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Salomon B, Sudhakar P, Bergemalm D, Andersson E, Grännö O, Carlson M, Hedin CRH, Söderholm JD, Öhman L, Lindqvist CM, Kruse R, Repsilber D, Verstockt B, Vermeire S, Halfvarson J. Characterization of Inflammatory Bowel Disease Heterogeneity Using Serum Proteomics: A Multicenter Study. J Crohns Colitis 2025; 19:jjae169. [PMID: 39495605 PMCID: PMC12063088 DOI: 10.1093/ecco-jcc/jjae169] [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: 05/15/2024] [Revised: 10/08/2024] [Accepted: 11/03/2024] [Indexed: 11/06/2024]
Abstract
BACKGROUND Recent genetic and transcriptomic data highlight the need for improved molecular characterization of inflammatory bowel disease (IBD). Proteomics may advance the delineation of IBD phenotypes since it accounts for post-transcriptional modifications. AIMS We aimed to assess the IBD spectrum based on inflammatory serum proteins and identify discriminative patterns of underlying biological subtypes across multiple European cohorts. METHODS Using proximity extension methodology, we measured 86 inflammation-related serum proteins in 1551 IBD patients and 312 healthy controls (HC). We screened for proteins exhibiting significantly different levels among IBD subtypes and between IBD and HC. Classification models for differentiating between Crohn's disease (CD) and ulcerative colitis (UC) were employed to explore the IBD spectrum based on estimated probability scores. RESULTS Levels of multiple proteins, such as interleukin-17A, matrix metalloproteinase-10, and fibroblast growth factor-19, differed (fold-change >1.2; false discovery rate <0.05) between ileal versus colonic IBD. Using multivariable models, a protein signature reflecting the IBD spectrum was identified, positioning colonic CD between UC and ileal CD, which were at opposite ends of the spectrum. Based on area under the curve (AUC) estimates, classification models more accurately differentiated UC from ileal CD (median AUCs > 0.73) than colonic CD (median AUCs < 0.62). Models differentiating colonic CD from ileal CD demonstrated intermediate performance (median AUCs: 0.67-0.69). CONCLUSIONS Our findings in serum proteins support the presence of a continuous IBD spectrum rather than a clear separation of CD and UC. Within the spectrum, disease location may reflect a more similar disease than CD versus UC, as colonic CD resembled UC more closely than ileal CD.
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Affiliation(s)
- Benita Salomon
- Faculty of Medicine and Health, School of Medical Sciences, Örebro University, Örebro, Sweden
| | - Padhmanand Sudhakar
- Department of Chronic Diseases and Metabolism, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
- Department of Biotechnology, Kumaraguru College of Technology, Coimbatore, Tamil Nadu, India
| | - Daniel Bergemalm
- Faculty of Medicine and Health, Department of Gastroenterology, Örebro University, Örebro, Sweden
| | - Erik Andersson
- Faculty of Medicine and Health, Department of Gastroenterology, Örebro University, Örebro, Sweden
| | - Olle Grännö
- Faculty of Medicine and Health, Department of Laboratory Medicine, Clinical Microbiology, Örebro University, Örebro, Sweden
| | - Marie Carlson
- Department of Medical Sciences, Gastroenterology Research Group, Uppsala University, Uppsala, Sweden
| | - Charlotte R H Hedin
- Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden
- Department of Gastroenterology, Dermatovenereology, and Rheumatology, Centre for Digestive Health, Karolinska University Hospital, Stockholm, Sweden
| | - Johan D Söderholm
- Department of Surgery, Linköping University, Linköping, Sweden
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Lena Öhman
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden
| | - Carl Mårten Lindqvist
- Faculty of Medicine and Health, School of Medical Sciences, Örebro University, Örebro, Sweden
| | - Robert Kruse
- Faculty of Medicine and Health, School of Medical Sciences, Örebro University, Örebro, Sweden
- Faculty of Medicine and Health, Inflammatory Response and Infection Susceptibility Centre (iRiSC), Örebro University, Örebro, Sweden
- Faculty of Medicine and Health, Department of Clinical Research Laboratory, Örebro University, Örebro, Sweden
| | - Dirk Repsilber
- Faculty of Medicine and Health, School of Medical Sciences, Örebro University, Örebro, Sweden
| | - Bram Verstockt
- Department of Chronic Diseases and Metabolism, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
- Department of Gastroenterology and Hepatology, KU Leuven, University Hospitals Leuven, Leuven, Belgium
| | - Séverine Vermeire
- Department of Chronic Diseases and Metabolism, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - Jonas Halfvarson
- Faculty of Medicine and Health, Department of Gastroenterology, Örebro University, Örebro, Sweden
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2
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Gustafsson JK, Hansson GC. Immune Regulation of Goblet Cell and Mucus Functions in Health and Disease. Annu Rev Immunol 2025; 43:169-189. [PMID: 39752567 DOI: 10.1146/annurev-immunol-101721-065224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/26/2025]
Abstract
The mucosal surfaces of the body are the most vulnerable points for infection because they are lined by single or multiple layers of very active epithelial cells. The main protector of these cells is the mucus system generated by the specialized goblet cell secreting its main components, the gel-forming mucins. The organization of the mucus varies from an attached mucus that is impenetrable to bacteria in the large intestine to a nonattached, more penetrable mucus in the small intestine. The respiratory tract mucus system clears particles and microorganisms from healthy lungs but causes disease if reorganized to an attached mucus that cannot be efficiently transported. Similarly, transformation of large intestine mucus from impenetrable to penetrable causes chronic inflammation directed toward the intestinal microbiota. Mucus-producing goblet cells are regulated by and responsive to signals from immune cells, and at the same time signal back to the immune system. In this review we focus on the relationship of immune cells with intestinal goblet cells and mucus, making parallels to the respiratory tract.
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Affiliation(s)
| | - Gunnar C Hansson
- Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden;
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3
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Xian S, Meng F, Chen X, Zhu L, Wang H. Reduction of colitis in mice by chemically programmed supramolecular nanoassemblies of vitamin-lipid conjugates. J Nanobiotechnology 2025; 23:247. [PMID: 40128782 PMCID: PMC11934663 DOI: 10.1186/s12951-025-03322-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 03/11/2025] [Indexed: 03/26/2025] Open
Abstract
Inflammatory bowel disease (IBD) is a relapsing disorder characterized by uncontrolled chronic inflammation of the gastrointestinal tract, posing a significant therapeutic challenge owing to the limited efficacy and undesirable side effects of current therapeutic options. A key pathological hallmark of IBD is the excessive production of reactive oxygen species (ROS). Hence, therapeutic strategies aimed at reducing ROS levels are promising for relieving these inflammatory conditions. Vitamin C-a natural nutrient for the human body-is well known for its potent antioxidant effects. However, the clinical development of vitamin C as a therapeutic drug has been hindered by its poor stability, rapid metabolism, and inadequate tissue accumulation. Herein, we report that the bioavailability of vitamin C can be enhanced by chemically reprogramming it with a small panel of long-chain fatty acids that aid in the aqueous self-assembly of the resulting drug conjugates to create self-deliverable nanoassemblies, enhancing their inflammation disease-oriented delivery and cellular uptake. In mice with dextran sulfate sodium-induced colitis, the optimal vitamin C-lipid nanoassemblies preferentially accumulated in inflamed colonic tissues following systemic administration and substantially ameliorated disease severity. We extended this strategy to incorporate the clinically approved glucocorticoid budesonide into the vitamin C nanosystem, facilitating a synergistic combination. In the chronic colitis model, the combination treatment reduced inflammation without compromising global immunity. Mechanistically, the treatment modulated the intestinal inflammatory microenvironment and altered the immune cell landscape, partly through regulation of the gut microbiome. Given its anticipated negligible side effects, this novel nanoassembly platform leveraging small-molecule lipidation may become a promising therapeutic for treating various inflammatory diseases.
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Affiliation(s)
- Shiyun Xian
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong Province, 250118, P. R. China
- The First Affiliated Hospital, NHC Key Laboratory of Combined Multi-Organ Transplantation, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310003, P. R. China
| | - Fanchao Meng
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong Province, 250118, P. R. China
- The First Affiliated Hospital, NHC Key Laboratory of Combined Multi-Organ Transplantation, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310003, P. R. China
| | - Xiaona Chen
- Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310003, P. R. China
| | - Liqing Zhu
- Department of Clinical Laboratory, Peking University Cancer Hospital and Institute, Beijing, P. R. China.
| | - Hangxiang Wang
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong Province, 250118, P. R. China.
- The First Affiliated Hospital, NHC Key Laboratory of Combined Multi-Organ Transplantation, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310003, P. R. China.
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Ito Y, Watanabe D, Okamoto N, Miyazaki H, Tokunaga E, Ku Y, Ooi M, Hoshi N, Kohashi M, Kanzawa M, Kodama Y. Activated type 17 helper T cells affect tofacitinib treatment outcomes. Sci Rep 2025; 15:6112. [PMID: 39971758 PMCID: PMC11840122 DOI: 10.1038/s41598-025-87076-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 01/15/2025] [Indexed: 02/21/2025] Open
Abstract
The incidence of ulcerative colitis (UC) is on the rise also in Japan. Simultaneously, therapeutic options, including biologics and Janus kinase (JAK) inhibitors, have significantly expanded over the past decade. Although tofacitinib (TOF), one of JAK inhibitors, is a viable option for patients with moderate to severe UC, there is insufficient data to predict responsiveness of TOF treatment. The present study aimed to determine whether the infiltration of IL-17 A-positive mononuclear cells into the colonic mucosa can predict responsiveness to TOF treatment. Patients with UC who underwent TOF treatment were divided into responder and failure groups. Subsequently, we conducted a comparative analysis to identify differences in the infiltration of IL-17 A-positive cells into the colonic mucosa through immunohistochemical examination of colon biopsy samples. The proportion of IL-17 A positive mononuclear cells in colon biopsy samples was significantly higher in the failure group than among responders (38.2% vs. 21.2%). Consistent with this finding, our re-analysis of RNA sequence datasets available in the Gene Expression Omnibus (GEO) database suggested that TOF exerts a more pronounced influence on Th1 cells compared with IL-17-producing Th17 cells. In summary, an abundance of IL-17 A-positive mononuclear cells in the colonic mucosa has the potential to predict the responsiveness to TOF treatment.
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Affiliation(s)
- Yuki Ito
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Hospital, Kobe, Japan
| | - Daisuke Watanabe
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Hospital, Kobe, Japan.
| | - Norihiro Okamoto
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Hospital, Kobe, Japan
| | - Haruka Miyazaki
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Hospital, Kobe, Japan
| | - Eri Tokunaga
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Hospital, Kobe, Japan
| | - Yuna Ku
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Hospital, Kobe, Japan
| | - Makoto Ooi
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Hospital, Kobe, Japan
| | - Namiko Hoshi
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Hospital, Kobe, Japan
| | - Michitaka Kohashi
- Department of Gastroenterology, Kakogawa Central City Hospital, Kakogawa, Hyogo, Japan
| | - Maki Kanzawa
- Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Yuzo Kodama
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Hospital, Kobe, Japan
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5
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Yue N, Hu P, Tian C, Kong C, Zhao H, Zhang Y, Yao J, Wei Y, Li D, Wang L. Dissecting Innate and Adaptive Immunity in Inflammatory Bowel Disease: Immune Compartmentalization, Microbiota Crosstalk, and Emerging Therapies. J Inflamm Res 2024; 17:9987-10014. [PMID: 39634289 PMCID: PMC11615095 DOI: 10.2147/jir.s492079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Accepted: 11/12/2024] [Indexed: 12/07/2024] Open
Abstract
The intestinal immune system is the largest immune organ in the human body. Excessive immune response to intestinal cavity induced by harmful stimuli including pathogens, foreign substances and food antigens is an important cause of inflammatory diseases such as celiac disease and inflammatory bowel disease (IBD). Although great progress has been made in the treatment of IBD by some immune-related biotherapeutic products, yet a considerable proportion of IBD patients remain unresponsive or immune tolerant to immunotherapeutic strategy. Therefore, it is necessary to further understand the mechanism of immune cell populations involved in enteritis, including dendritic cells, macrophages and natural lymphocytes, in the steady-state immune tolerance of IBD, in order to find effective IBD therapy. In this review, we discussed the important role of innate and adaptive immunity in the development of IBD. And the relationship between intestinal immune system disorders and microflora crosstalk were also presented. We also focus on the new findings in the field of T cell immunity, which might identify novel cytokines, chemokines or anti-cytokine antibodies as new approaches for the treatment of IBD.
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Affiliation(s)
- Ningning Yue
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Peng Hu
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, People’s Republic of China
| | - Chengmei Tian
- Department of Emergency, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Chen Kong
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Hailan Zhao
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Yuan Zhang
- Department of Medical Administration, Huizhou Institute of Occupational Diseases Control and Prevention, Huizhou, People’s Republic of China
| | - Jun Yao
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Yuqi Wei
- Department of Rehabilitation, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Defeng Li
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Lisheng Wang
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
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Mallick R, Basak S, Das RK, Banerjee A, Paul S, Pathak S, Duttaroy AK. Roles of the gut microbiota in human neurodevelopment and adult brain disorders. Front Neurosci 2024; 18:1446700. [PMID: 39659882 PMCID: PMC11628544 DOI: 10.3389/fnins.2024.1446700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Accepted: 11/05/2024] [Indexed: 12/12/2024] Open
Abstract
Growing evidence demonstrates the connection between gut microbiota, neurodevelopment, and adult brain function. Microbial colonization occurs before the maturation of neural systems and its association with brain development. The early microbiome interactions with the gut-brain axis evolved to stimulate cognitive activities. Gut dysbiosis can lead to impaired brain development, growth, and function. Docosahexaenoic acid (DHA) is critically required for brain structure and function, modulates gut microbiota, and impacts brain activity. This review explores how gut microbiota influences early brain development and adult functions, encompassing the modulation of neurotransmitter activity, neuroinflammation, and blood-brain barrier integrity. In addition, it highlights processes of how the gut microbiome affects fetal neurodevelopment and discusses adult brain disorders.
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Affiliation(s)
- Rahul Mallick
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Sanjay Basak
- Molecular Biology Division, ICMR-National Institute of Nutrition, Indian Council of Medical Research, Hyderabad, India
| | - Ranjit K. Das
- Department of Health and Biomedical Sciences, University of Texas Rio Grande Valley, Brownsville, TX, United States
| | - Antara Banerjee
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Chennai, India
| | - Sujay Paul
- Tecnologico de Monterrey, School of Engineering and Sciences, Queretaro, Mexico
| | - Surajit Pathak
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Chennai, India
| | - Asim K. Duttaroy
- Department of Nutrition, Faculty of Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
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Hsu CY, Mustafa MA, Moath Omar T, Taher SG, Ubaid M, Gilmanova NS, Nasrat Abdulraheem M, Saadh MJ, Athab AH, Mirzaei R, Karampoor S. Gut instinct: harnessing the power of probiotics to tame pathogenic signaling pathways in ulcerative colitis. Front Med (Lausanne) 2024; 11:1396789. [PMID: 39323474 PMCID: PMC11422783 DOI: 10.3389/fmed.2024.1396789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 08/22/2024] [Indexed: 09/27/2024] Open
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) marked by persistent inflammation of the mucosal lining of the large intestine, leading to debilitating symptoms and reduced quality of life. Emerging evidence suggests that an imbalance of the gut microbiota plays a crucial role in UC pathogenesis, and various signaling pathways are implicated in the dysregulated immune response. Probiotics are live microorganisms that confer health benefits to the host, have attracted significant attention for their potential to restore gut microbial balance and ameliorate inflammation in UC. Recent studies have elucidated the mechanisms by which probiotics modulate these signaling pathways, often by producing anti-inflammatory molecules and promoting regulatory immune cell function. For example, probiotics can inhibit the nuclear factor-κB (NF-κB) pathway by stabilizing Inhibitor of kappa B alpha (IκBα), dampening the production of proinflammatory cytokines. Similarly, probiotics can modulate the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, suppressing the activation of STAT1 and STAT3 and thus reducing the inflammatory response. A better understanding of the underlying mechanisms of probiotics in modulating pathogenic signaling pathways in UC will pave the way for developing more effective probiotic-based therapies. In this review, we explore the mechanistic role of probiotics in the attenuation of pathogenic signaling pathways, including NF-κB, JAK/STAT, mitogen-activated protein kinases (MAPKs), Wnt/β-catenin, the nucleotide-binding domain (NOD)-, leucine-rich repeat (LRR)- and pyrin domain-containing protein 3 (NLRP3) inflammasome, Toll-like receptors (TLRs), interleukin-23 (IL-23)/IL-17 signaling pathway in UC.
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Affiliation(s)
- Chou-Yi Hsu
- Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan, Taiwan
- Thunderbird School of Global Management, Arizona State University Tempe Campus, Phoenix, AZ, United States
| | - Mohammed Ahmed Mustafa
- Department of Medical Laboratory Technology, Imam Jaafar AL-Sadiq University, Baghdad, Iraq
- Department of Pathological Analyzes, College of Applied Sciences, University of Samarra, Samarra, Iraq
| | - Thabit Moath Omar
- Department of Medical Laboratory Technics, College of Health and Medical Technology, Alnoor University, Mosul, Iraq
| | - Sada Gh Taher
- Department of Pharmacy, National University of Science and Technology, Dhi Qar, Iraq
| | - Mohammed Ubaid
- Department of MTL, Medical Technical College, Al-Farahidi University, Baghdad, Iraq
| | - Nataliya S. Gilmanova
- Department of Prosthetic Dentistry, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | | | | | - Aya H. Athab
- Department of Pharmacy, Al-Zahrawi University College, Karbala, Iraq
| | - Rasoul Mirzaei
- Venom and Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Sajad Karampoor
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
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Van Den Houte M, Guadagnoli L, Öhman L, Bergstedt A, Johansson B, Simrén M, Strid H, Van Oudenhove L, Svedlund J. Predictors of Symptoms Trajectories in Newly Diagnosed Ulcerative Colitis: A 3-Year Follow-up Cohort Study. J Crohns Colitis 2024; 18:1394-1405. [PMID: 38551078 DOI: 10.1093/ecco-jcc/jjae046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 03/01/2024] [Accepted: 03/28/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND AND AIMS Psychological symptoms are associated with poorer ulcerative colitis [UC]-related outcomes. However, the majority of research is cross-sectional. We aimed to identify subgroups based on the longitudinal evolution of GI symptom levels and health-related quality of life [HRQoL], and to disentangle the directionality of effects between GI symptom levels and psychological distress. METHODS Self-reported gastrointestinal [GI] symptom severity, HRQoL, inflammatory biomarkers, and psychological distress were assessed in 98 newly diagnosed UC patients at disease onset and yearly for 3 consecutive years. Latent class growth analysis was used to determine subgroups based on longitudinal trajectories of symptom severity and HRQoL, and baseline predictors of trajectory group membership were determined. Cross-lagged structural equation models were used to disentangle temporal relationships between psychological functioning and symptom severity. RESULTS Patients with higher initial psychological distress had increased probability of maintaining higher levels of diarrhoea and abdominal pain. Conversely, patients with lower initial levels of diarrhoea and abdominal pain had higher chances of maintaining lower levels of psychological distress. Higher levels of C-reactive protein at baseline predicted greater improvements in mental health after anti-inflammatory treatment. Reductions in diarrhoea and abdominal pain preceded reductions in psychological symptoms over time. CONCLUSIONS Baseline psychological distress is predictive of increased GI symptom severity and reduced mental HRQoL over time, suggesting early assessment of psychological symptoms may identify patients who may have worse disease trajectories. Abdominal pain predicted increased psychological distress, but not the other way around. Intervening on abdominal pain may help prevent or reduce future psychological distress.
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Affiliation(s)
- Maaike Van Den Houte
- Laboratory for Brain-Gut Axis Studies [LaBGAS], Translational Research in Gastrointestinal Disorders [TARGID], Department of Chronic Diseases and Metabolism [CHROMETA], KU Leuven, Leuven, Belgium
- Leuven Brain Institute, KU Leuven, Leuven, Belgium
- Rehabilitation Research Center [REVAL], Hasselt University, Diepenbeek, Belgium
| | - Livia Guadagnoli
- Laboratory for Brain-Gut Axis Studies [LaBGAS], Translational Research in Gastrointestinal Disorders [TARGID], Department of Chronic Diseases and Metabolism [CHROMETA], KU Leuven, Leuven, Belgium
- Leuven Brain Institute, KU Leuven, Leuven, Belgium
| | - Lena Öhman
- Department of Microbiology and Immunology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Anders Bergstedt
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy; University of Gothenburg, Gothenburg, Sweden
| | - Berndt Johansson
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy; University of Gothenburg, Gothenburg, Sweden
| | - Magnus Simrén
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Hans Strid
- Department of Internal Medicine, Södra Älvsborgs Hospital, Borås, Sweden
| | - Lukas Van Oudenhove
- Laboratory for Brain-Gut Axis Studies [LaBGAS], Translational Research in Gastrointestinal Disorders [TARGID], Department of Chronic Diseases and Metabolism [CHROMETA], KU Leuven, Leuven, Belgium
- Leuven Brain Institute, KU Leuven, Leuven, Belgium
- Cognitive & Affective Neuroscience Lab [CANLab], Department of Psychological and Brain Sciences, Dartmouth College; Hanover, New Hampshire, USA
| | - Jan Svedlund
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy; University of Gothenburg, Gothenburg, Sweden
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Jiang X, Luo X, Cai C, Bai Y, Ding H, Yue H, Li Y, Yang Z, Zhang H, Liang Y, Peng C, Huang H, Liu M, Li Z, Shi Y, Han S, Li X, Zhang B. Umbilical cord mesenchymal stem cells in ulcerative colitis treatment: efficacy and possible mechanisms. Stem Cell Res Ther 2024; 15:272. [PMID: 39218946 PMCID: PMC11368034 DOI: 10.1186/s13287-024-03878-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Accepted: 08/01/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) possess powerful immunomodulatory ability. This study aimed to assess the efficacy and safety of human umbilical cord-derived mesenchymal stem cells (UMSCs) in patients with ulcerative colitis (UC) and to explore the potential mechanisms. METHODS This prospective, self-controlled clinical study was conducted at Henan Provincial People's Hospital. Patients with moderate-to-severe active UC, unresponsive to traditional drugs were continuously enrolled from September 2018 to March 2023. UMSCs were administered intravenously monthly for two months at a cell dosage of 1 × 106 per kg. The primary outcome was a clinical response at 2 months. The levels of cytokines and progerin in the plasma of the patients were analyzed using enzyme-linked immunosorbent assay kits, and longitudinal data was analyzed using generalized estimation equation. RESULTS Forty-one patients were enrolled and received UMSC therapy. At 2 months, 73.2% (30/41) of patients achieved a clinical response, and 41.5% (17/41) achieved a clinical remission. At 6 months, 2 patients were lost to follow-up; the corresponding figures were 70.0% (25/41) and 34.2% (14/41), respectively. After UMSC therapy, the Mayo score, Mayo endoscopy score, mean and maximum values of Ulcerative Colitis Endoscopic Index of Severity and Nancy index were significantly reduced compared with baseline values. Additionally, the levels of progerin and inflammatory markers, such as interleukin (IL)-1β, IL-6, IL-8, IL-12, and IL-17 A decreased, while hemoglobin, albumin, and IL-10/IL-17 A ratio increased, particularly in the response group. Multiple stepwise logistic regression analysis showed age was an independent risk factor affecting efficacy (odds ratio, 0.875 (95% confidence interval (0.787, 0.972)); the area under the receiver operating characteristic curve for age was 0.79. No serious adverse events were observed during or after UMSC therapy. CONCLUSION UMSCs are safe and effective for patients with UC, with age being an independent risk factor affecting efficacy. Mechanistically, UMSC treatment may ameliorate cell senescence and suppress the secretion of pro-inflammatory cytokines. TRIAL REGISTRATION The study was retrospectively registered at www.chictr.org.cn/ (ChiCTR1900026035) on September 18, 2019.
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Affiliation(s)
- Xiaoke Jiang
- Department of Gastroenterology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, School of Clinical Medicine, Henan University, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan Province, 450003, China
| | - Xiaoying Luo
- Department of Gastroenterology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, School of Clinical Medicine, Henan University, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan Province, 450003, China
- Microbiome Laboratory, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan Province, 450003, China
| | - Conghui Cai
- Department of Gastroenterology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, School of Clinical Medicine, Henan University, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan Province, 450003, China
- Microbiome Laboratory, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan Province, 450003, China
| | - Yangqiu Bai
- Department of Gastroenterology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, School of Clinical Medicine, Henan University, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan Province, 450003, China
| | - Hui Ding
- Department of Gastroenterology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, School of Clinical Medicine, Henan University, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan Province, 450003, China
| | - Han Yue
- Stem Cell Research Center, Henan Key Laboratory of Stem Cell Differentiation and Modification, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan Province, 450003, China
| | - Yalong Li
- Stem Cell Research Center, Henan Key Laboratory of Stem Cell Differentiation and Modification, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan Province, 450003, China
| | - Zhiyu Yang
- Department of Gastroenterology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, School of Clinical Medicine, Henan University, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan Province, 450003, China
- Microbiome Laboratory, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan Province, 450003, China
| | - Huimin Zhang
- Department of Gastroenterology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, School of Clinical Medicine, Henan University, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan Province, 450003, China
| | - Yuan Liang
- Department of Pulmonary and Critical Care Medicine, Xinyang Central Hospital, No.1, Siyi Road, Xinyang, Henan Province, 464000, China
| | - Cong Peng
- Department of Gastroenterology, Yunfu People's Hospital, No. 120, Huanshi East Road, Yunfu, Guangdong Province, 527300, China
| | - Huanrong Huang
- Department of Gastroenterology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, School of Clinical Medicine, Henan University, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan Province, 450003, China
- Microbiome Laboratory, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan Province, 450003, China
| | - Min Liu
- Department of Gastroenterology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, School of Clinical Medicine, Henan University, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan Province, 450003, China
- Microbiome Laboratory, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan Province, 450003, China
| | - Zhenjuan Li
- Department of Gastroenterology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, School of Clinical Medicine, Henan University, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan Province, 450003, China
| | - Yujie Shi
- Department of Gastroenterology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, School of Clinical Medicine, Henan University, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan Province, 450003, China
- Microbiome Laboratory, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan Province, 450003, China
- Department of Pathology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, School of Clinical Medicine, Henan University, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan Province, 450003, China
| | - Shuangyin Han
- Department of Gastroenterology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, School of Clinical Medicine, Henan University, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan Province, 450003, China.
| | - Xiuling Li
- Department of Gastroenterology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, School of Clinical Medicine, Henan University, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan Province, 450003, China.
| | - Bingyong Zhang
- Department of Gastroenterology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, School of Clinical Medicine, Henan University, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan Province, 450003, China.
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10
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Imazu N, Torisu T, Ihara Y, Umeno J, Kawasaki K, Fujioka S, Fuyuno Y, Matsuno Y, Moriyama T, Kitazono T. Ustekinumab Decreases Circulating Th17 Cells in Ulcerative Colitis. Intern Med 2024; 63:153-158. [PMID: 37197955 PMCID: PMC10864063 DOI: 10.2169/internalmedicine.1724-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 03/31/2023] [Indexed: 05/19/2023] Open
Abstract
Objective T helper (Th) cells play a central role in the pathogenesis of ulcerative colitis (UC). The present study analyzed the changes in circulating T cells by administration of ustekinumab (UST), an interleukin-12/23p40 antibody. Methods CD4 T cells were isolated from peripheral blood at 0 and 8 weeks after UST treatment, and we analyzed the proportion of CD4 T cells by flow cytometry. Clinical information and laboratory data were obtained at 0, 8, and 16 weeks. Patients We evaluated 13 patients with UC who received UST for the induction of remission between July 2020 and August 2021. Results The median partial Mayo score improved from 4 (1-7) to 0 (0-6) (p<0.001) with UST. Among serological parameters, albumin concentrations, C-reactive protein concentrations, the sedimentation rate, and leucine-rich alpha 2 glycoprotein concentrations showed significant improvement with UST. A flow cytometric analysis of circulating CD4 T cells showed that the percentage of Th17 cells was significantly decreased by UST treatment in all patients (1.85% to 0.98%, p<0.0001). Th1 cells were significantly increased by UST treatment (9.52% to 10.4%, p<0.05), but Th2 and regulatory T cells were not significantly different. The high-Th17 subgroup had a significantly better partial Mayo score than the low-Th17 subgroup at 16 weeks after UST treatment (0 vs. 1, p=0.028). Conclusion Treatment with UST decreases circulating Th17 cells, suggesting that this change may be related to the anti-inflammatory effect of UC.
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Affiliation(s)
- Noriyuki Imazu
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Japan
| | - Takehiro Torisu
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Japan
| | - Yutaro Ihara
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Japan
| | - Junji Umeno
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Japan
| | - Keisuke Kawasaki
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Japan
| | - Shin Fujioka
- Department of Endoscopic Diagnostics and Therapeutics, Kyushu University Hospital, Japan
| | - Yuta Fuyuno
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Japan
| | - Yuichi Matsuno
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Japan
| | - Tomohiko Moriyama
- Department of International Medical, Kyushu University Hospital, Japan
| | - Takanari Kitazono
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Japan
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11
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Khazdouz M, Daryani NE, Cheraghpour M, Alborzi F, Hasani M, Ghavami SB, Shidfar F. The effect of selenium supplementation on disease activity and immune-inflammatory biomarkers in patients with mild-to-moderate ulcerative colitis: a randomized, double-blind, placebo-controlled clinical trial. Eur J Nutr 2023; 62:3125-3134. [PMID: 37525068 DOI: 10.1007/s00394-023-03214-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 07/14/2023] [Indexed: 08/02/2023]
Abstract
PURPOSE Selenium (Se) supplementation may help reduce inflammation and disease activity in ulcerative colitis (UC) patients. We investigated the therapeutic effects of Se administration in cases with mild-to-moderate active UC. METHODS A multicenter, double-blind, randomized clinical trial (RCT) was conducted on 100 cases with active mild-to-moderate UC. The patients were randomly allocated to be given an oral selenomethionine capsule (200 mcg/day, n = 50) or a placebo capsule (n = 50) for 10 weeks. The primary outcome was defined as disease activity via the Simple Clinical Colitis Activity Index (SCCAI), and secondary outcomes were measured at the end of the study. RESULTS After 10 weeks, the SCCAI score's mean was reduced in the Se group (P < 0.001). At the end of the intervention, clinical improvement (decline of 3 ≥ score from baseline score) was observed in 19 patients (38%) of the Se group and 3 patients (6%) of the placebo group. The patients with clinical remission (defined as SCCAI ≤ 2) were assigned in the Se group (P = 0.014). The Se group's quality of life and Se serum levels were enhanced at the end of the study (P < 0/001). In the Se group, the mean concentration of interleukin-17 decreased (P < 0/001). However, the levels of interleukin-10 showed no considerable change between the two groups in the 10th week (P = 0.23). CONCLUSION Se supplementation as add-on therapy with medical management induced remission and improved the quality of life in patients with active mild-to-moderate UC. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION IRCT20091114002709N51; 2020-04-13.
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Affiliation(s)
- Maryam Khazdouz
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
- Growth and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Naser Ebrahimi Daryani
- Department of Gastroenterology and Hepatology, Imam Khomeini Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Makan Cheraghpour
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Foroogh Alborzi
- Department of Gastroenterology and Hepatology, Imam Khomeini Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Motahareh Hasani
- Department of Nutrition, School of Public Health, Golestan University of Medical Sciences, Gorgan, Iran
| | - Shaghayegh Baradaran Ghavami
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farzad Shidfar
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran.
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran.
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12
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Lian YZ, Chang CC, Chen YS, Tinkov AA, Skalny AV, Chao JCJ. Lycium barbarum polysaccharides and capsaicin modulate inflammatory cytokines and colonic microbiota in colitis rats induced by dextran sulfate sodium. J Clin Biochem Nutr 2022; 71:229-237. [PMID: 36447490 PMCID: PMC9701596 DOI: 10.3164/jcbn.21-174] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 05/11/2022] [Indexed: 08/30/2023] Open
Abstract
Active ingredients in the natural products have been considered to be used for alleviating the symptoms of ulcerative colitis, hence the effects of Lycium barbarum polysaccharides (LP) and capsaicin on dextran sulfate sodium (DSS)-induced colitis in rats were investigated. Rats were grouped into normal, DSS induced colitis, and colitis treated with 100 mg LP/kg body weight, 12 mg capsaicin/kg body weight, or combined 50 mg LP/kg body weight and 6 mg capsaicin/kg body weight. Treatment with LP or capsaicin was orally fed by gavage for 4 weeks, and 5% DSS was fed via drinking water for 6 days during week 3. Colon tissue and cecum content were collected for analysis. Treatments with LP and/or capsaicin ameliorated disease activity index scores, severity of colon distortion, and shrinkage of colon length. LP and capsaicin decreased colonic pro-inflammatory cytokine (IFN-γ, IL-17A, and IL-22) levels. Cecal microbiota in colitis rats were enriched with the genus Turicibacter and Lachnospira. The relative abundance of genus Ruminiclostridium_9 and Ruminoclostridium_1 was increased by LP and capsaicin treatment, respectively. Pretreatment with LP or capsaicin inhibits the severity of colonic damage in rats with DSS-induced colitis via anti-inflammation and modulation of colonic microbiota.
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Affiliation(s)
- Yu Zhi Lian
- School of Nutrition and Health Sciences, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110301, Taiwan
| | - Chun-Chao Chang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taipei Medical University Hospital, 252 Wu-Hsing Street, Taipei 110301, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110301, Taiwan
| | - Yu-Shan Chen
- School of Nutrition and Health Sciences, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110301, Taiwan
| | - Alexey A. Tinkov
- Laboratory of Molecular Dietetics, I.M. Sechenov First Moscow State Medical University, 2-4 Bolshaya Pirogovskaya Street, Moscow 119435, Russia
- Institute of Bioelementology, Orenburg State University, Pobedy Avenue, 13, Orenburg 460018, Russia
| | - Anatoly V. Skalny
- Laboratory of Molecular Dietetics, I.M. Sechenov First Moscow State Medical University, 2-4 Bolshaya Pirogovskaya Street, Moscow 119435, Russia
- Institute of Bioelementology, Orenburg State University, Pobedy Avenue, 13, Orenburg 460018, Russia
- Federal Research Centre of Biological Systems and Agrotechnologies of the Russian Academy of Sciences, 9 Yanvarya Street, 29, Orenburg 460000, Russia
| | - Jane C.-J. Chao
- School of Nutrition and Health Sciences, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110301, Taiwan
- Master Program in Global Health and Development, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110301, Taiwan
- Nutrition Research Center, Taipei Medical University Hospital, 252 Wu-Hsing Street, Taipei 110301, Taiwan
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13
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Moraes Holst L, Halfvarson J, Carlson M, Hedin C, Kruse R, Lindqvist CM, Bergemalm D, Almér S, Bresso F, Ling Lundström M, Repsilber D, D’Amato M, Keita Å, Hjortswang H, Söderholm J, Sundin J, Törnblom H, Simrén M, Strid H, Magnusson MK, Öhman L. Downregulated Mucosal Autophagy, Alpha Kinase-1 and IL-17 Signaling Pathways in Active and Quiescent Ulcerative Colitis. Clin Exp Gastroenterol 2022; 15:129-144. [PMID: 35928254 PMCID: PMC9343467 DOI: 10.2147/ceg.s368040] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 07/07/2022] [Indexed: 11/23/2022] Open
Abstract
Background Improved mucosal immune profiling in active and quiescent colonic inflammatory bowel disease (IBD) is needed to develop therapeutic options for treating and preventing flares. This study therefore aimed to provide a comprehensive mucosal characterization with emphasis on immunological host response of patients with active ulcerative colitis (UC active), UC during remission (UC remission) and active colonic Crohn’s disease (CD active). Methods Colonic biopsies from 47 study subjects were collected for gene expression and pathway analyses using the NanoString host-response panel, including 776 genes and 56 immune-related pathways. Results The majority of mucosal gene expression and signaling pathway scores were increased in active IBD (n=27) compared to healthy subjects (n=10). However, both active IBD and UC remission (n=10) demonstrated decreased gene expression and signaling pathway scores related to autophagy, alpha kinase-1 and IL-17 signaling pathways compared to healthy subjects. Further, UC remission was characterized by decreased scores of several signaling pathways linked to homeostasis along with increased mononuclear cell migration pathway score as compared to healthy subjects. No major differences in the colonic mucosal gene expression between CD active (n=7) and UC (n=20) active were observed. Conclusion This study indicates that autophagy, alpha kinase-1 and IL-17 signaling pathways are persistently downregulated in UC irrespective of disease activity. Further, UC patients in remission present a unique mucosal environment, potentially preventing patients from reaching and sustaining true homeostasis. These findings may enable better comprehension of the remitting and relapsing pattern of colonic IBD and guide future treatment and prevention of flares.
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Affiliation(s)
- Luiza Moraes Holst
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Jonas Halfvarson
- Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Marie Carlson
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Charlotte Hedin
- Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden
| | - Robert Kruse
- Department of Clinical Research Laboratory, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Carl Mårten Lindqvist
- School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Daniel Bergemalm
- Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Sven Almér
- Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden
| | - Francesca Bresso
- Karolinska University Hospital, Gastroenterology Unit, Department of Gastroenterology, Dermatovenereology and Rheumatology, Stockholm, Sweden
| | | | - Dirk Repsilber
- School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Mauro D’Amato
- Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
- Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio, Spain
| | - Åsa Keita
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Henrik Hjortswang
- Department of Clinical and Experimental Science, Linköping University, Linköping, Sweden
| | - Johan Söderholm
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Johanna Sundin
- Department of Internal Medicine & Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, Gothenburg, Sweden
| | - Hans Törnblom
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Magnus Simrén
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Center for Functional Gastrointestinal and Motility Disorders, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Hans Strid
- Department of Internal Medicine, Södra Älvsborg Hospital, Borås, Sweden
| | - Maria K Magnusson
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Lena Öhman
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Correspondence: Lena Öhman, Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden, Tel +46703616499, Email
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Abstract
Interleukin 23 [IL-23] plays a key role in the pathogenesis of both Crohn's disease [CD] and ulcerative colitis [UC], promoting a Th17 cell-related immune response. The combined blockade of IL-23 and IL-12 with ustekinumab has been demonstrated to be safe and effective in the treatment of inflammatory bowel disease [IBD]. Studies on preclinical models and observations of other immune-mediated diseases, such as psoriasis, suggest that the selective inhibition of IL-23 could be beneficial in IBD. Four monoclonal antibodies [risankizumab, mirikizumab, brazikumab and guselkumab] are currently in advance clinical trials for either CD or UC. In this review, we provide an overview of the main results from published studies of selective anti IL-23 agents.
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Affiliation(s)
- Tommaso Lorenzo Parigi
- Institute of Immunology and Immunotherapy NIHR Birmingham Biomedical Research Centre, University Hospitals NHS Foundation Trust and University of Birmingham, Birmingham, UK
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Marietta Iacucci
- Institute of Immunology and Immunotherapy NIHR Birmingham Biomedical Research Centre, University Hospitals NHS Foundation Trust and University of Birmingham, Birmingham, UK
| | - Subrata Ghosh
- APC Microbiome Ireland Centre, College of Medicine and Health, University College Cork, Ireland
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15
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Mou Y, Du Y, Zhou L, Yue J, Hu X, Liu Y, Chen S, Lin X, Zhang G, Xiao H, Dong B. Gut Microbiota Interact With the Brain Through Systemic Chronic Inflammation: Implications on Neuroinflammation, Neurodegeneration, and Aging. Front Immunol 2022; 13:796288. [PMID: 35464431 PMCID: PMC9021448 DOI: 10.3389/fimmu.2022.796288] [Citation(s) in RCA: 178] [Impact Index Per Article: 59.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Accepted: 02/22/2022] [Indexed: 02/05/2023] Open
Abstract
It has been noticed in recent years that the unfavorable effects of the gut microbiota could exhaust host vigor and life, yet knowledge and theory are just beginning to be established. Increasing documentation suggests that the microbiota-gut-brain axis not only impacts brain cognition and psychiatric symptoms but also precipitates neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). How the blood-brain barrier (BBB), a machinery protecting the central nervous system (CNS) from the systemic circulation, allows the risky factors derived from the gut to be translocated into the brain seems paradoxical. For the unique anatomical, histological, and immunological properties underpinning its permeable dynamics, the BBB has been regarded as a biomarker associated with neural pathogenesis. The BBB permeability of mice and rats caused by GM dysbiosis raises the question of how the GM and its metabolites change BBB permeability and causes the brain pathophysiology of neuroinflammation and neurodegeneration (NF&ND) and brain aging, a pivotal multidisciplinary field tightly associated with immune and chronic systemic inflammation. If not all, gut microbiota-induced systemic chronic inflammation (GM-SCI) mainly refers to excessive gut inflammation caused by gut mucosal immunity dysregulation, which is often influenced by dietary components and age, is produced at the interface of the intestinal barrier (IB) or exacerbated after IB disruption, initiates various common chronic diseases along its dispersal routes, and eventually impairs BBB integrity to cause NF&ND and brain aging. To illustrate the immune roles of the BBB in pathophysiology affected by inflammatory or "leaky" IB resulting from GM and their metabolites, we reviewed the selected publications, including the role of the BBB as the immune barrier, systemic chronic inflammation and inflammation influences on BBB permeability, NF&ND, and brain aging. To add depth to the bridging role of systemic chronic inflammation, a plausible mechanism indispensable for BBB corruption was highlighted; namely, BBB maintenance cues are affected by inflammatory cytokines, which may help to understand how GM and its metabolites play a major role in NF&ND and aging.
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Affiliation(s)
- Yi Mou
- Geroscience and Chronic Disease Department, The Eighth Municipal Hospital for the People, Chengdu, China
| | - Yu Du
- Department of Emergency and Critical Care Medicine, The Fourth West China Hospital, Sichuan University, Chengdu, China
| | - Lixing Zhou
- National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Jirong Yue
- National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Xianliang Hu
- Geroscience and Chronic Disease Department, The Eighth Municipal Hospital for the People, Chengdu, China
| | - Yixin Liu
- National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Sao Chen
- Geroscience and Chronic Disease Department, The Eighth Municipal Hospital for the People, Chengdu, China
| | - Xiufang Lin
- National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Gongchang Zhang
- National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Hengyi Xiao
- National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Birong Dong
- National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
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16
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Noviello D, Mager R, Roda G, Borroni RG, Fiorino G, Vetrano S. The IL23-IL17 Immune Axis in the Treatment of Ulcerative Colitis: Successes, Defeats, and Ongoing Challenges. Front Immunol 2021; 12:611256. [PMID: 34079536 PMCID: PMC8165319 DOI: 10.3389/fimmu.2021.611256] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 04/26/2021] [Indexed: 12/13/2022] Open
Abstract
Ulcerative colitis (UC) is a chronic relapsing disorder of the colonic tract, characterized by a dysregulated innate and adaptive immune response to gut microbiota that contributes to the perpetuation of intestinal inflammatory processes. The Interleukin (IL) 23/IL17 axis has been reported to play a key role in UC pathogenesis promoting Th17 cells and cytokines-related immune response. Recently, the blockade of IL23/IL17 pathways has been raised enormous interest in the treatment o several chronic inflammatory disorders. In this review, we summarize the emerging results from clinical trials that evoked both promise and discouragement in IL23/IL17 axis in the treatment of UC. Targeting IL23 p40 through Ustekinumab results safe and effective to induce and maintain clinical remission, low inflammatory indexes, mucosal healing, and a better quality of life. Studies targeting IL23 p19 through Mirikizumab, Risankizumab, Brazikumab and Guselkumab are still ongoing. To date, no clinical studies targeting IL17 pathway are ongoing in UC. IL-17 targeting is thought to have a context-dependent biological effect, based on whether cytokine is selectively targeted or if its function is dampened by the upstream block of IL23.
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MESH Headings
- Animals
- Antibodies, Monoclonal/pharmacology
- Antibodies, Monoclonal/therapeutic use
- Antibodies, Monoclonal, Humanized/pharmacology
- Antibodies, Monoclonal, Humanized/therapeutic use
- Colitis, Ulcerative/diagnosis
- Colitis, Ulcerative/drug therapy
- Colitis, Ulcerative/immunology
- Colitis, Ulcerative/metabolism
- Disease Management
- Disease Susceptibility
- Gastrointestinal Microbiome/drug effects
- Gastrointestinal Microbiome/immunology
- Humans
- Immunomodulation/drug effects
- Interleukin-17/metabolism
- Interleukin-23/metabolism
- Molecular Targeted Therapy
- Signal Transduction/drug effects
- Treatment Outcome
- Ustekinumab/pharmacology
- Ustekinumab/therapeutic use
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Affiliation(s)
- Daniele Noviello
- Institute of Life Sciences, Scuola Superiore Sant’Anna, Pisa, Italy
| | - Riccardo Mager
- Inflammatory Bowel Disease (IBD) Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center-IRCCS, Rozzano, Italy
| | - Giulia Roda
- Inflammatory Bowel Disease (IBD) Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center-IRCCS, Rozzano, Italy
- Inflammatory Bowel Disease (IBD) Center, Department of Gastroenterology, Humanitas Clinical and Research Center-IRCCS, Rozzano, Italy
| | - Riccardo G. Borroni
- Inflammatory Bowel Disease (IBD) Center, Department of Gastroenterology, Humanitas Clinical and Research Center-IRCCS, Rozzano, Italy
- Dermatology, Humanitas Clinical and Research Center-IRCCS, Rozzano, Italy
| | - Gionata Fiorino
- Inflammatory Bowel Disease (IBD) Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center-IRCCS, Rozzano, Italy
- Inflammatory Bowel Disease (IBD) Center, Department of Gastroenterology, Humanitas Clinical and Research Center-IRCCS, Rozzano, Italy
| | - Stefania Vetrano
- Inflammatory Bowel Disease (IBD) Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center-IRCCS, Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
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17
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Le Berre C, Peyrin-Biroulet L. Selecting End Points for Disease-Modification Trials in Inflammatory Bowel Disease: the SPIRIT Consensus From the IOIBD. Gastroenterology 2021; 160:1452-1460.e21. [PMID: 33421515 DOI: 10.1053/j.gastro.2020.10.065] [Citation(s) in RCA: 99] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 09/24/2020] [Accepted: 10/03/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Inflammatory bowel diseases (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), are chronic and disabling disorders. Prospective disease-modification trials to prevent disease progression are eagerly awaited. However, disease progression is not clearly defined. The objective of the Selecting End PoInts foR Disease-ModIfication Trials (SPIRIT) initiative was to achieve international expert consensus on the endpoints to be used in future IBD-disease modification trials. METHODS This initiative under the auspices of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) began with a systematic literature search to evaluate the current evidence on the definition of disease progression in IBD. On October 22, 2019, a consensus meeting took place during the United European Gastroenterology Week (UEGW) Congress in Barcelona, during which predefined proposed statements were discussed in a plenary session and voted on anonymously. Agreement was defined as at least 75% of participants voting for any one statement. RESULTS The group agreed that the ultimate therapeutic goal in both CD and UC is to prevent disease impact on patient's life (health-related quality of life, disability, fecal incontinence), midterm complications (encompass bowel damage in CD, IBD-related surgery and hospitalizations, disease extension in UC, extraintestinal manifestations, permanent stoma, short bowel syndrome), and long-term complications (gastrointestinal and extraintestinal dysplasia or cancer, mortality). CONCLUSIONS Recommendations on which goals to achieve in disease-modification trials for preventing disease progression in patients with IBD are proposed by the SPIRIT consensus. However, these recommendations will require validation in actual clinical studies before implementation in disease-modification trials.
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Affiliation(s)
- Catherine Le Berre
- Institut des Maladies de l'Appareil Digestif, Nantes University Hospital, Nantes, France
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology and INSERM NGERE U1256, Nancy University Hospital, University of Lorraine, Vandœuvre-lès-Nancy, France.
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Impaired Butyrate Induced Regulation of T Cell Surface Expression of CTLA-4 in Patients with Ulcerative Colitis. Int J Mol Sci 2021; 22:ijms22063084. [PMID: 33802979 PMCID: PMC8002718 DOI: 10.3390/ijms22063084] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/12/2021] [Accepted: 03/15/2021] [Indexed: 01/08/2023] Open
Abstract
Patients with ulcerative colitis (UC) have reduced intestinal levels of short-chain fatty acids (SCFAs), including butyrate, which are important regulators of host–microbiota crosstalk. The aim was therefore to determine effects of butyrate on blood and intestinal T cells from patients with active UC. T cells from UC patients and healthy subjects were polyclonally stimulated together with SCFAs and proliferation, activation, cytokine secretion, and surface expression of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) were analyzed. Butyrate induced comparable, dose dependent inhibition of activation and proliferation in blood T cells and activation in intestinal T cells from UC patients and healthy subjects. However, surface expression of the inhibitory molecule CTLA-4 on stimulated blood and intestinal T cells was impaired in UC patients and was not restored following butyrate treatment. Furthermore, unlike intestinal T cells from healthy subjects, butyrate was unable to downregulate secretion of interferon gamma (IFNγ), interleukin (IL)-4, IL-17A, and IL-10 in UC patients. Although seemingly normal inhibitory effects on T cell activation and proliferation, butyrate has an impaired ability to reduce cytokine secretion and induce surface expression of CTLA-4 in T cells from UC patients with active disease. Overall, these observations indicate a dysfunction in butyrate induced immune regulation linked to CTLA-4 signaling in T cells from UC patients during a flare.
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Krawiec P, Pac-Kożuchowska E. Serum interleukin 17A and interleukin 17F in children with inflammatory bowel disease. Sci Rep 2020; 10:12617. [PMID: 32724117 PMCID: PMC7387488 DOI: 10.1038/s41598-020-69567-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 07/14/2020] [Indexed: 12/18/2022] Open
Abstract
Interleukin 17A (IL-17A) and interleukin 17F (IL-17F) appear to play important role in pathogenesis of some autoimmune diseases. However, their role in inflammatory bowel disease (IBD) has not been yet fully elucidated. We aimed to determine serum IL-17A and IL-17F in children with IBD and to assess their association with IBD activity. Recruited children underwent blood tests including complete blood count, C-reactive protein, erythrocyte sedimentation rate, IL-17A and IL-17F and stool sampling for calprotectin. The study group comprised 68 children with IBD, including 43 with ulcerative colitis and 25 with Crohn's disease. Control group included 20 healthy children. IL-17A was significantly increased in children with IBD (median: 10.95 pg/ml; range: 0.65-200.54 pg/ml) compared to controls (median: 4.09 pg/ml; range: 0.67-26.20 pg/ml) (p = 0.002). IL-17A was significantly increased in patients with active phase of ulcerative colitis (median: 14.58 pg/ml; range: 0.65-200.54 pg/ml) compared to those in ulcerative colitis remission (median: 8.13 pg/ml; range: 1.61-58.56 pg/ml) (p = 0.04). There were no significant differences in IL-17A among patients with active and inactive Crohn's disease (p = 0.18). IL-17F did not differ significantly between children with IBD (median: 15.11 pg/ml; range: 0.09-189.84 pg/ml) and controls (median: 11.56 pg/ml; range: 0.19-32.49 pg/ml) (p = 0.33). Our study suggests that interleukin 17A may diverse active phase from remission only in ulcerative colitis but not in Crohn's disease.
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Affiliation(s)
- Paulina Krawiec
- Department of Paediatrics and Gastroenterology, Medical University of Lublin, Al. Racławickie 1, 20-059, Lublin, Poland.
| | - Elżbieta Pac-Kożuchowska
- Department of Paediatrics and Gastroenterology, Medical University of Lublin, Al. Racławickie 1, 20-059, Lublin, Poland
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20
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Wu ZY, Sang LX, Chang B. Isoflavones and inflammatory bowel disease. World J Clin Cases 2020; 8:2081-2091. [PMID: 32548137 PMCID: PMC7281056 DOI: 10.12998/wjcc.v8.i11.2081] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Revised: 03/27/2020] [Accepted: 04/24/2020] [Indexed: 02/05/2023] Open
Abstract
Isoflavones constitute a class of plant hormones including genistein, daidzein, glycitein, formononetin, biochanin A, and irilone, and the major source of human intake is soybeans. Inflammatory bowel disease (IBD) is a chronic recurrent inflammatory disease including ulcerative colitis, Crohn’s disease, and indeterminate colitis, which seriously affects the quality of life of patients and has become a global health problem. Although the pathogenesis of IBD is not very clear, many factors are thought to be related to the occurrence and development of IBD such as genes, immunity, and intestinal flora. How to control IBD effectively for a long time is still a problem for gastroenterologists. Diet has an important effect on IBD. Patients with IBD should pay more attention to diet. To date, many studies have reported that isoflavones have both good and bad effects on IBD. Isoflavones have many activities such as regulating the inflammatory signal pathways and affecting intestinal barrier functions and gut flora. They can also act through estrogen receptors, as they have a similar structure to estrogen. Isoflavones are easy to get from diet for human. Whether they are valuable to be applied to the treatment of IBD is worth studying. This review summarizes the relationship between isoflavones and IBD.
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Affiliation(s)
- Ze-Yu Wu
- Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Li-Xuan Sang
- Department of Geriatrics, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Bing Chang
- Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
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21
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Fukaura K, Iboshi Y, Ogino H, Ihara E, Nakamura K, Nishihara Y, Nishioka K, Chinen T, Iwasa T, Aso A, Goto A, Haraguchi K, Akiho H, Harada N, Ogawa Y. Mucosal Profiles of Immune Molecules Related to T Helper and Regulatory T Cells Predict Future Relapse in Patients With Quiescent Ulcerative Colitis. Inflamm Bowel Dis 2019; 25:1019-1027. [PMID: 30668727 DOI: 10.1093/ibd/izy395] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 10/26/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND T helper (Th)- and regulatory T (Treg) cell-related immune molecules are implicated in ulcerative colitis (UC). However, the association between their mucosal expression during remission and the subsequent clinical course of UC is unknown. METHODS The expression of cytokines and transcription factors related to Th1, Th2, Th17, and Treg in endoscopic mucosal biopsy specimens from 40 UC patients in clinical remission and 9 controls was measured by quantitative polymerase chain reaction. The relationship between their expression patterns, as stratified by Mayo Endoscopic Subscore (MES), and any future relapse was evaluated by univariate and multivariate analyses. RESULTS Six of 40 patients (baseline MES 0/1/2, 22/14/4) experienced a relapse during the study period (median, 37 months). At baseline, even in the MES0 patients, the interleukin (IL)-17A of the patients was significantly upregulated in comparison with controls (P = 0.0351). Future relapse was associated with a higher baseline expression of IL-17A, IL-17F, and IL-21 in MES0/1, and the upregulation of IL-17F and IL-21 remained statistically significant when limited to MES0 patients. Kaplan-Meier analysis revealed that as a single marker, a higher IL-21 level best grouped patients with an increased risk of relapse (P = 0.0042). Furthermore, a multivariate model that consisted of IL-21 and T-bet showed an even greater value (P = 0.0001). CONCLUSIONS The profiles of Th/Treg-related gene expression in the colonic mucosa are altered, even during clinical and endoscopic remission of UC, with a detectable Th17-predominant profile predicting future relapse. This association might represent latent immune dysregulation during disease quiescence and has the potential to be utilized to improve patient care.
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Affiliation(s)
- Keita Fukaura
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoichiro Iboshi
- Department of Gastroenterology, Clinical Research Institute, National Hospital Organization, Kyushu Medical Center, Fukuoka, Japan
| | - Haruei Ogino
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Eikichi Ihara
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kazuhiko Nakamura
- Department of Gastroenterology, Harasanshin Hospital, Fukuoka, Japan
| | - Yuichiro Nishihara
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kei Nishioka
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takatoshi Chinen
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tsutomu Iwasa
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Akira Aso
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Ayako Goto
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | | | - Hirotada Akiho
- Department of Gastroenterology, Kitakyushu Municipal Medical Center, Fukuoka, Japan
| | - Naohiko Harada
- Department of Gastroenterology, Clinical Research Institute, National Hospital Organization, Kyushu Medical Center, Fukuoka, Japan
| | - Yoshihiro Ogawa
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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22
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Song R, Li Y, Hao W, Wang B, Yang L, Xu F. Identification and analysis of key genes associated with ulcerative colitis based on DNA microarray data. Medicine (Baltimore) 2018; 97:e10658. [PMID: 29794741 PMCID: PMC6392526 DOI: 10.1097/md.0000000000010658] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
This study aimed to identify genes that may play a role in development of ulcerative colitis (UC) and gain insight into its pathogenesis.Gene expression profiling data, including samples collected from 13 early-stage UC (EUC), 8 advanced-stage UC (AUC), and 5 control subjects, were downloaded from the Gene Expression Omnibus database under the accession number of GSE9452. Differentially expressed genes (DEGs) were identified in EUC and AUC compared with controls. DEGs for EUC and AUC, as well as AUC-specific DEGs were subjected to pathway enrichment analysis. Random Walk with Restart (RWR) was used to identify DEGs that are critical in UC based on a protein-to-protein interaction (PPI) network and the inflammatory bowel disease (IBD) pathway downloaded from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. IL17 and transforming growth factor beta TGF-β) expression levels in colonic tissue from patients with UC and normal colonic mucosa from healthy adults were analyzed by immunohistochemistry (IHC).A total of 3511 and 911 DEGs were identified in AUC and EUC, respectively. The overlapping DEGs and the AUC-specific DEGs were both enriched in pathways related to immunity, such as antigen processing and presentation. AUC-specific DEGs were related to cell migration, such as ECM-receptor interaction. Following DEG prioritization, TLR4 and STAT1 were linked with EUC, AUC, and CD. The upregulated gene TGFB increased the number of Th17 cells, as verified by IHC. Furthermore, PIK3R1, CREBBP, and STAT1 were part of high-degree nodes in the PPI sub-network.The upregulated gene TGFB may regulate IL17 expression in UC. PIK3R1 may participate in immunity and CREBBP may interact with STAT1 in the development and progression of UC.
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The Mucosal Antibacterial Response Profile and Fecal Microbiota Composition Are Linked to the Disease Course in Patients with Newly Diagnosed Ulcerative Colitis. Inflamm Bowel Dis 2017; 23:956-966. [PMID: 28445247 DOI: 10.1097/mib.0000000000001130] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND The clinical disease course of ulcerative colitis (UC) varies substantially between individuals and can currently not be reliably predicted. The gut microbiota and the host's immune defense are key players for gut homeostasis and may be linked to disease outcome. The aim of this study was to determine fecal microbiota composition and mucosal antibacterial response profile in untreated patients with newly diagnosed UC and the impact of these factors on disease course. METHODS Stool samples and intestinal biopsies were obtained from therapy-naive newly diagnosed patients with UC. Patients were defined to have mild or moderate/severe disease course assessed by disease activity during the 3 years follow-up. Fecal microbiota was analyzed by the GA-map Dysbiosis test (n = 18), and gene expression in intestinal biopsies was analyzed by RT Profiler polymerase chain reaction array (n = 13) and real-time polymerase chain reaction (n = 44). RESULTS At the time of diagnosis of UC, the fecal microbiota composition discriminated between patients with mild versus moderate/severe disease course. Also, the mucosal antibacterial gene expression response profile differed between patients with mild versus moderate/severe disease course with bactericidal/permeability-increasing protein (BPI) being most important for the discrimination. Mucosal bactericidal/permeability-increasing protein gene expression at diagnosis was higher in patients with mild versus moderate/severe disease course when confirmed in a larger patient cohort (P = 0.0004, n = 44) and was a good predictor for the number of flares during the 3 years follow-up (R = 0.395, P < 0.0001). CONCLUSIONS In patients with newly diagnosed UC, fecal microbiota composition and mucosal antibacterial response profile, especially bactericidal/permeability-increasing protein, are linked to disease course.
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Larussa T, Oliverio M, Suraci E, Greco M, Placida R, Gervasi S, Marasco R, Imeneo M, Paolino D, Tucci L, Gulletta E, Fresta M, Procopio A, Luzza F. Oleuropein Decreases Cyclooxygenase-2 and Interleukin-17 Expression and Attenuates Inflammatory Damage in Colonic Samples from Ulcerative Colitis Patients. Nutrients 2017; 9:nu9040391. [PMID: 28420140 PMCID: PMC5409730 DOI: 10.3390/nu9040391] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 04/11/2017] [Accepted: 04/13/2017] [Indexed: 02/06/2023] Open
Abstract
Oleuropein (OLE) is the major phenolic secoiridoid of olive tree leaves, and its antioxidant and anti-inflammatory activities have been demonstrated in in vitro and in vivo animal models. The aim of this study was to investigate the activity of OLE in the colonic mucosa from patients with ulcerative colitis (UC). Biopsies obtained during colonoscopy from 14 patients with active UC were immediately placed in an organ culture chamber and challenged with lipopolysaccharide from Escherichia coli (EC-LPS) at 1 μg/mL in the presence or absence of 3 mM OLE. The expression of cyclooxygenase (COX)-2 and interleukin (IL)-17 was assessed in total protein extracts from treated colonic biopsies by Western blotting. Levels of IL-17 were also measured in culture supernatant by ELISA. A microscopic evaluation of the cultured biopsies was performed by conventional histology and immunohistochemistry. The expression of COX-2 and IL-17 were significantly lower in samples treated with OLE + EC-LPS compared with those treated with EC-LPS alone (0.80 ± 0.15 arbitrary units (a.u.) vs. 1.06 ± 0.19 a.u., p = 0.003, and 0.71 ± 0.08 a.u. vs. 1.26 ± 0.42 a.u., p = 0.03, respectively) as were the levels of IL-17 in culture supernatants of OLE + EC-LPS treated colonic samples (21.16 ± 8.64 pg/mL vs. 40.67 ± 9.24 pg/mL, p = 0.01). Histologically, OLE-treated colonic samples showed an amelioration of inflammatory damage with reduced infiltration of CD3, CD4, and CD20 cells, while CD68 numbers increased. The anti-inflammatory activity of OLE was demonstrated in colonic biopsies from UC patients. These new data support a potential role of OLE in the treatment of UC.
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Affiliation(s)
- Tiziana Larussa
- Department of Health Sciences, University of Catanzaro "Magna Graecia", 88100 Catanzaro, Italy.
| | - Manuela Oliverio
- Department of Health Sciences, University of Catanzaro "Magna Graecia", 88100 Catanzaro, Italy.
| | - Evelina Suraci
- Department of Health Sciences, University of Catanzaro "Magna Graecia", 88100 Catanzaro, Italy.
| | - Marta Greco
- Department of Health Sciences, University of Catanzaro "Magna Graecia", 88100 Catanzaro, Italy.
| | - Roberta Placida
- Department of Health Sciences, University of Catanzaro "Magna Graecia", 88100 Catanzaro, Italy.
| | - Serena Gervasi
- Department of Health Sciences, University of Catanzaro "Magna Graecia", 88100 Catanzaro, Italy.
| | - Raffaella Marasco
- Department of Health Sciences, University of Catanzaro "Magna Graecia", 88100 Catanzaro, Italy.
| | - Maria Imeneo
- Department of Health Sciences, University of Catanzaro "Magna Graecia", 88100 Catanzaro, Italy.
| | - Donatella Paolino
- Department of Health Sciences, University of Catanzaro "Magna Graecia", 88100 Catanzaro, Italy.
| | - Luigi Tucci
- Pathology Unit, Pugliese-Ciaccio Hospital, 88100 Catanzaro, Italy.
| | - Elio Gulletta
- Department of Health Sciences, University of Catanzaro "Magna Graecia", 88100 Catanzaro, Italy.
| | - Massimo Fresta
- Department of Health Sciences, University of Catanzaro "Magna Graecia", 88100 Catanzaro, Italy.
| | - Antonio Procopio
- Department of Health Sciences, University of Catanzaro "Magna Graecia", 88100 Catanzaro, Italy.
| | - Francesco Luzza
- Department of Health Sciences, University of Catanzaro "Magna Graecia", 88100 Catanzaro, Italy.
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Jonefjäll B, Simrén M, Lasson A, Öhman L, Strid H. Psychological distress, iron deficiency, active disease and female gender are independent risk factors for fatigue in patients with ulcerative colitis. United European Gastroenterol J 2017; 6:148-158. [PMID: 29435325 DOI: 10.1177/2050640617703868] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Accepted: 03/11/2017] [Indexed: 12/12/2022] Open
Abstract
Background Patients with ulcerative colitis often report fatigue. Objectives To investigate prevalence of and risk factors for fatigue in patients with ulcerative colitis with active disease and during deep remission. Methods In this cross-sectional study, disease activity was evaluated with endoscopy and calprotectin, and patients were classified as having active disease (n = 133) or being in deep remission (n = 155). Blood samples were analysed to assess anaemia, iron deficiency and systemic immune activity. Patients completed questionnaires to assess fatigue, psychological distress, gastrointestinal symptoms and quality of life. Results The prevalence of high fatigue (general fatigue ≥ 13, Multidimensional Fatigue Inventory) was 40% in the full study population. Among patients with high fatigue, female gender and iron deficiency were more prevalent, and these patients had more severe disease activity and reported higher levels of anxiety, depression and decreased quality of life compared with patients with no/mild fatigue. A logistic regression analysis identified probable psychiatric disorder (odds ratio (OR) (confidence interval) 6.1 (3.1-12.2)), iron deficiency (OR 2.5 (1.2-5.1)), active disease (OR 2.2 (1.2-3.9)) and female gender (OR 2.1 (1.1-3.7)) as independent risk factors for high fatigue. Similar results were found concerning psychological distress, gender and quality of life, but immune markers did not differ in patients in deep remission with high vs. no/mild fatigue. Conclusions Probable psychiatric disorder, iron deficiency, active disease and female gender are independent risk factors for high fatigue in patients with ulcerative colitis. Low-grade immune activity does not seem to be the cause of fatigue among patients in deep remission.
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Affiliation(s)
- Börje Jonefjäll
- Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Department of Internal Medicine and Clinical Nutrition, Gothenburg, Sweden.,Department of Internal Medicine, Kungälv Hospital, Kungälv, Sweden
| | - Magnus Simrén
- Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Department of Internal Medicine and Clinical Nutrition, Gothenburg, Sweden.,Center for Functional GI and Motility Disorders, University of North Carolina, Chapel Hill, NC, USA
| | - Anders Lasson
- Department of Internal Medicine, Södra Älvsborgs Hospital, Borås, Sweden
| | - Lena Öhman
- Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Department of Internal Medicine and Clinical Nutrition, Gothenburg, Sweden.,Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Department of Microbiology and Immunology, Gothenburg, Sweden.,School of Health and Education, University of Skövde, Skövde, Sweden
| | - Hans Strid
- Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Department of Internal Medicine and Clinical Nutrition, Gothenburg, Sweden.,Department of Internal Medicine, Södra Älvsborgs Hospital, Borås, Sweden
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26
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Iboshi Y, Nakamura K, Fukaura K, Iwasa T, Ogino H, Sumida Y, Ihara E, Akiho H, Harada N, Nakamuta M. Increased IL-17A/IL-17F expression ratio represents the key mucosal T helper/regulatory cell-related gene signature paralleling disease activity in ulcerative colitis. J Gastroenterol 2017; 52:315-326. [PMID: 27178567 DOI: 10.1007/s00535-016-1221-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Accepted: 04/26/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND T helper (Th) and regulatory T (Treg) cell-related cytokines are implicated in inflammatory bowel diseases, including ulcerative colitis (UC). While these cytokines are generally upregulated in inflamed mucosae, the key cytokine profile explaining disease severity has not been determined. METHODS The Rachmilewitz endoscopic index (REI) was assessed in 61 UC patients undergoing colonoscopy. Biopsies obtained from inflamed (REI 3-12) and noninflamed (REI 0-2) areas were analyzed by quantitative PCR for expression of mRNAs encoding cytokines and transcription factors related to Th1 (TNF-α, IFN-γ, IL-12p35, IL-12p40, and T-bet), Th2 (IL-4, IL-13, IL-33, and GATA3), Th17 (IL-17A, IL-17F, IL-21, IL-22, IL-23p19, IL-6, and RORC), Th9 (IL-9, IRF4, and PU.1), and Treg (TGF-β and Foxp3). Expression patterns associated with higher REI were determined by univariate and multivariate analyses. RESULTS Despite general upregulation, none of these mRNAs showed univariate correlation with REI in inflamed samples. Multiple regression analysis, however, found that joint expression of IL-17A, IL-17F, IL-21, RORC, and TGF-β was significantly predictive of REI (P < 0.0002, R2 = 0.380), with major individual contributions by IL-17A (P < 0.0001) and IL-17F (P < 0.0001), which were associated with increased and decreased REI, respectively. Partial correlation analysis, validating this model, indicated differences between IL-17A and IL-17F in correlating with other targets. The IL-17A/IL-17F ratio showed a significant correlation with REI (r = 0.5124, P < 0.0001), whereas no other mRNAs were essentially predictive of REI. CONCLUSIONS Mucosal IL-17A/IL-17F ratio significantly correlates with endoscopic score in UC patients, accompanied by their disparate interactions with other Th/Treg-related genes.
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Affiliation(s)
- Yoichiro Iboshi
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka, 812-8582, Japan.,Department of Gastroenterology, Kyushu Medical Center, Clinical Research Center, National Hospital Organization, Fukuoka, Japan
| | - Kazuhiko Nakamura
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka, 812-8582, Japan.
| | - Keita Fukaura
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka, 812-8582, Japan
| | - Tsutomu Iwasa
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka, 812-8582, Japan
| | - Haruei Ogino
- Department of Gastroenterology, Kitakyushu Municipal Medical Center, Kitakyushu, Japan
| | - Yorinobu Sumida
- Department of Gastroenterology, Kyushu Medical Center, Clinical Research Center, National Hospital Organization, Fukuoka, Japan
| | - Eikichi Ihara
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka, 812-8582, Japan
| | - Hirotada Akiho
- Department of Gastroenterology, Kitakyushu Municipal Medical Center, Kitakyushu, Japan
| | - Naohiko Harada
- Department of Gastroenterology, Kyushu Medical Center, Clinical Research Center, National Hospital Organization, Fukuoka, Japan
| | - Makoto Nakamuta
- Department of Gastroenterology, Kyushu Medical Center, Clinical Research Center, National Hospital Organization, Fukuoka, Japan
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Campaniello MA, Mavrangelos C, Eade S, Harrington AM, Blackshaw LA, Brierley SM, Smid SD, Hughes PA. Acute colitis chronically alters immune infiltration mechanisms and sensory neuro-immune interactions. Brain Behav Immun 2017; 60:319-332. [PMID: 27864046 DOI: 10.1016/j.bbi.2016.11.015] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Revised: 11/07/2016] [Accepted: 11/15/2016] [Indexed: 12/22/2022] Open
Abstract
OBJECTIVE Little is understood regarding how disease progression alters immune and sensory nerve function in colitis. We investigated how acute colitis chronically alters immune recruitment and the impact this has on re-activated colitis. To understand the impact of disease progress on sensory systems we investigated the mechanisms underlying altered colonic neuro-immune interactions after acute colitis. DESIGN Inflammation was compared in mouse models of health, acute tri-nitrobenzene sulphonic acid (TNBS) colitis, Remission and Reactivated colitis. Cytokine concentrations were compared by ELISA in-situ and in explanted colon tissue. Colonic infiltration by CD11b/F4-80 macrophage, CD4 THELPER (TH) and CD8 TCYTOTOXIC (TC) and α4β7 expression on mesenteric lymph node (MLN) TH and TC was determined by flow cytometry. Cytokine and effector receptor mRNA expression was determined on colo-rectal afferent neurons and the mechanisms underlying cytokinergic effects on high-threshold colo-rectal afferent function were investigated using electrophysiology. RESULTS Colonic damage, MPO activity, macrophage infiltration, IL-1β and IL-6 concentrations were lower in Reactivated compared to Acute colitis. TH infiltration and α4β7 expression on TH MLN was increased in Remission but not Acute colitis. IFN-γ concentrations, TH infiltration and α4β7 expression on TH and TC MLN increased in Reactivated compared to Acute colitis. Reactivated explants secreted more IL-1β and IL-6 than Acute explants. IL-6 and TNF-α inhibited colo-rectal afferent mechanosensitivity in Remission mice via a BKCa dependent mechanism. CONCLUSIONS Acute colitis persistently alters immune responses and afferent nerve signalling pathways to successive episodes of colitis. These findings highlight the complexity of viscero-sensory neuro-immune interactions in painful remitting and relapsing diseases.
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Affiliation(s)
- Melissa A Campaniello
- Centre for Nutrition and Gastrointestinal Diseases, University of Adelaide and South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia
| | - Chris Mavrangelos
- Centre for Nutrition and Gastrointestinal Diseases, University of Adelaide and South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia
| | - Samuel Eade
- Centre for Nutrition and Gastrointestinal Diseases, University of Adelaide and South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia; Department of Pharmacology, University of Adelaide, Adelaide, Australia
| | - Andrea M Harrington
- Centre for Nutrition and Gastrointestinal Diseases, University of Adelaide and South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia
| | - L Ashley Blackshaw
- Centre for Neuroscience and Trauma, Blizard Institute, Barts and the London School of Medicine & Dentistry, Queen Mary University of London, UK
| | - Stuart M Brierley
- Centre for Nutrition and Gastrointestinal Diseases, University of Adelaide and South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia
| | - Scott D Smid
- Department of Pharmacology, University of Adelaide, Adelaide, Australia
| | - Patrick A Hughes
- Centre for Nutrition and Gastrointestinal Diseases, University of Adelaide and South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia.
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Matusiak Ł, Szczęch J, Bieniek A, Nowicka-Suszko D, Szepietowski JC. Increased interleukin (IL)-17 serum levels in patients with hidradenitis suppurativa: Implications for treatment with anti-IL-17 agents. J Am Acad Dermatol 2016; 76:670-675. [PMID: 28041632 DOI: 10.1016/j.jaad.2016.10.042] [Citation(s) in RCA: 131] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Revised: 10/22/2016] [Accepted: 10/29/2016] [Indexed: 01/19/2023]
Abstract
BACKGROUND Biologics seem to offer a promising nonsurgical approach in hidradenitis suppurativa (HS), especially in disease with highly pronounced inflammation. Recent studies revealed increased expression of a broad range of cytokines in lesional HS skin, including interleukin (IL)-17. OBJECTIVE This study was undertaken to determine IL-17 serum levels in this group of patients. METHODS Our study was conducted on a group of 86 patients between 16 and 72 years of age with HS. A total of 86 matched healthy volunteers constituted the control group. Enzyme-linked immunosorbent assay kits were used to quantify IL-17 serum concentration. RESULTS The mean IL-17 serum level of patients with HS was 3.68 ± 2.08 pg/mL, which was significantly elevated (P < .0001) compared with that found in healthy volunteers (2.5 ± 1.11 pg/mL). Moreover, there was a tendency toward higher serum concentrations of IL-17 in patients with more advanced disease (P = .005). Disease duration; patient sex, age, and body mass index; and smoking habits were not determining factors for IL-17 serum concentration. LIMITATIONS Hospital-based study population was a limitation, as was a lack of posttreatment assessment. CONCLUSION In light of our findings and literature on increased expression of IL-17 in HS lesions, evaluating the clinical effectiveness of using anti-IL-17 agents in the treatment of patients with HS is justified.
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Affiliation(s)
- Łukasz Matusiak
- Department of Dermatology, Venereology, and Allergology, Wroclaw Medical University, Wrocław, Poland.
| | - Justyna Szczęch
- Department of Dermatology, Venereology, and Allergology, Wroclaw Medical University, Wrocław, Poland
| | - Andrzej Bieniek
- Department of Dermatology, Venereology, and Allergology, Wroclaw Medical University, Wrocław, Poland
| | - Danuta Nowicka-Suszko
- Department of Dermatology, Venereology, and Allergology, Wroclaw Medical University, Wrocław, Poland
| | - Jacek C Szepietowski
- Department of Dermatology, Venereology, and Allergology, Wroclaw Medical University, Wrocław, Poland
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Poland M, Ten Klooster JP, Wang Z, Pieters R, Boekschoten M, Witkamp R, Meijerink J. Docosahexaenoyl serotonin, an endogenously formed n-3 fatty acid-serotonin conjugate has anti-inflammatory properties by attenuating IL-23-IL-17 signaling in macrophages. BIOCHIMICA ET BIOPHYSICA ACTA 2016; 1861:2020-2028. [PMID: 27663185 DOI: 10.1016/j.bbalip.2016.09.012] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Revised: 08/24/2016] [Accepted: 09/16/2016] [Indexed: 01/01/2023]
Abstract
Conjugates of fatty acids and amines, including endocannabinoids, are known to play important roles as endogenous signaling molecules. Among these, the ethanolamine conjugate of the n-3 poly unsaturated long chain fatty acid (PUFA) docosahexaenoic acid (22:6n-3) (DHA) was shown to possess strong anti-inflammatory properties. Previously, we identified the serotonin conjugate of DHA, docosahexaenoyl serotonin (DHA-5-HT), in intestinal tissues and showed that its levels are markedly influenced by intake of n-3 PUFAs. However, its biological roles remain to be elucidated. Here, we show that DHA-5-HT possesses potent anti-inflammatory properties by attenuating the IL-23-IL-17 signaling cascade in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Transcriptome analysis revealed that DHA-5-HT down-regulates LPS-induced genes, particularly those involved in generating a CD4+ Th17 response. Hence, levels of PGE2, IL-6, IL-1β, and IL-23, all pivotal macrophage-produced mediators driving the activation of pathogenic Th17 cells in a concerted way, were found to be significantly suppressed by concentrations as low as 100-500nM DHA-5-HT. Furthermore, DHA-5-HT inhibited the ability of RAW264.7 cells to migrate and downregulated chemokines like MCP-1, CCL-20, and gene-expression of CCL-22 and of several metalloproteinases. Gene set enrichment analysis (GSEA) suggested negative overlap with gene sets linked to inflammatory bowel disease (IBD) and positive overlap with gene sets related to the Nrf2 pathway. The specific formation of DHA-5-HT in the gut, combined with increasing data underlining the importance of the IL-23-IL-17 signaling pathway in the etiology of many chronic inflammatory diseases merits further investigation into its potential as therapeutic compound in e.g. IBD or intestinal tumorigenesis.
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Affiliation(s)
- Mieke Poland
- Division of Human Nutrition, Wageningen University, PO Box 17, 6700 AA Wageningen, The Netherlands.
| | - Jean Paul Ten Klooster
- Institute for Life Sciences & Chemistry, Utrecht University of Applied Sciences, Utrecht, The Netherlands.
| | - Zheng Wang
- Division of Human Nutrition, Wageningen University, PO Box 17, 6700 AA Wageningen, The Netherlands.
| | - Raymond Pieters
- Institute for Life Sciences & Chemistry, Utrecht University of Applied Sciences, Utrecht, The Netherlands.
| | - Mark Boekschoten
- Division of Human Nutrition, Wageningen University, PO Box 17, 6700 AA Wageningen, The Netherlands.
| | - Renger Witkamp
- Division of Human Nutrition, Wageningen University, PO Box 17, 6700 AA Wageningen, The Netherlands.
| | - Jocelijn Meijerink
- Division of Human Nutrition, Wageningen University, PO Box 17, 6700 AA Wageningen, The Netherlands.
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Gunterberg V, Simrén M, Öhman L, Friberg P, Jones MP, Van Oudenhove L, Strid H. Autonomic nervous system function predicts the inflammatory response over three years in newly diagnosed ulcerative colitis patients. Neurogastroenterol Motil 2016; 28:1655-1662. [PMID: 27265090 DOI: 10.1111/nmo.12865] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2015] [Accepted: 04/27/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND The autonomic nervous system (ANS) modulates intestinal inflammation in animal models. Human evidence confirming such modulating influence is limited. We aimed to investigate whether ANS function is associated with inflammatory parameters at disease onset, and whether it predicts the evolution of inflammation in patients with ulcerative colitis (UC). METHODS We prospectively monitored 51 patients from onset of UC for 3 years. Upon remission of the onset flare, ANS activity was assessed by heart rate variability analysis and compared with healthy controls. Inflammatory parameters in blood, stool, and colonic biopsies obtained at onset and during follow-up visits were analyzed. Generalized linear models were used to test cross-sectional associations between ANS activity and inflammatory parameters at onset; linear mixed models were used to test whether ANS function at onset predicted the evolution of inflammation over the following 3 years. KEY RESULTS Sympathovagal balance was different in UC patients compared to healthy controls, and cross-sectional associated with higher levels of systemic (erythrocyte sedimentation rate [ESR], CRP, TNF-α, IFN-γ) and mucosal inflammation (interleukin-8, IFN-γ) at onset. Conversely, a negative cross-sectional association with parasympathetic activity was found for ESR & TNF-α. Longitudinally, parasympathetic activity at onset predicted systemic (ESR, WBC), but not mucosal inflammation during follow-up. CONCLUSIONS & INFERENCES This study further strengthens the association between the ANS system and intestinal inflammation previously found in animal models and recently in patients with inflammatory bowel disease. These results may have important implications for the pathogenesis and treatment of UC.
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Affiliation(s)
- V Gunterberg
- Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - M Simrén
- Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - L Öhman
- Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Microbiology and Immunology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - P Friberg
- Department of Clinical Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - M P Jones
- Psychology Faculty, Macquarie University, Sydney, NSW, Australia
| | - L Van Oudenhove
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Clinical and Experimental Medicine, University of Leuven, Leuven, Belgium
| | - H Strid
- Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
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Lebrero-Fernández C, Wenzel UA, Akeus P, Wang Y, Strid H, Simrén M, Gustavsson B, Börjesson LG, Cardell SL, Öhman L, Quiding-Järbrink M, Bas-Forsberg A. Altered expression of Butyrophilin ( BTN) and BTN-like ( BTNL) genes in intestinal inflammation and colon cancer. IMMUNITY INFLAMMATION AND DISEASE 2016; 4:191-200. [PMID: 27957327 PMCID: PMC4879465 DOI: 10.1002/iid3.105] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Revised: 02/09/2016] [Accepted: 02/24/2016] [Indexed: 12/22/2022]
Abstract
Several Butyrophilin (BTN) and Btn‐like (BTNL) molecules control T lymphocyte responses, and are genetically associated with inflammatory disorders and cancer. In this study, we present a comprehensive expression analysis of human and murine BTN and BTNL genes in conditions associated with intestinal inflammation and cancer. Using real‐time PCR, expression of human BTN and BTNL genes was analyzed in samples from patients with ulcerative colitis, irritable bowel syndrome, and colon tumors. Expression of murine Btn and Btnl genes was examined in mouse models of spontaneous colitis (Muc2−/−) and intestinal tumorigenesis (ApcMin/+). Our analysis indicates a strong association of several of the human genes with ulcerative colitis and colon cancer; while especially BTN1A1, BTN2A2, BTN3A3, and BTNL8 were significantly altered in inflammation, colonic tumors exhibited significantly decreased levels of BTNL2, BTNL3, BTNL8, and BTNL9 as compared to unaffected tissue. Colonic inflammation in Muc2−/− mice significantly down‐regulated the expression of particularly Btnl1, Btnl4, and Btnl6 mRNA, and intestinal polyps derived from ApcMin/+ mice displayed altered levels of Btn1a1, Btn2a2, and Btnl1 transcripts. Thus, our data present an association of BTN and BTNL genes with intestinal inflammation and cancer and represent a valuable resource for further studies of this gene family.
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Affiliation(s)
- Cristina Lebrero-Fernández
- Department of Microbiology and Immunology Institute of Biomedicine University of Gothenburg Gothenburg Sweden
| | - Ulf Alexander Wenzel
- Department of Microbiology and Immunology Institute of Biomedicine University of Gothenburg Gothenburg Sweden
| | - Paulina Akeus
- Department of Microbiology and Immunology Institute of Biomedicine University of Gothenburg Gothenburg Sweden
| | - Ying Wang
- Department of Microbiology and Immunology Institute of Biomedicine University of Gothenburg Gothenburg Sweden
| | - Hans Strid
- Department of Internal Medicine and Clinical Nutrition Institute of Medicine University of Gothenburg Gothenburg Sweden
| | - Magnus Simrén
- Department of Internal Medicine and Clinical NutritionInstitute of MedicineUniversity of GothenburgGothenburgSweden; Center for Functional GI and Motility DisordersUniversity of North CarolinaChapel HillNorth CarolinaUSA
| | - Bengt Gustavsson
- Department of Surgery Institute of Clinical Sciences University of Gothenburg Gothenburg Sweden
| | - Lars G Börjesson
- Department of Surgery Institute of Clinical Sciences University of Gothenburg Gothenburg Sweden
| | - Susanna L Cardell
- Department of Microbiology and Immunology Institute of Biomedicine University of Gothenburg Gothenburg Sweden
| | - Lena Öhman
- Department of Microbiology and ImmunologyInstitute of BiomedicineUniversity of GothenburgGothenburgSweden; Department of Internal Medicine and Clinical NutritionInstitute of MedicineUniversity of GothenburgGothenburgSweden; School of Health and EducationUniversity of SkövdeSkövdeSweden
| | - Marianne Quiding-Järbrink
- Department of Microbiology and Immunology Institute of Biomedicine University of Gothenburg Gothenburg Sweden
| | - Anna Bas-Forsberg
- Department of Microbiology and Immunology Institute of Biomedicine University of Gothenburg Gothenburg Sweden
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Dahlén R, Magnusson MK, Bajor A, Lasson A, Ung KA, Strid H, Öhman L. Global mucosal and serum cytokine profile in patients with ulcerative colitis undergoing anti-TNF therapy. Scand J Gastroenterol 2016; 50:1118-26. [PMID: 25877762 DOI: 10.3109/00365521.2015.1031167] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND OBJECTIVE The knowledge of the effects of anti-tumour necrosis factor (TNF) treatment on the global cytokine profile in patients with ulcerative colitis (UC) is limited. A better understanding of these mechanisms could improve the ability to select patients that should undergo the therapy. Therefore, the aim was to determine the global mucosal and serum cytokine profile before and during induction therapy with anti-TNF in UC patients. MATERIALS AND METHODS In total, mucosal biopsies (n = 28) and serum samples (n = 42) were collected from UC patients (total n = 48) before anti-TNF therapy. At week 14 response to the therapy was evaluated and again mucosal biopsies (n = 14) and serum samples (n = 42) were collected. Quantitative real-time PCR was used to determine mucosal cytokine mRNA expression and the MSD MULTI-ARRAY assay system platform was used for analysis of cytokines in serum. The global cytokine profile was evaluated by multivariate factor analysis. RESULTS At baseline, the global profile of mucosal cytokine mRNA expression and serum cytokines discriminated therapy responders from non-responders. Responders had lower mucosal mRNA expression of interleukin 1β (IL-1β), IL-17A, IL-6 and interferon γ (IFN-γ) than non-responders. Fourteen weeks after therapy start mucosal IL-1β and IL-6 were down-regulated in therapy responders but not in non-responders. At week 14, serum levels of IL-6 were decreased in therapy responders whereas IFN-γ and IL-12p70 were increased in non-responders. CONCLUSIONS Our data suggest that patients with a therapy failure have a more severe pro-inflammatory cytokine profile before start of anti-TNF treatment, which is less well suppressed by the treatment as compared to therapy responders.
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Affiliation(s)
- Rahil Dahlén
- Department of Microbioloy and Immunology, Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden
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Kaplan M, Yuksel M, Ates I, Yaln Kilic ZM, Kilic H, Ates H, Kayacetin E. Are sTWEAK and IL-17A Levels in Inflammatory Bowel Disease Associated with Disease Activity and Etiopathogenesis? Inflamm Bowel Dis 2016; 22:615-622. [PMID: 26650150 DOI: 10.1097/mib.0000000000000632] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND We aimed to identify the levels of soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) and interleukin 17A (IL-17A) in inflammatory bowel disease (IBD) and to examine their relationship with disease activity. METHODS A total of 92 patients with IBD, in which 54 patients were diagnosed with ulcerative colitis and 38 patients with Crohn's disease (CD), and 104 healthy controls were included in the study. The Rachmilewitz endoscopic activity index was calculated in ulcerative colitis, and the CD activity index was calculated in CD. RESULTS sTWEAK (P < 0.001) and IL-17A (P = 0.006) levels were higher in the IBD group than in the control group. Both in the IBD group and ulcerative colitis and CD subgroups, in active patients, sTWEAK and IL-17A levels were found to be higher than in inactive and control groups. In the IBD group, a positive correlation was determined between sTWEAK and IL-17A, and C-reactive protein, endoscopic activity index, and CD activity index. In multivariable regression analysis, C-reactive protein and sTWEAK levels were determined to be an independent risk factor for both endoscopic activity index and CD activity index. In receiver operating curve analysis, the sTWEAK level was determined to predict IBD with high sensitivity and specificity with a value of >588.34 pg/mL and activity with a value of >669.28 pg/mL. CONCLUSION Based on these results, we ascertain that sTWEAK has a role in etiopathogenesis of IBD. In addition, we believe that sTWEAK could be used as a marker for both disease activity criteria and treatment monitoring.
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Affiliation(s)
- Mustafa Kaplan
- *Department of Gastroenterology, Turkey Yuksek Ihtisas Training and Research Hospital, Ankara, Turkey; †Department of Internal Medicine, Ankara Numune Training and Research Hospital, Ankara, Turkey; ‡Department of Microbiology, Turkey Yuksek Ihtisas Training and Research Hospital, Ankara, Turkey; and §Department of Immunology and Allergy, Atatürk Chest Diseases and Thoracic Surgery Training and Research Hospital, Ankara, Turkey
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D’Ambrosio A, Cossu A, Amendola A, Zandri A, Butera A, Sanchez M, Biffoni M, Pronio A, Montesani C, Kohn A, Pica R, Boirivant M. Lamina Propria CD4+LAP+ Regulatory T Cells Are Increased in Active Ulcerative Colitis but Show Increased IL-17 Expression and Reduced Suppressor Activity. J Crohns Colitis 2016; 10:346-53. [PMID: 26589955 PMCID: PMC4957478 DOI: 10.1093/ecco-jcc/jjv216] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Accepted: 11/09/2015] [Indexed: 12/22/2022]
Abstract
BACKGROUND A CD4+CD25- regulatory T cell population expressing the surface TGF-β in its latent form LAP+ [latency associated peptide] cells was proved to be protective in experimental colitis and to be suppressive of human peripheral blood [PB] T proliferation. We investigated the frequency and function of lamina propria [LP] CD4+LAP+ T cells in inflammatory bowel disease [IBD] patients. METHODS Specimens from patients undergoing colonoscopy or bowel resection for IBD and colonic cancer were used as source of lamina propria mononuclear cells [LPMC]. The ulcerative colitis [UC] group was divided according to endoscopic activity evaluated with modified Baron Score. IL-17, IFN-γ, IL-10, LAP, and Foxp3 expression in CD3+CD8- [CD4] or CD3+/CD4+ gated cell population was assessed by immunofluorescence. The ability of FACS-sorted LP CD3+CD8-[CD4] LAP+CD25- to inhibit stimulated autologous PB CD3+CD8-[CD4] LAP- CD25- cells proliferation was assessed. RESULTS LP CD4LAP+ cells were significantly increased, when compared with controls, in active UC patients and not in Crohn's disease patients. The majority of LP CD4+LAP+ cells were Foxp3-. The percentage of IL-17+ cells in LP CD3+CD8-[CD4] LAP+ cells was significantly higher in active UC patients when compared with controls. LP CD3+CD8-[CD4]LAP+CD25- isolated from UC patients showed reduced or no ability to inhibit autologous PB CD3+CD8-[CD4]LAP-CD25- cell proliferation when compared with controls. Removal of IL-17+ cells from LP CD3+CD8-[CD4] LAP+ cells increases their suppressive ability. CONCLUSIONS The percentage of LP CD4LAP+ cells is increased in active UC, showing reduced suppressor activity due to their increased proportion of intracellular IL-17 expression.
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Affiliation(s)
- Antonella D’Ambrosio
- Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanita, Roma, Italy
| | - Andrea Cossu
- Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanita, Roma, Italy,Department of Internal Medicine and Medical Specialties,, University ‘Sapienza,’Roma, Italy
| | - Antonello Amendola
- Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanita, Roma, Italy
| | - Alessandro Zandri
- Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanita, Roma, Italy
| | - Alessia Butera
- Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanita, Roma, Italy
| | - Massimo Sanchez
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy
| | - Mauro Biffoni
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Annamaria Pronio
- Department of General Surgery, ‘P. Stefanini’, University ‘Sapienza’,Roma, Italy
| | - Chiara Montesani
- Department of General Surgery, ‘P. Stefanini’, University ‘Sapienza’,Roma, Italy
| | - Anna Kohn
- Division of Gastroenterology, Azienda Ospedaliera S. Camillo-Forlanini, Roma, Italy
| | - Roberta Pica
- IBD, GE Unit, Sandro Pertini Hospital, Roma, Italy
| | - Monica Boirivant
- Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanita, Roma, Italy
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Jonefjäll B, Simrén M, Öhman L, Lasson A, Svedlund J, Strid H. The severity of inflammation at onset of ulcerative colitis is not associated with IBS-like symptoms during clinical remission. J Crohns Colitis 2015; 9:776-83. [PMID: 26079726 DOI: 10.1093/ecco-jcc/jjv107] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Accepted: 06/01/2015] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Symptoms compatible with irritable bowel syndrome (IBS) are common in patients with ulcerative colitis (UC) in clinical remission. It has been suggested that these symptoms might arise due to post-inflammatory changes comparable with post-infectious IBS. The aim was to study factors at new onset of UC that predict development of IBS-like symptoms during clinical remission. METHODS In total, 98 patients with new onset of UC were followed prospectively for 3 years with yearly follow-up visits. Data from the first visit at the onset of UC were compared between a group of patients who fulfilled the criteria for IBS while in remission (UCR+IBS) during follow-up and a group who did not (UCR-IBS). RESULTS Among the UC patients, 87 met the criteria for clinical remission and 25 (29%) of these reported IBS-like symptoms in remission during follow-up. There was no difference in inflammatory disease activity at the initial flare or in the prevalence of previous IBS symptoms when comparing UCR+IBS and UCR-IBS patients. The UCR+IBS patients reported more severe gastrointestinal symptoms, including abdominal pain, during their primary flare. CONCLUSION The severity and extent of inflammation at onset of UC do not seem to affect the development of IBS-like symptoms in UC patients during clinical remission. The high prevalence of IBS-like symptoms is not explained by pre-existing IBS. UCR+IBS patients reported more severe gastrointestinal symptoms at disease onset, which might indicate a more sensitive gastrointestinal tract in this category of patients.
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Affiliation(s)
- Börje Jonefjäll
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Magnus Simrén
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden University of Gothenburg Centre for Person-Centered Care (GPCC), Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Lena Öhman
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Anders Lasson
- Department of Internal Medicine, Södra Älvsborgs Hospital, Borås, Sweden
| | - Jan Svedlund
- Department of Psychiatry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Hans Strid
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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Wenzel UA, Jonstrand C, Hansson GC, Wick MJ. CD103+ CD11b+ Dendritic Cells Induce Th17 T Cells in Muc2-Deficient Mice with Extensively Spread Colitis. PLoS One 2015; 10:e0130750. [PMID: 26121642 PMCID: PMC4487685 DOI: 10.1371/journal.pone.0130750] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Accepted: 05/23/2015] [Indexed: 12/22/2022] Open
Abstract
Mucus alterations are a feature of ulcerative colitis (UC) and can drive inflammation by compromising the mucosal barrier to luminal bacteria. The exact pathogenesis of UC remains unclear, but CD4+ T cells reacting to commensal antigens appear to contribute to pathology. Given the unique capacity of dendritic cells (DCs) to activate naive T cells, colon DCs may activate pathogenic T cells and contribute to disease. Using Muc2-/- mice, which lack a functional mucus barrier and develop spontaneous colitis, we show that colitic animals have reduced colon CD103+ CD11b- DCs and increased CD103- CD11b+ phagocytes. Moreover, changes in colonic DC subsets and distinct cytokine patterns distinguish mice with distally localized colitis from mice with colitis spread proximally. Specifically, mice with proximally spread, but not distally contained, colitis have increased IL-1β, IL-6, IL-17, TNFα, and IFNγ combined with decreased IL-10 in the distal colon. These individuals also have increased numbers of CD103+ CD11b+ DCs in the distal colon. CD103+ CD11b+ DCs isolated from colitic but not noncolitic mice induced robust differentiation of Th17 cells but not Th1 cells ex vivo. In contrast, CD103- CD11b+ DCs from colitic Muc2-/- mice induced Th17 as well as Th1 differentiation. Thus, the local environment influences the capacity of intestinal DC subsets to induce T cell proliferation and differentiation, with CD103+ CD11b+ DCs inducing IL-17-producing T cells being a key feature of extensively spread colitis.
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Affiliation(s)
- Ulf A. Wenzel
- Department of Microbiology and Immunology and the Mucosal Immunobiology and Vaccine Center (MIVAC), Institute of Biomedicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Caroline Jonstrand
- Department of Medical Biochemistry, Institute of Biomedicine at Sahlgrenska Academy and MIVAC, University of Gothenburg, Gothenburg, Sweden
| | - Gunnar C. Hansson
- Department of Medical Biochemistry, Institute of Biomedicine at Sahlgrenska Academy and MIVAC, University of Gothenburg, Gothenburg, Sweden
| | - Mary Jo Wick
- Department of Microbiology and Immunology and the Mucosal Immunobiology and Vaccine Center (MIVAC), Institute of Biomedicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- * E-mail:
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Korolkova OY, Myers JN, Pellom ST, Wang L, M’Koma AE. Characterization of Serum Cytokine Profile in Predominantly Colonic Inflammatory Bowel Disease to Delineate Ulcerative and Crohn's Colitides. CLINICAL MEDICINE INSIGHTS. GASTROENTEROLOGY 2015; 8:29-44. [PMID: 26078592 PMCID: PMC4459555 DOI: 10.4137/cgast.s20612] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/28/2014] [Revised: 11/23/2014] [Accepted: 11/23/2014] [Indexed: 02/05/2023]
Abstract
BACKGROUND As accessible diagnostic approaches fail to differentiate between ulcerative colitis (UC) and Crohn's colitis (CC) in one-third of patients with predominantly colonic inflammatory bowel disease (IBD), leading to inappropriate therapy, we aim to investigate the serum cytokine levels in these patients in search of molecular biometric markers delineating UC from CC. METHODS We measured 38 cytokines, chemokines, and growth factors using magnetic-bead-based multiplex immunoassay in 25 UC patients, 28 CC patients, and 30 controls. Our results are compared with those from a review of current literature regarding advances in serum cytokine profiles and associated challenges preventing their use for diagnostic/prognostic purposes. RESULTS Univariate analysis showed statistically significant increases of eotaxin, GRO, and TNF-α in UC patients compared to controls (Ctrl); interferon γ, interleukin (IL)-6, and IL-7 in CC group compared to Ctrl; and IL-8 in both UC and CC versus Ctrl. No cytokines were found to be different between UC and CC. A generalized linear model identified combinations of cytokines, allowing the identification of UC and CC patients, with area under the curve (AUC) = 0.936, as determined with receiver operating characteristic (ROC) analysis. CONCLUSIONS The current knowledge available about circulating cytokines in IBD is often contradictory. The development of an evidence-based tool using cytokines for diagnostic accuracy is still preliminary.
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Affiliation(s)
- Olga Y Korolkova
- Laboratory of Inflammatory Bowel Disease Research, Department of Biochemistry and Cancer Biology, Meharry Medical College School of Medicine, Nashville, Tennessee
| | - Jeremy N Myers
- Laboratory of Inflammatory Bowel Disease Research, Department of Biochemistry and Cancer Biology, Meharry Medical College School of Medicine, Nashville, Tennessee
| | - Samuel T Pellom
- Laboratory of Inflammatory Bowel Disease Research, Department of Biochemistry and Cancer Biology, Meharry Medical College School of Medicine, Nashville, Tennessee
| | - Li Wang
- Department of Statistics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Amosy E M’Koma
- Laboratory of Inflammatory Bowel Disease Research, Department of Biochemistry and Cancer Biology, Meharry Medical College School of Medicine, Nashville, Tennessee
- Department of General Surgery, Colon and Rectal Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee
- Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee
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Abstract
All of life is regulated by complex and organized chemical reactions that help dictate when to grow, to move, to reproduce, and to die. When these processes go awry, or are interrupted by pathological agents, diseases such as cancer, autoimmunity, or infections can result. Cytokines, chemokines, growth factors, adipokines, and other chemical moieties make up a vast subset of these chemical reactions that are altered in disease states, and monitoring changes in these molecules could provide for the identification of disease biomarkers. From the first identification of carcinoembryonic antigen, to the discovery of prostate-specific antigen, to numerous others described within, biomarkers of disease are detectable in a plethora of sample types. The growing number of biomarkers for infection, autoimmunity, and cancer allow for increasingly early detection, to identification of novel drug targets, to prognostic indicators of disease outcome. However, more and more studies are finding that a single cytokine or growth factor is insufficient as a true disease biomarker and that a more global perspective is needed to understand true disease biology. Such a broad view requires a multiplexed platform for chemical detection, and antibody arrays meet and exceed this need by performing this detection in a high-throughput fashion. Herein, we will discuss how antibody arrays have evolved, and how they have helped direct new drug target design, helped identify therapeutic disease markers, and helped in earlier disease detection. From asthma to renal disease, and neurological dysfunction to immunologic disorders, antibody arrays afford a bright future for new biomarkers discovery.
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Li J, Tian H, Jiang HJ, Han B. Interleukin-17 SNPs and serum levels increase ulcerative colitis risk: A meta-analysis. World J Gastroenterol 2014; 20:15899-15909. [PMID: 25400476 PMCID: PMC4229557 DOI: 10.3748/wjg.v20.i42.15899] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Revised: 04/05/2014] [Accepted: 06/13/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the associations of interleukin-17 (IL-17) genetic polymorphisms and serum levels with ulcerative colitis (UC) risk.
METHODS: Relevant articles were identified through a search of the following electronic databases, excluding language restriction: (1) the Cochrane Library Database (Issue 12, 2013); (2) Web of Science (1945-2013); (3) PubMed (1966-2013); (4) CINAHL (1982-2013); (5) EMBASE (1980-2013); and (6) the Chinese Biomedical Database (1982-2013). Meta-analysis was conducted using STATA 12.0 software. Crude odds ratios and standardized mean differences (SMDs) with corresponding 95% confidence intervals (CIs) were calculated. All of the included studies met all of the following five criteria: (1) the study design must be a clinical cohort or a case-control study; (2) the study must relate to the relationship between IL-17A/F genetic polymorphisms or serum IL-17 levels and the risk of UC; (3) all patients must meet the diagnostic criteria for UC; (4) the study must provide sufficient information about single nucleotide polymorphism frequencies or serum IL-17 levels; and (5) the genotype distribution of healthy controls must conform to the Hardy-Weinberg equilibrium (HWE). The Newcastle-Ottawa Scale (NOS) criteria were used to assess the methodological quality of the studies. The NOS criteria included three aspects: (1) subject selection: 0-4; (2) comparability of subjects: 0-2; and (3) clinical outcome: 0-3. NOS scores ranged from 0 to 9, with a score ≥ 7 indicating good quality.
RESULTS: Of the initial 177 articles, only 16 case-control studies met all of the inclusion criteria. A total of 1614 UC patients and 2863 healthy controls were included in this study. Fourteen studies were performed on Asian populations, and two studies on Caucasian populations. Results of the meta-analysis revealed that IL-17A and IL-17F genetic polymorphisms potentially increased UC risk under both allele and dominant models (P < 0.001 for all). The results also showed that UC patients had higher serum IL-17 levels than healthy controls (SMD = 5.95, 95%CI: 4.25-7.65, P < 0.001). Furthermore, serum IL-17 levels significantly correlated with the severity of UC (moderate vs mild: SMD = 2.59, 95%CI: 0.03-5.16, P < 0.05; severe vs mild: SMD = 7.09, 95%CI: 3.96-10.23, P < 0.001; severe vs moderate: SMD = 5.84, 95%CI: 5.09-6.59, P < 0.001). The NOS score was ≥ 5 for all of the included studies. Based on the sensitivity analysis, no single study influenced the overall pooled estimates. Neither the Begger’s funnel plots nor Egger’s test displayed strong statistical evidence for publication bias (IL-17A/F genetic polymorphisms: t = -2.60, P = 0.019; serum IL-17 levels: t = -1.54, P = 0.141).
CONCLUSION: The findings strongly suggest that IL-17A/F genetic polymorphisms and serum IL-17 levels contribute to the development and progression of UC.
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Coburn LA, Horst SN, Chaturvedi R, Brown CT, Allaman MM, Scull BP, Singh K, Piazuelo MB, Chitnavis MV, Hodges ME, Rosen MJ, Williams CS, Slaughter JC, Beaulieu DB, Schwartz DA, Wilson KT. High-throughput multi-analyte Luminex profiling implicates eotaxin-1 in ulcerative colitis. PLoS One 2013; 8:e82300. [PMID: 24367513 PMCID: PMC3867379 DOI: 10.1371/journal.pone.0082300] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2013] [Accepted: 11/01/2013] [Indexed: 12/12/2022] Open
Abstract
Accurate and high-throughput technologies are needed for identification of new therapeutic targets and for optimizing therapy in inflammatory bowel disease. Our aim was to assess multi-analyte protein-based assays of cytokines/chemokines using Luminex technology. We have reported that Luminex-based profiling was useful in assessing response to L-arginine therapy in the mouse model of dextran sulfate sodium colitis. Therefore, we studied prospectively collected samples from ulcerative colitis (UC) patients and control subjects. Serum, colon biopsies, and clinical information were obtained from subjects undergoing colonoscopy for evaluation of UC or for non-UC indications. In total, 38 normal controls and 137 UC cases completed the study. Histologic disease severity and the Mayo Disease Activity Index (DAI) were assessed. Serum and colonic tissue cytokine/chemokine profiles were measured by Luminex-based multiplex testing of 42 analytes. Only eotaxin-1 and G-CSF were increased in serum of patients with histologically active UC vs. controls. While 13 cytokines/chemokines were increased in active UC vs. controls in tissues, only eotaxin-1 was increased in all levels of active disease in both serum and tissue. In tissues, eotaxin-1 correlated with the DAI and with eosinophil counts. Increased eotaxin-1 levels were confirmed by real-time PCR. Tissue eotaxin-1 levels were also increased in experimental murine colitis induced by dextran sulfate sodium, oxazolone, or Citrobacter rodentium, but not in murine Helicobacter pylori infection. Our data implicate eotaxin-1 as an etiologic factor and therapeutic target in UC, and indicate that Luminex-based assays may be useful to assess IBD pathogenesis and to select patients for anti-cytokine/chemokine therapies.
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Affiliation(s)
- Lori A Coburn
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America ; Veterans Affairs Tennessee Valley Healthcare System, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Sara N Horst
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America ; Veterans Affairs Tennessee Valley Healthcare System, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Rupesh Chaturvedi
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Caroline T Brown
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Margaret M Allaman
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America ; Veterans Affairs Tennessee Valley Healthcare System, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Brooks P Scull
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Kshipra Singh
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - M Blanca Piazuelo
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Maithili V Chitnavis
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Mallary E Hodges
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Michael J Rosen
- Department of Pediatrics, Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Christopher S Williams
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America ; Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America ; Veterans Affairs Tennessee Valley Healthcare System, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - James C Slaughter
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Dawn B Beaulieu
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - David A Schwartz
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Keith T Wilson
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America ; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America ; Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America ; Veterans Affairs Tennessee Valley Healthcare System, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
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