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Zhang H, Gu X, He W, Zhao SL, Cao ZJ. Epstein-Barr virus infection is an independent risk factor for surgery in patients with moderate-to-severe ulcerative colitis. World J Gastroenterol 2025; 31:104758. [PMID: 40308799 PMCID: PMC12038525 DOI: 10.3748/wjg.v31.i16.104758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 03/18/2025] [Accepted: 04/14/2025] [Indexed: 04/27/2025] Open
Abstract
BACKGROUND Epstein-Barr virus (EBV) infection of the intestinal mucosa is associated with surgical risk in ulcerative colitis (UC); however, the exact effect remains unclear. AIM To determine whether EBV infection can predict the need for colectomy and to develop a surgical risk predictive model. METHODS This was a single-center retrospective study of 153 patients with moderate-to-severe UC between September 2012 and May 2023. EBV-encoded small RNA (EBER) in situ hybridization and immunohistochemistry (IHC) were used for EBV testing and assessment. Cytomegalovirus (CMV) was detected by IHC. Logistic regression analysis was conducted to identify risk factors for colectomy and develop a predictive risk model. RESULTS EBER-positivity in the intestinal mucosa was present in 40.4% (19/47) and 4.7% (5/106) of patients in the surgery and non-surgery groups, respectively, with significant differences between the groups (P < 0.01, odds ratio = 13.707). The result of multivariate logistic regression revealed that age, EBV infection in the colonic mucosa, CMV infection in the colonic mucosa, and treatment with three or more immunosuppressive agents before admission were significant independent predictors of colectomy. A nomogram incorporating these variables demonstrated good discriminative ability, and exhibited good calibration and clinical utility. IHC showed that EBV-infected cells mainly included B and T lymphocytes in patients with high EBER concentrations. CONCLUSION EBV infection of the intestinal mucosa is a significant independent risk factor for colectomy in patients with moderate-to-severe UC. The nomogram model, which includes EBV infection, effectively predicts colectomy risk.
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Affiliation(s)
- Hui Zhang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China
| | - Xi Gu
- Division of Pathology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China
| | - Wei He
- Division of Pathology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China
| | - Shu-Liang Zhao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China
| | - Zhi-Jun Cao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China
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2
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Wu Y, Cheng R, Lin H, Li L, Jia Y, Philips A, Zuo T, Zhang H. Gut virome and its implications in the pathogenesis and therapeutics of inflammatory bowel disease. BMC Med 2025; 23:183. [PMID: 40140901 PMCID: PMC11948845 DOI: 10.1186/s12916-025-04016-y] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Accepted: 03/18/2025] [Indexed: 03/28/2025] Open
Abstract
Inflammatory bowel disease (IBD) refers to chronic, recurrent inflammatory intestinal disorders, primarily including Crohn's disease (CD) and Ulcerative colitis (UC). Numerous studies have elucidated the importance of the gut microbiome in IBD. Recently, numerous studies have focused on the gut virome, an intriguing and enigmatic aspect of the gut microbiome. Alterations in the composition of phages, eukaryotic viruses, and human endogenous retroviruses that occur in IBD suggest potential involvement of the gut virome in IBD. Nevertheless, the mechanisms by which it maintains intestinal homeostasis and interacts with diseases are only beginning to be understood. Here, we thoroughly reviewed the composition of the gut virome in both healthy individuals and IBD patients, emphasizing the key viruses implicated in the onset and progression of IBD. Furthermore, the complex connections between the gut virome and the intestinal barrier, immunity, and gut microbiome were dissected to advance the interpretation of IBD pathogenesis. The updated discussion of the evidence regarding the gut virome will advance our knowledge in gut virome and chronic gastrointestinal diseases. Targeting the gut virome is a promising avenue for IBD treatment in future.
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Affiliation(s)
- Yushan Wu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Rui Cheng
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Hao Lin
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Lili Li
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Yongbin Jia
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Anna Philips
- Laboratory of Bioinformatics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
| | - Tao Zuo
- Key Laboratory of Human Microbiome and Chronic Diseases, Ministry of Education, Sun Yat-Sen University, Guangzhou, China.
- Guangdong Institute of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
- Biomedical Innovation Centre, the Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
- The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
| | - Hu Zhang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China.
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China.
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.
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Borghol AH, Bitar ER, Hanna A, Naim G, Rahal EA. The role of Epstein-Barr virus in autoimmune and autoinflammatory diseases. Crit Rev Microbiol 2025; 51:296-316. [PMID: 38634723 DOI: 10.1080/1040841x.2024.2344114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 03/15/2024] [Accepted: 04/11/2024] [Indexed: 04/19/2024]
Abstract
Epstein-Barr Virus (EBV), a dsDNA herpesvirus, is believed to play a significant role in exacerbating and potentially triggering autoimmune and autoinflammatory maladies. Around 90% of the world is infected with the virus, which establishes latency within lymphocytes. EBV is also known to cause infectious mononucleosis, a self-limited flu-like illness, in adolescents. EBV is often reactivated and it employs several mechanisms of evading the host immune system. It has also been implicated in inducing host immune dysfunction potentially resulting in exacerbation or triggering of inflammatory processes. EBV has therefore been linked to a number of autoimmune diseases, including systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, and Sjögren's syndrome. The review examines the molecular mechanisms through which the virus alters host immune system components thus possibly resulting in autoimmune processes. Understanding the mechanisms underpinning EBV-associated autoimmunity is pivotal; however, the precise causal pathways remain elusive. Research on therapeutic agents and vaccines for EBV has been stagnant for a long number of years until recent advances shed light on potential therapeutic targets. The implications of EBV in autoimmunity underscore the importance of developing targeted therapeutic strategies and, potentially, vaccines to mitigate the autoimmune burden associated with this ubiquitous virus.
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Affiliation(s)
- Abdul Hamid Borghol
- Department of Experimental Pathology, Immunology and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- Center for Infectious Diseases Research (CIDR), American University of Beirut, Beirut, Lebanon
| | - Elio R Bitar
- Department of Experimental Pathology, Immunology and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- Center for Infectious Diseases Research (CIDR), American University of Beirut, Beirut, Lebanon
| | - Aya Hanna
- Department of Experimental Pathology, Immunology and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- Center for Infectious Diseases Research (CIDR), American University of Beirut, Beirut, Lebanon
| | - Georges Naim
- Department of Experimental Pathology, Immunology and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- Center for Infectious Diseases Research (CIDR), American University of Beirut, Beirut, Lebanon
| | - Elias A Rahal
- Department of Experimental Pathology, Immunology and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- Center for Infectious Diseases Research (CIDR), American University of Beirut, Beirut, Lebanon
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Wang Z, Chen Y, Wu Y, Xue Y, Lin K, Zhang J, Xiao Y. Enhancing Epstein-Barr virus detection in IBD patients with XAI and clinical data integration. Comput Biol Med 2025; 184:109465. [PMID: 39579664 DOI: 10.1016/j.compbiomed.2024.109465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 11/20/2024] [Accepted: 11/20/2024] [Indexed: 11/25/2024]
Abstract
BACKGROUND There is increasing evidence of a link between Epstein-Barr virus (EBV) and gastrointestinal cancers, particularly in immunocompromised patients and those on thiopurines. Traditional endoscopic techniques have limitations in diagnosing EBV, whereas standard methods for diagnosing EBV have practical challenges in regular clinical settings related to their invasiveness and high costs. METHODS An explainable AI (XAI) model was developed to analyze 1598 endoscopic images from 287 patients with inflammatory bowel disease (IBD), with a focus on detecting EBV infection. Following the application of data augmentation and transfer learning techniques, the model accurately classified the presence of EBV, and its performance was quantified through receiver operating characteristic (ROC) curve analysis, including calculation of the area under the curve (AUC). Furthermore, a combination of the Grad-CAM method and clinical data analysis significantly improved the interpretability and diagnostic accuracy of the model. RESULTS Our model significantly outperformed other models, including those developed with ResNet50, Vision Transformer (ViT), and MobileNet v2 architectures, in detecting EBV on endoscopic images, achieving an accuracy of 73.83 % and an F1-score of 73.70 %. The model showed good performance in distinguishing between EBV-positive and EBV-negative images according to the confusion matrix and ROC curve analysis, with metrics including a true negative rate of 79.76 %, a true positive rate of 67.32 %, and an AUC of 0.74. Additionally, the generated salience maps effectively identified key regions in the images, enhancing lesion detection in patients with EBV infection. Our correlational analysis revealed significant associations between EBV infection and clinical parameters such as age, illness duration, and total bilirubin, and suggested that EBV infection had a notably greater incidence in ulcerative colitis (UC) patients than in Crohn's disease (CD) patients. CONCLUSION Our study successfully created an XAI-assisted system that allows the accurate detection of EBV in endoscopic images and improves the diagnosis of EBV infection through the integration of clinical data.
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Affiliation(s)
- Zheng Wang
- School of Computer Science, Hunan First Normal University, Changsha, 410205, China
| | - Yiqian Chen
- Gastroenterology Department of Xiangya Hospital, Central South University, Changsha, 410008, China; Hunan International Scientific and Technological Cooperation Base of Artificial Intelligence Computer Aided Diagnosis and Treatment for Digestive Disease, Changsha, 410011, China
| | - Yi Wu
- School of Computer Science, Hunan First Normal University, Changsha, 410205, China
| | - Yang Xue
- School of Computer Science, Hunan First Normal University, Changsha, 410205, China
| | - Kaibin Lin
- School of Computer Science, Hunan First Normal University, Changsha, 410205, China
| | - Jianglin Zhang
- Department of Dermatology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China; Candidate Branch of National Clinical Research Center for Skin Diseases, Shenzhen, 518020, Guangdong, China; Department of Geriatrics, Shenzhen People's Hospital, (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China
| | - Ying Xiao
- Gastroenterology Department of Xiangya Hospital, Central South University, Changsha, 410008, China; Hunan International Scientific and Technological Cooperation Base of Artificial Intelligence Computer Aided Diagnosis and Treatment for Digestive Disease, Changsha, 410011, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
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5
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Wang W, Chen X, Pan J, Zhang X, Zhang L. Epstein-Barr Virus and Human Cytomegalovirus Infection in Intestinal Mucosa of Chinese Patients With Inflammatory Bowel Disease. Front Microbiol 2022; 13:915453. [PMID: 35711779 PMCID: PMC9195000 DOI: 10.3389/fmicb.2022.915453] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 05/09/2022] [Indexed: 12/30/2022] Open
Abstract
Objective This study aimed to determine the frequency of Epstein–Barr virus (EBV), cytomegalovirus (CMV) in mucosa and blood of inflammatory bowel disease (IBD) patients in China and evaluate their correlation with the clinical disease activities. Methods Peripheral blood and endoscopic fresh colonic mucosal samples were collected from a cohort of 287 IBD patients and 50 controls. Viral DNA load was analyzed through quantitative real-time PCR. The clinical disease activity of ulcerative colitis (UC) and Crohn’s disease (CD) was assessed by the Mayo Clinic Score and Crohn’s disease activity index, respectively. Results Among 287 IBD patients, 228 (79.4%) were positive for EBV and 99 (34.5%) were positive for CMV. EBV and CMV infection rates are significantly higher than those in the control group (28.0%, p < 0.05; 4.0%, p < 0.05). In addition, EBV/CMV prevalence increases as clinical activities progress [For EBV infection, the prevalence was 53.93% (48/89) in the mild group, 87.00% (87/100) in the moderate group, and 94.90% (93/98) in the severe group; and for CMV infection, the prevalence was 3.37% (3/89) in the mild group, 27.00% (27/100) in the moderate group, and 70.41% (69/98) in the severe group]. EBV and CMV loads are related to clinical disease activities (p < 0.05). In addition, viral load in the intestinal mucosa of patients with acute exacerbation of IBD is higher than that of patients in remission. Conclusion High prevalence of EBV and CMV is found in patients with IBD, and their prevalence is related to clinical disease activities. In addition, the viral load in the intestinal mucosa is associated with the status of mucosa in the same patients (active phase versus remission phase). Detection of viral load on mucosal specimens with quantitative real-time PCR is a feasible method to monitor EBV and CMV infection in IBD patients.
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Affiliation(s)
- Wei Wang
- Department of Laboratory Medicine, Shanxi Provincial People's Hospital, Taiyuan, China
| | - Xin Chen
- Department of Laboratory Medicine, The 908th Hospital of Chinese PLA Joint Logistics Support Force, Nanchang, China
| | - Jie Pan
- Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, United States
| | - Xianhui Zhang
- Department of Rheumatology, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Tongji Medical College, Huazhong University of Science and Technology, Taiyuan, China
| | - Liyun Zhang
- Department of Rheumatology, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Tongji Medical College, Huazhong University of Science and Technology, Taiyuan, China
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Ishikawa E, Satou A, Nakamura M, Nakamura S, Fujishiro M. Epstein-Barr Virus Positive B-Cell Lymphoproliferative Disorder of the Gastrointestinal Tract. Cancers (Basel) 2021; 13:3815. [PMID: 34359715 PMCID: PMC8345108 DOI: 10.3390/cancers13153815] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 07/23/2021] [Accepted: 07/25/2021] [Indexed: 12/12/2022] Open
Abstract
Epstein-Barr virus positive B-cell lymphoproliferative disorder (EBV+ B-LPD) encompasses a broad clinicopathological spectrum and distinct clinical behavior that relatively favors the gastrointestinal (GI) tract. In this review, we provide an update on the clinicopathological features and biological behavior of EBV-positive mucocutaneous ulcer (EBVMCU) and primary EBV+ diffuse large B-cell lymphoma (DLBCL) of the GI tract. EBVMCU is a newly recognized entity but well known as an indolent and self-limited EBV+ B-LPD occurring in various immunodeficiencies. In contrast, EBV+ DLBCL constitutes the largest group of EBV+ B-LPDs and is regarded as an aggressive neoplasm. These two distinct diseases have historically been distinguished in the reappraisal of age-related EBV-associated B-LPDs but are challenging in routine practice regarding their differential diagnostic and therapeutic approaches. An increasing number of reports indicate that they are epidemiologically prevalent beyond western and eastern countries, but their comprehensive analysis is still limited. We also describe the PD-L1 positivity of tumorous large cells and non-malignant immune cells, which is relevant for the prognostic delineation among patients with primary DLBCL of the GI tract with and without EBV on tumor cells.
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Affiliation(s)
- Eri Ishikawa
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan; (M.N.); (M.F.)
| | - Akira Satou
- Department of Surgical Pathology, Aichi Medical University Hospital, Nagakute 480-1195, Japan;
| | - Masanao Nakamura
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan; (M.N.); (M.F.)
| | - Shigeo Nakamura
- Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya 466-8550, Japan;
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan; (M.N.); (M.F.)
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7
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Núñez Ortiz A, Rojas Feria M, de la Cruz Ramírez MD, Gómez Izquierdo L, Trigo Salado C, Herrera Justiniano JM, Leo Carnerero E. Impact of Epstein-Barr virus infection on inflammatory bowel disease (IBD) clinical outcomes. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2021; 114:259-265. [PMID: 34315215 DOI: 10.17235/reed.2021.7915/2021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To evaluate the role of Epstein-Barr virus (EBV) on the intestinal mucosa in the evolution of inflammatory bowel disease (IBD), to investigate the risk factors for EBV infection and the frequency of EBV-associated lymphoproliferative disorders in IBD patients. METHODS Intestinal biopsies of IBD patients with available EBV status determined by Epstein-Barr-encoding RNA (EBER) in situ hybridization were searched in the Pathology Database of our center. Clinical information, including phenotypic characteristics of IBD, previous treatments, diagnosis of lymphoma, and patient outcome, were reviewed for all cases. RESULTS 56 patients with IBD (28 Crohn´s disease, 27 ulcerative colitis and one unclassified colitis) were included. EBV in intestinal mucosa was positive in 26 patients (46%), in one case associated to a lymphoproliferative syndrome. EBV positivity was associated with severe histological activity (52% vs. 17.2%; p 0.007), presence of a lymphoplasmacytic infiltrate (50% vs. 33.3%; p 0.03) and active steroid treatment (61.5% vs. 33.3%; p 0.03). Multivariate analyses only found association between EBV and lymphoplasmacytosis (p 0.001). Escalation in previous treatment was significantly more frequent in the EBER+ group (53.8% vs. 26.7%; p 0.038). No cases developed lymphoma in the follow-up. CONCLUSIONS EBV on the intestinal mucosa is associated with a poor outcome of IBD and the need for escalation in therapy. Lymphoplasmacytic infiltrate is associated with EBV infection. EBER+ patients used steroids more frequently compared with EBER- patients. No EBER+ patients developed a lymphoma during follow-up.
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Alruwaii ZI, Montgomery EA. Select Epstein-Barr Virus-Associated Digestive Tract Lesions for the Practicing Pathologist. Arch Pathol Lab Med 2021; 145:562-570. [PMID: 32320275 DOI: 10.5858/arpa.2019-0703-ra] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/14/2020] [Indexed: 12/24/2022]
Abstract
CONTEXT.— Epstein-Barr virus is a ubiquitous oncogenic virus. During the past 5 decades, the virus has been linked to several disease entities, both neoplastic and nonneoplastic. Several Epstein-Barr virus-associated conditions affect the digestive organs, ranging from mild transient inflammatory conditions to more debilitating and even fatal diseases. OBJECTIVE.— To discuss the clinicopathologic aspects of some newly or recently recognized Epstein-Barr virus-related conditions encountered in the digestive system and their therapeutic implications. DATA SOURCES.— Published peer-reviewed literature was reviewed. CONCLUSIONS.— This article highlights the importance of recognizing the discussed lesions because they influence the direct clinical management or serve as a potential predictive marker for therapy.
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Affiliation(s)
- Zainab I Alruwaii
- From the Department of Pathology, Regional Laboratory and Blood Bank, Eastern Province, Dammam, Saudi Arabia (Alruwaii)
| | - Elizabeth A Montgomery
- and the Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland (Montgomery)
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9
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Axelrad JE, Cadwell KH, Colombel JF, Shah SC. The role of gastrointestinal pathogens in inflammatory bowel disease: a systematic review. Therap Adv Gastroenterol 2021; 14:17562848211004493. [PMID: 33868457 PMCID: PMC8020742 DOI: 10.1177/17562848211004493] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 03/04/2021] [Indexed: 02/04/2023] Open
Abstract
The inflammatory bowel diseases (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), are chronic, progressive, inflammatory conditions of the gastrointestinal tract. Imbalance in the gut microbial community, or dysbiosis, and the subsequent immune response, represent the critical relationship between genetic susceptibility, microbes, and environment factors, that result in IBD. Gastrointestinal pathogens - a common cause of dysbiosis - have been implicated as an environmental trigger in new onset IBD, as well as flare of existing IBD. In this article, we systematically review clinical data regarding the association between specific gastrointestinal pathogens and IBD. Numerous bacteria, viruses, fungi, and parasites have been implicated in the pathogenesis of IBD, and exacerbations of existing disease. In this article, we will also specifically discuss the less recognized microbes that have an inverse association with IBD, including certain bacterial pathogens, such as Helicobacter pylori, and parasites, such as Trichuris species. Future prospective and experimental studies are required to establish causality and clarify potential mechanisms of enteric pathogens in modifying the risk and course of IBD.
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Affiliation(s)
| | - Ken H. Cadwell
- Division of Gastroenterology, Department of Medicine, NYU Grossman School of Medicine, New York, NY, USA,Kimmel Center for Biology and Medicine at the Skirball Institute, NYU Grossman School of Medicine, New York, NY, USA,Department of Microbiology, NYU Grossman School of Medicine, New York, NY, USA
| | - Jean-Frederic Colombel
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Shailja C. Shah
- Section of Gastroenterology, Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN,San Diego Health System, La Jolla, CA, USA,Division of Gastroenterology, University of California, San Diego, La Jolla, CA, USA
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10
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Kato S, Shimizu H, Tomii S, Uchida H, Kawamoto A, Hibiya S, Motobayashi M, Takenaka K, Fujii T, Saito E, Nagahori M, Ohtsuka K, Negi M, Akashi T, Matsuyama T, Kinugasa Y, Watanabe M. Substantial Epstein-Barr virus reactivation in a case of severe refractory ulcerative colitis: a possible role in exacerbation. Clin J Gastroenterol 2021; 14:584-588. [PMID: 33400186 DOI: 10.1007/s12328-020-01319-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 12/08/2020] [Indexed: 11/30/2022]
Abstract
Ulcerative colitis (UC) is an inflammatory bowel disease that causes chronic inflammation in the colon. 5-aminosalicylic acid and immunosuppressive medications such as corticosteroids, immunomodulators, and biologic agents are used to treat these patients. However, patients with UC who receive immunosuppressive medications may be at risk for certain opportunistic infections. Epstein-Barr virus (EBV) is one of those opportunistic infections, and its pathogenic role has been implicated in refractory UC, but its pathogenicity should be further investigated. Here, we report a surgical case of refractory UC that demonstrated a serologically post-infected pattern of EBV at admission but that later had a high load of EBV in both the peripheral blood and colonic mucosa. These findings suggest that EBV may have been reactivated in the colon, after which it damaged the colonic mucosa and aggravated inflammation in this patient with UC. Thus, EBV might lead to severity and a refractory response against corticosteroids and anti-TNFα agents, necessitating emergency surgery. Viral surveillance for EBV in patients with refractory UC may facilitate understanding of the patient's pathophysiology and predicting response to medications, and the development of antiviral intervention for those patients may improve their prognosis.
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Affiliation(s)
- Shu Kato
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Hiromichi Shimizu
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
| | - Shohei Tomii
- Division of Surgical Pathology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Hitoshi Uchida
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Ami Kawamoto
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Shuji Hibiya
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Maiko Motobayashi
- Department of Endoscopy, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Kento Takenaka
- Department of Endoscopy, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Toshimitsu Fujii
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Eiko Saito
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Masakazu Nagahori
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Kazuo Ohtsuka
- Department of Endoscopy, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Mariko Negi
- Division of Surgical Pathology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Takumi Akashi
- Division of Surgical Pathology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Takatoshi Matsuyama
- Department of Gastrointestinal Surgery, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Yusuke Kinugasa
- Department of Gastrointestinal Surgery, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Mamoru Watanabe
- Institute of Advanced Study, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
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11
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Xu S, Chen H, Zu X, Hao X, Feng R, Zhang S, Chen B, Zeng Z, Chen M, Ye Z, He Y. Epstein-Barr virus infection in ulcerative colitis: a clinicopathologic study from a Chinese area. Therap Adv Gastroenterol 2020; 13:1756284820930124. [PMID: 32913442 PMCID: PMC7444145 DOI: 10.1177/1756284820930124] [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: 12/23/2019] [Accepted: 05/05/2020] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Opportunistic Epstein-Barr virus (EBV) infection in patients with ulcerative colitis (UC) has attracted increasing attention. This study aimed to evaluate the clinicopathological characteristics and clinical outcomes of UC with intestinal EBV infection and to explore the predictive value of blood EBV DNA for the presence of EBV in the intestine. METHODS Both peripheral blood and intestinal biopsies from 92 consecutive UC inpatients were included in this study. Normal colonic mucosal tissues from 20 colon cancer patients were used as controls. EBV testing and assessment were performed by EBV-DNA polymerase chain reaction (PCR), EBV-encoded small RNA in situ hybridization (EBER-ISH) and immunohistochemistry. RESULTS A total of 36 patients (39.1%) had UC with superimposed EBV colitis [EBER greater than 2/high-power field (HPF)]. EBER counts and disease activity were significantly correlated (p < 0.05). The major endoscopic findings revealed more irregular and longitudinal ulcers in patients with superimposed EBV colitis (p = 0.016, p = 0.021, respectively). Age, steroid dependence, and irregular ulcerations were identified as possible risk factors. The best EBER cut-off point for outcome prediction was 2.5/HPF. At a cut-off value of 2035 copies/ml, the sensitivity and specificity of the blood EBV-DNA PCR analysis for predicting EBV presence in the intestine were 76.5% and 68.5%, respectively. EBV-infected cells in UC with high EBV concentrations mainly included B lymphocytes by clinicopathology, and the infection might have progressed from the latent to the lytic phase of the EBV life cycle. CONCLUSION The EBER count is positively correlated with disease activity. The best cut-off point for outcome prediction is 2.5/HPF. A high EBV viremia load may effectively predict EBV presence in the colonic mucosa.
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Affiliation(s)
| | | | - Xiaoman Zu
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xiuxue Hao
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Rui Feng
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Shenghong Zhang
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Baili Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zhirong Zeng
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Minhu Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Ziyin Ye
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, NO.58 Zhongshan Road II, Guangzhou 510080, Guangdong Province, P.R. China
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Goetgebuer RL, van der Woude CJ, de Ridder L, Doukas M, de Vries AC. Clinical and endoscopic complications of Epstein-Barr virus in inflammatory bowel disease: an illustrative case series. Int J Colorectal Dis 2019; 34:923-926. [PMID: 30739187 DOI: 10.1007/s00384-019-03257-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/29/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIM Epstein-Barr virus (EBV) is a proposed trigger in the etiopathogenesis of inflammatory bowel disease (IBD) and is associated with lymphoproliferative diseases. Nevertheless, testing for EBV DNA in the intestinal mucosa and screening for EBV infection before initiation of a drug therapy are not routinely performed. The aim of this article is to increase awareness of the relevance of EBV infection in specific clinical situations. METHODS In this short communication, we describe the disease course of three IBD patients with EBV infection, varying from EBV reactivation during disease flare up to a trigger of EBV-related mucocutaneous ulcer (EBV-MCU) and haemophagocytic lymphohistiocytosis (HLH). RESULTS Our first patient was diagnosed with EBV reactivation-associated severe colitis and showed a rapid clinical improvement after induction therapy with infliximab and azathioprine. Without antiviral treatment, the patient remained in complete remission and no complications of EBV were seen. After diagnosing EBV-MCU in the second patient, immunosuppressive medication was discontinued and four infusions of rituximab resulted in a rapid clinical recovery and eventually complete response. After discontinuation of the immunosuppression in our last patient with haemophagocytic lymphohistiocytosis, treatment with a combination of corticosteroid and antiviral therapy resulted in a complete recovery over a time span of several weeks. CONCLUSION EBV infection has a wide variety of potentially life-threatening clinical manifestations in IBD patients. Testing for EBV in case of a flare up and screening for EBV before the start of immunosuppressive therapy will create awareness for EBV-related symptoms or complications during follow-up.
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Affiliation(s)
- R L Goetgebuer
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
| | - C J van der Woude
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - L de Ridder
- Department of Pediatric Gastroenterology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - M Doukas
- Department of Pathology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - A C de Vries
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
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Refractory inflammatory bowel disease: is there a role for Epstein-Barr virus? A case-controlled study using highly sensitive Epstein-Barr virus-encoded small RNA1 in situ hybridization. Hum Pathol 2018; 82:187-192. [PMID: 30120969 DOI: 10.1016/j.humpath.2018.08.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 07/24/2018] [Accepted: 08/01/2018] [Indexed: 12/12/2022]
Abstract
A potential role for viral infections has been implicated in inflammatory bowel disease (IBD) unresponsive to medical treatment. It is well known that Epstein-Barr virus (EBV) infection can elicit a brisk mononuclear response in the gastrointestinal tract. The aim of this study was to further evaluate the role of EBV in patients with refractory IBD and compare them with nonrefractory IBD cases. Surgically resected colonic specimens from 67 patients with refractory IBD (62 with ulcerative colitis, 3 patients with Crohn disease, and 2 patients with indeterminate colitis) were retrieved. Twelve colectomy specimens from patients with ulcerative colitis who had undergone resections for dysplasia or endometriosis were included as controls. Highly sensitive EBV-encoded small RNA1 (EBER-1) in situ hybridization was performed on a representative block from each specimen. EBER-1 reactivity was graded as absent, focal, or diffuse. EBV was detected in 60% (40/67) of patients with refractory IBD compared with 25% (3/12) of the control group (P < .05). Focal EBER-1 positivity was present in 45% of cases of refractory IBD compared with 25% of controls. Diffuse EBER-1 reactivity was seen in 15% of cases of refractory IBD (10/67); none of the samples from the control group contained diffuse EBER-1 positivity. There was a positive correlation between EBER positivity and depth of inflammation and mucosal ulceration in patients with refractory IBD. Our findings suggest a potential role for EBV infection in patients with refractory IBD.
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14
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Hosomi S, Watanabe K, Nishida Y, Yamagami H, Yukawa T, Otani K, Nagami Y, Tanaka F, Taira K, Kamata N, Tanigawa T, Shiba M, Watanabe T, Nagahara H, Maeda K, Fujiwara Y. Combined Infection of Human Herpes Viruses: A Risk Factor for Subsequent Colectomy in Ulcerative Colitis. Inflamm Bowel Dis 2018; 24:1307-1315. [PMID: 29668948 DOI: 10.1093/ibd/izy005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Little is known about the prevalence and pathogenicity of human herpes viruses except for cytomegalovirus (CMV) in patients with inflammatory bowel disease (IBD). The aim of this study was to determine the prevalence of human herpes viruses on colonic mucosa in patients with IBD and assess the long-term outcomes in these patients. METHODS We examined the colonic mucosal specimens from 66 patients with ulcerative colitis (UC), 54 patients with Crohn's disease (CD), and 29 healthy patients to identify the 6 most common types of human herpes virus, using multiplex polymerase chain reaction (PCR) technique. RESULTS Herpes simplex virus (HSV)-1/2 and varicella-zoster virus (VZV) were not detected in any of the groups. There was a higher prevalence of Epstein-Barr virus (EBV) (21.2%) and CMV (15.1%) in patients with UC than in patients with CD (EBV 9.3%, CMV 0%) and patents in the healthy control group (EBV 0%, CMV 3.4%). The prevalence of human herpes virus (HHV)-6A/B and HHV-7 was not statistically different among the groups. Five UC patients with inflammation had coexisting CMV and EBV or HHV-6. The combined infection of CMV with EBV or HHV-6 was a significant and independent prognostic factor for subsequent colectomy in patients with UC. CONCLUSIONS The increased prevalence of CMV coexisting with EBV/HHV-6 infection was associated with the clinical course in patients with UC. 10.1093/ibd/izy005_video1izy005_Video_15786489376001.
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Affiliation(s)
- Shuhei Hosomi
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Kenji Watanabe
- Department of Inflammatory Bowel Disease, Hyogo College of Medicine, Hyogo, Japan
| | - Yu Nishida
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Hirokazu Yamagami
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Tomomi Yukawa
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Koji Otani
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yasuaki Nagami
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Fumio Tanaka
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Koichi Taira
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Noriko Kamata
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Tetsuya Tanigawa
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Masatsugu Shiba
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Toshio Watanabe
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Hisashi Nagahara
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Kiyoshi Maeda
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yasuhiro Fujiwara
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
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15
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Pandey S, Jha HC, Shukla SK, Shirley MK, Robertson ES. Epigenetic Regulation of Tumor Suppressors by Helicobacter pylori Enhances EBV-Induced Proliferation of Gastric Epithelial Cells. mBio 2018; 9:e00649-18. [PMID: 29691341 PMCID: PMC5915740 DOI: 10.1128/mbio.00649-18] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Accepted: 03/27/2018] [Indexed: 12/11/2022] Open
Abstract
Helicobacter pylori and Epstein-Barr virus (EBV) are two well-known contributors to cancer and can establish lifelong persistent infection in the host. This leads to chronic inflammation, which also contributes to development of cancer. Association with H. pylori increases the risk of gastric carcinoma, and coexistence with EBV enhances proliferation of infected cells. Further, H. pylori-EBV coinfection causes chronic inflammation in pediatric patients. We have established an H. pylori-EBV coinfection model system using human gastric epithelial cells. We showed that H. pylori infection can increase the oncogenic phenotype of EBV-infected cells and that the cytotoxin-associated gene (CagA) protein encoded by H. pylori stimulated EBV-mediated cell proliferation in this coinfection model system. This led to increased expression of DNA methyl transferases (DNMTs), which reprogrammed cellular transcriptional profiles, including those of tumor suppressor genes (TSGs), through hypermethylation. These findings provide new insights into a molecular mechanism whereby cooperativity between two oncogenic agents leads to enhanced oncogenic activity of gastric cancer cells.IMPORTANCE We have studied the cooperativity between H. pylori and EBV, two known oncogenic agents. This led to an enhanced oncogenic phenotype in gastric epithelial cells. We now demonstrate that EBV-driven epigenetic modifications are enhanced in the presence of H. pylori, more specifically, in the presence of its CagA secretory antigen. This results in increased proliferation of the infected gastric cells. Our findings now elucidate a molecular mechanism whereby expression of cellular DNA methyl transferases is induced influencing infection by EBV. Hypermethylation of the regulatory genomic regions of tumor suppressor genes results in their silencing. This drastically affects the expression of cell cycle, apoptosis, and DNA repair genes, which dysregulates their associated processes, and promotion of the oncogenic phenotype.
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Affiliation(s)
- Saurabh Pandey
- Departments of Otorhinolaryngology-Head and Neck Surgery, and Microbiology, the Tumor Virology Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Hem Chandra Jha
- Departments of Otorhinolaryngology-Head and Neck Surgery, and Microbiology, the Tumor Virology Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Sanket Kumar Shukla
- Departments of Otorhinolaryngology-Head and Neck Surgery, and Microbiology, the Tumor Virology Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Meghan K Shirley
- Departments of Otorhinolaryngology-Head and Neck Surgery, and Microbiology, the Tumor Virology Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Erle S Robertson
- Departments of Otorhinolaryngology-Head and Neck Surgery, and Microbiology, the Tumor Virology Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
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16
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Abstract
BACKGROUND Although there is some evidence suggesting that certain viruses may be involved in the onset of inflammatory bowel disease (IBD), data regarding viral prevalence and viral load in blood and mucosa of patients with IBD are scarce. The main aim of this study is to evaluate the prevalence and viral load of common Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpes virus 6 in blood and mucosa of adult patients with endoscopic active IBD. METHODS From January to December 2014, ulcerative colitis and Crohn's disease patients with active endoscopic disease were consecutively enrolled. Subjects undergoing colonoscopy for colorectal cancer screening served as healthy controls (HCs). Paired blood and mucosal samples from each patient and HC were collected for EBV, CMV, and human herpes virus 6 quantitative real time polymerase chain reaction assessment of the viral load. RESULTS One hundred forty-five subjects were included; 95 IBD patients with active endoscopic disease (43 ulcerative colitis and 52 Crohn's disease) and 50 healthy subjects. CMV and EBV DNA were detected more frequently in the mucosa of patients with IBD compared with HCs (CMV P = 0.017; EBV P < 0.001), irrespective of IBD type. The frequency of human herpes virus 6 DNA detection both in the blood and in the mucosa did not differ between patients with IBD and HCs. EBV median viral load was similar in the inflamed and noninflamed mucosa was not affected by the use of immunomodulators and/or anti-tumor necrosis factor alpha agents, and did not correlate with endoscopic disease activity. CONCLUSIONS EBV, and to a lesser extent CMV, were more prevalent in patients with IBD than in HCs. Mucosal viral load was not influenced by the therapeutic regimen, did not differ between inflamed and noninflamed mucosa, and did not seem to be influenced by the endoscopic activity of the disease, suggesting that EBV may be more involved in the onset of IBD than in its severity and clinical evolution.
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17
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Ciccocioppo R, Racca F, Scudeller L, Piralla A, Formagnana P, Pozzi L, Betti E, Vanoli A, Riboni R, Kruzliak P, Baldanti F, Corazza GR. Differential cellular localization of Epstein-Barr virus and human cytomegalovirus in the colonic mucosa of patients with active or quiescent inflammatory bowel disease. Immunol Res 2016; 64:191-203. [PMID: 26659090 DOI: 10.1007/s12026-015-8737-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The role of human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) in the exacerbation of inflammatory bowel disease (IBD) is still uncertain. We prospectively investigated the presence of EBV and HCMV infection in both epithelial and immune cells of colonic mucosa of IBD patients, both refractory and responders to standard therapies, in comparison with patients suffering from irritable bowel syndrome who were considered as controls, by using quantitative real-time polymerase chain reaction, immunohistochemistry and in situ hybridization, in an attempt to assess viral localization, DNA load, life cycle phase and possible correlation with disease activity indexes. We obtained clear evidence of the presence of high DNA loads of both viruses in either enterocytes or immune cells of refractory IBD patients, whereas we observed low levels in the responder group and an absence of detectable copies in all cell populations of controls. Remarkably, the values of EBV and HCMV DNA in inflamed mucosa were invariably higher than in non-inflamed areas in both IBD groups, and the EBV DNA loads in the cell populations of diseased mucosa of refractory IBD patients positively correlated with the severity of mucosal damage and clinical indexes of activity. Moreover, EBV infection resulted the most prevalent either alone or in combination with HCMV, while immunohistochemistry and in situ hybridization did not allow us to distinguish between the different phases of viral life cycle. Finally, as regards treatment, these novel findings could pave the way for the use of new antiviral molecules in the treatment of this condition.
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Affiliation(s)
- Rachele Ciccocioppo
- Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation, University of Pavia, Piazzale Golgi, 19, 27100, Pavia, Italy.
| | - Francesca Racca
- Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation, University of Pavia, Piazzale Golgi, 19, 27100, Pavia, Italy
| | - Luigia Scudeller
- Biometry and Clinical Epidemiology Unit, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
| | - Antonio Piralla
- SS Virologia Molecolare - SC Virologia e Microbiologia, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
| | - Pietro Formagnana
- Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation, University of Pavia, Piazzale Golgi, 19, 27100, Pavia, Italy
| | - Lodovica Pozzi
- Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation, University of Pavia, Piazzale Golgi, 19, 27100, Pavia, Italy
| | - Elena Betti
- Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation, University of Pavia, Piazzale Golgi, 19, 27100, Pavia, Italy
| | - Alessandro Vanoli
- Department of Human Pathology, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
| | - Roberta Riboni
- Department of Human Pathology, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
| | - Peter Kruzliak
- 2nd Department of Internal Medicine, St. Anne's University Hospital and Masaryk University, Pekarska 53, 656 91, Brno, Czech Republic. .,Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Odborarov 10, 832 32, Bratislava, Slovak Republic.
| | - Fausto Baldanti
- SS Virologia Molecolare - SC Virologia e Microbiologia, IRCCS Policlinico San Matteo Foundation, Pavia, Italy.,Department of Clinical Sciences, Surgery, Diagnostics and Pediatrics, University of Pavia, Pavia, Italy
| | - Gino Roberto Corazza
- Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation, University of Pavia, Piazzale Golgi, 19, 27100, Pavia, Italy
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18
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Abegunde AT, Muhammad BH, Bhatti O, Ali T. Environmental risk factors for inflammatory bowel diseases: Evidence based literature review. World J Gastroenterol 2016; 22:6296-6317. [PMID: 27468219 PMCID: PMC4945988 DOI: 10.3748/wjg.v22.i27.6296] [Citation(s) in RCA: 136] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Revised: 05/19/2016] [Accepted: 06/28/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: Advances in genetics and immunology have contributed to the current understanding of the pathogenesis of inflammatory bowel diseases (IBD).
METHODS: The current opinion on the pathogenesis of IBD suggests that genetically susceptible individuals develop intolerance to dysregulated gut microflora (dysbiosis) and chronic inflammation develops as a result of environmental insults. Environmental exposures are innumerable with varying effects during the life course of individuals with IBD. Studying the relationship between environmental factors and IBD may provide the missing link to increasing our understanding of the etiology and increased incidence of IBD in recent years with implications for prevention, diagnosis, and treatment. Environmental factors are heterogeneous and genetic predisposition, immune dysregulation, or dysbiosis do not lead to the development of IBD in isolation.
RESULTS: Current challenges in the study of environmental factors and IBD are how to effectively translate promising results from experimental studies to humans in order to develop models that incorporate the complex interactions between the environment, genetics, immunology, and gut microbiota, and limited high quality interventional studies assessing the effect of modifying environmental factors on the natural history and patient outcomes in IBD.
CONCLUSION: This article critically reviews the current evidence on environmental risk factors for IBD and proposes directions for future research.
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Lam GY, Halloran BP, Peters AC, Fedorak RN. Lymphoproliferative disorders in inflammatory bowel disease patients on immunosuppression: Lessons from other inflammatory disorders. World J Gastrointest Pathophysiol 2015; 6:181-192. [PMID: 26600976 PMCID: PMC4644882 DOI: 10.4291/wjgp.v6.i4.181] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Accepted: 09/28/2015] [Indexed: 02/06/2023] Open
Abstract
Immunosuppressive agents, such as thiopurines, methotrexate, and biologics, have revolutionized the treatment of inflammatory bowel disease (IBD). However, a number of case reports, case control studies and retrospective studies over the last decade have identified a concerning link between immunosuppression and lymphoproliferative disorders (LPDs), the oncological phenomenon whereby lymphocytes divide uncontrollably. These LPDs have been associated with Epstein-Barr virus (EBV) infection in which the virus provides the impetus for malignant transformation while immunosuppression hampers the immune system’s ability to detect and clear these malignant cells. As such, the use of immunosuppressive agents may come at the cost of increased risk of developing LPD. While little is known about the LPD risk in IBD, more is known about immunosuppression in the post-transplantation setting and the development of EBV associated post-transplantation lymphoproliferative disorders (PTLD). In review of the PTLD literature, evidence is available to demonstrate that certain immune suppressants such as cyclosporine and T-lymphocyte modulators in particular are associated with an increased risk of PTLD development. As well, high doses of immunosuppressive agents and multiple immunosuppressive agent use are also linked to increased PTLD development. Here, we discuss these findings in context of IBD and what future studies can be taken to understand and reduce the risk of EBV-associated LPD development from immunosuppression use in IBD.
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Lapsia S, Koganti S, Spadaro S, Rajapakse R, Chawla A, Bhaduri-McIntosh S. Anti-TNFα therapy for inflammatory bowel diseases is associated with Epstein-Barr virus lytic activation. J Med Virol 2015; 88:312-8. [PMID: 26307954 DOI: 10.1002/jmv.24331] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/12/2015] [Indexed: 01/19/2023]
Abstract
Anti-TNFα therapy, known to suppress T-cell immunity, is increasingly gaining popularity for treatment of autoimmune diseases including inflammatory bowel diseases (IBD). T-cell suppression increases the risk of B-cell EBV-lymphoproliferative diseases and lymphomas. Since EBV-lytic activation is essential for development of EBV-lymphomas and there have been reports of EBV-lymphomas in patients treated with anti-TNFα therapy, we investigated if patients treated with anti-TNFα antibodies demonstrate greater EBV-lytic activity in blood. Peripheral blood mononuclear cells from 10 IBD patients solely on anti-TNFα therapy compared to 3 control groups (10 IBD patients not on immunosuppressive therapy, 10 patients with abdominal pain but without IBD, and 10 healthy subjects) were examined for the percentage of T-cells, EBV load and EBV-lytic transcripts. Patients on anti-TNFα therapy had significantly fewer T-cells, greater EBV load, and increased levels of transcripts from EBV-lytic genes of all kinetic classes compared to controls. Furthermore, exposure of EBV-infected B-cell lines to anti-TNFα antibodies resulted in increased levels of BZLF1 mRNA; BZLF1 encodes for ZEBRA, the viral latency-to-lytic cycle switch. Thus, IBD patients treated with anti-TNFα antibodies have greater EBV loads likely due to enhanced EBV-lytic gene expression and anti-TNFα antibodies may be sufficient to activate the EBV lytic cycle. Findings from this pilot study lay the groundwork for additional scientific and clinical investigation into the effects of anti-TNFα therapy on the life cycle of EBV, a ubiquitous oncovirus that causes lymphomas in the setting of immunocompromise.
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Affiliation(s)
- Sameer Lapsia
- Division of Gastroenterology, Department of Pediatrics, Stony Brook University School of Medicine, Stony Brook, New York
| | - Siva Koganti
- Division of Infectious Diseases, Department of Pediatrics, Stony Brook University School of Medicine, Stony Brook, New York
| | - Salvatore Spadaro
- Division of Infectious Diseases, Department of Pediatrics, Stony Brook University School of Medicine, Stony Brook, New York
| | - Ramona Rajapakse
- Division of Gastroenterology, Department of Internal Medicine, Stony Brook University School of Medicine, Stony Brook, New York
| | - Anupama Chawla
- Division of Gastroenterology, Department of Pediatrics, Stony Brook University School of Medicine, Stony Brook, New York
| | - Sumita Bhaduri-McIntosh
- Division of Infectious Diseases, Department of Pediatrics, Stony Brook University School of Medicine, Stony Brook, New York.,Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York
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21
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Metagenomic analysis of microbiome in colon tissue from subjects with inflammatory bowel diseases reveals interplay of viruses and bacteria. Inflamm Bowel Dis 2015; 21:1419-27. [PMID: 25939040 PMCID: PMC4450971 DOI: 10.1097/mib.0000000000000344] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis, are poorly understood disorders affecting the intestinal tract. The current model for disease suggests that genetically susceptible patients develop intolerance to gut microflora, and chronic inflammation develops as a result of environmental insults. Although interest has mainly focused on studying genetic variants and gut bacterial flora, little is known about the potential of viral infection to contribute to disease. Accordingly, we conducted a metagenomic analysis to document the baseline virome in colonic biopsy samples from patients with IBD in order to assess the contribution of viral infection to IBD. Libraries were generated from colon RNA to create approximately 2 GB sequence data per library. Using a bioinformatic pipeline designed to detect viral sequences, more than 1000 viral reads were derived directly from tissue without any coculture or isolation procedure. Herein, we describe the complexity and abundance of viruses, bacteria/bacteriophage, and human endogenous retroviral sequences from 10 patients with IBD and 5 healthy subjects undergoing surveillance colonoscopy. Differences in gut microflora and the abundance of mammalian viruses and human endogenous retroviruses were readily detected in the metagenomic analyses. Specifically, patients with herpesviridae sequences in their colon demonstrated increased expression of human endogenous viral sequences and differences in the diversity of their microbiome. This study provides a promising metagenomic approach to describe the colonic microbiome that can be used to better understand virus-host and phage-bacteria interactions in IBD.
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Skovbjerg S, Roos K, Olofsson S, Lindh M, Ljung A, Hynsjö L, Holm SE, Adlerberth I, Wold AE. High Cytokine Levels in Tonsillitis Secretions Regardless of Presence of Beta-Hemolytic Streptococci. J Interferon Cytokine Res 2015; 35:682-9. [PMID: 26060912 DOI: 10.1089/jir.2014.0123] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Acute pharyngotonsillitis denotes tonsillar inflammation caused by bacteria or viruses. Here, we investigated if beta-hemolytic streptococci (β-HS) tonsillitis would differ in inflammatory mediator response from tonsillitis of other causes. Tonsillar secretions were obtained from 36 acute pharyngotonsillitis patients and 16 controls. Bacteria were cultured quantitatively and 18 different viruses were quantified by real-time polymerase chain reaction. Cytokine and prostaglandin E2 (PGE2) levels were determined by enzyme-linked immunosorbent assays. Almost half of the patients' tonsillar secretions yielded high counts of β-HS, and most samples contained viruses, irrespective of whether β-HS were present or not. The Epstein-Barr virus (EBV) was the most common virus (patients 62% and controls 13%). Compared to controls, patients' secretions had higher levels of interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor (TNF), and PGE2, while few samples contained IL-12, IL-10, or interferon-gamma (IFN-γ). The presence of β-HS in tonsillitis secretions could not be distinguished by any of the measured mediators, while the presence of EBV DNA tended to be associated with enhanced levels of IL-1β and IL-8. The results suggest a common inflammatory response in acute pharyngotonsillitis, regardless of causative agent. The suggested correlation between intense inflammation and the presence of EBV DNA in tonsillitis secretions may be due to reactivation of the virus and/or the EBV-containing B cells.
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Affiliation(s)
- Susann Skovbjerg
- 1 Department of Infectious Diseases, University of Gothenburg , Gothenburg, Sweden .,2 Clinical Microbiology, Sahlgrenska University Hospital , Gothenburg, Sweden
| | - Kristian Roos
- 3 ENT Department, Capio Lundby Hospital , Gothenburg, Sweden
| | - Sigvard Olofsson
- 1 Department of Infectious Diseases, University of Gothenburg , Gothenburg, Sweden .,2 Clinical Microbiology, Sahlgrenska University Hospital , Gothenburg, Sweden
| | - Magnus Lindh
- 1 Department of Infectious Diseases, University of Gothenburg , Gothenburg, Sweden .,2 Clinical Microbiology, Sahlgrenska University Hospital , Gothenburg, Sweden
| | - Annika Ljung
- 1 Department of Infectious Diseases, University of Gothenburg , Gothenburg, Sweden .,2 Clinical Microbiology, Sahlgrenska University Hospital , Gothenburg, Sweden
| | - Lars Hynsjö
- 4 Department of Clinical Chemistry and Transfusion Medicine, University of Gothenburg , Gothenburg, Sweden .,5 Clinical Chemistry, Sahlgrenska University Hospital , Gothenburg, Sweden
| | - Stig E Holm
- 6 Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg , Gothenburg, Sweden
| | - Ingegerd Adlerberth
- 1 Department of Infectious Diseases, University of Gothenburg , Gothenburg, Sweden .,2 Clinical Microbiology, Sahlgrenska University Hospital , Gothenburg, Sweden
| | - Agnes E Wold
- 1 Department of Infectious Diseases, University of Gothenburg , Gothenburg, Sweden .,2 Clinical Microbiology, Sahlgrenska University Hospital , Gothenburg, Sweden
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Bosca-Watts MM, Tosca J, Anton R, Mora M, Minguez M, Mora F. Pathogenesis of Crohn’s disease: Bug or no bug. World J Gastrointest Pathophysiol 2015; 6:1-12. [PMID: 25685606 PMCID: PMC4325296 DOI: 10.4291/wjgp.v6.i1.1] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2014] [Revised: 07/04/2014] [Accepted: 12/31/2014] [Indexed: 02/07/2023] Open
Abstract
The possibility of an infectious origin in inflammatory bowel disease (IBD) has been postulated since the first description of Crohn’s disease (CD). Many observations implicate bacteria as a trigger for the development of CD: lesions occur in regions with higher bacterial concentrations; aphthous ulcers occur in Peyer’s patches; inflammation resolves when the fecal stream is diverted and is reactivated following reinfusion of bowel contents; severity of the disease is correlated with bacterial density in the mucosa; granulomas can contain bacteria; and susceptible mice raised in germ-free conditions develop inflammation when bacteria are introduced in the 1990’s, several studies sought to establish a relationship with viral infections and the onset of IBD, finally concluding that no direct link had been demonstrated. In the past fifteen years, evidence relating IBD pathogenesis to Mycobacterium avium paratuberculosis, salmonella, campylobacter, etc., has been found. The tendency now under discussion to regard microbiota as the primary catalyst has led to the latest studies on microbiota as pathogens, focusing on Escherichia coli, mainly in ileal CD. The present review discusses the literature available on these “bugs”.
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Ciccocioppo R, Racca F, Paolucci S, Campanini G, Pozzi L, Betti E, Riboni R, Vanoli A, Baldanti F, Corazza GR. Human cytomegalovirus and Epstein-Barr virus infection in inflammatory bowel disease: Need for mucosal viral load measurement. World J Gastroenterol 2015; 21:1915-1926. [PMID: 25684960 PMCID: PMC4323471 DOI: 10.3748/wjg.v21.i6.1915] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2014] [Revised: 10/03/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the best diagnostic technique and risk factors of the human Cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) infection in inflammatory bowel disease (IBD).
METHODS: A cohort of 40 IBD patients (17 refractory) and 40 controls underwent peripheral blood and endoscopic colonic mucosal sample harvest. Viral infection was assessed by quantitative real-time polymerase chain reaction and immunohistochemistry, and correlations with clinical and endoscopic indexes of activity, and risk factors were investigated.
RESULTS: All refractory patients carried detectable levels of HCMV and/or EBV mucosal load as compared to 13/23 (56.5%) non-refractory and 13/40 (32.5%) controls. The median DNA value was significantly higher in refractory (HCMV 286 and EBV 5.440 copies/105 cells) than in non-refractory (HCMV 0 and EBV 6 copies/105 cells; P < 0.05 and < 0.001) IBD patients and controls (HCMV and EBV 0 copies/105 cells; P < 0.001 for both). Refractory patients showed DNA peak values ≥ 103 copies/105 cells in diseased mucosa in comparison to non-diseased mucosa (P < 0.0121 for HCMV and < 0.0004 for EBV), while non-refractory patients and controls invariably displayed levels below this threshold, thus allowing us to differentiate viral colitis from mucosal infection. Moreover, the mucosal load positively correlated with the values found in the peripheral blood, whilst no correlation with the number of positive cells at immunohistochemistry was found. Steroid use was identified as a significant risk factor for both HCMV (P = 0.018) and EBV (P = 0.002) colitis. Finally, a course of specific antiviral therapy with ganciclovir was successful in all refractory patients with HCMV colitis, whilst refractory patients with EBV colitis did not show any improvement despite steroid tapering and discontinuation of the other medications.
CONCLUSION: Viral colitis appeared to contribute to mucosal lesions in refractory IBD, and its correct diagnosis and management require quantitative real-time polymerase chain reaction assay of mucosal specimens.
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Intestinal Microbiome, Small Intestinal Bacterial Overgrowth and Inflammatory Bowel Diseases - What are the Connections? CURRENT HEALTH SCIENCES JOURNAL 2015; 41:197-203. [PMID: 30534422 PMCID: PMC6246988 DOI: 10.12865/chsj.41.03.01] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/24/2015] [Accepted: 01/29/2015] [Indexed: 12/18/2022]
Abstract
IBD (inflammatory bowel diseases) represent chronic idiopathic inflammatory diseases, prone to relapse in the digestive tract; it is estimated that they result from the interaction of the intestinal microbiome with the intestinal immune system. The inflammatory microbiome exerts multiple beneficial roles. Perhaps the central element to developing IBD is dysbiosis; there is still an incompletely established association between intestinal microbiome changes in patients with IBD and SIBO (small intestinal bacterial overgrowth). Influencing the intestinal microbiome may play an adjuvant therapeutic role in the treatment of IBD. We present a synthesis of the connections between the entities mentioned above.
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Use of animal models in elucidating disease pathogenesis in IBD. Semin Immunopathol 2014; 36:541-51. [PMID: 25212688 DOI: 10.1007/s00281-014-0444-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Accepted: 08/14/2014] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel diseases (IBD) are a collection of diseases characterized by chronic gastrointestinal inflammation resulting from an exuberant immune response to commensal flora in genetically susceptible individuals. Rapid advances in the field of genomics have resulted in the identification of at least 163 loci that contribute susceptibility to both Crohn's disease (CD) and ulcerative colitis (UC). Similar to other complex diseases, however, the "curse of missing heritability" remains a significant concern in understanding the mechanisms underlying IBD. While genetic discoveries, to date, only account for 7-14% of disease variance for IBD, studies have increasingly demonstrated a role for environmental factors in disease pathogenesis. Furthermore, the use of animal models of IBD has led to a greater understanding of disease pathogenesis implicating various aspects of the innate immune response including the bacterial, fungal, and viral microbiome and adaptive immune response such as the interleukin (IL)-23/IL-17 pathway.
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Sena A, Grishina I, Thai A, Goulart L, Macal M, Fenton A, Li J, Prindiville T, Oliani SM, Dandekar S, Goulart L, Sankaran-Walters S. Dysregulation of anti-inflammatory annexin A1 expression in progressive Crohns Disease. PLoS One 2013; 8:e76969. [PMID: 24130820 PMCID: PMC3794972 DOI: 10.1371/journal.pone.0076969] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2013] [Accepted: 08/29/2013] [Indexed: 12/19/2022] Open
Abstract
Background Development of inflammatory bowel disease (IBD) involves the interplay of environmental and genetic factors with the host immune system. Mechanisms contributing to immune dysregulation in IBD are not fully defined. Development of novel therapeutic strategies is focused on controlling aberrant immune response in IBD. Current IBD therapy utilizes a combination of immunomodulators and biologics to suppress pro-inflammatory effectors of IBD. However, the role of immunomodulatory factors such as annexin A1 (ANXA1) is not well understood. The goal of this study was to examine the association between ANXA1 and IBD, and the effects of anti-TNF-α, Infliximab (IFX), therapy on ANXA1 expression. Methods ANXA1 and TNF-α transcript levels in PBMC were measured by RT PCR. Clinical follow up included the administration of serial ibdQs. ANXA1 expression in the gut mucosa was measured by IHC. Plasma ANXA1 levels were measured by ELISA. Results We found that the reduction in ANXA1 protein levels in plasma coincided with a decrease in the ANXA1 mRNA expression in peripheral blood of IBD patients. ANXA1 expression is upregulated during IFX therapy in patients with a successful intervention but not in clinical non-responders. The IFX therapy also modified the cellular immune activation in the peripheral blood of IBD patients. Decreased expression of ANXA1 was detected in the colonic mucosa of IBD patients with incomplete resolution of inflammation during continuous therapy, which correlated with increased levels of TNF-α transcripts. Gut mucosal epithelial barrier disruption was evident by increased plasma bacterial 16S levels. Conclusion Loss of ANXA1 expression may support inflammation during IBD and can serve as a biomarker of disease progression. Changes in ANXA1 levels may be predictive of therapeutic efficacy.
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Affiliation(s)
- Angela Sena
- Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, United States of America
- Nanobiotechnology Laboratory, Institute of Genetics and Biochemistry, Federal University of Uberlandia, Uberlandia, Minas Gerais, Brazil
| | - Irina Grishina
- Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, United States of America
| | - Anne Thai
- UCDHS: Division of Hepatology and Gastroenterology, University of California Davis, Davis, California, United States of America
| | - Larissa Goulart
- Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, United States of America
| | - Monica Macal
- Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, United States of America
| | - Anne Fenton
- Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, United States of America
| | - Jay Li
- Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, United States of America
| | - Thomas Prindiville
- UCDHS: Division of Hepatology and Gastroenterology, University of California Davis, Davis, California, United States of America
| | - Sonia Maria Oliani
- Department of Biology, Sao Paulo State University, UNESP, Sao José do Rio Preto, SP, Brazil
| | - Satya Dandekar
- Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, United States of America
| | - Luiz Goulart
- Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, United States of America
- Nanobiotechnology Laboratory, Institute of Genetics and Biochemistry, Federal University of Uberlandia, Uberlandia, Minas Gerais, Brazil
| | - Sumathi Sankaran-Walters
- Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, United States of America
- * E-mail:
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Abstract
BACKGROUND Epstein-Barr virus infection is associated with inflammatory bowel disease, but its role as a pathogenetic or exacerbating factor remains unclear. OBJECTIVE The aim of this study was to evaluate the association between Epstein-Barr virus infection and inflammatory bowel disease, particularly in regard to exacerbation of disease activity. DESIGN This was a nonrandomized crosssectional study in subgroups of patients with inflammatory bowel disease compared with a control group with noninflammatory disease. SETTINGS AND PATIENTS Participants were patients treated for ulcerative colitis or Crohn's disease and individuals undergoing evaluation for noninflammatory disease recruited from 2 urban adult gastrointestinal referral centers in Greece. MAIN OUTCOME MEASURES Diagnosis of inflammatory bowel disease was based on standard clinical and endoscopic criteria. Demographic and clinical characteristics of all participants were recorded. Whole blood samples and fresh tissue samples from biopsy of intestinal sites were obtained from each participant. The presence of Epstein-Barr virus was determined by amplifying the LMP1 gene of the virus in blood and intestinal tissue samples. RESULTS The study comprised 94 patients with inflammatory bowel disease (63 with ulcerative colitis and 31 with Crohn's disease) and 45 controls with noninflammatory disease. Of the 94 patients, 67 (71.3%) had disease exacerbation and 27 (28.7%) were in remission. The prevalence of Epstein-Barr virus genome was significantly higher in patients than in controls for intestinal tissue (44 patients, 46.8% vs 6 controls, 13.3%; p = 0.001), but not for whole blood (24 patients, 25.5% vs 9 controls, 20%; p = 0.3). The viral genome was found significantly more frequently in intestinal samples from patients with disease exacerbation compared with patients in remission (38 patients with exacerbation, 56.7% vs 6 patients in remission, 22.2%; p = 0.001), but no significant difference was found for whole blood (18 patients with exacerbation, 26.8% vs 6 patients in remission, 22.2%; p = 0.79). Neither disease exacerbation nor the presence of virus genome was related to demographic or clinical characteristics. LIMITATIONS The exact location of Epstein-Barr virus in the intestinal tissues could not be specified because morphological data by immunohistochemistry or in situ hybridization were not available. CONCLUSIONS Although causality could not be determined, the significantly higher prevalence of Epstein-Barr virus in intestinal tissue from patients with inflammatory bowel disease compared with controls and in patients with exacerbation compared with patients in remission suggests a potential viral involvement in the severity of inflammatory bowel disease. These findings merit further investigation in view of a potential for usefulness of antiviral therapy against Epstein-Barr virus infection in patients with exacerbation of inflammatory bowel disease.
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Abreu NA, Nagalingam NA, Song Y, Roediger FC, Pletcher SD, Goldberg AN, Lynch SV. Sinus microbiome diversity depletion and Corynebacterium tuberculostearicum enrichment mediates rhinosinusitis. Sci Transl Med 2013; 4:151ra124. [PMID: 22972842 DOI: 10.1126/scitranslmed.3003783] [Citation(s) in RCA: 313] [Impact Index Per Article: 26.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Persistent mucosal inflammation and microbial infection are characteristics of chronic rhinosinusitis (CRS). Mucosal microbiota dysbiosis is found in other chronic inflammatory diseases; however, the relationship between sinus microbiota composition and CRS is unknown. Using comparative microbiome profiling of a cohort of CRS patients and healthy subjects, we demonstrate that the sinus microbiota of CRS patients exhibits significantly reduced bacterial diversity compared with that of healthy controls. In our cohort of CRS patients, multiple, phylogenetically distinct lactic acid bacteria were depleted concomitant with an increase in the relative abundance of a single species, Corynebacterium tuberculostearicum. We recapitulated the conditions observed in our human cohort in a murine model and confirmed the pathogenic potential of C. tuberculostearicum and the critical necessity for a replete mucosal microbiota to protect against this species. Moreover, Lactobacillus sakei, which was identified from our comparative microbiome analyses as a potentially protective species, defended against C. tuberculostearicum sinus infection, even in the context of a depleted sinus bacterial community. These studies demonstrate that sinus mucosal health is highly dependent on the composition of the resident microbiota as well as identify both a new sino-pathogen and a strong bacterial candidate for therapeutic intervention.
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Affiliation(s)
- Nicole A Abreu
- Department of Biology, San Francisco State University, Hensill 534, 1600 Holloway Avenue, San Francisco, CA 94132, USA.,Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Nabeetha A Nagalingam
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Yuanlin Song
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Frederick C Roediger
- Department of Otolaryngology - Head and Neck Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Steven D Pletcher
- Department of Otolaryngology - Head and Neck Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Andrew N Goldberg
- Department of Otolaryngology - Head and Neck Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Susan V Lynch
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
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CD8+ T-Cell Deficiency, Epstein-Barr Virus Infection, Vitamin D Deficiency, and Steps to Autoimmunity: A Unifying Hypothesis. Autoimmune Dis 2012; 2012:189096. [PMID: 22312480 PMCID: PMC3270541 DOI: 10.1155/2012/189096] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2011] [Revised: 10/03/2011] [Accepted: 10/16/2011] [Indexed: 12/16/2022] Open
Abstract
CD8+ T-cell deficiency is a feature of many chronic autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, dermatomyositis, primary biliary cirrhosis, primary sclerosing cholangitis, ulcerative colitis, Crohn's disease, psoriasis, vitiligo, bullous pemphigoid, alopecia areata, idiopathic dilated cardiomyopathy, type 1 diabetes mellitus, Graves' disease, Hashimoto's thyroiditis, myasthenia gravis, IgA nephropathy, membranous nephropathy, and pernicious anaemia. It also occurs in healthy blood relatives of patients with autoimmune diseases, suggesting it is genetically determined. Here it is proposed that this CD8+ T-cell deficiency underlies the development of chronic autoimmune diseases by impairing CD8+ T-cell control of Epstein-Barr virus (EBV) infection, with the result that EBV-infected autoreactive B cells accumulate in the target organ where they produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells which would otherwise die in the target organ by activation-induced apoptosis. Autoimmunity is postulated to evolve in the following steps: (1) CD8+ T-cell deficiency, (2) primary EBV infection, (3) decreased CD8+ T-cell control of EBV, (4) increased EBV load and increased anti-EBV antibodies, (5) EBV infection in the target organ, (6) clonal expansion of EBV-infected autoreactive B cells in the target organ, (7) infiltration of autoreactive T cells into the target organ, and (8) development of ectopic lymphoid follicles in the target organ. It is also proposed that deprivation of sunlight and vitamin D at higher latitudes facilitates the development of autoimmune diseases by aggravating the CD8+ T-cell deficiency and thereby further impairing control of EBV. The hypothesis makes predictions which can be tested, including the prevention and successful treatment of chronic autoimmune diseases by controlling EBV infection.
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Hubbard VM, Cadwell K. Viruses, autophagy genes, and Crohn's disease. Viruses 2011; 3:1281-311. [PMID: 21994779 PMCID: PMC3185787 DOI: 10.3390/v3071281] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2011] [Revised: 07/12/2011] [Accepted: 07/13/2011] [Indexed: 02/08/2023] Open
Abstract
The etiology of the intestinal disease Crohn's disease involves genetic factors as well as ill-defined environmental agents. Several genetic variants linked to this disease are associated with autophagy, a process that is critical for proper responses to viral infections. While a role for viruses in this disease remains speculative, accumulating evidence indicate that this possibility requires serious consideration. In this review, we will examine the three-way relationship between viruses, autophagy genes, and Crohn's disease and discuss how host-pathogen interactions can mediate complex inflammatory disorders.
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Affiliation(s)
| | - Ken Cadwell
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +1-212-263-8891; Fax: +1-212-263-5711
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