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1
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Halvorsen S, Thomas M, Mino-Kenudson M, Kinowaki Y, Burke KE, Morgan D, Miller KC, Williams KM, Gurung J, McGoldrick J, Hopton M, Hoppe B, Samanta N, Martin S, Tirard A, Arnold BY, Tantivit J, Yarze J, Staller K, Chung DC, Villani AC, Sassi S, Khalili H. Single-cell transcriptomic characterization of microscopic colitis. Nat Commun 2025; 16:4618. [PMID: 40383833 PMCID: PMC12086216 DOI: 10.1038/s41467-025-59648-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 04/30/2025] [Indexed: 05/20/2025] Open
Abstract
Microscopic colitis (MC) is a chronic inflammatory disease of the large intestine and a common cause of chronic diarrhea in older adults. Here, we use single-cell RNA sequencing analysis of colonic mucosal tissue to build a cellular and molecular model for MC. Our results show that in MC, there is a substantial expansion of tissue CD8+ T cells, likely arising from local expansion following T cell receptor engagement. Within the T cell compartment, MC is characterized by a shift in CD8 tissue-resident memory T cells towards a highly cytotoxic and inflammatory phenotype and expansion of CD4+ T regulatory cells. These results provide insight into inflammatory cytokines shaping MC pathogenesis and highlight notable similarities and differences with other immune-mediated intestinal diseases, including a common upregulation of IL26 and an MC-specific upregulation of IL10. These data help identify targets against enteric T cell subsets as an effective strategy for treatment of MC.
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Affiliation(s)
- Stefan Halvorsen
- Center for Computational and Integrative Biology, Massachusetts General Hospital (MGH), Boston, MA, USA
| | - Molly Thomas
- Center for Immunology and Inflammatory Diseases, Department of Medicine, MGH, Boston, MA, USA
- Krantz Family Center for Cancer Research, Department of Medicine, MGH, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA
- Harvard Medical School (HMS), Boston, MA, USA
- Division of Gastroenterology, Department of Medicine, MGH, Boston, MA, USA
| | - Mari Mino-Kenudson
- Harvard Medical School (HMS), Boston, MA, USA
- Department of Pathology, HMS, MGH, Boston, MA, USA
| | | | - Kristin E Burke
- Division of Gastroenterology, Department of Medicine, MGH, Boston, MA, USA
- Clinical and Translational Epidemiology Unit, MGH, Boston, MA, USA
| | - David Morgan
- Clinical and Translational Epidemiology Unit, MGH, Boston, MA, USA
| | - Kaia C Miller
- Clinical and Translational Epidemiology Unit, MGH, Boston, MA, USA
- Department of Medicine, Duke University Health System, NC, Durham, USA
| | | | - Jenny Gurung
- Clinical and Translational Epidemiology Unit, MGH, Boston, MA, USA
| | | | - Megan Hopton
- Center for Computational and Integrative Biology, Massachusetts General Hospital (MGH), Boston, MA, USA
| | - Brooke Hoppe
- Center for Computational and Integrative Biology, Massachusetts General Hospital (MGH), Boston, MA, USA
| | - Nandini Samanta
- Center for Immunology and Inflammatory Diseases, Department of Medicine, MGH, Boston, MA, USA
- Krantz Family Center for Cancer Research, Department of Medicine, MGH, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA
| | - Sidney Martin
- Center for Immunology and Inflammatory Diseases, Department of Medicine, MGH, Boston, MA, USA
- Krantz Family Center for Cancer Research, Department of Medicine, MGH, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA
| | - Alice Tirard
- Center for Immunology and Inflammatory Diseases, Department of Medicine, MGH, Boston, MA, USA
- Krantz Family Center for Cancer Research, Department of Medicine, MGH, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA
| | - Benjamin Y Arnold
- Center for Immunology and Inflammatory Diseases, Department of Medicine, MGH, Boston, MA, USA
- Krantz Family Center for Cancer Research, Department of Medicine, MGH, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA
| | - Jessica Tantivit
- Center for Immunology and Inflammatory Diseases, Department of Medicine, MGH, Boston, MA, USA
- Krantz Family Center for Cancer Research, Department of Medicine, MGH, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA
| | - Joseph Yarze
- Division of Gastroenterology, Department of Medicine, MGH, Boston, MA, USA
| | - Kyle Staller
- Division of Gastroenterology, Department of Medicine, MGH, Boston, MA, USA
- Clinical and Translational Epidemiology Unit, MGH, Boston, MA, USA
| | - Daniel C Chung
- Division of Gastroenterology, Department of Medicine, MGH, Boston, MA, USA
| | - Alexandra-Chloé Villani
- Center for Immunology and Inflammatory Diseases, Department of Medicine, MGH, Boston, MA, USA
- Krantz Family Center for Cancer Research, Department of Medicine, MGH, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA
- Harvard Medical School (HMS), Boston, MA, USA
| | - Slim Sassi
- Center for Computational and Integrative Biology, Massachusetts General Hospital (MGH), Boston, MA, USA
- Harvard Medical School (HMS), Boston, MA, USA
- Department of Orthopedic Surgery, MGH, Boston, MA, USA
| | - Hamed Khalili
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA.
- Division of Gastroenterology, Department of Medicine, MGH, Boston, MA, USA.
- Clinical and Translational Epidemiology Unit, MGH, Boston, MA, USA.
- Institute of Environmental Medicine, Nutrition Epidemiology, Karolinska Institutet, Stockholm, Sweden.
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2
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Wiley JW, Higgins GA. Epigenomics and the Brain-gut Axis: Impact of Adverse Childhood Experiences and Therapeutic Challenges. JOURNAL OF TRANSLATIONAL GASTROENTEROLOGY 2024; 2:125-130. [PMID: 40012740 PMCID: PMC11864786 DOI: 10.14218/jtg.2024.00017] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/28/2025]
Abstract
The brain-gut axis represents a bidirectional communication network that integrates neural, hormonal, and immunological signaling between the central nervous system and the gastrointestinal tract. Adverse childhood experiences (ACEs) have increasingly been recognized for their profound impact on this axis, with implications for both mental and physical health outcomes. This mini-review explores the emerging field of epigenomics-specifically, how epigenetic modifications incurred by ACEs can influence the brain-gut axis and contribute to the pathophysiology of various disorders. We examine the evidence linking epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNAs to the modulation of gene expression involved in stress responses, neurodevelopment, and immune function-all of which intersect at the brain-gut axis. Additionally, we discuss the emerging potential of the gut microbiome as both a target and mediator of epigenetic changes, further influencing brain-gut communication in the context of ACEs. The methodological and therapeutic challenges posed by these insights are significant. The reversibility of epigenetic marks and the long-term consequences of early life stress require innovative and comprehensive approaches to intervention. This underscores the need for comprehensive strategies encompassing psychosocial, pharmacological, neuromodulation, and lifestyle interventions tailored to address ACEs' individualized and persistent effects. Future directions call for a multi-disciplinary approach and longitudinal studies to uncover the full extent of ACEs' impact on epigenetic regulation and the brain-gut axis, with the goal of developing targeted therapies to mitigate the long-lasting effects on health.
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Affiliation(s)
- John W. Wiley
- Department of Internal Medicine, University of Michigan Medicine, Ann Arbor, MI, USA
| | - Gerald A. Higgins
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
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Wu YQ, Zou ZP, Zhou Y, Ye BC. Dual engineered bacteria improve inflammatory bowel disease in mice. Appl Microbiol Biotechnol 2024; 108:333. [PMID: 38739270 DOI: 10.1007/s00253-024-13163-w] [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: 08/09/2023] [Revised: 04/23/2024] [Accepted: 04/28/2024] [Indexed: 05/14/2024]
Abstract
Currently, there are many different therapies available for inflammatory bowel disease (IBD), including engineered live bacterial therapeutics. However, most of these studies focus on producing a single therapeutic drug using individual bacteria, which may cause inefficacy. The use of dual drugs can enhance therapeutic effects. However, expressing multiple therapeutic drugs in one bacterial chassis increases the burden on the bacterium and hinders good secretion and expression. Therefore, a dual-bacterial, dual-drug expression system allows for the introduction of two probiotic chassis and enhances both therapeutic and probiotic effects. In this study, we constructed a dual bacterial system to simultaneously neutralize pro-inflammatory factors and enhance the anti-inflammatory pathway. These bacteria for therapy consist of Escherichia coli Nissle 1917 that expressed and secreted anti-TNF-α nanobody and IL-10, respectively. The oral administration of genetically engineered bacteria led to a decrease in inflammatory cell infiltration in colon and a reduction in the levels of pro-inflammatory cytokines. Additionally, the administration of engineered bacteria did not markedly aggravate gut fibrosis and had a moderating effect on intestinal microbes. This system proposes a dual-engineered bacterial drug combination treatment therapy for inflammatory bowel disease, which provides a new approach to intervene and treat IBD. KEY POINTS: • The paper discusses the effects of using dual engineered bacteria on IBD • Prospects of engineered bacteria in the clinical treatment of IBD.
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Affiliation(s)
- Yong-Qi Wu
- Laboratory of Biosystems and Microanalysis, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, China
| | - Zhen-Ping Zou
- Laboratory of Biosystems and Microanalysis, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, China
| | - Ying Zhou
- Laboratory of Biosystems and Microanalysis, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, China.
| | - Bang-Ce Ye
- Laboratory of Biosystems and Microanalysis, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, China.
- Institute of Engineering Biology and Health, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China.
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Madka V, Chiliveru S, Panneerselvam J, Pathuri G, Zhang Y, Stratton N, Kumar N, Sanghera DK, Rao CV. Targeting IL-23 for the interception of obesity-associated colorectal cancer. Neoplasia 2023; 45:100939. [PMID: 37813000 PMCID: PMC10568285 DOI: 10.1016/j.neo.2023.100939] [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: 05/10/2023] [Revised: 09/21/2023] [Accepted: 09/22/2023] [Indexed: 10/11/2023]
Abstract
Inflammation and obesity are two major factors that promote Colorectal cancer (CRC). Our recent data suggests that interleukin (IL)-23, is significantly elevated in CRC tumors and correlates with patient obesity, tumor grade and survival. Thus, we hypothesize that obesity and CRC may be linked via inflammation and IL-23 may be a potential target for intervention in high-risk patients. TCGA dataset and patient sera were evaluated for IL-23A levels. IL-23A [IL-23 p19-/-] knockout (KO) mice were crossed to Apcmin/+ mice and progeny were fed low-fat or high-fat diets. At termination intestines were evaluated for tumorigenesis. Tumors, serum, and fecal contents were analyzed for protein biomarkers, cytokines, and microbiome profile respectively. IL-23A levels are elevated in the sera of patients with obesity and colon tumors. Genetic ablation of IL-23A significantly suppressed colonic tumor multiplicity (76-96 %) and incidence (72-95 %) in male and female mice. Similarly, small-intestinal tumor multiplicity and size were also significantly reduced in IL-23A KO mice. IL-23A knockdown in Apcmin/+ mice fed high-fat diet, also resulted in significant suppression of colonic (50-58 %) and SI (41-48 %) tumor multiplicity. Cytokine profiling showed reduction in several circulating pro-inflammatory cytokines including loss of IL-23A. Biomarker analysis suggested reduced tumor cell proliferation and immune modulation with an increase in tumor-infiltrating CD4+ and CD8+ T-lymphocytes in the IL-23A KO mice compared to controls. Fecal microbiome analysis revealed potentially beneficial changes in the bacterial population profile. In summary, our data indicates a tumor promoting role for IL-23 in CRC including diet-induced obesity. With several IL-23 targeted therapies in clinical trials, there is a great potential for targeting this cytokine for CRC prevention and therapy.
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Affiliation(s)
- Venkateshwar Madka
- Center for Cancer Prevention and Drug Development, Stephenson Cancer Center, Hem-Onc Section, Department of Medicine, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1203, Oklahoma City, OK 73104, USA
| | - Srikanth Chiliveru
- Center for Cancer Prevention and Drug Development, Stephenson Cancer Center, Hem-Onc Section, Department of Medicine, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1203, Oklahoma City, OK 73104, USA
| | - Janani Panneerselvam
- Center for Cancer Prevention and Drug Development, Stephenson Cancer Center, Hem-Onc Section, Department of Medicine, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1203, Oklahoma City, OK 73104, USA
| | - Gopal Pathuri
- Center for Cancer Prevention and Drug Development, Stephenson Cancer Center, Hem-Onc Section, Department of Medicine, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1203, Oklahoma City, OK 73104, USA
| | - Yuting Zhang
- Center for Cancer Prevention and Drug Development, Stephenson Cancer Center, Hem-Onc Section, Department of Medicine, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1203, Oklahoma City, OK 73104, USA
| | - Nicole Stratton
- Center for Cancer Prevention and Drug Development, Stephenson Cancer Center, Hem-Onc Section, Department of Medicine, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1203, Oklahoma City, OK 73104, USA
| | - Nandini Kumar
- Center for Cancer Prevention and Drug Development, Stephenson Cancer Center, Hem-Onc Section, Department of Medicine, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1203, Oklahoma City, OK 73104, USA
| | - Dharambir K Sanghera
- Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Chinthalapally V Rao
- Center for Cancer Prevention and Drug Development, Stephenson Cancer Center, Hem-Onc Section, Department of Medicine, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1203, Oklahoma City, OK 73104, USA; VA Medical Center, Oklahoma City, OK, USA.
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5
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Chua KJ, Ling H, Hwang IY, Lee HL, March JC, Lee YS, Chang MW. An Engineered Probiotic Produces a Type III Interferon IFNL1 and Reduces Inflammations in in vitro Inflammatory Bowel Disease Models. ACS Biomater Sci Eng 2023; 9:5123-5135. [PMID: 36399014 PMCID: PMC10498420 DOI: 10.1021/acsbiomaterials.2c00202] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 11/01/2022] [Indexed: 11/21/2022]
Abstract
The etiology of inflammatory bowel diseases (IBDs) frequently results in the uncontrolled inflammation of intestinal epithelial linings and the local environment. Here, we hypothesized that interferon-driven immunomodulation could promote anti-inflammatory effects. To test this hypothesis, we engineered probiotic Escherichia coli Nissle 1917 (EcN) to produce and secrete a type III interferon, interferon lambda 1 (IFNL1), in response to nitric oxide (NO), a well-known colorectal inflammation marker. We then validated the anti-inflammatory effects of the engineered EcN strains in two in vitro models: a Caco-2/Jurkat T cell coculture model and a scaffold-based 3D coculture IBD model that comprises intestinal epithelial cells, myofibroblasts, and T cells. The IFNL1-expressing EcN strains upregulated Foxp3 expression in T cells and thereafter reduced the production of pro-inflammatory cytokines such as IL-13 and -33, significantly ameliorating inflammation. The engineered strains also rescued the integrity of the inflamed epithelial cell monolayer, protecting epithelial barrier integrity even under inflammation. In the 3D coculture model, IFNL1-expressing EcN treatment enhanced the population of regulatory T cells and increased anti-inflammatory cytokine IL-10. Taken together, our study showed the anti-inflammatory effects of IFNL1-expressing probiotics in two in vitro IBD models, demonstrating their potential as live biotherapeutics for IBD immunotherapy.
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Affiliation(s)
- Koon Jiew Chua
- NUS
Synthetic Biology for Clinical and Technological Innovation (SynCTI), National University of Singapore, 117456, Singapore
- Synthetic
Biology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, 117456, Singapore
- Department
of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore,117596, Singapore
- Wilmar-NUS
Corporate Laboratory, National University
of Singapore, 117599, Singapore
| | - Hua Ling
- NUS
Synthetic Biology for Clinical and Technological Innovation (SynCTI), National University of Singapore, 117456, Singapore
- Synthetic
Biology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, 117456, Singapore
- Department
of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore,117596, Singapore
- Wilmar-NUS
Corporate Laboratory, National University
of Singapore, 117599, Singapore
| | - In Young Hwang
- NUS
Synthetic Biology for Clinical and Technological Innovation (SynCTI), National University of Singapore, 117456, Singapore
- Synthetic
Biology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, 117456, Singapore
- Department
of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore,117596, Singapore
- Wilmar-NUS
Corporate Laboratory, National University
of Singapore, 117599, Singapore
| | - Hui Ling Lee
- NUS
Synthetic Biology for Clinical and Technological Innovation (SynCTI), National University of Singapore, 117456, Singapore
- Synthetic
Biology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, 117456, Singapore
- Department
of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore,117596, Singapore
- Wilmar-NUS
Corporate Laboratory, National University
of Singapore, 117599, Singapore
| | - John C. March
- Department
of Biological and Environmental Engineering, Cornell University, Ithaca, New York 14853, United States
| | - Yung Seng Lee
- NUS
Synthetic Biology for Clinical and Technological Innovation (SynCTI), National University of Singapore, 117456, Singapore
- Synthetic
Biology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, 117456, Singapore
- Department
of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, 119228, Singapore
| | - Matthew Wook Chang
- NUS
Synthetic Biology for Clinical and Technological Innovation (SynCTI), National University of Singapore, 117456, Singapore
- Synthetic
Biology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, 117456, Singapore
- Department
of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore,117596, Singapore
- Wilmar-NUS
Corporate Laboratory, National University
of Singapore, 117599, Singapore
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Marcos-Fernández R, Riestra S, Alonso-Arias R, Ruiz L, Sánchez B, Margolles A. Immunomagnetic Capture of Faecalibacterium prausnitzii Selectively Modifies the Fecal Microbiota and Its Immunomodulatory Profile. Microbiol Spectr 2023; 11:e0181722. [PMID: 36598219 PMCID: PMC9927134 DOI: 10.1128/spectrum.01817-22] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Faecalibacterium represents one of the most abundant bacterial groups in the human intestinal microbiota of healthy adults and can represent more than 10% of the total bacterial population, Faecalibacterium prausnitzii being the only recognized species up to the past year. Reduction in the abundance of F. prausnitzii in the human gut has been linked to several human disorders, such as Crohn's disease. In this study, we developed a strategy to modify the relative abundance of F. prausnitzii in fecal microbiotas as a means of evaluating its contribution to the immunomodulatory effect of intestinal microbiotas with different F. prausnitzii contents using a peripheral blood mononuclear cell (PBMC) model. We used a polyclonal antibody against the surface of F. prausnitzii M21 to capture the bacterium from synthetic and human fecal microbiotas using immunoseparation techniques. As a proof-of-principle study, the levels of immunomodulation exerted by microbiotas of healthy donors (HDs) with different relative abundances of F. prausnitzii, achieved with the above-mentioned immunoseparation technique, were evaluated in a PBMC model. For this purpose, PBMCs were cocultivated with the modified microbiotas or a pure culture of F. prausnitzii and, subsequently, the microbiota of Crohn's donors was added to the coculture. The cytokine concentration was determined, showing that our experimental model supports the anti-inflammatory effects of this bacterium. IMPORTANCE There is increasing interest in deciphering the contribution of gut microbiota species to health and disease amelioration. The approach proposed herein provides a novel and affordable strategy to probe deeply into microbiota-host interactions by strategically modifying the relative abundance of specific gut microbes, hence facilitating the study of their contribution to a given trait of the microbiota.
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Affiliation(s)
- Raquel Marcos-Fernández
- Departamento de Microbiología y Bioquímica, Instituto de Productos Lácteos de Asturias, Consejo Superior de Investigaciones Científicas (IPLA-CSIC), Villaviciosa, Asturias, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Asturias, Spain
| | - Sabino Riestra
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Asturias, Spain
- Departamento de Gastroenterología, Unidad de Enfermedad Inflamatoria Intestinal, Hospital Universitario Central de Asturias (HUCA), Oviedo, Asturias, Spain
| | - Rebeca Alonso-Arias
- Departamento de Inmunología, Hospital Universitario Central de Asturias (HUCA), Oviedo, Asturias, Spain
- Department of Cardiac Pathology, Health Research Institute of the Principality of Asturias (ISPA), Oviedo, Asturias, Spain
| | - Lorena Ruiz
- Departamento de Microbiología y Bioquímica, Instituto de Productos Lácteos de Asturias, Consejo Superior de Investigaciones Científicas (IPLA-CSIC), Villaviciosa, Asturias, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Asturias, Spain
| | - Borja Sánchez
- Departamento de Microbiología y Bioquímica, Instituto de Productos Lácteos de Asturias, Consejo Superior de Investigaciones Científicas (IPLA-CSIC), Villaviciosa, Asturias, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Asturias, Spain
| | - Abelardo Margolles
- Departamento de Microbiología y Bioquímica, Instituto de Productos Lácteos de Asturias, Consejo Superior de Investigaciones Científicas (IPLA-CSIC), Villaviciosa, Asturias, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Asturias, Spain
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Voitalov I, Zhang L, Kilpatrick C, Withers JB, Saleh A, Akmaev VR, Ghiassian SD. The module triad: a novel network biology approach to utilize patients' multi-omics data for target discovery in ulcerative colitis. Sci Rep 2022; 12:21685. [PMID: 36522454 PMCID: PMC9755270 DOI: 10.1038/s41598-022-26276-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
Tumor necrosis factor-[Formula: see text] inhibitors (TNFi) have been a standard treatment in ulcerative colitis (UC) for nearly 20 years. However, insufficient response rate to TNFi therapies along with concerns around their immunogenicity and inconvenience of drug delivery through injections calls for development of UC drugs targeting alternative proteins. Here, we propose a multi-omic network biology method for prioritization of protein targets for UC treatment. Our method identifies network modules on the Human Interactome-a network of protein-protein interactions in human cells-consisting of genes contributing to the predisposition to UC (Genotype module), genes whose expression needs to be modulated to achieve low disease activity (Response module), and proteins whose perturbation alters expression of the Response module genes to a healthy state (Treatment module). Targets are prioritized based on their topological relevance to the Genotype module and functional similarity to the Treatment module. We demonstrate utility of our method in UC and other complex diseases by efficiently recovering the protein targets associated with compounds in clinical trials and on the market . The proposed method may help to reduce cost and time of drug development by offering a computational screening tool for identification of novel and repurposing therapeutic opportunities in UC and other complex diseases.
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Affiliation(s)
- Ivan Voitalov
- Scipher Medicine Corporation, 221 Crescent St Suite 103A, Waltham, MA 02453 USA
| | - Lixia Zhang
- Scipher Medicine Corporation, 221 Crescent St Suite 103A, Waltham, MA 02453 USA
| | - Casey Kilpatrick
- Scipher Medicine Corporation, 221 Crescent St Suite 103A, Waltham, MA 02453 USA
| | - Johanna B. Withers
- Scipher Medicine Corporation, 221 Crescent St Suite 103A, Waltham, MA 02453 USA
| | - Alif Saleh
- Scipher Medicine Corporation, 221 Crescent St Suite 103A, Waltham, MA 02453 USA
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8
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Sun A, Li W, Shang S. Association of polymorphisms in the
IL‐10
promoter region with Crohn's disease. J Clin Lab Anal 2022; 36:e24780. [DOI: 10.1002/jcla.24780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 11/03/2022] [Accepted: 11/07/2022] [Indexed: 11/22/2022] Open
Affiliation(s)
- Anna Sun
- Department of Clinical Laboratory, The Children's Hospital, Zhejiang University School of Medicine National Clinical Research Center For Child Health Hangzhou China
| | - Wei Li
- Department of Clinical Laboratory, The Children's Hospital, Zhejiang University School of Medicine National Clinical Research Center For Child Health Hangzhou China
| | - Shiqiang Shang
- Department of Clinical Laboratory, The Children's Hospital, Zhejiang University School of Medicine National Clinical Research Center For Child Health Hangzhou China
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Carrasco A, Tristán E, Fernández‐Bañares F, Martín‐Cardona A, Aceituno M, Zabana Y, Fluvià L, Hernández JM, Lorén V, Manyé J, Salas A, Andújar X, Loras C, Esteve M. Mucosal Interleukin-10 depletion in steroid-refractory Crohn's disease patients. Immun Inflamm Dis 2022; 10:e710. [PMID: 36169258 PMCID: PMC9514060 DOI: 10.1002/iid3.710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 08/25/2022] [Accepted: 08/29/2022] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Previous studies suggested that Interleukin-10 (IL-10) depletion in Crohn's disease (CD) could predict outcome. AIM To determine IL-10 in blood and at different intestinal locations in patients with active CD and to assess its potential prognostic capacity to identify aggressive CD. METHODS Twenty-three patients with CD were included. Ulcerative colitis (UC), infectious colitis and healthy individuals acted as controls. Serum and mucosal samples were taken at baseline and 1 month after steroid initiation in CD patients. Patients were classified according to steroid response. Control samples were obtained from different intestinal locations. IL-10 expression was measured with real-time polymerase chain reaction, immunofluorescence (intestine) and ELISA (serum, biopsy cultures' supernatants and tissue homogenates). RESULTS CD and UC showed an increase in IL-10 messenger RNA (mRNA) versus controls (p < .0001) in mucosa, whereas IL-10 protein secretion was increased in all types of intestinal inflammation (p < .001). No differences in IL-10 mRNA were found in CD at baseline regarding steroid response, but levels decreased in non-responders versus responders (p = .027) and were restored with rescue therapy. Serum IL-10 was increased in steroid-refractory CD at baseline and after treatment. CONCLUSIONS Abnormal IL-10 levels in refractory patients in both mucosa and blood have physiopathological relevance and may have potential clinical applications.
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Affiliation(s)
- Anna Carrasco
- Department of Gastroenterology, Hospital Universitari Mútua TerrassaUniversitat de BarcelonaCataloniaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)MadridSpain
| | - Eva Tristán
- Department of Gastroenterology, Hospital Universitari Mútua TerrassaUniversitat de BarcelonaCataloniaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)MadridSpain
| | - Fernando Fernández‐Bañares
- Department of Gastroenterology, Hospital Universitari Mútua TerrassaUniversitat de BarcelonaCataloniaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)MadridSpain
| | - Albert Martín‐Cardona
- Department of Gastroenterology, Hospital Universitari Mútua TerrassaUniversitat de BarcelonaCataloniaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)MadridSpain
| | - Montserrat Aceituno
- Department of Gastroenterology, Hospital Universitari Mútua TerrassaUniversitat de BarcelonaCataloniaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)MadridSpain
| | - Yamile Zabana
- Department of Gastroenterology, Hospital Universitari Mútua TerrassaUniversitat de BarcelonaCataloniaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)MadridSpain
| | - Lourdes Fluvià
- Proteomics and Metabolomics Core Facility, Institut de Recerca Germans Trias i Pujol (IGTP)BadalonaSpain
| | - José María Hernández
- Proteomics and Metabolomics Core Facility, Institut de Recerca Germans Trias i Pujol (IGTP)BadalonaSpain
| | - Violeta Lorén
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)MadridSpain
- Research Group in Inflammatory Bowel Diseases, Institut de Recerca Germans Trias i Pujol (IGTP)BadalonaSpain
| | - Josep Manyé
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)MadridSpain
- Research Group in Inflammatory Bowel Diseases, Institut de Recerca Germans Trias i Pujol (IGTP)BadalonaSpain
| | - Antonio Salas
- Department of PathologyHospital Universitari Mutua Terrassa, Universitat de BarcelonaCataloniaSpain
| | - Xavier Andújar
- Department of Gastroenterology, Hospital Universitari Mútua TerrassaUniversitat de BarcelonaCataloniaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)MadridSpain
| | - Carme Loras
- Department of Gastroenterology, Hospital Universitari Mútua TerrassaUniversitat de BarcelonaCataloniaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)MadridSpain
| | - Maria Esteve
- Department of Gastroenterology, Hospital Universitari Mútua TerrassaUniversitat de BarcelonaCataloniaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)MadridSpain
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Fcα Receptor-1-Activated Monocytes Promote B Lymphocyte Migration and IgA Isotype Switching. Int J Mol Sci 2022; 23:ijms231911132. [PMID: 36232432 PMCID: PMC9569671 DOI: 10.3390/ijms231911132] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/18/2022] [Accepted: 09/19/2022] [Indexed: 11/17/2022] Open
Abstract
Patients with inflammatory bowel disease (IBD) produce enhanced immunoglobulin A (IgA) against the microbiota compared to healthy individuals, which has been correlated with disease severity. Since IgA complexes can potently activate myeloid cells via the IgA receptor FcαRI (CD89), excessive IgA production may contribute to IBD pathology. However, the cellular mechanisms that contribute to dysregulated IgA production in IBD are poorly understood. Here, we demonstrate that intestinal FcαRI-expressing myeloid cells (i.e., monocytes and neutrophils) are in close contact with B lymphocytes in the lamina propria of IBD patients. Furthermore, stimulation of FcαRI-on monocytes triggered production of cytokines and chemokines that regulate B-cell differentiation and migration, including interleukin-6 (IL6), interleukin-10 (IL10), tumour necrosis factor-α (TNFα), a proliferation-inducing ligand (APRIL), and chemokine ligand-20 (CCL20). In vitro, these cytokines promoted IgA isotype switching in human B cells. Moreover, when naïve B lymphocytes were cultured in vitro in the presence of FcαRI-stimulated monocytes, enhanced IgA isotype switching was observed compared to B cells that were cultured with non-stimulated monocytes. Taken together, FcαRI-activated monocytes produced a cocktail of cytokines, as well as chemokines, that stimulated IgA switching in B cells, and close contact between B cells and myeloid cells was observed in the colons of IBD patients. As such, we hypothesize that, in IBD, IgA complexes activate myeloid cells, which in turn can result in excessive IgA production, likely contributing to disease pathology. Interrupting this loop may, therefore, represent a novel therapeutic strategy.
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11
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Liu D, Saikam V, Skrada KA, Merlin D, Iyer SS. Inflammatory bowel disease biomarkers. Med Res Rev 2022; 42:1856-1887. [PMID: 35603998 PMCID: PMC10321231 DOI: 10.1002/med.21893] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 11/16/2021] [Accepted: 05/05/2022] [Indexed: 12/16/2022]
Abstract
Inflammatory bowel disease (IBD) is characterized as chronic inflammation in the gastrointestinal tract, which includes two main subtypes, Crohn's disease and ulcerative colitis. Endoscopy combined with biopsy is the most effective way to establish IBD diagnosis and disease management. Imaging techniques have also been developed to monitor IBD. Although effective, the methods are expensive and invasive, which leads to pain and discomfort. Alternative noninvasive biomarkers are being explored as tools for IBD prognosis and disease management. This review focuses on novel biomarkers that have emerged in recent years. These serological biomarkers and microRNAs could potentially be used for disease management in IBD, thereby decreasing patient discomfort and morbidity.
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Affiliation(s)
- Dandan Liu
- Department of Chemistry, 788 Petit Science Center, Georgia State University, Atlanta, Georgia, USA
| | - Varma Saikam
- Department of Chemistry, 788 Petit Science Center, Georgia State University, Atlanta, Georgia, USA
| | - Katie A Skrada
- Department of Chemistry, 788 Petit Science Center, Georgia State University, Atlanta, Georgia, USA
| | - Didier Merlin
- 790 Petit Science Center, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, USA
- Atlanta Veterans Medical Center, Decatur, Georgia, USA
| | - Suri S Iyer
- Department of Chemistry, 788 Petit Science Center, Georgia State University, Atlanta, Georgia, USA
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12
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Inflammatory Bowel Disease: A Review of Pre-Clinical Murine Models of Human Disease. Int J Mol Sci 2022; 23:ijms23169344. [PMID: 36012618 PMCID: PMC9409205 DOI: 10.3390/ijms23169344] [Citation(s) in RCA: 82] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 08/15/2022] [Accepted: 08/17/2022] [Indexed: 12/11/2022] Open
Abstract
Crohn’s disease (CD) and ulcerative colitis (UC) are both highly inflammatory diseases of the gastrointestinal tract, collectively known as inflammatory bowel disease (IBD). Although the cause of IBD is still unclear, several experimental IBD murine models have enabled researchers to make great inroads into understanding human IBD pathology. Here, we discuss the current pre-clinical experimental murine models for human IBD, including the chemical-induced trinitrobenzene sulfonic acid (TNBS) model, oxazolone and dextran sulphate sodium (DSS) models, the gene-deficient I-kappa-B kinase gamma (Iκκ-γ) and interleukin(IL)-10 models, and the CD4+ T-cell transfer model. We offer a comprehensive review of how these models have been used to dissect the etiopathogenesis of disease, alongside their limitations. Furthermore, the way in which this knowledge has led to the translation of experimental findings into novel clinical therapeutics is also discussed.
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13
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Wang D, Jin H, Sheng J, Cheng L, Lin Q, Lazerev M, Jin P, Li X. A high salt diet protects interleukin 10-deficient mice against chronic colitis by improving the mucosal barrier function. Mol Immunol 2022; 150:39-46. [PMID: 35944464 DOI: 10.1016/j.molimm.2022.07.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 07/04/2022] [Accepted: 07/31/2022] [Indexed: 11/24/2022]
Abstract
A high salt diet (HSD) is often associated with a high risk for a variety of diseases, such as obesity and cardiovascular disease. Previous studies have demonstrated that an HSD enhances Th17 responses and increases the severity of autoimmune diseases. In this study, we investigated the effects of HSD (4% NaCl w/w) on colitis in IL-10-/- mice by comparing it with IL-10-/- mice on a normal salt diet (NSD, 1% NaCl w/w). The colonic epithelial barrier integrity in IL-10-/- mice, as well as differentiated Caco-2 cells exposed to high NaCl and proinflammatory cytokines, was also evaluated. Surprisingly, an HSD significantly ameliorated macroscopic colitis, improved the intestinal permeability of FITC-dextran, and decreased multiple proinflammatory cytokines in the colonic mucosa of IL-10-/- mice. While occludin and claudin-1, two major tight-junction proteins, were markedly down-regulated in IL-10-/- mice, HSD effectively restored their expressions. In Caco-2 cells, proinflammatory cytokines (TNF-α and IL-1β) potently decreased the expression of occludin and claudin-1 regardless of salt conditions [0.9% (standard), 1.2%, or 1.5% NaCl]. Under high salt conditions (1.5% NaCl), transepithelial electrical resistance (TEER) was elevated, while the addition of IL-10 further downregulated occludin and claudin-1 expressions by ~50% and lowered TEER. These findings suggest that, in the absence of IL-10, HSD promotes intestinal epithelial integrity and exerts an anti-inflammatory role as demonstrated by alleviated colitis in IL-10-/- mice. Moreover, Caco-2 data indicate that, in an inflammatory environment and under high NaCl conditions, IL-10 may play a proinflammatory role by disrupting colonic epithelial integrity and thus further promoting inflammation.
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Affiliation(s)
- Dezhi Wang
- Department of Gastroenterology, the Seventh Medical Center of PLA General Hospital, Beijing 100700, China; Department of Medicine/GI Division, School of Medicine, Johns Hopkins University, Baltimore 21205, United States
| | - Hua Jin
- Department of Pathology, the Seventh Medical Center of PLA General Hospital, Beijing 100700, China
| | - Jianqiu Sheng
- Department of Gastroenterology, the Seventh Medical Center of PLA General Hospital, Beijing 100700, China
| | - Leon Cheng
- Division of Pediatric Allergy and Immunology, Johns Hopkins University, Baltimore 21205, United States
| | - Qing Lin
- Department of Anesthesiology and Critical Care Medicine, School of Medicine, Johns Hopkins University, Baltimore 21205, United States
| | - Mark Lazerev
- Department of Medicine/GI Division, School of Medicine, Johns Hopkins University, Baltimore 21205, United States
| | - Peng Jin
- Department of Gastroenterology, the Seventh Medical Center of PLA General Hospital, Beijing 100700, China; Senior Department of Gastroenterology, the First Medical Center of PLA General Hospital, Beijing 100853, China.
| | - Xuhang Li
- Department of Medicine/GI Division, School of Medicine, Johns Hopkins University, Baltimore 21205, United States.
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14
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Enver A, Ozmeric N, Isler SC, Toruner M, Fidan C, Demirci G, Elgun S, DA Silva APB. An Evaluation of Periodontal Status and Cytokine Levels in Saliva and Gingival Crevicular Fluid of Patients with Inflammatory Bowel Diseases. J Periodontol 2022; 93:1649-1660. [PMID: 35665507 PMCID: PMC10083950 DOI: 10.1002/jper.22-0065] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 05/08/2022] [Accepted: 05/26/2022] [Indexed: 11/09/2022]
Abstract
AIMS Periodontal diseases and inflammatory bowel diseases (IBD, ulcerative colitis [UC] and Crohn's disease [CD]) have been reported to present with increased salivary and gingival crevicular fluid (GCF) concentrations of cytokines. The aim of this study was to evaluate the salivary and GCF levels of TNF-α, IL-1β, IL-10, and IL-17A and their associations with the periodontal statuses of UC, CD and non-IBD patients, and to analyze the interrelationships among these cytokines, IBD conditions, and periodontal diseases. MATERIALS AND METHODS This cross-sectional study was performed with a total of 131 patients (62 women and 69 men, mean age 42.96±13.02 years). Patients were divided into three groups: UC, CD, and non-IBD. Periodontal status was defined according to the 2017 World Workshop Disease Classification. Salivary and GCF cytokine levels were analyzed using ELISA. RESULTS UC and CD patients diagnosed as having periodontitis and gingivitis presented with significantly higher levels of TNF-α and lower levels of IL-10 as compared with non-IBD patients (p<0.05). UC patients diagnosed with periodontitis exhibited significantly higher scores of bleeding on probing (p = 0.011) and increased salivary and GCF IL-1β levels as compared with CD patients (p = 0.005, and 0.012 respectively). Considering the active and remission status of IBD, salivary IL-1β was found to be correlated with the parameters representing the severity of periodontal diseases in active UC and CD patients. CONCLUSION(S) In the presence of periodontal diseases, UC and CD patients showed different expression levels of TNF-α, IL-1β, and IL-10 in oral secretions as compared with non-IBD patients. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Ayaz Enver
- Faculty of Dentistry, Department of Periodontology, Gazi University, Ankara, Turkey
| | - Nurdan Ozmeric
- Faculty of Dentistry, Department of Periodontology, Gazi University, Ankara, Turkey
| | - Sila Cagri Isler
- Faculty of Dentistry, Department of Periodontology, Gazi University, Ankara, Turkey.,School of Dental Medicine, Department of Periodontology, University of Bern, Bern, Switzerland
| | - Murat Toruner
- Faculty of Medicine, Department of Gastroenterology, Ankara University, Ankara, Turkey
| | - Cigdem Fidan
- Faculty of Medicine, Department of Medical Biochemistry, Ankara University, Ankara, Turkey
| | - Gulsah Demirci
- Faculty of Medicine, Department of Medical Biochemistry, Ankara University, Ankara, Turkey
| | - Serenay Elgun
- Faculty of Medicine, Department of Medical Biochemistry, Ankara University, Ankara, Turkey
| | - Andre Paes B DA Silva
- Faculty of Medicine, Department of Medical Biochemistry, Ankara University, Ankara, Turkey
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Kim HY, Park ES, Choi YS, Park SJ, Kim JH, Chang HK, Park KY. Kimchi improves irritable bowel syndrome: results of a randomized, double-blind placebo-controlled study. Food Nutr Res 2022; 66:8268. [PMID: 35721806 PMCID: PMC9180131 DOI: 10.29219/fnr.v66.8268] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 04/12/2022] [Accepted: 04/14/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Irritable bowel syndrome (IBS) can be caused by abnormal bowel movements, altered brain-gut axis, gut microbiota change, and low levels of inflammation or immune activation. The intake of food containing much fiber and lactic acid bacteria (LABs) can alleviate IBS. OBJECTIVE This study was undertaken to confirm the alleviative effect of kimchi on symptoms of IBS. DESIGN Three types of kimchi (standard kimchi, SK; dead nano-sized Lactobacillus plantarum nF1 (nLp) added to standard kimchi, nLpSK; or functional kimchi, FK) were given to 30 individuals in each of three groups, that is, the SK group (n = 30), the nLpSK group (n = 30), or the FK group (n = 30) at 210 g a day for 12 weeks. Food intake records, serum levels of inflammatory factors, fecal levels of harmful enzymes, and microbiome changes were investigated over the 12-week study period. RESULTS After intervention, dietary fiber intake was increased in all groups. Typical IBS symptoms (abdominal pain or inconvenience, desperation, incomplete evacuation, and bloating), defecation time, and stool type were also improved. In serum, all groups showed reductions in tumor necrosis factor (TNF)-α (P < 0.001) levels. In addition, serum IL-4 (P < 0.001), IL-10 (P < 0.001), and IL-12 (P < 0.01) were significantly reduced in the nLpSK and FK groups, and serum monocyte chemotactic protein (MCP)-1 (P < 0.05) was significantly reduced in the nLpSK group. Furthermore, activities of fecal β-glucosidase and β-glucuronidase were significantly decreased in all three groups, and these reductions were greatest in the nLpSK group. Gut microbiome analysis showed that kimchi consumption increased Firmicutes populations at the expense of Bacteroidetes and Tenericutes populations. In addition, the Bifidobacterium adolescentis population increased significantly in the FK group (P = 0.026). CONCLUSION Kimchi intake helps alleviate IBS by increasing dietary fiber intake and reducing serum inflammatory cytokine levels and harmful fecal enzyme activities. Notably, nLp improved the immune system, and several functional ingredients in FK promoted the growth of Bifidobacterium adolescentis in gut.
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Affiliation(s)
- Hee-Young Kim
- Korean Medicine Research Center for Healthy Aging, Pusan National University, Yangsan, Gyeongsangnam-do, Republic of Korea
| | - Eui-Seong Park
- Yuhan Care R&D Center, Yongin, Gyeonggi-do, Republic of Korea
| | - Young Sik Choi
- Department of Internal Medicine, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan, Republic of Korea
| | - Seun Ja Park
- Department of Internal Medicine, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan, Republic of Korea
| | - Jae Hyun Kim
- Department of Internal Medicine, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan, Republic of Korea
| | - Hee Kyung Chang
- Department of Pathology, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan, Republic of Korea
| | - Kun-Young Park
- Department of Food Science and Biotechnology, Cha University, Seongnam, Gyeonggi-do, Republic of Korea
- Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education, Chongqing, China
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16
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Inoue CJ, Flauzino T, Gonçalves BP, Paula JCCD, Galvão TC, Miyazaki PK, Alcantara CCD, Westmore LRES, Lozovoy MAB, Reiche EMV, Simão ANC. FOXP3 variants are independently associated with transforming growth factor Β1 plasma levels in female patients with inflammatory bowel disease. Clinics (Sao Paulo) 2022; 77:100084. [PMID: 35905575 PMCID: PMC9335380 DOI: 10.1016/j.clinsp.2022.100084] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 10/28/2021] [Indexed: 11/18/2022] Open
Abstract
OBJECTIVE The aim of this study was to evaluate the association of -924 G>A (rs2232365) and -3279 C>A (rs3761548) FOXP3 variants with IBD susceptibility, clinical and endoscopic activity, and IL-10 and TGF-β1 plasma levels. METHOD The study included 110 IBD female patients, 60 with Ulcerative Colitis (UC) and 50 with Crohn's Disease (CD), and 154 female controls. FOXP3 variants were determined with Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). Plasma levels of IL-10 and TGF-β1 were determined using immunofluorimetric assay. RESULTS AA genotype of rs2232365 and rs3761548 was associated with CD (OR = 3.147, 95% CI 1.015-9.758, p = 0.047) and UC (OR = 3.221, 95% CI 1.050-9.876, p = 0.041) susceptibility, respectively. However, were not associated with TGF-β1 and IL-10 levels, and endoscopic/clinical activity disease. GAGA haplotype was associated with IBD (OR = 4.003, 95% CI 1.100-14.56, p = 0.035) and UC susceptibility (OR = 6.107, 95% CI 1.609-23.18, p = 0.008). In addition, IBD patients with the GAGA haplotype had lower TGF-β1 levels (p = 0.041). Moreover, G/C haplotype (dominant model) had a protective effect of 60% in CD susceptibility and lower Endoscopic Severity Index. CONCLUSIONS These results suggest that FOXP3 variants could exert a role in the Treg, which could be one of the factors involved in the susceptibility and pathogenesis of IBD.
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Affiliation(s)
- Cláudia Junko Inoue
- Laboratory of Research in Applied Immunology, Universidade Estadual de Londrina, Londrina, PR, Brazil; Outpatient Clinic of Gastroenterology, Hospital Universitário, Universidade Estadual de Londrina, Londrina, PR, Brazil
| | - Tamires Flauzino
- Laboratory of Research in Applied Immunology, Universidade Estadual de Londrina, Londrina, PR, Brazil
| | - Beatriz Piantoni Gonçalves
- Laboratory of Research in Applied Immunology, Universidade Estadual de Londrina, Londrina, PR, Brazil; Outpatient Clinic of Gastroenterology, Hospital Universitário, Universidade Estadual de Londrina, Londrina, PR, Brazil
| | | | - Talita Cristina Galvão
- Laboratory of Research in Applied Immunology, Universidade Estadual de Londrina, Londrina, PR, Brazil
| | - Paula Kikuchi Miyazaki
- Laboratory of Research in Applied Immunology, Universidade Estadual de Londrina, Londrina, PR, Brazil
| | | | | | - Marcell Alysson Batisti Lozovoy
- Department of Pathology, Clinical Analysis and Toxicology, Health Sciences Center, Universidade Estadual de Londrina, Londrina, PR, Brazil
| | - Edna Maria Vissoci Reiche
- Department of Pathology, Clinical Analysis and Toxicology, Health Sciences Center, Universidade Estadual de Londrina, Londrina, PR, Brazil
| | - Andréa Name Colado Simão
- Department of Pathology, Clinical Analysis and Toxicology, Health Sciences Center, Universidade Estadual de Londrina, Londrina, PR, Brazil.
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Kwon SH, Kothari D, Jung HI, Lim JM, Kim WL, Kwon HC, Han SG, Seo SM, Choi YK, Kim SK. Noni juice-fortified yogurt mitigates dextran sodium sulfate-induced colitis in mice through the modulation of inflammatory cytokines. J Funct Foods 2021. [DOI: 10.1016/j.jff.2021.104652] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
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18
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Liu M, Yuan W, Park S. Association between IL-10 rs3024505 and susceptibility to inflammatory bowel disease: A systematic review and meta-analysis. Cytokine 2021; 149:155721. [PMID: 34628128 DOI: 10.1016/j.cyto.2021.155721] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 06/03/2021] [Accepted: 09/20/2021] [Indexed: 02/08/2023]
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease that affects the small intestine, colon, and rectum. We evaluated associations between the interleukin 10 (IL-10) rs3024505 polymorphism and IBD, ulcerative colitis (UC), and Crohn's disease (CD) by meta-analysis. All peer-reviewed manuscripts concerning the relationship between IL-10_rs3024505 and IBD identified by searing the PubMed, Cochrane Library, EMBASE, and Chinese Medical Database were examined. The association between IL-10_rs3024505 and IBD was evaluated in allele (AG), recessive (RG), dominant (DG), homozygous (HMG), and heterozygous (HTG) genetic models. Associations were also conducted on IBD subtypes, CD and UC, and ethnicity (Non-Europeans and Europeans) subgroups. The meta-analysis included 13 studies, 8552 cases (IBD patients), and 12,830 healthy controls. Subgroup analysis of IBD (UC and CD) revealed heterogeneity in AG, DG, and HTG but no heterogeneity in RG or HMG. Moreover, AG, DG, and HTG did not show publication bias in IBD, CD, or UC, but RG and HMG exhibited publication bias. No heterogeneity and no publication bias were found among the five genetic models by a subgroup analysis of Non-Europeans and European ethnicities. The minor allele(T) of rs3024505 was significantly related to IBD: 1.37 (1.30-1.45) for AG, 2.06 (1.74-2.45) for RG, 1.39 (1.27-1.52) for DG, 2.25 (1.89-2.67) for HMG, and 1.32 (1.23-1.40) for HTG (all P < 0.00001). In the subgroup analysis of ethnicity, there was a significant effect of rs3024505 on IBD in Europeans but not non-Europeans: 1.38 (1.31-1.46) for AG, 2.07 (1.73-2.48) for RG, 1.39 (1.31-1.49) for DG, 2.26 (1.89-2.71) for HMG, and 1.33 (1.24-1.42) for HTG in Europeans (all P < 0.00001). Sensitivity analysis showed no dominant study in Europeans, but one study had a dominant impact in Non-Europeans. In conclusion, IL-10_rs3024505 polymorphism confers susceptibility to CD and UC in Europeans, but its impact should have conducted more studies in Non-Europeans.
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Affiliation(s)
- Meiling Liu
- Dept. of Food and Nutrition, Obesity/Diabetes Research Center, Hoseo University, Asan, Chungnam 31499, Republic of Korea
| | - Wang Yuan
- Dept. of Bio-Convergence System, Hoseo University, Asan, 31499, Republic of Korea
| | - Sunmin Park
- Dept. of Food and Nutrition, Obesity/Diabetes Research Center, Hoseo University, Asan, Chungnam 31499, Republic of Korea; Dept. of Bio-Convergence System, Hoseo University, Asan, 31499, Republic of Korea.
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19
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Interplay between Cytokine Circuitry and Transcriptional Regulation Shaping Helper T Cell Pathogenicity and Plasticity in Inflammatory Bowel Disease. Int J Mol Sci 2020; 21:ijms21093379. [PMID: 32403220 PMCID: PMC7247009 DOI: 10.3390/ijms21093379] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 05/07/2020] [Accepted: 05/09/2020] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic disorder manifested as Crohn’s disease (CD) and ulcerative colitis (UC) characterized by intestinal inflammation and involves a dysregulated immune response against commensal microbiota through the activation of CD4 T helper cells. T helper cell differentiation to effector or regulatory phenotypes is controlled by cytokine networks and transcriptional regulators. Distinct polarized T helper cells are able to alter their phenotypes to adapt to diverse and fluctuating physiological environments. T helper cells exhibit intrinsic instability and flexibility to express cytokines of other lineages or transdifferentiate from one T helper cell type to another in response to various perturbations from physiological cytokine milieu as a means of promoting local immunity in response to injury or ensure tissue homeostasis. Furthermore, functional plasticity and diversity of T helper cells are associated with pathogenicity and are critical for immune homeostasis and prevention of autoimmunity. In this review, we provide deeper insights into the combinatorial extrinsic and intrinsic signals that control plasticity and transdifferentiation of T helper cells and also highlight the potential of exploiting the genetic reprogramming plasticity of T helper cells in the treatment of IBD.
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20
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Escherichiacoli-Specific CD4+ T Cells Have Public T-Cell Receptors and Low Interleukin 10 Production in Crohn's Disease. Cell Mol Gastroenterol Hepatol 2020; 10:507-526. [PMID: 32361018 PMCID: PMC7385044 DOI: 10.1016/j.jcmgh.2020.04.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 04/23/2020] [Accepted: 04/24/2020] [Indexed: 01/07/2023]
Abstract
BACKGROUND & AIMS Crohn's disease (CD) likely represents decreased immune tolerance to intestinal bacterial antigens. Most CD patients have high titers of antibodies to intestinal commensal proteins, including the outer membrane porin C (OmpC) of Escherichia coli. METHODS By using major histocompatibility complex II tetramers, we identified an HLA-DRB1∗15:01-restricted peptide epitope of OmpC recognized by CD4+ T cells in peripheral blood mononuclear cells from HLA-DRB1∗15:01+ healthy control (HC) and CD patients. RESULTS The precursor frequency of these cells in CD correlated with anti-OmpC IgA titers, but did not differ from that of HCs. In both cohorts, they showed a CD161+, integrin α4β7+ phenotype ex vivo by flow cytometry, distinct from the C-X-C Motif Chemokine Receptor 3 phenotype of autologous influenza hemagglutinin (Flu) peptide-specific T cells. The T-cell receptor α and β chains of in vitro-expanded OmpC-specific T-cell clones often contained public amino acid sequences that were identical in cells from different patients. Expanded T-cell clones from CD subjects produced significantly less interleukin (IL)10 (P < .0001) than those from HCs, and a trend toward decreased production of the T helper 2 cell-associated IL4, IL5, and IL13 by CD clones also was seen. CONCLUSIONS Both HCs and CD patients have detectable OmpC-specific T cells in circulation, with similar immunophenotypes and often identical T-cell-receptor sequences. However, expanded clones from patients with CD produce less of the immunoregulatory cytokine IL10, showing a selective defect in the regulatory function of intestinal microbial antigen-specific T cells in patients with CD.
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Serratane triterpenoids isolated from Lycopodium clavatum by bioactivity-guided fractionation attenuate the production of inflammatory mediators. Bioorg Chem 2020; 96:103632. [PMID: 32059153 DOI: 10.1016/j.bioorg.2020.103632] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 12/27/2019] [Accepted: 01/28/2020] [Indexed: 12/26/2022]
Abstract
Lycopodium clavatum has been used in traditional medicine for the treatment of kidney disorders, rheumatic arthritis, cystitis, and gastritis. We isolated a new serratane triterpenoid (2), and five known triterpenoids (1, 3-6) from the ethyl acetate fraction of L. clavatum by bioactivity-guided fractionation based on their suppression of inflammatory cytokines. Two different cell lines, RAW 264.7 and HT-29 were used to determine the anti-inflammatory activity of the isolated compounds. Among them, compounds 1, 2, 4, and 5 significantly inhibited the production of lipopolysaccharide (LPS)-induced NO in macrophages. Compounds 1, 2, 4, and 5 reduced inducible nitric oxide (iNOS) expression in RAW 264.7 cells and compounds 1 and 6 downregulated COX-2, which correlated with the reduced expression of PGE2. Compounds 1, 2, 4, and 5 downregulated pro-inflammatory cytokines, such as interleukin-1β (IL-1β) in macrophages, and additionally suppressed the levels of IL-8 in HT-29 cells. To determine the signaling pathways involved in the suppression of NO production by these compounds, we investigated ERK1/2 and nuclear factor-kappa B (NF-κB) expression by western blot analysis. We observed that these compounds downregulated the expression of LPS-induced NF-κB and pERK 1/2 in RAW 264.7 cells. Our results demonstrate that serratane triterpenoids isolated from L. clavatum may be used as potential candidates for treating inflammatory bowel disease (IBD) due to their anti-inflammatory effects.
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22
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Chaudhary CL, Gurung P, Jang S, Banskota S, Nam TG, Kim JA, Jeong BS. Synthesis, activity and mechanism of alkoxy-, carbamato-, sulfonamido-, thioureido-, and ureido-derivatives of 2,4,5-trimethylpyridin-3-ol against inflammatory bowel disease. J Enzyme Inhib Med Chem 2020; 35:1-20. [PMID: 31619080 PMCID: PMC6807866 DOI: 10.1080/14756366.2019.1677637] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic immuno-inflammation in gastrointestinal tract. We have evaluated the activity of the compounds to inhibit the adhesion of monocytes to colon epithelial cells is triggered by a pro-inflammatory cytokine, tumour necrosis factor (TNF)-α. The in vitro activity of the compounds, 13b (an ureido-derivative), 14c, 14j, 14k, 14n (thioureido-), 18c and 18d (sulfonamido-), was in correlation with in vivo anti-colitis activity revealed as significant recovery in body- and colon-weights and colon myeloperoxidase level, a biochemical marker of inflammation reflecting neutrophil infiltration. In vivo, TNBS-induced changes in the expression of inflammatory cytokines (TNF-α, IL-6, IL-1β, IL-10, and TGF-β), NLRP3 inflammasome components (NLRP-3, Caspase-1, and IL-18), and epithelial junction molecules (E-cadherin, claudin2/3, and ZO-1) were blocked and recovered by oral administration of the compounds (1 mg/kg). Compound 14n which showed the best efficacy can be a promising lead for orally available therapeutics for pathology of IBD.
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Affiliation(s)
- Chhabi Lal Chaudhary
- College of Pharmacy and Institute for Drug Research, Yeungnam University , Gyeongsan , Republic of Korea
| | - Pallavi Gurung
- College of Pharmacy and Institute for Drug Research, Yeungnam University , Gyeongsan , Republic of Korea
| | - Seoul Jang
- Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University , Ansan , Republic of Korea
| | - Suhrid Banskota
- College of Pharmacy and Institute for Drug Research, Yeungnam University , Gyeongsan , Republic of Korea
| | - Tae-Gyu Nam
- Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University , Ansan , Republic of Korea
| | - Jung-Ae Kim
- College of Pharmacy and Institute for Drug Research, Yeungnam University , Gyeongsan , Republic of Korea
| | - Byeong-Seon Jeong
- College of Pharmacy and Institute for Drug Research, Yeungnam University , Gyeongsan , Republic of Korea
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23
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Oka A, Mishima Y, Liu B, Herzog JW, Steinbach EC, Kobayashi T, Plevy SE, Sartor RB. Phosphoinositide 3-Kinase P110δ-Signaling Is Critical for Microbiota-Activated IL-10 Production by B Cells that Regulate Intestinal Inflammation. Cells 2019; 8:1121. [PMID: 31546615 PMCID: PMC6829312 DOI: 10.3390/cells8101121] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 09/18/2019] [Accepted: 09/20/2019] [Indexed: 12/15/2022] Open
Abstract
The phosphoinositide 3-kinase catalytic subunit p110δ (PI3Kδ) gene maps to a human inflammatory bowel diseases (IBD) susceptibility locus, and genetic deletion of PI3Kδ signaling causes spontaneous colitis in mice. However, little is known regarding the role of PI3Kδ on IL-10-producing B cells that help regulate mucosal inflammation in IBD. We investigated the role of PI3Kδ signaling in B cell production of IL-10, following stimulation by resident bacteria and B cell regulatory function against colitis. In vitro, B cells from PI3KδD910A/D910A mice or wild-type B cells treated with PI3K specific inhibitors secreted significantly less IL-10 with greater IL-12p40 following bacterial stimulation. These B cells failed to suppress inflammatory cytokines by co-cultured microbiota-activated macrophages or CD4+ T cells. In vivo, co-transferred wild-type B cells ameliorated T cell-mediated colitis, while PI3KδD910A/D910A B cells did not confer protection from mucosal inflammation. These results indicate that PI3Kδ-signaling mediates regulatory B cell immune differentiation when stimulated with resident microbiota or their components, and is critical for induction and regulatory function of IL-10-producing B cells in intestinal homeostasis and inflammation.
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Affiliation(s)
- Akihiko Oka
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
- Department of Internal Medicine II, Shimane University Faculty of Medicine, Izumo, Shimane 693-8501, Japan.
| | - Yoshiyuki Mishima
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
- Department of Internal Medicine II, Shimane University Faculty of Medicine, Izumo, Shimane 693-8501, Japan.
| | - Bo Liu
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
| | - Jeremy W Herzog
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
| | - Erin C Steinbach
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
- Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
| | - Taku Kobayashi
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
- Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Minato-ku, Tokyo 108-8642, Japan.
| | - Scott E Plevy
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
- Synlogic Therapeutics, Boston, MA 02139, USA.
| | - R Balfour Sartor
- Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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Valizadeh A, Sanaei R, Rezaei N, Azizi G, Fekrvand S, Aghamohammadi A, Yazdani R. Potential role of regulatory B cells in immunological diseases. Immunol Lett 2019; 215:48-59. [PMID: 31442542 DOI: 10.1016/j.imlet.2019.08.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 08/04/2019] [Accepted: 08/20/2019] [Indexed: 12/21/2022]
Abstract
Regulatory B cells (Bregs) are immune-modulating cells that affect the immune system by producing cytokines or cellular interactions. These cells have immunomodulatory effects on the immune system by cytokine production. The abnormalities in Bregs could be involved in various disorders such as autoimmunity, chronic infectious disease, malignancies, allergies, and primary immunodeficiencies are immune-related scenarios. Ongoing investigation could disclose the biology and the exact phenotype of these cells and also the assigned mechanisms of action of each subset, as a result, potential therapeutic strategies for treating immune-related anomalies. In this review, we collect the findings of human and mouse Bregs and the therapeutic efforts to change the pathogenicity of these cells in diverse disease.
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Affiliation(s)
- Amir Valizadeh
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran, Iran
| | - Roozbeh Sanaei
- Immunology Research Center (IRC), Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran, Iran; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Gholamreza Azizi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Saba Fekrvand
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran, Iran
| | - Asghar Aghamohammadi
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran, Iran
| | - Reza Yazdani
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran, Iran.
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25
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Cao L, Xu H, Wang G, Liu M, Tian D, Yuan Z. Extracellular vesicles derived from bone marrow mesenchymal stem cells attenuate dextran sodium sulfate-induced ulcerative colitis by promoting M2 macrophage polarization. Int Immunopharmacol 2019; 72:264-274. [PMID: 31005036 DOI: 10.1016/j.intimp.2019.04.020] [Citation(s) in RCA: 121] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 04/04/2019] [Accepted: 04/08/2019] [Indexed: 12/15/2022]
Abstract
Extracellular vesicles (EVs) secreted by bone marrow mesenchymal stem cells (BMSCs) have shown repairing effects in tissue damage. However, their efficacy and mechanism in the treatment of ulcerative colitis (UC), a type of chronic inflammatory bowel disease, are unclear. To investigate the effects and possible mechanism of EVs in UC treatment, we established an in vitro model using lipopolysaccharide (LPS)-treated macrophages and an in vivo dextran sulfate sodium (DSS)-induced mouse model to mimic UC. In vitro, EVs promoted the proliferation and suppressed inflammatory response in LPS-induced macrophages, as demonstrated by the up-regulation of pro-inflammatory factors (TNF-α, IL-6, and IL-12) and down-regulation of the anti-inflammatory factor IL-10. In the in vivo model, EV administration ameliorated the symptoms of UC by reducing weight loss, disease activity index, and colon mucosa damage and severity while increasing colon length. This was additionally accompanied by the increase in IL-10 and TGF-β levels and the decline in VEGF-A, IFN-γ, IL-12, TNF-α, CCL-24, and CCL-17 levels. In terms of the mechanism, EVs promoted M2-like macrophage polarization, characterized by the increase in the M2 marker CD163. Furthermore, the positive effect of EVs on UC repair seemed to be related to the JAK1/STAT1/STAT6 signaling pathway. Collectively, BMSC-derived EVs exerted positive therapeutic effects against DSS-induced UC, which could be due to a negative inflammatory response.
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Affiliation(s)
- Li Cao
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, Hubei, China
| | - Hanxin Xu
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan 430022, Hubei, China
| | - Ge Wang
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, Hubei, China
| | - Mei Liu
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, Hubei, China
| | - Dean Tian
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, Hubei, China
| | - Zhenglin Yuan
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan 430022, Hubei, China.
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26
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Meng D, Liang L, Guo X. Serum interleukin-10 level in patients with inflammatory bowel disease: A meta-analysis. EUR J INFLAMM 2019. [DOI: 10.1177/2058739219843405] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Interleukin-10 (IL-10) is a key anti-inflammatory cytokine, and it is associated with the pathogenesis of inflammatory bowel disease (IBD). However, the relationship between serum IL-10 level and IBD remains controversial. In this study, a meta-analysis was performed using STATA 12.0 software. Articles were gathered by searching PubMed, Web of Science, Embase, and the Chinese Biomedical Database. Relevant studies were examined to identify their eligibility. Finally, eight studies met the inclusion criteria; these studies consisted of 211 patients diagnosed with ulcerative colitis (UC), 134 patients diagnosed with Crohn’s disease (CD), and 131 healthy control subjects. The IL-10 levels in the serum samples of UC patients significantly increased (pooled standardized mean difference (SMD) = 0.55, 95% confidence interval (CI): 0.08–1.03, P = 0.022). No significant association was observed in both adult (>17 years old) and pediatric (<17 years old) UC patients in a subgroup analysis performed in terms of age among all UC patients. The relationship between serum IL-10 concentration and UC patients did not differ as determined by enzyme-linked immunosorbent assay (ELISA), and no significant differences were observed when Bio-Plex technology and Luminex assay were used for analyses. There is no statistical difference of serum IL-10 levels between patients with UC and CD. Results suggest that the IL-10 levels increased in UC patients compared with the control group, and such increase contributes to the pathogenesis and progression of UC. Therefore, serum IL-10 level may be a noninvasive biomarker for UC patients.
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Affiliation(s)
- Danli Meng
- Department of Gastroenterology, People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, P.R. China
| | - Liexin Liang
- Department of Gastroenterology, People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, P.R. China
| | - Xianwen Guo
- Department of Gastroenterology, People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, P.R. China
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27
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Zhang M, Zhao Y, Wu N, Yao Y, Xu M, Du H, Tu Y. The anti-inflammatory activity of peptides from simulated gastrointestinal digestion of preserved egg white in DSS-induced mouse colitis. Food Funct 2019; 9:6444-6454. [PMID: 30462121 DOI: 10.1039/c8fo01939h] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Peptides DEDTQAMPFR (DR-10), MLGATSL (ML-7), SLSFASR (SR-7), and MSYSAGF (MF-7) derived from simulated gastrointestinal digestion of preserved egg white (SGD-PEW) exerted anti-inflammatory effects on Caco-2 cells. Here, we aimed to evaluate the anti-inflammatory effects of these peptides derived from SGD-PEW in a mouse model of dextran sodium sulfate (DSS)-induced colitis. The results showed that DR-10, ML-7, SR-7 and MF-7 significantly ameliorated the clinical symptoms of DSS-induced mice colitis, such as weight loss, disease activity index (DAI), colon shortening, spleen hypertrophy and histological scores. Treatment with DR-10, ML-7, SR-7 and MF-7 also significantly inhibited the local secretion of pro-inflammatory cytokines TNF-α and IL-6 and markedly decreased the gene expression of pro-inflammatory cytokines, including TNF-α, IL-6, IL-17, IL-1β, IFN-γ and MCP-1, in DSS-induced mice colitis. Overall, MF-7 showed the best effect of alleviating DSS-induced colitis among the four peptides. These results suggested that MF-7, DR-10, ML-7 and SR-7 may be a potential promising candidate for the treatment of inflammatory bowel disease (IBD).
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Affiliation(s)
- Mengya Zhang
- Jiangxi Key Laboratory of Natural Products and Functional Food, Jiangxi Agricultural University, Nanchang 330045, China.
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28
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Jing L, Yu Z, Gao X, Liu C, Lv X, Zheng S. Inhibition of tumor necrosis factor alpha and increased of interleukin 10 by Lactobacillus: a molecular mechanism protection against TNBS-induced ulcerative colitis in chicks. Immunopharmacol Immunotoxicol 2019; 41:1-6. [PMID: 30821556 DOI: 10.1080/08923973.2019.1566360] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The purpose of this study was to evaluate the effects and mechanism of Lactobacillus on ameliorating ulcerative colitis chicks induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS). There are three groups in this study, control, Lactobacillus and ulcerative colitis groups. 1-day-old chicks were fed with microcapsules containing Lactobacillus LA-5 daily for Lactobacillus group and clustered with 2,4,6-trinitrobenzene sulfonic acid (TNBS) to make the model of ulcerative colitis at ten-day-old. Chicks in control and ulcerative colitis groups were fed with empty microcapsules daily at 1-day-old and then chicks in ulcerative colitis group were induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS) for preparation of ulcerative colitis model at 10-day-old. We detected the changes of mRNA and protein expression of TNF-α and IL-10 in the colon by Real-Time PCR and Western Blot. Histopathology evaluation on colon was conducted. Results showed that chicks pretreated with Lactobacillus had striking injury improvement compared with ulcerative colitis group in histopathology. Compared with ulcerative colitis group, down-regulation of TNF-α and up-regulation of IL-10 were observed in Lactobacillus group chicks. Therefore, Lactobacillus could improve the injury of intestinal mucosa and reduce inflammatory response by regulating mRNA and protein expression levels of TNF-α and IL-10, respectively. In conclusion, Lactobacillus could ameliorate the effects on chicks of TNBS-induced ulcerative colitis by reducing the inflammation and regulating the expression of TNF-α and IL-10, respectively.
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Affiliation(s)
- Long Jing
- a Heilongjiang Key Laboratory of Laboratory Animal and Comparative Medicine , College of Veterinary Medicine, Northeast Agricultural University , Harbin , PR China
| | - Zhiqiang Yu
- a Heilongjiang Key Laboratory of Laboratory Animal and Comparative Medicine , College of Veterinary Medicine, Northeast Agricultural University , Harbin , PR China
| | - Xueli Gao
- a Heilongjiang Key Laboratory of Laboratory Animal and Comparative Medicine , College of Veterinary Medicine, Northeast Agricultural University , Harbin , PR China
| | - Chaonan Liu
- a Heilongjiang Key Laboratory of Laboratory Animal and Comparative Medicine , College of Veterinary Medicine, Northeast Agricultural University , Harbin , PR China
| | - Xiaoping Lv
- a Heilongjiang Key Laboratory of Laboratory Animal and Comparative Medicine , College of Veterinary Medicine, Northeast Agricultural University , Harbin , PR China
| | - Shimin Zheng
- a Heilongjiang Key Laboratory of Laboratory Animal and Comparative Medicine , College of Veterinary Medicine, Northeast Agricultural University , Harbin , PR China
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29
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Li Q, Shan Q, Sang X, Zhu R, Chen X, Cao G. Total Glycosides of Peony Protects Against Inflammatory Bowel Disease by Regulating IL-23/IL-17 Axis and Th17/Treg Balance. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2019; 47:177-201. [PMID: 30612460 DOI: 10.1142/s0192415x19500095] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Inflammatory bowel disease (IBD) is a group of autoimmune diseases, including ulcerative colitis and Crohn’s disease, characterized by nonspecific inflammation in the gut. Total glycoside of peony (TGP) has been widely used for treatment of autoimmune diseases because of its pharmacological effects. However, it is lack of depth in whether TGP regulate T helper 17 cell (Th17) / T regulatory cell (Treg) immune balance or interleukin 23 (IL-23) / IL-17 axis to achieve the goal of treating IBD. Hence, the aim of this study was to investigate the effects of TGP on experimental colitis mice and the related mechanisms. In the present study, we demonstrated that administration of TGP effectively attenuates colonic inflammation of TNBS-induced colitis mice, mainly reflected in significantly improved clinical parameters, reduced inflammatory response and myeloperoxidase (MPO) activity, even stronger systemic immune ability and effective improvement of Th17/Treg immune disorders. In addition, there was a stronger immunosuppressive ability in a positive cluster of differentiation 4 (CD4[Formula: see text]) T-lymphocytes from the TGP treated mouse colon, characterized by the inhibition of high levels of inflammatory factors and increased regulatory T cells. Importantly, high-dose TGP has similar therapeutic effects as salicylazosulfapyridine (SASP) on IBD treatment. The potential mechanisms might be, at least in part, related to the adjustment of imbalance of Th17/Treg cells and the inhibition of IL-23/IL17 inflammatory signal axis.
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Affiliation(s)
- Qinglin Li
- Zhejiang Cancer Hospital, Hangzhou 310022, P. R. China
| | - Qiyuan Shan
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, P. R. China
| | - Xianan Sang
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, P. R. China
| | - Ruyi Zhu
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, P. R. China
| | - Xiaocheng Chen
- The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, P. R. China
| | - Gang Cao
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, P. R. China
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30
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Molecular and functional heterogeneity of IL-10-producing CD4 + T cells. Nat Commun 2018; 9:5457. [PMID: 30575716 PMCID: PMC6303294 DOI: 10.1038/s41467-018-07581-4] [Citation(s) in RCA: 86] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2018] [Accepted: 11/06/2018] [Indexed: 02/07/2023] Open
Abstract
IL-10 is a prototypical anti-inflammatory cytokine, which is fundamental to the maintenance of immune homeostasis, especially in the intestine. There is an assumption that cells producing IL-10 have an immunoregulatory function. However, here we report that IL-10-producing CD4+ T cells are phenotypically and functionally heterogeneous. By combining single cell transcriptome and functional analyses, we identified a subpopulation of IL-10-producing Foxp3neg CD4+ T cells that displays regulatory activity unlike other IL-10-producing CD4+ T cells, which are unexpectedly pro-inflammatory. The combinatorial expression of co-inhibitory receptors is sufficient to discriminate IL-10-producing CD4+ T cells with regulatory function from others and to identify them across different tissues and disease models in mice and humans. These regulatory IL-10-producing Foxp3neg CD4+ T cells have a unique transcriptional program, which goes beyond the regulation of IL-10 expression. Finally, we found that patients with Inflammatory Bowel Disease demonstrate a deficiency in this specific regulatory T-cell subpopulation. Tr1 cells are considered an immunosuppressive CD4 T cell population producing IL-10. Here the authors show that IL-10 is insufficient for Tr1 immunosuppression, define surface markers and transcriptional program of the immunosuppressive subset within Tr1, and reveal its deficiency in patients with IBD.
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31
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Sun MC, Zhang FC, Yin X, Cheng BJ, Zhao CH, Wang YL, Zhang ZZ, Hao HW, Zhang TH, Ye HQ. Lactobacillus reuteri F-9-35 Prevents DSS-Induced Colitis by Inhibiting Proinflammatory Gene Expression and Restoring the Gut Microbiota in Mice. J Food Sci 2018; 83:2645-2652. [PMID: 30216448 DOI: 10.1111/1750-3841.14326] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Revised: 06/25/2018] [Accepted: 07/21/2018] [Indexed: 12/14/2022]
Abstract
Probiotics are considered to be a potential treatment for ulcerative colitis (UC). The aim of this study was to compare the preventive effect of a space flight-induced mutant L. reuteri F-9-35 and its wild type on UC in vivo. Female mice were randomly assigned to five groups: one normal and four colitic. Mice from colitis groups were daily gavaged with 0.2 mL 12% (w/v) skim milk containing the mutant or wild type (1 × 1011 CFU/mL), skim milk alone or distilled water for the whole experiment period, starting 7 days before colitis induction. UC was induced by administrating mice with 3.5% (w/v) dextran sulfate sodium (DSS) in drinking water for 7 days, after which DSS was removed and maintained for 3 days as a recovery phase. The results showed that the mice fed with L. reuteri F-9-35 had less inflammatory phenotype according to macroscopic and histological analysis, reduced myeloperoxidase activity, and lower expression of proinflammatory genes (Tumor necrosis factor-α, cyclooxygenase-2 and interleukin-6) in colonic tissue compared with control. Furthermore, L. reuteri F-9-35 protected the mice from gut microbiota dysbiosis from DDS induced colitis. Neither wild type nor the milk alone had such beneficial effects. From above we conclude that L. reuteri F-9-35 has great potential in the prevention of UC as a dietary supplement. PRACTICAL APPLICATION Ulcerative colitis (UC) is the most common inflammatory bowel diseases and there is still a lack of safe and effective treatments. Consumption of L. reuteri F-9-35 may effective in preventing human UC.
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Affiliation(s)
- Mao-Cheng Sun
- College of Food Science and Engineering, Jilin Univ., Changchun, China.,School of Public Health, Jilin Medical Univ., Jilin City, China
| | - Fu-Cheng Zhang
- College of Food Science and Engineering, Jilin Univ., Changchun, China
| | - Xue Yin
- College of Food Science and Engineering, Jilin Univ., Changchun, China
| | - Bi-Jun Cheng
- College of Food Science and Engineering, Jilin Univ., Changchun, China
| | - Chang-Hui Zhao
- College of Food Science and Engineering, Jilin Univ., Changchun, China
| | - Yan-Ling Wang
- School of Pharmaceutical Sciences, Jilin Univ., Changchun, China
| | - Zheng-Zhe Zhang
- College of Food Science and Engineering, Jilin Univ., Changchun, China
| | - Hong-Wei Hao
- Fullarton Bioengineering Technology Co., Ltd, Beijing, China
| | - Tie-Hua Zhang
- College of Food Science and Engineering, Jilin Univ., Changchun, China
| | - Hai-Qing Ye
- College of Food Science and Engineering, Jilin Univ., Changchun, China
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Ebrahimi Daryani N, Saghazadeh A, Moossavi S, Sadr M, Shahkarami S, Soltani S, Farhadi E, Rezaei N. Interleukin-4 and Interleukin-10 Gene Polymorphisms in Patients with Inflammatory Bowel Disease. Immunol Invest 2018; 46:714-729. [PMID: 28872970 DOI: 10.1080/08820139.2017.1360343] [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: 12/16/2022]
Abstract
BACKGROUND Changes in cytokine expression have been frequently found in patients with inflammatory bowel disease (IBD). Cytokine values outside the normal range may be somewhat related to common polymorphisms within cytokine genes. OBJECTIVE The present study was designed to investigate the possible association between polymorphisms within Interleukin IL-4 and IL-10 genes and susceptibility to and clinical features of IBD. METHODS The study population was composed of 140 healthy controls and 75 patients with IBD (40 patients with Crohn's disease (CD) and 35 patients with ulcerative colitis (UC)). Genotyping was performed using polymerase chain reaction with sequence-specific primers. RESULTS Higher frequencies for the C allele of IL-4-590 polymorphism (P < 0.0001; odds ratio [OR], 5.68; 95% confidence interval [95% CI], 3.28-9.83) and for the T allele of IL-4-1098 polymorphism (P = 0.016; OR, 1.83; 95% CI, 1.11-3.02) were observed in the whole group of IBD patients. The IL-4-590 C allele was also significantly overrepresented when IBD patients were subdivided into CD and UC (P < 0.0001; OR, 5.2-6.28). While the IL-4-1098 T allele was present at higher frequencies in patients with UC (P = 0.05; OR, 1.95), but not in CD (P = 0.09). Multiple pairwise comparisons indicated that genotypes of all polymorphisms investigated within IL-4 gene are correlated with IBD, CD, and UC. Haplotype analysis showed that the IL-4-1098/-590 TC haplotype might predispose individuals to IBD, CD, and UC whereas the IL-4-1098/-590 TT and GC haplotypes have a protective effect. On the contrary, neither allele nor genotype frequencies of IL-10 polymorphisms (IL-10-1082 A > G, IL-10-592 A > C, and IL-10-819 T > C) were associated with IBD, CD, or UC. CONCLUSIONS The present study suggests that IL-4 polymorphisms might play a role in susceptibility to IBD and its major subtypes in the Iranian population.
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Affiliation(s)
- Nasser Ebrahimi Daryani
- a Department of Gastroenterology and Hepatology , Tehran University of Medical Sciences , Tehran , Iran
| | - Amene Saghazadeh
- b Molecular Immunology Research Center , Tehran University of Medical Sciences , Tehran , Iran.,c Systematic Review and Mata-analysis Expert Group (SRMEG) , Universal Scientific Education and Research Network (USERN) , Tehran , Iran
| | - Shirin Moossavi
- d Digestive Oncology Research Center, Digestive Disease Research Institute , Tehran University of Medical Sciences , Tehran , Iran
| | - Maryam Sadr
- b Molecular Immunology Research Center , Tehran University of Medical Sciences , Tehran , Iran
| | - Sepideh Shahkarami
- b Molecular Immunology Research Center , Tehran University of Medical Sciences , Tehran , Iran.,e Medical Genetics Network (MeGeNe) , Universal Scientific Education and Research Network (USERN) , Tehran , Iran
| | - Samaneh Soltani
- b Molecular Immunology Research Center , Tehran University of Medical Sciences , Tehran , Iran
| | - Elham Farhadi
- f Hematology Department , School of Allied Medical Science, Iran University of Medical Sciences , Tehran , Iran
| | - Nima Rezaei
- g Research Center for Immunodeficiencies, Children's Medical Center , Tehran University of Medical Sciences , Tehran , Iran.,h Department of Immunology , School of Medicine, Tehran University of Medical Sciences , Tehran , Iran.,i Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA) , Universal Scientific Education and Research Network (USERN) , Tehran , Iran
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Cardoso A, Gil Castro A, Martins AC, Carriche GM, Murigneux V, Castro I, Cumano A, Vieira P, Saraiva M. The Dynamics of Interleukin-10-Afforded Protection during Dextran Sulfate Sodium-Induced Colitis. Front Immunol 2018; 9:400. [PMID: 29545807 PMCID: PMC5837963 DOI: 10.3389/fimmu.2018.00400] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Accepted: 02/13/2018] [Indexed: 12/15/2022] Open
Abstract
Inflammatory bowel disease encompasses a group of chronic-inflammatory conditions of the colon and small intestine. These conditions are characterized by exacerbated inflammation of the organ that greatly affects the quality of life of patients. Molecular mechanisms counteracting this hyperinflammatory status of the gut offer strategies for therapeutic intervention. Among these regulatory molecules is the anti-inflammatory cytokine interleukin (IL)-10, as shown in mice and humans. Indeed, IL-10 signaling, particularly in macrophages, is essential for intestinal homeostasis. We sought to investigate the temporal profile of IL-10-mediated protection during chemical colitis and which were the underlying mechanisms. Using a novel mouse model of inducible IL-10 overexpression (pMT-10), described here, we show that mice preconditioned with IL-10 for 8 days before dextran sulfate sodium (DSS) administration developed a milder colitic phenotype. In IL-10-induced colitic mice, Ly6C cells isolated from the lamina propria showed a decreased inflammatory profile. Because our mouse model leads to transcription of the IL-10 transgene in the bone marrow and elevated seric IL-10 concentration, we investigated whether IL-10 could imprint immune cells in a long-lasting way, thus conferring sustained protection to colitis. We show that this was not the case, as IL-10-afforded protection was only observed if IL-10 induction immediately preceded DSS-mediated colitis. Thus, despite the protection afforded by IL-10 in colitis, novel strategies are required, specifically to achieve long-lasting protection.
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Affiliation(s)
- Ana Cardoso
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal.,IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.,Department of Immunology, Unité Lymphopoièse, Institut Pasteur, Paris, France.,University Paris Diderot, Sorbonne Paris Cité, Cellule Pasteur, Paris, France.,INSERM U1223, Paris, France.,ICVS, University of Minho, Braga, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga, Portugal
| | - Antonio Gil Castro
- ICVS, University of Minho, Braga, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga, Portugal
| | - Ana Catarina Martins
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal.,IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal
| | - Guilhermina M Carriche
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal.,IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal
| | - Valentine Murigneux
- Department of Immunology, Unité Intégrité du génome, immunité et cancer, Institut Pasteur, Paris, France.,Department of Genomes and Genetics, Unité Intégrité du génome, immunité et cancer, Institut Pasteur, Paris, France
| | - Isabel Castro
- ICVS, University of Minho, Braga, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga, Portugal
| | - Ana Cumano
- Department of Immunology, Unité Lymphopoièse, Institut Pasteur, Paris, France.,University Paris Diderot, Sorbonne Paris Cité, Cellule Pasteur, Paris, France.,INSERM U1223, Paris, France
| | - Paulo Vieira
- Department of Immunology, Unité Lymphopoièse, Institut Pasteur, Paris, France.,University Paris Diderot, Sorbonne Paris Cité, Cellule Pasteur, Paris, France.,INSERM U1223, Paris, France
| | - Margarida Saraiva
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal.,IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal
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Ahmed AU, Yim HCH, Alorro M, Ernst M, Williams BRG. Integrin-Linked Kinase Expression in Myeloid Cells Promotes Inflammatory Signaling during Experimental Colitis. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2017; 199:2128-2139. [PMID: 28794235 DOI: 10.4049/jimmunol.1700125] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Accepted: 07/19/2017] [Indexed: 12/15/2022]
Abstract
The pathology of inflammatory bowel diseases is driven by the inflammatory signaling pathways associated with mucosal epithelial damage. Myeloid cells are known to play an essential role in mediating epithelial inflammatory responses during injury. However, the precise role of these cells in stimulating intestinal inflammation and the subsequent tissue damage is unclear. In this article, we show that expression of integrin-linked kinase (ILK) in myeloid cells is critical for the epithelial inflammatory signaling during colitis induced by dextran sodium sulfate. Myeloid ILK (M-ILK) deficiency significantly ameliorates the pathology of experimental colitis. In response to dextran sodium sulfate, colonic infiltration of neutrophils and inflammatory cytokine production are impaired in M-ILK-deficient mice, and activation of epithelial NF-κB and PI3K signaling pathways are restricted by the M-ILK deficiency. In contrast, reduced epithelial damage in M-ILK-deficient mice is correlated with elevated levels of epithelial Stat3 activation and proliferation. Moreover, M-ILK-dependent inflammatory signaling in the mucosal epithelium can be therapeutically targeted by the pharmacological inhibition of ILK during experimental colitis. Collectively, these findings identify M-ILK as a critical regulator of epithelial inflammatory signaling pathways during colitis and, as a consequence, targeting M-ILK could provide therapeutic benefit.
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Affiliation(s)
- Afsar U Ahmed
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia
- Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia
| | - Howard C H Yim
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia
- Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia
| | - Mariah Alorro
- Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria 3084, Australia; and
- School of Cancer Medicine, La Trobe University, Heidelberg, Victoria 3084, Australia
| | - Matthias Ernst
- Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria 3084, Australia; and
- School of Cancer Medicine, La Trobe University, Heidelberg, Victoria 3084, Australia
| | - Bryan R G Williams
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia;
- Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia
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Quiros M, Nishio H, Neumann PA, Siuda D, Brazil JC, Azcutia V, Hilgarth R, O'Leary MN, Garcia-Hernandez V, Leoni G, Feng M, Bernal G, Williams H, Dedhia PH, Gerner-Smidt C, Spence J, Parkos CA, Denning TL, Nusrat A. Macrophage-derived IL-10 mediates mucosal repair by epithelial WISP-1 signaling. J Clin Invest 2017; 127:3510-3520. [PMID: 28783045 DOI: 10.1172/jci90229] [Citation(s) in RCA: 144] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Accepted: 06/27/2017] [Indexed: 12/24/2022] Open
Abstract
In response to injury, epithelial cells migrate and proliferate to cover denuded mucosal surfaces and repair the barrier defect. This process is orchestrated by dynamic crosstalk between immune cells and the epithelium; however, the mechanisms involved remain incompletely understood. Here, we report that IL-10 was rapidly induced following intestinal mucosal injury and was required for optimal intestinal mucosal wound closure. Conditional deletion of IL-10 specifically in CD11c-expressing cells in vivo implicated macrophages as a critical innate immune contributor to IL-10-induced wound closure. Consistent with these findings, wound closure in T cell- and B cell-deficient Rag1-/- mice was unimpaired, demonstrating that adaptive immune cells are not absolutely required for this process. Further, following mucosal injury, macrophage-derived IL-10 resulted in epithelial cAMP response element-binding protein (CREB) activation and subsequent synthesis and secretion of the pro-repair WNT1-inducible signaling protein 1 (WISP-1). WISP-1 induced epithelial cell proliferation and wound closure by activating epithelial pro-proliferative pathways. These findings define the involvement of macrophages in regulating an IL-10/CREB/WISP-1 signaling axis, with broad implications in linking innate immune activation to mucosal wound repair.
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Affiliation(s)
- Miguel Quiros
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Hikaru Nishio
- Department of Pathology, Emory University, Atlanta, Georgia, USA
| | - Philipp A Neumann
- Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Dorothee Siuda
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Jennifer C Brazil
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Veronica Azcutia
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Roland Hilgarth
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Monique N O'Leary
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | | | - Giovanna Leoni
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilian University (LMU) Munich, Munich, Germany
| | - Mingli Feng
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Gabriela Bernal
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Holly Williams
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Priya H Dedhia
- Department of Internal Medicine and Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA
| | | | - Jason Spence
- Department of Internal Medicine and Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA
| | - Charles A Parkos
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Timothy L Denning
- Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, USA
| | - Asma Nusrat
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
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Celiberto LS, Bedani R, Dejani NN, Ivo de Medeiros A, Sampaio Zuanon JA, Spolidorio LC, Tallarico Adorno MA, Amâncio Varesche MB, Carrilho Galvão F, Valentini SR, Font de Valdez G, Rossi EA, Cavallini DCU. Effect of a probiotic beverage consumption (Enterococcus faecium CRL 183 and Bifidobacterium longum ATCC 15707) in rats with chemically induced colitis. PLoS One 2017; 12:e0175935. [PMID: 28437455 PMCID: PMC5402984 DOI: 10.1371/journal.pone.0175935] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Accepted: 04/03/2017] [Indexed: 12/11/2022] Open
Abstract
Background Some probiotic strains have the potential to assist in relieving the symptoms of inflammatory bowel disease. The impact of daily ingestion of a soy-based product fermented by Enterococcus faecium CRL 183 and Lactobacillus helveticus 416 with the addition of Bifidobacterium longum ATCC 15707 on chemically induced colitis has been investigated thereof within a period of 30 days. Methods Colitis was induced by dextran sulfate sodium. The animals were randomly assigned into five groups: Group C: negative control; Group CL: positive control; Group CLF: DSS with the fermented product; Group CLP: DSS with the non-fermented product (placebo); Group CLS: DSS with sulfasalazine. The following parameters were monitored: disease activity index, fecal microbial analyses, gastrointestinal survival of probiotic microorganisms and short-chain fatty acids concentration in the feces. At the end of the protocol the animals’ colons were removed so as to conduct a macroscopical and histopathological analysis, cytokines and nitrite quantification. Results Animals belonging to the CLF group showed fewer symptoms of colitis during the induction period and a lower degree of inflammation and ulceration in their colon compared to the CL, CLS and CLP groups (p<0.05). The colon of the animals in groups CL and CLS presented severe crypt damage, which was absent in CLF and CLP groups. A significant increase in the population of Lactobacillus spp. and Bifidobacterium spp. at the end of the protocol was verified only in the CLF animals (p<0.05). This group also showed an increase in short-chain fatty acids (propionate and acetate). Furthermore, the intestinal survival of E. faecium CRL 183 and B. longum ATCC 15707 in the CLF group has been confirmed by biochemical and molecular analyzes. Conclusions The obtained results suggest that a regular intake of the probiotic product, and placebo to a lesser extent, can reduce the severity of DSS-induced colitis on rats.
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Affiliation(s)
- Larissa Sbaglia Celiberto
- Universidade Estadual Paulista (UNESP), Faculdade de Ciências Farmacêuticas, Araraquara. Departamento de Alimentos e Nutrição, SP, Brasil
| | - Raquel Bedani
- Departamento de Tecnologia Bioquímico-Farmacêutica, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP, Brasil
| | - Naiara Naiana Dejani
- Universidade de São Paulo (USP), Faculdade de Medicina de Ribeirão Preto, Ribeirão Preto. Departamento de Bioquimica e Imunologia, SP, Brasil
- Universidade Estadual Paulista (UNESP), Faculdade de Ciências Farmacêuticas, Araraquara. Departamento de Ciências Biológicas, SP, Brasil
| | - Alexandra Ivo de Medeiros
- Universidade Estadual Paulista (UNESP), Faculdade de Ciências Farmacêuticas, Araraquara. Departamento de Ciências Biológicas, SP, Brasil
| | - José Antonio Sampaio Zuanon
- Universidade Estadual Paulista (UNESP), Faculdade de Odontologia, Araraquara. Departametno de Fisiologia e Patologia, SP, Brasil
| | - Luis Carlos Spolidorio
- Universidade Estadual Paulista (UNESP), Faculdade de Odontologia, Araraquara. Departametno de Fisiologia e Patologia, SP, Brasil
| | - Maria Angela Tallarico Adorno
- Universidade de São Paulo (USP), Faculdade de Engenharia, São Carlos. Departamento de Hidraúlica e Saneamento, SP, Brasil
| | | | - Fábio Carrilho Galvão
- Universidade Estadual Paulista (UNESP), Faculdade de Ciências Farmacêuticas, Araraquara. Departamento de Ciências Biológicas, SP, Brasil
| | - Sandro Roberto Valentini
- Universidade Estadual Paulista (UNESP), Faculdade de Ciências Farmacêuticas, Araraquara. Departamento de Ciências Biológicas, SP, Brasil
| | | | - Elizeu Antonio Rossi
- Universidade Estadual Paulista (UNESP), Faculdade de Ciências Farmacêuticas, Araraquara. Departamento de Alimentos e Nutrição, SP, Brasil
| | - Daniela Cardoso Umbelino Cavallini
- Universidade Estadual Paulista (UNESP), Faculdade de Ciências Farmacêuticas, Araraquara. Departamento de Alimentos e Nutrição, SP, Brasil
- * E-mail:
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Metzger CE, Narayanan A, Zawieja DC, Bloomfield SA. Inflammatory Bowel Disease in a Rodent Model Alters Osteocyte Protein Levels Controlling Bone Turnover. J Bone Miner Res 2017; 32:802-813. [PMID: 27796050 DOI: 10.1002/jbmr.3027] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Revised: 10/26/2016] [Accepted: 10/28/2016] [Indexed: 12/30/2022]
Abstract
Bone loss is a common comorbidity of inflammatory bowel disease (IBD), leading to elevated fracture risk in these patients. Inflammatory factors associated with IBD cause increased bone resorption and decreased bone formation with multiple factors implicated as instigators of these alterations. In this project, we examined the influence of IBD on osteocyte proteins in male rats (2 months old) divided into two groups: induced gut inflammation via 2,4,6-trinitrobenzenesulfonic acid (TNBS) enema, and vehicle control. We examined the prevalence of two pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), an anti-inflammatory cytokine, interleukin-10 (IL-10), the anabolic factor insulin-like growth factor-I (IGF-I), osteoclastogenesis regulators RANKL and OPG, and the bone formation inhibitor sclerostin in osteocytes in three bone compartments 4 weeks after initiation of gut inflammation. Histomorphometry of the proximal tibia and fourth lumbar vertebra revealed lower bone volume, lower bone formation rate (BFR), lower osteoid surface (OS), and higher osteoclast surface (Oc.S) with TNBS. Tibial mid-shaft periosteal BFR was also lower with TNBS. Immunohistochemical staining of the distal femur demonstrated that %TNF-α+ , %IL-6+ , %RANKL+ , and %OPG+ osteocytes were elevated in cancellous bone in TNBS animals compared to vehicle. These changes were coincident with increased bone resorption. With regression analysis, %RANKL+ osteocytes statistically predicted the increase in cancellous Oc.S (R2 = 0.565). Increased %sclerostin+ osteocytes observed in the TNBS treatment predicted declines in cancellous OS (R2 = 0.581) as well as BFR in cancellous and cortical bone (R2 = 0.674, R2 = 0.908, respectively). Contrary to our hypothesis, %IGF-I+ osteocytes increased in TNBS animals. In conclusion, the IBD model produced a systemic inflammation that altered the regulatory protein profile in osteocytes that control bone resorption and bone formation, likely contributing to IBD-induced bone loss. These data highlight a potential mechanistic role of osteocytes in inflammatory bone loss associated with IBD and systemic inflammation. © 2017 American Society for Bone and Mineral Research.
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Affiliation(s)
- Corinne E Metzger
- Department of Health and Kinesiology, Texas A&M University Health Science Center, College Station, TX, USA
| | - Anand Narayanan
- Department of Medical Physiology, College of Medicine, Texas A&M University, College Station, TX, USA
| | - David C Zawieja
- Department of Medical Physiology, College of Medicine, Texas A&M University, College Station, TX, USA
| | - Susan A Bloomfield
- Department of Health and Kinesiology, Texas A&M University Health Science Center, College Station, TX, USA.,Graduate Faculty of Nutrition, Texas A&M University, College Station, TX, USA
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Legaki E, Roubelakis MG, Theodoropoulos GE, Lazaris A, Kollia A, Karamanolis G, Marinos E, Gazouli M. Therapeutic Potential of Secreted Molecules Derived from Human Amniotic Fluid Mesenchymal Stem/Stroma Cells in a Mice Model of Colitis. Stem Cell Rev Rep 2016; 12:604-612. [PMID: 27503204 DOI: 10.1007/s12015-016-9677-1] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Inflammatory bowel diseases (IBDs) are the result of pathological immune responses due to environmental factors or microbial antigens into a genetically predisposed individual. Mainly due to their trophic properties, a mounting interest is focused on the use of human mesenchymal stem/stromal cells (hMSCs) to treat IBD disease in animal models. The aim of the study is to test whether the secreted molecules, derived from a specific population of second trimester amniotic fluid mesenchymal stem/stromal cells, the spindle-shaped MSCs (SS-AF-MSCs), could be utilized as a novel therapeutic, cell free approach for IBD therapy. Induction of colitis was achieved by oral administration of dextran sulphate sodium (DSS) (3 % w/v in tap water), for 5 days, to 8-week-old NOD/SCID mice. The progression of colitis was assessed on a daily basis through recording the body weight, stool consistency and bleeding. Conditioned media (CM) derived from SS-AF-MSCs were collected, concentrated and then delivered intraperitoneally into DSS treated mice. To evaluate and determine the inflammatory cytokine levels, histopathological approach was applied. Administration of CM derived from SS-AF-MSCs cells reduced the severity of colitis in mice. More importantly, TGFb1 protein levels were increased in the mice received CM, while TNFa and MMP2 protein levels were decreased, respectively. Accordingly, IL-10 was significantly increased in mice received CM, whereas TNFa and IL-1b were decreased at mRNA level. Our results demonstrated that CM derived from SS-AF-MSCs cells is able to ameliorate DSS-induced colitis in immunodeficient colitis mouse model, and thus, it has a potential for use in IBD therapy.
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Affiliation(s)
- E Legaki
- Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Michalakopoulou, 176, Athens, Greece
| | - M G Roubelakis
- Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Michalakopoulou, 176, Athens, Greece
| | - G E Theodoropoulos
- First Propaedeutic Surgical Department, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - A Lazaris
- Department of Pathology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - A Kollia
- Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Michalakopoulou, 176, Athens, Greece
| | - G Karamanolis
- Gastroenterology Unit, 2nd Surgical Department, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - E Marinos
- Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Michalakopoulou, 176, Athens, Greece
| | - M Gazouli
- Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Michalakopoulou, 176, Athens, Greece.
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Roth S, Spalinger MR, Gottier C, Biedermann L, Zeitz J, Lang S, Weber A, Rogler G, Scharl M. Bilberry-Derived Anthocyanins Modulate Cytokine Expression in the Intestine of Patients with Ulcerative Colitis. PLoS One 2016; 11:e0154817. [PMID: 27152519 PMCID: PMC4859486 DOI: 10.1371/journal.pone.0154817] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Accepted: 04/19/2016] [Indexed: 01/30/2023] Open
Abstract
Background/Aims We previously demonstrated that anthocyanin-rich bilberry extract (ARBE) inhibits IFN-γ-induced signalling and downstream effects in human monocytic cells and ameliorates disease activity in ulcerative colitis (UC) patients. Here, we studied the molecular mechanisms of ARBE-mediated effects in vitro and by analysing colonic tissue and serum samples of UC patients treated with an oral anthocyanin-rich bilberry preparation during an open label clinical trial. Methods Colon specimens obtained during an open pilot study using ARBE for the treatment of mild-to-moderate UC were analyzed by immunohistochemistry. Cytokine levels in patients’ serum were quantified by ELISA. Cell culture experiments were performed using THP-1 monocytic cells. Results ARBE treatment inhibited the expression of IFN-γ-receptor 2 in human THP-1 monocytic cells. Colon biopsies of UC patients who responded to the 6-week long ARBE treatment revealed reduced amounts of the pro-inflammatory cytokines IFN-γ and TNF-α. Levels of phosphorylated (activated) p65-NF-κB were reduced in these patients. Further, patients with successful ARBE treatment featured enhanced levels of Th17-cell specific cytokine IL-22 and immunoregulatory cytokine IL-10 as well as reduced serum levels of TNF-α and MCP-1, but enhanced levels of IL-17A, in contrast to patients that did not reach remission after ARBE treatment. Conclusions Our data suggest a molecular mechanism underlying the anti-inflammatory effects of ARBE treatment in UC patients by modulating T-cell cytokine signalling and inhibiting IFN-γ signal transduction. These data are of particular interest, since ARBE is a promising therapeutic approach for the treatment of IBD.
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Affiliation(s)
- Sofia Roth
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Marianne R. Spalinger
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Claudia Gottier
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Luc Biedermann
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Jonas Zeitz
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Silvia Lang
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Achim Weber
- Institute for Surgical Pathology, University Hospital Zürich, Zurich, Switzerland
| | - Gerhard Rogler
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
- Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Michael Scharl
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
- Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
- * E-mail:
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Abd Allah ESH, Makboul R, Mohamed AO. Role of serotonin and nuclear factor-kappa B in the ameliorative effect of ginger on acetic acid-induced colitis. PATHOPHYSIOLOGY : THE OFFICIAL JOURNAL OF THE INTERNATIONAL SOCIETY FOR PATHOPHYSIOLOGY 2016; 23:35-42. [PMID: 26776295 DOI: 10.1016/j.pathophys.2015.12.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Revised: 12/07/2015] [Accepted: 12/16/2015] [Indexed: 02/06/2023]
Abstract
The current study was designed to investigate the role of serotonin (5-HT) and nuclear factor-kappa beta (NF-κB) in the ameliorative effect of ginger on acetic acid (AA)-induced colitis rat model. Colitis was induced by intra-colonic instillation of 3% AA, preceded or followed by daily administration of ginger (400mg/kg) by gavage for 5 days. Colons were assessed macroscopically and microscopically and the expression of NF-κB was evaluated by immunohistochemistry. Colonic tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), total peroxide (TP), and serum 5-HT levels were assessed. Administration of ginger ameliorated the effects of AA-induced colitis by plummeting colon weight-to-length ratio, macroscopic and microscopic scores. These effects were further supported by down-regulation of NF-κB and reduction of colonic TNF-α, IL-10, TP and serum 5-HT levels. Moreover, there were significant positive correlations between serum 5-HT and macroscopic, microscopic, immunoreactivity scores and colonic TNF-α level. In conclusion, ginger ameliorated AA-induced colitis not only through its anti-inflammatory and anti-oxidant properties, but also through the reduction of 5-HT which may contribute to the down-regulation of NF-κB-dependent TNF-α expression and the reduction of lipid peroxidation and tissue damage. In addition, the therapeutic effect of ginger was more pronounced than its preventive effect.
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Affiliation(s)
- Eman S H Abd Allah
- Medical Physiology Department, Faculty of Medicine, Assiut University, Assiut, Egypt.
| | - Rania Makboul
- Pathology Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Amany O Mohamed
- Medical Biochemistry Department, Faculty of Medicine, Assiut University, Assiut, Egypt
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Mine Y, Zhang H. Anti-inflammatory Effects of Poly-L-lysine in Intestinal Mucosal System Mediated by Calcium-Sensing Receptor Activation. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2015; 63:10437-10447. [PMID: 26588227 DOI: 10.1021/acs.jafc.5b03812] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
Calcium-sensing receptor (CaSR) is involved in maintaining cellular homeostasis and promoting recovery of damaged intestinal epithelial cells (IECs). Poly-L-lysine (PL) is a basic polypeptide identified for its role in the activation of CaSR through allosteric binding. The primary goal of the current study was to identify the modulatory effect of PL on intestinal inflammation and to determine whether these effects were mediated by CaSR activation. We used human intestinal epithelial cell lines, Caco-2 and HT-29, to assess PL anti-inflammatory activities in vitro. We found that PL reduced the IL-8 secretion from tumor necrosis factor (TNF)-α-treated human intestinal epithelial cell lines. On the other hand, the gene expression of pro-inflammatory cytokines TNF-α, IL-6, and IL-1β was inhibited by PL supplementation. We subsequently evaluated the anti-inflammatory activity of PL in vivo using a DSS-induced mouse colitis model. PL supplementation was shown to prevent dextran sulfate sodium salt (DSS)-induced loss of weight, colitic symptoms, and shortening of colon length but maintained colonic morphology. The pro-inflammatory cytokine expression in the mouse colon, including TNF-α, IL-6, INF-γ, IL-17, and IL-1β, was significantly up-regulated by DSS treatment, but was inhibited upon PL administration. As shown by the results from both in vitro and in vivo studies, the reduction of inflammatory cytokine production caused by PL was reversed by NPS-2143 pretreatment. In the present study, we provide evidence that PL exerts anti-inflammatory effects on the gut system, which is primarily mediated by allosteric ligand activation of CaSR.
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Affiliation(s)
- Yoshinori Mine
- Department of Food Science, University of Guelph , Guelph, Ontario N1G 2W1, Canada
| | - Hua Zhang
- Department of Food Science, University of Guelph , Guelph, Ontario N1G 2W1, Canada
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Durda P, Sabourin J, Lange EM, Nalls MA, Mychaleckyj JC, Jenny NS, Li J, Walston J, Harris TB, Psaty BM, Valdar W, Liu Y, Cushman M, Reiner AP, Tracy RP, Lange LA. Plasma Levels of Soluble Interleukin-2 Receptor α: Associations With Clinical Cardiovascular Events and Genome-Wide Association Scan. Arterioscler Thromb Vasc Biol 2015; 35:2246-53. [PMID: 26293465 PMCID: PMC5395092 DOI: 10.1161/atvbaha.115.305289] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Accepted: 08/03/2015] [Indexed: 11/16/2022]
Abstract
OBJECTIVE Interleukin (IL) -2 receptor subunit α regulates lymphocyte activation, which plays an important role in atherosclerosis. Associations between soluble IL-2Rα (sIL-2Rα) and cardiovascular disease (CVD) have not been widely studied and little is known about the genetic determinants of sIL-2Rα levels. APPROACH AND RESULTS We measured baseline levels of sIL-2Rα in 4408 European American (EA) and 766 African American (AA) adults from the Cardiovascular Health Study (CHS) and examined associations with baseline CVD risk factors, subclinical CVD, and incident CVD events. We also performed a genome-wide association study for sIL-2Rα in CHS (2964 EAs and 683 AAs) and further combined CHS EA results with those from two other EA cohorts in a meta-analysis (n=4464 EAs). In age, sex- and race- adjusted models, sIL-2Rα was positively associated with current smoking, type 2 diabetes mellitus, hypertension, insulin, waist circumference, C-reactive protein, IL-6, fibrinogen, internal carotid wall thickness, all-cause mortality, CVD mortality, and incident CVD, stroke, and heart failure. When adjusted for baseline CVD risk factors and subclinical CVD, associations with all-cause mortality, CVD mortality, and heart failure remained significant in both EAs and AAs. In the EA genome-wide association study analysis, we observed 52 single-nucleotide polymorphisms in the chromosome 10p15-14 region, which contains IL2RA, IL15RA, and RMB17, that reached genome-wide significance (P<5×10(-8)). The most significant single-nucleotide polymorphism was rs7911500 (P=1.31×10(-75)). The EA meta-analysis results were highly consistent with CHS-only results. No single-nucleotide polymorphisms reached statistical significance in the AAs. CONCLUSIONS These results support a role for sIL-2Rα in atherosclerosis and provide evidence for multiple-associated single-nucleotide polymorphisms at chromosome 10p15-14.
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Affiliation(s)
- Peter Durda
- From the Departments of Pathology (P.D., N.S.J., M.C., R.P.T.), Medicine (M.C.), and Biochemistry (R.P.T.), University of Vermont College of Medicine, Burlington; Departments of Genetics (J.S., E.M.L., J.L., W.V., L.A.L.), Biostatistics (E.M.L., W.V.), Lineberger Comprehensive Cancer Center, School of Medicine (J.S., E.M.L., W.V.), University of North Carolina, Chapel Hill; Laboratory of Neurogenetics, Porter Neuroscience Research Center, National Institute on Aging, National Institute of Health, Bethesda, MD (M.A.N.); Center for Public Health Genomics, School of Medicine, University of Virginia, Charlottesville (J.C.M.); Johns Hopkins Medical Institutions, Department of Medicine Geriatrics, Johns Hopkins University, John R. Burton Pavilion, Baltimore, MD (J.D.W.); Geriatric Epidemiology Section, National Institute on Aging, National Institute of Health, Bethesda, MD (T.B.H.); Cardiovascular Health Research Unit (B.M.P.), Departments of Medicine (B.M.P.) and Epidemiology (B.M.P., A.P.R.), University of Washington, Seattle; Group Health Research Institute, Division of Cardiology, Group Health Cooperative, Seattle, WA (B.M.P.); and Wake Forest University School of Medicine, Center for Genomics and Personalized Medicine Research, Winston-Salem, NC (Y.L.)
| | - Jeremy Sabourin
- From the Departments of Pathology (P.D., N.S.J., M.C., R.P.T.), Medicine (M.C.), and Biochemistry (R.P.T.), University of Vermont College of Medicine, Burlington; Departments of Genetics (J.S., E.M.L., J.L., W.V., L.A.L.), Biostatistics (E.M.L., W.V.), Lineberger Comprehensive Cancer Center, School of Medicine (J.S., E.M.L., W.V.), University of North Carolina, Chapel Hill; Laboratory of Neurogenetics, Porter Neuroscience Research Center, National Institute on Aging, National Institute of Health, Bethesda, MD (M.A.N.); Center for Public Health Genomics, School of Medicine, University of Virginia, Charlottesville (J.C.M.); Johns Hopkins Medical Institutions, Department of Medicine Geriatrics, Johns Hopkins University, John R. Burton Pavilion, Baltimore, MD (J.D.W.); Geriatric Epidemiology Section, National Institute on Aging, National Institute of Health, Bethesda, MD (T.B.H.); Cardiovascular Health Research Unit (B.M.P.), Departments of Medicine (B.M.P.) and Epidemiology (B.M.P., A.P.R.), University of Washington, Seattle; Group Health Research Institute, Division of Cardiology, Group Health Cooperative, Seattle, WA (B.M.P.); and Wake Forest University School of Medicine, Center for Genomics and Personalized Medicine Research, Winston-Salem, NC (Y.L.)
| | - Ethan M Lange
- From the Departments of Pathology (P.D., N.S.J., M.C., R.P.T.), Medicine (M.C.), and Biochemistry (R.P.T.), University of Vermont College of Medicine, Burlington; Departments of Genetics (J.S., E.M.L., J.L., W.V., L.A.L.), Biostatistics (E.M.L., W.V.), Lineberger Comprehensive Cancer Center, School of Medicine (J.S., E.M.L., W.V.), University of North Carolina, Chapel Hill; Laboratory of Neurogenetics, Porter Neuroscience Research Center, National Institute on Aging, National Institute of Health, Bethesda, MD (M.A.N.); Center for Public Health Genomics, School of Medicine, University of Virginia, Charlottesville (J.C.M.); Johns Hopkins Medical Institutions, Department of Medicine Geriatrics, Johns Hopkins University, John R. Burton Pavilion, Baltimore, MD (J.D.W.); Geriatric Epidemiology Section, National Institute on Aging, National Institute of Health, Bethesda, MD (T.B.H.); Cardiovascular Health Research Unit (B.M.P.), Departments of Medicine (B.M.P.) and Epidemiology (B.M.P., A.P.R.), University of Washington, Seattle; Group Health Research Institute, Division of Cardiology, Group Health Cooperative, Seattle, WA (B.M.P.); and Wake Forest University School of Medicine, Center for Genomics and Personalized Medicine Research, Winston-Salem, NC (Y.L.)
| | - Mike A Nalls
- From the Departments of Pathology (P.D., N.S.J., M.C., R.P.T.), Medicine (M.C.), and Biochemistry (R.P.T.), University of Vermont College of Medicine, Burlington; Departments of Genetics (J.S., E.M.L., J.L., W.V., L.A.L.), Biostatistics (E.M.L., W.V.), Lineberger Comprehensive Cancer Center, School of Medicine (J.S., E.M.L., W.V.), University of North Carolina, Chapel Hill; Laboratory of Neurogenetics, Porter Neuroscience Research Center, National Institute on Aging, National Institute of Health, Bethesda, MD (M.A.N.); Center for Public Health Genomics, School of Medicine, University of Virginia, Charlottesville (J.C.M.); Johns Hopkins Medical Institutions, Department of Medicine Geriatrics, Johns Hopkins University, John R. Burton Pavilion, Baltimore, MD (J.D.W.); Geriatric Epidemiology Section, National Institute on Aging, National Institute of Health, Bethesda, MD (T.B.H.); Cardiovascular Health Research Unit (B.M.P.), Departments of Medicine (B.M.P.) and Epidemiology (B.M.P., A.P.R.), University of Washington, Seattle; Group Health Research Institute, Division of Cardiology, Group Health Cooperative, Seattle, WA (B.M.P.); and Wake Forest University School of Medicine, Center for Genomics and Personalized Medicine Research, Winston-Salem, NC (Y.L.)
| | - Josyf C Mychaleckyj
- From the Departments of Pathology (P.D., N.S.J., M.C., R.P.T.), Medicine (M.C.), and Biochemistry (R.P.T.), University of Vermont College of Medicine, Burlington; Departments of Genetics (J.S., E.M.L., J.L., W.V., L.A.L.), Biostatistics (E.M.L., W.V.), Lineberger Comprehensive Cancer Center, School of Medicine (J.S., E.M.L., W.V.), University of North Carolina, Chapel Hill; Laboratory of Neurogenetics, Porter Neuroscience Research Center, National Institute on Aging, National Institute of Health, Bethesda, MD (M.A.N.); Center for Public Health Genomics, School of Medicine, University of Virginia, Charlottesville (J.C.M.); Johns Hopkins Medical Institutions, Department of Medicine Geriatrics, Johns Hopkins University, John R. Burton Pavilion, Baltimore, MD (J.D.W.); Geriatric Epidemiology Section, National Institute on Aging, National Institute of Health, Bethesda, MD (T.B.H.); Cardiovascular Health Research Unit (B.M.P.), Departments of Medicine (B.M.P.) and Epidemiology (B.M.P., A.P.R.), University of Washington, Seattle; Group Health Research Institute, Division of Cardiology, Group Health Cooperative, Seattle, WA (B.M.P.); and Wake Forest University School of Medicine, Center for Genomics and Personalized Medicine Research, Winston-Salem, NC (Y.L.)
| | - Nancy Swords Jenny
- From the Departments of Pathology (P.D., N.S.J., M.C., R.P.T.), Medicine (M.C.), and Biochemistry (R.P.T.), University of Vermont College of Medicine, Burlington; Departments of Genetics (J.S., E.M.L., J.L., W.V., L.A.L.), Biostatistics (E.M.L., W.V.), Lineberger Comprehensive Cancer Center, School of Medicine (J.S., E.M.L., W.V.), University of North Carolina, Chapel Hill; Laboratory of Neurogenetics, Porter Neuroscience Research Center, National Institute on Aging, National Institute of Health, Bethesda, MD (M.A.N.); Center for Public Health Genomics, School of Medicine, University of Virginia, Charlottesville (J.C.M.); Johns Hopkins Medical Institutions, Department of Medicine Geriatrics, Johns Hopkins University, John R. Burton Pavilion, Baltimore, MD (J.D.W.); Geriatric Epidemiology Section, National Institute on Aging, National Institute of Health, Bethesda, MD (T.B.H.); Cardiovascular Health Research Unit (B.M.P.), Departments of Medicine (B.M.P.) and Epidemiology (B.M.P., A.P.R.), University of Washington, Seattle; Group Health Research Institute, Division of Cardiology, Group Health Cooperative, Seattle, WA (B.M.P.); and Wake Forest University School of Medicine, Center for Genomics and Personalized Medicine Research, Winston-Salem, NC (Y.L.)
| | - Jin Li
- From the Departments of Pathology (P.D., N.S.J., M.C., R.P.T.), Medicine (M.C.), and Biochemistry (R.P.T.), University of Vermont College of Medicine, Burlington; Departments of Genetics (J.S., E.M.L., J.L., W.V., L.A.L.), Biostatistics (E.M.L., W.V.), Lineberger Comprehensive Cancer Center, School of Medicine (J.S., E.M.L., W.V.), University of North Carolina, Chapel Hill; Laboratory of Neurogenetics, Porter Neuroscience Research Center, National Institute on Aging, National Institute of Health, Bethesda, MD (M.A.N.); Center for Public Health Genomics, School of Medicine, University of Virginia, Charlottesville (J.C.M.); Johns Hopkins Medical Institutions, Department of Medicine Geriatrics, Johns Hopkins University, John R. Burton Pavilion, Baltimore, MD (J.D.W.); Geriatric Epidemiology Section, National Institute on Aging, National Institute of Health, Bethesda, MD (T.B.H.); Cardiovascular Health Research Unit (B.M.P.), Departments of Medicine (B.M.P.) and Epidemiology (B.M.P., A.P.R.), University of Washington, Seattle; Group Health Research Institute, Division of Cardiology, Group Health Cooperative, Seattle, WA (B.M.P.); and Wake Forest University School of Medicine, Center for Genomics and Personalized Medicine Research, Winston-Salem, NC (Y.L.)
| | - Jeremy Walston
- From the Departments of Pathology (P.D., N.S.J., M.C., R.P.T.), Medicine (M.C.), and Biochemistry (R.P.T.), University of Vermont College of Medicine, Burlington; Departments of Genetics (J.S., E.M.L., J.L., W.V., L.A.L.), Biostatistics (E.M.L., W.V.), Lineberger Comprehensive Cancer Center, School of Medicine (J.S., E.M.L., W.V.), University of North Carolina, Chapel Hill; Laboratory of Neurogenetics, Porter Neuroscience Research Center, National Institute on Aging, National Institute of Health, Bethesda, MD (M.A.N.); Center for Public Health Genomics, School of Medicine, University of Virginia, Charlottesville (J.C.M.); Johns Hopkins Medical Institutions, Department of Medicine Geriatrics, Johns Hopkins University, John R. Burton Pavilion, Baltimore, MD (J.D.W.); Geriatric Epidemiology Section, National Institute on Aging, National Institute of Health, Bethesda, MD (T.B.H.); Cardiovascular Health Research Unit (B.M.P.), Departments of Medicine (B.M.P.) and Epidemiology (B.M.P., A.P.R.), University of Washington, Seattle; Group Health Research Institute, Division of Cardiology, Group Health Cooperative, Seattle, WA (B.M.P.); and Wake Forest University School of Medicine, Center for Genomics and Personalized Medicine Research, Winston-Salem, NC (Y.L.)
| | - Tamara B Harris
- From the Departments of Pathology (P.D., N.S.J., M.C., R.P.T.), Medicine (M.C.), and Biochemistry (R.P.T.), University of Vermont College of Medicine, Burlington; Departments of Genetics (J.S., E.M.L., J.L., W.V., L.A.L.), Biostatistics (E.M.L., W.V.), Lineberger Comprehensive Cancer Center, School of Medicine (J.S., E.M.L., W.V.), University of North Carolina, Chapel Hill; Laboratory of Neurogenetics, Porter Neuroscience Research Center, National Institute on Aging, National Institute of Health, Bethesda, MD (M.A.N.); Center for Public Health Genomics, School of Medicine, University of Virginia, Charlottesville (J.C.M.); Johns Hopkins Medical Institutions, Department of Medicine Geriatrics, Johns Hopkins University, John R. Burton Pavilion, Baltimore, MD (J.D.W.); Geriatric Epidemiology Section, National Institute on Aging, National Institute of Health, Bethesda, MD (T.B.H.); Cardiovascular Health Research Unit (B.M.P.), Departments of Medicine (B.M.P.) and Epidemiology (B.M.P., A.P.R.), University of Washington, Seattle; Group Health Research Institute, Division of Cardiology, Group Health Cooperative, Seattle, WA (B.M.P.); and Wake Forest University School of Medicine, Center for Genomics and Personalized Medicine Research, Winston-Salem, NC (Y.L.)
| | - Bruce M Psaty
- From the Departments of Pathology (P.D., N.S.J., M.C., R.P.T.), Medicine (M.C.), and Biochemistry (R.P.T.), University of Vermont College of Medicine, Burlington; Departments of Genetics (J.S., E.M.L., J.L., W.V., L.A.L.), Biostatistics (E.M.L., W.V.), Lineberger Comprehensive Cancer Center, School of Medicine (J.S., E.M.L., W.V.), University of North Carolina, Chapel Hill; Laboratory of Neurogenetics, Porter Neuroscience Research Center, National Institute on Aging, National Institute of Health, Bethesda, MD (M.A.N.); Center for Public Health Genomics, School of Medicine, University of Virginia, Charlottesville (J.C.M.); Johns Hopkins Medical Institutions, Department of Medicine Geriatrics, Johns Hopkins University, John R. Burton Pavilion, Baltimore, MD (J.D.W.); Geriatric Epidemiology Section, National Institute on Aging, National Institute of Health, Bethesda, MD (T.B.H.); Cardiovascular Health Research Unit (B.M.P.), Departments of Medicine (B.M.P.) and Epidemiology (B.M.P., A.P.R.), University of Washington, Seattle; Group Health Research Institute, Division of Cardiology, Group Health Cooperative, Seattle, WA (B.M.P.); and Wake Forest University School of Medicine, Center for Genomics and Personalized Medicine Research, Winston-Salem, NC (Y.L.)
| | - William Valdar
- From the Departments of Pathology (P.D., N.S.J., M.C., R.P.T.), Medicine (M.C.), and Biochemistry (R.P.T.), University of Vermont College of Medicine, Burlington; Departments of Genetics (J.S., E.M.L., J.L., W.V., L.A.L.), Biostatistics (E.M.L., W.V.), Lineberger Comprehensive Cancer Center, School of Medicine (J.S., E.M.L., W.V.), University of North Carolina, Chapel Hill; Laboratory of Neurogenetics, Porter Neuroscience Research Center, National Institute on Aging, National Institute of Health, Bethesda, MD (M.A.N.); Center for Public Health Genomics, School of Medicine, University of Virginia, Charlottesville (J.C.M.); Johns Hopkins Medical Institutions, Department of Medicine Geriatrics, Johns Hopkins University, John R. Burton Pavilion, Baltimore, MD (J.D.W.); Geriatric Epidemiology Section, National Institute on Aging, National Institute of Health, Bethesda, MD (T.B.H.); Cardiovascular Health Research Unit (B.M.P.), Departments of Medicine (B.M.P.) and Epidemiology (B.M.P., A.P.R.), University of Washington, Seattle; Group Health Research Institute, Division of Cardiology, Group Health Cooperative, Seattle, WA (B.M.P.); and Wake Forest University School of Medicine, Center for Genomics and Personalized Medicine Research, Winston-Salem, NC (Y.L.)
| | - Yongmei Liu
- From the Departments of Pathology (P.D., N.S.J., M.C., R.P.T.), Medicine (M.C.), and Biochemistry (R.P.T.), University of Vermont College of Medicine, Burlington; Departments of Genetics (J.S., E.M.L., J.L., W.V., L.A.L.), Biostatistics (E.M.L., W.V.), Lineberger Comprehensive Cancer Center, School of Medicine (J.S., E.M.L., W.V.), University of North Carolina, Chapel Hill; Laboratory of Neurogenetics, Porter Neuroscience Research Center, National Institute on Aging, National Institute of Health, Bethesda, MD (M.A.N.); Center for Public Health Genomics, School of Medicine, University of Virginia, Charlottesville (J.C.M.); Johns Hopkins Medical Institutions, Department of Medicine Geriatrics, Johns Hopkins University, John R. Burton Pavilion, Baltimore, MD (J.D.W.); Geriatric Epidemiology Section, National Institute on Aging, National Institute of Health, Bethesda, MD (T.B.H.); Cardiovascular Health Research Unit (B.M.P.), Departments of Medicine (B.M.P.) and Epidemiology (B.M.P., A.P.R.), University of Washington, Seattle; Group Health Research Institute, Division of Cardiology, Group Health Cooperative, Seattle, WA (B.M.P.); and Wake Forest University School of Medicine, Center for Genomics and Personalized Medicine Research, Winston-Salem, NC (Y.L.)
| | - Mary Cushman
- From the Departments of Pathology (P.D., N.S.J., M.C., R.P.T.), Medicine (M.C.), and Biochemistry (R.P.T.), University of Vermont College of Medicine, Burlington; Departments of Genetics (J.S., E.M.L., J.L., W.V., L.A.L.), Biostatistics (E.M.L., W.V.), Lineberger Comprehensive Cancer Center, School of Medicine (J.S., E.M.L., W.V.), University of North Carolina, Chapel Hill; Laboratory of Neurogenetics, Porter Neuroscience Research Center, National Institute on Aging, National Institute of Health, Bethesda, MD (M.A.N.); Center for Public Health Genomics, School of Medicine, University of Virginia, Charlottesville (J.C.M.); Johns Hopkins Medical Institutions, Department of Medicine Geriatrics, Johns Hopkins University, John R. Burton Pavilion, Baltimore, MD (J.D.W.); Geriatric Epidemiology Section, National Institute on Aging, National Institute of Health, Bethesda, MD (T.B.H.); Cardiovascular Health Research Unit (B.M.P.), Departments of Medicine (B.M.P.) and Epidemiology (B.M.P., A.P.R.), University of Washington, Seattle; Group Health Research Institute, Division of Cardiology, Group Health Cooperative, Seattle, WA (B.M.P.); and Wake Forest University School of Medicine, Center for Genomics and Personalized Medicine Research, Winston-Salem, NC (Y.L.)
| | - Alex P Reiner
- From the Departments of Pathology (P.D., N.S.J., M.C., R.P.T.), Medicine (M.C.), and Biochemistry (R.P.T.), University of Vermont College of Medicine, Burlington; Departments of Genetics (J.S., E.M.L., J.L., W.V., L.A.L.), Biostatistics (E.M.L., W.V.), Lineberger Comprehensive Cancer Center, School of Medicine (J.S., E.M.L., W.V.), University of North Carolina, Chapel Hill; Laboratory of Neurogenetics, Porter Neuroscience Research Center, National Institute on Aging, National Institute of Health, Bethesda, MD (M.A.N.); Center for Public Health Genomics, School of Medicine, University of Virginia, Charlottesville (J.C.M.); Johns Hopkins Medical Institutions, Department of Medicine Geriatrics, Johns Hopkins University, John R. Burton Pavilion, Baltimore, MD (J.D.W.); Geriatric Epidemiology Section, National Institute on Aging, National Institute of Health, Bethesda, MD (T.B.H.); Cardiovascular Health Research Unit (B.M.P.), Departments of Medicine (B.M.P.) and Epidemiology (B.M.P., A.P.R.), University of Washington, Seattle; Group Health Research Institute, Division of Cardiology, Group Health Cooperative, Seattle, WA (B.M.P.); and Wake Forest University School of Medicine, Center for Genomics and Personalized Medicine Research, Winston-Salem, NC (Y.L.)
| | - Russell P Tracy
- From the Departments of Pathology (P.D., N.S.J., M.C., R.P.T.), Medicine (M.C.), and Biochemistry (R.P.T.), University of Vermont College of Medicine, Burlington; Departments of Genetics (J.S., E.M.L., J.L., W.V., L.A.L.), Biostatistics (E.M.L., W.V.), Lineberger Comprehensive Cancer Center, School of Medicine (J.S., E.M.L., W.V.), University of North Carolina, Chapel Hill; Laboratory of Neurogenetics, Porter Neuroscience Research Center, National Institute on Aging, National Institute of Health, Bethesda, MD (M.A.N.); Center for Public Health Genomics, School of Medicine, University of Virginia, Charlottesville (J.C.M.); Johns Hopkins Medical Institutions, Department of Medicine Geriatrics, Johns Hopkins University, John R. Burton Pavilion, Baltimore, MD (J.D.W.); Geriatric Epidemiology Section, National Institute on Aging, National Institute of Health, Bethesda, MD (T.B.H.); Cardiovascular Health Research Unit (B.M.P.), Departments of Medicine (B.M.P.) and Epidemiology (B.M.P., A.P.R.), University of Washington, Seattle; Group Health Research Institute, Division of Cardiology, Group Health Cooperative, Seattle, WA (B.M.P.); and Wake Forest University School of Medicine, Center for Genomics and Personalized Medicine Research, Winston-Salem, NC (Y.L.).
| | - Leslie A Lange
- From the Departments of Pathology (P.D., N.S.J., M.C., R.P.T.), Medicine (M.C.), and Biochemistry (R.P.T.), University of Vermont College of Medicine, Burlington; Departments of Genetics (J.S., E.M.L., J.L., W.V., L.A.L.), Biostatistics (E.M.L., W.V.), Lineberger Comprehensive Cancer Center, School of Medicine (J.S., E.M.L., W.V.), University of North Carolina, Chapel Hill; Laboratory of Neurogenetics, Porter Neuroscience Research Center, National Institute on Aging, National Institute of Health, Bethesda, MD (M.A.N.); Center for Public Health Genomics, School of Medicine, University of Virginia, Charlottesville (J.C.M.); Johns Hopkins Medical Institutions, Department of Medicine Geriatrics, Johns Hopkins University, John R. Burton Pavilion, Baltimore, MD (J.D.W.); Geriatric Epidemiology Section, National Institute on Aging, National Institute of Health, Bethesda, MD (T.B.H.); Cardiovascular Health Research Unit (B.M.P.), Departments of Medicine (B.M.P.) and Epidemiology (B.M.P., A.P.R.), University of Washington, Seattle; Group Health Research Institute, Division of Cardiology, Group Health Cooperative, Seattle, WA (B.M.P.); and Wake Forest University School of Medicine, Center for Genomics and Personalized Medicine Research, Winston-Salem, NC (Y.L.)
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Saxena A, Khosraviani S, Noel S, Mohan D, Donner T, Hamad ARA. Interleukin-10 paradox: A potent immunoregulatory cytokine that has been difficult to harness for immunotherapy. Cytokine 2015; 74:27-34. [PMID: 25481648 PMCID: PMC4454631 DOI: 10.1016/j.cyto.2014.10.031] [Citation(s) in RCA: 223] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2014] [Revised: 10/28/2014] [Accepted: 10/29/2014] [Indexed: 12/21/2022]
Abstract
Interleukin-10 (IL-10) is arguably the most potent anti-inflammatory cytokine. It is produced by almost all the innate and adaptive immune cells. These cells also serve as its targets, indicating that IL-10 secretion and action is highly regulated and perhaps compartmentalized. Consistent with this notion, various efforts directed at systemic administration of IL-10 to modulate autoimmune diseases (type 1 diabetes, multiple sclerosis, rheumatoid arthritis, psoriasis) have produced conflicting and largely inconsequential effects. On the other hand, IL-10 can promote humoral immune responses, enhancing class II expression on B cells and inducing immunoglobulin (Ig) production. Consequently, the high IL-10 level in systemic lupus erythematosus (SLE) patients is considered pathogenic and its blockade ameliorates the disease. In this perspective, we review preclinical findings and results of recent clinical studies using exogenous IL-10 to treat the aforementioned autoimmune diseases. In addition, given the limited success of IL-10 supplementation, we suggest that future studies should be expanded beyond modulating the delivery modes to include developing new strategies to protect and replenish the endogenous sources of IL-10. As an example, we provide evidence that aberrant Fas-mediated deletion of IL-10-producing B cells subverts the immunoregulatory role of IL-10 in autoimmune diabetes and that modulation of the Fas pathway preserves the IL-10-producing B cells and completely protects NOD mice from developing the disease.
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Affiliation(s)
- Ankit Saxena
- Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA
| | - Sam Khosraviani
- Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA
| | - Sanjeev Noel
- Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21287, USA
| | - Divya Mohan
- Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21287, USA
| | - Thomas Donner
- Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21287, USA
| | - Abdel Rahim A Hamad
- Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA; Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21287, USA.
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Abstract
Importance of chronic fibroproliferative diseases (FDs) including pulmonary fibrosis, chronic kidney diseases, inflammatory bowel disease, and cardiovascular or liver fibrosis is rapidly increasing and they have become a major public health problem. According to some estimates about 45% of all deaths are attributed to FDs in the developed world. Independently of their etiology the common hallmark of FDs is chronic inflammation. Infiltrating immune cells, endothelial, epithelial, and other resident cells of the injured organ release an orchestra of inflammatory mediators, which stimulate the proliferation and excessive extracellular matrix (ECM) production of myofibroblasts, the effector cells of organ fibrosis. Abnormal amount of ECM disturbs the original organ architecture leading to the decline of function. Although our knowledge is rapidly expanding, we still have neither a diagnostic tool to detect nor a drug to specifically target fibrosis. Therefore, there is an urgent need for the more comprehensive understanding of the pathomechanism of fibrosis and development of novel diagnostic and therapeutic strategies. In the present review we provide an overview of the common key mediators of organ fibrosis highlighting the role of interleukin-10 (IL-10) cytokine family members (IL-10, IL-19, IL-20, IL-22, IL-24, and IL-26), which recently came into focus as tissue remodeling-related inflammatory cytokines.
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Korolkova OY, Myers JN, Pellom ST, Wang L, M’Koma AE. Characterization of Serum Cytokine Profile in Predominantly Colonic Inflammatory Bowel Disease to Delineate Ulcerative and Crohn's Colitides. CLINICAL MEDICINE INSIGHTS. GASTROENTEROLOGY 2015; 8:29-44. [PMID: 26078592 PMCID: PMC4459555 DOI: 10.4137/cgast.s20612] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/28/2014] [Revised: 11/23/2014] [Accepted: 11/23/2014] [Indexed: 02/05/2023]
Abstract
BACKGROUND As accessible diagnostic approaches fail to differentiate between ulcerative colitis (UC) and Crohn's colitis (CC) in one-third of patients with predominantly colonic inflammatory bowel disease (IBD), leading to inappropriate therapy, we aim to investigate the serum cytokine levels in these patients in search of molecular biometric markers delineating UC from CC. METHODS We measured 38 cytokines, chemokines, and growth factors using magnetic-bead-based multiplex immunoassay in 25 UC patients, 28 CC patients, and 30 controls. Our results are compared with those from a review of current literature regarding advances in serum cytokine profiles and associated challenges preventing their use for diagnostic/prognostic purposes. RESULTS Univariate analysis showed statistically significant increases of eotaxin, GRO, and TNF-α in UC patients compared to controls (Ctrl); interferon γ, interleukin (IL)-6, and IL-7 in CC group compared to Ctrl; and IL-8 in both UC and CC versus Ctrl. No cytokines were found to be different between UC and CC. A generalized linear model identified combinations of cytokines, allowing the identification of UC and CC patients, with area under the curve (AUC) = 0.936, as determined with receiver operating characteristic (ROC) analysis. CONCLUSIONS The current knowledge available about circulating cytokines in IBD is often contradictory. The development of an evidence-based tool using cytokines for diagnostic accuracy is still preliminary.
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Affiliation(s)
- Olga Y Korolkova
- Laboratory of Inflammatory Bowel Disease Research, Department of Biochemistry and Cancer Biology, Meharry Medical College School of Medicine, Nashville, Tennessee
| | - Jeremy N Myers
- Laboratory of Inflammatory Bowel Disease Research, Department of Biochemistry and Cancer Biology, Meharry Medical College School of Medicine, Nashville, Tennessee
| | - Samuel T Pellom
- Laboratory of Inflammatory Bowel Disease Research, Department of Biochemistry and Cancer Biology, Meharry Medical College School of Medicine, Nashville, Tennessee
| | - Li Wang
- Department of Statistics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Amosy E M’Koma
- Laboratory of Inflammatory Bowel Disease Research, Department of Biochemistry and Cancer Biology, Meharry Medical College School of Medicine, Nashville, Tennessee
- Department of General Surgery, Colon and Rectal Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee
- Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee
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Nguyen PM, Putoczki TL, Ernst M. STAT3-Activating Cytokines: A Therapeutic Opportunity for Inflammatory Bowel Disease? J Interferon Cytokine Res 2015; 35:340-50. [PMID: 25760898 PMCID: PMC4426323 DOI: 10.1089/jir.2014.0225] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Accepted: 01/15/2015] [Indexed: 01/08/2023] Open
Abstract
The gastrointestinal tract is lined by a single layer of epithelial cells that secrete mucus toward the lumen, which collectively separates the immune sentinels in the underlying lamina propria from the intestinal microflora to prevent aberrant immune responses. Inflammatory bowel disease (IBD) describes a group of autoimmune diseases that arise from defects in epithelial barrier function and, as a consequence, aberrant production of inflammatory cytokines. Among these, interleukin (IL)-6, IL-11, and IL-22 are elevated in human IBD patients and corresponding mouse models and, through activation of the JAK/STAT3 pathway, can both propagate and ameliorate disease. In particular, cytokine-mediated activation of STAT3 in the epithelial lining cells affords cellular protection, survival, and proliferation, thereby affording therapeutic opportunities for the prevention and treatment of colitis. In this review, we focus on recent insights gained from therapeutic modulation of the activities of IL-6, IL-11, and IL-22 in models of IBD and advocate a cautionary approach with these cytokines to minimize their tumor-promoting activities on neoplastic epithelium.
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Affiliation(s)
- Paul M. Nguyen
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, Australia
| | - Tracy L. Putoczki
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, Australia
| | - Matthias Ernst
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, Australia
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Shi Y, Rupa P, Jiang B, Mine Y. Hydrolysate from eggshell membrane ameliorates intestinal inflammation in mice. Int J Mol Sci 2014; 15:22728-42. [PMID: 25501329 PMCID: PMC4284733 DOI: 10.3390/ijms151222728] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2014] [Revised: 10/27/2014] [Accepted: 11/04/2014] [Indexed: 01/20/2023] Open
Abstract
Inflammatory bowel diseases (IBD) comprises of ulcerative colitis (UC) and Cohn’s disease (CD) as two main idiopathic pathologies resulting in immunologically mediated chronic inflammatory conditions. Several bioactive peptides and hydro lysates from natural sources have now been tested in animal models of human diseases for potential anti-inflammatory effects. Eggshell membrane (ESM) is a well-known natural bioactive material. In this study, we aim to study the anti-inflammatory activity of ESM hydro lysate (AL-PS) in vitro and in vivo. In vitro, AL-PS was shown to inhibit pro-inflammatory cytokine IL-8 secretion. In vivo treatment with AL-PS was shown to reduce dextran sodium sulphate (DSS)-induced weight loss, clinical signs of colitis and secretion of interleukin (IL)-6 (p < 0.05). In addition, treatment with AL-PS also attenuated the severity of intestinal inflammation via down-regulation of IL-10 an anti-inflammatory cytokine. This validates potential benefits of AL-PS as a novel preventative target molecule for treatment of IBD.
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Affiliation(s)
- Yaning Shi
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China.
| | - Prithy Rupa
- Department of Food Science, University of Guelph, 50 Stone Road East, Guelph, ON N1G 2W1, Canada.
| | - Bo Jiang
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China.
| | - Yoshinori Mine
- Department of Food Science, University of Guelph, 50 Stone Road East, Guelph, ON N1G 2W1, Canada.
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Rana SV, Sharma S, Kaur J, Prasad KK, Sinha SK, Kochhar R, Malik A, Morya RK. Relationship of cytokines, oxidative stress and GI motility with bacterial overgrowth in ulcerative colitis patients. J Crohns Colitis 2014; 8:859-65. [PMID: 24456736 DOI: 10.1016/j.crohns.2014.01.007] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2013] [Revised: 01/08/2014] [Accepted: 01/08/2014] [Indexed: 12/18/2022]
Abstract
BACKGROUND Ulcerative colitis (UC) is idiopathic, chronic and relapsing inflammatory bowel disease. Factors which initiate and perpetuate UC are not well understood. It is still unclear if any relationship exists between cytokines, oxidative stress, gastrointestinal (GI) motility, and small intestinal bacterial overgrowth (SIBO) in UC patients. GOALS To examine the relationship between these factors among UC patients. METHODS A total of 120 UC patients and 125 age and sex matched controls with no GI symptoms were enrolled. Plasma levels of IL-6, IL-8, TNF-α and IL-10 were measured in all subjects by using ELISA. Lipid peroxidation (LPO) and reduced glutathione (GSH) were measured by standard methods. Orocecal transit time (OCTT) and SIBO were measured by lactulose and glucose hydrogen breath tests respectively. RESULTS Out of the 120 UC patients, 74 were male with mean±SD age of 45.6±17.5years. Plasma levels of IL-6, IL-8, TNF-α and IL-10 in UC patients were significantly higher (p<0.01) as compared to controls. LPO in UC patients was significantly increased (p<0.01) while GSH was significantly decreased (p<0.01) as compared to controls. OCTT and SIBO were significantly higher in UC patients as compared to controls. UC patients with elevated inflammatory cytokines showed delayed OCTT and increased SIBO. It was also observed that there was a significant correlation between SIBO with IL-6, IL-8, TNF-α, and IL-10, LPO and GSH. CONCLUSION This study indicates that increase in cytokines and decrease in anti-oxidants in UC patients would have resulted in oxidative stress causing delayed GI motility leading to SIBO.
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Affiliation(s)
- Satya Vati Rana
- Department of Super Specialty of Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India.
| | - Surendra Sharma
- Department of Super Specialty of Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Jaspreet Kaur
- Department of Super Specialty of Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Kaushal Kishore Prasad
- Department of Super Specialty of Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Saroj Kant Sinha
- Department of Super Specialty of Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Rakesh Kochhar
- Department of Super Specialty of Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Aastha Malik
- Department of Super Specialty of Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Rajesh Kumar Morya
- Department of Super Specialty of Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
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Telmisartan attenuates colon inflammation, oxidative perturbations and apoptosis in a rat model of experimental inflammatory bowel disease. PLoS One 2014; 9:e97193. [PMID: 24831514 PMCID: PMC4022743 DOI: 10.1371/journal.pone.0097193] [Citation(s) in RCA: 109] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
Accumulating evidence has indicated the implication of angiotensin II in the pathogenesis of inflammatory bowel diseases (IBD) via its proinflammatory features. Telmisartan (TLM) is an angiotensin II receptor antagonist with marked anti-inflammatory and antioxidant actions that mediated its cardio-, reno- and hepatoprotective actions. However, its impact on IBD has not been previously explored. Thus, we aimed to investigate the potential alleviating effects of TLM in tri-nitrobenezene sulphonic acid (TNBS)-induced colitis in rats. Pretreatment with TLM (10 mg/kg p.o.) attenuated the severity of colitis as evidenced by decrease of disease activity index (DAI), colon weight/length ratio, macroscopic damage, histopathological findings and leukocyte migration. TLM suppressed the inflammatory response via attenuation of tumor necrosis factor-α (TNF-α), prostaglandin E2 (PGE2) and myeloperoxidase (MPO) activity as a marker of neutrophil infiltration besides restoration of interleukin-10 (IL-10). TLM also suppressed mRNA and protein expression of nuclear factor kappa B (NF-κB) p65 and mRNA of cyclo-oxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) proinflammatory genes with concomitant upregulation of PPAR-γ. The alleviation of TLM to colon injury was also associated with inhibition of oxidative stress as evidenced by suppression of lipid peroxides and nitric oxide (NO) besides boosting glutathione (GSH), total anti-oxidant capacity (TAC) and the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx). With respect to apoptosis, TLM downregulated the increased mRNA, protein expression and activity of caspase-3. It also suppressed the elevation of cytochrome c and Bax mRNA besides the upregulation of Bcl-2. Together, these findings highlight evidences for the beneficial effects of TLM in IBD which are mediated through modulation of colonic inflammation, oxidative stress and apoptosis.
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Arab HH, Salama SA, Eid AH, Omar HA, Arafa ESA, Maghrabi IA. Camel's milk ameliorates TNBS-induced colitis in rats via downregulation of inflammatory cytokines and oxidative stress. Food Chem Toxicol 2014; 69:294-302. [PMID: 24788059 DOI: 10.1016/j.fct.2014.04.032] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2013] [Revised: 04/12/2014] [Accepted: 04/18/2014] [Indexed: 02/06/2023]
Abstract
Current treatment strategies for inflammatory bowel diseases (IBD) are associated with several adverse effects, and thus, the search for effective agents with minimal side effects merits attention. Camel's milk (CM) is endowed with antioxidant/anti-inflammatory features and has been reported to protect against diabetes and hepatic injury, however, its effects on IBD have not been previously explored. In the current study, we aimed to investigate the potential alleviating effects of CM against TNBS-induced colitis in rats. CM (10 ml/kg b.i.d. by oral gavage) effectively suppressed the severity of colon injury as evidenced by amelioration of macroscopic damage, colon weight/length ratio, histopathological alterations, leukocyte influx and myeloperoxidase activity. Administration of CM mitigated the colonic levels of TNF-α and IL-10 cytokines. The attenuation of CM to colon injury was also associated with suppression of oxidative stress via reduction of lipid peroxides and nitric oxide along with boosting the antioxidant defenses through restoration of colon glutathione and total anti-oxidant capacity. In addition, caspases-3 activity, an apoptotic marker, was inhibited. Together, our study highlights evidences for the promising alleviating effects of CM in colitis. Thus, CM may be an interesting complementary approach for the management of IBD.
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Affiliation(s)
- Hany H Arab
- Biochemistry Division and GTMR Unit, Department of Pharmacology and Toxicology, Faculty of Pharmacy, Taif University, Taif 21974, Saudi Arabia; Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
| | - Samir A Salama
- Biochemistry Division and GTMR Unit, Department of Pharmacology and Toxicology, Faculty of Pharmacy, Taif University, Taif 21974, Saudi Arabia; Department of Biochemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11751, Egypt
| | - Ahmed H Eid
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Taif University, Taif 21974, Saudi Arabia; Department of Pharmacology, National Organization for Drug Control and Research (NODCAR), Dokki, Cairo, Egypt
| | - Hany A Omar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Taif University, Taif 21974, Saudi Arabia; Department of Pharmacology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt
| | - El-Shaimaa A Arafa
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Taif University, Taif 21974, Saudi Arabia; Department of Pharmacology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt
| | - Ibrahim A Maghrabi
- Department of Clinical Pharmacy, Faculty of Pharmacy, Taif University, Taif 21974, Saudi Arabia
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