|
1
|
Kayali S, Fantasia S, Gaiani F, Cavallaro LG, de’Angelis GL, Laghi L. NOD2 and Crohn's Disease Clinical Practice: From Epidemiology to Diagnosis and Therapy, Rewired. Inflamm Bowel Dis 2025; 31:552-562. [PMID: 38582044 PMCID: PMC11808579 DOI: 10.1093/ibd/izae075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Indexed: 04/08/2024]
Abstract
Crohn's disease (CD) is a chronic inflammatory bowel disease with a multifactorial pathogenesis involving environmental and genetic factors. Since the late 20th century, the discovery of the first susceptibility gene (NOD2, previously referred to as CARD15) for CD has paved the way for further investigations into the correlations between clinical features and genetics, and its potential impact on clinical practice has fueled the research in the last 2 decades. Recent therapeutic advancements involving novel biologic drugs and small molecules have shifted inflammatory bowel disease management from a disease-centered to a patient-centric approach. To date, the role of NOD2 has not been fully understood yet. Recent data suggest that its clinical impact may be greater than currently recognized. This review overviews the most common NOD2 variants' role in real-life clinical practice. These genetic variants increase the risk of developing the disease and can aid in tailoring diagnosis and treatment. They are associated with the stricturing phenotype and ileal involvement and increase the risk of steroid refractoriness. In the meantime, limited and inconclusive evidence exists regarding their predictive role in response to azathioprine, biologic drugs, and small molecules. Eventually, their role in increasing the risk for surgery is evident, especially in those with the L1007fs variant. If further trials will support the initial evidence reported so far, NOD2 genetic variants will emerge as possible candidates for developing precision medicine in CD.
Collapse
Affiliation(s)
- Stefano Kayali
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Stefano Fantasia
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Federica Gaiani
- Department of Medicine and Surgery, University of Parma, Parma, Italy
- Gastroenterology and Endoscopy Unit, University Hospital of Parma, Parma, Italy
| | | | | | - Luigi Laghi
- Department of Medicine and Surgery, University of Parma, Parma, Italy
- Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research Centre, Rozzano, Italy
| |
Collapse
|
|
2
|
Su Y, Li J, Chen Y, Bao J, Lei Z, Ma M, Zhang W, Liu Q, Xu B, Hu T, Hu Y. α-Methyl-Tryptophan Inhibits SLC6A14 Expression and Exhibits Immunomodulatory Effects in Crohn's Disease. J Inflamm Res 2025; 18:1127-1145. [PMID: 39877135 PMCID: PMC11774106 DOI: 10.2147/jir.s495855] [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: 09/19/2024] [Accepted: 01/19/2025] [Indexed: 01/31/2025] Open
Abstract
Introduction Crohn's disease (CD) is a chronic inflammatory condition of the intestines with a rising global incidence. Traditional diagnostic and therapeutic methods have limitations, necessitating the exploration of more effective strategies. Methods In this study, we employed the Gene Expression Omnibus database to identify genes that are differentially expressed in CD. RT-PCR and immunohistochemical analysis were used to SLC6A14 RNA and protein expression in the colons of CD mice and CD tissues from patients. The mouse model of CD was induced by dextran sodium sulfate (DSS). Infiltrating immune cells in mouse model were screened by flow cytometry. Results We discovered that SLC6A14 is significantly overexpressed in CD samples, and its expression is positively correlated with the degree of infiltration by CD4+ and CD8+ T cells. The elevated levels of SLC6A14 RNA and protein were confirmed in clinical CD tissues. The SLC6A14 inhibitor α-methyl-tryptophan (α-MT) significantly decreased the expression of SLC6A14 RNA and protein in the colons of CD mice. The α-MT treatment group also exhibited reduced levels of cytokines involved in T cell differentiation (IFN-γ and TNF-α) and the expression of immune cell surface markers CXCR-3 and LAG-3. Flow cytometry analysis revealed a significant increase in the infiltration of CD4+ and CD8+ T cells in the DSS-treated group compared to the control group. Conversely, the α-MT treatment group showed a significant reduction in CD4+ and CD8+ T cell infiltration and the restoration of intestinal parameters in CD mice. These findings underscore the role of SLC6A14 in regulating intestinal immune cell infiltration during CD progression. Discussion Our findings suggest that SLC6A14 could serve as a potential diagnostic biomarker and therapeutic target for CD. Furthermore, α-MT offers a novel approach for the clinical diagnosis and treatment of CD by targeting SLC6A14 for therapeutic intervention.
Collapse
Affiliation(s)
- YongCheng Su
- Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, People’s Republic of China
| | - Jiangquan Li
- Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, People’s Republic of China
| | - Yijia Chen
- Department of Gastroenterology, The National Key Clinical Specialty, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361004, People’s Republic of China
| | - Jiachen Bao
- Department of Gastroenterology, The National Key Clinical Specialty, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361004, People’s Republic of China
| | - Ziyu Lei
- Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, People’s Republic of China
| | - Miaomiao Ma
- Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, People’s Republic of China
| | - Wenqing Zhang
- Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, People’s Republic of China
| | - Qian Liu
- Integrated Chinese and Western Medicine Institute for Children Health & Drug Innovation, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, 330004, People’s Republic of China
| | - Beibei Xu
- Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, People’s Republic of China
| | - Tianhui Hu
- Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, People’s Republic of China
- Integrated Chinese and Western Medicine Institute for Children Health & Drug Innovation, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, 330004, People’s Republic of China
| | - Yiqun Hu
- Department of Gastroenterology, The National Key Clinical Specialty, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361004, People’s Republic of China
| |
Collapse
|
|
3
|
Boye TL, Hammerhøj A, Nielsen OH, Wang Y. Metabolomics for enhanced clinical understanding of inflammatory bowel disease. Life Sci 2024; 359:123238. [PMID: 39537099 DOI: 10.1016/j.lfs.2024.123238] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 11/07/2024] [Accepted: 11/08/2024] [Indexed: 11/16/2024]
Abstract
Metabolomics is an emerging field involving the systematic identification and quantification of numerous metabolites in biological samples. Precision medicine applies multiomics systems biology to individual patients for reliable diagnostic classification, disease monitoring, and treatment. Multiomics systems biology encompasses genomics, transcriptomics, proteomics, epigenomics, and metabolomics. Therefore, metabolomic techniques could be highly valuable for future clinical decision-making. This review provides a technical overview of two commonly used techniques for metabolomics measurements: mass spectrometry (MS) and proton nuclear magnetic resonance (1H NMR) spectroscopy. We also discuss recent clinical advances in these techniques. Individuals with inflammatory bowel disease (IBD) exhibit significant variability in prognosis and response to treatment. Since both genetic predisposition and environmental factors contribute to this condition, targeting the metabolome may provide key insights for distinguishing and profiling patients with different clinical needs. Additionally, the considerable overlap in the clinical presentation of various disease subtypes emphasizes the need for enhanced diagnostic methods to improve patient care.
Collapse
Affiliation(s)
- Theresa Louise Boye
- Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Denmark
| | - Alexander Hammerhøj
- Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Denmark
| | - Ole Haagen Nielsen
- Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Denmark.
| | - Yulan Wang
- Singapore Phenome Center, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| |
Collapse
|
|
4
|
Sosna B, Aebisher D, Myśliwiec A, Dynarowicz K, Bartusik-Aebisher D, Oleś P, Cieślar G, Kawczyk-Krupka A. Selected Cytokines and Metalloproteinases in Inflammatory Bowel Disease. Int J Mol Sci 2023; 25:202. [PMID: 38203373 PMCID: PMC10779120 DOI: 10.3390/ijms25010202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 12/19/2023] [Accepted: 12/20/2023] [Indexed: 01/12/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a collective term for two diseases: ulcerative colitis (UC) and Crohn's disease (CD). There are many factors, e.g., genetic, environmental and immunological, that increase the likelihood of these diseases. Indicators of IBDs include extracellular matrix metalloproteinases (MMPs). The aim of this review is to present data on the role of selected cytokines and metalloproteinases in IBD. In recent years, more and more transcriptomic studies are emerging. These studies are improving the characterization of the cytokine microenvironment inside inflamed tissue. It is observed that the levels of several cytokines are consistently increased in inflamed tissue in IBD, both in UC and CD. This review shows that MMPs play a major role in the pathology of inflammatory processes, cancer, and IBD. IBD-associated inflammation is associated with increased expression of MMPs and reduced ability of tissue inhibitors of metalloproteinases (TIMPs) to inhibit their action. In IBD patients in tissues that are inflamed, MMPs are produced in excess and TIMP activity is not sufficient to block MMPs. This review is based on our personal selection of the literature that was retrieved by a selective search in PubMed using the terms "Inflammatory bowel disease" and "pathogenesis of Inflammatory bowel diseases" that includes systematic reviews, meta-analyses, and clinical trials. The involvement of the immune system in the pathophysiology of IBD is reviewed in terms of the role of the cytokines and metalloproteinases involved.
Collapse
Affiliation(s)
- Barbara Sosna
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
| | - David Aebisher
- Department of Photomedicine and Physical Chemistry, Medical College, University of Rzeszów, 35-959 Rzeszów, Poland;
| | - Angelika Myśliwiec
- Center for Innovative Research in Medical and Natural Sciences, Medical College, University of Rzeszów, 35-310 Rzeszów, Poland; (A.M.); (K.D.)
| | - Klaudia Dynarowicz
- Center for Innovative Research in Medical and Natural Sciences, Medical College, University of Rzeszów, 35-310 Rzeszów, Poland; (A.M.); (K.D.)
| | - Dorota Bartusik-Aebisher
- Department of Biochemistry and General Chemistry, Medical College, University of Rzeszów, 35-959 Rzeszów, Poland;
| | - Piotr Oleś
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
| | - Grzegorz Cieślar
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
| | - Aleksandra Kawczyk-Krupka
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
| |
Collapse
|
|
5
|
Hu C, Liao S, Lv L, Li C, Mei Z. Intestinal Immune Imbalance is an Alarm in the Development of IBD. Mediators Inflamm 2023; 2023:1073984. [PMID: 37554552 PMCID: PMC10406561 DOI: 10.1155/2023/1073984] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 07/06/2023] [Accepted: 07/08/2023] [Indexed: 08/10/2023] Open
Abstract
Immune regulation plays a crucial role in human health and disease. Inflammatory bowel disease (IBD) is a chronic relapse bowel disease with an increasing incidence worldwide. Clinical treatments for IBD are limited and inefficient. However, the pathogenesis of immune-mediated IBD remains unclear. This review describes the activation of innate and adaptive immune functions by intestinal immune cells to regulate intestinal immune balance and maintain intestinal mucosal integrity. Changes in susceptible genes, autophagy, energy metabolism, and other factors interact in a complex manner with the immune system, eventually leading to intestinal immune imbalance and the onset of IBD. These events indicate that intestinal immune imbalance is an alarm for IBD development, further opening new possibilities for the unprecedented development of immunotherapy for IBD.
Collapse
Affiliation(s)
- Chunli Hu
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Shengtao Liao
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Lin Lv
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Chuanfei Li
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Zhechuan Mei
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| |
Collapse
|
|
6
|
Richard N, Savoye G, Leboutte M, Amamou A, Ghosh S, Marion-Letellier R. Crohn’s disease: Why the ileum? World J Gastroenterol 2023; 29:3222-3240. [PMID: 37377591 PMCID: PMC10292140 DOI: 10.3748/wjg.v29.i21.3222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/23/2023] [Accepted: 05/08/2023] [Indexed: 06/01/2023] Open
Abstract
Crohn’s disease (CD) is an inflammatory bowel disease characterized by immune-mediated flares affecting any region of the intestine alternating with remission periods. In CD, the ileum is frequently affected and about one third of patients presents with a pure ileal type. Moreover, the ileal type of CD presents epidemiological specificities like a younger age at onset and often a strong link with smoking and genetic susceptibility genes. Most of these genes are associated with Paneth cell dysfunction, a cell type found in the intestinal crypts of the ileum. Besides, a Western-type diet is associated in epidemiological studies with CD onset and increasing evidence shows that diet can modulate the composition of bile acids and gut microbiota, which in turn modulates the susceptibility of the ileum to inflammation. Thus, the interplay between environmental factors and the histological and anatomical features of the ileum is thought to explain the specific transcriptome profile observed in CD ileitis. Indeed, both immune response and cellular healing processes harbour differences between ileal and non-ileal CD. Taken together, these findings advocate for a dedicated therapeutic approach to managing ileal CD. Currently, interventional pharmacological studies have failed to clearly demonstrate distinct response profiles according to disease site. However, the high rate of stricturing disease in ileal CD requires the identification of new therapeutic targets to significantly change the natural history of this debilitating disease.
Collapse
Affiliation(s)
- Nicolas Richard
- University of Rouen Normandie, INSERM, ADEN UMR 1073, Nutrition, Inflammation and Microbiota-Gut-Brain Axis, Rouen F-76000, France
- CHU Rouen, Department of Gastroenterology, Rouen University Hospital-Charles Nicolle, Rouen F-76000, France
- Institute for Research and Innovation in Biomedicine, University of Rouen Normandie, Rouen F-76000, France
| | - Guillaume Savoye
- University of Rouen Normandie, INSERM, ADEN UMR 1073, Nutrition, Inflammation and Microbiota-Gut-Brain Axis, Rouen F-76000, France
- CHU Rouen, Department of Gastroenterology, Rouen University Hospital-Charles Nicolle, Rouen F-76000, France
- Institute for Research and Innovation in Biomedicine, University of Rouen Normandie, Rouen F-76000, France
| | - Mathilde Leboutte
- University of Rouen Normandie, INSERM, ADEN UMR 1073, Nutrition, Inflammation and Microbiota-Gut-Brain Axis, Rouen F-76000, France
- Institute for Research and Innovation in Biomedicine, University of Rouen Normandie, Rouen F-76000, France
| | - Asma Amamou
- APC Microbiome Ireland, Biosciences Building, University College Cork, Cork T12 YT20, Ireland
| | - Subrata Ghosh
- APC Microbiome Ireland, Biosciences Building, University College Cork, Cork T12 YT20, Ireland
| | - Rachel Marion-Letellier
- University of Rouen Normandie, INSERM, ADEN UMR 1073, Nutrition, Inflammation and Microbiota-Gut-Brain Axis, Rouen F-76000, France
- Institute for Research and Innovation in Biomedicine, University of Rouen Normandie, Rouen F-76000, France
| |
Collapse
|
|
7
|
Abstract
Mycobacteria are responsible for several human and animal diseases. NOD2 is a pattern recognition receptor that has an important role in mycobacterial recognition. However, the mechanisms by which mutations in NOD2 alter the course of mycobacterial infection remain unclear. Herein, we aimed to review the totality of studies directly addressing the relationship between NOD2 and mycobacteria as a foundation for moving the field forward. NOD2 was linked to mycobacterial infection at 3 levels: (1) genetic, through association with mycobacterial diseases of humans; (2) chemical, through the distinct NOD2 ligand in the mycobacterial cell wall; and (3) immunologic, through heightened NOD2 signaling caused by the unique modification of the NOD2 ligand. The immune response to mycobacteria is shaped by NOD2 signaling, responsible for NF-κB and MAPK activation, and the production of various immune effectors like cytokines and nitric oxide, with some evidence linking this to bacteriologic control. Absence of NOD2 during mycobacterial infection of mice can be detrimental, but the mechanism remains unknown. Conversely, the success of immunization with mycobacteria has been linked to NOD2 signaling and NOD2 has been targeted as an avenue of immunotherapy for diseases even beyond mycobacteria. The mycobacteria-NOD2 interaction remains an important area of study, which may shed light on immune mechanisms in disease.
Collapse
Affiliation(s)
- Jean-Yves Dubé
- Department of Microbiology and Immunology, McGill University, Montréal, Canada
| | - Marcel A. Behr
- Department of Medicine, McGill University Health Centre, Montréal, Canada
| |
Collapse
|
|
8
|
Wu Y, Gettler K, Kars ME, Giri M, Li D, Bayrak CS, Zhang P, Jain A, Maffucci P, Sabic K, Van Vleck T, Nadkarni G, Denson LA, Ostrer H, Levine AP, Schiff ER, Segal AW, Kugathasan S, Stenson PD, Cooper DN, Philip Schumm L, Snapper S, Daly MJ, Haritunians T, Duerr RH, Silverberg MS, Rioux JD, Brant SR, McGovern DPB, Cho JH, Itan Y. Identifying high-impact variants and genes in exomes of Ashkenazi Jewish inflammatory bowel disease patients. Nat Commun 2023; 14:2256. [PMID: 37080976 PMCID: PMC10119186 DOI: 10.1038/s41467-023-37849-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 04/03/2023] [Indexed: 04/22/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a group of chronic digestive tract inflammatory conditions whose genetic etiology is still poorly understood. The incidence of IBD is particularly high among Ashkenazi Jews. Here, we identify 8 novel and plausible IBD-causing genes from the exomes of 4453 genetically identified Ashkenazi Jewish IBD cases (1734) and controls (2719). Various biological pathway analyses are performed, along with bulk and single-cell RNA sequencing, to demonstrate the likely physiological relatedness of the novel genes to IBD. Importantly, we demonstrate that the rare and high impact genetic architecture of Ashkenazi Jewish adult IBD displays significant overlap with very early onset-IBD genetics. Moreover, by performing biobank phenome-wide analyses, we find that IBD genes have pleiotropic effects that involve other immune responses. Finally, we show that polygenic risk score analyses based on genome-wide high impact variants have high power to predict IBD susceptibility.
Collapse
Affiliation(s)
- Yiming Wu
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Kyle Gettler
- Department of Genetics, Yale University, New Haven, CT, USA
| | - Meltem Ece Kars
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Mamta Giri
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Dalin Li
- Translational Genomics Unit, F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Cigdem Sevim Bayrak
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Peng Zhang
- St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY, USA
| | - Aayushee Jain
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
| | - Patrick Maffucci
- Immunology Institute, Graduate School, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
| | - Ksenija Sabic
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Tielman Van Vleck
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Girish Nadkarni
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Lee A Denson
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Harry Ostrer
- Department of Pathology, Albert Einstein College of Medicine, New York, NY, USA
| | - Adam P Levine
- Division of Medicine, University College London (UCL), London, UK
- Research Department of Pathology, University College London (UCL), London, UK
| | - Elena R Schiff
- Division of Medicine, University College London (UCL), London, UK
- Moorfields Eye Hospital NHS Foundation Trust, London, UK
| | - Anthony W Segal
- Division of Medicine, University College London (UCL), London, UK
| | | | - Peter D Stenson
- Institute of Medical Genetics, Cardiff University, Cardiff, UK
| | - David N Cooper
- Institute of Medical Genetics, Cardiff University, Cardiff, UK
| | - L Philip Schumm
- Department of Public Health Sciences, University of Chicago, Chicago, IL, USA
| | - Scott Snapper
- Division of Gastroenterology, Hepatology and Nutrition, Oncology Boston Children's Hospital, Boston, MA, USA
| | - Mark J Daly
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
- Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
- Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
| | - Talin Haritunians
- Translational Genomics Unit, F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Richard H Duerr
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA
| | - Mark S Silverberg
- Inflammatory Bowel Disease Centre, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - John D Rioux
- Research Center, Montreal Heart Institute, Montréal, Québec, Canada
- Department of Medicine, Université de Montréal, Montréal, Québec, Canada
| | - Steven R Brant
- Division of Gastroenterology, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
- Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ, USA
- Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Dermot P B McGovern
- Translational Genomics Unit, F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Judy H Cho
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Yuval Itan
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| |
Collapse
|
|
9
|
de Mesquita TGR, Junior JDES, de Souza JL, da Silva LS, do Nascimento TA, de Souza MLG, Guerra MVDF, Ramasawmy R. Variants of NOD2 in Leishmania guyanensis-infected patients with cutaneous leishmaniasis and correlations with plasma circulating pro-inflammatory cytokines. PLoS One 2023; 18:e0281814. [PMID: 36795715 PMCID: PMC9934361 DOI: 10.1371/journal.pone.0281814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 02/01/2023] [Indexed: 02/17/2023] Open
Abstract
Leishmaniases, a group of vector-borne diseases, are caused by the protozoan intracellular parasite Leishmania (L.) and are transmitted by the phlebotomine sandflies. A wide range of clinical manifestations in L- infection is observed. The clinical outcome ranges from asymptomatic, cutaneous leishmaniasis (CL) to severe mucosal leishmaniasis (ML) or visceral leishmaniasis (VL), depending on the L. species. Interestingly, only a fraction of L.-infected individuals progress to disease development, suggesting a key role of host genetics in the clinical outcome. NOD2 plays a critical role in the control of host defense and inflammation. The NOD2-RIK2 pathway is involved in developing a Th1- type response in patients with VL and C57BL/6 mice infected with L. infantum. We investigated whether variants in the NOD2 gene (R702W rs2066844, G908R rs2066845, and L1007fsinsC rs2066847) are associated with susceptibility to CL caused by L. guyanensis (Lg) in 837 patients with Lg-Cl and 797 healthy controls (HC) with no history of leishmaniasis. Both patients and HC are from the same endemic area of the Amazonas state of Brazil. The variants R702W and G908R were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and L1007fsinsC was by direct nucleotide sequencing. The minor allele frequency (MAF) of L1007fsinsC was 0.5% among the patients with Lg-CL and 0.6% in the healthy controls group. R702W genotypes frequencies were similar in both groups. Only 1% and 1.6% were heterozygous for G908R among the patients with Lg-CL and HC, respectively. None of the variants revealed any association with susceptibility to the development of Lg-CL. Correlations of genotypes with the level of plasma cytokines revealed that individuals with the mutant alleles of R702W tend to have low levels of IFN-γ. G908R heterozygotes also tend to have low IFN-γ, TNF-α, IL-17, and IL-8. Variants of NOD2 are not involved in the pathogenesis of Lg-CL.
Collapse
Affiliation(s)
- Tirza Gabrielle Ramos de Mesquita
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas, Manaus, Brazil
- Fundação de Medicina Tropical Doutor Heitor Vieira Dourado, Manaus, Brazil
| | - José do Espírito Santo Junior
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Instituto de Ciências Biológicas, Universidade Federal do Amazonas, Manaus, Amazonas, Brazil
- Faculdade de Medicina Nilton Lins, Universidade Nilton Lins, Manaus, Brazil
| | - Josué Lacerda de Souza
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Instituto de Ciências Biológicas, Universidade Federal do Amazonas, Manaus, Amazonas, Brazil
- Faculdade de Medicina Nilton Lins, Universidade Nilton Lins, Manaus, Brazil
| | - Lener Santos da Silva
- Programa de Pós-Graduação em Biodiversidade e Biotecnologia da Amazonia Legal (Rede Bionorte), Universidade do Estado do Amazonas, Manaus, Brazil
| | | | - Mara Lúcia Gomes de Souza
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Instituto de Ciências Biológicas, Universidade Federal do Amazonas, Manaus, Amazonas, Brazil
| | - Marcus Vinitius de Farias Guerra
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas, Manaus, Brazil
- Fundação de Medicina Tropical Doutor Heitor Vieira Dourado, Manaus, Brazil
| | - Rajendranath Ramasawmy
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas, Manaus, Brazil
- Fundação de Medicina Tropical Doutor Heitor Vieira Dourado, Manaus, Brazil
- Faculdade de Medicina Nilton Lins, Universidade Nilton Lins, Manaus, Brazil
- Programa de Pós-Graduação em Biodiversidade e Biotecnologia da Amazonia Legal (Rede Bionorte), Universidade do Estado do Amazonas, Manaus, Brazil
- Genomic Health Surveillance Network: Optimization of Assistance and Research in The State of Amazonas – REGESAM, Manaus, Amazonas, Brazil
- * E-mail:
| |
Collapse
|
|
10
|
Jans D, Cleynen I. The genetics of non-monogenic IBD. Hum Genet 2023; 142:669-682. [PMID: 36720734 DOI: 10.1007/s00439-023-02521-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 01/10/2023] [Indexed: 02/02/2023]
Abstract
Inflammatory bowel disease (IBD), with Crohn's disease and ulcerative colitis as main subtypes, is a prototypical multifactorial disease with both genetic and environmental factors involved. Genetically, IBD covers a wide spectrum from monogenic to polygenic forms. In polygenic disease, many genetic variants each contribute a small amount to disease risk. With the advent of genome-wide association studies (GWAS), it became possible to find these variants and corresponding genes, leading so far to the discovery of ca 240 loci associated with IBD. Together, these however explain only 20-25% of the heritability of IBD, leaving a large portion unaccounted for. This missing heritability might be hidden in common variants with even lower effect than the ones currently found through GWAS, but also in rare variants which can be found through large-scale sequencing studies or potentially in multiplex families. In this review, we will give an overview of the current knowledge about the genetics of non-monogenic IBD and how it differs from the monogenic form(s), and future perspectives. The history of IBD genetic studies from twin studies over linkage studies to GWAS, and finally large-scale sequencing studies and the revisiting of multiplex families will be discussed.
Collapse
Affiliation(s)
- Deborah Jans
- Laboratory for Complex Genetics, Department of Human Genetics, KU Leuven, Herestraat 49, box610, 3000, Louvain, Belgium
| | - Isabelle Cleynen
- Laboratory for Complex Genetics, Department of Human Genetics, KU Leuven, Herestraat 49, box610, 3000, Louvain, Belgium.
| |
Collapse
|
|
11
|
Vieujean S, Louis E. Precision medicine and drug optimization in adult inflammatory bowel disease patients. Therap Adv Gastroenterol 2023; 16:17562848231173331. [PMID: 37197397 PMCID: PMC10184262 DOI: 10.1177/17562848231173331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 04/16/2023] [Indexed: 05/19/2023] Open
Abstract
Inflammatory bowel diseases (IBD) encompass two main entities including ulcerative colitis and Crohn's disease. Although having a common global pathophysiological mechanism, IBD patients are characterized by a significant interindividual heterogeneity and may differ by their disease type, disease locations, disease behaviours, disease manifestations, disease course as well as treatment needs. Indeed, although the therapeutic armamentarium for these diseases has expanded rapidly in recent years, a proportion of patients remains with a suboptimal response to medical treatment due to primary non-response, secondary loss of response or intolerance to currently available drugs. Identifying, prior to treatment initiation, which patients are likely to respond to a specific drug would improve the disease management, avoid unnecessary side effects and reduce the healthcare expenses. Precision medicine classifies individuals into subpopulations according to clinical and molecular characteristics with the objective to tailor preventative and therapeutic interventions to the characteristics of each patient. Interventions would thus be performed only on those who will benefit, sparing side effects and expense for those who will not. This review aims to summarize clinical factors, biomarkers (genetic, transcriptomic, proteomic, metabolic, radiomic or from the microbiota) and tools that could predict disease progression to guide towards a step-up or top-down strategy. Predictive factors of response or non-response to treatment will then be reviewed, followed by a discussion about the optimal dose of drug required for patients. The time at which these treatments should be administered (or rather can be stopped in case of a deep remission or in the aftermath of a surgery) will also be addressed. IBD remain biologically complex, with multifactorial etiopathology, clinical heterogeneity as well as temporal and therapeutic variabilities, which makes precision medicine especially challenging in this area. Although applied for many years in oncology, it remains an unmet medical need in IBD.
Collapse
Affiliation(s)
- Sophie Vieujean
- Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, Liège, Belgium
| | | |
Collapse
|
|
12
|
Ashton JJ, Seaby EG, Beattie RM, Ennis S. NOD2 in Crohn's disease- unfinished business. J Crohns Colitis 2022; 17:450-458. [PMID: 36006803 PMCID: PMC10069614 DOI: 10.1093/ecco-jcc/jjac124] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Indexed: 01/01/2023]
Abstract
Studies of Crohn's disease consistently implicate NOD2 as the most important gene in disease pathogenesis since first being identified in 2001. Since this point, genome-wide association, next-generation sequencing, and functional analyses have all confirmed a key role for NOD2, but despite this, NOD2 also has significant unresolved complexity. More recent studies have reinvigorated an early hypothesis that NOD2 may be a single-gene cause of disease, and the distinct ileal stricturing phenotype seen with NOD2-related disease presents an opportunity for personalised diagnosis, disease prediction and targeted therapy. The genomics of NOD2 has much that remains unknown, including the role of rare variation, phasing of variants across the haplotype block and the role of variation in the NOD2-regulatory regions. Here, we discuss the evidence and the unmet needs of NOD2-research, based on recently published evidence, and suggest methods that may meet these requirements.
Collapse
Affiliation(s)
- James J Ashton
- Department of Human Genetics and Genomic Medicine, University of Southampton, Southampton, UK.,Department of Paediatric Gastroenterology, Southampton Children's Hospital, Southampton, UK
| | - Eleanor G Seaby
- Department of Human Genetics and Genomic Medicine, University of Southampton, Southampton, UK
| | - R Mark Beattie
- Department of Paediatric Gastroenterology, Southampton Children's Hospital, Southampton, UK
| | - Sarah Ennis
- Department of Human Genetics and Genomic Medicine, University of Southampton, Southampton, UK
| |
Collapse
|
|
13
|
Berger K, Arafat D, Chandrakasan S, Snapper SB, Gibson G. Targeted RNAseq Improves Clinical Diagnosis of Very Early-Onset Pediatric Immune Dysregulation. J Pers Med 2022; 12:919. [PMID: 35743704 PMCID: PMC9224647 DOI: 10.3390/jpm12060919] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 05/26/2022] [Accepted: 05/27/2022] [Indexed: 02/05/2023] Open
Abstract
Despite increased use of whole exome sequencing (WES) for the clinical analysis of rare disease, overall diagnostic yield for most disorders hovers around 30%. Previous studies of mRNA have succeeded in increasing diagnoses for clearly defined disorders of monogenic inheritance. We asked if targeted RNA sequencing could provide similar benefits for primary immunodeficiencies (PIDs) and very early-onset inflammatory bowel disease (VEOIBD), both of which are difficult to diagnose due to high heterogeneity and variable severity. We performed targeted RNA sequencing of a panel of 260 immune-related genes for a cohort of 13 patients (seven suspected PID cases and six VEOIBD) and analyzed variants, splicing, and exon usage. Exonic variants were identified in seven cases, some of which had been previously prioritized by exome sequencing. For four cases, allele specific expression or lack thereof provided additional insights into possible disease mechanisms. In addition, we identified five instances of aberrant splicing associated with four variants. Three of these variants had been previously classified as benign in ClinVar based on population frequency. Digenic or oligogenic inheritance is suggested for at least two patients. In addition to validating the use of targeted RNA sequencing, our results show that rare disease research will benefit from incorporating contributing genetic factors into the diagnostic approach.
Collapse
Affiliation(s)
- Kiera Berger
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30332, USA; (K.B.); (D.A.)
| | - Dalia Arafat
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30332, USA; (K.B.); (D.A.)
| | - Shanmuganathan Chandrakasan
- Division of Bone Marrow Transplant, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA 30322, USA;
| | - Scott B. Snapper
- Division of Gastroenterology, Hepatology, and Nutrition, Boston Children’s Hospital, Boston, MA 02115, USA;
| | - Greg Gibson
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30332, USA; (K.B.); (D.A.)
| |
Collapse
|
|
14
|
Azab B, Rabab’h O, Aburizeg D, Mohammad H, Dardas Z, Mustafa L, Khasawneh RA, Awad H, Hatmal MM, Altamimi E. Potential Composite Digenic Contribution of NPC1 and NOD2 Leading to Atypical Lethal Niemann-Pick Type C with Initial Crohn’s Disease-like Presentation: Genotype-Phenotype Correlation Study. Genes (Basel) 2022; 13:genes13060973. [PMID: 35741735 PMCID: PMC9223108 DOI: 10.3390/genes13060973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 03/31/2022] [Accepted: 05/25/2022] [Indexed: 11/29/2022] Open
Abstract
Niemann–Pick disease type C (NPC) is an autosomal recessive neurovisceral disease characterized by progressive neurodegeneration with variable involvement of multisystemic abnormalities. Crohn’s disease (CD) is an inflammatory bowel disease (IBD) with a multifactorial etiology influenced by variants in NOD2. Here, we investigated a patient with plausible multisystemic overlapping manifestations of both NPC and CD. Her initial hospitalization was due to a prolonged fever and non-bloody diarrhea. A few months later, she presented with recurrent skin tags and anal fissures. Later, her neurological and pulmonary systems progressively deteriorated, leading to her death at the age of three and a half years. Differential diagnosis of her disease encompassed a battery of clinical testing and genetic investigations. The patient’s clinical diagnosis was inconclusive. Specifically, the histopathological findings were directed towards an IBD disease. Nevertheless, the diagnosis of IBD was not consistent with the patient’s subsequent neurological and pulmonary deterioration. Consequently, we utilized a genetic analysis approach to guide the diagnosis of this vague condition. Our phenotype–genotype association attempts led to the identification of candidate disease-causing variants in both NOD2 and NPC1. In this study, we propose a potential composite digenic impact of these two genes as the underlying molecular etiology. This work lays the foundation for future functional and mechanistic studies to unravel the digenic role of NOD2 and NPC1.
Collapse
Affiliation(s)
- Bilal Azab
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA
- Department of Pathology and Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman 11942, Jordan; (D.A.); (H.M.); (L.M.); (H.A.)
- Correspondence: (B.A.); (E.A.)
| | - Omar Rabab’h
- Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA;
| | - Dunia Aburizeg
- Department of Pathology and Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman 11942, Jordan; (D.A.); (H.M.); (L.M.); (H.A.)
| | - Hashim Mohammad
- Department of Pathology and Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman 11942, Jordan; (D.A.); (H.M.); (L.M.); (H.A.)
| | - Zain Dardas
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA;
| | - Lina Mustafa
- Department of Pathology and Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman 11942, Jordan; (D.A.); (H.M.); (L.M.); (H.A.)
| | - Ruba A. Khasawneh
- Department of Diagnostic Radiology and Nuclear Medicine, Faculty of Medicine King Abdullah University Hospital, Jordan University of Science and Technology, Irbid 22110, Jordan;
| | - Heyam Awad
- Department of Pathology and Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman 11942, Jordan; (D.A.); (H.M.); (L.M.); (H.A.)
| | - Ma’mon M. Hatmal
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, The Hashemite University, Zarqa 13133, Jordan;
| | - Eyad Altamimi
- Pediatric Department, Faculty of Medicine, Jordan University of Science and Technology, Irbid 22110, Jordan
- Correspondence: (B.A.); (E.A.)
| |
Collapse
|
|
15
|
Verstockt B, Bressler B, Martinez-Lozano H, McGovern D, Silverberg MS. Time to Revisit Disease Classification in Inflammatory Bowel Disease: Is the Current Classification of Inflammatory Bowel Disease Good Enough for Optimal Clinical Management? Gastroenterology 2022; 162:1370-1382. [PMID: 34995534 DOI: 10.1053/j.gastro.2021.12.246] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 12/08/2021] [Accepted: 12/09/2021] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel disease (IBD), historically subdivided into Crohn's disease and ulcerative colitis, is a very heterogeneous condition. While the tendency in medicine is to try to reduce complexity, IBD is a disease that cannot justify a one-size-fits-all principle. Our current clinical classification tools are suboptimal and need further refinement to capture, at least in part, the variety of phenotypes encountered in daily clinical practice. Although these revised classification tools alone will not be sufficient and should be complemented by more detailed molecular subclassifications, optimized clinical phenotypes can contribute to improved trial designs, future translational research approaches, and better treatment outcomes. In the current review, we discuss key clinical features important in IBD disease heterogeneity, tackle limitations of the current classification systems, propose some potential improvements, and raise priorities for future research in this domain.
Collapse
Affiliation(s)
- Bram Verstockt
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Katholieke Universiteit Leuven, Leuven, Belgium; Department of Chronic Diseases and Metabolism, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Brian Bressler
- Division of Gastroenterology, Department of Medicine, St. Paul's Hopsital, University of British Columbia, Vancouver, British Columbia, Canada
| | - Helena Martinez-Lozano
- Division of Gastroenterology, Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Dermot McGovern
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Mark S Silverberg
- Division of Gastroenterology, Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
| |
Collapse
|
|
16
|
Abstract
Vitamin D, best known for its role in skeletal health, has emerged as a key regulator of innate immune responses to microbial threat. In immune cells such as macrophages, expression of CYP27B1, the 25-hydroxyvitamin D 1α-hydroxylase, is induced by immune-specific inputs, leading to local production of hormonal 1,25-dihydroxyvitamin D (1,25D) at sites of infection, which in turn directly induces the expression of genes encoding antimicrobial peptides. Vitamin D signaling is active upstream and downstream of pattern recognition receptors, which promote front-line innate immune responses. Moreover, 1,25D stimulates autophagy, which has emerged as a mechanism critical for control of intracellular pathogens such as M. tuberculosis. Strong laboratory and epidemiological evidence links vitamin D deficiency to increased rates of conditions such as dental caries, as well as inflammatory bowel diseases arising from dysregulation of innate immune handling intestinal flora. 1,25D is also active in signaling cascades that promote antiviral innate immunity; 1,25D-induced expression of the antimicrobial peptide CAMP/LL37, originally characterized for its antibacterial properties, is a key component of antiviral responses. Poor vitamin D status is associated with greater susceptibility to viral infections, including those of the respiratory tract. Although the severity of the COVID-19 pandemic has been alleviated in some areas by the arrival of vaccines, it remains important to identify therapeutic interventions that reduce disease severity and mortality, and accelerate recovery. This review outlines of our current knowledge of the mechanisms of action of vitamin D signaling in the innate immune system. It also provides an assessment of the therapeutic potential of vitamin D supplementation in infectious diseases, including an up-to-date analysis of the putative benefits of vitamin D supplementation in the ongoing COVID-19 crisis.
Collapse
Affiliation(s)
- Aiten Ismailova
- Departments of Physiology, McGill University, Montreal, Qc, Canada
| | - John H White
- Departments of Physiology, McGill University, Montreal, Qc, Canada.
- Departments of Medicine, McGill University, Montreal, Qc, Canada.
| |
Collapse
|
|
17
|
Atreya R, Bojarski C, Kühl AA, Trajanoski Z, Neurath MF, Siegmund B. Ileal and colonic Crohn'´s disease: Ddoes location makes a difference in therapy efficacy? CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2022; 3:100097. [PMID: 35345820 PMCID: PMC8956925 DOI: 10.1016/j.crphar.2022.100097] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 03/07/2022] [Accepted: 03/16/2022] [Indexed: 12/05/2022] Open
Abstract
Within the IBD entity of Crohn's disease, there is currently no differentiation between ileal and colonic manifestation for recruitment of patients in clinical trials, well-powered analysis of study results or therapeutic decisions in daily clinical practice. However, there is accumulating evidence from epidemiological, genetic, microbial, immunological, and clinical characteristics that clearly indicate that ileal Crohn's disease represents a distinct disease entity, which differentiates itself from colonic Crohn's disease. This is also reflected by lower efficacy of targeted therapies in isolated ileal compared to colonic Crohn's disease. The distinct site-specific mechanisms that drive heightened non-response in ileal disease need to be analysed in-depth in the future, to enable optimized therapy in the individual Crohn's disease patient.
Collapse
|
|
18
|
Ogundepo S, Chiamaka AM, Olatinwo M, Adepoju D, Aladesanmi MT, Celestine UO, Ali KC, Umezinwa OJ, Olasore J, Alausa A. The role of diosgenin in crohn’s disease. CLINICAL PHYTOSCIENCE 2022. [DOI: 10.1186/s40816-022-00338-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
AbstractInflammatory bowel disease (IBD) is a chronic idiopathic inflammation that can grossly affect the entire gastrointestinal tract (GIT) from the mouth to the anus. Crohn’s disease is the most known type of IBD and has been the focus of attention due to its increase in prevalence worldwide. Although the etiology is yet to be elucidated, recent studies have pointed out Crohn’s disease to arise from a complex interaction between environmental influences, genetic predisposition, and altered gut microbiota, resulting in dysregulated adaptive and innate responses. The presenting hallmarks of Crohn’s disease may include weight loss, nausea, vomiting, abdominal pain, diarrhea, fever, or chills. Treatment is usually done with many approved immunosuppressive drugs and surgery. However, a promising avenue from natural compounds is a safer therapy due to its safe natural active ingredients and the strong activity it shows in the treatment and management of diseases. Diosgenin, “a major biologically active natural steroidal sapogenin found in Chinese yam,” has been widely reported as a therapeutic agent in the treatment of various classes of disorders such as hyperlipidemia, inflammation, diabetes, cancer, infection, and immunoregulation. In this review, an analysis of literature data on diosgenin employed as a therapeutic agent for the treatment of Crohn’s disease is approached, to strengthen the scientific database and curtail the dreadful impact of Crohn’s disease.
Collapse
|
|
19
|
Schardey J, Zehl S, Kappenberger AS, Zimmermann P, Beigel F, Schiergens TS, Kasparek MS, Kühn F, Werner J, Wirth U. It is not NOD2 - genetic and clinical risk factors for postoperative complications following ileocolic resection in Crohn's disease. Int J Colorectal Dis 2022; 37:1901-1908. [PMID: 35913516 PMCID: PMC9388399 DOI: 10.1007/s00384-022-04223-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/13/2022] [Indexed: 02/04/2023]
Abstract
PURPOSE To evaluate the role of the nucleotide oligomerization domain 2 (NOD2) mutation status and other risk factors for the incidence of postoperative complications after ileocolic resection for Crohn's disease (CD). METHODS Data of 138 patients consecutively undergoing ileocolic resection for CD at a tertiary academic referral center were retrospectively analyzed including single nucleotide polymorphism (SNP) data of the NOD2 gene. Uni- and multivariate regression analysis was performed to identify factors associated with increased risk of severe postoperative complications. RESULTS From 114 patients (83%), the NOD2 mutation status was available. Of these, 60 (53%) had a NOD2 wildtype, whereas eleven (10%) were homozygous for the high risk p.Leu1007fsX1008 (rs2066847) variant. Major postoperative complications occurred in 28 patients (20%). Twenty-seven of these (96%) were intraabdominal septic complications such as anastomotic leakage or abscess. Male gender (P = 0.029; OR 3.052, the duration of CD (time [months] from initial diagnosis of CD to surgery; P = 0.001; OR 1.009), previous abdominal surgery for CD (P = 0.017; OR 3.49), and the presence of enteric fistulas (P = 0.023; OR 3.21) were identified as independent risk factors for major postoperative complications. Homozygosity for the NOD2 high-risk variant p.Leu1007fsX1008 did not show increased postoperative morbidity in the short and long-term outcome. CONCLUSIONS We could detect independent risk factors for major postoperative complications after ileocolic resection for Crohn's disease. However, patients with the high-risk variant p.Leu1007fsX1008 of the NOD2 gene did not show increased postoperative morbidity.
Collapse
Affiliation(s)
- Josefine Schardey
- grid.5252.00000 0004 1936 973XDepartment of General, Visceral and Transplant Surgery, Ludwig-Maximilians-University Munich, Marchioninistr. 15, 81377 Munich, Germany
| | - Sophie Zehl
- grid.5252.00000 0004 1936 973XDepartment of General, Visceral and Transplant Surgery, Ludwig-Maximilians-University Munich, Marchioninistr. 15, 81377 Munich, Germany
| | - Alina S. Kappenberger
- grid.5252.00000 0004 1936 973XDepartment of General, Visceral and Transplant Surgery, Ludwig-Maximilians-University Munich, Marchioninistr. 15, 81377 Munich, Germany
| | - Petra Zimmermann
- grid.5252.00000 0004 1936 973XDepartment of General, Visceral and Transplant Surgery, Ludwig-Maximilians-University Munich, Marchioninistr. 15, 81377 Munich, Germany
| | - Florian Beigel
- grid.5252.00000 0004 1936 973XDepartment of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Tobias S. Schiergens
- grid.5252.00000 0004 1936 973XDepartment of General, Visceral and Transplant Surgery, Ludwig-Maximilians-University Munich, Marchioninistr. 15, 81377 Munich, Germany
| | - Michael S. Kasparek
- grid.5252.00000 0004 1936 973XDepartment of General, Visceral and Transplant Surgery, Ludwig-Maximilians-University Munich, Marchioninistr. 15, 81377 Munich, Germany ,Department of Visceral Surgery, Josephinum, Munich, Germany
| | - Florian Kühn
- grid.5252.00000 0004 1936 973XDepartment of General, Visceral and Transplant Surgery, Ludwig-Maximilians-University Munich, Marchioninistr. 15, 81377 Munich, Germany
| | - Jens Werner
- grid.5252.00000 0004 1936 973XDepartment of General, Visceral and Transplant Surgery, Ludwig-Maximilians-University Munich, Marchioninistr. 15, 81377 Munich, Germany
| | - Ulrich Wirth
- grid.5252.00000 0004 1936 973XDepartment of General, Visceral and Transplant Surgery, Ludwig-Maximilians-University Munich, Marchioninistr. 15, 81377 Munich, Germany
| |
Collapse
|
|
20
|
Zhu Y, Qian W, Huang L, Xu Y, Guo Z, Cao L, Gong J, Coffey JC, Shen B, Li Y, Zhu W. Role of Extended Mesenteric Excision in Postoperative Recurrence of Crohn's Colitis: A Single-Center Study. Clin Transl Gastroenterol 2021; 12:e00407. [PMID: 34597277 PMCID: PMC8483874 DOI: 10.14309/ctg.0000000000000407] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Accepted: 08/10/2021] [Indexed: 01/08/2023] Open
Abstract
INTRODUCTION The mesentery is involved in Crohn's disease. The impact of the extent of mesenteric resection on postoperative disease progression in Crohn's disease remains unconfirmed. This study aimed to determine the association between resection of the mesentery and postoperative outcomes in patients with Crohn's colitis (CC) undergoing colorectal surgery. METHODS Patients with CC who underwent colorectal resection between January 2000 and December 2018 were reviewed, and the data were gathered from a prospectively maintained database. Patients were divided into 2 groups according to the extent of mesenteric resection, the extensive mesenteric excision (EME) group and the limited mesenteric excision (LME) group. Outcomes including early postoperative morbidities and surgical recurrence were compared between the 2 groups. RESULTS Of the 126 patients included, 60 were in the LME group and 66 in the EME group. There was no significant difference between the 2 groups in early postsurgical outcomes except the intraoperative blood loss was increased in the LME group (P = 0.002). Patients in the EME group had a longer postoperative surgical recurrence-free survival time when compared with those in the LME group (P = 0.01). LME was an independent predictor of postoperative surgical recurrence (hazard ratio 2.67, 95% confidence interval 1.04-6.85, P = 0.04). This was further confirmed in the subgroup analysis of patients undergoing colorectal resection and anastomosis (hazard ratio 2.83, 95% confidence interval 1.01-7.96, P = 0.048). DISCUSSION In patients undergoing surgery for CC, inclusion of the mesentery is associated with similar short-term outcomes and improved long-term outcomes compared with those seen when the mesentery is retained.
Collapse
Affiliation(s)
- Yipeng Zhu
- Department of General Surgery, Jinling Hospital, Medical School of Southeast University, Nanjing, PR China;
| | - Wenwei Qian
- Department of General Surgery, Jinling Hospital, Medical School of Southeast University, Nanjing, PR China;
| | - Liangyu Huang
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China;
| | - Yihan Xu
- Department of General Surgery, Jinling Hospital, School of Nanjing Medical University, Nanjing, PR China;
| | - Zhen Guo
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China;
| | - Lei Cao
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China;
| | - Jianfeng Gong
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China;
| | - J. Calvin Coffey
- Department of Surgery, University Hospital Limerick, Limerick, Ireland
| | - Bo Shen
- Section of Inflammatory Bowel Diseases and Center for Interventional IBD, Columbia University Irving Medical Center-New York Presbyterian, New York, New York, USA
| | - Yi Li
- Department of General Surgery, Jinling Hospital, Medical School of Southeast University, Nanjing, PR China;
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China;
| | - Weiming Zhu
- Department of General Surgery, Jinling Hospital, Medical School of Southeast University, Nanjing, PR China;
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China;
| |
Collapse
|
|
21
|
Pierre N, Salée C, Vieujean S, Bequet E, Merli AM, Siegmund B, Meuwis MA, Louis E. Review article: distinctions between ileal and colonic Crohn's disease: from physiology to pathology. Aliment Pharmacol Ther 2021; 54:779-791. [PMID: 34297423 DOI: 10.1111/apt.16536] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 05/15/2021] [Accepted: 07/05/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND Ileal and colonic Crohn's disease seem to be two separate entities. AIMS To describe the main physiological distinctions between the small and the large intestine and to analyse the differences between ileal and colonic Crohn's disease. METHODS The relevant literature was critically examined and synthesised. RESULTS The small and large intestine have fundamental distinctions (anatomy, cellular populations, immune defence, microbiota). The differences between ileal and colonic Crohn's disease are highlighted by a heterogeneous body of evidence including clinical features (natural history of the disease, efficacy of treatments, and monitoring), epidemiological data (smoking status, age, gender) and biological data (genetics, microbiota, immunity, mesenteric fat). However, the contribution of these factors to disease location remains poorly understood. CONCLUSION The classification of ileal and colonic Crohn's disease as distinct subphenotypes is well supported by the literature. Understanding of these differences could be exploited to develop more individualised patient care.
Collapse
Affiliation(s)
- Nicolas Pierre
- Laboratory of Translational Gastroenterology, GIGA-Institute, University of Liège, Liège, Belgium
| | - Catherine Salée
- Laboratory of Translational Gastroenterology, GIGA-Institute, University of Liège, Liège, Belgium
| | - Sophie Vieujean
- Laboratory of Translational Gastroenterology, GIGA-Institute, University of Liège, Liège, Belgium.,Hepato-Gastroenterology and Digestive Oncology Department, Liège University Hospital, Liège, Belgium
| | - Emeline Bequet
- Laboratory of Translational Gastroenterology, GIGA-Institute, University of Liège, Liège, Belgium.,Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Liège University Hospital, Liège, Belgium
| | - Angela-Maria Merli
- Laboratory of Translational Gastroenterology, GIGA-Institute, University of Liège, Liège, Belgium
| | - Britta Siegmund
- Division of Gastroenterology, Infectiology and Rheumatology, Medical Department, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Marie-Alice Meuwis
- Laboratory of Translational Gastroenterology, GIGA-Institute, University of Liège, Liège, Belgium.,Hepato-Gastroenterology and Digestive Oncology Department, Liège University Hospital, Liège, Belgium
| | - Edouard Louis
- Laboratory of Translational Gastroenterology, GIGA-Institute, University of Liège, Liège, Belgium.,Hepato-Gastroenterology and Digestive Oncology Department, Liège University Hospital, Liège, Belgium
| |
Collapse
|
|
22
|
Cho CW, You MW, Oh CH, Lee CK, Moon SK. Long-term Disease Course of Crohn's Disease: Changes in Disease Location, Phenotype, Activities, and Predictive Factors. Gut Liver 2021; 16:157-170. [PMID: 34456186 PMCID: PMC8924800 DOI: 10.5009/gnl210118] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 07/01/2021] [Accepted: 07/13/2021] [Indexed: 11/04/2022] Open
Abstract
Crohn's disease (CD) is a chronic destructive inflammatory bowel disease that affects young people and is associated with significant morbidity. The clinical spectrum and disease course of CD are heterogeneous and often difficult to predict based on the initial presentation. In this article, changes in the disease location, behavior, clinical course during long-term follow-up, and predictive factors are reviewed. Generally, four different patterns of clinical course are discussed: remission, stable disease, chronic relapsing disease, and chronic refractory disease. Understanding the long-term disease course of CD is mandatory to reveal the underlying pathophysiology of the disease and to move toward a more optimistic disease course, such as remission or stability, and less adverse outcomes or devastating sequelae.
Collapse
Affiliation(s)
- Choong Wui Cho
- Department of Radiology, Kyung Hee University Hospital, Seoul, Korea
| | - Myung-Won You
- Department of Radiology, Kyung Hee University Hospital, Seoul, Korea
| | - Chi Hyuk Oh
- Department of Internal Medicine, Kyung Hee University Hospital, Seoul, Korea
| | - Chang Kyun Lee
- Department of Internal Medicine, Kyung Hee University Hospital, Seoul, Korea
| | - Sung Kyoung Moon
- Department of Radiology, Kyung Hee University Hospital, Seoul, Korea
| |
Collapse
|
|
23
|
Siddique I, Mustafa AS, Khan I, Ziyab AH, Altarrah M, Sulaiman R, Kadungothayil N, Shaheed F. Detection of mutations in NOD2/CARD15 gene in Arab patients with Crohn's disease. Saudi J Gastroenterol 2021; 27:240-248. [PMID: 34380868 PMCID: PMC8448013 DOI: 10.4103/sjg.sjg_582_20] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
BACKGROUND Mutations in NOD2/CARD15 gene have been linked to an increased risk of Crohn's disease (CD). The objective of this study is to determine NOD2/CARD15 gene mutations, and their association with the risk of CD in Arabs in Kuwait. METHODS Four NOD2 gene mutations, including Pro268Ser (SNP5), Arg702Trp (SNP8), Gly908Arg (SNP12), and Leu1007FsinsC (SNP13) were examined in Arab CD patients (n = 103) and control subjects (n = 100). The genomic DNA was isolated and used in polymerase chain reaction (PCR) with four sets of specific primers. The PCR-amplified DNA fragments were sequenced and analyzed for the NOD2 mutations. Logistic regression was used to estimate the adjusted odds ratios (aOR) and 95% confidence intervals (CI). RESULTS Of the four genotyped variants, the Arg702Trp (SNP8) and Leu1007FsinsC (SNP13) variants were not informative in our study sample due to minor allele frequency of <1%. The Pro268Ser (SNP5) mutation was detected in 17 (16.5%) CD patients and 32 (32.0%) controls. The Gly908Arg (SNP12) mutation was observed in 24 (23.3%) patients and 10 (10.0%) controls. In the dominant genetic risk model (i.e. carrying at least one minor allele), CD patients compared to controls were less likely to carry either the "CT" or "TT" genotype of variant Pro268Ser (SNP5; aOR = 0.43, 95% CI: 0.22-0.84). In contrast, CD patients compared to controls were more likely to carry the homozygous for the minor allele or the heterozygous genotypes of variant Gly908Arg (SNP12; aOR = 2.67, 95% CI: 1.19-5.97). CONCLUSIONS In this Arab population, carrying at least one copy of the minor allele of Gly908Arg (SNP12) mutation in NOD2 gene was associated with increased susceptibility to CD, while having the heterozygous or homozygous for the minor allele genotype of the Pro268Ser (SNP5) mutation provided protection against CD. Mutations in Arg702Trp (SNP8) and Leu1007FsinsC (SNP13) were not detected in this sample of the Arab population in Kuwait.
Collapse
Affiliation(s)
- Iqbal Siddique
- Department of Medicine, Faculty of Medicine, Kuwait University, Kuwait City, Al-Amiri Hospital, Kuwait,Thunayan Al-Ghanim Gastroenterology Center, Al-Amiri Hospital, Kuwait,Address for correspondence: Prof. Iqbal Siddique, Department of Medicine, Faculty of Medicine, Kuwait University, P. O. Box 24923, Safat - 13110, Kuwait. E-mail:
| | - Abu S. Mustafa
- Department of Microbiology, OMICS Research Unit, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait,Department of Research Core Facility, OMICS Research Unit, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Islam Khan
- Department of Biochemistry, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Ali H. Ziyab
- Department of Community Medicine and Behavioral Sciences, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Munira Altarrah
- Thunayan Al-Ghanim Gastroenterology Center, Al-Amiri Hospital, Kuwait
| | - Riyas Sulaiman
- Department of Research Core Facility, OMICS Research Unit, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Numeer Kadungothayil
- Department of Research Core Facility, OMICS Research Unit, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Faraz Shaheed
- Department of Research Core Facility, OMICS Research Unit, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
| |
Collapse
|
|
24
|
Atreya R, Siegmund B. Location is important: differentiation between ileal and colonic Crohn's disease. Nat Rev Gastroenterol Hepatol 2021; 18:544-558. [PMID: 33712743 DOI: 10.1038/s41575-021-00424-6] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/29/2021] [Indexed: 01/31/2023]
Abstract
Crohn's disease can affect any part of the gastrointestinal tract; however, current European and national guidelines worldwide do not differentiate between small-intestinal and colonic Crohn's disease for medical treatment. Data from the past decade provide evidence that ileal Crohn's disease is distinct from colonic Crohn's disease in several intestinal layers. Remarkably, colonic Crohn's disease shows an overlap with regard to disease behaviour with ulcerative colitis, underlining the fact that there is more to inflammatory bowel disease than just Crohn's disease and ulcerative colitis, and that subtypes, possibly defined by location and shared pathophysiology, are also important. This Review provides a structured overview of the differentiation between ileal and colonic Crohn's disease using data in the context of epidemiology, genetics, macroscopic differences such as creeping fat and histological findings, as well as differences in regard to the intestinal barrier including gut microbiota, mucus layer, epithelial cells and infiltrating immune cell populations. We also discuss the translation of these basic findings to the clinic, emphasizing the important role of treatment decisions. Thus, this Review provides a conceptual outlook on a new mechanism-driven classification of Crohn's disease.
Collapse
Affiliation(s)
- Raja Atreya
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Britta Siegmund
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
| |
Collapse
|
|
25
|
Strong association of common variants in the miRNA-binding site of NOD2 gene with clinicopathological characteristics and disease activity of systemic lupus erythematosus. Clin Rheumatol 2021; 40:4559-4567. [PMID: 34173079 DOI: 10.1007/s10067-021-05812-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 05/27/2021] [Accepted: 06/06/2021] [Indexed: 02/07/2023]
Abstract
INTRODUCTION/OBJECTIVES Systemic lupus erythematosus (SLE) is a multifactorial systemic autoimmune disease, in which genetic susceptibility plays a pivotal role. The nucleotide oligomerization domain 2 (NOD2) gene is one of the main regulators of chronic inflammatory conditions and could be involved in SLE pathogenesis. Single nucleotide polymorphisms (SNPs) in miRNA binding sites which are located in 3'UTR of the NOD2 gene could be associated with SLE risk by dysregulation of NOD2 expression. In the present study, we assessed the possible association between SNPs rs3135500 and rs3135499 in the NOD2 gene with SLE risk in the Iranian population. METHODS A case-control study using 110 SLE patients and 120 control subjects was undertaken to estimate rs3135500 (G > A) and rs3135499 (A > C) genotypes via real-time PCR high-resolution melting method (HRM). RESULTS No significant association was observed between allele and genotype frequencies of rs3135500 and rs3135499 polymorphisms and SLE risk in this population (P > 0.05). However, there was an obvious association between rs3135500 (A allele) with laboratory factors that are associated with disease activity (P < 0.05) and some clinical manifestations that are associated with disease severity such as neurological symptoms, skin manifestations, renal involvements, and higher serum concentration of creatinine (P < 0.05). Besides, rs3135499 (C allele) was correlated with renal involvement and also the concentration of creatinine (P < 0.05). Moreover, in the patients group, the risk alleles in these polymorphisms were associated with lower age of onset (P < 0.05). CONCLUSIONS Our results suggest a substantial association between NOD2 polymorphisms with clinicopathological characteristics and SLE disease activity. Key Points • Single nucleotide polymorphisms (SNPs) in miRNA binding sites which are located in 3'UTR of the NOD2 gene could be associated with SLE risk by dysregulation of NOD2 expression. • Our results suggested that two miRSNPs (rs3135500 and rs3135499) in the NOD2 gene were meaningfully correlated with clinicopathological characteristics and disease activity of SLE.
Collapse
|
|
26
|
Li X, Liang D, Meng J, Zhou J, Chen Z, Huang S, Lu B, Qiu Y, Baker ME, Ye Z, Cao Q, Wang M, Yuan C, Chen Z, Feng S, Zhang Y, Iacucci M, Ghosh S, Rieder F, Sun C, Chen M, Li Z, Mao R, Huang B, Feng ST. Development and Validation of a Novel Computed-Tomography Enterography Radiomic Approach for Characterization of Intestinal Fibrosis in Crohn's Disease. Gastroenterology 2021; 160:2303-2316.e11. [PMID: 33609503 PMCID: PMC8903088 DOI: 10.1053/j.gastro.2021.02.027] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 01/07/2021] [Accepted: 02/09/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS No reliable method for evaluating intestinal fibrosis in Crohn's disease (CD) exists; therefore, we developed a computed-tomography enterography (CTE)-based radiomic model (RM) for characterizing intestinal fibrosis in CD. METHODS This retrospective multicenter study included 167 CD patients with 212 bowel lesions (training, 98 lesions; test, 114 lesions) who underwent preoperative CTE and bowel resection at 1 of the 3 tertiary referral centers from January 2014 through June 2020. Bowel fibrosis was histologically classified as none-mild or moderate-severe. In the training cohort, 1454 radiomic features were extracted from venous-phase CTE and a machine learning-based RM was developed based on the reproducible features using logistic regression. The RM was validated in an independent external test cohort recruited from 3 centers. The diagnostic performance of RM was compared with 2 radiologists' visual interpretation of CTE using receiver operating characteristic (ROC) curve analysis. RESULTS In the training cohort, the area under the ROC curve (AUC) of RM for distinguishing moderate-severe from none-mild intestinal fibrosis was 0.888 (95% confidence interval [CI], 0.818-0.957). In the test cohort, the RM showed robust performance across 3 centers with an AUC of 0.816 (95% CI, 0.706-0.926), 0.724 (95% CI, 0.526-0.923), and 0.750 (95% CI, 0.560-0.940), respectively. Moreover, the RM was more accurate than visual interpretations by either radiologist (radiologist 1, AUC = 0.554; radiologist 2, AUC = 0.598; both, P < .001) in the test cohort. Decision curve analysis showed that the RM provided a better net benefit to predicting intestinal fibrosis than the radiologists. CONCLUSIONS A CTE-based RM allows for accurate characterization of intestinal fibrosis in CD.
Collapse
Affiliation(s)
- Xuehua Li
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Dong Liang
- Medical AI Lab, School of Biomedical Engineering, Health Science Center, Shenzhen University, People's Republic of China
| | - Jixin Meng
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Jie Zhou
- Department of Radiology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Zhao Chen
- Department of Medical Imaging Center, Nan Fang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Siyun Huang
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Baolan Lu
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Yun Qiu
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Mark E Baker
- Section of Abdominal Imaging, Imaging Institute, Digestive Disease Institute and Cancer Institute, Cleveland Clinic, Cleveland, Ohio
| | - Ziyin Ye
- Department of Pathology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Qinghua Cao
- Department of Pathology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Mingyu Wang
- Medical AI Lab, School of Biomedical Engineering, Health Science Center, Shenzhen University, People's Republic of China
| | - Chenglang Yuan
- Medical AI Lab, School of Biomedical Engineering, Health Science Center, Shenzhen University, People's Republic of China
| | - Zhihui Chen
- Department of Gastrointestinal and Pancreatic Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Shengyu Feng
- Medical AI Lab, School of Biomedical Engineering, Health Science Center, Shenzhen University, People's Republic of China
| | - Yuxuan Zhang
- Medical AI Lab, School of Biomedical Engineering, Health Science Center, Shenzhen University, People's Republic of China
| | - Marietta Iacucci
- National Institute for Health Research Biomedical Research Institute, Institute of Translational Medicine, University of Birmingham, University Hospitals Birmingham National Health Service Foundation Trust, United Kingdom
| | - Subrata Ghosh
- National Institute for Health Research Biomedical Research Institute, Institute of Translational Medicine, University of Birmingham, University Hospitals Birmingham National Health Service Foundation Trust, United Kingdom
| | - Florian Rieder
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, Ohio
| | - Canhui Sun
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Minhu Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Ziping Li
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Ren Mao
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China; Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, Ohio.
| | - Bingsheng Huang
- Medical AI Lab, School of Biomedical Engineering, Health Science Center, Shenzhen University, People's Republic of China.
| | - Shi-Ting Feng
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China.
| |
Collapse
|
|
27
|
|
|
28
|
Marafini I, Monteleone G. Precision Medicine in Inflammatory Bowel Diseases. Front Pharmacol 2021; 12:653924. [PMID: 33927628 PMCID: PMC8076955 DOI: 10.3389/fphar.2021.653924] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 03/10/2021] [Indexed: 12/19/2022] Open
Abstract
During the last decades, a better understanding of the mechanisms sustaining the pathogenic process in inflammatory bowel diseases (IBD) has contributed to expand the therapeutic armamentarium for patients with these disorders. Alongside with traditional therapies, monoclonal antibodies against tumor necrosis factor-α, the interleukin (IL)-12/IL-23 p40 subunit and the α4β7 integrin, and tofacitinib, a small molecule inhibiting intracellular pathways downstream to cytokine receptors, have entered into the clinic. However, these drugs are not effective in all patients and some responders can lose response over time. Such a therapeutic failure is, at least in part, dependent on the fact that, in IBD, the tissue damage is driven by simultaneous activation of multiple and distinct immune-inflammatory signals and the detrimental mucosal immune response changes over time even in the same patient. Therefore, personalized approaches aimed at identifying which patient should be treated with a specific drug at a precise time point are worth pursuing. A such approach has the advantage to improve efficacy of the drug and limit adverse reactions, thereby improving quality of the life of the patients and reducing costs. In this review, we summarize all the available evidence about the possible role of precision medicine in IBD.
Collapse
Affiliation(s)
- Irene Marafini
- Gastroenterology Unit, Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Giovanni Monteleone
- Gastroenterology Unit, Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy
| |
Collapse
|
|
29
|
Li XH, Feng ST, Cao QH, Coffey JC, Baker ME, Huang L, Fang ZN, Qiu Y, Lu BL, Chen ZH, Li Y, Bettenworth D, Iacucci M, Sun CH, Ghosh S, Rieder F, Chen MH, Li ZP, Mao R. Degree of Creeping Fat Assessed by Computed Tomography Enterography is Associated with Intestinal Fibrotic Stricture in Patients with Crohn's Disease: A Potentially Novel Mesenteric Creeping Fat Index. J Crohns Colitis 2021; 15:1161-1173. [PMID: 33411893 PMCID: PMC8427713 DOI: 10.1093/ecco-jcc/jjab005] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Emerging evidence points to a link between creeping fat and the pathogenesis of Crohn's disease [CD]. Non-invasive assessment of the severity of creeping fat on cross-sectional imaging modality has seldom been investigated. This study aimed to develop and characterize a novel mesenteric creeping fat index [MCFI] based on computed tomography [CT] in CD patients. METHODS MCFI was developed based on vascular findings on CT in a retrospective cohort [n = 91] and validated in a prospective cohort [n = 30]. The severity of creeping fat was graded based on the extent to which mesenteric fat extended around the intestinal circumference using the vessels in the fat as a marker. The accuracy of MCFI was assessed by comparing it with the degree of creeping fat observed in surgical specimens. The relationship between MCFI and fibrostenosis was characterized by determining if these correlated. The accuracy of MCFI was compared with other radiographic indices [i.e. visceral to subcutaneous fat area ratio and fibrofatty proliferation score]. RESULTS In the retrospective cohort, MCFI had moderate accuracy in differentiating moderate-severe from mild fibrostenosis (area under the receiver operating characteristic [ROC] curve [AUC] = 0.799; p = 0.000). ROC analysis in the retrospective cohort identified a threshold MCFI of > 3 which accurately differentiated fibrostenosis severity in the prospective cohort [AUC = 0.756; p = 0.018]. An excellent correlation was shown between MCFI and the extent of fat wrapping in specimens in the prospective cohort [r = 0.840, p = 0.000]. Neither visceral to subcutaneous fat area ratio nor fibrofatty proliferation score correlated well with the degree of intestinal fibrosis. CONCLUSIONS MCFI can accurately characterize the extent of mesenteric fat wrapping in surgical specimens. It may become another non-invasive measure of CD fibrostenosis.
Collapse
Affiliation(s)
- Xue-Hua Li
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China
| | - Shi-Ting Feng
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China
| | - Qing-Hua Cao
- Department of Pathology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China
| | - J Calvin Coffey
- Department of Surgery, University Hospital Group Limerick and School of Medicine, University of Limerick, Limerick, Ireland
| | - Mark E Baker
- Section of Abdominal Imaging, Imaging Institute, Digestive Disease Institute and Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Li Huang
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China
| | - Zhuang-Nian Fang
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China
| | - Yun Qiu
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China
| | - Bao-Lan Lu
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China
| | - Zhi-Hui Chen
- Department of Gastrointestinal and Pancreatic Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China
| | - Yi Li
- Center for Inflammatory Bowel Diseases, Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, People’s Republic of China
| | - Dominik Bettenworth
- Department of Medicine B for Gastroenterology and Hepatology, University Hospital Münster, Münster, Germany
| | - Marietta Iacucci
- NIHR Biomedical Research Institute, Institute of Translational Medicine, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, UK
| | - Can-Hui Sun
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China
| | - Subrata Ghosh
- NIHR Biomedical Research Institute, Institute of Translational Medicine, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, UK
| | - Florian Rieder
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Min-Hu Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China
| | - Zi-Ping Li
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China
| | - Ren Mao
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China,Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA,Corresponding author: Ren Mao, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan Road 2nd, Guangzhou 510080, People’s Republic of China; Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA. Tel: 86-20-87755766-8471; Fax: 86-20-87615805;
| |
Collapse
|
|
30
|
Macrophage Deficiency Makes Intestinal Epithelial Cells Susceptible to NSAID-Induced Damage. BIOMED RESEARCH INTERNATIONAL 2020; 2020:6757495. [PMID: 33282952 PMCID: PMC7685797 DOI: 10.1155/2020/6757495] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 08/31/2020] [Accepted: 09/29/2020] [Indexed: 01/21/2023]
Abstract
Objectives In Crohn's disease (CD), the mechanisms underlying the regulation by granulocyte-macrophage colony-stimulating factor (GM-CSF) of mucosal barrier function in the ileum are unclear. We analyzed the molecular mechanisms underlying the regulation by GM-CSF of the mucosal barrier function. Methods We examined the role of GM-CSF in the intestinal barrier function in CD at the molecular-, cellular-, and animal-model levels. Results Macrophages directly secreted GM-CSF, promoting intestinal epithelial proliferation and inhibiting apoptosis, which maintained intestinal barrier function. Macrophages were absent in NSAID-induced ileitis, causing GM-CSF deficiency, increasing the apoptosis rate, decreasing the proliferation rate, increasing inter- and paracellular permeabilities, decreasing the TJP levels, and reducing the numbers of mesenteric lymph nodes, memory T cells, and regulatory T cells in Csf1op/op transgenic mice. Conclusions GM-CSF is required for the maintenance of intestinal barrier function. Macrophages directly secrete GM-CSF, promoting intestinal epithelial proliferation and inhibiting apoptosis.
Collapse
|
|
31
|
Bi K, Zhang X, Chen W, Diao H. MicroRNAs Regulate Intestinal Immunity and Gut Microbiota for Gastrointestinal Health: A Comprehensive Review. Genes (Basel) 2020; 11:genes11091075. [PMID: 32932716 PMCID: PMC7564790 DOI: 10.3390/genes11091075] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 08/24/2020] [Accepted: 09/09/2020] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs are small non-coding RNAs regulating gene expression at the post-transcriptional level. The regulation of microRNA expression in the gut intestine is gradually recognized as one of the crucial contributors of intestinal homeostasis and overall health. Recent studies indicated that both the microRNAs endogenous in the gut intestine and exogenous from diets could play influential roles in modulating microbial colonization and intestinal immunity. In this review, we discuss the biological functions of microRNAs in regulating intestinal homeostasis by modulating intestinal immune responses and gut microbiota. We particularly focus on addressing the microRNA-dependent communication and interactions among microRNA, gut microbiota, and intestinal immune system. Besides, we also summarize the roles of diet-derived microRNAs in host-microbiome homeostasis and their benefits on intestinal health. A better understanding of the relationships among intestinal disorders, microRNAs, and other factors influencing intestinal health can facilitate the application of microRNA-based therapeutics for gastrointestinal diseases.
Collapse
|
|
32
|
Truta B, Wohler E, Sobreira N, Datta LW, Brant SR. Role of telomere shortening in anticipation of inflammatory bowel disease. World J Gastrointest Pharmacol Ther 2020; 11:69-78. [PMID: 32953227 PMCID: PMC7475772 DOI: 10.4292/wjgpt.v11.i4.69] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Revised: 06/25/2020] [Accepted: 08/15/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The existence of genetic anticipation has been long disputed in inflammatory bowel disease (IBD) in the absence of the explanatory mechanism. AIM To determine whether it was predictive of genetic anticipation, we evaluated telomere length in IBD. We hypothesized that multiplex IBD families exhibit a genetic defect impacting telomere maintenance mechanisms. METHODS We studied three IBD families with multiple affected members in three successive generations. We determined telomere length (TL) in lymphocytes and granulocytes from peripheral blood of the affected members using flow cytometry and fluorescence in-situ hybridization (flow FISH). We also performed whole exome sequencing in the blood of all available family members and used PhenoDB to identify potential candidate gene variants with recessive or dominant modes of inheritance. RESULTS Out of twenty-four patients of European descent selected to participate in the study, eleven patients, eight parent-child pairs affected by IBD, were included in the genetic anticipation analysis. Median difference in age at diagnosis between two successive generations was 16.5 years, with earlier age at onset in the younger generations. In most of the affected members, the disease harbored similar gastrointestinal and extraintestinal involvement but was more aggressive among the younger generations. TL was not associated with earlier age at onset or more severe disease in members of successive generations affected by IBD. NOD2 gene mutations were present in the Crohn's disease patients of one family. However, no gene variants were identified as potential candidates for inheritance. CONCLUSION Telomere shortening appears unlikely to be involved in mechanisms of possible genetic anticipation in IBD. Further studies using a larger sample size are required to confirm or refute our findings.
Collapse
Affiliation(s)
- Brindusa Truta
- Steven R Brant, Division of Gastroenterology & Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD 21210, United States
| | - Elizabeth Wohler
- McKusick-Nathan Institute of Genetics, Johns Hopkins School of Medicine, Baltimore, MD 21205, United States
| | - Nara Sobreira
- McKusick-Nathan Institute of Genetics, Johns Hopkins School of Medicine, Baltimore, MD 21205, United States
| | - Lisa W. Datta
- Steven R Brant, Division of Gastroenterology & Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD 21210, United States
| | - Steven R. Brant
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers-Robert Wood Johnson Medical School, NJ, 08901, United States
| |
Collapse
|
|
33
|
Schnitzler F, Friedrich M, Angelberger M, Diegelmann J, Stallhofer J, Wolf C, Dütschler J, Truniger S, Olszak T, Beigel F, Tillack C, Lohse P, Brand S. Development of a uniform, very aggressive disease phenotype in all homozygous carriers of the NOD2 mutation p.Leu1007fsX1008 with Crohn's disease and active smoking status resulting in ileal stenosis requiring surgery. PLoS One 2020; 15:e0236421. [PMID: 32716958 PMCID: PMC7384669 DOI: 10.1371/journal.pone.0236421] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Accepted: 07/06/2020] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND NOD2 variants are the strongest genetic predictors for susceptibility to Crohn's disease (CD). However, the clinical value of NOD2 on an individual patient level remains controversial. We aimed to define the predictive power of the major NOD2 mutations regarding complicated CD in a large single center cohort. METHODS 1076 CD patients were prospectively genotyped for the three common CD-associated NOD2 mutations rs2066844, rs2066845, and rs2066847, followed by detailed genotype-phenotype analyses. RESULTS Overall, 434 CD patients (40.3%) carried at least one of the three main NOD2 mutations. A significantly higher minor allele frequency (15.6%) of the NOD2 frameshift mutation p.Leu1007fsX1008 (rs2066847) was seen in patients with aggressive disease compared to 8.2% in patients with mild disease (p = 2.6 x 10-5). Moreover, a total of 54 CD patients (5.0%) were homozygous for this NOD2 frameshift mutation. 100% of these patients had ileal disease compared to 82% of NOD2 wild-type carriers (p<0.0001). In homozygous carriers of the NOD2 frameshift mutation, 87% presented with ileal stenosis, 68.5% had fistulas, and 72.2% required CD-related surgery despite immunosuppressive therapy in 87% of these patients. All homozygous carriers of the 1007fs mutation who were active smokers had ileal stenosis and required CD-related surgery. CONCLUSION Homozygosity for Leu1007fsX1008 is an excellent biomarker for predicting complicated CD on an individual patient level. Active smoking and homozygosity for this mutation is associated with a 100% risk for developing ileal stenosis requiring CD-related surgery. In these patients, smoking cessation and early initiation of immunosuppressive strategies may be beneficial.
Collapse
Affiliation(s)
- Fabian Schnitzler
- Department of Medicine II—Grosshadern, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany
- * E-mail: (FS); (SB)
| | - Matthias Friedrich
- Nuffield Department of Orthopaedics, Kennedy Institute of Rheumatology, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
| | - Marianne Angelberger
- Department of Medicine II—Grosshadern, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany
| | - Julia Diegelmann
- Department of Preventive Dentistry and Periodontology, LMU Munich, Munich, Germany
| | - Johannes Stallhofer
- Department of Medicine II—Grosshadern, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany
- Department of Medicine IV, University Hospital, Friedrich-Schiller University, Jena, Germany
| | | | - Joel Dütschler
- Department of Gastroenterology and Hepatology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Samuel Truniger
- Department of Gastroenterology and Hepatology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Torsten Olszak
- Department of Medicine II—Grosshadern, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany
| | - Florian Beigel
- Department of Medicine II—Grosshadern, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany
| | - Cornelia Tillack
- Department of Medicine II—Grosshadern, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany
| | - Peter Lohse
- Institute of Laboratory Medicine and Human Genetics, Singen, Germany
| | - Stephan Brand
- Department of Medicine II—Grosshadern, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany
- Department of Gastroenterology and Hepatology, Kantonsspital St. Gallen, St. Gallen, Switzerland
- * E-mail: (FS); (SB)
| |
Collapse
|
|
34
|
Trindade BC, Chen GY. NOD1 and NOD2 in inflammatory and infectious diseases. Immunol Rev 2020; 297:139-161. [PMID: 32677123 DOI: 10.1111/imr.12902] [Citation(s) in RCA: 114] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 06/23/2020] [Accepted: 06/24/2020] [Indexed: 12/12/2022]
Abstract
It has been long recognized that NOD1 and NOD2 are critical players in the host immune response, primarily by their sensing bacterial peptidoglycan-conserved motifs. Significant advances have been made from efforts that characterize their upstream activators, assembly of signaling complexes, and activation of downstream signaling pathways. Disruption in NOD1 and NOD2 signaling has also been associated with impaired host defense and resistance to the development of inflammatory diseases. In this review, we will describe how NOD1 and NOD2 sense microbes and cellular stress to regulate host responses that can affect disease pathogenesis and outcomes.
Collapse
Affiliation(s)
- Bruno C Trindade
- Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Grace Y Chen
- Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| |
Collapse
|
|
35
|
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.
Collapse
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
| |
Collapse
|
|
36
|
Digby-Bell JL, Atreya R, Monteleone G, Powell N. Interrogating host immunity to predict treatment response in inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 2020; 17:9-20. [PMID: 31767987 DOI: 10.1038/s41575-019-0228-5] [Citation(s) in RCA: 81] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/14/2019] [Indexed: 02/07/2023]
Abstract
IBD treatment is undergoing a transformation with an expanding repertoire of drugs targeting different aspects of the immune response. Three novel classes of drugs have emerged in the past decade that target leukocyte trafficking to the gut (vedolizumab), neutralize key cytokines with antibodies (ustekinumab) and inhibit cytokine signalling pathways (tofacitinib). In advanced development are other drugs for IBD, including therapies targeting other cytokines such as IL-23 and IL-6. However, all agents tested so far are hampered by primary and secondary loss of response, so it is desirable to develop personalized strategies to identify which patients should be treated with which drugs. Stratification of patients with IBD by clinical parameters alone lacks sensitivity, and alternative modalities are now needed to deliver precision medicine in IBD. High-resolution profiling of immune response networks in individual patients is a promising approach and different technical platforms, including in vivo real-time molecular endoscopy, tissue transcriptomics and germline genetics, are promising tools to help predict responses to specific therapies. However, important challenges remain regarding the clinical utility of these technologies, including their scalability and accessibility. This Review focuses on unravelling some of the complexity of mucosal immune responses in IBD pathogenesis and how current and emerging analytical platforms might be harnessed to effectively stratify and individualise IBD therapy.
Collapse
Affiliation(s)
| | - Raja Atreya
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | | | - Nick Powell
- School of Immunology and Microbial Sciences, King's College London, London, UK. .,Department of Medicine, Imperial College London, London, UK.
| |
Collapse
|
|
37
|
Abstract
The organic cation transporters (OCTs) OCT1, OCT2, OCT3, novel OCT (OCTN)1, OCTN2, multidrug and toxin exclusion (MATE)1, and MATE kidney-specific 2 are polyspecific transporters exhibiting broadly overlapping substrate selectivities. They transport organic cations, zwitterions, and some uncharged compounds and operate as facilitated diffusion systems and/or antiporters. OCTs are critically involved in intestinal absorption, hepatic uptake, and renal excretion of hydrophilic drugs. They modulate the distribution of endogenous compounds such as thiamine, L-carnitine, and neurotransmitters. Sites of expression and functions of OCTs have important impact on energy metabolism, pharmacokinetics, and toxicity of drugs, and on drug-drug interactions. In this work, an overview about the human OCTs is presented. Functional properties of human OCTs, including identified substrates and inhibitors of the individual transporters, are described. Sites of expression are compiled, and data on regulation of OCTs are presented. In addition, genetic variations of OCTs are listed, and data on their impact on transport, drug treatment, and diseases are reported. Moreover, recent data are summarized that indicate complex drug-drug interaction at OCTs, such as allosteric high-affinity inhibition of transport and substrate dependence of inhibitor efficacies. A hypothesis about the molecular mechanism of polyspecific substrate recognition by OCTs is presented that is based on functional studies and mutagenesis experiments in OCT1 and OCT2. This hypothesis provides a framework to imagine how observed complex drug-drug interactions at OCTs arise. Finally, preclinical in vitro tests that are performed by pharmaceutical companies to identify interaction of novel drugs with OCTs are discussed. Optimized experimental procedures are proposed that allow a gapless detection of inhibitory and transported drugs.
Collapse
Affiliation(s)
- Hermann Koepsell
- Institute of Anatomy and Cell Biology and Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute, University of Würzburg, Würzburg, Germany
| |
Collapse
|
|
38
|
Silva F, Gatica T, Pavez C. ETIOLOGÍA Y FISIOPATOLOGÍA DE LA ENFERMEDAD INFLAMATORIA INTESTINAL. REVISTA MÉDICA CLÍNICA LAS CONDES 2019. [DOI: 10.1016/j.rmclc.2019.06.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022] Open
|
|
39
|
Mukherjee T, Hovingh ES, Foerster EG, Abdel-Nour M, Philpott DJ, Girardin SE. NOD1 and NOD2 in inflammation, immunity and disease. Arch Biochem Biophys 2019; 670:69-81. [DOI: 10.1016/j.abb.2018.12.022] [Citation(s) in RCA: 144] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2018] [Revised: 12/14/2018] [Accepted: 12/18/2018] [Indexed: 12/21/2022]
|
|
40
|
Ince MN, Elliott DE. Effective Use of the Laboratory in the Management of Patients with Inflammatory Bowel Diseases. Gastroenterol Clin North Am 2019; 48:237-258. [PMID: 31046973 DOI: 10.1016/j.gtc.2019.02.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Inflammatory bowel disease (IBD) comprises a group of chronic, intestinal inflammatory disorders, including ulcerative colitis and Crohn's disease. IBD is characterized by periods of relapse and remission. Long-term progressive intestinal inflammation can result in severe and devastating complications, such as intestinal strictures and/or fistulae. Immune suppressive medications with potent side effects are often used to control inflammation and limit disease activity. Laboratory tests guide various decisions in clinical management of IBD. We discuss tests used to diagnose IBD, assess for relapse or remission, monitor the effectiveness of therapeutic regimen, screen for the maintenance of health, and diagnose or prevent complications.
Collapse
Affiliation(s)
- M Nedim Ince
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Iowa, Carver College of Medicine, University of Iowa Hospitals and Clinics, 4546 JCP, 200 Hawkins Drive, Iowa City, IA 52242, USA.
| | - David E Elliott
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Iowa, Carver College of Medicine, University of Iowa Hospitals and Clinics, 4607 JCP, 200 Hawkins Drive, Iowa City, IA 52242, USA
| |
Collapse
|
|
41
|
Intestinal Organoids as a Novel Complementary Model to Dissect Inflammatory Bowel Disease. Stem Cells Int 2019; 2019:8010645. [PMID: 31015842 PMCID: PMC6444246 DOI: 10.1155/2019/8010645] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 02/04/2019] [Indexed: 12/13/2022] Open
Abstract
Inflammatory bowel diseases (IBDs) include colitis ulcerosa and Crohn's disease, besides the rare microscopic colitis. Both diseases show a long-lasting, relapsing-remitting, or even chronic active course with tremendous impact on quality of life. IBDs frequently cause disability, surgical interventions, and high costs; as in other autoimmune diseases, their prevalent occurrence at an early phase of life raises the burden on health care systems. Unfortunately, our understanding of the pathogenesis is still incomplete and treatment therefore largely focuses on suppressing the resulting excessive inflammation. One obstacle for deciphering the causative processes is the scarcity of models that parallel the development of the disease, since intestinal inflammation is mostly induced artificially; moreover, the intestinal epithelium, which strongly contributes to IBD pathogenesis, is difficult to assess. Recently, the development of intestinal epithelial organoids has overcome many of those problems. Here, we give an overview on the current understanding of the pathogenesis of IBDs with reference to the limitations of previous well-established experimental models. We highlight the advantages and detriments of recent organoid-based experimental setups within the IBD field and suggest possible future applications.
Collapse
|
|
42
|
Li E, Zhang Y, Tian X, Wang X, Gathungu G, Wolber A, Shiekh SS, Sartor RB, Davidson NO, Ciorba MA, Zhu W, Nelson LM, Robertson CE, Frank DN. Influence of Crohn's disease related polymorphisms in innate immune function on ileal microbiome. PLoS One 2019; 14:e0213108. [PMID: 30818349 PMCID: PMC6395037 DOI: 10.1371/journal.pone.0213108] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Accepted: 02/14/2019] [Indexed: 12/13/2022] Open
Abstract
We have previously identified NOD2 genotype and inflammatory bowel diseases (IBD) phenotype, as associated with shifts in the ileal microbiome ("dysbiosis") in a patient cohort. Here we report an integrative analysis of an expanded number of Crohn's disease (CD) related genetic defects in innate immune function (NOD2, ATG16L1, IRGM, CARD9, XBP1, ORMDL3) and composition of the ileal microbiome by combining the initial patient cohort (Batch 1, 2005-2010, n = 165) with a second consecutive patient cohort (Batch 2, 2010-2012, n = 118). These combined patient cohorts were composed of three non-overlapping phenotypes: 1.) 106 ileal CD subjects undergoing initial ileocolic resection for diseased ileum, 2.) 88 IBD colitis subjects without ileal disease (predominantly ulcerative colitis but also Crohn's colitis and indeterminate colitis, and 3.) 89 non-IBD subjects. Significant differences (FDR < 0.05) in microbiota were observed between macroscopically disease unaffected and affected regions of resected ileum in ileal CD patients. Accordingly, analysis of the effects of genetic and clinical factors were restricted to disease unaffected regions of the ileum. Beta-diversity differed across the three disease categories by PERMANOVA (p < 0.001), whereas no significant differences in alpha diversity were noted. Using negative binomial models, we confirmed significant effects of IBD phenotype, C. difficile infection, and NOD2 genotype on ileal dysbiosis in the expanded analysis. The relative abundance of the Proteobacteria phylum was positively associated with ileal CD and colitis phenotypes, but negatively associated with NOD2R genotype. Additional associations with ORMDL3 and XBP1 were detected at the phylum/subphylum level. IBD medications, such as immunomodulators and anti-TNFα agents, may have a beneficial effect on reversing dysbiosis associated with the IBD phenotype. Exploratory analysis comparing microbial composition of the disease unaffected region of the resected ileum between 27 ileal CD patients who subsequently developed endoscopic recurrence within 6-12 months versus 34 patients who did not, suggested that microbial biomarkers in the resected specimen helped stratify patients with respect to risk of post-surgical recurrence.
Collapse
Affiliation(s)
- Ellen Li
- Department of Medicine, Stony Brook University, Stony Brook, NY, United States of America
| | - Yuanhao Zhang
- Department of Medicine, Stony Brook University, Stony Brook, NY, United States of America
| | - Xinyu Tian
- Department of Medicine, Stony Brook University, Stony Brook, NY, United States of America
| | - Xuefeng Wang
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States of America
| | - Grace Gathungu
- Department of Pediatrics, Stony Brook University, Stony Brook, NY, United States of America
| | - Ashley Wolber
- Department of Medicine, University of North Carolina, Chapel Hill, NC, United States of America
| | - Shehzad S. Shiekh
- Department of Medicine, University of North Carolina, Chapel Hill, NC, United States of America
| | - R. Balfour Sartor
- Department of Medicine, University of North Carolina, Chapel Hill, NC, United States of America
| | - Nicholas O. Davidson
- Department of Medicine, Washington University St. Louis, St. Louis, MO, United States of America
| | - Matthew A. Ciorba
- Department of Medicine, Washington University St. Louis, St. Louis, MO, United States of America
| | - Wei Zhu
- Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY, United States of America
| | - Leah M. Nelson
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States of America
| | - Charles E. Robertson
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States of America
| | - Daniel N. Frank
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States of America
| |
Collapse
|
|
43
|
Kredel LI, Jödicke LJ, Scheffold A, Gröne J, Glauben R, Erben U, Kühl AA, Siegmund B. T-cell Composition in Ileal and Colonic Creeping Fat - Separating Ileal from Colonic Crohn's Disease. J Crohns Colitis 2019; 13:79-91. [PMID: 30272118 DOI: 10.1093/ecco-jcc/jjy146] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Creeping fat [CF] is a hyperplasia of adipose tissue adjacent to inflamed intestine in Crohn's disease [CD]. Data from genome-wide association studies [GWAS] distinguished Crohn's colitis from ileal CD and ulcerative colitis [UC]. This study analysed the T-cell compartments of ileal and colonic mesenteric fat and corresponding mucosa to provide cellular proof for the suggested GWAS classification. METHODS Samples were obtained from 34 CD or UC patients. Cells were analysed by immunohistochemistry and flow cytometry, and tissue cytokine release was assessed by cytometric bead array. RESULTS Only ileal CF revealed the distinct adipocyte hyperplasia combined with dense T-cell infiltration and fibrosis; colonic fat from CD and UC patients lacked these findings. T-cell subpopulations differed between mesenteric fat in ileal CD, colonic CD and UC: ileal CF had nearly 10 times more T-cells than colonic fat. The proportions of regulatory and central memory T-cells were significantly higher in ileal CF compared with colonic fat in CD and UC. In all groups, the mucosal T-cell compartment was distinct from the mesenteric fat. Remarkably, correlation between disease activity and proportion of pro- and anti-inflammatory T-cell subpopulations was inverse, comparing ileal and colonic fat in CD. CONCLUSIONS This first in-depth analysis of the T-cell compartment in ileal and colonic mesenteric adipose tissue in CD and UC identifies a unique T-cell niche in the ileal mesenteric fat tissue in CD. From a clinical point of view, our findings underscore the novel concept of colonic and ileal CD as distinct IBD entities.
Collapse
Affiliation(s)
- Lea I Kredel
- Medical Department, Division of Gastroenterology, Infectiology and Rheumatology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Lisa J Jödicke
- Medical Department, Division of Gastroenterology, Infectiology and Rheumatology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Alexander Scheffold
- Medical Department [Rheumatology, Clinical Immunology], Department of Cellular Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Jörn Gröne
- Department of Surgery, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.,Department of Surgery, Rotes Kreuz Krankenhaus Bremen, Bremen, Germany
| | - Rainer Glauben
- Medical Department, Division of Gastroenterology, Infectiology and Rheumatology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Ulrike Erben
- Medical Department, Division of Gastroenterology, Infectiology and Rheumatology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.,iPATH, Core Unit/Research Center ImmunoSciences, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Anja A Kühl
- Medical Department, Division of Gastroenterology, Infectiology and Rheumatology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.,iPATH, Core Unit/Research Center ImmunoSciences, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Britta Siegmund
- Medical Department, Division of Gastroenterology, Infectiology and Rheumatology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| |
Collapse
|
|
44
|
Crowley E, Muise A. Inflammatory Bowel Disease: What Very Early Onset Disease Teaches Us. Gastroenterol Clin North Am 2018; 47:755-772. [PMID: 30337031 DOI: 10.1016/j.gtc.2018.07.004] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2023]
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract, of which ulcerative colitis and Crohn's disease are the 2 most prevailing entities. Very early onset IBD (VEO-IBD) children diagnosed with IBD under age 6 years. Although the etiology of IBD is mostly unknown, it involves a complex interaction among host genetics, microbiota, environmental factors, and aberrant immune responses. Advances in the understanding of the genetic contribution, which appears to be much more significant in younger children, gives us a useful insight into the pathogenesis and potential future therapeutic targets in IBD.
Collapse
Affiliation(s)
- Eileen Crowley
- Cell Biology Program, Division of Gastroenterology, Hepatology and Nutrition, Inflammatory Bowel Disease Center, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; School of Medicine, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland; Department of Pediatric Gastroenterology, Hepatology and Nutrition, SickKids, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada
| | - Aleixo Muise
- Department of Biochemistry, Institute of Medical Science, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Department of Pediatrics, Institute of Medical Science, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Division of Gastroenterology, Hepatology and Nutrition, Cell Biology Program, Research Institute, The Hospital for Sick Children, University of Toronto, SickKids, Inflammatory Bowel Disease Centre, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.
| |
Collapse
|
|
45
|
Fröhling M, Tepasse P, Intemann J, Sambale M, Sherwood J, Paruzel P, Tiemeyer NM, Nowacki TM, Brückner M, Mennigen R, Lügering A, Echtermeyer F, Pap T, Stratis A, Bettenworth D. Syndecan-4 Modulates Epithelial Gut Barrier Function and Epithelial Regeneration in Experimental Colitis. Inflamm Bowel Dis 2018; 24:2579-2589. [PMID: 30053064 DOI: 10.1093/ibd/izy248] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND The transmembrane heparan sulfate proteoglycan Syndecan-4 (Sdc4) plays an important role in the regulation of various inflammatory disorders. However, the involvement of Sdc4 in intestinal inflammation remains unknown. Therefore, we assessed the impact of Sdc4 deficiency on experimental colitis and epithelial wound healing in vitro and in vivo. METHODS Dextran sulfate sodium (DSS)-induced colitis was monitored in wild type and Sdc4-deficient (Sdc4-/-) mice by assessment of body weight, histology, inflammatory cellular infiltration, and colon length. Syndecan-4 expression was measured by immunohistochemistry, Western blot, and quantitative real-time PCR. Epithelial permeability was evaluated by Evans blue measurements, Western blot, and immunohistological analysis of tight junction protein expression. Impact of Sdc4 on epithelial wound healing was determined by scratch assay in vitro and by colonoscopy following mechanical wounding in vivo. RESULTS In Sdc4-/- mice, colitis-like symptoms including severe weight loss, shortened colon length, histological damage, and invasion of macrophages and granulocytes were markedly aggravated compared with wild type (WT) animals. Moreover, colonic epithelial permeability in Sdc4-/- mice was enhanced, while tight junction protein expression decreased. Furthermore, Sdc4-/- colonic epithelial cells had lower cell proliferation and migration rates which presented in vivo as a prolonged intestinal wound healing phenotype. Strikingly, in WT animals, Sdc4 expression was reduced during colitis and was elevated during recovery. CONCLUSIONS The loss of Sdc4 aggravates the course of experimental colitis, potentially through impaired epithelial cell integrity and regeneration. In view of the development of current treatment approaches involving Sdc4 inhibition for inflammatory disorders like arthritis, particular caution should be taken in case of adverse gastrointestinal side-effects.
Collapse
Affiliation(s)
- Mareike Fröhling
- Institute of Musculoskeletal Medicine, University Hospital Münster, Münster, Germany
| | - Phil Tepasse
- Department of Medicine B, Gastroenterology and Hepatology, University Hospital Münster, Münster, Germany
| | - Johanna Intemann
- Institute of Musculoskeletal Medicine, University Hospital Münster, Münster, Germany
| | - Meike Sambale
- Institute of Musculoskeletal Medicine, University Hospital Münster, Münster, Germany
| | - Joanna Sherwood
- Institute of Musculoskeletal Medicine, University Hospital Münster, Münster, Germany
| | - Peter Paruzel
- Institute of Musculoskeletal Medicine, University Hospital Münster, Münster, Germany
| | - Nina-Marie Tiemeyer
- Institute of Musculoskeletal Medicine, University Hospital Münster, Münster, Germany
| | - Tobias M Nowacki
- Department of Medicine B, Gastroenterology and Hepatology, University Hospital Münster, Münster, Germany
| | - Markus Brückner
- Department of Medicine B, Gastroenterology and Hepatology, University Hospital Münster, Münster, Germany
| | - Rudolf Mennigen
- Department of General Surgery, University Hospital Münster, Münster, Germany
| | | | - Frank Echtermeyer
- Department of Anesthesiology and Intensive Care Medicine, Medical University Hannover, Hannover, Germany
| | - Thomas Pap
- Institute of Musculoskeletal Medicine, University Hospital Münster, Münster, Germany
| | - Athanasios Stratis
- Institute of Musculoskeletal Medicine, University Hospital Münster, Münster, Germany
| | - Dominik Bettenworth
- Department of Medicine B, Gastroenterology and Hepatology, University Hospital Münster, Münster, Germany
| |
Collapse
|
|
46
|
Zhang H, Zeng Z, Mukherjee A, Shen B. Molecular diagnosis and classification of inflammatory bowel disease. Expert Rev Mol Diagn 2018; 18:867-886. [PMID: 30152711 DOI: 10.1080/14737159.2018.1516549] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Traditional diagnosis and classification of inflammatory bowel diseases (IBDs) have been based on clinical evaluation, laboratory testing, endoscopy, imaging, and histological examinations. With the advancement of medical technology, an increasing number of molecular surrogates are playing a key role in diagnosis, differential diagnosis, assessment of disease activity, prediction of clinical course, and therapeutic response of IBD. Areas covered: The authors review roles of both existing and emerging surrogates including genetic, serological, histologic, and fecal markers in diagnosis and classification of IBD. Comparisons in advantages and disadvantages of different markers have also been discussed. In addition, this review underscores controversial and unclear aspects which need further study. Expert commentary: IBD is characteristic of chronicity, relapse-remission and destructiveness. It is of great importance for clinicians to make an accurate diagnosis and classification. Current and new molecular markers perform well with acceptable sensitivity and specificity. The use of molecular markers in clinical practice needs to be further explored and then generalized. More work is warranted to identify novel useful markers and elucidate how to apply them together with current markers in clinical settings.
Collapse
Affiliation(s)
- Hu Zhang
- a Center for Inflammatory Bowel Disease & Department of Gastroenterology , West China Hospital, Sichuan University , Chengdu , China
| | - Zhen Zeng
- a Center for Inflammatory Bowel Disease & Department of Gastroenterology , West China Hospital, Sichuan University , Chengdu , China
| | - Arjudeb Mukherjee
- b West China School of Medicine , Sichuan University , Chengdu , China
| | - Bo Shen
- c Center for Inflammatory Bowel Disease, Digestive Disease and Surgery Institute, The Cleveland Clinic Foundation , Cleveland , Ohio , USA
| |
Collapse
|
|
47
|
Askarian F, Wagner T, Johannessen M, Nizet V. Staphylococcus aureus modulation of innate immune responses through Toll-like (TLR), (NOD)-like (NLR) and C-type lectin (CLR) receptors. FEMS Microbiol Rev 2018; 42:656-671. [PMID: 29893825 PMCID: PMC6098222 DOI: 10.1093/femsre/fuy025] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Accepted: 06/07/2018] [Indexed: 02/07/2023] Open
Abstract
Early recognition of pathogens by the innate immune system is crucial for bacterial clearance. Many pattern recognition receptors (PRRs) such as Toll-like (TLRs) and (NOD)-like (NLRs) receptors have been implicated in initial sensing of bacterial components. The intracellular signaling cascades triggered by these receptors result in transcriptional upregulation of inflammatory pathways. Although this step is crucial for bacterial elimination, it is also associated with the potential for substantial immunopathology, which underscores the need for tight control of inflammatory responses. The leading human bacterial pathogen Staphylococcus aureus expresses over 100 virulence factors that exert numerous effects upon host cells. In this manner, the pathogen seeks to avoid host recognition or perturb PRR-induced innate immune responses to allow optimal survival in the host. These immune system interactions may result in enhanced bacterial proliferation but also provoke systemic cytokine responses associated with sepsis. This review summarizes recent findings on the various mechanisms applied by S. aureus to modulate or interfere with inflammatory responses through PRRs. Detailed understanding of these complex interactions can provide new insights toward future immune-stimulatory therapeutics against infection or immunomodulatory therapeutics to suppress or correct dysregulated inflammation.
Collapse
Affiliation(s)
- Fatemeh Askarian
- Research Group of Host Microbe Interaction, Faculty of Health Sciences, UiT-The Arctic University of Norway, 9037 Tromsø, Norway
- Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, UC San Diego, La Jolla, CA 92093, USA
| | - Theresa Wagner
- Research Group of Host Microbe Interaction, Faculty of Health Sciences, UiT-The Arctic University of Norway, 9037 Tromsø, Norway
| | - Mona Johannessen
- Research Group of Host Microbe Interaction, Faculty of Health Sciences, UiT-The Arctic University of Norway, 9037 Tromsø, Norway
| | - Victor Nizet
- Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, UC San Diego, La Jolla, CA 92093, USA
- Skaggs School of Pharmacy and Pharmaceutical Sciences, UC San Diego, La Jolla, CA 92093, USA
| |
Collapse
|
|
48
|
Mahadevan U, Silverberg MS. Inflammatory Bowel Disease-Gastroenterology Diamond Jubilee Review. Gastroenterology 2018; 154:1555-1558. [PMID: 29550591 DOI: 10.1053/j.gastro.2017.12.025] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Accepted: 12/08/2017] [Indexed: 12/16/2022]
Affiliation(s)
- Uma Mahadevan
- University of California, San Francisco, California, and Mount Sinai Hospital Inflammatory Bowel Disease Centre, University of Toronto, Toronto, Canada.
| | - Mark S Silverberg
- University of California, San Francisco, California, and Mount Sinai Hospital Inflammatory Bowel Disease Centre, University of Toronto, Toronto, Canada
| |
Collapse
|
|
49
|
Wu WK, Sun R, Zuo T, Tian Y, Zeng Z, Ho J, Wu JC, Chan FK, Chan MT, Yu J, Sung JJ, Wong SH, Wang MH, Ng SC. A novel susceptibility locus in MST1 and gene-gene interaction network for Crohn's disease in the Chinese population. J Cell Mol Med 2018; 22:2368-2377. [PMID: 29441677 PMCID: PMC5867068 DOI: 10.1111/jcmm.13530] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2017] [Accepted: 12/11/2017] [Indexed: 12/13/2022] Open
Abstract
The incidence of Crohn's disease is increasing in many Asian countries, but considerable differences in genetic susceptibility have been reported between Western and Asian populations. This study aimed to fine-map 23 previously reported Crohn's disease genes and identify their interactions in the Chinese population by Illumina-based targeted capture sequencing. Our results showed that the genetic polymorphism A>G at rs144982232 in MST1 showed the most significant association (P = 1.78 × 10-5 ; odds ratio = 4.87). JAK2 rs1159782 (T>C) was also strongly associated with Crohn's disease (P = 2.34 × 10-4 ; odds ratio = 3.72). Gene-gene interaction analysis revealed significant interactions between MST1 and other susceptibility genes, including NOD2, MUC19 and ATG16L1 in contributing to Crohn's disease risk. Main genetic associations and gene-gene interactions were verified using ImmunoChip data set. In conclusion, a novel susceptibility locus in MST1 was identified. Our analysis suggests that MST1 might interact with key susceptibility genes involved in autophagy and bacterial recognition. These findings provide insight into the genetic architecture of Crohn's disease in Chinese and may partially explain the disparity of genetic signals in Crohn's disease susceptibility across different ethnic populations by highlighting the contribution of gene-gene interactions.
Collapse
Affiliation(s)
- William K.K. Wu
- State Key Laboratory of Digestive DiseasesInstitute of Digestive Diseases and Department of Medicine & TherapeuticsLKS Institute of Health SciencesCUHK Shenzhen Research InstituteThe Chinese University of Hong KongHong Kong
- Department of Anaesthesia and Intensive CareThe Chinese University of Hong KongHong Kong
| | - Rui Sun
- The Jockey Club School of Public Health and Primary CareThe Chinese University of Hong KongHong Kong
| | - Tao Zuo
- State Key Laboratory of Digestive DiseasesInstitute of Digestive Diseases and Department of Medicine & TherapeuticsLKS Institute of Health SciencesCUHK Shenzhen Research InstituteThe Chinese University of Hong KongHong Kong
| | - Yuanyuan Tian
- Department of Anaesthesia and Intensive CareThe Chinese University of Hong KongHong Kong
| | - Zhirong Zeng
- Department of GastroenterologyThe First Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Jeffery Ho
- Department of Anaesthesia and Intensive CareThe Chinese University of Hong KongHong Kong
| | - Justin C.Y. Wu
- State Key Laboratory of Digestive DiseasesInstitute of Digestive Diseases and Department of Medicine & TherapeuticsLKS Institute of Health SciencesCUHK Shenzhen Research InstituteThe Chinese University of Hong KongHong Kong
| | - Francis K.L. Chan
- State Key Laboratory of Digestive DiseasesInstitute of Digestive Diseases and Department of Medicine & TherapeuticsLKS Institute of Health SciencesCUHK Shenzhen Research InstituteThe Chinese University of Hong KongHong Kong
| | - Matthew T.V. Chan
- Department of Anaesthesia and Intensive CareThe Chinese University of Hong KongHong Kong
| | - Jun Yu
- State Key Laboratory of Digestive DiseasesInstitute of Digestive Diseases and Department of Medicine & TherapeuticsLKS Institute of Health SciencesCUHK Shenzhen Research InstituteThe Chinese University of Hong KongHong Kong
| | - Joseph J.Y. Sung
- State Key Laboratory of Digestive DiseasesInstitute of Digestive Diseases and Department of Medicine & TherapeuticsLKS Institute of Health SciencesCUHK Shenzhen Research InstituteThe Chinese University of Hong KongHong Kong
| | - Sunny H. Wong
- State Key Laboratory of Digestive DiseasesInstitute of Digestive Diseases and Department of Medicine & TherapeuticsLKS Institute of Health SciencesCUHK Shenzhen Research InstituteThe Chinese University of Hong KongHong Kong
| | - Maggie H. Wang
- The Jockey Club School of Public Health and Primary CareThe Chinese University of Hong KongHong Kong
| | - Siew C. Ng
- State Key Laboratory of Digestive DiseasesInstitute of Digestive Diseases and Department of Medicine & TherapeuticsLKS Institute of Health SciencesCUHK Shenzhen Research InstituteThe Chinese University of Hong KongHong Kong
| |
Collapse
|
|
50
|
Viennois E, Pujada A, Zen J, Merlin D. Function, Regulation, and Pathophysiological Relevance of the POT Superfamily, Specifically PepT1 in Inflammatory Bowel Disease. Compr Physiol 2018; 8:731-760. [PMID: 29687900 DOI: 10.1002/cphy.c170032] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Mammalian members of the proton-coupled oligopeptide transporter family are integral membrane proteins that mediate the cellular uptake of di/tripeptides and peptide-like drugs and couple substrate translocation to the movement of H+ , with the transmembrane electrochemical proton gradient providing the driving force. Peptide transporters are responsible for the (re)absorption of dietary and/or bacterial di- and tripeptides in the intestine and kidney and maintaining homeostasis of neuropeptides in the brain. These proteins additionally contribute to absorption of a number of pharmacologically important compounds. In this overview article, we have provided updated information on the structure, function, expression, localization, and activities of PepT1 (SLC15A1), PepT2 (SLC15A2), PhT1 (SLC15A4), and PhT2 (SLC15A3). Peptide transporters, in particular, PepT1 are discussed as drug-delivery systems in addition to their implications in health and disease. Particular emphasis has been placed on the involvement of PepT1 in the physiopathology of the gastrointestinal tract, specifically, its role in inflammatory bowel diseases. © 2018 American Physiological Society. Compr Physiol 8:731-760, 2018.
Collapse
Affiliation(s)
- Emilie Viennois
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia, USA
| | - Adani Pujada
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia, USA
| | - Jane Zen
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia, USA
| | - Didier Merlin
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia, USA.,Veterans Affairs Medical Center, Decatur, Georgia, USA
| |
Collapse
|