pathways that influence the progression of IBD, such as the biosynthesis of amino acids and inflammation-related pathways. This study corroborated the efficacy of Bifidobacterium in alleviating intestinal inflammation. The impact of IL10RA mutations on VEO-IBD may be mediated by alterations in microbes. M16V demonstrates efficacy in alleviating colitis and holds promise as a novel microbial therapy.
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Affiliation(s)
- Xu Xu
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuanqi Gao
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuan Xiao
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yi Yu
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiebin Huang
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wen Su
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Na Li
- Department of Tropical Diseases, The Second Affiliated Hospital of Hainan Medical University, Key Laboratory of Tropical Translational Medicine of Ministry of Education, NHC Key Laboratory of Tropical Disease Control, School of Tropical Medicine, Hainan Medical University, Haikou, Hainan, China
| | - Chundi Xu
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shenshen Gao
- Clinical Research and Development Center of Shanghai Municipal Hospitals, Shanghai Shenkang Hospital Development Center, Shanghai, China
| | - Xinqiong Wang
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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2
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Geesala R, Gongloor P, Recharla N, Shi XZ. Mechanisms of Action of Exclusive Enteral Nutrition and Other Nutritional Therapies in Crohn's Disease. Nutrients 2024; 16:3581. [PMID: 39519414 PMCID: PMC11547457 DOI: 10.3390/nu16213581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 10/18/2024] [Accepted: 10/19/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND AND OBJECTIVES Crohn's disease (CD) is an inflammatory bowel disease (IBD) characterized by transmural inflammation and intestinal fibrosis involving mostly the small intestine and colon. The pathogenic mechanisms of CD remain incompletely understood and cures are unavailable. Current medical therapies are aimed at inducing prolonged remission. Most of the medical therapies such as corticosteroids have substantial adverse effects. Consequently, many dietary therapies have been explored for the management of CD. Up to now, exclusive enteral nutrition (EEN) has been considered the only established dietary treatment for IBD, especially CD. In this article, we aim to give a concise review about the current therapeutic options and challenges in the management of CD and aim to compare the efficacy of EEN with other dietary therapies and update on the possible mechanisms of the benefits of EEN and other nutritional therapies. METHODS We searched the literature up to August 2024 through PubMed, Web of Science, and other sources using search terms such as EEN, nutritional therapy, IBD, Crohn's disease, ulcerative colitis. Clinical studies in patients and preclinical studies in rodent models of IBD were included in the summary of the therapeutic benefits. RESULTS AND CONCLUSIONS EEN involves oral or nasogastric tube feeding of a complete liquid diet with exclusion of normal foods for a defined period (usually 6 to 8 weeks). EEN treatment is demonstrated to have anti-inflammatory and healing effects in CD through various potential pathways, including altering gut bacteria and their metabolites, restoring the barrier function, direct anti-inflammatory action, and indirect anti-inflammatory action by eliminating mechanical stress in the bowel. However, efficacy of other nutritional therapies is not well established in CD, and mechanisms of action are largely unknown.
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Affiliation(s)
- Ramasatyaveni Geesala
- Department of Internal Medicine, The University of Texas Medical Branch, Galveston, TX 77555, USA; (R.G.); (N.R.)
| | - Pratik Gongloor
- John Sealy School of Medicine, The University of Texas Medical Branch, Galveston, TX 77555, USA;
| | - Neeraja Recharla
- Department of Internal Medicine, The University of Texas Medical Branch, Galveston, TX 77555, USA; (R.G.); (N.R.)
| | - Xuan-Zheng Shi
- Department of Internal Medicine, The University of Texas Medical Branch, Galveston, TX 77555, USA; (R.G.); (N.R.)
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3
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Cheema MRS, Farooq M, Jalal U, Shahzad M. Comment on "Echopattern parameter as an aid to profile Crohn's disease patients". Dig Liver Dis 2024; 56:1410-1411. [PMID: 38643021 DOI: 10.1016/j.dld.2024.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Accepted: 04/03/2024] [Indexed: 04/22/2024]
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Pierce R, Jan NJ, Kumar P, Middleton J, Petri WA, Marie C. Persistent dysbiosis of duodenal microbiota in patients with controlled pediatric Crohn's disease after resolution of inflammation. Sci Rep 2024; 14:12668. [PMID: 38830904 PMCID: PMC11148174 DOI: 10.1038/s41598-024-63299-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 05/27/2024] [Indexed: 06/05/2024] Open
Abstract
Crohn's disease is an inflammatory condition of the intestine characterized by largely unknown etiology and a relapse remission cycle of disease control. While possible triggers have been identified, research is inconsistent on the precise cause of these relapses, especially in the under-researched pediatric population. We hypothesized that patients in remission would have persistent microbial and inflammatory changes in small intestinal tissue that might trigger relapse. To this end, we analyzed intestinal biopsy samples from six patients with pediatric Crohn's disease in remission and a control group of 16 pediatric patients with no evident pathogenic abnormality. We identified compositional microbiota differences, including decreases in the genera Streptococcus and Actinobacillus as well as increases in Oribacterium and Prevotella in patients with controlled Crohn's disease compared to controls. Further, a histologic analysis found that patients with controlled Crohn's disease had increased epithelial integrity, and decreased intraepithelial lymphocytes compared with controls. Additionally, we observed increased peripheral CD4+ T cells in patients with pediatric Crohn's disease. These results indicate that markers of intestinal inflammation are responsive to Crohn's disease treatment, however the interventions may not resolve the underlying dysbiosis. These findings suggest that persistent dysbiosis may increase vulnerability to relapse of pediatric Crohn's disease. This study used a nested cohort of patients from the Bangladesh Environmental Enteric Dysfunction (BEED) study (ClinicalTrials.gov ID: NCT02812615 Date of first registration: 24/06/2016).
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Affiliation(s)
- Rebecca Pierce
- Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Ning-Jiun Jan
- Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Pankaj Kumar
- Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Jeremy Middleton
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - William A Petri
- Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Chelsea Marie
- Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, USA.
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5
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Zhang Q, Wang X, Zheng J, Lü Q, Li R, Jia X, Gu M. Heterozygous variants of NOD2, IL10RA, PLA2G6 and COL7A1 correlate with Crohn's disease. Heliyon 2024; 10:e22968. [PMID: 38163100 PMCID: PMC10754897 DOI: 10.1016/j.heliyon.2023.e22968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 11/12/2023] [Accepted: 11/22/2023] [Indexed: 01/03/2024] Open
Abstract
To identify candidate pathogenic genes of early-stage Crohn's disease (CD) and predict potential roles of genetic factors in CD, we performed whole exome sequencing on a child with early-stage Crohn's disease (CD) and her parents (core family), found that the patient carried heterozygous variants of 4 genes: NOD2 c. 2257 C > T, IL10RA c. 301 C > T, PLA2G6 c. 2029 C > T, COL7A1 c. 3190 G > A. Heterozygous variants of NOD2, IL10RA, PLA2G6 and COL7A1, intestinal inflammatory response is triggered, normal intestinal wall tissue damage, leading to CD phenotype.
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Affiliation(s)
| | | | | | - Qiang Lü
- Joint Laboratory for Translational Medicine Research, Liaocheng People's Hospital, Liaocheng, China
| | - Rongrong Li
- Joint Laboratory for Translational Medicine Research, Liaocheng People's Hospital, Liaocheng, China
| | - Xiaodong Jia
- Joint Laboratory for Translational Medicine Research, Liaocheng People's Hospital, Liaocheng, China
| | - Mingliang Gu
- Joint Laboratory for Translational Medicine Research, Liaocheng People's Hospital, Liaocheng, China
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6
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Gustafsson JK, Johansson MEV. The role of goblet cells and mucus in intestinal homeostasis. Nat Rev Gastroenterol Hepatol 2022; 19:785-803. [PMID: 36097076 DOI: 10.1038/s41575-022-00675-x] [Citation(s) in RCA: 242] [Impact Index Per Article: 80.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/04/2022] [Indexed: 12/08/2022]
Abstract
The intestinal tract faces numerous challenges that require several layers of defence. The tight epithelium forms a physical barrier that is further protected by a mucus layer, which provides various site-specific protective functions. Mucus is produced by goblet cells, and as a result of single-cell RNA sequencing identifying novel goblet cell subpopulations, our understanding of their various contributions to intestinal homeostasis has improved. Goblet cells not only produce mucus but also are intimately linked to the immune system. Mucus and goblet cell development is tightly regulated during early life and synchronized with microbial colonization. Dysregulation of the developing mucus systems and goblet cells has been associated with infectious and inflammatory conditions and predisposition to chronic disease later in life. Dysfunctional mucus and altered goblet cell profiles are associated with inflammatory conditions in which some mucus system impairments precede inflammation, indicating a role in pathogenesis. In this Review, we present an overview of the current understanding of the role of goblet cells and the mucus layer in maintaining intestinal health during steady-state and how alterations to these systems contribute to inflammatory and infectious disease.
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Affiliation(s)
- Jenny K Gustafsson
- Department of Physiology, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
| | - Malin E V Johansson
- Department of Medical Biochemisty and Cell biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
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7
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Multivariate genome-wide association study models to improve prediction of Crohn’s disease risk and identification of potential novel variants. Comput Biol Med 2022; 145:105398. [DOI: 10.1016/j.compbiomed.2022.105398] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Revised: 03/09/2022] [Accepted: 03/09/2022] [Indexed: 12/21/2022]
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8
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Garza-Hernandez D, Sepulveda-Villegas M, Garcia-Pelaez J, Aguirre-Gamboa R, Lakatos PL, Estrada K, Martinez-Vazquez M, Trevino V. A systematic review and functional bioinformatics analysis of genes associated with Crohn's disease identify more than 120 related genes. BMC Genomics 2022; 23:302. [PMID: 35418025 PMCID: PMC9008988 DOI: 10.1186/s12864-022-08491-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 02/28/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Crohn's disease is one of the two categories of inflammatory bowel diseases that affect the gastrointestinal tract. The heritability estimate has been reported to be 0.75. Several genes linked to Crohn's disease risk have been identified using a plethora of strategies such as linkage-based studies, candidate gene association studies, and lately through genome-wide association studies (GWAS). Nevertheless, to our knowledge, a compendium of all the genes that have been associated with CD is lacking. METHODS We conducted functional analyses of a gene set generated from a systematic review where genes potentially related to CD found in the literature were analyzed and classified depending on the genetic evidence reported and putative biological function. For this, we retrieved and analyzed 2496 abstracts comprising 1067 human genes plus 22 publications regarding 133 genes from GWAS Catalog. Then, each gene was curated and categorized according to the type of evidence associated with Crohn's disease. RESULTS We identified 126 genes associated with Crohn's disease risk by specific experiments. Additionally, 71 genes were recognized associated through GWAS alone, 18 to treatment response, 41 to disease complications, and 81 to related diseases. Bioinformatic analysis of the 126 genes supports their importance in Crohn's disease and highlights genes associated with specific aspects such as symptoms, drugs, and comorbidities. Importantly, most genes were not included in commercial genetic panels suggesting that Crohn's disease is genetically underdiagnosed. CONCLUSIONS We identified a total of 126 genes from PubMed and 71 from GWAS that showed evidence of association to diagnosis, 18 to treatment response, and 41 to disease complications in Crohn's disease. This prioritized gene catalog can be explored at http://victortrevino.bioinformatics.mx/CrohnDisease .
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Affiliation(s)
- Debora Garza-Hernandez
- Tecnologico de Monterrey, Escuela de Medicina, Cátedra de Bioinformática, Av. Morones Prieto No. 3000, Colonia Los Doctores, 64710, Monterrey, Nuevo León, Mexico
| | - Maricruz Sepulveda-Villegas
- Tecnologico de Monterrey, Escuela de Medicina, Cátedra de Bioinformática, Av. Morones Prieto No. 3000, Colonia Los Doctores, 64710, Monterrey, Nuevo León, Mexico
| | - Jose Garcia-Pelaez
- Instituto de Investigação e Inovação em Saude-i3S, Universidade do Porto, Porto, Portugal.,Ipatimup, Institute of Molecular Pathology and Immunology at the University of Porto, Porto, Portugal
| | | | - Peter L Lakatos
- McGill University Health Centre, Division of Gastroenterology, IBD Centre, Montreal General Hospital, 1650 Ave. Cedar, D16.173.1, Montreal, QC, H3G 1A4, Canada
| | - Karol Estrada
- Graduate Professional Studies, Brandeis University, Waltham, MA, 02453, USA
| | - Manuel Martinez-Vazquez
- Tecnologico de Monterrey, Instituto de Medicina Interna, Centro Médico Zambrano Hellion, Av. Batallón de San Patricio No. 112, Colonia Real San Agustín, 66278, San Pedro Garza García, Nuevo León, Mexico
| | - Victor Trevino
- Tecnologico de Monterrey, Escuela de Medicina, Cátedra de Bioinformática, Av. Morones Prieto No. 3000, Colonia Los Doctores, 64710, Monterrey, Nuevo León, Mexico. .,Tecnologico de Monterrey, The Institute for Obesity Research, Integrative Biology Unit, Eugenio Garza Sada 2501 Avenue, 64849, Monterrey, Nuevo Leon, Mexico.
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9
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Parigi SM, Larsson L, Das S, Ramirez Flores RO, Frede A, Tripathi KP, Diaz OE, Selin K, Morales RA, Luo X, Monasterio G, Engblom C, Gagliani N, Saez-Rodriguez J, Lundeberg J, Villablanca EJ. The spatial transcriptomic landscape of the healing mouse intestine following damage. Nat Commun 2022; 13:828. [PMID: 35149721 PMCID: PMC8837647 DOI: 10.1038/s41467-022-28497-0] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 01/28/2022] [Indexed: 12/12/2022] Open
Abstract
The intestinal barrier is composed of a complex cell network defining highly compartmentalized and specialized structures. Here, we use spatial transcriptomics to define how the transcriptomic landscape is spatially organized in the steady state and healing murine colon. At steady state conditions, we demonstrate a previously unappreciated molecular regionalization of the colon, which dramatically changes during mucosal healing. Here, we identified spatially-organized transcriptional programs defining compartmentalized mucosal healing, and regions with dominant wired pathways. Furthermore, we showed that decreased p53 activation defined areas with increased presence of proliferating epithelial stem cells. Finally, we mapped transcriptomics modules associated with human diseases demonstrating the translational potential of our dataset. Overall, we provide a publicly available resource defining principles of transcriptomic regionalization of the colon during mucosal healing and a framework to develop and progress further hypotheses.
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Affiliation(s)
- Sara M Parigi
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institute and University Hospital, Stockholm, Sweden
- Center of Molecular Medicine, Stockholm, Sweden
| | - Ludvig Larsson
- Science for Life Laboratory, Department of Gene Technology, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Srustidhar Das
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institute and University Hospital, Stockholm, Sweden
- Center of Molecular Medicine, Stockholm, Sweden
| | - Ricardo O Ramirez Flores
- Heidelberg University, Faculty of Medicine, and Heidelberg University Hospital, Institute for Computational Biomedicine, Bioquant, Heidelberg, Germany
| | - Annika Frede
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institute and University Hospital, Stockholm, Sweden
- Center of Molecular Medicine, Stockholm, Sweden
| | - Kumar P Tripathi
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institute and University Hospital, Stockholm, Sweden
- Center of Molecular Medicine, Stockholm, Sweden
| | - Oscar E Diaz
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institute and University Hospital, Stockholm, Sweden
- Center of Molecular Medicine, Stockholm, Sweden
| | - Katja Selin
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institute and University Hospital, Stockholm, Sweden
- Center of Molecular Medicine, Stockholm, Sweden
| | - Rodrigo A Morales
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institute and University Hospital, Stockholm, Sweden
- Center of Molecular Medicine, Stockholm, Sweden
| | - Xinxin Luo
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institute and University Hospital, Stockholm, Sweden
- Center of Molecular Medicine, Stockholm, Sweden
| | - Gustavo Monasterio
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institute and University Hospital, Stockholm, Sweden
- Center of Molecular Medicine, Stockholm, Sweden
| | - Camilla Engblom
- Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden
| | - Nicola Gagliani
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institute and University Hospital, Stockholm, Sweden
- Center of Molecular Medicine, Stockholm, Sweden
- I. Department of Medicine and Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Julio Saez-Rodriguez
- Heidelberg University, Faculty of Medicine, and Heidelberg University Hospital, Institute for Computational Biomedicine, Bioquant, Heidelberg, Germany
| | - Joakim Lundeberg
- Science for Life Laboratory, Department of Gene Technology, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Eduardo J Villablanca
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institute and University Hospital, Stockholm, Sweden.
- Center of Molecular Medicine, Stockholm, Sweden.
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10
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Karunakaran G, Yang Y, Tremblay V, Ning Z, Martin J, Belaouad A, Figeys D, Brunzelle J, Giguere PM, Stintzi A, Couture JF. Structural analysis of Atopobium parvulum SufS cysteine desulfurase linked to Crohn's disease. FEBS Lett 2022; 596:898-909. [PMID: 35122247 DOI: 10.1002/1873-3468.14295] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 12/20/2021] [Accepted: 12/21/2021] [Indexed: 11/09/2022]
Abstract
Crohn's Disease (CD) is characterized by the chronic inflammation of the gastrointestinal tract. A dysbiotic microbiome and a defective immune system are linked to CD, where hydrogen sulfide (H2 S) microbial producers positively correlate with the severity of the disease. Atopobium parvulum is a key H2 S producer from the microbiome of CD patients. In this study, the biochemical characterization of two Atopobium parvulum cysteine desulfurases, ApSufS and ApCsdB, show that the enzymes are allosterically regulated. Structural analyses reveal that ApSufS forms a dimer with conserved characteristics observed in type II cysteine desulfurases. Four residues surrounding the active site are essential to catalyze cysteine desulfurylation, and a segment of short-chain residues grant access for substrate binding. A better understanding of ApSufS will help future avenues for CD treatment.
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Affiliation(s)
- Gapisha Karunakaran
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.,Shanghai Institute of Materia Medica-University of Ottawa Joint Research Centre on Systems and Personalized Pharmacology, University of Ottawa, Ottawa, ON, Canada.,Faculty of Medicine, Ottawa, ON, Canada
| | - Yidai Yang
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.,Shanghai Institute of Materia Medica-University of Ottawa Joint Research Centre on Systems and Personalized Pharmacology, University of Ottawa, Ottawa, ON, Canada.,Faculty of Medicine, Ottawa, ON, Canada
| | - Véronique Tremblay
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.,Shanghai Institute of Materia Medica-University of Ottawa Joint Research Centre on Systems and Personalized Pharmacology, University of Ottawa, Ottawa, ON, Canada.,Faculty of Medicine, Ottawa, ON, Canada
| | - Zhibin Ning
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.,Shanghai Institute of Materia Medica-University of Ottawa Joint Research Centre on Systems and Personalized Pharmacology, University of Ottawa, Ottawa, ON, Canada.,Faculty of Medicine, Ottawa, ON, Canada
| | - Jade Martin
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.,Shanghai Institute of Materia Medica-University of Ottawa Joint Research Centre on Systems and Personalized Pharmacology, University of Ottawa, Ottawa, ON, Canada.,Faculty of Medicine, Ottawa, ON, Canada
| | - Amine Belaouad
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.,Shanghai Institute of Materia Medica-University of Ottawa Joint Research Centre on Systems and Personalized Pharmacology, University of Ottawa, Ottawa, ON, Canada.,Faculty of Medicine, Ottawa, ON, Canada
| | - Daniel Figeys
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.,Shanghai Institute of Materia Medica-University of Ottawa Joint Research Centre on Systems and Personalized Pharmacology, University of Ottawa, Ottawa, ON, Canada.,Faculty of Medicine, Ottawa, ON, Canada
| | - Joseph Brunzelle
- Feinberg School of Medicine, Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, Chicago, Illinois, 60611, USA
| | - Patrick M Giguere
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.,Faculty of Medicine, Ottawa, ON, Canada
| | - Alain Stintzi
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.,Shanghai Institute of Materia Medica-University of Ottawa Joint Research Centre on Systems and Personalized Pharmacology, University of Ottawa, Ottawa, ON, Canada.,Faculty of Medicine, Ottawa, ON, Canada
| | - Jean-François Couture
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.,Shanghai Institute of Materia Medica-University of Ottawa Joint Research Centre on Systems and Personalized Pharmacology, University of Ottawa, Ottawa, ON, Canada.,Faculty of Medicine, Ottawa, ON, Canada
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11
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Snyder EF, Davis S, Aldrich K, Veerabagu M, Larussa T, Abenavoli L, Boccuto L. Crohn disease: Identification, diagnosis, and clinical management. Nurse Pract 2021; 46:22-30. [PMID: 34808643 DOI: 10.1097/01.npr.0000798212.61425.4f] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
ABSTRACT Crohn disease is an inflammatory bowel disorder affecting children and adults. With its increasing prevalence, healthcare providers need adequate resources to assist with diagnosis and management. This article discusses early diagnosis, disease severity and classification, familial predisposition and genomics, and clinical management in the primary care setting.
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12
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İlgen U, Emmungil H, Tezel HA. On the Coexistence of Takayasu Arteritis and Inflammatory Bowel Disease. J Clin Rheumatol 2021; 27:S864. [PMID: 33843772 DOI: 10.1097/rhu.0000000000001739] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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13
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Machine Learning Modeling from Omics Data as Prospective Tool for Improvement of Inflammatory Bowel Disease Diagnosis and Clinical Classifications. Genes (Basel) 2021; 12:genes12091438. [PMID: 34573420 PMCID: PMC8466305 DOI: 10.3390/genes12091438] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 08/21/2021] [Accepted: 09/14/2021] [Indexed: 12/14/2022] Open
Abstract
Research of inflammatory bowel disease (IBD) has identified numerous molecular players involved in the disease development. Even so, the understanding of IBD is incomplete, while disease treatment is still far from the precision medicine. Reliable diagnostic and prognostic biomarkers in IBD are limited which may reduce efficient therapeutic outcomes. High-throughput technologies and artificial intelligence emerged as powerful tools in search of unrevealed molecular patterns that could give important insights into IBD pathogenesis and help to address unmet clinical needs. Machine learning, a subtype of artificial intelligence, uses complex mathematical algorithms to learn from existing data in order to predict future outcomes. The scientific community has been increasingly employing machine learning for the prediction of IBD outcomes from comprehensive patient data-clinical records, genomic, transcriptomic, proteomic, metagenomic, and other IBD relevant omics data. This review aims to present fundamental principles behind machine learning modeling and its current application in IBD research with the focus on studies that explored genomic and transcriptomic data. We described different strategies used for dealing with omics data and outlined the best-performing methods. Before being translated into clinical settings, the developed machine learning models should be tested in independent prospective studies as well as randomized controlled trials.
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14
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Khan IA, Nayak B, Markandey M, Bajaj A, Verma M, Kumar S, Singh MK, Kedia S, Ahuja V. Differential prevalence of pathobionts and host gene polymorphisms in chronic inflammatory intestinal diseases: Crohn's disease and intestinal tuberculosis. PLoS One 2021; 16:e0256098. [PMID: 34407136 PMCID: PMC8372915 DOI: 10.1371/journal.pone.0256098] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 07/31/2021] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND AND OBJECTIVES Crohn's disease (CD) and Intestinal tuberculosis (ITB) are chronic inflammatory ulcero-constrictive intestinal diseases with similar phenotype. Although both are disease models of chronic inflammation and their clinical presentations, imaging, histological and endoscopic findings are very similar, yet their etiologies are diverse. Hence, we aimed to look at differences in the prevalence of pathobionts like adherent-invasive Escherichia coli (AIEC), Listeria monocytogenes, Campylobacter jejuni and Yersinia enterocolitica in CD and ITB as well as their associations with host-associated genetic polymorphisms in genes majorly involved in pathways of microbial handling and immune responses. METHODS The study cohort included 142 subjects (69 patients with CD, 32 with ITB and 41 controls). RT- PCR amplification was used to detect the presence of AIEC, L. monocytogenes, C. jejuni, and Y. enterocolitica DNA in colonic mucosal biopsies. Additionally, we tested three SNPs in IRGM (rs13361189, rs10065172, and rs4958847), one SNP in ATG16L1 (rs2241880) and one SNP in TNFRSF1A (rs4149570) by real-time PCR with SYBR green from peripheral blood samples in this cohort. RESULTS In patients with CD, AIEC was most frequently present (16/ 69, 23.19%) followed by L. monocytogenes (14/69, 20.29%), C. jejuni (9/69, 13.04%), and Y. enterocolitica (7/69, 10.14%). Among them, L. monocytogenes and Y. enterocolitica were significantly associated with CD (p = 0.02). In addition, we identified all the three SNPs in IRGM (rs13361189, rs10065172, and rs4958847), one SNP in ATG16L1 (rs2241880) and TNFRSF1A (rs4149570) with a significant difference in frequency in patients with CD compared with ITB and controls (p<0.05). CONCLUSION Higher prevalence of host gene polymorphisms, as well as the presence of pathobionts, was seen in the colonic mucosa of patients with CD as compared to ITB, although both are disease models of chronic inflammation.
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Affiliation(s)
- Imteyaz Ahmad Khan
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, India
| | - Baibaswata Nayak
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, India
| | - Manasvini Markandey
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, India
| | - Aditya Bajaj
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, India
| | - Mahak Verma
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, India
| | - Sambudhha Kumar
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, India
| | - Mukesh Kumar Singh
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, India
| | - Saurabh Kedia
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, India
| | - Vineet Ahuja
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, India
- * E-mail:
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15
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Chung WS, Chung S, Hsu CY, Lin CL. Risk of Inflammatory Bowel Disease Following Appendectomy in Adulthood. Front Med (Lausanne) 2021; 8:661752. [PMID: 34150801 PMCID: PMC8206496 DOI: 10.3389/fmed.2021.661752] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 05/10/2021] [Indexed: 12/18/2022] Open
Abstract
Background: The appendix has a complicated immune function, and appendectomy may derange the immune system. Studies on the relationship between appendectomy and subsequent inflammatory bowel disease (IBD) have been inconsistent. We conducted a nationwide cohort study consisting of individuals who underwent appendectomy to evaluate the incidence and risk of ulcerative colitis (UC) and Crohn's disease (CD). Methods: We identified patients aged >20 years who underwent appendectomy between 2000 and 2012 from inpatient claims of the National Health Insurance Research Database (NHIRD) and assigned them to the appendectomy cohort. Then, we randomly selected patients without appendectomy in the NHIRD and assigned them to the comparison cohort in a frequency-matched 1:1 ratio based on sex, age, and index year. We tracked down all participants until IBD diagnosis, death, or the end of 2013. Cox models were used to estimate the hazard ratio (HR), and 95% confidence intervals (CIs) were used to compare the IBD risk between the appendectomy and comparison cohorts. Results: The appendectomy and comparison cohorts in the study consisted of 246 562 patients each. The appendectomy cohort exhibited a 2.23- and 3.48-fold higher risk of UC (adjusted HR = 2.23, 95% CI = 1.59-3.12) and CD (adjusted HR = 3.48, 95% CI = 2.42-4.99), respectively, than did the comparison cohort. UC and CD risks significantly increased in the appendectomy cohort regardless of whether appendicitis was present. Conclusions: Our study suggests that appendectomy increases UC and CD risks irrespective of appendicitis.
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Affiliation(s)
- Wei-Sheng Chung
- Department of Internal Medicine, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan.,Department of Health Services Administration, China Medical University, Taichung, Taiwan.,Department of Healthcare Administration, Central Taiwan University of Science and Technology, Taichung, Taiwan
| | - Sunny Chung
- Department of Chemistry, Point Loma Nazarene University, San Diego, CA, United States
| | - Chung-Y Hsu
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - Cheng-Li Lin
- Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan.,College of Medicine, China Medical University, Taichung, Taiwan
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16
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Grasberger H, Magis AT, Sheng E, Conomos MP, Zhang M, Garzotto LS, Hou G, Bishu S, Nagao-Kitamoto H, El-Zaatari M, Kitamoto S, Kamada N, Stidham RW, Akiba Y, Kaunitz J, Haberman Y, Kugathasan S, Denson LA, Omenn GS, Kao JY. DUOX2 variants associate with preclinical disturbances in microbiota-immune homeostasis and increased inflammatory bowel disease risk. J Clin Invest 2021; 131:141676. [PMID: 33651715 DOI: 10.1172/jci141676] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 02/25/2021] [Indexed: 12/18/2022] Open
Abstract
A primordial gut-epithelial innate defense response is the release of hydrogen peroxide by dual NADPH oxidase (DUOX). In inflammatory bowel disease (IBD), a condition characterized by an imbalanced gut microbiota-immune homeostasis, DUOX2 isoenzyme is the highest induced gene. Performing multiomic analyses using 2872 human participants of a wellness program, we detected a substantial burden of rare protein-altering DUOX2 gene variants of unknown physiologic significance. We identified a significant association between these rare loss-of-function variants and increased plasma levels of interleukin-17C, which is induced also in mucosal biopsies of patients with IBD. DUOX2-deficient mice replicated increased IL-17C induction in the intestine, with outlier high Il17c expression linked to the mucosal expansion of specific Proteobacteria pathobionts. Integrated microbiota/host gene expression analyses in patients with IBD corroborated IL-17C as a marker for epithelial activation by gram-negative bacteria. Finally, the impact of DUOX2 variants on IL-17C induction provided a rationale for variant stratification in case control studies that substantiated DUOX2 as an IBD risk gene. Thus, our study identifies an association of deleterious DUOX2 variants with a preclinical hallmark of disturbed microbiota-immune homeostasis that appears to precede the manifestation of IBD.
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Affiliation(s)
- Helmut Grasberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Andrew T Magis
- Institute for Systems Biology, Seattle, Washington, USA.,Arivale Inc., Seattle, Washington, USA
| | | | - Matthew P Conomos
- Arivale Inc., Seattle, Washington, USA.,Department of Biostatistics, University of Washington, Seattle, Washington, USA
| | - Min Zhang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Lea S Garzotto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Guoqing Hou
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Shrinivas Bishu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Hiroko Nagao-Kitamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Mohamad El-Zaatari
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Sho Kitamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Nobuhiko Kamada
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Ryan W Stidham
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Yasutada Akiba
- West Los Angeles VA Medical Center and Departments of Medicine and Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Jonathan Kaunitz
- West Los Angeles VA Medical Center and Departments of Medicine and Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Yael Haberman
- Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Subra Kugathasan
- Departments of Pediatrics and Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Lee A Denson
- Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Gilbert S Omenn
- Departments of Computational Medicine & Bioinformatics, Internal Medicine, Human Genetics, and School of Public Health, University of Michigan, Ann Arbor, Michigan, USA
| | - John Y Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
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Wu D, Ye X, Linhardt RJ, Liu X, Zhu K, Yu C, Ding T, Liu D, He Q, Chen S. Dietary pectic substances enhance gut health by its polycomponent: A review. Compr Rev Food Sci Food Saf 2021; 20:2015-2039. [PMID: 33594822 DOI: 10.1111/1541-4337.12723] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 01/17/2021] [Accepted: 01/19/2021] [Indexed: 12/15/2022]
Abstract
Pectic substances, one of the cell wall polysaccharides, exist widespread in vegetables and fruits. A surge of recent research has revealed that pectic substances can inhibit gut inflammation and relieve inflammatory bowel disease symptoms. However, physiological functions of pectins are strongly structure dependent. Pectic substances are essentially heteropolysaccharides composed of homogalacturonan and rhamnogalacturonan backbones substituted by various neutral sugar sidechains. Subtle changes in the architecture of pectic substances may remarkably influence the nutritional function of gut microbiota and the host homeostasis of immune system. In this context, developing a structure-function understanding of how pectic substances have an impact on an inflammatory bowel is of primary importance for diet therapy and new drugs. Therefore, the present review has summarized the polycomponent nature of pectic substances, the activities of different pectic polymers, the effects of molecular characteristics and the underlying mechanisms of pectic substances. The immunomodulated property of pectic substances depends on not only the chemical composition but also the physical structure characteristics, such as molecular weight (Mw ) and chain conformation. The potential mechanisms by which pectic substances exert their protective effects are mainly reversing the disordered gut microbiota, regulating immune cells, enhancing barrier function, and inhibiting pathogen adhesion. The manipulation of pectic substances on gut health is sophisticated, and the link between structural specificity of pectins and selective regulation needs further exploration.
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Affiliation(s)
- Dongmei Wu
- National-Local Joint Engineering Laboratory of Intelligent Food Technology and Equipment, Zhejiang Key Laboratory for Agro-Food Processing, Integrated Research Base of Southern Fruit and Vegetable Preservation Technology, Zhejiang International Scientific and Technological Cooperation Base of Health Food Manufacturing and Quality Control, College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, China
| | - Xingqian Ye
- National-Local Joint Engineering Laboratory of Intelligent Food Technology and Equipment, Zhejiang Key Laboratory for Agro-Food Processing, Integrated Research Base of Southern Fruit and Vegetable Preservation Technology, Zhejiang International Scientific and Technological Cooperation Base of Health Food Manufacturing and Quality Control, College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, China.,Fuli Institute of Food Science, Zhejiang University, Hangzhou, China.,Ningbo Research Institute, Zhejiang University, Hangzhou, China
| | - Robert J Linhardt
- Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York, USA
| | - Xuwei Liu
- UMR408, Sécurité et Qualité des Produits d'Origine Végétale (SQPOV), INRAE, Avignon, France
| | - Kai Zhu
- National-Local Joint Engineering Laboratory of Intelligent Food Technology and Equipment, Zhejiang Key Laboratory for Agro-Food Processing, Integrated Research Base of Southern Fruit and Vegetable Preservation Technology, Zhejiang International Scientific and Technological Cooperation Base of Health Food Manufacturing and Quality Control, College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, China
| | - Chengxiao Yu
- National-Local Joint Engineering Laboratory of Intelligent Food Technology and Equipment, Zhejiang Key Laboratory for Agro-Food Processing, Integrated Research Base of Southern Fruit and Vegetable Preservation Technology, Zhejiang International Scientific and Technological Cooperation Base of Health Food Manufacturing and Quality Control, College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, China
| | - Tian Ding
- National-Local Joint Engineering Laboratory of Intelligent Food Technology and Equipment, Zhejiang Key Laboratory for Agro-Food Processing, Integrated Research Base of Southern Fruit and Vegetable Preservation Technology, Zhejiang International Scientific and Technological Cooperation Base of Health Food Manufacturing and Quality Control, College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, China
| | - Donghong Liu
- National-Local Joint Engineering Laboratory of Intelligent Food Technology and Equipment, Zhejiang Key Laboratory for Agro-Food Processing, Integrated Research Base of Southern Fruit and Vegetable Preservation Technology, Zhejiang International Scientific and Technological Cooperation Base of Health Food Manufacturing and Quality Control, College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, China
| | - Qiaojun He
- Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Shiguo Chen
- National-Local Joint Engineering Laboratory of Intelligent Food Technology and Equipment, Zhejiang Key Laboratory for Agro-Food Processing, Integrated Research Base of Southern Fruit and Vegetable Preservation Technology, Zhejiang International Scientific and Technological Cooperation Base of Health Food Manufacturing and Quality Control, College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, China.,Fuli Institute of Food Science, Zhejiang University, Hangzhou, China.,Ningbo Research Institute, Zhejiang University, Hangzhou, China
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18
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Yadav RK, Minz E, Mehan S. Understanding Abnormal c-JNK/p38MAPK Signaling in Amyotrophic Lateral Sclerosis: Potential Drug Targets and Influences on Neurological Disorders. CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS 2021; 20:417-429. [PMID: 33557726 DOI: 10.2174/1871527320666210126113848] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 09/29/2020] [Accepted: 10/07/2020] [Indexed: 11/22/2022]
Abstract
c-JNK (c-Jun N-terminal kinase) and p38 mitogen-activated protein kinase (MAPK) family members work in a cell-specific manner to regulate neuronal signals. The abnormal activation of these cellular signals can cause glutamate excitotoxicity, disrupted protein homeostasis, defective axonal transport, and synaptic dysfunction. Various pre-clinical and clinical findings indicate that the up-regulation of c-JNK and p38MAPK signaling is associated with neurological disorders. Exceptionally, a significant amount of experimental data has recently shown that dysregulated c-JNK and p38MAPK are implicated in the damage to the central nervous system, including amyotrophic lateral sclerosis. Furthermore, currently available information has shown that c- JNK/p38MAPK signaling inhibitors may be a promising therapeutic alternative for improving histopathological, functional, and demyelination defects related to motor neuron disabilities. Understanding the abnormal activation of c-JNK/p38MAPK signaling and the prediction of motor neuron loss may help identify important therapeutic interventions that could prevent neurocomplications. Based on the involvement of c-JNK/p38MAPK signaling in the brain, we have assumed that the downregulation of the c-JNK/p38MAPK signaling pathway could trigger neuroprotection and neurotrophic effects towards clinicopathological presentations of ALS and other brain diseases. Thus, this research-based review also outlines the inhibition of c-JNK and p38MAPK signal downregulation in the pursuit of disease-modifying therapies for ALS.
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Affiliation(s)
- Rajeshwar Kumar Yadav
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
| | - Elizabeth Minz
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
| | - Sidharth Mehan
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
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19
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IL6 genetic variants haplotype is associated with susceptibility and disease activity but not with therapy response in patients with inflammatory bowel disease. Int J Colorectal Dis 2021; 36:383-393. [PMID: 33047210 DOI: 10.1007/s00384-020-03743-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/08/2020] [Indexed: 02/07/2023]
Abstract
PURPOSE The aim of the present study was to evaluate the IL6 -174 G>C (rs1800795) and -572 G>C (rs1800796) genetic variants and their association with inflammatory bowel diseases (IBDs), disease activity, and response to TNF-α inhibitors. METHODS The study included 178 patients with IBD and 224 healthy controls. Among the IBD patients, 66 of them were in use of TNF-α inhibitors therapy and were followed during 48 weeks and categorized as responders and non-responders. RESULTS In total, 89 (50.0%) had ulcerative colitis (UC) and 89 (50.0%) had Crohn's disease (CD). The IL6 -572 CC genotype presented a protective effect in CD patients in codominant and recessive models, while the IL6 -174 CC genotype was associated with susceptibility to UC and CD. The presence of G/C haplotype in the recessive model (GCGC) was associated with UC. The Crohn's disease endoscopic index of severity was low in those patients carrying the GCGC haplotype. It was observed that there was no association between the IL6 genetic variants and TNF-α inhibitor therapy response. CONCLUSION The G/C haplotype (recessive model) was associated with susceptibility to UC but not to CD. However, the G/C haplotype (dominant model) was associated with the endoscopic activity of CD. Moreover, these IL6 variants did not predict the TNF-α inhibitor therapy response.
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20
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Amaro F, Chiarelli F. Growth and Puberty in Children with Inflammatory Bowel Diseases. Biomedicines 2020; 8:biomedicines8110458. [PMID: 33138015 PMCID: PMC7692295 DOI: 10.3390/biomedicines8110458] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 10/27/2020] [Accepted: 10/28/2020] [Indexed: 12/11/2022] Open
Abstract
Inflammatory bowel diseases (IBD) are gastrointestinal tract pathologies of unknown etiology; they have an alternating trend, with active and silent phases. IBD are classified in two main forms: ulcerative colitis (UC) and Crohn’s disease (CD). Both have chronic and recurrent course, gastrointestinal symptoms, and extraintestinal manifestations. The altered immune response role seems to be important both in UC and CD. In the majority of cases, CD begins with abdominal pain, diarrhea, decrease in appetite, and weight loss; there can be also perianal fistulas, rhagades, and perianal recurrent abscesses. In addition, retarded growth and delayed puberty can precede the development of the disease or can even be predominant at onset. Growth retardation is found in 40% of IBD patients, but the underlying mechanism of this and other extra-intestinal manifestations are partially known: the main hypotheses are represented by malnutrition and inflammatory response during the active phase of the disease. The increased level of pro-inflammatory cytokines can influence growth, but also the onset of puberty and its progression. In addition, it could be essential to clarify the role and the possible effects of all the currently used treatments concerning growth failure and delayed puberty.
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21
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Zabana Y, Lorén V, Domènech E, Aterido A, Garcia-Jaraquemada A, Julià A, Vicario M, Pedrosa E, Ferreiro M, Troya J, Lozano JJ, Sarrias MR, Cabré E, Mañosa M, Manyé J. Transcriptomic identification of TMIGD1 and its relationship with the ileal epithelial cell differentiation in Crohn's disease. Am J Physiol Gastrointest Liver Physiol 2020; 319:G109-G120. [PMID: 32508154 DOI: 10.1152/ajpgi.00027.2020] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Crohn's disease (CD) is a complex and multifactorial illness. There are still considerable gaps in our knowledge regarding its pathophysiology. A transcriptomic approach could shed some light on little-known biological alterations of the disease. We therefore aimed to explore the ileal transcriptome to gain knowledge about CD. We performed whole transcriptome gene expression analysis on ileocecal resections from CD patients and inflammatory bowel disease-free controls, as well as on a CD-independent cohort to replicate selected results. Normalized data were hierarchically clustered, and gene ontology and the molecular network were studied. Cell cultures and molecular methods were used for further evaluations. Genome-wide expression data analysis identified a robust transmembrane immunoglobulin domain-containing 1 (TMIGD1) gene underexpression in CD tissue, which was even more marked in inflamed ileum, and which was replicated in the validation cohort. Immunofluorescence showed TMIGD1 to be located in the apical microvilli of well-differentiated enterocytes but not in intestinal crypt. This apical TMIGD1 was lower in the noninflamed tissue and almost disappeared in the inflamed mucosa of surgical resections. In vitro studies showed hypoxic-dependent TMIGD1 decreased its expression in enterocyte-like cells. The gene enrichment analysis linked TMIGD1 with cell recovery and tissue remodeling in CD settings, involving guanylate cyclase activities. Transcriptomics may be useful for finding new targets that facilitate studies of the CD pathology. This is how TMIGD1 was identified in CD patients, which was related to multiciliate ileal epithelial cell differentiation.NEW & NOTEWORTHY This is a single-center translational research study that aimed to look for key targets involved in Crohn's disease and define molecular pathways through different functional analysis strategies. With this approach, we have identified and described a novel target, the almost unknown TMIGD1 gene, which may be key in the recovery of injured mucosa involving intestinal epithelial cell differentiation.
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Affiliation(s)
- Yamile Zabana
- IBD Research Group, Germans Trias i Pujol Research Institute (IGTP), Badalona, Catalonia, Spain.,Centro de Investigación Biomédica en Red (CIBER), Madrid, Spain
| | - Violeta Lorén
- IBD Research Group, Germans Trias i Pujol Research Institute (IGTP), Badalona, Catalonia, Spain.,Centro de Investigación Biomédica en Red (CIBER), Madrid, Spain
| | - Eugeni Domènech
- IBD Research Group, Germans Trias i Pujol Research Institute (IGTP), Badalona, Catalonia, Spain.,Centro de Investigación Biomédica en Red (CIBER), Madrid, Spain.,Gastroenterology Department, Germans Trias i Pujol University Hospital, Badalona, Catalonia, Spain
| | - Adrià Aterido
- Rheumatology Research Group, Vall d'Hebron Research Institute, Barcelona, Catalonia, Spain.,Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Catalonia, Spain
| | - Arce Garcia-Jaraquemada
- IBD Research Group, Germans Trias i Pujol Research Institute (IGTP), Badalona, Catalonia, Spain
| | - Antonio Julià
- Rheumatology Research Group, Vall d'Hebron Research Institute, Barcelona, Catalonia, Spain
| | - Maria Vicario
- Centro de Investigación Biomédica en Red (CIBER), Madrid, Spain.,Laboratory of Translational Mucosal Immunology & Department of Gastroenterology, Digestive Diseases Research Unit, Vall d'Hebron Research University Hospital, Badalona, Catalonia, Spain
| | - Elisabet Pedrosa
- IBD Research Group, Germans Trias i Pujol Research Institute (IGTP), Badalona, Catalonia, Spain
| | - Miriam Ferreiro
- IBD Research Group, Germans Trias i Pujol Research Institute (IGTP), Badalona, Catalonia, Spain
| | - José Troya
- Colorectal Surgery Unit, General and Digestive Surgery Department, Germans Trias i Pujol University Hospital, Badalona, Catalonia, Spain
| | - Juan J Lozano
- Centro de Investigación Biomédica en Red (CIBER), Madrid, Spain
| | - Maria R Sarrias
- Centro de Investigación Biomédica en Red (CIBER), Madrid, Spain.,Innate Immunity Group, IGTP (AGAUR 2017-SGR-490 group), Badalona, Catalonia, Spain
| | - Eduard Cabré
- IBD Research Group, Germans Trias i Pujol Research Institute (IGTP), Badalona, Catalonia, Spain.,Centro de Investigación Biomédica en Red (CIBER), Madrid, Spain.,Gastroenterology Department, Germans Trias i Pujol University Hospital, Badalona, Catalonia, Spain
| | - Miriam Mañosa
- IBD Research Group, Germans Trias i Pujol Research Institute (IGTP), Badalona, Catalonia, Spain.,Centro de Investigación Biomédica en Red (CIBER), Madrid, Spain.,Gastroenterology Department, Germans Trias i Pujol University Hospital, Badalona, Catalonia, Spain
| | - Josep Manyé
- IBD Research Group, Germans Trias i Pujol Research Institute (IGTP), Badalona, Catalonia, Spain.,Centro de Investigación Biomédica en Red (CIBER), Madrid, Spain
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22
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Salgado VCL, Luiz RR, Boéchat NLF, Leão IS, Schorr BDC, Parente JML, Lima DC, Silveira Júnior ES, Silva GOS, Almeida NP, Vieira A, de Bueno MLQ, Chebli JM, Bertges ÉR, Brugnara LMDC, Junqueira Neto C, Campbell SBG, Discacciati LL, Cézar JPS, Nunes T, Kaplan GG, Zaltman C. Risk factors associated with inflammatory bowel disease: A multicenter case-control study in Brazil. World J Gastroenterol 2020; 26:3611-3624. [PMID: 32742130 PMCID: PMC7366056 DOI: 10.3748/wjg.v26.i25.3611] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2019] [Revised: 06/16/2020] [Accepted: 06/18/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The etiology of inflammatory bowel disease (IBD) is unknown, but it is believed to be multifactorial. The hygiene hypothesis proposes that better hygiene conditions would lead to less infectious disease during childhood and favor the development of immune-mediated diseases. AIM To test the hygiene hypothesis in IBD by assessing the environmental risk factors associated with IBD development in different regions of Brazil with diverse socioeconomic development indices. METHODS A multicenter case-control study was carried out with 548 Crohn's disease (CD) and 492 ulcerative colitis (UC) outpatients and 416 healthy controls, from six IBD centers within different Brazilian states at diverse socioeconomic development stages. A semi-structured questionnaire with 87 socioeconomic and environmental questions was applied. Logistic regression model was created to assess the odds ratio (OR) with P value and 95% confidence intervals (CI). RESULTS Predictive variables for both diseases (CD and UC) were women [odd ratios (OR) = 1.31; OR = 1.69], low monthly family income (OR = 1.78; OR = 1.57), lower number of cohabitants (OR = 1.70; OR = 1.60), absence of vaccination (OR = 3.11; OR = 2.51), previous history of bowel infections (OR = 1.78; OR = 1.49), and family history of IBD (OR = 5.26; OR = 3.33). Associated risk factors for CD were age (18-39 years) (OR = 1.73), higher educational level (OR = 2.22), absence of infectious childhood diseases (OR = 1.99). The UC predictive variables were living in an urban area (OR = 1.62), inadequate living conditions (OR = 1.48) and former smokers (OR = 3.36). Appendectomy was a risk factor for CD (OR = 1.58) with inverse association with UC (OR = 4.79). Consumption of treated and untreated water was associated with risk of CD (OR = 1.38) and UC (OR = 1.53), respectively. CONCLUSION This is the first examining environmental exposures as risk factors for inflammatory bowel disease in Brazil. Most of the variables associated with disease risk support the role of the hygiene hypothesis in IBD development.
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Affiliation(s)
- Valéria Cristina Loureiro Salgado
- Division of Gastroenterology, Department of Internal Medicine, Clementino Fraga Filho Hospital, Federal University of Rio de Janeiro, Rio de Janeiro 21940-230, Brazil
| | - Ronir Raggio Luiz
- Institute for Studies in Public Health, Federal University of Rio de Janeiro, Rio de Janeiro 21940-230, Brazil
| | - Neio Lucio Fernandes Boéchat
- Multidisciplinary Research Laboratory, Clementino Fraga Filho Hospital, Institute of Thoracic Diseases, Faculty of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21940-230, Brazil
| | - Isabella Sued Leão
- Division of Gastroenterology, Department of Internal Medicine, Clementino Fraga Filho Hospital, Federal University of Rio de Janeiro, Rio de Janeiro 21940-230, Brazil
| | - Bianca do Carmo Schorr
- Division of Gastroenterology, Department of Internal Medicine, Clementino Fraga Filho Hospital, Federal University of Rio de Janeiro, Rio de Janeiro 21940-230, Brazil
| | - José Miguel Luz Parente
- Division of Gastroenterology, Department of Internal Medicine, Hospital University, Faculty of Medicine, Federal University of Piauí, Piauí 64049-550, Brazil
| | - Daniela Calado Lima
- Division of Gastroenterology, Department of Internal Medicine, Hospital University, Faculty of Medicine, Federal University of Piauí, Piauí 64049-550, Brazil
| | - Eduardo Santos Silveira Júnior
- Division of Gastroenterology, Department of Internal Medicine, Hospital University, Faculty of Medicine, Federal University of Piauí, Piauí 64049-550, Brazil
| | - Genoile Oliveira Santana Silva
- Division of Gastroenterology, Inflammatory Bowel Disease Outpatient Clinic, Roberto Santos General Hospital (HGRS) of the Bahia State Department of Health, Bahia 40110-060, Brazil
| | - Neogélia Pereira Almeida
- Division of Gastroenterology, Inflammatory Bowel Disease Outpatient Clinic, Roberto Santos General Hospital (HGRS) of the Bahia State Department of Health, Bahia 40110-060, Brazil
| | - Andrea Vieira
- Division of Gastroenterology, Inflammatory Bowel Disease Outpatient Clinic, Irmandade Santa Casa da Misericórdia of São Paulo, São Paulo 01221020, Brazil
| | - Maria Luiza Queiroz de Bueno
- Division of Gastroenterology, Inflammatory Bowel Disease Outpatient Clinic, Irmandade Santa Casa da Misericórdia of São Paulo, São Paulo 01221020, Brazil
| | - Júlio Maria Chebli
- Division of Gastroenterology, Department of Internal Medicine, Hospital University, Faculty of Medicine, Federal University of Juiz de Fora, Minas Gerais 36036-247, Brazil
| | - Érika Ruback Bertges
- Division of Gastroenterology, Department of Internal Medicine, Hospital University, Faculty of Medicine, Federal University of Juiz de Fora, Minas Gerais 36036-247, Brazil
| | - Luísa Martins da Costa Brugnara
- Division of Gastroenterology, Department of Internal Medicine, Hospital University, Faculty of Medicine, Federal University of Juiz de Fora, Minas Gerais 36036-247, Brazil
| | - Columbano Junqueira Neto
- Division of Gastroenterology, Inflammatory Bowel Disease Outpatient Clinic, Federal District Base Hospital, Brasília 70330-150, Brazil
| | - Stefania Burjack Gabriel Campbell
- Division of Gastroenterology, Inflammatory Bowel Disease Outpatient Clinic, Federal District Base Hospital, Brasília 70330-150, Brazil
| | - Luana Letiza Discacciati
- Division of Gastroenterology, Inflammatory Bowel Disease Outpatient Clinic, Federal District Base Hospital, Brasília 70330-150, Brazil
| | - João Paulo Silva Cézar
- Division of Gastroenterology, Inflammatory Bowel Disease Outpatient Clinic, Federal District Base Hospital, Brasília 70330-150, Brazil
| | - Tiago Nunes
- Gastrointestinal Physiology, Institute of Nutritional Science, Nestle Research Center, Lausanne 1000, Switzerland
| | - Gilaad G Kaplan
- Departments of Medicine and Community Health Sciences, University of Calgary, Calgary T2N4Z6, Canada
| | - Cyrla Zaltman
- Division of Gastroenterology, Department of Internal Medicine, Clementino Fraga Filho Hospital, Federal University of Rio de Janeiro, Rio de Janeiro 21940-230, Brazil
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Li Yim AY, Duijvis NW, Ghiboub M, Sharp C, Ferrero E, Mannens MM, D’Haens GR, de Jonge WJ, te Velde AA, Henneman P. Whole-Genome DNA Methylation Profiling of CD14+ Monocytes Reveals Disease Status and Activity Differences in Crohn's Disease Patients. J Clin Med 2020; 9:E1055. [PMID: 32276386 PMCID: PMC7230341 DOI: 10.3390/jcm9041055] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 04/04/2020] [Accepted: 04/06/2020] [Indexed: 12/13/2022] Open
Abstract
Crohn's disease (CD) is a multifactorial incurable chronic disorder. Current medical treatment seeks to induce and maintain a state of remission. During episodes of inflammation, monocytes infiltrate the inflamed mucosa whereupon they differentiate into macrophages with a pro-inflammatory phenotype. Here, we sought to characterize the circulating monocytes by profiling their DNA methylome and relate it to the level of CD activity. We gathered an all-female age-matched cohort of 16 CD patients and 7 non-CD volunteers. CD patients were further subdivided into 8 CD patients with active disease (CD-active) and 8 CD patients in remission (CD-remissive) as determined by the physician global assessment. We identified 15 and 12 differentially methylated genes (DMGs) when comparing CD with non-CD and CD-active with CD-remissive, respectively. Differential methylation was predominantly found in the promoter regions of inflammatory genes. Comparing our observations with gene expression data on classical (CD14++CD16-), non-classical (CD14+CD16++) and intermediate (CD14++CD16+) monocytes indicated that while 7 DMGs were differentially expressed across the 3 subsets, the remaining DMGs could not immediately be associated with differences in known populations. We conclude that CD activity is associated with differences in DNA methylation at the promoter region of inflammation-associated genes.
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Affiliation(s)
- Andrew Y.F. Li Yim
- Department of Clinical Genetics, Amsterdam University Medical Centers, University of Amsterdam, Genome Diagnostics Laboratory, Amsterdam Reproduction & Development, 1105 AZ Amsterdam, The Netherlands
- R&D GlaxoSmithKline, Stevenage SG1 2NY, UK; (M.G.); (C.S.); (E.F.)
| | - Nicolette W. Duijvis
- Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam Gastroenterology & Metabolism, 1105 BK Amsterdam, The Netherlands; (N.W.D.); (W.J.d.J.)
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam Gastroenterology & Metabolism, 1105 AZ Amsterdam, The Netherlands;
| | - Mohammed Ghiboub
- R&D GlaxoSmithKline, Stevenage SG1 2NY, UK; (M.G.); (C.S.); (E.F.)
- Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam Gastroenterology & Metabolism, 1105 BK Amsterdam, The Netherlands; (N.W.D.); (W.J.d.J.)
| | - Catriona Sharp
- R&D GlaxoSmithKline, Stevenage SG1 2NY, UK; (M.G.); (C.S.); (E.F.)
| | - Enrico Ferrero
- R&D GlaxoSmithKline, Stevenage SG1 2NY, UK; (M.G.); (C.S.); (E.F.)
| | - Marcel M.A.M. Mannens
- Department of Clinical Genetics, Amsterdam University Medical Centers, University of Amsterdam, Genome Diagnostics Laboratory, Amsterdam Reproduction & Development, 1105 AZ Amsterdam, The Netherlands
| | - Geert R. D’Haens
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam Gastroenterology & Metabolism, 1105 AZ Amsterdam, The Netherlands;
| | - Wouter J. de Jonge
- Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam Gastroenterology & Metabolism, 1105 BK Amsterdam, The Netherlands; (N.W.D.); (W.J.d.J.)
- Department of Surgery, University Clinic of Bonn, 53127 Bonn, Germany
| | - Anje A. te Velde
- Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam Gastroenterology & Metabolism, 1105 BK Amsterdam, The Netherlands; (N.W.D.); (W.J.d.J.)
| | - Peter Henneman
- Department of Clinical Genetics, Amsterdam University Medical Centers, University of Amsterdam, Genome Diagnostics Laboratory, Amsterdam Reproduction & Development, 1105 AZ Amsterdam, The Netherlands
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Nutrition, IBD and Gut Microbiota: A Review. Nutrients 2020; 12:nu12040944. [PMID: 32235316 PMCID: PMC7230231 DOI: 10.3390/nu12040944] [Citation(s) in RCA: 198] [Impact Index Per Article: 39.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Revised: 03/11/2020] [Accepted: 03/25/2020] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic relapsing–remitting systemic disease of the gastrointestinal tract, characterized by an inflammatory process that requires lifelong treatment. The underlying causes of IBD are still unclear, as this heterogeneous disorder results from a complex interplay between genetic variability, the host immune system and environmental factors. The current knowledge recognizes diet as a risk factor for the development of IBD and attributes a substantial pathogenic role to the intestinal dysbiosis inducing an aberrant mucosal immune response in genetically predisposed individuals. This review focused on the clinical evidence available that considers the impact of some nutrients on IBD onset and the role of different diets in the management of IBD and their effects on the gut microbiota composition. The effects of the Specific Carbohydrate Diet, low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet, gluten free diet, anti-inflammatory diet and Mediterranean diet are investigated with regard to their impact on microbiota and on the evolution of the disease. At present, no clear indications toward a specific diet are available but the assessment of dysbiosis prior to the recommendation of a specific diet should become a standard clinical approach in order to achieve a personalized therapy.
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25
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Escudero-Hernández C, Bernardo D, Arranz E, Garrote JA. Is celiac disease really associated with inflammatory bowel disease? REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2019; 112:4-6. [PMID: 31830796 DOI: 10.17235/reed.2019.6779/2019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Celiac disease (CeD) and inflammatory bowel disease (IBD) are chronic gastrointestinal disorders of inflammatory origin that develop in response to environmental triggers in genetically predisposed individuals. CeD localizes in the duodenal mucosa, where intolerance develops to dietary gluten from wheat, barley, rye, and some varieties of oats. IBD, in turn, is subdivided primarily into Crohn's disease (CD) and colitis, with ulcerative colitis (UC) being the most thoroughly investigated form.
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Affiliation(s)
| | - David Bernardo
- Unidad Inmunología de las mucosas. IBGM, Universidad de Valladolid
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26
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Oliynyk RT. Future Preventive Gene Therapy of Polygenic Diseases from a Population Genetics Perspective. Int J Mol Sci 2019; 20:E5013. [PMID: 31658652 PMCID: PMC6834143 DOI: 10.3390/ijms20205013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 10/01/2019] [Accepted: 10/08/2019] [Indexed: 12/15/2022] Open
Abstract
With the accumulation of scientific knowledge of the genetic causes of common diseases and continuous advancement of gene-editing technologies, gene therapies to prevent polygenic diseases may soon become possible. This study endeavored to assess population genetics consequences of such therapies. Computer simulations were used to evaluate the heterogeneity in causal alleles for polygenic diseases that could exist among geographically distinct populations. The results show that although heterogeneity would not be easily detectable by epidemiological studies following population admixture, even significant heterogeneity would not impede the outcomes of preventive gene therapies. Preventive gene therapies designed to correct causal alleles to a naturally-occurring neutral state of nucleotides would lower the prevalence of polygenic early- to middle-age-onset diseases in proportion to the decreased population relative risk attributable to the edited alleles. The outcome would manifest differently for late-onset diseases, for which the therapies would result in a delayed disease onset and decreased lifetime risk; however, the lifetime risk would increase again with prolonging population life expectancy, which is a likely consequence of such therapies. If the preventive heritable gene therapies were to be applied on a large scale, the decreasing frequency of risk alleles in populations would reduce the disease risk or delay the age of onset, even with a fraction of the population receiving such therapies. With ongoing population admixture, all groups would benefit over generations.
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Affiliation(s)
- Roman Teo Oliynyk
- Centre for Computational Evolution, University of Auckland, Auckland 1010, New Zealand.
- Department of Computer Science, University of Auckland, Auckland 1010, New Zealand.
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27
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Todd Kuenstner J, Kali M, Welch C. Whole exome sequencing of patients who resolved Crohn's disease and complex regional pain syndrome following treatment for paratuberculosis. Gut Pathog 2019; 11:34. [PMID: 31249631 PMCID: PMC6587279 DOI: 10.1186/s13099-019-0311-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Accepted: 05/30/2019] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND A whole exome sequencing study was performed on an extended family including a patient with Crohn's disease (CD) and a patient with complex regional pain syndrome (CRPS). The patient with CD and the patient with CRPS have experienced resolution of their disease following treatment for paratuberculosis. The study was performed in order to determine if there is an unusual mutation in this extended family that would explain the susceptibility to mycobacterial infection among many of the members. RESULTS We identified sets of rare single nucleotide polymorphisms (SNPs) that were shared among affected family members, including variants in two genes, IL15RA and CASP10, which have established roles in the immune response. In addition, the CD and CRPS patients were found to have heterozygous mutations in MBL2 and DDX58, mutations that have been associated with susceptibility to tuberculosis. CONCLUSIONS The IL15RA and CASP10 variants may contribute to the disease symptoms exhibited in this family. The finding of SNPs associated with immune function supports a complementary role of infection and genetics in these diseases.
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Affiliation(s)
- J. Todd Kuenstner
- Department of Pathology, Temple University Hospital, 3401 N. Broad St., Philadelphia, PA 19140 USA
| | - Maher Kali
- CAMC Clinical Trials Center, 3100 MacCorkle Avenue S.E., Suite 806, Charleston, WV 25304 USA
| | - Christine Welch
- Outcomes Research, 3100 MacCorkle Avenue S.E., Suite 806, Charleston, WV 25304 USA
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28
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Szymanski AM, Ombrello MJ. Using genes to triangulate the pathophysiology of granulomatous autoinflammatory disease: NOD2, PLCG2 and LACC1. Int Immunol 2019. [PMID: 29538758 DOI: 10.1093/intimm/dxy021] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
The intersection of granulomatosis and autoinflammatory disease is a rare occurrence that can be generally subdivided into purely granulomatous phenotypes and disease spectra that are inclusive of granulomatous features. NOD2 (nucleotide-binding oligomerization domain-containing protein 2)-related disease, which includes Blau syndrome and early-onset sarcoidosis, is the prototypic example of granulomatous inflammation in the context of monogenic autoinflammation. Granulomatous inflammation has also been observed in two related autoinflammatory diseases caused by mutations in PLCG2 (phospholipase Cγ2). More recently, mutations in LACC1 (laccase domain-containing protein 1) have been identified as the cause of a monogenic form of systemic juvenile idiopathic arthritis, which does not itself manifest granulomatous inflammation, but the same LACC1 mutations have also been shown to cause an early-onset, familial form of a well-known granulomatous condition, Crohn's disease (CD). Rare genetic variants of PLCG2 have also been shown to cause a monogenic form of CD, and moreover common variants of all three of these genes have been implicated in polygenic forms of CD. Additionally, common variants of NOD2 and LACC1 have been implicated in susceptibility to leprosy, a granulomatous infection. Although no specific mechanistic link exists between these three genes, they form an intriguing web of susceptibility to both monogenic and polygenic autoinflammatory and granulomatous phenotypes.
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Affiliation(s)
- Ann Marie Szymanski
- Translational Genetics and Genomics Unit, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, US Department of Health & Human Services, Bethesda, MD, USA
| | - Michael J Ombrello
- Translational Genetics and Genomics Unit, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, US Department of Health & Human Services, Bethesda, MD, USA
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Sorrentino D, Nguyen VQ, Chitnavis MV. Capturing the Biologic Onset of Inflammatory Bowel Diseases: Impact on Translational and Clinical Science. Cells 2019; 8:E548. [PMID: 31174359 PMCID: PMC6627618 DOI: 10.3390/cells8060548] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Revised: 05/30/2019] [Accepted: 06/04/2019] [Indexed: 12/16/2022] Open
Abstract
While much progress has been made in the last two decades in the treatment and the management of inflammatory bowel diseases (IBD)-both ulcerative colitis (UC) and Crohn's Disease (CD)-as of today these conditions are still diagnosed only after they have become symptomatic. This is a major drawback since by then the inflammatory process has often already caused considerable damage and the disease might have become partially or totally unresponsive to medical therapy. Late diagnosis in IBD is due to the lack of accurate, non-invasive indicators that would allow disease identification during the pre-clinical stage-as it is often done in many other medical conditions. Here, we will discuss what is known about the biologic onset and pre-clinical CD with an emphasis on studies conducted in patients' first degree relatives. We will then review the possible strategies to diagnose IBD very early in time including screening, available disease markers and imaging, and the possible clinical implications of treating these conditions at or close to their biologic onset. Later, we will review the potential impact of conducting translational research in IBD during the pre-clinical stage, especially focusing on the role of the microbiome in disease etiology and pathogenesis. Finally, we will highlight possible future developments in the field and how they can impact IBD management and our scientific knowledge of these conditions.
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Affiliation(s)
- Dario Sorrentino
- IBD Center, Division of Gastroenterology, Virginia Tech Carilion School of Medicine, FRACP 3 Riverside Circle, Roanoke, VA 24016, USA.
- Department of Clinical and Experimental Medical Sciences, University of Udine School of Medicine, 33100 Udine, Italy.
| | - Vu Q Nguyen
- IBD Center, Division of Gastroenterology, Virginia Tech Carilion School of Medicine, FRACP 3 Riverside Circle, Roanoke, VA 24016, USA.
| | - Maithili V Chitnavis
- IBD Center, Division of Gastroenterology, Virginia Tech Carilion School of Medicine, FRACP 3 Riverside Circle, Roanoke, VA 24016, USA.
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30
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The Unique Lifestyle of Crohn's Disease-Associated Adherent-Invasive Escherichia coli. J Mol Biol 2019; 431:2970-2981. [PMID: 31029703 DOI: 10.1016/j.jmb.2019.04.023] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 04/09/2019] [Accepted: 04/16/2019] [Indexed: 02/07/2023]
Abstract
Escherichia coli is one of the most genetically and phenotypically diverse species of bacteria. This remarkable diversity produces a plethora of clinical outcomes following infection and has informed much of what we currently know about host-pathogen interactions for a wide range of bacteria-host relationships. In studying the role of microbes in disease, adherent-invasive E. coli (AIEC) has emerged as having a strong association with Crohn's disease (CD). Thus, there has been an equally strong effort to uncover the root origins of AIEC, to appreciate how AIEC differs from other well-known pathogenic E. coli variants, and to understand its connection to disease. Emerging from a growing body of research on AIEC is the understanding that AIEC itself is remarkably diverse, both in phylogenetic origins, genetic makeup, and behavior in the host setting. Here, we describe the unique lifestyle of CD-associated AIEC and review recent research that is uncovering the inextricable link between AIEC and its host in the context of CD.
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Adjuvant Treatment of Crohn's Disease with Traditional Chinese Medicine: A Meta-Analysis. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2019; 2019:6710451. [PMID: 30949220 PMCID: PMC6425422 DOI: 10.1155/2019/6710451] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 01/30/2019] [Accepted: 02/20/2019] [Indexed: 11/17/2022]
Abstract
The objective of the meta-analysis was to evaluate the efficacy and safety of Traditional Chinese Medicine (TCM) in the treatment of Crohn's disease (CD). Pubmed, Embase, Medline, Web of Science, China National Knowledge Infrastructure, Chinese Biomedical Literature, Wanfang Database, and Cochrane Central Register of Controlled Trials were searched (through October 2018). The quality of randomized clinical trials meeting the inclusion criteria was assessed and the data were extracted according to the Cochrane Review Handbook v5.0 by two evaluators. A meta-analysis was performed using the software Stata 12.0. Twelve randomized controlled trials (RCTs) were selected. The studies were of low methodological quality. The meta-analysis indicated that treatment with TCM and Western Medicine (WM) was significantly superior compared to treatment with WM alone with regard to total effective rate, remission maintenance rate, reduction of C-reactive protein (CRP), reduction of erythrocyte sedimentation rate (ESR), clinical score reduction, and reduction of adverse events. Mucosal healing was improved in both the TCM-WM and WM groups; however, there were no significant differences between the two groups. There was a certain publication bias in the studies with regard to efficiency, adverse reactions, mucosal healing, and recurrence rate; however, there was no obvious publication bias with regard to other indicators. TCM, as an adjuvant therapy with WM, shows advantages in inducing remission in CD. The current evidence suggests that TCM-WM treatment might be more efficient in terms of total effective rate, remission maintenance rate, CRP reduction, ESR reduction, clinical score reduction, and reduction of adverse events than treatment with WM alone. Because of the low quality of the included RCTs, high quality confirmatory evidence is needed to assess the clinical value of TCM in the treatment of CD.
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M'Koma AE. The Multifactorial Etiopathogeneses Interplay of Inflammatory Bowel Disease: An Overview. GASTROINTESTINAL DISORDERS 2019; 1:75-105. [PMID: 37577036 PMCID: PMC10416806 DOI: 10.3390/gidisord1010007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The gastrointestinal system where inflammatory bowel disease occurs is central to the immune system where the innate and the adaptive/acquired immune systems are balanced in interactions with gut microbes under homeostasis conditions. This article overviews the high-throughput research screening on multifactorial interplay between genetic risk factors, the intestinal microbiota, urbanization, modernization, Westernization, the environmental influences and immune responses in the etiopathogenesis of inflammatory bowel disease in humans. Inflammatory bowel disease is an expensive multifactorial debilitating disease that affects thousands new people annually worldwide with no known etiology or cure. The conservative therapeutics focus on the established pathology where the immune dysfunction and gut injury have already happened but do not preclude or delay the progression. Inflammatory bowel disease is evolving globally and has become a global emergence disease. It is largely known to be a disease in industrial-urbanized societies attributed to modernization and Westernized lifestyle associated with environmental factors to genetically susceptible individuals with determined failure to process certain commensal antigens. In the developing nations, increasing incidence and prevalence of inflammatory bowel disease (IBD) has been associated with rapid urbanization, modernization and Westernization of the population. In summary, there are identified multiple associations to host exposures potentiating the landscape risk hazards of inflammatory bowel disease trigger, that include: Western life-style and diet, host genetics, altered innate and/or acquired/adaptive host immune responses, early-life microbiota exposure, change in microbiome symbiotic relationship (dysbiosis/dysbacteriosis), pollution, changing hygiene status, socioeconomic status and several other environmental factors have long-standing effects/influence tolerance. The ongoing multipronged robotic studies on gut microbiota composition disparate patterns between the rural vs. urban locations may help elucidate and better understand the contribution of microbiome disciplines/ecology and evolutionary biology in potentially protecting against the development of inflammatory bowel disease.
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Affiliation(s)
- Amosy E M'Koma
- Meharry Medical College School of Medicine, Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, Nashville, TN 37208, USA
- Vanderbilt University School of Medicine, Department of Surgery, Colon and Rectal Surgery, Nashville, TN 37232, USA
- The American Society of Colon and Rectal Surgeons (ASCRS), Arlington Heights, IL 60005, USA
- The American Gastroenterological Association (AGA), Bethesda, MD 20814, USA
- Vanderbilt-Ingram Cancer Center (VICC), Vanderbilt University Medical Center, Nashville, TN 37232, USA
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33
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Zhang L, Wu TT. Inflammatory Bowel Disease. SURGICAL PATHOLOGY OF NON-NEOPLASTIC GASTROINTESTINAL DISEASES 2019:373-424. [DOI: 10.1007/978-3-030-15573-5_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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RIP2 filament formation is required for NOD2 dependent NF-κB signalling. Nat Commun 2018; 9:4043. [PMID: 30279485 PMCID: PMC6168553 DOI: 10.1038/s41467-018-06451-3] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Accepted: 09/06/2018] [Indexed: 11/08/2022] Open
Abstract
Activation of the innate immune pattern recognition receptor NOD2 by the bacterial muramyl-dipeptide peptidoglycan fragment triggers recruitment of the downstream adaptor kinase RIP2, eventually leading to NF-κB activation and proinflammatory cytokine production. Here we show that full-length RIP2 can form long filaments mediated by its caspase recruitment domain (CARD), in common with other innate immune adaptor proteins. We further show that the NOD2 tandem CARDs bind to one end of the RIP2 CARD filament, suggesting a mechanism for polar filament nucleation by activated NOD2. We combine X-ray crystallography, solid-state NMR and high-resolution cryo-electron microscopy to determine the atomic structure of the helical RIP2 CARD filament, which reveals the intermolecular interactions that stabilize the assembly. Using structure-guided mutagenesis, we demonstrate the importance of RIP2 polymerization for the activation of NF-κB signalling by NOD2. Our results could be of use to develop new pharmacological strategies to treat inflammatory diseases characterised by aberrant NOD2 signalling.
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Abstract
In the 21st century, urbanization represents a major demographic shift in developed and developing countries. Rapid urbanization in the developing world has been associated with an increasing incidence of several autoimmune diseases, including IBD. Patients with IBD exhibit a decrease in the diversity and richness of the gut microbiota, while urbanization attenuates the gut microbial diversity and might have a role in the pathogenesis of IBD. Environmental exposures during urbanization, including Westernization of diet, increased antibiotic use, pollution, improved hygiene status and early-life microbial exposure, have been shown to affect the gut microbiota. The disparate patterns of the gut microbiota composition in rural and urban areas offer an opportunity to understand the contribution of a 'rural microbiome' in potentially protecting against the development of IBD. This Perspective discusses the effect of urbanization and its surrogates on the gut microbiome (bacteriome, virome, mycobiome and helminths) in both human health and IBD and how such changes might be associated with the development of IBD.
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Abstract
Defining the etiology of inflammatory bowel disease (IBD) continues to elude researchers, in part due to the possibility that there may be different triggers for a spectrum of disease phenotypes that are currently classified as either Crohn's disease (CD) or ulcerative colitis (UC). What is clear is that genetic susceptibility plays an important role in the development of IBD, and large genome-wide association studies using case-control approaches have identified more than 230 risk alleles. Many of these identified risk alleles are located in a variety of genes important in host-microbiome interactions. In spite of these major advances, the mechanisms behind the genetic influence on disease development remain unknown. In addition, the identified genetic risks have thus far failed to fully define the hereditability of IBD. Host genetics influence host interactions with the gut microbiota in maintaining health through a balance of regulated immune responses and coordinated microbial composition and function. What remains to be defined is how alterations in these interactions can lead to disease. The nature and cause of changes in the microbiota in patients with IBD are poorly understood. In spite of the large catalog of alterations in the microbiota of IBD patients, inflammation itself can alter the microbiota, leaving open the question of which is cause or effect. The composition and function of the gut microbiota are influenced by many factors, including environmental factors, dietary factors, and, as recent studies have shown, host genetic makeup. More than 200 loci have shown potential to influence the microbiota, but replication and larger studies are still required to validate these findings. It would seem reasonable to consider the combination of both host genetic makeup and the inheritance of the microbiota as interdependent heritable forces that could explain the nature of an individual's susceptibility to IBD or indeed the actual cause of IBD. In this review, we will consider the contribution of the host genetics, the microbiome, and the influence of host genetics on the microbiota to the heritability of IBD.
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Affiliation(s)
- Williams Turpin
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada
- Department of Medicine and Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Ashleigh Goethel
- Department of Medicine and Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Larbi Bedrani
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada
- Department of Medicine and Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Kenneth Croitoru, MDCM
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada
- Department of Medicine and Immunology, University of Toronto, Toronto, Ontario, Canada
- Correspondence: Kenneth Croitoru, Zane Cohen Centre for Digestive Diseases, Division of Gastroenterology, Department of Medicine and Immunology, University of Toronto, Mount Sinai Hospital, 600 University Avenue Room 437, Toronto, Ontario, M5G 1X5, Canada ()
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Wu WK, Sun R, Zuo T, Tian Y, Zeng Z, Ho J, Wu JC, Chan FK, Chan MT, Yu J, Sung JJ, Wong SH, Wang MH, Ng SC. A novel susceptibility locus in MST1 and gene-gene interaction network for Crohn's disease in the Chinese population. J Cell Mol Med 2018; 22:2368-2377. [PMID: 29441677 PMCID: PMC5867068 DOI: 10.1111/jcmm.13530] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2017] [Accepted: 12/11/2017] [Indexed: 12/13/2022] Open
Abstract
The incidence of Crohn's disease is increasing in many Asian countries, but considerable differences in genetic susceptibility have been reported between Western and Asian populations. This study aimed to fine-map 23 previously reported Crohn's disease genes and identify their interactions in the Chinese population by Illumina-based targeted capture sequencing. Our results showed that the genetic polymorphism A>G at rs144982232 in MST1 showed the most significant association (P = 1.78 × 10-5 ; odds ratio = 4.87). JAK2 rs1159782 (T>C) was also strongly associated with Crohn's disease (P = 2.34 × 10-4 ; odds ratio = 3.72). Gene-gene interaction analysis revealed significant interactions between MST1 and other susceptibility genes, including NOD2, MUC19 and ATG16L1 in contributing to Crohn's disease risk. Main genetic associations and gene-gene interactions were verified using ImmunoChip data set. In conclusion, a novel susceptibility locus in MST1 was identified. Our analysis suggests that MST1 might interact with key susceptibility genes involved in autophagy and bacterial recognition. These findings provide insight into the genetic architecture of Crohn's disease in Chinese and may partially explain the disparity of genetic signals in Crohn's disease susceptibility across different ethnic populations by highlighting the contribution of gene-gene interactions.
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Affiliation(s)
- William K.K. Wu
- State Key Laboratory of Digestive DiseasesInstitute of Digestive Diseases and Department of Medicine & TherapeuticsLKS Institute of Health SciencesCUHK Shenzhen Research InstituteThe Chinese University of Hong KongHong Kong
- Department of Anaesthesia and Intensive CareThe Chinese University of Hong KongHong Kong
| | - Rui Sun
- The Jockey Club School of Public Health and Primary CareThe Chinese University of Hong KongHong Kong
| | - Tao Zuo
- State Key Laboratory of Digestive DiseasesInstitute of Digestive Diseases and Department of Medicine & TherapeuticsLKS Institute of Health SciencesCUHK Shenzhen Research InstituteThe Chinese University of Hong KongHong Kong
| | - Yuanyuan Tian
- Department of Anaesthesia and Intensive CareThe Chinese University of Hong KongHong Kong
| | - Zhirong Zeng
- Department of GastroenterologyThe First Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Jeffery Ho
- Department of Anaesthesia and Intensive CareThe Chinese University of Hong KongHong Kong
| | - Justin C.Y. Wu
- State Key Laboratory of Digestive DiseasesInstitute of Digestive Diseases and Department of Medicine & TherapeuticsLKS Institute of Health SciencesCUHK Shenzhen Research InstituteThe Chinese University of Hong KongHong Kong
| | - Francis K.L. Chan
- State Key Laboratory of Digestive DiseasesInstitute of Digestive Diseases and Department of Medicine & TherapeuticsLKS Institute of Health SciencesCUHK Shenzhen Research InstituteThe Chinese University of Hong KongHong Kong
| | - Matthew T.V. Chan
- Department of Anaesthesia and Intensive CareThe Chinese University of Hong KongHong Kong
| | - Jun Yu
- State Key Laboratory of Digestive DiseasesInstitute of Digestive Diseases and Department of Medicine & TherapeuticsLKS Institute of Health SciencesCUHK Shenzhen Research InstituteThe Chinese University of Hong KongHong Kong
| | - Joseph J.Y. Sung
- State Key Laboratory of Digestive DiseasesInstitute of Digestive Diseases and Department of Medicine & TherapeuticsLKS Institute of Health SciencesCUHK Shenzhen Research InstituteThe Chinese University of Hong KongHong Kong
| | - Sunny H. Wong
- State Key Laboratory of Digestive DiseasesInstitute of Digestive Diseases and Department of Medicine & TherapeuticsLKS Institute of Health SciencesCUHK Shenzhen Research InstituteThe Chinese University of Hong KongHong Kong
| | - Maggie H. Wang
- The Jockey Club School of Public Health and Primary CareThe Chinese University of Hong KongHong Kong
| | - Siew C. Ng
- State Key Laboratory of Digestive DiseasesInstitute of Digestive Diseases and Department of Medicine & TherapeuticsLKS Institute of Health SciencesCUHK Shenzhen Research InstituteThe Chinese University of Hong KongHong Kong
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Berkowitz L, Schultz BM, Salazar GA, Pardo-Roa C, Sebastián VP, Álvarez-Lobos MM, Bueno SM. Impact of Cigarette Smoking on the Gastrointestinal Tract Inflammation: Opposing Effects in Crohn's Disease and Ulcerative Colitis. Front Immunol 2018; 9:74. [PMID: 29441064 PMCID: PMC5797634 DOI: 10.3389/fimmu.2018.00074] [Citation(s) in RCA: 120] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2017] [Accepted: 01/11/2018] [Indexed: 01/06/2023] Open
Abstract
Cigarette smoking is a major risk factor for gastrointestinal disorders, such as peptic ulcer, Crohn’s disease (CD), and several cancers. The mechanisms proposed to explain the role of smoking in these disorders include mucosal damage, changes in gut irrigation, and impaired mucosal immune response. Paradoxically, cigarette smoking is a protective factor for the development and progression of ulcerative colitis (UC). UC and CD represent the two most important conditions of inflammatory bowel diseases, and share several clinical features. The opposite effects of smoking on these two conditions have been a topic of great interest in the last 30 years, and has not yet been clarified. In this review, we summarize the most important and well-understood effects of smoking in the gastrointestinal tract; and particularly, in intestinal inflammation, discussing available studies that have addressed the causes that would explain the opposite effects of smoking in CD and UC.
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Affiliation(s)
- Loni Berkowitz
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.,Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Bárbara M Schultz
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Geraldyne A Salazar
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Catalina Pardo-Roa
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Valentina P Sebastián
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Manuel M Álvarez-Lobos
- Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Susan M Bueno
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
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Crawford KM, Gallego-Fabrega C, Kourkoulis C, Miyares L, Marini S, Flannick J, Burtt NP, von Grotthuss M, Alexander B, Costanzo MC, Vaishnav NH, Malik R, Hall JL, Chong M, Rosand J, Falcone GJ. Cerebrovascular Disease Knowledge Portal: An Open-Access Data Resource to Accelerate Genomic Discoveries in Stroke. Stroke 2018; 49:470-475. [PMID: 29335331 DOI: 10.1161/strokeaha.117.018922] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 11/16/2017] [Accepted: 12/06/2017] [Indexed: 11/16/2022]
Affiliation(s)
- Katherine M Crawford
- From the Center for Genomic Medicine (K.C., C.G.-F., C.K., S.M., N.V., J.R.), Division of Neurocritical Care and Emergency Neurology, Department of Neurology (J.R.), and J. Philip Kistler Stroke Research Center (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (K.C., C.G.-F., C.K., S.M., J.F., N.B., M.v.G., B.A., M.C., N.V., J.R., G.J.F.); Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale University School of Medicine, New Haven, CT (L.M., G.J.F.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilian University, Munich, Germany (R.M.); Institute for Precision Cardiovascular Medicine, American Heart Association National Center, Dallas, TX (J.L.H.); Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis (J.L.H.); and McMaster University, Hamilton, Ontario, Canada (M.C.)
| | - Cristina Gallego-Fabrega
- From the Center for Genomic Medicine (K.C., C.G.-F., C.K., S.M., N.V., J.R.), Division of Neurocritical Care and Emergency Neurology, Department of Neurology (J.R.), and J. Philip Kistler Stroke Research Center (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (K.C., C.G.-F., C.K., S.M., J.F., N.B., M.v.G., B.A., M.C., N.V., J.R., G.J.F.); Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale University School of Medicine, New Haven, CT (L.M., G.J.F.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilian University, Munich, Germany (R.M.); Institute for Precision Cardiovascular Medicine, American Heart Association National Center, Dallas, TX (J.L.H.); Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis (J.L.H.); and McMaster University, Hamilton, Ontario, Canada (M.C.)
| | - Christina Kourkoulis
- From the Center for Genomic Medicine (K.C., C.G.-F., C.K., S.M., N.V., J.R.), Division of Neurocritical Care and Emergency Neurology, Department of Neurology (J.R.), and J. Philip Kistler Stroke Research Center (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (K.C., C.G.-F., C.K., S.M., J.F., N.B., M.v.G., B.A., M.C., N.V., J.R., G.J.F.); Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale University School of Medicine, New Haven, CT (L.M., G.J.F.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilian University, Munich, Germany (R.M.); Institute for Precision Cardiovascular Medicine, American Heart Association National Center, Dallas, TX (J.L.H.); Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis (J.L.H.); and McMaster University, Hamilton, Ontario, Canada (M.C.)
| | - Laura Miyares
- From the Center for Genomic Medicine (K.C., C.G.-F., C.K., S.M., N.V., J.R.), Division of Neurocritical Care and Emergency Neurology, Department of Neurology (J.R.), and J. Philip Kistler Stroke Research Center (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (K.C., C.G.-F., C.K., S.M., J.F., N.B., M.v.G., B.A., M.C., N.V., J.R., G.J.F.); Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale University School of Medicine, New Haven, CT (L.M., G.J.F.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilian University, Munich, Germany (R.M.); Institute for Precision Cardiovascular Medicine, American Heart Association National Center, Dallas, TX (J.L.H.); Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis (J.L.H.); and McMaster University, Hamilton, Ontario, Canada (M.C.)
| | - Sandro Marini
- From the Center for Genomic Medicine (K.C., C.G.-F., C.K., S.M., N.V., J.R.), Division of Neurocritical Care and Emergency Neurology, Department of Neurology (J.R.), and J. Philip Kistler Stroke Research Center (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (K.C., C.G.-F., C.K., S.M., J.F., N.B., M.v.G., B.A., M.C., N.V., J.R., G.J.F.); Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale University School of Medicine, New Haven, CT (L.M., G.J.F.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilian University, Munich, Germany (R.M.); Institute for Precision Cardiovascular Medicine, American Heart Association National Center, Dallas, TX (J.L.H.); Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis (J.L.H.); and McMaster University, Hamilton, Ontario, Canada (M.C.)
| | - Jason Flannick
- From the Center for Genomic Medicine (K.C., C.G.-F., C.K., S.M., N.V., J.R.), Division of Neurocritical Care and Emergency Neurology, Department of Neurology (J.R.), and J. Philip Kistler Stroke Research Center (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (K.C., C.G.-F., C.K., S.M., J.F., N.B., M.v.G., B.A., M.C., N.V., J.R., G.J.F.); Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale University School of Medicine, New Haven, CT (L.M., G.J.F.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilian University, Munich, Germany (R.M.); Institute for Precision Cardiovascular Medicine, American Heart Association National Center, Dallas, TX (J.L.H.); Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis (J.L.H.); and McMaster University, Hamilton, Ontario, Canada (M.C.)
| | - Noel P Burtt
- From the Center for Genomic Medicine (K.C., C.G.-F., C.K., S.M., N.V., J.R.), Division of Neurocritical Care and Emergency Neurology, Department of Neurology (J.R.), and J. Philip Kistler Stroke Research Center (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (K.C., C.G.-F., C.K., S.M., J.F., N.B., M.v.G., B.A., M.C., N.V., J.R., G.J.F.); Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale University School of Medicine, New Haven, CT (L.M., G.J.F.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilian University, Munich, Germany (R.M.); Institute for Precision Cardiovascular Medicine, American Heart Association National Center, Dallas, TX (J.L.H.); Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis (J.L.H.); and McMaster University, Hamilton, Ontario, Canada (M.C.)
| | - Marcin von Grotthuss
- From the Center for Genomic Medicine (K.C., C.G.-F., C.K., S.M., N.V., J.R.), Division of Neurocritical Care and Emergency Neurology, Department of Neurology (J.R.), and J. Philip Kistler Stroke Research Center (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (K.C., C.G.-F., C.K., S.M., J.F., N.B., M.v.G., B.A., M.C., N.V., J.R., G.J.F.); Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale University School of Medicine, New Haven, CT (L.M., G.J.F.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilian University, Munich, Germany (R.M.); Institute for Precision Cardiovascular Medicine, American Heart Association National Center, Dallas, TX (J.L.H.); Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis (J.L.H.); and McMaster University, Hamilton, Ontario, Canada (M.C.)
| | - Benjamin Alexander
- From the Center for Genomic Medicine (K.C., C.G.-F., C.K., S.M., N.V., J.R.), Division of Neurocritical Care and Emergency Neurology, Department of Neurology (J.R.), and J. Philip Kistler Stroke Research Center (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (K.C., C.G.-F., C.K., S.M., J.F., N.B., M.v.G., B.A., M.C., N.V., J.R., G.J.F.); Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale University School of Medicine, New Haven, CT (L.M., G.J.F.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilian University, Munich, Germany (R.M.); Institute for Precision Cardiovascular Medicine, American Heart Association National Center, Dallas, TX (J.L.H.); Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis (J.L.H.); and McMaster University, Hamilton, Ontario, Canada (M.C.)
| | - Maria C Costanzo
- From the Center for Genomic Medicine (K.C., C.G.-F., C.K., S.M., N.V., J.R.), Division of Neurocritical Care and Emergency Neurology, Department of Neurology (J.R.), and J. Philip Kistler Stroke Research Center (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (K.C., C.G.-F., C.K., S.M., J.F., N.B., M.v.G., B.A., M.C., N.V., J.R., G.J.F.); Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale University School of Medicine, New Haven, CT (L.M., G.J.F.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilian University, Munich, Germany (R.M.); Institute for Precision Cardiovascular Medicine, American Heart Association National Center, Dallas, TX (J.L.H.); Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis (J.L.H.); and McMaster University, Hamilton, Ontario, Canada (M.C.)
| | - Neil H Vaishnav
- From the Center for Genomic Medicine (K.C., C.G.-F., C.K., S.M., N.V., J.R.), Division of Neurocritical Care and Emergency Neurology, Department of Neurology (J.R.), and J. Philip Kistler Stroke Research Center (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (K.C., C.G.-F., C.K., S.M., J.F., N.B., M.v.G., B.A., M.C., N.V., J.R., G.J.F.); Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale University School of Medicine, New Haven, CT (L.M., G.J.F.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilian University, Munich, Germany (R.M.); Institute for Precision Cardiovascular Medicine, American Heart Association National Center, Dallas, TX (J.L.H.); Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis (J.L.H.); and McMaster University, Hamilton, Ontario, Canada (M.C.)
| | - Rainer Malik
- From the Center for Genomic Medicine (K.C., C.G.-F., C.K., S.M., N.V., J.R.), Division of Neurocritical Care and Emergency Neurology, Department of Neurology (J.R.), and J. Philip Kistler Stroke Research Center (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (K.C., C.G.-F., C.K., S.M., J.F., N.B., M.v.G., B.A., M.C., N.V., J.R., G.J.F.); Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale University School of Medicine, New Haven, CT (L.M., G.J.F.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilian University, Munich, Germany (R.M.); Institute for Precision Cardiovascular Medicine, American Heart Association National Center, Dallas, TX (J.L.H.); Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis (J.L.H.); and McMaster University, Hamilton, Ontario, Canada (M.C.)
| | - Jennifer L Hall
- From the Center for Genomic Medicine (K.C., C.G.-F., C.K., S.M., N.V., J.R.), Division of Neurocritical Care and Emergency Neurology, Department of Neurology (J.R.), and J. Philip Kistler Stroke Research Center (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (K.C., C.G.-F., C.K., S.M., J.F., N.B., M.v.G., B.A., M.C., N.V., J.R., G.J.F.); Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale University School of Medicine, New Haven, CT (L.M., G.J.F.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilian University, Munich, Germany (R.M.); Institute for Precision Cardiovascular Medicine, American Heart Association National Center, Dallas, TX (J.L.H.); Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis (J.L.H.); and McMaster University, Hamilton, Ontario, Canada (M.C.)
| | - Michael Chong
- From the Center for Genomic Medicine (K.C., C.G.-F., C.K., S.M., N.V., J.R.), Division of Neurocritical Care and Emergency Neurology, Department of Neurology (J.R.), and J. Philip Kistler Stroke Research Center (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (K.C., C.G.-F., C.K., S.M., J.F., N.B., M.v.G., B.A., M.C., N.V., J.R., G.J.F.); Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale University School of Medicine, New Haven, CT (L.M., G.J.F.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilian University, Munich, Germany (R.M.); Institute for Precision Cardiovascular Medicine, American Heart Association National Center, Dallas, TX (J.L.H.); Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis (J.L.H.); and McMaster University, Hamilton, Ontario, Canada (M.C.)
| | - Jonathan Rosand
- From the Center for Genomic Medicine (K.C., C.G.-F., C.K., S.M., N.V., J.R.), Division of Neurocritical Care and Emergency Neurology, Department of Neurology (J.R.), and J. Philip Kistler Stroke Research Center (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (K.C., C.G.-F., C.K., S.M., J.F., N.B., M.v.G., B.A., M.C., N.V., J.R., G.J.F.); Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale University School of Medicine, New Haven, CT (L.M., G.J.F.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilian University, Munich, Germany (R.M.); Institute for Precision Cardiovascular Medicine, American Heart Association National Center, Dallas, TX (J.L.H.); Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis (J.L.H.); and McMaster University, Hamilton, Ontario, Canada (M.C.).
| | - Guido J Falcone
- From the Center for Genomic Medicine (K.C., C.G.-F., C.K., S.M., N.V., J.R.), Division of Neurocritical Care and Emergency Neurology, Department of Neurology (J.R.), and J. Philip Kistler Stroke Research Center (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (K.C., C.G.-F., C.K., S.M., J.F., N.B., M.v.G., B.A., M.C., N.V., J.R., G.J.F.); Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale University School of Medicine, New Haven, CT (L.M., G.J.F.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilian University, Munich, Germany (R.M.); Institute for Precision Cardiovascular Medicine, American Heart Association National Center, Dallas, TX (J.L.H.); Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis (J.L.H.); and McMaster University, Hamilton, Ontario, Canada (M.C.)
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40
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Hao X, Zeng P, Zhang S, Zhou X. Identifying and exploiting trait-relevant tissues with multiple functional annotations in genome-wide association studies. PLoS Genet 2018; 14:e1007186. [PMID: 29377896 PMCID: PMC5805369 DOI: 10.1371/journal.pgen.1007186] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Revised: 02/08/2018] [Accepted: 01/04/2018] [Indexed: 12/18/2022] Open
Abstract
Genome-wide association studies (GWASs) have identified many disease associated loci, the majority of which have unknown biological functions. Understanding the mechanism underlying trait associations requires identifying trait-relevant tissues and investigating associations in a trait-specific fashion. Here, we extend the widely used linear mixed model to incorporate multiple SNP functional annotations from omics studies with GWAS summary statistics to facilitate the identification of trait-relevant tissues, with which to further construct powerful association tests. Specifically, we rely on a generalized estimating equation based algorithm for parameter inference, a mixture modeling framework for trait-tissue relevance classification, and a weighted sequence kernel association test constructed based on the identified trait-relevant tissues for powerful association analysis. We refer to our analytic procedure as the Scalable Multiple Annotation integration for trait-Relevant Tissue identification and usage (SMART). With extensive simulations, we show how our method can make use of multiple complementary annotations to improve the accuracy for identifying trait-relevant tissues. In addition, our procedure allows us to make use of the inferred trait-relevant tissues, for the first time, to construct more powerful SNP set tests. We apply our method for an in-depth analysis of 43 traits from 28 GWASs using tissue-specific annotations in 105 tissues derived from ENCODE and Roadmap. Our results reveal new trait-tissue relevance, pinpoint important annotations that are informative of trait-tissue relationship, and illustrate how we can use the inferred trait-relevant tissues to construct more powerful association tests in the Wellcome trust case control consortium study.
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Affiliation(s)
- Xingjie Hao
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan, Hubei, China
- Department of Biostatistics, University of Michigan, Ann Arbor, MI, United States of America
- Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, United States of America
| | - Ping Zeng
- Department of Biostatistics, University of Michigan, Ann Arbor, MI, United States of America
- Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, United States of America
| | - Shujun Zhang
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan, Hubei, China
| | - Xiang Zhou
- Department of Biostatistics, University of Michigan, Ann Arbor, MI, United States of America
- Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, United States of America
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41
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Zhou M, He J, Shen Y, Zhang C, Wang J, Chen Y. New Frontiers in Genetics, Gut Microbiota, and Immunity: A Rosetta Stone for the Pathogenesis of Inflammatory Bowel Disease. BIOMED RESEARCH INTERNATIONAL 2017; 2017:8201672. [PMID: 28831399 PMCID: PMC5558637 DOI: 10.1155/2017/8201672] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Revised: 06/03/2017] [Accepted: 07/03/2017] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel disease (IBD), which encompasses ulcerative colitis (UC) and Crohn's disease (CD), is a complicated, uncontrolled, and multifactorial disorder characterized by chronic, relapsing, or progressive inflammatory conditions that may involve the entire gastrointestinal tract. The protracted nature has imposed enormous economic burdens on patients with IBD, and the treatment is far from optimal due to the currently limited comprehension of IBD pathogenesis. In spite of the exact etiology still remaining an enigma, four identified components, including personal genetic susceptibility, external environment, internal gut microbiota, and the host immune response, are responsible for IBD pathogenesis, and compelling evidence has suggested that IBD may be triggered by aberrant and continuing immune responses to gut microbiota in genetically susceptibility individuals. The past decade has witnessed the flourishing of research on genetics, gut microbiota, and immunity in patients with IBD. Therefore, in this review, we will comprehensively exhibit a series of novel findings and update the major advances regarding these three fields. Undoubtedly, these novel findings have opened a new horizon and shed bright light on the causality research of IBD.
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Affiliation(s)
- Mingxia Zhou
- Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
| | - Jing He
- Department of General Surgery, Huashan Hospital of Fudan University, Shanghai 200040, China
| | - Yujie Shen
- Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
| | - Cong Zhang
- Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
| | - Jiazheng Wang
- Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
| | - Yingwei Chen
- Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
- Shanghai Institute for Pediatric Research, Shanghai 200092, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
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RNA-seq Reveals Transcriptomic Differences in Inflamed and Noninflamed Intestinal Mucosa of Crohn's Disease Patients Compared with Normal Mucosa of Healthy Controls. Inflamm Bowel Dis 2017; 23:1098-1108. [PMID: 28613228 DOI: 10.1097/mib.0000000000001066] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Aberrant gene expression in the gut mucosa might contribute to the initiation and progression of Crohn's disease (CD). RNA sequencing (RNA-seq) provides precise measurements of expression levels of transcripts and their isoforms. The aim of this study was to use RNA-seq to investigate transcriptomic differences and identify significantly differentially expressed transcripts in inflamed and noninflamed intestinal mucosa of CD patients. METHODS RNA-seq was performed on 13 pairs of inflamed and noninflamed intestinal mucosa from 13 CD patients and on sex-matched normal mucosa of 13 healthy controls. Significantly differentially expressed transcripts were validated by immunohistochemistry, quantitative reverse transcriptase polymerase chain reaction, and enzyme-linked immunosorbent assay. RESULTS RNA-seq revealed genome-wide transcriptomic differences between normal mucosa, noninflamed, and inflamed CD mucosa. Among 950 differentially expressed genes, 19 were up- or downregulated (upregulation: ANGPT2, CHN1, CPXM1, CPZ, CXCL1, FCN3, GJC1, HSD11B1, LZTS1, MEOX1, MMP12, PLA1A, SERPINE1, SGIP1, and TRPC4; downregulation: FAM189A1, PDE6A, SLC38A4, and HMGCS2) with statistical significance (p < 0.01 and q < 0.05). Among them, CXCL1 exhibited the highest fold change between groups. Immunohistochemistry for CXCL1 revealed no expression in normal mucosa, slightly increased expression in noninflamed CD mucosa, and highly increased expression in inflamed CD mucosa. Quantitative reverse transcriptase polymerase chain reaction showed that CXCL1 expression was significantly associated with epithelial damage, increased infiltration of polymorphonuclear leukocytes, and submucosal fibrosis. Serum CXCL1 concentration measured by enzyme-linked immunosorbent assay was better correlated with CD activity index (r = 0.660) than with C-reactive protein (r = 0.204). CONCLUSIONS RNA-seq revealed transcriptomic differences between normal mucosa, noninflamed CD mucosa, and inflamed CD mucosa. Intestinal and serum CXCL1 was substantially increased with CD activity and can be used as a potential biomarker of CD.
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Cheung AC, LaRusso NF, Gores GJ, Lazaridis KN. Epigenetics in the Primary Biliary Cholangitis and Primary Sclerosing Cholangitis. Semin Liver Dis 2017; 37:159-174. [PMID: 28564724 PMCID: PMC5553635 DOI: 10.1055/s-0037-1603324] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Epigenomics, the study of modifications to genetic material that do not alter the underlying DNA sequence, is generating increasing interest as a means to help clarify disease pathogenesis and outcomes. Although genome-wide association studies have identified several potential candidate genes that may be implicated in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), it is estimated that these genes explain less than 20% of the heritability of these diseases. Thus, to date, the origins of “missing heritability” for PBC and PSC remain elusive. The epigenome may provide a potentially elegant solution to this phenomenon, as it can be modified by both internal and external exposures (coined the “exposome”). This may explain differences in disease presentation, treatment response, and rates of progression between individuals. Epigenetic changes may also provide a framework for discovering potential biomarkers for diagnosis and screening of PBC and PSC. Importantly, because the epigenome is modifiable, it may also highlight novel pathways for therapeutic discovery and interventions of these diseases.
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Affiliation(s)
- Angela C. Cheung
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Nicholas F. LaRusso
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Gregory J. Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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Yao Q, Shen B. A Systematic Analysis of Treatment and Outcomes of NOD2-Associated Autoinflammatory Disease. Am J Med 2017; 130:365.e13-365.e18. [PMID: 27984003 DOI: 10.1016/j.amjmed.2016.09.028] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2016] [Revised: 09/22/2016] [Accepted: 09/22/2016] [Indexed: 12/15/2022]
Abstract
OBJECTIVES Yao syndrome, formerly named NOD2-associated autoinflammatory disease, is a periodic disease characterized by fever, dermatitis, polyarthritis/leg swelling, and gastrointestinal and sicca-like symptoms associated with specific NOD2 sequence variants. Our aim was to evaluate the treatment and outcomes of the disease. METHODS A total of 52 adult patients with autoinflammatory disease phenotype were diagnosed with Yao syndrome and enrolled at the Cleveland Clinic between November 2009 and May 2015. All patients were genotyped for the NOD2 variants, and systematically studied for treatment outcomes. RESULTS Among the 52 Yao syndrome patients, all were white, and 72% were women. The mean age at diagnosis was 38.0 ± 12.0 years, and the disease duration was 8.8 ± 5.8 years. In the multi-organ disease, more common and typical manifestations were recurrent dermatitis and inflammatory arthritis with or without distal leg swelling besides recurrent fever. It was genotypically associated with the NOD2 IVS8+158 or R702W. Therapeutically, glucocorticoids markedly decreased the disease severity and duration of flares in 19 patients (36.6%), sulfasalazine treatment achieved a significant symptomatic improvement in 22 (42%) patients, and 3 patients received canakinumab or tocilizumab with benefits. Prognostically, 13% of the 52 patients had somewhat physical impairment, and there was no mortality during the follow-up. Associated comorbidities were fibromyalgia, asthma, renal stones, and ventricular hypertrophy. CONCLUSIONS As a systemic disease, Yao syndrome uncommonly affects the solid internal organs, but it can be complicated with chronic pain syndrome and even disability. Glucocorticoids or sulfasalazine may be considered as the first-line treatment option, and interleukin (IL)-1/IL-6 inhibitors may be tried for refractory cases. The potential associations between certain comorbidities and Yao syndrome deserve further study.
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Affiliation(s)
- Qingping Yao
- Department of Rheumatic and Immunologic Disease, Cleveland Clinic, Ohio; Division of Rheumatology, Allergy and Immunology, Stony Brook University, NY.
| | - Bo Shen
- Department of Gastroenterology/Hepatology, Cleveland Clinic, Ohio
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Confounding effects of microbiome on the susceptibility of TNFSF15 to Crohn's disease in the Ryukyu Islands. Hum Genet 2017; 136:387-397. [PMID: 28197769 DOI: 10.1007/s00439-017-1764-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 02/08/2017] [Indexed: 12/30/2022]
Abstract
Crohn's disease (CD) involves chronic inflammation in the gastrointestinal tract due to dysregulation of the host immune response to the gut microbiome. Even though the host-microbiome interactions are likely contributors to the development of CD, a few studies have detected genetic variants that change bacterial compositions and increase CD risk. We focus on one of the well-replicated susceptible genes, tumor necrosis factor superfamily member 15 (TNFSF15), and apply statistical analyses for personal profiles of genotypes and salivary microbiota collected from CD cases and controls in the Ryukyu Islands, southernmost islands of the Japanese archipelago. Our association test confirmed the susceptibility of TNFSF15 in the Ryukyu Islands. We found that the recessive model was supported to fit the observed genotype frequency of risk alleles slightly better than the additive model, defining the genetic effect on CD if a pair of the chromosomes in an individual consists of all risk alleles. The combined analysis of haplotypes and salivary microbiome from a small set of samples showed a significant association of the genetic effect with the increase of Prevotella, which led to a significant increase of CD risk. However, the genetic effect on CD disappeared if the abundance of Prevotella was low, suggesting the genetic contribution to CD is conditionally independent given a fixed amount of Prevotella. Although our statistical power is limited due to the small sample size, these results support an idea that the genetic susceptibility of TNFSF15 to CD may be confounded, in part, by the increase of Prevotella.
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Genetics of inflammatory bowel disease: beyond NOD2. Lancet Gastroenterol Hepatol 2017; 2:224-234. [PMID: 28404137 DOI: 10.1016/s2468-1253(16)30111-x] [Citation(s) in RCA: 113] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 09/02/2016] [Accepted: 09/02/2016] [Indexed: 01/11/2023]
Abstract
The study of the genetic underpinnings of inflammatory bowel disease has made great progress since the identification of NOD2 as a major susceptibility gene. Novel genotyping and sequencing technologies have led to the discovery of 242 common susceptibility loci, 45 of which have been fine-mapped to statistically conclusive causal variants; 50 genes associated with very-early-onset inflammatory disease have been identified. The evolving genetic architecture of inflammatory bowel disease has deepened our understanding of its pathogenesis through identification of major disease associated pathways-knowledge that has the potential to indicate novel drug targets or markers for personalised medicine. However, many causal variants have yet to be identified, and a large proportion of missing heritability still needs to be accounted for. In addition, the medical and scientific communities are probably not yet fully harnessing the power of these genetic discoveries.
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Budanur T, Şirin M, Sepet E, Ünür M, Güllüoğlu M, Cantez S, Uğurcan D. Orofacial Crohn’s disease: A case report. BALKAN JOURNAL OF DENTAL MEDICINE 2017. [DOI: 10.1515/bjdm-2017-0021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Background: Crohn’s disease (CD) and ulcerative colitis (UC) are the two major relapsing conditions of inflammatory bowel diseases. Case Report: A case of Crohn’s disease with orofacial manifestations in a 10 year old girl is described. She had suffered from fever, dysphagia, arthralgia, painful recurrent ulcers of the oral mucosa and swelling of the lower lip lasting over 6 weeks. Clinical examination and the punch biopsy from the buccal mucosa revealed major recurrent aphthous ulcerations. A partial regression and significant relief of lesions were achieved two weeks after the treatment, but the patient suffered from abdominal pain, irregular bowel movements, arthritis, multiple hyperplastic and swollen mucosal folds, after 3 months. The patient was referred to a pediatric gastroenterologist. Esophagogastroduodenoscopy showed pyloric ulcer formation. Abdominal ultrasound showed increased thickening of the ileal wall with multiple enlarged lympadenopathies in the periileal region. Colonoscopy images showed deep ulcers with surrounding erythema. The histopathological examination of biopsies from the terminal ileum and the colon showed basal plasmacytosis, minimal crypt distortions and aphthous ulcerations. The diagnosis of Orofacial Crohn’s disease was made. Exclusive enteral nutrition for 8 weeks, followed by azathiopurine treatment was started with an excellent clinical response on abdominal and oral symptoms. Conclusion: Diagnosis of the disease by dentists and other clinicians through the evaluation of oral clinical findings is very rare. Mucocutaneous and granulomatous lesions of the oral cavity should alert the clinician to pursue an underlying systemic cause. Early communication with a gastroenterologist can help early diagnosis of Crohn’s disease for better patient management and prognosis.
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Raghuraman P, Jesu Jaya Sudan R, Lesitha Jeeva Kumari J, Sudandiradoss C. Casting the critical regions in nucleotide binding oligomerization domain 2 protein: a signature mediated structural dynamics approach. J Biomol Struct Dyn 2016; 35:3297-3315. [PMID: 27790943 DOI: 10.1080/07391102.2016.1254116] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Nucleotide binding oligomerization domain 2 (NOD2), a protein involved in the first line defence mechanism has a pivotal role in innate immunity. Impaired function of this protein is implicated in disorders such as Blau syndrome and Crohn's disease. Since an altered function is linked to protein's structure, we framed a systematic strategy to interpret the structure-function relationship of the protein. Initiated with mutation-based pattern prediction and identified a distant ortholog (DO) of NOD2 from which the intra-residue interaction network was elucidated. The network was used to identify hotspots that serve as critical points to maintain the stable architecture of the protein. Structural comparison of NOD2 domains with a DO revealed the minimal number of intra-protein interactions required by the protein to maintain the structural fold. In addition, the conventional molecular dynamics simulation emphasized the conformational transitions at hot spot residues between native NOD2 domains and its respective mutants (G116R, R42W and R54A) structures. The analysis of intra-protein interactions globally and the displacement of residues locally around the mutational site revealed loss of several critical bonds and residues vital for the protein's function. Conclusively we report, about 10 residues in leucine-rich repeat, 13 residues in NOD and 6 residues in CARD domain are required by the NOD2 to maintain its function. This protocol will help the researchers to achieve for more prospective studies to attest druggable site utility in discovering novel drug candidates.
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Affiliation(s)
- P Raghuraman
- a Department of Biotechnology , School of Bioscience and Technology, VIT University , Vellore 632301 , India
| | - R Jesu Jaya Sudan
- a Department of Biotechnology , School of Bioscience and Technology, VIT University , Vellore 632301 , India
| | - J Lesitha Jeeva Kumari
- a Department of Biotechnology , School of Bioscience and Technology, VIT University , Vellore 632301 , India
| | - C Sudandiradoss
- a Department of Biotechnology , School of Bioscience and Technology, VIT University , Vellore 632301 , India
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49
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Ye BD, McGovern DP. Genetic variation in IBD: progress, clues to pathogenesis and possible clinical utility. Expert Rev Clin Immunol 2016; 12:1091-107. [PMID: 27156530 PMCID: PMC5083126 DOI: 10.1080/1744666x.2016.1184972] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Epidemiological and clinical studies have suggested that the pathogenesis of inflammatory bowel disease (IBD) is strongly influenced by genetic predisposition. Beyond the limitations of linkage analysis, multiple genome-wide association studies, their meta-analyses, and targeted genotyping array techniques have broadened our understanding of the genetic architecture of IBD. Currently, over 200 single nucleotide polymorphisms are known to be associated with susceptibility to IBD and through functional analysis of genes and loci, a substantial proportion of pathophysiologic mechanisms have been revealed. However, because only a modest fraction of predicted heritability can be explained by known genes/loci, additional strategies are needed including the identification of rare variants with large effect sizes to help explain the missing heritability. Considerable progress is also being made on applying outcomes of genetic research in diagnostics, classification, prognostics, and the development of new therapeutics of IBD.
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Affiliation(s)
- Byong Duk Ye
- Department of Gastroenterology and Inflammatory Bowel Disease Center, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Dermot P.B. McGovern
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
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50
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Lees JA, Vehkala M, Välimäki N, Harris SR, Chewapreecha C, Croucher NJ, Marttinen P, Davies MR, Steer AC, Tong SYC, Honkela A, Parkhill J, Bentley SD, Corander J. Sequence element enrichment analysis to determine the genetic basis of bacterial phenotypes. Nat Commun 2016; 7:12797. [PMID: 27633831 PMCID: PMC5028413 DOI: 10.1038/ncomms12797] [Citation(s) in RCA: 121] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Accepted: 07/28/2016] [Indexed: 02/07/2023] Open
Abstract
Bacterial genomes vary extensively in terms of both gene content and gene sequence. This plasticity hampers the use of traditional SNP-based methods for identifying all genetic associations with phenotypic variation. Here we introduce a computationally scalable and widely applicable statistical method (SEER) for the identification of sequence elements that are significantly enriched in a phenotype of interest. SEER is applicable to tens of thousands of genomes by counting variable-length k-mers using a distributed string-mining algorithm. Robust options are provided for association analysis that also correct for the clonal population structure of bacteria. Using large collections of genomes of the major human pathogens Streptococcus pneumoniae and Streptococcus pyogenes, SEER identifies relevant previously characterized resistance determinants for several antibiotics and discovers potential novel factors related to the invasiveness of S. pyogenes. We thus demonstrate that our method can answer important biologically and medically relevant questions. Plasticity and clonal population structure in bacterial genomes can hinder traditional SNP-based genetic association studies. Here, Corander and colleagues present a method to identify variable-length sequence elements enriched in a phenotype of interest, and demonstrate its use in human pathogens.
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Affiliation(s)
- John A Lees
- Pathogen Genomics, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK
| | - Minna Vehkala
- Department of Mathematics and Statistics, University of Helsinki, Helsinki FI-00014, Finland
| | - Niko Välimäki
- Department of Medical and Clinical Genetics, Genome-Scale Biology Research Program, University of Helsinki, Helsinki FI-00014, Finland
| | - Simon R Harris
- Pathogen Genomics, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK
| | | | - Nicholas J Croucher
- Department of Infectious Disease Epidemiology, Imperial College, London W2 1NY, UK
| | - Pekka Marttinen
- Department of Computer Science, Aalto University, Espoo FI-00076, Finland.,Helsinki Institute of Information Technology HIIT, Department of Computer Science, Aalto University, Espoo FI-00076, Finland
| | - Mark R Davies
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria 3010, Australia
| | - Andrew C Steer
- Centre for International Child Health, Department of Paediatrics, University of Melbourne, Melbourne, Victoria 3052, Australia.,Group A Streptococcal Research Group, Murdoch Children's Research Institute, Parkville, Victoria 3052, Australia
| | - Steven Y C Tong
- Menzies School of Health Research, Darwin, Northern Territory 0811, Australia
| | - Antti Honkela
- Helsinki Institute for Information Technology HIIT, Department of Computer Science, University of Helsinki, Helsinki FI-00014, Finland
| | - Julian Parkhill
- Pathogen Genomics, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK
| | - Stephen D Bentley
- Pathogen Genomics, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK
| | - Jukka Corander
- Pathogen Genomics, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.,Department of Mathematics and Statistics, University of Helsinki, Helsinki FI-00014, Finland.,Department of Biostatistics, University of Oslo, 0317 Oslo, Norway
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