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Chauhan G, Rieder F. The Pathogenesis of Inflammatory Bowel Diseases. Surg Clin North Am 2025; 105:201-215. [PMID: 40015812 DOI: 10.1016/j.suc.2024.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/01/2025]
Abstract
Inflammatory bowel diseases (IBDs) are relapsing, remitting inflammatory diseases of the intestinal tract. Familial aggregation and genome-wide association studies revealed susceptibility variants that point toward a combination of innate immune and adaptive immune dysregulation that in concert with environmental factors, such as our microbiome, can initiate and perpetuate inflammation. Innate immune perturbations include functional abnormalities in the intestinal barrier, endoplasmic reticulum stress, and abnormal recognition of microbes. Adaptive immune changes include dysregulation of cytokines, regulatory T cells, and leukocyte migration. IBD is linked with an abnormal wound-healing response leading to fibrosis. This article summarizes key pathogenic mechanisms in the pathogenesis of IBDs.
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Affiliation(s)
- Gaurav Chauhan
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA
| | - Florian Rieder
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA; Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases Institute; Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
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Mi N, He Q, Liu Y, Li Y, Li Y, Wu Y, Yang M, Zhao Y, Xie P, Li W, Wu S, Li Z, Wang D, Qin X, Yuan J, Lei P, Qi J, Xia B. Metabolic health and genetic predisposition in inflammatory bowel disease: Insights from a prospective cohort study. Eur J Intern Med 2024; 128:119-126. [PMID: 38955589 DOI: 10.1016/j.ejim.2024.06.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 05/21/2024] [Accepted: 06/19/2024] [Indexed: 07/04/2024]
Abstract
BACKGROUND Metabolic disorders exhibit strong inflammatory underpinnings and vice versa. This study aimed to investigate the association between metabolic health status, genetic predisposition, and the risk of inflammatory bowel disease (IBD), and to explore the potential benefits of maintaining ideal metabolic status for individuals with a predetermined genetic risk of IBD. METHOD This population-based prospective study included 385,820 unrelated European descent participants from the UK Biobank. Using multivariable Cox regression, we assessed the relationship of metabolic phenotypes with risk of IBD and its subtypes. We also developed a polygenic risk score to examine how metabolic health status interacted with genetic risk in relation to IBD risk. RESULTS During the follow-up period of 4,328,895 person-years, 2,044 newly-diagnosed IBD cases were identified. Higher genetic risk and an increasing number of abnormal metabolic phenotypes were associated with elevated IBD risk (p-trend <0.001). Individuals with high genetic risk and poor metabolic health had a significantly higher risk of IBD (HR=4.56, 95 % CI=3.27-6.36) compared to those with low genetic risk and ideal metabolic health. These results remained consistent for IBD subtypes. Maintaining ideal metabolic status reduced IBD risk within each genetic risk category and jointly decreased subsequent risk by 40 % in high genetic risk individuals. CONCLUSION Our study reveals a combined impact of poor metabolic health and genetic risk on IBD incidence. Those with low genetic risk and optimal metabolic health exhibit the lowest IBD risk, offering insights into potential management strategies for individuals at predefined genetic risk.
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Affiliation(s)
- Ningning Mi
- Department of Epidemiology and Biostatistics, Clinical Big Data Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China; Chinese Health Risk Management Collaboration (CHRIMAC), Shenzhen, Guangdong, China; The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
| | - Qiangsheng He
- Department of Epidemiology and Biostatistics, Clinical Big Data Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China; Chinese Health Risk Management Collaboration (CHRIMAC), Shenzhen, Guangdong, China
| | - Yuyao Liu
- Department of Oncology, Cancer Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yingmei Li
- Department of Pharmacy, Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Ying Li
- Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Yingjie Wu
- Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Man Yang
- Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Yingya Zhao
- Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Peng Xie
- Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Wenjing Li
- Department of Epidemiology and Biostatistics, Clinical Big Data Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Siqin Wu
- Department of Epidemiology and Biostatistics, Clinical Big Data Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Zijun Li
- Evidence Based Social Science Research Center/Health Technology Assessment Center, School of Public Health, Lanzhou University, Lanzhou, China
| | - Danni Wang
- Department of Epidemiology and Biostatistics, Clinical Big Data Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Xiwen Qin
- Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; Laboratory of Data Discovery for Health (D24H), The University of Hong Kong, Hong Kong SAR, China; School of Population and Global Health, Faculty of Medicine, Density and Health Sciences, University of Western Australia, Perth, Australia
| | - Jinqiu Yuan
- Department of Epidemiology and Biostatistics, Clinical Big Data Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China; Chinese Health Risk Management Collaboration (CHRIMAC), Shenzhen, Guangdong, China
| | - Pingguang Lei
- Department of Gastroenterology, Shenzhen Bao'an District Songgang People's Hospital, Shenzhen, Guangdong, China
| | - Jian Qi
- Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Bin Xia
- Department of Epidemiology and Biostatistics, Clinical Big Data Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China; Chinese Health Risk Management Collaboration (CHRIMAC), Shenzhen, Guangdong, China.
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Erfan R, Shaker OG, Khalil MAF, Mahmoud FAM, Gomaa MS, Abu-El-Azayem AK, Zaki OM, Ahmed AM, Samy A, Mohammed A. Circulating miR-199a and long noncoding-RNA ANRIL as Promising Diagnostic Biomarkers for Inflammatory Bowel Disease. Inflamm Bowel Dis 2024; 30:1500-1509. [PMID: 38190238 DOI: 10.1093/ibd/izad210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Indexed: 01/09/2024]
Abstract
BACKGROUND & AIMS Inflammatory bowel disease (IBD), involving both Crohn's disease (CD) and ulcerative colitis (UC), represents a chronic, immune-mediated inflammatory disease due to an uncontrolled, ongoing inflammatory response to intestinal bacteria in those with genetic susceptibility. MicroRNA (miRNA) extrusion from relevant remote organs or tissues is reflected in the expression of miRNAs in serum and plasma. Both UC and CD patients had higher blood levels of expressed miR-199a. Long noncoding RNA (lncRNA) ANRIL is a proinflammatory gene that mediates nuclear factor κB to play a role in inflammatory diseases, such as IBD. The aim of the current study is to investigate the potential role of both miR-199a and ANRIL in diagnosing IBD in adult patients. METHODS Sixty-seven IBD patients diagnosed clinically, radiologically, endoscopically, and histologically were included in this prospective cohort study. Participants were classified into 3 groups: the UC group (n = 35), the CD group (n = 32), and the control group (n = 30). Demographics, history taking, laboratory characteristics, and treatments were recorded. Tumor necrosis factor α, miR-199a, and ANRIL were measured. RESULTS The findings suggested that miR-199a and ANRIL might be associated with the occurrence or progression of IBD because both genes were substantially expressed in the peripheral blood of patients with this condition. Receiver-operating characteristic curve analysis indicated that the detection of miR-199a and ANRIL had a predictive sensitivity of 62.9% and 88.6% and a specificity of 70.7% and 96.7% for the occurrence of UC cases, respectively, and a predictive sensitivity of 72.4% and 46.9% and a specificity of 96.7% and 34.7% for the occurrence of CD cases, respectively. CONCLUSIONS Both miR-199a and ANRIL are abundant in the sera of IBD adult Egyptian patients (UC and CD). Both can represent a noninvasive marker for early disease diagnosis.
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Affiliation(s)
- Randa Erfan
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Olfat G Shaker
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mahmoud A F Khalil
- Department of Microbiology and Immunology, Faculty of Pharmacy, Fayoum University, Fayoum, Egypt
| | - Fatma A M Mahmoud
- Department of Tropical Medicine, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Mohamed S Gomaa
- Department of General Medicine, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Abeer K Abu-El-Azayem
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Othman M Zaki
- Department of Clinical Pathology, Faculty of Medicine, Damietta University, Damietta, Egypt
| | - Azza M Ahmed
- Department of Rheumatology, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Amira Samy
- Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Asmaa Mohammed
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Fayoum University, Fayoum, Egypt
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Thacker N, Duncanson K, Eslick GD, Dutt S, O'Loughlin EV, Hoedt EC, Collins CE. Antibiotics, passive smoking, high socioeconomic status and sweetened foods contribute to the risk of paediatric inflammatory bowel disease: A systematic review with meta-analysis. J Pediatr Gastroenterol Nutr 2024; 79:610-621. [PMID: 39020449 DOI: 10.1002/jpn3.12303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 05/27/2024] [Accepted: 06/05/2024] [Indexed: 07/19/2024]
Abstract
OBJECTIVE Genetic and environmental factors influence pathogenesis and rising incidence of paediatric inflammatory bowel disease (PIBD). The aim was to meta-analyse evidence of diet and environmental factors in PIBD. METHODS A systematic search was conducted to identify diet and environmental factors with comparable risk outcome measures and had been reported in two or more PIBD studies for inclusion in meta-analyses. Those with ≥2 PIBD risk estimates were combined to provide pooled risk estimates. RESULTS Of 4763 studies identified, 36 studies were included. PIBD was associated with higher risk with exposure to ≥/=4 antibiotic courses (includes prescriptions/purchases/courses), passive smoking, not being breastfed, sugary drink intake, being a non-Caucasian child living in a high-income country and infection history (odds ratio [OR] range: 2-3.8). Paediatric Crohn's disease (CD) was associated with higher risk with exposure to antibiotics during early childhood, ≥/=4 antibiotic courses, high socioeconomic status (SES), maternal smoking, history of atopic conditions and infection history (OR range: 1.6-4.4). A history of infection was also associated with higher risk of paediatric ulcerative colitis (UC) (OR: 3.73). Having a higher number of siblings (≥2) was associated with lower risk of paediatric CD (OR: 0.6) and paediatric UC (OR: 0.7). Pet exposure was associated with lower risk of paediatric UC (OR: 0.5). CONCLUSION Several factors associated with PIBD risk were identified that could potentially be used to develop a disease screening tool. Future research is needed to address risk reduction in PIBD.
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Affiliation(s)
- Nisha Thacker
- School of Health Sciences, College of Health Medicine and Wellbeing, The University of Newcastle, Sydney, New South Wales, Australia
- Food and Nutrition Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia
| | - Kerith Duncanson
- Food and Nutrition Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia
- School of Medicine and Public Health, College of Health Medicine and Wellbeing, The University of Newcastle, Sydney, New South Wales, Australia
- NHMRC Centre of Research Excellence in Digestive Health, The University of Newcastle, Sydney, New South Wales, Australia
| | - Guy D Eslick
- NHMRC Centre of Research Excellence in Digestive Health, The University of Newcastle, Sydney, New South Wales, Australia
| | - Shoma Dutt
- Department of Gastroenterology, The Children's Hospital at Westmead, Sydney Children's Hospital Network, Westmead, New South Wales, Australia
- Children's Hospital at Westmead Clinical School, Sydney Medical Program, University of Sydney, Sydney, New South Wales, Australia
| | - Edward V O'Loughlin
- Department of Gastroenterology, The Children's Hospital at Westmead, Sydney Children's Hospital Network, Westmead, New South Wales, Australia
| | - Emily C Hoedt
- NHMRC Centre of Research Excellence in Digestive Health, The University of Newcastle, Sydney, New South Wales, Australia
- School of Biomedical Sciences and Pharmacy, College of Health Medicine and Wellbeing, The University of Newcastle, Sydney, New South Wales, Australia
| | - Clare E Collins
- School of Health Sciences, College of Health Medicine and Wellbeing, The University of Newcastle, Sydney, New South Wales, Australia
- Food and Nutrition Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia
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Wei S, Li M, Wang Q, Zhao Y, Du F, Chen Y, Deng S, Shen J, Wu K, Yang J, Sun Y, Gu L, Li X, Li W, Chen M, Ling X, Yu L, Xiao Z, Dong L, Wu X. Mesenchymal Stromal Cells: New Generation Treatment of Inflammatory Bowel Disease. J Inflamm Res 2024; 17:3307-3334. [PMID: 38800593 PMCID: PMC11128225 DOI: 10.2147/jir.s458103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 05/09/2024] [Indexed: 05/29/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract, which has a high recurrence rate and is incurable due to a lack of effective treatment. Mesenchymal stromal cells (MSCs) are a class of pluripotent stem cells that have recently received a lot of attention due to their strong self-renewal ability and immunomodulatory effects, and a large number of experimental and clinical models have confirmed the positive therapeutic effect of MSCs on IBD. In preclinical studies, MSC treatment for IBD relies on MSCs paracrine effects, cell-to-cell contact, and its mediated mitochondrial transfer for immune regulation. It also plays a therapeutic role in restoring the intestinal mucosal barrier through the homing effect, regulation of the intestinal microbiome, and repair of intestinal epithelial cells. In the latest clinical trials, the safety and efficacy of MSCs in the treatment of IBD have been confirmed by transfusion of autologous or allogeneic bone marrow, umbilical cord, and adipose MSCs, as well as their derived extracellular vesicles. However, regarding the stable and effective clinical use of MSCs, several concerns emerge, including the cell sources, clinical management (dose, route and frequency of administration, and pretreatment of MSCs) and adverse reactions. This article comprehensively summarizes the effects and mechanisms of MSCs in the treatment of IBD and its advantages over conventional drugs, as well as the latest clinical trial progress of MSCs in the treatment of IBD. The current challenges and future directions are also discussed. This review would add knowledge into the understanding of IBD treatment by applying MSCs.
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Affiliation(s)
- Shulin Wei
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Mingxing Li
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Qin Wang
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Yueshui Zhao
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Fukuan Du
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Yu Chen
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Shuai Deng
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Jing Shen
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Ke Wu
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Jiayue Yang
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Yuhong Sun
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Li Gu
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Xiaobing Li
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Wanping Li
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Meijuan Chen
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Xiao Ling
- Department of Obstetrics, Luzhou Maternal & Child Health Hospital (Luzhou Second People’s Hospital), Luzhou, Sichuan, 646100, People’s Republic of China
| | - Lei Yu
- Department of Obstetrics, Luzhou Maternal & Child Health Hospital (Luzhou Second People’s Hospital), Luzhou, Sichuan, 646100, People’s Republic of China
| | - Zhangang Xiao
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Lishu Dong
- Department of Obstetrics, Luzhou Maternal & Child Health Hospital (Luzhou Second People’s Hospital), Luzhou, Sichuan, 646100, People’s Republic of China
| | - Xu Wu
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
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Holcomb L, Holman JM, Hurd M, Lavoie B, Colucci L, Hunt B, Hunt T, Kinney M, Pathak J, Mawe GM, Moses PL, Perry E, Stratigakis A, Zhang T, Chen G, Ishaq SL, Li Y. Early life exposure to broccoli sprouts confers stronger protection against enterocolitis development in an immunological mouse model of inflammatory bowel disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.27.525953. [PMID: 36747766 PMCID: PMC9900910 DOI: 10.1101/2023.01.27.525953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Crohn's Disease (CD) is a presentation of Inflammatory Bowel Disease (IBD) that manifests in childhood and adolescence, and involves chronic and severe enterocolitis, immune and gut microbiome dysregulation, and other complications. Diet and gut-microbiota-produced metabolites are sources of anti-inflammatories which could ameliorate symptoms. However, questions remain on how IBD influences biogeographic patterns of microbial location and function in the gut, how early life transitional gut communities are affected by IBD and diet interventions, and how disruption to biogeography alters disease mediation by diet components or microbial metabolites. Many studies on diet and IBD use a chemically induced ulcerative colitis model, despite the availability of an immune-modulated CD model. Interleukin-10-knockout (IL-10-KO) mice on a C57BL/6 background, beginning at age 4 or 7 weeks, were fed a control diet or one containing 10% (w/w) raw broccoli sprouts, which was high in the sprout-sourced anti-inflammatory sulforaphane. Diets began 7 days prior to, and for 2 weeks after inoculation with Helicobacter hepaticus, which triggers Crohn's-like symptoms in these immune-impaired mice. The broccoli sprout diet increased sulforaphane in plasma; decreased weight stagnation, fecal blood, and diarrhea associated; and increased microbiota richness in the gut, especially in younger mice. Sprout diets resulted in some anatomically specific bacteria in younger mice, and reduced the prevalence and abundance of pathobiont bacteria which trigger inflammation in the IL-10-KO mouse, for example; Escherichia coli and Helicobacter. Overall, the IL-10-KO mouse model is responsive to a raw broccoli sprout diet and represents an opportunity for more diet-host-microbiome research.
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Affiliation(s)
- Lola Holcomb
- Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, Maine, USA 04469
| | - Johanna M. Holman
- School of Food and Agriculture, University of Maine, Orono, Maine, USA 04469
| | - Molly Hurd
- Larner College of Medicine, University of Vermont, Burlington, Vermont, USA 05401
| | - Brigitte Lavoie
- Larner College of Medicine, University of Vermont, Burlington, Vermont, USA 05401
| | - Louisa Colucci
- Department of Biology, Husson University, Bangor, Maine, USA 04401
| | - Benjamin Hunt
- Department of Biology, University of Maine, Orono, Maine, USA 04469
| | - Timothy Hunt
- Department of Biology, University of Maine, Orono, Maine, USA 04469
| | - Marissa Kinney
- School of Food and Agriculture, University of Maine, Orono, Maine, USA 04469
| | - Jahnavi Pathak
- Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, Maine, USA 04469
| | - Gary M. Mawe
- Larner College of Medicine, University of Vermont, Burlington, Vermont, USA 05401
| | - Peter L. Moses
- Larner College of Medicine, University of Vermont, Burlington, Vermont, USA 05401
- Finch Therapeutics, Somerville, Massachusetts, USA 02143
| | - Emma Perry
- Electron Microscopy Laboratory, University of Maine, Orono, Maine, USA 04469
| | - Allesandra Stratigakis
- School of Pharmacy and Pharmaceutical Sciences, SUNY Binghamton University, Johnson City, New York, USA 13790
| | - Tao Zhang
- School of Pharmacy and Pharmaceutical Sciences, SUNY Binghamton University, Johnson City, New York, USA 13790
| | - Grace Chen
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA 48109
| | - Suzanne L. Ishaq
- Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, Maine, USA 04469
| | - Yanyan Li
- Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, Maine, USA 04469
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Jamieson PE, Carbonero F, Stevens JF. Dietary (poly)phenols mitigate inflammatory bowel disease: Therapeutic targets, mechanisms of action, and clinical observations. Curr Res Food Sci 2023; 6:100521. [PMID: 37266414 PMCID: PMC10230173 DOI: 10.1016/j.crfs.2023.100521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 05/14/2023] [Accepted: 05/16/2023] [Indexed: 06/03/2023] Open
Abstract
Inflammatory bowel diseases (IBD), which include Crohn's disease and ulcerative colitis, are a rapidly growing public health concern worldwide. These diseases are heterogeneous at the clinical, immunological, molecular, genetic, and microbial level, but characteristically involve a disrupted immune-microbiome axis. Shortcomings in conventional treatment options warrant the need for novel therapeutic strategies to mitigate these life-long and relapsing disorders of the gastrointestinal tract. Polyphenols, a diverse group of phytochemicals, have gained attention as candidate treatments due to their array of biological effects. Polyphenols exert broad anti-inflammatory and antioxidant effects through the modulation of cellular signaling pathways and transcription factors important in IBD progression. Polyphenols also bidirectionally modulate the gut microbiome, supporting commensals and inhibiting pathogens. One of the primary means by which gut microbiota interface with the host is through the production of metabolites, which are small molecules produced as intermediate or end products of metabolism. There is growing evidence to support that modulation of the gut microbiome by polyphenols restores microbially derived metabolites critical to the maintenance of intestinal homeostasis that are adversely disrupted in IBD. This review aims to define the therapeutic targets of polyphenols that may be important for mitigation of IBD symptoms, as well as to collate evidence for their clinical use from randomized clinical trials.
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Affiliation(s)
- Paige E. Jamieson
- School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR, 97331, USA
- Linus Pauling Institute, Oregon State University, Corvallis, OR, 97331, USA
| | - Franck Carbonero
- Department of Nutrition and Exercise Physiology, Washington State University, Spokane, WA, 99202, USA
| | - Jan F. Stevens
- Linus Pauling Institute, Oregon State University, Corvallis, OR, 97331, USA
- Department of Pharmaceutical Sciences, Oregon State University, Corvallis, OR, 97331, USA
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8
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Mu C, Zhao Q, Zhao Q, Yang L, Pang X, Liu T, Li X, Wang B, Fung SY, Cao H. Multi-omics in Crohn's disease: New insights from inside. Comput Struct Biotechnol J 2023; 21:3054-3072. [PMID: 37273853 PMCID: PMC10238466 DOI: 10.1016/j.csbj.2023.05.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 05/10/2023] [Accepted: 05/11/2023] [Indexed: 06/06/2023] Open
Abstract
Crohn's disease (CD) is an inflammatory bowel disease (IBD) with complex clinical manifestations such as chronic diarrhea, weight loss and hematochezia. Despite the increasing incidence worldwide, cure of CD remains extremely difficult. The rapid development of high-throughput sequencing technology with integrated-omics analyses in recent years has provided a new means for exploring the pathogenesis, mining the biomarkers and designing targeted personalized therapeutics of CD. Host genomics and epigenomics unveil heredity-related mechanisms of susceptible individuals, while microbiome and metabolomics map host-microbe interactions in CD patients. Proteomics shows great potential in searching for promising biomarkers. Nonetheless, single omics technology cannot holistically connect the mechanisms with heterogeneity of pathological behavior in CD. The rise of multi-omics analysis integrates genetic/epigenetic profiles with protein/microbial metabolite functionality, providing new hope for comprehensive and in-depth exploration of CD. Herein, we emphasized the different omics features and applications of CD and discussed the current research and limitations of multi-omics in CD. This review will update and deepen our understanding of CD from integration of broad omics spectra and will provide new evidence for targeted individualized therapeutics.
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Affiliation(s)
- Chenlu Mu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Qianjing Zhao
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Qing Zhao
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Lijiao Yang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Xiaoqi Pang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Tianyu Liu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Xiaomeng Li
- Department of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Science, Tianjin Medical University, Tianjin, China
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Shan-Yu Fung
- Department of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Science, Tianjin Medical University, Tianjin, China
| | - Hailong Cao
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
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9
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Joustra V, Hageman IL, Satsangi J, Adams A, Ventham NT, de Jonge WJ, Henneman P, D’Haens GR, Li Yim AYF. Systematic Review and Meta-analysis of Peripheral Blood DNA Methylation Studies in Inflammatory Bowel Disease. J Crohns Colitis 2023; 17:185-198. [PMID: 35998097 PMCID: PMC10024549 DOI: 10.1093/ecco-jcc/jjac119] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Indexed: 12/23/2022]
Abstract
BACKGROUND AND AIMS Over the past decade, the DNA methylome has been increasingly studied in peripheral blood of inflammatory bowel disease [IBD] patients. However, a comprehensive summary and meta-analysis of peripheral blood leukocyte [PBL] DNA methylation studies has thus far not been conducted. Here, we systematically reviewed all available literature up to February 2022 and summarized the observations by means of meta-analysis. METHODS We conducted a systematic search and critical appraisal of IBD-associated DNA methylation studies in PBL using the biomarker-based cross-sectional studies [BIOCROSS] tool. Subsequently, we performed meta-analyses on the summary statistics obtained from epigenome-wide association studies [EWAS] that included patients with Crohn's disease [CD], ulcerative colitis [UC] and/or healthy controls [HC]. RESULTS Altogether, we included 15 studies for systematic review. Critical appraisal revealed large methodological and outcome heterogeneity between studies. Summary statistics were obtained from four studies based on a cumulative 552 samples [177 CD, 132 UC and 243 HC]. Consistent differential methylation was identified for 256 differentially methylated probes [DMPs; Bonferroni-adjusted p ≤ 0.05] when comparing CD with HC and 103 when comparing UC with HC. Comparing IBD [CD + UC] with HC resulted in 224 DMPs. Importantly, several of the previously identified DMPs, such as VMP1/TMEM49/MIR21 and RPS6KA2, were consistently differentially methylated across all studies. CONCLUSION Methodological homogenization of IBD epigenetic studies is needed to allow for easier aggregation and independent validation. Nonetheless, we were able to confirm previous observations. Our results can serve as the basis for future IBD epigenetic biomarker research in PBL.
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Affiliation(s)
| | | | - Jack Satsangi
- Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK
| | - Alex Adams
- Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK
| | - Nicholas T Ventham
- Institute of Genetics and Molecular Medicine, University of Edinburgh, UK
| | - Wouter J de Jonge
- Amsterdam UMC location University of Amsterdam, Department of Gastroenterology and Hepatology, Meibergdreef 9, Amsterdam, Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, Netherlands
- Amsterdam UMC location University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam, Netherlands
| | - Peter Henneman
- Amsterdam UMC location University of Amsterdam, Department of Human Genetics, Genome Diagnostics Laboratory, Amsterdam, Netherlands
- Amsterdam Reproduction & Development, Amsterdam, Netherlands
| | - Geert R D’Haens
- Amsterdam UMC location University of Amsterdam, Department of Gastroenterology and Hepatology, Meibergdreef 9, Amsterdam, Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, Netherlands
| | - Andrew Y F Li Yim
- Corresponding author: Andrew Y. F. Li Yim, Amsterdam UMC location University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam, Netherlands.
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10
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Dipasquale V, Romano C. Genes vs environment in inflammatory bowel disease: an update. Expert Rev Clin Immunol 2022; 18:1005-1013. [PMID: 35912838 DOI: 10.1080/1744666x.2022.2108407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 07/28/2022] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Inflammatory bowel diseases (IBDs) are known to be caused by a combination of genetic and environmental factors that vary in their influence on the development of the disease. Environmental exposures seem to influence IBD susceptibility, whereas genetic background is thought to modulate the impact of the environment on disease course and phenotype. AREAS COVERED A broad review of the involvement of genes and the environment in IBD pathogenesis was performed, and information regarding the main genetic and environmental factors - categorized into lifestyle factors, drugs, diet, and microbes - was updated. Monogenic very early onset IBD (VEO-IBD) was also discussed. EXPERT OPINION In the upcoming years, better understanding of gene-environment interactions will contribute to the possibility of a better prediction of disease course, response to therapy, and therapy-related adverse events with the final goal of personalized and more efficient patient management.
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Affiliation(s)
- Valeria Dipasquale
- Pediatric Gastroenterology and Cystic Fibrosis Unit, Department of Human Pathology in Adulthood and Childhood 'G. Barresi,' University of Messina, Messina, Italy
| | - Claudio Romano
- Pediatric Gastroenterology and Cystic Fibrosis Unit, Department of Human Pathology in Adulthood and Childhood 'G. Barresi,' University of Messina, Messina, Italy
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11
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Renuzza SSS, Vieira ER, Cornel CA, Lima MN, Ramos Junior O. INCIDENCE, PREVALENCE, AND EPIDEMIOLOGICAL CHARACTERISTICS OF INFLAMMATORY BOWEL DISEASES IN THE STATE OF PARANÁ IN SOUTHERN BRAZIL. ARQUIVOS DE GASTROENTEROLOGIA 2022; 59:327-333. [PMID: 36102427 DOI: 10.1590/s0004-2803.202203000-60] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 04/25/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND The epidemiology of inflammatory bowel diseases (IBD) varies between different regions of Brazil. This cross-sectional study examined the epidemiological characteristics of IBD in the Southern Brazilian state of Paraná. METHODS We included patients with IBD (n=6.748) selected across 11,468,818 population of Paraná. All patients had a known diagnosis of either Crohn's disease (CD) or ulcerative colitis (UC) and had started treatment through the Government Program of the Brazilian Unified Health System (2010-2019). The primary outcomes were changes in the incidence and prevalence rates of IBD. RESULTS The study population consisted of 4.931 (73.1%) patients with UC and 1.817 (26.9%) patients with CD. In participants aged 11-30 years, CD was more common, while in participants aged 40-80 years, UC predominated. UC was more common in female compared to male patients, with a similar incidence between the sexes evident for CD. In 2010, the incidence of IBD was 2.00/100,00 population; this increased to 13.77/100,000 population by 2019. The highest concentration of IBD patients was found in the eastern macro-region of Paraná, which includes the 2nd Health Regional of Curitiba, where the capital of the state is located. CONCLUSION This is the first study to describe the epidemiological characteristics of IBD in the state of Paraná and showed an increase in its incidence and prevalence. We also identified that IBD was concentrated in the eastern macro-region of this Brazilian state.
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Affiliation(s)
| | - Elizabete Regina Vieira
- Universidade Federal do Paraná, Programa de Pós-Graduação em Medicina Interna e Ciências da Saúde, Curitiba, PR, Brasil
| | - César Augusto Cornel
- Universidade Federal do Paraná, Programa de Pós-Graduação em Medicina Interna e Ciências da Saúde, Curitiba, PR, Brasil
| | - Mônica Nunes Lima
- Universidade Federal do Paraná, Programa de Pós-Graduação em Medicina Interna e Ciências da Saúde, Curitiba, PR, Brasil
| | - Odery Ramos Junior
- Universidade Federal do Paraná, Programa de Pós-Graduação em Medicina Interna e Ciências da Saúde, Curitiba, PR, Brasil
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12
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Gordon H, Blad W, Trier Møller F, Orchard T, Steel A, Trevelyan G, Ng S, Harbord M. UK IBD Twin Registry: Concordance and Environmental Risk Factors of Twins with IBD. Dig Dis Sci 2022; 67:2444-2450. [PMID: 34097167 DOI: 10.1007/s10620-021-07080-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 05/26/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS Twin studies have long been used to infer heritability. Within the 'omics era, twin cohorts have even greater research potential. This study describes the formation of the UK IBD Twin Registry and analysis of concordance and environmental factors. METHOD Twin pairs with IBD were recruited by advertising via IBD charities and social media, re-tracing a dormant IBD database and clinician referral. Details of zygosity, concordance, disease history and environmental factors were assessed. Pair concordance was calculated, and environmental factors were analysed with logistic regression models adjusted for zygosity and concordance. RESULTS Ninety-one twin pairs were included in the analysis; forty-two with CD and forty-nine with UC. More MZ twin pairs with CD were concordant compared with DZ pairs, thus inferring heritability (Chi-sq. 15.6. P < 0.001). In UC, MZ concordance was also numerically greater. Cigarette smoking was predictive of CD (OR 2.66, 95% CI 1.16 to 6.07 P = 0.02); there may be an independent association with cannabis smoking (OR 2.59 95% CI 0.89 to 7.55 P = 0.08). Breastfeeding was protective against UC (OR 0.48, 95% CI 0.25-0.93, P = 0.03), but not CD. Self-reports of less occurrences of gastroenteritis than peers were protective against future UC onset (OR 0.33 95% CI 0.15 to 0.74, P = 0.01). Method of delivery, parental attitudes towards hygiene and recall of diet did not impact future IBD concordance. CONCLUSIONS This study supports the heritability of IBD. Twin study analysis was able to elucidate environmental factors associated with IBD.
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Affiliation(s)
- Hannah Gordon
- Department of Gastroenterology, Royal London Hospital, Whitechapel Rd, Whitechapel, London, E1 1FR, UK.
| | - William Blad
- Department of Gastroenterology, Royal London Hospital, Whitechapel Rd, Whitechapel, London, E1 1FR, UK
| | - Frederik Trier Møller
- Department of Gastroenterology, Royal London Hospital, Whitechapel Rd, Whitechapel, London, E1 1FR, UK
| | - Timothy Orchard
- Department of Gastroenterology, Royal London Hospital, Whitechapel Rd, Whitechapel, London, E1 1FR, UK
| | - Alan Steel
- Department of Gastroenterology, Royal London Hospital, Whitechapel Rd, Whitechapel, London, E1 1FR, UK
| | - Gareth Trevelyan
- Department of Gastroenterology, Royal London Hospital, Whitechapel Rd, Whitechapel, London, E1 1FR, UK
| | - Siew Ng
- Department of Gastroenterology, Royal London Hospital, Whitechapel Rd, Whitechapel, London, E1 1FR, UK
| | - Marcus Harbord
- Department of Gastroenterology, Royal London Hospital, Whitechapel Rd, Whitechapel, London, E1 1FR, UK
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13
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Abstract
Current practice in IBD is to classify patients based on clinical signs and symptoms and provide treatments accordingly. However, the response of IBD patients to available treatments is highly variable, highlighting clinically significant heterogeneity among patients. Thus, more accurate patient stratification is urgently needed to more effectively target therapeutic interventions to specific patients. Here we review the degree of heterogeneity in IBD, discussing how the microbiota, genetics, and immune system may contribute to the variation among patients. We highlight how molecular heterogeneity may relate to clinical phenotype, but in other situations may be independent of clinical phenotype, encouraging future studies to fill the gaps. Finally, we discuss novel stratification methodologies as a foundation for precision medicine, in particular a novel stratification strategy based on conserved genes across species. All of these dimensions of heterogeneity have potential to provide strategies for patient stratification and move IBD practice towards personalised medicine.
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Affiliation(s)
- Katja A Selin
- Division of Immunology and Allergy, Department of Medicine, Solna, Karolinska Institutet and University Hospital, Stockholm, Sweden
- Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
- Gastroenterology Unit, Patient Area Gastroenterology, Dermatovenereology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine, Solna, Division of Clinical Medicine, Karolinska Institutet, Solna, Sweden
| | - Charlotte R H Hedin
- Gastroenterology Unit, Patient Area Gastroenterology, Dermatovenereology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine, Solna, Division of Clinical Medicine, Karolinska Institutet, Solna, Sweden
| | - Eduardo J Villablanca
- Division of Immunology and Allergy, Department of Medicine, Solna, Karolinska Institutet and University Hospital, Stockholm, Sweden
- Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Medicine, Solna, Division of Clinical Medicine, Karolinska Institutet, Solna, Sweden
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14
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Enck P, Goebel-Stengel M, Rieß O, Hübener-Schmid J, Kagan KO, Nieß AM, Tümmers H, Wiesing U, Zipfel S, Stengel A. [Twin research in Germany]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2021; 64:1298-1306. [PMID: 34524474 PMCID: PMC8441034 DOI: 10.1007/s00103-021-03400-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 07/23/2021] [Indexed: 12/16/2022]
Abstract
Nach dem Zweiten Weltkrieg wurden weltweit Zwillingskohorten aufgebaut, die inzwischen ca. 1,5 Mio. Zwillinge umfassen und zwischen 1950 und 2012 über 2748 Zwillingsstudien hervorgebracht haben. Diese Zahl steigt jedes Jahr um weitere 500 bis 1000. Die Unterrepräsentanz deutscher Zwillingsstudien in diesen Datenbanken lässt sich nicht allein durch den Missbrauch medizinischer Forschung im Nationalsozialismus erklären. Entwicklung und Ausbau großer Zwillingskohorten sind ethisch und datenschutzrechtlich eine Herausforderung. Zwillingskohorten ermöglichen jedoch die Langzeit- und Echtzeiterforschung vieler medizinischer Fragestellungen; und die Zwillingsstudien tragen auch nach der Entschlüsselung des Humangenoms erheblich zur Beantwortung der Frage nach Anlage oder Umwelt als mögliche Erkrankungsauslöser bei. Derzeit gibt es 2 deutsche Zwillingskohorten: die biomedizinische Kohorte HealthTwiSt mit ca. 1500 Zwillingspaaren und TwinLife, eine soziologisch-psychologische Kohorte mit ca. 4000 Zwillingspaaren. Daneben gibt es krankheitsspezifische Kohorten. 2016 startete das TwinHealth-Konsortium der Medizinischen Fakultät der Universität Tübingen mit dem Ziel, eine forschungsoffene und nachhaltige Zwillingsforschung am Standort Tübingen zur Bearbeitung unterschiedlicher Fragestellungen zu etablieren. Der Artikel bietet mithilfe einer systematischen Literaturrecherche und einer medizinhistorischen Betrachtung einen Überblick über die weltweite und nationale Entwicklung von Zwillingsstudien und -datenbanken der letzten 100 Jahre. Anhand der Tübinger TwinHealth-Initiative beleuchtet er den Aufbau eines Zwillingskollektivs und dessen juristische, ethische und Datenschutzaspekte.
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Affiliation(s)
- Paul Enck
- Innere Medizin VI, Psychosomatische Medizin und Psychotherapie, Universitätsklinikum Tübingen, Osianderstr. 5, 72076, Tübingen, Deutschland
| | - Miriam Goebel-Stengel
- Innere Medizin VI, Psychosomatische Medizin und Psychotherapie, Universitätsklinikum Tübingen, Osianderstr. 5, 72076, Tübingen, Deutschland. .,Klinik für Innere Medizin, Helios Klinik Rottweil, Rottweil, Deutschland.
| | - Olaf Rieß
- Institut für Medizinische Genetik und Angewandte Genomik, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | - Jeannette Hübener-Schmid
- Institut für Medizinische Genetik und Angewandte Genomik, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | - Karl Oliver Kagan
- Department für Frauengesundheit, Universitäts-Frauenklinik, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | - Andreas Michael Nieß
- Innere Medizin V, Sportmedizin, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | - Henning Tümmers
- Institut für Ethik und Geschichte der Medizin, Universität Tübingen, Tübingen, Deutschland
| | - Urban Wiesing
- Institut für Ethik und Geschichte der Medizin, Universität Tübingen, Tübingen, Deutschland
| | - Stephan Zipfel
- Innere Medizin VI, Psychosomatische Medizin und Psychotherapie, Universitätsklinikum Tübingen, Osianderstr. 5, 72076, Tübingen, Deutschland
| | - Andreas Stengel
- Innere Medizin VI, Psychosomatische Medizin und Psychotherapie, Universitätsklinikum Tübingen, Osianderstr. 5, 72076, Tübingen, Deutschland
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15
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Jung H, Kim JS, Lee KH, Tizaoui K, Terrazzino S, Cargnin S, Smith L, Koyanagi A, Jacob L, Li H, Hong SH, Yon DK, Lee SW, Kim MS, Wasuwanich P, Karnsakul W, Shin JI, Kronbichler A. Roles of microRNAs in inflammatory bowel disease. Int J Biol Sci 2021; 17:2112-2123. [PMID: 34131410 PMCID: PMC8193269 DOI: 10.7150/ijbs.59904] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 05/08/2021] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract that mainly affects young people. IBD is associated with various gastrointestinal symptoms, and thus, affects the quality of life of patients. Currently, the pathogenesis of IBD is poorly understood. Although intestinal bacteria and host immune response are thought to be major factors in its pathogenesis, a sufficient explanation of their role in its pathophysiologic mechanism has not been presented. MicroRNAs (miRNAs), which are small RNA molecules that regulate gene expression, have gained attention as they are known to participate in the molecular interactions of IBD. Recent studies have confirmed the important role of miRNAs in targeting certain molecules in signaling pathways that regulate the homeostasis of the intestinal barrier, inflammatory reactions, and autophagy of the intestinal epithelium. Several studies have identified the specific miRNAs associated with IBD from colon tissues or serum samples of IBD patients and have attempted to use them as useful diagnostic biomarkers. Furthermore, some studies have attempted to treat IBD through intracolonic administration of specific miRNAs in the form of nanoparticle. This review summarizes the latest findings on the role of miRNAs in the pathogenesis, diagnosis, and treatment of IBD.
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Affiliation(s)
- HyunTaek Jung
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jae Seok Kim
- Department of Nephrology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Keum Hwa Lee
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Kalthoum Tizaoui
- Laboratory Microorganisms and Active Biomolecules, Sciences Faculty of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Salvatore Terrazzino
- Department of Pharmaceutical Sciences and Interdepartmental Research Center of Pharmacogenetics and Pharmacogenomics (CRIFF), University of Piemonte Orientale, Novara, Italy
| | - Sarah Cargnin
- Department of Pharmaceutical Sciences and Interdepartmental Research Center of Pharmacogenetics and Pharmacogenomics (CRIFF), University of Piemonte Orientale, Novara, Italy
| | - Lee Smith
- The Cambridge Centre for Sport and Exercise Science, Anglia Ruskin University, Cambridge, CB1 1PT, UK
| | - Ai Koyanagi
- Research and Development Unit, Parc Sanitari Sant Joan de Déu, CIBERSAM, 08830 Barcelona, Spain.,ICREA, Pg. Lluis Companys 23, 08010 Barcelona, Spain
| | - Louis Jacob
- Research and Development Unit, Parc Sanitari Sant Joan de Déu, CIBERSAM, 08830 Barcelona, Spain.,Faculty of Medicine, University of Versailles Saint-Quentin-en-Yvelines, 78000 Versailles, France
| | - Han Li
- University of Florida College of Medicine, Gainesville, FL 32610, USA
| | - Sung Hwi Hong
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Dong Keon Yon
- Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Seung Won Lee
- Department of Data Science, Sejong University College of Software Convergence, Seoul, Republic of Korea
| | - Min Seo Kim
- Korea University, College of Medicine, Seoul, Republic of Korea
| | - Paul Wasuwanich
- University of Florida College of Medicine, Gainesville, FL 32610, USA
| | - Wikrom Karnsakul
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Jae Il Shin
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Andreas Kronbichler
- Department of Internal Medicine IV (Nephrology and Hypertension), Medical University Innsbruck, Innsbruck, Austria
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16
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Kamperidis N, Kamperidis V, Zegkos T, Kostourou I, Nikolaidou O, Arebi N, Karvounis H. Atherosclerosis and Inflammatory Bowel Disease-Shared Pathogenesis and Implications for Treatment. Angiology 2020; 72:303-314. [PMID: 33601945 DOI: 10.1177/0003319720974552] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Atherosclerosis and inflammatory bowel disease (IBD) are often regarded as 2 distinct entities. The commonest manifestation of atherosclerosis is ischemic heart disease (IHD), and an association between IHD and IBD has been reported. Atherosclerosis and IBD share common pathophysiological mechanisms in terms of their genetics, immunology, and contributing environmental factors. Factors associated with atherosclerosis are implicated in the development of IBD and vice versa. Therefore, treatments targeting the common pathophysiology pathways may be effective in both conditions. The current review considers the pathophysiological pathways that are shared between the 2 conditions and discusses the implications for treatment and research.
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Affiliation(s)
- Nikolaos Kamperidis
- 3749St Mark's Hospital, Harrow, London, United Kingdom.,* Nikolaos Kamperidis and Vasileios Kamperidis are sharing first authorship
| | - Vasileios Kamperidis
- 1st Cardiology Department, 37788AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.,* Nikolaos Kamperidis and Vasileios Kamperidis are sharing first authorship
| | - Thomas Zegkos
- 1st Cardiology Department, 37788AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | | | - Olga Nikolaidou
- Radiology Department, Pananikolaou General Hospital, Thessaloniki, Greece
| | - Naila Arebi
- 3749St Mark's Hospital, Harrow, London, United Kingdom
| | - Haralambos Karvounis
- 1st Cardiology Department, 37788AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
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17
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Mishra R, Dhawan P, Srivastava AS, Singh AB. Inflammatory bowel disease: Therapeutic limitations and prospective of the stem cell therapy. World J Stem Cells 2020; 12:1050-1066. [PMID: 33178391 PMCID: PMC7596447 DOI: 10.4252/wjsc.v12.i10.1050] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 06/02/2020] [Accepted: 09/22/2020] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD), consisting primarily of ulcerative colitis and Crohn’s disease, is a group of debilitating auto-immune disorders, which also increases the risk of colitis-associated cancer. However, due to the chronic nature of the disease and inconsistent treatment outcomes of current anti-IBD drugs (e.g., approximately 30% non-responders to anti-TNFα agents), and related serious side effects, about half of all IBD patients (in millions) turn to alternative treatment options. In this regard, mucosal healing is gaining acceptance as a measure of disease activity in IBD patients as recent studies have correlated the success of mucosal healing with improved prognosis. However, despite the increasing clinical realization of the significance of the concept of mucosal healing, its regulation and means of therapeutic targeting remain largely unclear. Here, stem-cell therapy, which uses hematopoietic stem cells or mesenchymal stem cells, remains a promising option. Stem cells are the pluripotent cells with ability to differentiate into the epithelial and/or immune-modulatory cells. The over-reaching concept is that the stem cells can migrate to the damaged areas of the intestine to provide curative help in the mucosal healing process. Moreover, by differentiating into the mature intestinal epithelial cells, the stem cells also help in restoring the barrier integrity of the intestinal lining and hence prevent the immunomodulatory induction, the root cause of the IBD. In this article, we elaborate upon the current status of the clinical management of IBD and potential role of the stem cell therapy in improving IBD therapy and patient’s quality of life.
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Affiliation(s)
- Rangnath Mishra
- Global Institute of Stem Cell Therapy and Research, San Diego, CA 92122, United States
| | - Punita Dhawan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68118, United States
- Fred and Pamela Buffett Cancer Center, Omaha, NE 68118, United States
- VA Nebraska-Western Iowa Health Care System, Omaha, NE 68118, United States
| | - Anand S Srivastava
- Global Institute of Stem Cell Therapy and Research, San Diego, CA 92122, United States
| | - Amar B Singh
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68118, United States
- Fred and Pamela Buffett Cancer Center, Omaha, NE 68118, United States
- VA Nebraska-Western Iowa Health Care System, Omaha, NE 68118, United States
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18
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Mifflin L, Ofengeim D, Yuan J. Receptor-interacting protein kinase 1 (RIPK1) as a therapeutic target. Nat Rev Drug Discov 2020; 19:553-571. [PMID: 32669658 PMCID: PMC7362612 DOI: 10.1038/s41573-020-0071-y] [Citation(s) in RCA: 295] [Impact Index Per Article: 59.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/20/2020] [Indexed: 02/08/2023]
Abstract
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a key mediator of cell death and inflammation. The unique hydrophobic pocket in the allosteric regulatory domain of RIPK1 has enabled the development of highly selective small-molecule inhibitors of its kinase activity, which have demonstrated safety in preclinical models and clinical trials. Potential applications of these RIPK1 inhibitors for the treatment of monogenic and polygenic autoimmune, inflammatory, neurodegenerative, ischaemic and acute conditions, such as sepsis, are emerging. This article reviews RIPK1 biology and disease-associated mutations in RIPK1 signalling pathways, highlighting clinical trials of RIPK1 inhibitors and potential strategies to mitigate development challenges. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) — a key mediator of cell death and inflammation — is activated in human diseases. Here, Yuan and colleagues discuss current understanding of RIPK1 biology and its association with diseases including inflammatory and autoimmune disorders, neurodegenerative diseases and sepsis. The clinical development of small-molecule RIPK1 inhibitors and associated challenges are discussed.
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Affiliation(s)
- Lauren Mifflin
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Dimitry Ofengeim
- Rare and Neurologic Disease Research, Sanofi, Framingham, MA, USA
| | - Junying Yuan
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
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19
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Abstract
Lay Summary
A person’s diet may impact inflammatory bowel disease (IBD) risk. IBD is an inflammatory condition. We explore how certain foods may trigger, or indeed attenuate, inflammation in some IBD patients, but not others. Greater knowledge is needed underpinning personalized nutrition within effective medical management.
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Affiliation(s)
- Colm B Collins
- UCD School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
| | - Helen M Roche
- Nutrigenomics Research Group, School of Public Health, Physiotherapy and Sports Science, UCD Institute of Food and Health, Diabetes Complications Research Centre, University College Dublin, Dublin, Ireland,Institute for Global Food Security, Queen’s University Belfast, Northern Ireland, UK,Address correspondence to: Helen M. Roche, PhD, UCD Conway Institute and School of Public Health, Physiotherapy and Sports Science, University College Dublin, Belfield, Dublin 4, Ireland ()
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20
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Annese V. Genetics and epigenetics of IBD. Pharmacol Res 2020; 159:104892. [PMID: 32464322 DOI: 10.1016/j.phrs.2020.104892] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 05/03/2020] [Accepted: 05/03/2020] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel diseases (IBD) are chronic intermittent inflammatory disorders of the gastrointestinal tract of unknown etiology but a clear genetic predisposition. Prompted by the first investigations on IBD families and twins, the genetic and epigenetic studies have produced an unprecedented amount of information in comparison with other immune-mediated or complex diseases. New inflammatory pathways and possible mechanisms of action have been disclosed, potentially leading to new-targeted therapy. However, the identification of genetic markers due to the great disease heterogeneity and the overwhelming contribution of environmental risk factors has not modified yet the disease management. The possibility for the future of a better prediction of disease course, response to therapy and therapy-related adverse events may allow a more efficient and personalized strategy. This review will focus on more recent discoveries that may potentially be of relevance in daily clinical practice.
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Affiliation(s)
- Vito Annese
- Head of Gastroenterology and Medical Director, Valiant Clinic, Dubai, United Arab Emirates; CBP American Hospital, Dubai, United Arab Emirates; Aggregate Professor United Arabian Emirates University, College of Medicine & Health Science, Al Ain, United Arab Emirates.
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21
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Epidemiologische Forschung und Behandlungsdatenanalyse zu chronisch-entzündlichen Darmerkrankungen. Monatsschr Kinderheilkd 2020. [DOI: 10.1007/s00112-020-00852-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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22
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Borg-Bartolo SP, Boyapati RK, Satsangi J, Kalla R. Precision medicine in inflammatory bowel disease: concept, progress and challenges. F1000Res 2020; 9:F1000 Faculty Rev-54. [PMID: 32047622 PMCID: PMC6993839 DOI: 10.12688/f1000research.20928.1] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/16/2020] [Indexed: 12/12/2022] Open
Abstract
Crohn's disease and ulcerative colitis are increasingly prevalent, relapsing and remitting inflammatory bowel diseases (IBDs) with variable disease courses and complications. Their aetiology remains unclear but current evidence shows an increasingly complex pathophysiology broadly centring on the genome, exposome, microbiome and immunome. Our increased understanding of disease pathogenesis is providing an ever-expanding arsenal of therapeutic options, but these can be expensive and patients can lose response or never respond to certain therapies. Therefore, there is now a growing need to personalise therapies on the basis of the underlying disease biology and a desire to shift our approach from "reactive" management driven by disease complications to "proactive" care with an aim to prevent disease sequelae. Precision medicine is the tailoring of medical treatment to the individual patient, encompassing a multitude of data-driven (and multi-omic) approaches to foster accurate clinical decision-making. In IBD, precision medicine would have significant benefits, enabling timely therapy that is both effective and appropriate for the individual. In this review, we summarise some of the key areas of progress towards precision medicine, including predicting disease susceptibility and its course, personalising therapies in IBD and monitoring response to therapy. We also highlight some of the challenges to be overcome in order to deliver this approach.
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Affiliation(s)
- Simon P. Borg-Bartolo
- Department of Gastroenterology, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Southmoor Road, Wythenshawe, Manchester, M23 9LT, UK
| | - Ray Kiran Boyapati
- Department of Gastroenterology, Monash Health, Clayton, Victoria, Australia
- Faculty of Medicine, Nursing & Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Jack Satsangi
- Translational Gastroenterology Unit, Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Rahul Kalla
- Department of Gastroenterology, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh, EH16 4SA, UK
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23
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Valmiki S, Ahuja V, Puri N, Paul J. miR-125b and miR-223 Contribute to Inflammation by Targeting the Key Molecules of NFκB Pathway. Front Med (Lausanne) 2020; 6:313. [PMID: 32039213 PMCID: PMC6990118 DOI: 10.3389/fmed.2019.00313] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 12/11/2019] [Indexed: 12/12/2022] Open
Abstract
The contribution of miRNA in the pathogenesis of ulcerative colitis (UC) has emerged in the past few decades. Differential miRNA expression has been demonstrated in UC patients, and their ability to target the genes involved in inflammatory pathway has also been explored in recent years. miR-125b and miR-223 have been demonstrated to get upregulated within the colonic mucosa of UC patients. Here, we explored the biological relevance of miR-125b and miR-223 altered expression during UC by identifying the potential gene targets for miR-125b and miR-223. TRAF6 and A20, the signaling molecules involved in the NFκB pathway, were identified as target genes for miR-125b while IKKα was identified as a gene target for miR-223. The colonic mucosal samples from UC patients exhibited a significant rise in miR-125b and miR-223 expression while a subsequent downregulation was observed in the expression of TRAF6, A20, and IKKα. This negative correlation between miRNAs and their respective target genes was validated by co-transfecting miR-125b and miR-223 in HT29 cells. Co-transfection with miR-125b resulted in a marked decline in the expression of TRAF6 and A20, while the miR-223 co-transfected cells exhibited lower IKKα expression levels. Additionally, co-transfection with miR-125b or miR-223 in HT29 cells caused higher p65 and pro-inflammatory cytokines (IL-8 and IL-1β) expression upon LPS stimulation. From our findings, we highlight the possible contribution of miR-125b and miR-223 in regulating the inflammatory response during UC by negatively regulating the expression of TRAF6, A20, and IKKα. Therefore, we conclude that these two miRNAs could be considered as potential candidates for developing promising biomarkers for screening and diagnosis of UC.
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Affiliation(s)
- Swati Valmiki
- School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Vineet Ahuja
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Niti Puri
- School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Jaishree Paul
- School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
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24
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Sharifi A, Vahedi H, Honarvar MR, Alipoor B, Nikniaz Z, Rafiei H, Hosseinzadeh-Attar MJ. Vitamin D Increases CTLA-4 Gene Expression in Patients with Mild to Moderate Ulcerative Colitis. Middle East J Dig Dis 2019; 11:199-204. [PMID: 31824622 PMCID: PMC6895856 DOI: 10.15171/mejdd.2019.149] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Accepted: 08/14/2019] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Ulcerative colitis (UC) is a chronic inflammatory disorder of the large intestine. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a member of the immunoglobulin superfamily, which binds B7-1 and B7-2 on APCs (antigen-presenting cells), and induces APCs to produce an inhibitory signal to T cells. The aim of this study was to investigate the effect of vitamin D on CTLA-4 gene expression in whole blood samples of patients with UC. METHODS 90 patients with mild to moderate UC were randomized to receive either a single injection of 7.5 mg vitamin D3 or 1 mL normal saline. 90 days following the intervention fold changes in CTLA-4 mRNA expression were determined and statistical comparisons between the two groups were performed. RESULTS Serum vitamin D increased significantly only in the vitamin D group. CTLA-4 fold changes were significantly higher in the vitamin D group compared with the placebo group (median ± IQR: 1.21 ± 2.3 vs. 1.00 ± 1.5, respectively; p = 0.007). CONCLUSION The results of this study revealed that vitamin D administration in patients with UC enhances the CTLA-4 gene expression.
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Affiliation(s)
- Amrollah Sharifi
- Assistant Professor; Golestan Research Center of Gastroenterology and Hepatology (GRCGH), Faculty of health, Golestan University of Medical Sciences (GOUMS), Gorgan, Iran
| | - Homayoon Vahedi
- Associate Professor; Digestive Disease Research Center, Digestive Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Honarvar
- Assistant Professor, Health Management and Social Development Research Center, Faculty of Health, Golestan University of Medical Sciences, Gorgan, Iran
| | - Behnam Alipoor
- Assistant Professor; Department of Laboratory Sciences, Faculty of Paramedicine, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Zeinab Nikniaz
- Assistant Professor; Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hossein Rafiei
- Faculty of Health and Social Development, College of Health and Exercise Sciences, University of British Columbia Okanagan, Kelowna, BC, Canada
| | - Mohammad Javad Hosseinzadeh-Attar
- Professor; Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
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25
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Interactions between taste receptors and the gastrointestinal microbiome in inflammatory bowel disease. JOURNAL OF NUTRITION & INTERMEDIARY METABOLISM 2019. [DOI: 10.1016/j.jnim.2019.100106] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
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26
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Inflammatory Bowel Disease: A Stressed "Gut/Feeling". Cells 2019; 8:cells8070659. [PMID: 31262067 PMCID: PMC6678997 DOI: 10.3390/cells8070659] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 06/22/2019] [Accepted: 06/28/2019] [Indexed: 12/21/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic and relapsing intestinal inflammatory condition, hallmarked by a disturbance in the bidirectional interaction between gut and brain. In general, the gut/brain axis involves direct and/or indirect communication via the central and enteric nervous system, host innate immune system, and particularly the gut microbiota. This complex interaction implies that IBD is a complex multifactorial disease. There is increasing evidence that stress adversely affects the gut/microbiota/brain axis by altering intestinal mucosa permeability and cytokine secretion, thereby influencing the relapse risk and disease severity of IBD. Given the recurrent nature, therapeutic strategies particularly aim at achieving and maintaining remission of the disease. Alternatively, these strategies focus on preventing permanent bowel damage and concomitant long-term complications. In this review, we discuss the gut/microbiota/brain interplay with respect to chronic inflammation of the gastrointestinal tract and particularly shed light on the role of stress. Hence, we evaluated the therapeutic impact of stress management in IBD.
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27
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Garcia-Carbonell R, Yao SJ, Das S, Guma M. Dysregulation of Intestinal Epithelial Cell RIPK Pathways Promotes Chronic Inflammation in the IBD Gut. Front Immunol 2019; 10:1094. [PMID: 31164887 PMCID: PMC6536010 DOI: 10.3389/fimmu.2019.01094] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 04/29/2019] [Indexed: 12/22/2022] Open
Abstract
Crohn's disease (CD) and ulcerative colitis (UC) are common intestinal bowel diseases (IBD) characterized by intestinal epithelial injury including extensive epithelial cell death, mucosal erosion, ulceration, and crypt abscess formation. Several factors including activated signaling pathways, microbial dysbiosis, and immune deregulation contribute to disease progression. Although most research efforts to date have focused on immune cells, it is becoming increasingly clear that intestinal epithelial cells (IEC) are important players in IBD pathogenesis. Aberrant or exacerbated responses to how IEC sense IBD-associated microbes, respond to TNF stimulation, and regenerate and heal the injured mucosa are critical to the integrity of the intestinal barrier. The role of several genes and pathways in which single nucleotide polymorphisms (SNP) showed strong association with IBD has recently been studied in the context of IEC. In patients with IBD, it has been shown that the expression of specific dysregulated genes in IECs plays an important role in TNF-induced cell death and microbial sensing. Among them, the NF-κB pathway and its target gene TNFAIP3 promote TNF-induced and receptor interacting protein kinase (RIPK1)-dependent intestinal epithelial cell death. On the other hand, RIPK2 functions as a key signaling protein in host defense responses induced by activation of the cytosolic microbial sensors nucleotide-binding oligomerization domain-containing proteins 1 and 2 (NOD1 and NOD2). The RIPK2-mediated signaling pathway leads to the activation of NF-κB and MAP kinases that induce autophagy following infection. This article will review these dysregulated RIPK pathways in IEC and their role in promoting chronic inflammation. It will also highlight future research directions and therapeutic approaches involving RIPKs in IBD.
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Affiliation(s)
| | - Shih-Jing Yao
- Department of Pathology, University of California, San Diego, San Diego, CA, United States
| | - Soumita Das
- Department of Pathology, University of California, San Diego, San Diego, CA, United States
| | - Monica Guma
- Medicine, School of Medicine, University of California, San Diego, San Diego, CA, United States
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28
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Alagón Fernández Del Campo P, De Orta Pando A, Straface JI, López Vega JR, Toledo Plata D, Niezen Lugo SF, Alvarez Hernández D, Barrientos Fortes T, Gutiérrez-Kobeh L, Solano-Gálvez SG, Vázquez-López R. The Use of Probiotic Therapy to Modulate the Gut Microbiota and Dendritic Cell Responses in Inflammatory Bowel Diseases. ACTA ACUST UNITED AC 2019; 7:medsci7020033. [PMID: 30813381 PMCID: PMC6410300 DOI: 10.3390/medsci7020033] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 01/28/2019] [Accepted: 02/13/2019] [Indexed: 12/23/2022]
Abstract
Recent investigations have shown that different conditions such as diet, the overuse of antibiotics or the colonization of pathogenic microorganisms can alter the population status of the intestinal microbiota. This modification can produce a change from homeostasis to a condition known as imbalance or dysbiosis; however, the role-played by dysbiosis and the development of inflammatory bowel diseases (IBD) has been poorly understood. It was actually not until a few years ago that studies started to develop regarding the role that dendritic cells (DC) of intestinal mucosa play in the sensing of the gut microbiota population. The latest studies have focused on describing the DC modulation, specifically on tolerance response involving T regulatory cells or on the inflammatory response involving reactive oxygen species and tissue damage. Furthermore, the latest studies have also focused on the protective and restorative effect of the population of the gut microbiota given by probiotic therapy, targeting IBD and other intestinal pathologies. In the present work, the authors propose and summarize a recently studied complex axis of interaction between the population of the gut microbiota, the sensing of the DC and its modulation towards tolerance and inflammation, the development of IBD and the protective and restorative effect of probiotics on other intestinal pathologies.
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Affiliation(s)
- Pablo Alagón Fernández Del Campo
- Departamento de Microbiología del Centro de Investigación en Ciencias de la Salud (CICSA), FCS, Universidad Anáhuac México Campus Norte, 52786 Cuidad de México, Mexico.
| | - Alejandro De Orta Pando
- Departamento de Microbiología del Centro de Investigación en Ciencias de la Salud (CICSA), FCS, Universidad Anáhuac México Campus Norte, 52786 Cuidad de México, Mexico.
| | - Juan Ignacio Straface
- Departamento de Microbiología del Centro de Investigación en Ciencias de la Salud (CICSA), FCS, Universidad Anáhuac México Campus Norte, 52786 Cuidad de México, Mexico.
| | - José Ricardo López Vega
- Departamento de Microbiología del Centro de Investigación en Ciencias de la Salud (CICSA), FCS, Universidad Anáhuac México Campus Norte, 52786 Cuidad de México, Mexico.
| | - Diego Toledo Plata
- Departamento de Microbiología del Centro de Investigación en Ciencias de la Salud (CICSA), FCS, Universidad Anáhuac México Campus Norte, 52786 Cuidad de México, Mexico.
| | - Sebastian Felipe Niezen Lugo
- Departamento de Microbiología del Centro de Investigación en Ciencias de la Salud (CICSA), FCS, Universidad Anáhuac México Campus Norte, 52786 Cuidad de México, Mexico.
| | - Diego Alvarez Hernández
- Departamento de Microbiología del Centro de Investigación en Ciencias de la Salud (CICSA), FCS, Universidad Anáhuac México Campus Norte, 52786 Cuidad de México, Mexico.
| | - Tomás Barrientos Fortes
- Director Facultad de Ciencias de la Salud, Universidad Anáhuac México, 52786 Cuidad de México, Mexico.
| | - Laila Gutiérrez-Kobeh
- Unidad de Investigación UNAM-INC, División Investigación, Facultad de Medicina, Universidad Nacional Autónoma de México-Instituto Nacional de Cardiología "Ignacio Chávez," Mexico City 14080, Mexico.
| | - Sandra Georgina Solano-Gálvez
- Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico.
| | - Rosalino Vázquez-López
- Departamento de Microbiología del Centro de Investigación en Ciencias de la Salud (CICSA), FCS, Universidad Anáhuac México Campus Norte, 52786 Cuidad de México, Mexico.
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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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Abstract
Inflammatory bowel diseases (IBDs), represented by Crohn disease and ulcerative colitis, are associated with major morbidity in Western countries and with increasing incidence in the developing world. Although analysis of the genome of patients with IBD, especially through genome-wide association studies, has unraveled multiple pathways involved in IBD pathogenesis, only part of IBD heritability has been explained by genetic studies. This finding has revealed that environmental factors also play a major role in promoting intestinal inflammation, mostly through their effects in the composition of the microbiome. However, in order for microbial dysbiosis to result in uncontrolled intestinal inflammation, the intestinal barrier formed by intestinal epithelial cells and the innate immune system should also be compromised. Finally, activation of the immune system depends on the working balance between effector and regulatory cells present in the intestinal mucosa, which have also been found to be dysregulated in this patient population. Therefore, IBD pathogenesis is a result of the interplay of genetic susceptibility and environmental impact on the microbiome that through a weakened intestinal barrier will lead to inappropriate intestinal immune activation. In this article, we will review the mechanisms proposed to cause IBD from the genetic, environmental, intestinal barrier, and immunologic perspectives.
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31
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Abstract
Inflammatory bowel diseases (IBD), categorized as ulcerative colitis (UC), Crohn's disease (CD), or IBD-undetermined (IBDU), are increasing in incidence. IBD is understood to result from environmental factors interacting with a pre-existing genetic susceptibility. Approximately 1% of all patients with inflammatory bowel disease (IBD) are diagnosed before the age of 6 years, designated as very-early-onset IBD (VEOIBD). This cohort of patients is distinguished from other age groups by differences in disease phenotype and by a higher burden of genetic mutations. Recent studies have linked mutations in NADPH oxidase function to VEOIBD and even pediatric IBD. Loss-of-function NOX2 variants expressed in phagocytes and NOX1/DUOX2 variants expressed in intestinal epithelial cells have been associated with VEOIBD and pediatric and adult IBD in patients. Cell and animal studies suggest a protective role for these reactive oxygen species (ROS)-producing enzymes in intestinal homeostasis-a paradigm that challenges the conventional concept that only increased ROS result in cell and tissue damage. Examining the role of NADPH oxidases in VEOIBD may improve our understanding of the pathophysiology of this disease and will uncover new therapeutic possibilities.
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Affiliation(s)
- Emily Stenke
- Conway Institute, School of Medicine, University College Dublin, Dublin, Ireland
| | - Billy Bourke
- Conway Institute, School of Medicine, University College Dublin, Dublin, Ireland.,Department of Paediatric Gastroenterology, Our Lady's Children's Hospital Crumlin, Dublin, Ireland
| | - Ulla G Knaus
- Conway Institute, School of Medicine, University College Dublin, Dublin, Ireland.
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32
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Su HJ, Chiu YT, Chiu CT, Lin YC, Wang CY, Hsieh JY, Wei SC. Inflammatory bowel disease and its treatment in 2018: Global and Taiwanese status updates. J Formos Med Assoc 2018; 118:1083-1092. [PMID: 30054112 DOI: 10.1016/j.jfma.2018.07.005] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 06/27/2018] [Accepted: 07/04/2018] [Indexed: 12/22/2022] Open
Abstract
The global incidence and prevalence of inflammatory bowel disease (IBD) has increased over the last 2-4 decades, likely because of the adoption of a more "western" lifestyle as well as improved detection and awareness, and Taiwan is no exception. To characterize the increasing burden of IBD, we conducted a comprehensive review of IBD in the existing literature. The following parameters were reviewed: background knowledge and current standard care for IBD, including natural history, epidemiology, pathogenesis, diagnosis, monitoring, and treatment. In addition, new imaging modalities and treatment options such as combined positron emission tomography and magnetic resonance enterography, new biologic agents, small-molecule therapy, biosimilar therapeutics, mesenchymal stem cell transplantation, and fecal microbiota transplantation, all of which have been introduced for IBD management, were reviewed. We also used the hospital-based as well as population-based Taiwan National Health Insurance Research Database to assess Taiwan-specific trends for comparison with global trends.
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Affiliation(s)
- Hau-Jyun Su
- Departments of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
| | - Yu-Tse Chiu
- Departments of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
| | - Chuan-Tai Chiu
- Departments of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
| | - Yen-Chun Lin
- Departments of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
| | - Chen-Yu Wang
- Departments of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
| | - Jui-Ying Hsieh
- Departments of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
| | - Shu-Chen Wei
- Departments of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.
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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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Hvas CL, Bendix M, Dige A, Dahlerup JF, Agnholt J. Current, experimental, and future treatments in inflammatory bowel disease: a clinical review. Immunopharmacol Immunotoxicol 2018; 40:446-460. [PMID: 29745777 DOI: 10.1080/08923973.2018.1469144] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel diseases (IBDs) may result from dysregulated mucosal immune responses directed toward the resident intestinal microbiota. This review describes the hallmark immunobiology of Crohn's disease and ulcerative colitis as well as therapeutic targets and mechanisms of action for current, experimental, and future treatments in IBD. Conventional therapies include 5-aminosalicylic acid, glucocorticosteroids, thiopurines, and methotrexate. Since 1997, monoclonal antibodies have gained widespread use. These consist of antibodies directed against pro-inflammatory cytokines such as tumor necrosis factor α, interleukin (IL)-12, and IL-23, or anti-homing antibodies directed against α4β7 integrin. Emerging oral therapies include modulators of intracellular signal transduction such as Janus kinase inhibitors. Vitamin D may help to regulate innate and adaptive immune responses. Modulation of the intestinal microbiota, using live microorganisms (probiotics), substrates for the colonic microbiota (prebiotics), or fecal microbiota transplantation (FMT), is in development. Dietary supplements are in widespread use, but providing evidence for their benefit is challenging. Stem cell treatment and nervous stimulation are promising future treatments.
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Affiliation(s)
- Christian L Hvas
- a Department of Hepatology and Gastroenterology , Aarhus University Hospital , Aarhus C , Denmark
| | - Mia Bendix
- a Department of Hepatology and Gastroenterology , Aarhus University Hospital , Aarhus C , Denmark.,b Medical Department, Randers Regional Hospital , Randers , Denmark
| | - Anders Dige
- a Department of Hepatology and Gastroenterology , Aarhus University Hospital , Aarhus C , Denmark
| | - Jens F Dahlerup
- a Department of Hepatology and Gastroenterology , Aarhus University Hospital , Aarhus C , Denmark
| | - Jørgen Agnholt
- a Department of Hepatology and Gastroenterology , Aarhus University Hospital , Aarhus C , Denmark
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Miyoshi J, Qiao Y, Chang EB. The role of the intestinal microbiota in the pathogenesis and treatment of inflammatory bowel diseases. SEMINARS IN COLON AND RECTAL SURGERY 2018. [DOI: 10.1053/j.scrs.2017.09.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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36
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Lipner EM, Greenberg DA. The Rise and Fall and Rise of Linkage Analysis as a Technique for Finding and Characterizing Inherited Influences on Disease Expression. Methods Mol Biol 2018; 1706:381-397. [PMID: 29423810 DOI: 10.1007/978-1-4939-7471-9_21] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
For many years, family-based studies using linkage analysis represented the primary approach for identifying disease genes. This strategy is responsible for the identification of the greatest number of genes proven to cause human disease. However, technical advancements in next generation sequencing and high throughput genotyping, coupled with the apparent simplicity of association testing, led to the rejection of family-based studies and of linkage analysis. At present, genetic association methods, using case-control comparisons, have become the exclusive approach for detecting disease-related genes, particularly those underlying common, complex diseases. In this chapter, we present a historical overview of linkage analysis, including a description of how the approach works, as well as its strengths and weaknesses. We discuss how the transition from family-based studies to population comparison association studies led to a critical loss of information with respect to genetic etiology and inheritance, and we present historical and contemporary examples of linkage analysis "success stories" in identifying genes contributing to the development of human disease. Currently, linkage analysis is re-emerging as a useful approach for identifying disease genes, determining genetic parameters, and resolving genetic heterogeneity. We posit that the combination of linkage analysis, association testing, and high throughput sequencing provides a powerful approach for identifying disease-causing genes.
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Affiliation(s)
- Ettie M Lipner
- Center for Genes, Environment, and Health, National Jewish Health, 1400 Jackson Street, Denver, CO, 80602, USA.
- Department of Pharmacology, University of Colorado Denver, School of Medicine, Aurora, CO, USA.
| | - David A Greenberg
- Battelle Center for Mathematical Medicine, Nationwide Children's Hospital, Columbus, OH, USA
- Department of Pediatrics, Wexner Medical Center, Ohio State University, Columbus, OH, USA
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Aniwan S, Tremaine WJ, Raffals LE, Kane SV, Loftus EV. Antibiotic Use and New-Onset Inflammatory Bowel Disease in Olmsted County, Minnesota: A Population-Based Case-Control Study. J Crohns Colitis 2018; 12:137-144. [PMID: 29029150 PMCID: PMC5881749 DOI: 10.1093/ecco-jcc/jjx135] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Accepted: 09/22/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Several studies have suggested significant associations between environmental factors and the risk of developing inflammatory bowel disease [IBD]. However, data supporting the role of antibiotics are conflicting. The aim of this study was to evaluate the association between antibiotic use and new-onset IBD. METHODS We conducted a population-based case-control study using the Rochester Epidemiology Project of Olmsted County, Minnesota. We identified 736 county residents diagnosed with IBD between 1980 and 2010 who were matched to 1472 controls, based on age, sex and date of IBD diagnosis. Data on antibiotic use between 3 months and 5 years before IBD diagnosis were collected. Logistic regression models were used to estimate associations between antibiotic use and IBD, and were expressed as adjusted odds ratio [AOR] with 95% confidence interval [CI]. RESULTS Antibiotic use occurred in 455 IBD cases [61.8%] and 495 controls [33.6%] [p < 0.001]. In multivariate analysis, there were statistically significant associations between antibiotic use and new-onset IBD [AOR, 2.93; 95% CI, 2.40-3.58], Crohn's disease [CD] [AOR, 3.01; 2.27-4.00] and ulcerative colitis [UC] [AOR, 2.94; 95% CI, 2.23-3.88]. A cumulative duration of antibiotic use ≥ 30 days had the strongest AOR [6.01; 95% CI, 4.34-8.45]. AOR for those receiving antibiotics under the age of 18 years was 4.27 [95% CI, 2.39-7.91], 2.97 for age 18-60 years [2.36-3.75] and 2.72 for age > 60 years [1.60-4.67]. CONCLUSIONS This population-based case-control study suggests a strong association between antibiotic use and the risk of both new-onset CD and new-onset UC. The risk was increased among all age-onset IBD.
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Affiliation(s)
- Satimai Aniwan
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
- Division of Gastroenterology, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | - William J Tremaine
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Laura E Raffals
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Sunanda V Kane
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Edward V Loftus
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
- Corresponding author: Edward V. Loftus, Jr, MD, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. E-mail:
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Besson JCF, de Carvalho Picoli C, Matioli G, Natali MRM. Methyl jasmonate: a phytohormone with potential for the treatment of inflammatory bowel diseases. ACTA ACUST UNITED AC 2017; 70:178-190. [PMID: 29072315 DOI: 10.1111/jphp.12839] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Accepted: 09/21/2017] [Indexed: 12/30/2022]
Abstract
OBJECTIVES The phytohormone methyl jasmonate (MeJA) has been identified as a vital cell regulator in plants. This substance is analogous to eicosanoids and similar to that of anti-inflammatory prostaglandins. In animals and in animal cells, it displayed an efficient neuroprotective, anti-inflammatory and antioxidant action; while in tumoral strains, it demonstrates a potentially highly attractive mechanism of apoptosis induction through various cellular and molecular mechanisms. The aim of the present review was to explore two new hypotheses that explain the action of MeJA, a lipid phytohormone and its potentially anti-apoptotic mechanism for use as a therapeutic target for future treatment of Inflammatory bowel diseases (IBDs). KEY FINDINGS Methyl jasmonate is a new candidate for the treatment of IBDs, modulating the expression of the major classes of caspase-type protease families that selectively act on the extrinsic and intrinsic pathways of the apoptotic process. Its action is based on the reduction of the expression in tumour necrosis factor tissue levels and the modulating action of reactive oxygen species production, acting only on the destruction of cells that express the diseased phenotype, and preserving cells that are not transformed. CONCLUSIONS Methyl jasmonate may represent an alternative for the transduction processes of important signals in the cellular renewal of the intestinal mucosa.
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Affiliation(s)
| | | | - Graciette Matioli
- Department of Pharmacology and Therapeutics, State University of Maringá, Maringá, PR, Brazil
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Santos MPC, Gomes C, Torres J. Familial and ethnic risk in inflammatory bowel disease. Ann Gastroenterol 2017; 31:14-23. [PMID: 29333063 PMCID: PMC5759609 DOI: 10.20524/aog.2017.0208] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 09/21/2017] [Indexed: 02/07/2023] Open
Abstract
Familial aggregation in inflammatory bowel disease (IBD) has been established for several decades, reflecting shared genetic and environmental susceptibility. A positive family history remains the strongest recognizable risk factor for the development of IBD and is reported in around 8-12% of IBD patients. Crohn’s disease shows a more frequent familial pattern than ulcerative colitis. The risk of developing IBD in first-degree relatives of an affected proband is increased 4- to 8-fold. The risk for twins and children born from couples who both have IBD is also substantially higher; a cumulative effect of the number of family members affected has been described, with the highest incidence being described for families with three or more affected members. Herein, we review the available evidence regarding familial IBD, and briefly discuss the variation of IBD across different races and ethnicities, hoping to provide a useful update and a practical guide that can serve clinicians as a guide for counseling.
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Affiliation(s)
- Maria Pia Costa Santos
- Gastroenterology Division, Surgical Department, Hospital Beatriz Ângelo, Loures, Portugal
| | - Catarina Gomes
- Gastroenterology Division, Surgical Department, Hospital Beatriz Ângelo, Loures, Portugal
| | - Joana Torres
- Gastroenterology Division, Surgical Department, Hospital Beatriz Ângelo, Loures, Portugal
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40
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Abstract
OBJECTIVE During the last decade, experimental and observational studies have shown that patients with inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) may have an altered intestinal microbial composition compared with healthy individuals. However, no uniform microbial signature has as yet been detected for either IBD or IBS. This review summarizes the current knowledge of microbial dysbiosis and its potential relationship to the pathophysiology in IBD and IBS. METHODS A selective review was conducted to summarize the current knowledge of gut microbiota in the pathophysiology of IBD and IBS. RESULTS Experimental and observational studies provide good evidence for intestinal microbial dysbiosis in subgroups of IBD and IBS. Still, no uniform disease pattern has been detected. This is most likely due to the heterogeneous nature of IBD and IBS, in combination with the effects of intrinsic and extrinsic factors. Such intrinsic factors include genetics, the gastrointestinal environment, and the host immune system, whereas extrinsic factors include early life diet, breastfeeding, and method of infant delivery. CONCLUSIONS Recent and ongoing work to define microbial dysbiosis in IBD and IBS shows promise, but future well-designed studies with well-characterized study individuals are needed. It is likely that the microbial dysbiosis in IBD and IBS is dependent on the natural disease course of IBD and symptom pattern in IBS. Therefore, assessment of the entire microbiota along the gastrointestinal tract, in relationship to confounding factors, symptom fluctuations, and other pathophysiological factors, is needed for further understanding of the etiology of these common diseases.
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41
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The gut bacterium and pathobiont Bacteroides vulgatus activates NF-κB in a human gut epithelial cell line in a strain and growth phase dependent manner. Anaerobe 2017; 47:209-217. [DOI: 10.1016/j.anaerobe.2017.06.002] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Revised: 05/17/2017] [Accepted: 06/01/2017] [Indexed: 01/06/2023]
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Grigg JB, Sonnenberg GF. Host-Microbiota Interactions Shape Local and Systemic Inflammatory Diseases. THE JOURNAL OF IMMUNOLOGY 2017; 198:564-571. [PMID: 28069751 DOI: 10.4049/jimmunol.1601621] [Citation(s) in RCA: 85] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Accepted: 10/31/2016] [Indexed: 02/06/2023]
Abstract
Recent advances in understanding how the mammalian immune system and intestinal microbiota functionally interact have yielded novel insights for human health and disease. Modern technologies to quantitatively measure specific members and functional characteristics of the microbiota in the gastrointestinal tract, along with fundamental and emerging concepts in the field of immunology, have revealed numerous ways in which host-microbiota interactions proceed beneficially, neutrally, or detrimentally for mammalian hosts. It is clear that the gut microbiota has a strong influence on the shape and quality of the immune system; correspondingly, the immune system guides the composition and localization of the microbiota. In the following review, we examine the evidence that these interactions encompass homeostasis and inflammation in the intestine and, in certain cases, extraintestinal tissues. Lastly, we discuss translational therapies stemming from research on host-microbiota interactions that could be used for the treatment of chronic inflammatory diseases.
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Affiliation(s)
- John B Grigg
- Gastroenterology and Hepatology Division, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY 10021; Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065; and The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY 10021
| | - Gregory F Sonnenberg
- Gastroenterology and Hepatology Division, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY 10021; Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065; and The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY 10021
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43
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Emmett RA, Davidson KL, Gould NJ, Arasaradnam RP. DNA methylation patterns in ulcerative colitis-associated cancer: a systematic review. Epigenomics 2017; 9:1029-1042. [PMID: 28621161 DOI: 10.2217/epi-2017-0025] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 04/19/2017] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Evidence points to the role of DNA methylation in ulcerative colitis (UC)-associated cancer (UCC), the most serious complication of ulcerative colitis. A better understanding of the etiology of UCC may facilitate the development of new therapeutic targets and help to identify biomarkers of the disease risk. METHODS A search was performed in three databases following PRISMA protocol. DNA methylation in UCC was compared with sporadic colorectal cancer (SCRC), and individual genes differently methylated in UCC identified. RESULTS While there were some similarities in the methylation patterns of UCC compared with SCRC, generally lower levels of hypermethylation in promoter regions of individual genes was evident in UCC. Certain individual genes are, however, highly methylated in colitis-associated cancer: RUNX3, MINT1, MYOD and p16 exon1 and the promoter regions of EYA4 and ESR. CONCLUSION Patterns of DNA methylation differ between UCC and SCRC. Seven genes appear to be promising putative biomarkers.
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Affiliation(s)
- Ruth A Emmett
- Warwick Medical School, University of Warwick, Coventry, UK
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Generali E, Ceribelli A, Stazi MA, Selmi C. Lessons learned from twins in autoimmune and chronic inflammatory diseases. J Autoimmun 2017; 83:51-61. [PMID: 28431796 DOI: 10.1016/j.jaut.2017.04.005] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Accepted: 04/10/2017] [Indexed: 12/16/2022]
Abstract
Autoimmunity and chronic inflammation recognize numerous shared factors and, as a result, the resulting diseases frequently coexist in the same patients or respond to the same treatments. Among the convenient truths of autoimmune and chronic inflammatory diseases, there is now agreement that these are complex conditions in which the individual genetic predisposition provides a rate of heritability. The concordance rates in monozygotic and dizygotic twins allows to estimate the weight of the environment in determining disease susceptibility, despite recent data supporting that only a minority of immune markers depend on hereditary factors. Concordance rates in monozygotic and dizygotic twins should be evaluated over an observation period to minimize the risk of false negatives and this is well represented by type I diabetes mellitus. Further, concordance rates in monozygotic twins should be compared to those in dizygotic twins, which share 50% of their genes, as in regular siblings, but also young-age environmental factors. Twin studies have been extensively performed in several autoimmune conditions and cumulatively suggest that some diseases, i.e. celiac disease and psoriasis, are highly genetically determined, while rheumatoid arthritis or systemic sclerosis have a limited role for genetics. These observations are necessary to interpret data gathered by genome-wide association studies of polymorphisms and DNA methylation in MZ twins. New high-throughput technological platforms are awaited to provide new insights into the mechanisms of disease discordance in twins beyond strong associations such as those with HLA alleles.
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Affiliation(s)
- Elena Generali
- Division of Rheumatology and Clinical Immunology, Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Angela Ceribelli
- Division of Rheumatology and Clinical Immunology, Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Maria Antonietta Stazi
- Italian Twin Registry, Centre for Behavioural Sciences and Mental Health, Istituto Superiore di Sanità, Rome, Italy
| | - Carlo Selmi
- Division of Rheumatology and Clinical Immunology, Humanitas Research Hospital, Rozzano, Milan, Italy; BIOMETRA Department, University of Milan, Milan, Italy.
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45
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Petersen BS, Fredrich B, Hoeppner MP, Ellinghaus D, Franke A. Opportunities and challenges of whole-genome and -exome sequencing. BMC Genet 2017; 18:14. [PMID: 28193154 PMCID: PMC5307692 DOI: 10.1186/s12863-017-0479-5] [Citation(s) in RCA: 142] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Accepted: 01/26/2017] [Indexed: 01/08/2023] Open
Abstract
Recent advances in the development of sequencing technologies provide researchers with unprecedented possibilities for genetic analyses. In this review, we will discuss the history of genetic studies and the progress driven by next-generation sequencing (NGS), using complex inflammatory bowel diseases as an example. We focus on the opportunities, but also challenges that researchers are facing when working with NGS data to unravel the genetic causes underlying diseases.
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Affiliation(s)
| | - Broder Fredrich
- Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany
| | - Marc P Hoeppner
- Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany
| | - David Ellinghaus
- Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany
| | - Andre Franke
- Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.
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46
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Takahashi S, Andreoletti G, Chen R, Munehira Y, Batra A, Afzal NA, Beattie RM, Bernstein JA, Ennis S, Snyder M. De novo and rare mutations in the HSPA1L heat shock gene associated with inflammatory bowel disease. Genome Med 2017; 9:8. [PMID: 28126021 PMCID: PMC5270254 DOI: 10.1186/s13073-016-0394-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Accepted: 12/23/2016] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disease of the gastrointestinal tract which includes ulcerative colitis and Crohn's disease. Genetic risk factors for IBD are not well understood. METHODS We performed a family-based whole exome sequencing (WES) analysis on a core family (Family A) to identify potential causal mutations and then analyzed exome data from a Caucasian pediatric cohort (136 patients and 106 controls) to validate the presence of mutations in the candidate gene, heat shock 70 kDa protein 1-like (HSPA1L). Biochemical assays of the de novo and rare (minor allele frequency, MAF < 0.01) mutation variant proteins further validated the predicted deleterious effects of the identified alleles. RESULTS In the proband of Family A, we found a heterozygous de novo mutation (c.830C > T; p.Ser277Leu) in HSPA1L. Through analysis of WES data of 136 patients, we identified five additional rare HSPA1L mutations (p.Gly77Ser, p.Leu172del, p.Thr267Ile, p.Ala268Thr, p.Glu558Asp) in six patients. In contrast, rare HSPA1L mutations were not observed in controls, and were significantly enriched in patients (P = 0.02). Interestingly, we did not find non-synonymous rare mutations in the HSP70 isoforms HSPA1A and HSPA1B. Biochemical assays revealed that all six rare HSPA1L variant proteins showed decreased chaperone activity in vitro. Moreover, three variants demonstrated dominant negative effects on HSPA1L and HSPA1A protein activity. CONCLUSIONS Our results indicate that de novo and rare mutations in HSPA1L are associated with IBD and provide insights into the pathogenesis of IBD, and also expand our understanding of the roles of HSP70s in human disease.
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Affiliation(s)
- Shinichi Takahashi
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.,Rare Disease & LCM Laboratories, R & D Division, Daiichi Sankyo Co., Ltd, Tokyo, Japan
| | - Gaia Andreoletti
- Human Genetics and Genomic Medicine, University of Southampton, Southampton General Hospital, Southampton, UK
| | - Rui Chen
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Yoichi Munehira
- Department of Biology, Stanford University, Stanford, CA, USA.,Oncology Laboratories, Oncology Function, Daiichi Sankyo Co., Ltd, Tokyo, Japan
| | - Akshay Batra
- Department of Paediatric Gastroenterology, University Hospital Southampton NHS Foundation Trust, Southampton General Hospital, Tremona Road, Southampton, UK
| | - Nadeem A Afzal
- Department of Paediatric Gastroenterology, University Hospital Southampton NHS Foundation Trust, Southampton General Hospital, Tremona Road, Southampton, UK
| | - R Mark Beattie
- Department of Paediatric Gastroenterology, University Hospital Southampton NHS Foundation Trust, Southampton General Hospital, Tremona Road, Southampton, UK
| | - Jonathan A Bernstein
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
| | - Sarah Ennis
- Human Genetics and Genomic Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
| | - Michael Snyder
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
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Shi N, Li N, Duan X, Niu H. Interaction between the gut microbiome and mucosal immune system. Mil Med Res 2017; 4:14. [PMID: 28465831 PMCID: PMC5408367 DOI: 10.1186/s40779-017-0122-9] [Citation(s) in RCA: 377] [Impact Index Per Article: 47.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Accepted: 04/10/2017] [Indexed: 12/15/2022] Open
Abstract
The gut microbiota, the largest symbiotic ecosystem with the host, has been shown to play important roles in maintaining intestinal homeostasis. Dysbiosis of the gut microbiome is caused by the imbalance between the commensal and pathogenic microbiomes. The commensal microbiome regulates the maturation of the mucosal immune system, while the pathogenic microbiome causes immunity dysfunction, resulting in disease development. The gut mucosal immune system, which consists of lymph nodes, lamina propria and epithelial cells, constitutes a protective barrier for the integrity of the intestinal tract. The composition of the gut microbiota is under the surveillance of the normal mucosal immune system. Inflammation, which is caused by abnormal immune responses, influences the balance of the gut microbiome, resulting in intestinal diseases. In this review, we briefly outlined the interaction between the gut microbiota and the immune system and provided a reference for future studies.
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Affiliation(s)
- Na Shi
- Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS) and Comparative Medicine Center, Peking Union Medical Collage (PUMC), Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Beijing, 100021 China
| | - Na Li
- Department of Rheumatology, the Second Affiliated Hospital of Nanchang University, Nanchang, 330006 China
| | - Xinwang Duan
- Department of Rheumatology, the Second Affiliated Hospital of Nanchang University, Nanchang, 330006 China
| | - Haitao Niu
- Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS) and Comparative Medicine Center, Peking Union Medical Collage (PUMC), Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Beijing, 100021 China
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48
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Miyoshi J, Chang EB. The gut microbiota and inflammatory bowel diseases. Transl Res 2017; 179:38-48. [PMID: 27371886 PMCID: PMC5156589 DOI: 10.1016/j.trsl.2016.06.002] [Citation(s) in RCA: 100] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2016] [Revised: 06/02/2016] [Accepted: 06/06/2016] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel diseases (IBDs) are chronic diseases of unclear etiology that affect over 1 million individuals in the United States and over 2.5 million people in Europe. However, they are also expanding globally, affecting populations in Asia, South America, and the Middle East as they become more industrialized. These diseases are believed to arise from the convergence of genetic, environmental, and microbial factors that trigger aberrant immune and tissue responses, resulting in intestinal inflammation. Advances in cultivation-independent investigations, experimental models, and bioinformatics approaches have improved our understanding of the role of gut microbiota in IBD. However, determining and understanding the functional consequences of gut dysbiosis and altered host-microbiota interactions in IBD remain a challenge due to the limits of current experimental models and difficulty in establishing causal links in human-based investigations. Continued development of new methodologies and improvements in clinical study design are needed to better understand the interplay of genetic, microbial, and immunological factors in IBD. This knowledge can then be applied clinically to improve therapeutic strategies and outcomes for IBD.
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Affiliation(s)
- Jun Miyoshi
- Department of Medicine, The University of Chicago, Chicago, Ill
| | - Eugene B Chang
- Department of Medicine, The University of Chicago, Chicago, Ill.
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Gabbani T, Deiana S, Annese AL, Lunardi S, Annese V. The genetic burden of inflammatory bowel diseases: implications for the clinic? Expert Rev Gastroenterol Hepatol 2016; 10:1109-1117. [PMID: 27258545 DOI: 10.1080/17474124.2016.1196131] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Inflammatory bowel diseases (IBD), which include Crohn's disease (CD) and ulcerative colitis (UC), are characterized by chronic intestinal inflammation. Their etiology is multifactorial, with complex interactions between genetic and environmental factors, which are still largely unclear. Areas covered: The influence of genetics is clearly demonstrated by important epidemiological data, including familial aggregation and concordance in twins. In 2001, the first genetic susceptibility gene for IBD, the NOD2 gene, was identified. Currently, thanks to genetic wide association studies, over 200 susceptibility genetic markers are know. Expert commentary: However, clinically highly relevant gene associations are still very limited and the usefulness of these information in the current clinical strategies for treatment and surveillance of IBD is weak. Nevertheless, the recent identification of some genetic risk variants has clarified some newbiological pathways of these diseases thus paving the way for the discoveries in the near future of new targeted therapies.
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Affiliation(s)
- Tommaso Gabbani
- a Division of Gastroenterology , AOU Careggi University Hospital , Florence , Italy
| | - Simona Deiana
- a Division of Gastroenterology , AOU Careggi University Hospital , Florence , Italy
| | - Antonio Luca Annese
- a Division of Gastroenterology , AOU Careggi University Hospital , Florence , Italy
| | - Sarah Lunardi
- b Division of Internal Medicine 4 , AOU Careggi University Hospital , Florence , Italy
| | - Vito Annese
- a Division of Gastroenterology , AOU Careggi University Hospital , Florence , Italy
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Abstract
PURPOSE OF REVIEW MicroRNAs (miRNAs), small noncoding RNA molecules of approximately 22 nucleotides, have emerged as critical mediators of gene expression. As the dysregulation of gene expression can have far reaching impact on health and disease, miRNAs are being examined as potent new mediators of disease as either biomarkers or potential therapeutic targets. The purpose of this review is to evaluate the contribution of miRNAs to inflammatory bowel disease (IBD) pathophysiology. RECENT FINDINGS Recent studies have evaluated the expression of miRNAs in tissue and body fluid specimens from patients with the main subtypes of IBD - Crohn's disease and ulcerative colitis. Unique miRNA expression patterns that may distinguish IBD subtypes have been uncovered. SUMMARY Significant progress has been made in illuminating the complex interactive networks of miRNAs and gene targets in IBD. The potential use of miRNAs as disease biomarkers or therapeutics shows promise. However, there are still significant hurdles to overcome before miRNA-based therapeutics and diagnostics will be of clinical utility.
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