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An C, Jiang C, Pei W, Li A, Wang M, Wang Y, Wang H, Zuo L. Intestinal epithelial cells in health and disease. Tissue Barriers 2025:2504744. [PMID: 40401816 DOI: 10.1080/21688370.2025.2504744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Revised: 04/23/2025] [Accepted: 05/06/2025] [Indexed: 05/23/2025] Open
Abstract
This comprehensive review delves into the pivotal role of intestinal epithelial cells in the context of various diseases. It provides an in-depth analysis of the diverse types and functions of these cells, explores the influence of multiple signaling pathways on their differentiation, and elucidates their critical roles in a spectrum of diseases. The significance of the gastrointestinal tract in maintaining overall health is extremely important and cannot be exaggerated. This complex and elongated organ acts as a crucial link between the internal and external environments, making it vulnerable to various harmful influences. Preserving the normal structure and function of the gut is essential for well-being. Intestinal epithelial cells serve as the primary defense mechanism within the gastrointestinal tract and play a crucial role in preventing harmful substances from infiltrating the body. As the main components of the digestive system, they not only participate in the absorption and secretion of nutrients and the maintenance of barrier function but also play a pivotal role in immune defense. Therefore, the health of intestinal epithelial cells is of vital importance for overall health.
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Affiliation(s)
- Chenchen An
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Science, Anhui Medical University, Hefei, China
- Innovation and Entrepreneurship Laboratory for college students, Anhui Medical University, Hefei, China
| | - Chonggui Jiang
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Science, Anhui Medical University, Hefei, China
- Innovation and Entrepreneurship Laboratory for college students, Anhui Medical University, Hefei, China
| | - Wangxiang Pei
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Science, Anhui Medical University, Hefei, China
- Innovation and Entrepreneurship Laboratory for college students, Anhui Medical University, Hefei, China
| | - Ao Li
- Innovation and Entrepreneurship Laboratory for college students, Anhui Medical University, Hefei, China
- The 904th Hospital of PLA, Medical School of Anhui Medical University, Wuxi, China
| | - Minghui Wang
- Innovation and Entrepreneurship Laboratory for college students, Anhui Medical University, Hefei, China
- The First College of Clinical Medicine, Anhui Medical University, Hefei, China
| | - Yufei Wang
- Innovation and Entrepreneurship Laboratory for college students, Anhui Medical University, Hefei, China
- The First College of Clinical Medicine, Anhui Medical University, Hefei, China
| | - Hua Wang
- Inflammation and Immune- Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Li Zuo
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Science, Anhui Medical University, Hefei, China
- Innovation and Entrepreneurship Laboratory for college students, Anhui Medical University, Hefei, China
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2
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Sparks J, Meggyes M, Makszin L, Jehn V, Lugosi H, Reglodi D, Szereday L. Effects of PACAP Deficiency on Immune Dysfunction and Peyer's Patch Integrity in Adult Mice. Int J Mol Sci 2024; 25:10676. [PMID: 39409005 PMCID: PMC11476422 DOI: 10.3390/ijms251910676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 09/20/2024] [Accepted: 09/26/2024] [Indexed: 10/20/2024] Open
Abstract
PACAP (pituitary adenylate cyclase activating polypeptide) is a widespread neuropeptide with cytoprotective and anti-inflammatory effects. It plays a role in innate and adaptive immunity, but data are limited about gut-associated lymphoid tissue. We aimed to reveal differences in Peyer's patches between wild-type (WT) and PACAP-deficient (KO) mice. Peyer's patch morphology from young (3-months-old) and aging (12-15-months-old) mice was examined, along with flow cytometry to assess immune cell populations, expression of checkpoint molecules (PD-1, PD-L1, TIM-3, Gal-9) and functional markers (CD69, granzyme B, perforin) in CD3+, CD4+, and CD8+ T cells. We found slight differences between aging, but not in young, WT, and KO mice. In WT mice, aging reduced CD8+ T cell numbers frequency and altered checkpoint molecule expression (higher TIM-3, granzyme B; lower Gal-9, CD69). CD4+ T cell frequency was higher with similar checkpoint alterations, indicating a regulatory shift. In PACAP KO mice, aging did not change cell population frequencies but led to higher TIM-3, granzyme B and lower PD-1, PD-L1, Gal-9, and CD69 expression in CD4+ and CD8+ T cells, with reduced overall T cell activity. Thus, PACAP deficiency impacts immune dysfunction by altering checkpoint molecules and T cell functionality, particularly in CD8+ T cells, suggesting complex immune responses by PACAP, highlighting its role in intestinal homeostasis and potential implications for inflammatory bowel diseases.
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MESH Headings
- Animals
- Pituitary Adenylate Cyclase-Activating Polypeptide/genetics
- Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism
- Pituitary Adenylate Cyclase-Activating Polypeptide/deficiency
- Mice
- Peyer's Patches/immunology
- Peyer's Patches/metabolism
- Mice, Knockout
- Antigens, Differentiation, T-Lymphocyte/metabolism
- Antigens, Differentiation, T-Lymphocyte/genetics
- CD8-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/metabolism
- Programmed Cell Death 1 Receptor/metabolism
- Programmed Cell Death 1 Receptor/genetics
- Granzymes/metabolism
- CD4-Positive T-Lymphocytes/immunology
- CD4-Positive T-Lymphocytes/metabolism
- Antigens, CD/metabolism
- Antigens, CD/genetics
- Lectins, C-Type/metabolism
- Lectins, C-Type/genetics
- Hepatitis A Virus Cellular Receptor 2/metabolism
- Hepatitis A Virus Cellular Receptor 2/genetics
- Aging/immunology
- B7-H1 Antigen/metabolism
- B7-H1 Antigen/genetics
- Mice, Inbred C57BL
- Perforin/metabolism
- Perforin/genetics
- Male
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Affiliation(s)
- Jason Sparks
- Department of Anatomy, HUN-REN-PTE PACAP Research Team, Centre for Neuroscience, Medical School, University of Pecs, 7624 Pecs, Hungary; (J.S.); (V.J.); (H.L.)
| | - Matyas Meggyes
- Department of Medical Microbiology and Immunology, Medical School, University of Pecs, 7624 Pecs, Hungary; (M.M.); (L.S.)
- Janos Szentagothai Research Center, 7624 Pecs, Hungary;
| | - Lilla Makszin
- Janos Szentagothai Research Center, 7624 Pecs, Hungary;
- Institute of Bioanalysis, Medical School, University of Pecs, 7624 Pecs, Hungary
| | - Viktoria Jehn
- Department of Anatomy, HUN-REN-PTE PACAP Research Team, Centre for Neuroscience, Medical School, University of Pecs, 7624 Pecs, Hungary; (J.S.); (V.J.); (H.L.)
| | - Hedvig Lugosi
- Department of Anatomy, HUN-REN-PTE PACAP Research Team, Centre for Neuroscience, Medical School, University of Pecs, 7624 Pecs, Hungary; (J.S.); (V.J.); (H.L.)
| | - Dora Reglodi
- Department of Anatomy, HUN-REN-PTE PACAP Research Team, Centre for Neuroscience, Medical School, University of Pecs, 7624 Pecs, Hungary; (J.S.); (V.J.); (H.L.)
| | - Laszlo Szereday
- Department of Medical Microbiology and Immunology, Medical School, University of Pecs, 7624 Pecs, Hungary; (M.M.); (L.S.)
- Janos Szentagothai Research Center, 7624 Pecs, Hungary;
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Asgari R, Bazzazan MA, Karimi Jirandehi A, Yousefzadeh S, Alaei M, Keshavarz Shahbaz S. Peyer's Patch: Possible target for modulating the Gut-Brain-Axis through microbiota. Cell Immunol 2024; 401-402:104844. [PMID: 38901288 DOI: 10.1016/j.cellimm.2024.104844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 06/05/2024] [Accepted: 06/17/2024] [Indexed: 06/22/2024]
Abstract
The gastrointestinal (GI) tract and the brain form bidirectional nervous, immune, and endocrine communications known as the gut-brain axis. Several factors can affect this axis; among them, various studies have focused on the microbiota and imply that alterations in microbiota combinations can influence both the brain and GI. Also, many studies have shown that the immune system has a vital role in varying gut microbiota combinations. In the current paper, we will review the multidirectional effects of gut microbiota, immune system, and nervous system on each other. Specifically, this review mainly focuses on the impact of Peyer's patches as a critical component of the gut immune system on the gut-brain axis through affecting the gut's microbial composition. In this way, some factors were discussed as proposed elements of missing gaps in this field.
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Affiliation(s)
- Reza Asgari
- Student Research Committee, Qazvin University of Medical Sciences, Qazvin, Iran; USERN Office, Qazvin University of Medical science, Qazvin, Iran
| | - Mohammad Amin Bazzazan
- Student Research Committee, Qazvin University of Medical Sciences, Qazvin, Iran; USERN Office, Qazvin University of Medical science, Qazvin, Iran
| | - Ashkan Karimi Jirandehi
- Student Research Committee, Qazvin University of Medical Sciences, Qazvin, Iran; USERN Office, Qazvin University of Medical science, Qazvin, Iran
| | - Salar Yousefzadeh
- Student Research Committee, Qazvin University of Medical Sciences, Qazvin, Iran; USERN Office, Qazvin University of Medical science, Qazvin, Iran
| | - Masood Alaei
- Student Research Committee, Qazvin University of Medical Sciences, Qazvin, Iran; USERN Office, Qazvin University of Medical science, Qazvin, Iran
| | - Sanaz Keshavarz Shahbaz
- USERN Office, Qazvin University of Medical science, Qazvin, Iran; Cellular and Molecular Research Center, Research Institute for prevention of Non- Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran.
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Műzes G, Bohusné Barta B, Sipos F. Colitis and Colorectal Carcinogenesis: The Focus on Isolated Lymphoid Follicles. Biomedicines 2022; 10:226. [PMID: 35203436 PMCID: PMC8869724 DOI: 10.3390/biomedicines10020226] [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: 12/06/2021] [Revised: 01/09/2022] [Accepted: 01/20/2022] [Indexed: 02/05/2023] Open
Abstract
Gut-associated lymphoid tissue is one of the most diverse and complex immune compartments in the human body. The subepithelial compartment of the gut consists of immune cells of innate and adaptive immunity, non-hematopoietic mesenchymal cells, and stem cells of different origins, and is organized into secondary (and even tertiary) lymphoid organs, such as Peyer's patches, cryptopatches, and isolated lymphoid follicles. The function of isolated lymphoid follicles is multifaceted; they play a role in the development and regeneration of the large intestine and the maintenance of (immune) homeostasis. Isolated lymphoid follicles are also extensively associated with the epithelium and its conventional and non-conventional immune cells; hence, they can also function as a starting point or maintainer of pathological processes such as inflammatory bowel diseases or colorectal carcinogenesis. These relationships can significantly affect both physiological and pathological processes of the intestines. We aim to provide an overview of the latest knowledge of isolated lymphoid follicles in colonic inflammation and colorectal carcinogenesis. Further studies of these lymphoid organs will likely lead to an extended understanding of how immune responses are initiated and controlled within the large intestine, along with the possibility of creating novel mucosal vaccinations and ways to treat inflammatory bowel disease or colorectal cancer.
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Affiliation(s)
| | | | - Ferenc Sipos
- Department of Internal Medicine and Hematology, Semmelweis University, 1088 Budapest, Hungary; (G.M.); (B.B.B.)
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5
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Chen G, Huo X, Luo X, Cheng Z, Zhang Y, Xu X. E-waste polycyclic aromatic hydrocarbon (PAH) exposure leads to child gut-mucosal inflammation and adaptive immune response. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:53267-53281. [PMID: 34031825 DOI: 10.1007/s11356-021-14492-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 05/17/2021] [Indexed: 02/07/2023]
Abstract
Polycyclic aromatic hydrocarbon (PAH) exposure alters immunological responses. Research concerning PAH exposure on intestinal immunity of children in electronic waste (e-waste) areas is scarce. The aim of this study was to evaluate the effects of polycyclic aromatic hydrocarbon (PAH) pollutants on intestinal mucosal immunity of children in e-waste areas. Results showed higher hydroxylated PAH (OH-PAH) concentrations in e-waste-exposed children, accompanied with higher sialyl Lewis A (SLA) level, absolute lymphocyte and monocyte counts, decreased of percentage of CD4+ T cells, and had a higher risk of diarrhea. OH-PAH concentrations were negative with child growth. 1-OHNap mediated through WBCs, along with 1-OHPyr, was correlated with an increase SLA concentration. 2-OHFlu, 1-OHPhe, 2-OHPhe, 1-OHPyr, and 6-OHChr were positively correlated with secretory immunoglobulin A (sIgA) concentration. Our results indicated that PAH pollutants caused inflammation, affected the intestinal epithelium, and led to transformation of microfold cell (M cell). M cells initiating mucosal immune responses and the subsequent increasing sIgA production might be an adaptive immune respond of children in the e-waste areas. To our knowledge, this is the first study of PAH exposure on children intestinal immunity in e-waste area, showing that PAH exposure plays a negative role in child growth and impairs the intestinal immune function.
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Affiliation(s)
- Guangcan Chen
- Laboratory of Environmental Medicine and Developmental Toxicology, Shantou University Medical College, 22 Xinling Rd, Shantou, 515041, Guangdong, China
| | - Xia Huo
- Laboratory of Environmental Medicine and Developmental Toxicology, Guangdong Key Laboratory of Environmental Pollution and Health, School of Environment, Jinan University, Guangzhou, 511443, Guangdong, China
| | - Xiuli Luo
- Laboratory of Environmental Medicine and Developmental Toxicology, Shantou University Medical College, 22 Xinling Rd, Shantou, 515041, Guangdong, China
| | - Zhiheng Cheng
- Laboratory of Environmental Medicine and Developmental Toxicology, Shantou University Medical College, 22 Xinling Rd, Shantou, 515041, Guangdong, China
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands
| | - Yuling Zhang
- Laboratory of Environmental Medicine and Developmental Toxicology, Shantou University Medical College, 22 Xinling Rd, Shantou, 515041, Guangdong, China
| | - Xijin Xu
- Laboratory of Environmental Medicine and Developmental Toxicology, Shantou University Medical College, 22 Xinling Rd, Shantou, 515041, Guangdong, China.
- Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, 515041, Guangdong, China.
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6
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Pandya P, Giram P, Bhole RP, Chang HI, Raut SY. Nanocarriers based oral lymphatic drug targeting: Strategic bioavailability enhancement approaches. J Drug Deliv Sci Technol 2021. [DOI: 10.1016/j.jddst.2021.102585] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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7
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Human gut-associated lymphoid tissues (GALT); diversity, structure, and function. Mucosal Immunol 2021; 14:793-802. [PMID: 33753873 DOI: 10.1038/s41385-021-00389-4] [Citation(s) in RCA: 217] [Impact Index Per Article: 54.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 02/05/2021] [Accepted: 02/06/2021] [Indexed: 02/07/2023]
Abstract
Gut-associated lymphoid tissues (GALT) are the key antigen sampling and adaptive immune inductive sites within the intestinal wall. Human GALT includes the multi-follicular Peyer's patches of the ileum, the vermiform appendix, and the numerous isolated lymphoid follicles (ILF) which are distributed along the length of the intestine. Our current understanding of GALT diversity and function derives primarily from studies in mice, and the relevance of many of these findings to human GALT remains unclear. Here we review our current understanding of human GALT diversity, structure, and composition as well as their potential for regulating intestinal immune responses during homeostasis and inflammatory bowel disease (IBD). Finally, we outline some key remaining questions regarding human GALT, the answers to which will advance our understanding of intestinal immune responses and provide potential opportunities to improve the treatment of intestinal diseases.
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8
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Jørgensen PB, Fenton TM, Mörbe UM, Riis LB, Jakobsen HL, Nielsen OH, Agace WW. Identification, isolation and analysis of human gut-associated lymphoid tissues. Nat Protoc 2021; 16:2051-2067. [PMID: 33619391 DOI: 10.1038/s41596-020-00482-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Accepted: 12/09/2020] [Indexed: 02/06/2023]
Abstract
Gut-associated lymphoid tissues (GALTs) comprise key intestinal immune inductive sites, including the Peyer's patches of the small intestine and different types of isolated lymphoid follicle (ILF) found along the length of the gut. Our understanding of human GALT is limited due to a lack of protocols for their isolation. Here we describe a technique that, uniquely among intestinal cell isolation protocols, allows identification and isolation of all human GALT, as well as GALT-free intestinal lamina propria (LP). The technique involves the mechanical separation of intestinal mucosa from the submucosa, allowing the identification and isolation of submucosal ILF (SM-ILF), LP-embedded mucosal ILF (M-ILF) and LP free of contaminating lymphoid tissue. Individual SM-ILF, M-ILF and Peyer's patch follicles can be subsequently digested for downstream cellular and molecular characterization. The technique, which takes 4-10 h, will be useful for researchers interested in intestinal immune development and function in health and disease.
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Affiliation(s)
- Peter B Jørgensen
- Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Thomas M Fenton
- Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Urs M Mörbe
- Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Lene B Riis
- Department of Pathology, Herlev Hospital, University of Copenhagen, Herlev, Denmark
| | - Henrik L Jakobsen
- Department of Gastroenterology, Surgical Section, Herlev Hospital, University of Copenhagen, Herlev, Denmark
| | - Ole H Nielsen
- Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Herlev, Denmark
| | - William W Agace
- Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark. .,Immunology Section, Lund University, Lund, Sweden.
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Derer S, Brethack AK, Pietsch C, Jendrek ST, Nitzsche T, Bokemeyer A, Hov JR, Schäffler H, Bettenworth D, Grassl GA, Sina C. Inflammatory Bowel Disease-associated GP2 Autoantibodies Inhibit Mucosal Immune Response to Adherent-invasive Bacteria. Inflamm Bowel Dis 2020; 26:1856-1868. [PMID: 32304568 DOI: 10.1093/ibd/izaa069] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Indexed: 02/06/2023]
Abstract
Adherent-invasive Escherichia coli have been suggested to play a pivotal role within the pathophysiology of inflammatory bowel disease (IBD). Autoantibodies against distinct splicing variants of glycoprotein 2 (GP2), an intestinal receptor of the bacterial adhesin FimH, frequently occur in IBD patients. Hence, we aimed to functionally characterize GP2-directed autoantibodies as a putative part of IBD's pathophysiology. Ex vivo, GP2-splicing variant 4 (GP2#4) but not variant 2 was expressed on intestinal M or L cells with elevated expression patterns in IBD patients. The GP2#4 expression was induced in vitro by tumor necrosis factor (TNF)-α. The IBD-associated GP2 autoantibodies inhibited FimH binding to GP2#4 and were decreased in anti-TNFα-treated Crohn's disease patients with ileocolonic disease manifestation. In vivo, mice immunized against GP2 before infection with adherent-invasive bacteria displayed exacerbated intestinal inflammation. In summary, autoimmunity against intestinal expressed GP2#4 results in enhanced attachment of flagellated bacteria to the intestinal epithelium and thereby may drive IBD's pathophysiology.
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Affiliation(s)
- Stefanie Derer
- Institute of Nutritional Medicine, Molecular Gastroenterology, University Hospital Schleswig- Holstein, Campus Lübeck, Lübeck, Germany
| | - Ann-Kathrin Brethack
- Institute of Nutritional Medicine, Molecular Gastroenterology, University Hospital Schleswig- Holstein, Campus Lübeck, Lübeck, Germany
| | - Carlotta Pietsch
- Institute of Nutritional Medicine, Molecular Gastroenterology, University Hospital Schleswig- Holstein, Campus Lübeck, Lübeck, Germany
| | - Sebastian T Jendrek
- Department of Rheumatology, University of Schleswig-Holstein, Lübeck, Germany
| | - Thomas Nitzsche
- Institute of Nutritional Medicine, Molecular Gastroenterology, University Hospital Schleswig- Holstein, Campus Lübeck, Lübeck, Germany.,Institute for Experimental Immunology, Euroimmun Corp., Lübeck, Germany
| | - Arne Bokemeyer
- Department of Medicine B, Gastroenterology and Hepatology, University of Münster, Münster, Germany
| | - Johannes R Hov
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Norwegian PSC Research Center, Section of Gastroenterology and Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway
| | - Holger Schäffler
- Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, Rostock, Germany
| | - Dominik Bettenworth
- Department of Medicine B, Gastroenterology and Hepatology, University of Münster, Münster, Germany
| | - Guntram A Grassl
- Institute of Medical Microbiology and Hospital Epidemiology and German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover Medical School, Hannover, Germany
| | - Christian Sina
- Institute of Nutritional Medicine, Molecular Gastroenterology, University Hospital Schleswig- Holstein, Campus Lübeck, Lübeck, Germany.,1st Department of Medicine, Section of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
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Differential miRNA-Gene Expression in M Cells in Response to Crohn's Disease-Associated AIEC. Microorganisms 2020; 8:microorganisms8081205. [PMID: 32784656 PMCID: PMC7466023 DOI: 10.3390/microorganisms8081205] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 08/04/2020] [Accepted: 08/05/2020] [Indexed: 12/21/2022] Open
Abstract
Adherent-invasive Escherichia coli (AIEC), which abnormally colonize the ileal mucosa of Crohn’s disease (CD) patients, are able to invade intestinal epithelial cells (IECs) and translocate through M cells overlying Peyer’s patches. The levels of microRNA (miRNA) and gene expression in IECs and M cells upon AIEC infection have not been investigated. Here, we used human intestinal epithelial Caco-2 monolayers and an in vitro M-cell model of AIEC translocation to analyze comprehensive miRNA and gene profiling under basal condition and upon infection with the reference AIEC LF82 strain. Our results showed that AIEC LF82 translocated through M cells but not Caco-2 monolayers. Both differential gene expression and miRNA profile in M cells compared to Caco-2 cells were obtained. In addition, AIEC infection induces changes in gene and miRNA profiles in both Caco-2 and M cells. In silico analysis showed that certain genes dysregulated upon AIEC infection were potential targets of AIEC-dysregulated miRNAs, suggesting a miRNA-mediated regulation of gene expression during AIEC infection in Caco-2, as well as M cells. This study facilitates the discovery of M cell-specific and AIEC response-specific gene-miRNA signature and enhances the molecular understanding of M cell biology under basal condition and in response to infection with CD-associated AIEC.
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Triantafillidis JK, Thomaidis T, Papalois A. Terminal Ileitis due to Yersinia Infection: An Underdiagnosed Situation. BIOMED RESEARCH INTERNATIONAL 2020; 2020:1240626. [PMID: 32566652 PMCID: PMC7273408 DOI: 10.1155/2020/1240626] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 04/29/2020] [Indexed: 01/08/2023]
Abstract
Endoscopy is currently the gold standard for the diagnosis of inflammatory bowel disease (IBD). The presence of macroscopic lesions along with the microscopic detection of inflammatory infiltration in the terminal ileum often leads the gastroenterologist to the diagnosis of Crohn's disease (CD). However, some of these cases could be, in fact, an infection caused by Yersinia spp., accompanied or not with CD, which could be easily diagnosed with the identification of serum antibodies against Yersinia outer protein antigens (YOP antigens). Since Yersiniosis is considered to be an uncommon situation, food and water are not usually checked for the possibility of contamination by Yersinia. Therefore, it is reasonable to assume that the true prevalence of Yersinia infection in patients with terminal ileitis is probably underestimated. In this article, we review the most important data regarding the various aspects of Yersinia infection with special focus on its pathophysiology and diagnosis. We recommend testing for serum antibodies against YOP antigens in all patients with an endoscopic and histological image of terminal ileitis in order to identify Yersiniosis in conjunction or not with terminal ileum CD.
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Affiliation(s)
| | - Thomas Thomaidis
- Universitätsmedizin Mainz, Germany, “Hygeia” Hospital, Athens, Greece
| | - Apostolos Papalois
- Experimental, Educational, and Research Center ELPEN, Athens, Greece
- European University Cyprus, School of Medicine, Nicosia, Cyprus
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12
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Dhaliwal J, Walters TD, Mack DR, Huynh HQ, Jacobson K, Otley AR, Debruyn J, El-Matary W, Deslandres C, Sherlock ME, Critch JN, Bax K, Seidman E, Jantchou P, Ricciuto A, Rashid M, Muise AM, Wine E, Carroll M, Lawrence S, Van Limbergen J, Benchimol EI, Church P, Griffiths AM. Phenotypic Variation in Paediatric Inflammatory Bowel Disease by Age: A Multicentre Prospective Inception Cohort Study of the Canadian Children IBD Network. J Crohns Colitis 2020; 14:445-454. [PMID: 31136648 PMCID: PMC7242003 DOI: 10.1093/ecco-jcc/jjz106] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS Incidence of paediatric inflammatory bowel disease [IBD] in Canada is among the highest worldwide, and age of onset may be decreasing. In a multicentre nationwide inception cohort study, we examined variation in phenotype of IBD throughout the paediatric age spectrum. METHODS Children aged ≥2 years [y] and <17y [A1 age at diagnosis], with new onset IBD, were systematically evaluated at sites of the Canadian Children IBD Network. Prospectively recorded phenotypic data were compared between age groups. RESULTS Among 1092 children (70% Caucasian; 64% Crohn's disease [CD], 36% ulcerative colitis/inflammatory bowel disease unclassified [UC/IBD-U]; median age 13 y, interquartile range [IQR] 11-15 y), 210 [19%] were diagnosed before the age of age 10 y [Paris A1a] and 43 [4%] before age 6 y (very-early-onset [VEO-IBD]). CD was less common in younger children [42%, 56%, 66%, respectively, of VEO-IBD, A1a; A1b]. Colon-only IBD [UC/IBDU or CD-colon] was present in 81% of VEO-IBD and 65% of A1a; ileal disease increased progressively, reaching plateau at age 10 y. CD location was ileocolonic [L3] in 53% overall. Ileitis [L1] increased with age [6% of VEO-IBD; 13% of A1a; 21% of A1b], as did stricturing/penetrating CD [4% of A1a; 11% of A1b]. At all ages UC was extensive [E3/E4] in >85%, and disease activity moderate to severe according to Physician's Global Assessment [PGA] and weighted Paediatric Crohn's Disease Activity Index/Paediatric Ulcerative Colitis Activity Index [wPCDAI/PUCAI] in >70%. Heights were modestly reduced in CD [mean height z score -0.30 ± 1.23], but normal in UC/IBD-U. CONCLUSIONS Paris classification of age at diagnosis is supported by age-related increases in ileal disease until age 10 years. Other phenotypic features, including severity, are similar across all ages. Linear growth is less impaired in CD than in historical cohorts, reflecting earlier diagnosis.
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Affiliation(s)
- J Dhaliwal
- SickKids Hospital, University of Toronto, Toronto, ON, Canada
| | - T D Walters
- SickKids Hospital, University of Toronto, Toronto, ON, Canada
| | - D R Mack
- Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada
| | - H Q Huynh
- Stollery Children’s Hospital, University of Alberta, Edmonton, AB, Canada
| | - K Jacobson
- B.C. Children’s Hospital, University of British Columbia, Vancouver, BC, Canada
| | - A R Otley
- IWK Health Centre, Dalhousie University, Halifax, NS, Canada
| | - J Debruyn
- Alberta Children’s Hospital, University of Calgary, Calgary, AB, Canada
| | - W El-Matary
- Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada
| | - C Deslandres
- CHU Sainte-Justine, Universite de Montreal, Montreal, QC, Canada
| | - M E Sherlock
- McMaster Children’s Hospital, McMaster University, Hamilton, ON, Canada
| | - J N Critch
- Janeway Children’s Health and Rehabilitation Centre, Memorial University, St John’s, NL, Canada
| | - K Bax
- Children’s Hospital of Western Ontario, University of Western Ontario, London, ON, Canada
| | - E Seidman
- Montreal Children’s Hospital, McGill University Faculty of Medicine, Montreal, QC, Canada
| | - P Jantchou
- CHU Sainte-Justine, Universite de Montreal, Montreal, QC, Canada
| | - A Ricciuto
- SickKids Hospital, University of Toronto, Toronto, ON, Canada
| | - M Rashid
- IWK Health Centre, Dalhousie University, Halifax, NS, Canada
| | - A M Muise
- SickKids Hospital, University of Toronto, Toronto, ON, Canada
| | - E Wine
- Stollery Children’s Hospital, University of Alberta, Edmonton, AB, Canada
| | - M Carroll
- Stollery Children’s Hospital, University of Alberta, Edmonton, AB, Canada
| | - S Lawrence
- B.C. Children’s Hospital, University of British Columbia, Vancouver, BC, Canada
| | - J Van Limbergen
- IWK Health Centre, Dalhousie University, Halifax, NS, Canada
| | - E I Benchimol
- Montreal Children’s Hospital, McGill University Faculty of Medicine, Montreal, QC, Canada
| | - P Church
- SickKids Hospital, University of Toronto, Toronto, ON, Canada
| | - A M Griffiths
- SickKids Hospital, University of Toronto, Toronto, ON, Canada
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13
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Camprubí-Font C, Martinez-Medina M. Why the discovery of adherent-invasive Escherichia coli molecular markers is so challenging? World J Biol Chem 2020; 11:1-13. [PMID: 32405343 PMCID: PMC7205867 DOI: 10.4331/wjbc.v11.i1.1] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 03/18/2020] [Accepted: 03/31/2020] [Indexed: 02/05/2023] Open
Abstract
Adherent-invasive Escherichia coli (AIEC) strains have been extensively related to Crohn’s disease (CD) etiopathogenesis. Higher AIEC prevalence in CD patients versus controls has been reported, and its mechanisms of pathogenicity have been linked to CD physiopathology. In CD, the therapeutic armamentarium remains limited and non-curative; hence, the necessity to better understand AIEC as a putative instigator or propagator of the disease is certain. Nonetheless, AIEC identification is currently challenging because it relies on phenotypic assays based on infected cell cultures which are highly time-consuming, laborious and non-standardizable. To address this issue, AIEC molecular mechanisms and virulence genes have been studied; however, a specific and widely distributed genetic AIEC marker is still missing. The finding of molecular tools to easily identify AIEC could be useful in the identification of AIEC carriers who could profit from personalized treatment. Also, it would significantly promote AIEC epidemiological studies. Here, we reviewed the existing data regarding AIEC genetics and presented those molecular markers that could assist with AIEC identification. Finally, we highlighted the problems behind the discovery of exclusive AIEC biomarkers and proposed strategies to facilitate the search of AIEC signature sequences.
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Affiliation(s)
- Carla Camprubí-Font
- Laboratory of Molecular Microbiology, Department of Biology, University of Girona, Girona 17003, Spain
| | - Margarita Martinez-Medina
- Laboratory of Molecular Microbiology, Department of Biology, University of Girona, Girona 17003, Spain
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14
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Fenton TM, Jørgensen PB, Niss K, Rubin SJS, Mörbe UM, Riis LB, Da Silva C, Plumb A, Vandamme J, Jakobsen HL, Brunak S, Habtezion A, Nielsen OH, Johansson-Lindbom B, Agace WW. Immune Profiling of Human Gut-Associated Lymphoid Tissue Identifies a Role for Isolated Lymphoid Follicles in Priming of Region-Specific Immunity. Immunity 2020; 52:557-570.e6. [PMID: 32160523 PMCID: PMC7155934 DOI: 10.1016/j.immuni.2020.02.001] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 01/09/2020] [Accepted: 02/13/2020] [Indexed: 12/19/2022]
Abstract
The intestine contains some of the most diverse and complex immune compartments in the body. Here we describe a method for isolating human gut-associated lymphoid tissues (GALTs) that allows unprecedented profiling of the adaptive immune system in submucosal and mucosal isolated lymphoid follicles (SM-ILFs and M-ILFs, respectively) as well as in GALT-free intestinal lamina propria (LP). SM-ILF and M-ILF showed distinct patterns of distribution along the length of the intestine, were linked to the systemic circulation through MAdCAM-1+ high endothelial venules and efferent lymphatics, and had immune profiles consistent with immune-inductive sites. IgA sequencing analysis indicated that human ILFs are sites where intestinal adaptive immune responses are initiated in an anatomically restricted manner. Our findings position ILFs as key inductive hubs for regional immunity in the human intestine, and the methods presented will allow future assessment of these compartments in health and disease.
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Affiliation(s)
- Thomas M Fenton
- Mucosal Immunology Group, Department of Health Technology, Technical University of Denmark, Kemitorvet, 2800 Kgs. Lyngby, Denmark.
| | - Peter B Jørgensen
- Mucosal Immunology Group, Department of Health Technology, Technical University of Denmark, Kemitorvet, 2800 Kgs. Lyngby, Denmark
| | - Kristoffer Niss
- Translational Disease Systems Biology, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Samuel J S Rubin
- Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Urs M Mörbe
- Immunology Section, Lund University, BMC D14, 221-84 Lund, Sweden
| | - Lene B Riis
- Department of Pathology, Herlev Hospital, University of Copenhagen, 2730 Herlev, Denmark
| | - Clément Da Silva
- Immunology Section, Lund University, BMC D14, 221-84 Lund, Sweden
| | - Adam Plumb
- Immunological Memory Group, Department of Health Technology, Technical University of Denmark, Kemitorvet, 2800 Kgs. Lyngby, Denmark
| | - Julien Vandamme
- Mucosal Immunology Group, Department of Health Technology, Technical University of Denmark, Kemitorvet, 2800 Kgs. Lyngby, Denmark
| | - Henrik L Jakobsen
- Department of Gastroenterology, Surgical Section, Herlev Hospital, University of Copenhagen, 2730 Herlev, Denmark
| | - Søren Brunak
- Translational Disease Systems Biology, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Aida Habtezion
- Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Ole H Nielsen
- Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, 2730 Herlev, Denmark
| | - Bengt Johansson-Lindbom
- Immunology Section, Lund University, BMC D14, 221-84 Lund, Sweden; Immunological Memory Group, Department of Health Technology, Technical University of Denmark, Kemitorvet, 2800 Kgs. Lyngby, Denmark
| | - William W Agace
- Mucosal Immunology Group, Department of Health Technology, Technical University of Denmark, Kemitorvet, 2800 Kgs. Lyngby, Denmark; Immunology Section, Lund University, BMC D14, 221-84 Lund, Sweden.
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15
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Lopens S, Krawczyk M, Papp M, Milkiewicz P, Schierack P, Liu Y, Wunsch E, Conrad K, Roggenbuck D. The search for the Holy Grail: autoantigenic targets in primary sclerosing cholangitis associated with disease phenotype and neoplasia. AUTO- IMMUNITY HIGHLIGHTS 2020; 11:6. [PMID: 32178720 PMCID: PMC7077156 DOI: 10.1186/s13317-020-00129-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 03/06/2020] [Indexed: 12/22/2022]
Abstract
Unlike in other autoimmune liver diseases such as autoimmune hepatitis and primary biliary cholangitis, the role and nature of autoantigenic targets in primary sclerosing cholangitis (PSC), a progressive, chronic, immune-mediated, life threatening, genetically predisposed, cholestatic liver illness, is poorly elucidated. Although anti-neutrophil cytoplasmic antibodies (ANCA) have been associated with the occurrence of PSC, their corresponding targets have not yet been identified entirely. Genome-wide association studies revealed a significant number of immune-related and even disease-modifying susceptibility loci for PSC. However, these loci did not allow discerning a clear autoimmune pattern nor do the therapy options and the male gender preponderance in PSC support a pathogenic role of autoimmune responses. Nevertheless, PSC is characterized by the co-occurrence of inflammatory bowel diseases (IBD) demonstrating autoimmune responses. The identification of novel autoantigenic targets in IBD such as the major zymogen granule membrane glycoprotein 2 (GP2) or the appearance of proteinase 3 (PR3) autoantibodies (autoAbs) have refocused the interest on a putative association of loss of tolerance with the IBD phenotype and consequently with the PSC phenotype. Not surprisingly, the report of an association between GP2 IgA autoAbs and disease severity in patients with PSC gave a new impetus to autoAb research for autoimmune liver diseases. It might usher in a new era of serological research in this field. The mucosal loss of tolerance against the microbiota-sensing GP2 modulating innate and adaptive intestinal immunity and its putative role in the pathogenesis of PSC will be elaborated in this review. Furthermore, other potential PSC-related autoantigenic targets such as the neutrophil PR3 will be discussed. GP2 IgA may represent a group of new pathogenic antibodies, which share characteristics of both type 2 and 3 of antibody-mediated hypersensitive reactions according to Coombs and Gell.
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Affiliation(s)
| | - Marcin Krawczyk
- Department of Medicine II, Saarland University Hospital, Saarland University, Homburg/Saar, Germany
- Liver and Internal Medicine Unit, Medical University of Warsaw, Warsaw, Poland
| | - Maria Papp
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Piotr Milkiewicz
- Liver and Internal Medicine Unit, Medical University of Warsaw, Warsaw, Poland
| | - Peter Schierack
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
| | - Yudong Liu
- Department of Laboratory Medicine, Peking University People's Hospital, Beijing, China
| | - Ewa Wunsch
- Translational Medicine Group, Pomeranian Medical University, Szczecin, Poland
| | - Karsten Conrad
- Institute of Immunology, Technical University Dresden, Dresden, Germany
| | - Dirk Roggenbuck
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany.
- Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology Cottbus-Senftenberg, the Brandenburg Medical School Theodor Fontane and the University of Potsdam, Universitätsplatz 1, 01968, Senftenberg, Germany.
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16
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Qi D, Shi W, Black AR, Kuss MA, Pang X, He Y, Liu B, Duan B. Repair and regeneration of small intestine: A review of current engineering approaches. Biomaterials 2020; 240:119832. [PMID: 32113114 DOI: 10.1016/j.biomaterials.2020.119832] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 01/21/2020] [Accepted: 01/25/2020] [Indexed: 02/06/2023]
Abstract
The small intestine (SI) is difficult to regenerate or reconstruct due to its complex structure and functions. Recent developments in stem cell research, advanced engineering technologies, and regenerative medicine strategies bring new hope of solving clinical problems of the SI. This review will first summarize the structure, function, development, cell types, and matrix components of the SI. Then, the major cell sources for SI regeneration are introduced, and state-of-the-art biofabrication technologies for generating engineered SI tissues or models are overviewed. Furthermore, in vitro models and in vivo transplantation, based on intestinal organoids and tissue engineering, are highlighted. Finally, current challenges and future perspectives are discussed to help direct future applications for SI repair and regeneration.
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Affiliation(s)
- Dianjun Qi
- Department of General Practice, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China; Mary & Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE, USA; Division of Cardiology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Wen Shi
- Mary & Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE, USA; Division of Cardiology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Adrian R Black
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Mitchell A Kuss
- Mary & Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE, USA; Division of Cardiology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Xining Pang
- Department of General Practice, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China; Department of Academician Expert Workstation and Liaoning Province Human Amniotic Membrane Dressings Stem Cells and Regenerative Medicine Engineering Research Center, Shenyang Amnion Biological Engineering Technology Research and Development Center Co., Ltd, Shenyang, Liaoning, China
| | - Yini He
- Department of General Practice, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Bing Liu
- Department of Anorectal Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Bin Duan
- Mary & Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE, USA; Division of Cardiology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA; Department of Surgery, University of Nebraska Medical Center, Omaha, NE, USA; Department of Mechanical and Materials Engineering, University of Nebraska-Lincoln, Lincoln, NE, USA.
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17
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Apine I, Baduna M, Pitura R, Pokrotnieks J, Krumina G. The Influence of Bowel Preparation on ADC Measurements: Comparison between Conventional DWI and DWIBS Sequences. Medicina (B Aires) 2019; 55:medicina55070394. [PMID: 31330916 PMCID: PMC6681204 DOI: 10.3390/medicina55070394] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 07/10/2019] [Accepted: 07/18/2019] [Indexed: 11/16/2022] Open
Abstract
Background and objectives: The aim of the study was to assess whether there were differences between apparent diffusion coefficient (ADC) values of diffusion-weighted imaging (DWI) and diffusion-weighted imaging with background body signal suppression (DWIBS) sequences in non-prepared and prepared bowels before and after preparation with an enteric hyperosmolar agent, to assess whether ADC measurements have the potential to avoid bowel preparation and whether ADC-DWIBS has advantages over ADC-DWI. Materials and Methods: 106 adult patients without evidence of inflammatory bowel disease (IBD) underwent magnetic resonance (MR) enterography before and after bowel preparation. ADC-DWI and ADC-DWIBS values were measured in the intestinal and colonic walls demonstrating high signal intensity (SI) at DWI tracking images of b = 800 s/mm2 before and after preparation. Results: There were significant difference (p < 0.0001) in both ADC-DWI and ADC-DWIBS results between non-prepared and prepared jejunum for DWI being 1.09 × 10−3 mm2/s and 1.76 × 10−3 mm2/s, respectively, and for DWIBS being 0.91 × 10−3 mm2/s and 1.75 × 10−3 mm2/s, respectively. Both ADC-DWI and DWIBS also showed significant difference between non-prepared and prepared colon (p < 0.0001), with DWI values 1.41 × 10−3 mm2/s and 2.13 × 10−3 mm2/s, and DWIBS—1.01 × 10−3 mm2/s and 2.04 × 10−3 mm2/s, respectively. No significant difference between ADC-DWI and ADC-DWIBS was found in prepared jejunum (p = 0.84) and prepared colon (p = 0.58), whereas a significant difference was found in non-prepared jejunum and non-prepared colon (p = 0.0001 in both samples). Conclusions: ADC between DWI and DWIBS does not differ in prepared bowel walls but demonstrates a difference in non-prepared bowel. ADC in non-prepared bowel is lower than in prepared bowel and possible overlap with the ADC range of IBD is possible in non-prepared bowel. ADC-DWIBS has no advantage over ADC-DWI in regard to IBD assessment.
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Affiliation(s)
- Ilze Apine
- Children Clinical University Hospital, LV-1004 Riga, Latvia.
- Department of Diagnostic Radiology, Riga Stradin's University, LV-1038 Riga, Latvia.
| | - Monta Baduna
- Department of Diagnostic Radiology, Riga Stradin's University, LV-1038 Riga, Latvia
| | - Reinis Pitura
- Faculty of Medicine, Riga Stradin's University, LV-1007 Riga, Latvia
| | - Juris Pokrotnieks
- Department of Internal Diseases, Riga Stradin's University, LV-1038 Riga, Latvia
| | - Gaida Krumina
- Department of Diagnostic Radiology, Riga Stradin's University, LV-1038 Riga, Latvia
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18
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Mirsepasi-Lauridsen HC, Vallance BA, Krogfelt KA, Petersen AM. Escherichia coli Pathobionts Associated with Inflammatory Bowel Disease. Clin Microbiol Rev 2019; 32:e00060-18. [PMID: 30700431 PMCID: PMC6431131 DOI: 10.1128/cmr.00060-18] [Citation(s) in RCA: 226] [Impact Index Per Article: 37.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Gut bacteria play a key role in initiating and maintaining the inflammatory process in the gut tissues of inflammatory bowel disease (IBD) patients, by supplying antigens or other stimulatory factors that trigger immune cell activation. Changes in the composition of the intestinal microbiota in IBD patients compared to that in healthy controls and a reduced diversity of intestinal microbial species are linked to the pathogenesis of IBD. Adherent invasive Escherichia coli (AIEC) has been linked to Crohn's disease (CD) patients, while diffusely adherent E. coli (DAEC) has been associated with ulcerative colitis (UC). Bacteriological analysis of intestinal biopsy specimens and fecal samples from IBD patients shows an increased number of E. coli strains belonging to the B2 phylogenetic group, which are typically known as extraintestinal pathogenic E. coli (ExPEC). Results from studies of both cell cultures and animal models reveal pathogenic features of these E. coli pathobionts, which may link them to IBD pathogenesis. This suggests that IBD-associated E. coli strains play a facilitative role during IBD flares. In this review, we explain IBD-associated E. coli and its role in IBD pathogenesis.
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Affiliation(s)
| | - Bruce Andrew Vallance
- Division of Gastroenterology, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
| | - Karen Angeliki Krogfelt
- Department of Bacteria, Parasites and Fungi, Statens Serum Institut, Copenhagen, Denmark
- Department of Viral and Microbiological Diagnostics, Statens Serum Institut, Copenhagen, Denmark
| | - Andreas Munk Petersen
- Department of Gastroenterology, Hvidovre University Hospital, Copenhagen, Denmark
- Department of Clinical Microbiology, Hvidovre University Hospital, Copenhagen, Denmark
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19
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Managuli RS, Raut SY, Reddy MS, Mutalik S. Targeting the intestinal lymphatic system: a versatile path for enhanced oral bioavailability of drugs. Expert Opin Drug Deliv 2018; 15:787-804. [PMID: 30025212 DOI: 10.1080/17425247.2018.1503249] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION The major challenge of first pass metabolism in oral drug delivery can be surmounted by directing delivery toward intestinal lymphatic system (ILS). ILS circumvents the liver and transports drug directly into systemic circulation via thoracic duct. Lipid and polymeric nanoparticles are transported into ILS through lacteal and Peyer's patches. Moreover, surface modification of nanoparticles with ligand which is specific for Peyer's patches enhances the uptake of drugs into ILS. Bioavailability enhancement by lymphatic uptake is an advantageous approach adopted by scientists today. Therefore, it is important to understand clear insight of ILS in targeted drug delivery and challenges involved in it. AREAS COVERED Current review includes an overview of ILS, factors governing lymphatic transport of nanoparticles and absorption mechanism of lipid and polymeric nanoparticles into ILS. Various ligands used to target Peyer's patch and their conjugation strategies to nanoparticles are explained in detail. In vitro and in vivo models used to assess intestinal lymphatic transport of molecules are discussed further. EXPERT OPINION Although ILS offers a versatile pathway for nanotechnology based targeted drug delivery, extensive investigations on validation of the lymphatic transport models and on the strategies for gastric protection of targeted nanocarriers have to be perceived in for excellent performance of ILS in oral drug delivery.
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Affiliation(s)
- Renuka Suresh Managuli
- a Department of Pharmaceutics , Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education , Manipal Karnataka State , India
| | - Sushil Yadaorao Raut
- a Department of Pharmaceutics , Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education , Manipal Karnataka State , India
| | - Meka Sreenivasa Reddy
- a Department of Pharmaceutics , Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education , Manipal Karnataka State , India
| | - Srinivas Mutalik
- a Department of Pharmaceutics , Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education , Manipal Karnataka State , India
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20
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Palmela C, Chevarin C, Xu Z, Torres J, Sevrin G, Hirten R, Barnich N, Ng SC, Colombel JF. Adherent-invasive Escherichia coli in inflammatory bowel disease. Gut 2018; 67:574-587. [PMID: 29141957 DOI: 10.1136/gutjnl-2017-314903] [Citation(s) in RCA: 352] [Impact Index Per Article: 50.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Revised: 09/20/2017] [Accepted: 10/28/2017] [Indexed: 02/06/2023]
Abstract
Intestinal microbiome dysbiosis has been consistently described in patients with IBD. In the last decades, Escherichia coli, and the adherent-invasive E coli (AIEC) pathotype in particular, has been implicated in the pathogenesis of IBD. Since the discovery of AIEC, two decades ago, progress has been made in unravelling these bacteria characteristics and its interaction with the gut immune system. The mechanisms of adhesion of AIEC to intestinal epithelial cells (via FimH and cell adhesion molecule 6) and its ability to escape autophagy when inside macrophages are reviewed here. We also explore the existing data on the prevalence of AIEC in patients with Crohn's disease and UC, and the association between the presence of AIEC and disease location, activity and postoperative recurrence. Finally, we highlight potential therapeutic strategies targeting AIEC colonisation of gut mucosa, including the use of phage therapy, bacteriocins and antiadhesive molecules. These strategies may open new avenues for the prevention and treatment of IBD in the future.
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Affiliation(s)
- Carolina Palmela
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.,Division of Gastroenterology, Hospital Beatriz Ângelo, Loures, Portugal
| | - Caroline Chevarin
- Université Clermont Auvergne, Inserm U1071, USC-INRA 2018, M2iSH, CRNH Auvergne, F-63000 Clermont-Ferrand, France
| | - Zhilu Xu
- Department of Medicine and Therapeutics, Institute of Digestive Diseases, LKS Institute of Health Science, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Joana Torres
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.,Division of Gastroenterology, Hospital Beatriz Ângelo, Loures, Portugal
| | - Gwladys Sevrin
- Université Clermont Auvergne, Inserm U1071, USC-INRA 2018, M2iSH, CRNH Auvergne, F-63000 Clermont-Ferrand, France
| | - Robert Hirten
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
| | - Nicolas Barnich
- Université Clermont Auvergne, Inserm U1071, USC-INRA 2018, M2iSH, CRNH Auvergne, F-63000 Clermont-Ferrand, France
| | - Siew C Ng
- Department of Medicine and Therapeutics, Institute of Digestive Diseases, LKS Institute of Health Science, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Jean-Frederic Colombel
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
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21
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Zhang L, Song J, Bai T, Qian W, Hou XH. Stress induces more serious barrier dysfunction in follicle-associated epithelium than villus epithelium involving mast cells and protease-activated receptor-2. Sci Rep 2017; 7:4950. [PMID: 28694438 PMCID: PMC5503989 DOI: 10.1038/s41598-017-05064-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Accepted: 05/23/2017] [Indexed: 02/08/2023] Open
Abstract
Psychological stress has been associated with intestinal epithelial hyperpermeability, the basic process in various functional and organic bowel diseases. In the present study, we aimed to clarify the differences and underlining mechanisms in stress-induced barrier disruption in functionally and structurally distinct epitheliums, including the villus epithelium (VE) and follicle-associated epithelium (FAE), a specialized epithelium overlaid the domes of Peyer's lymphoid follicles. Employing an Ussing Chamber system, the epithelial permeability was assessed in rats following water avoidance stress (WAS) in vivo and in mucosa tissues exposed to corticotropin-releasing factor (CRF) ex vivo. Decreased transepithelial resistance (TER) and increased paracellular and transcellular macromolecular permeability in colon, ileal VE and FAE had been observed in WAS rats and in CRF-exposed mucosa. Especially, the barrier dysfunction was more serious in the FAE. Moreover, WAS upregulated the expression of mast cell tryptase and protease-activated receptor-2 (PAR2), which positively correlated with epithelial conductance. Mast cell stabilizer cromolyn sodium obviously alleviated the barrier disruption induced by WAS in vivo and CRF in vitro. Serine protease inhibitor aprotinin and FUT-175, and selective PAR2 antagonist ENMD-1068 effectively inhibited the CRF-induced FAE hyperpermeability. Altogether, it concluded that the FAE was more susceptible to stress, and the mast cells and PAR2 signaling played crucial roles in this process.
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Affiliation(s)
- Lei Zhang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Jun Song
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Tao Bai
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Wei Qian
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xiao-Hua Hou
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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He Y, Wen Q, Yao F, Xu D, Huang Y, Wang J. Gut-lung axis: The microbial contributions and clinical implications. Crit Rev Microbiol 2016; 43:81-95. [PMID: 27781554 DOI: 10.1080/1040841x.2016.1176988] [Citation(s) in RCA: 194] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Gut microbiota interacts with host immune system in ways that influence the development of disease. Advances in respiratory immune system also broaden our knowledge of the interaction between host and microbiome in the lung. Increasing evidence indicated the intimate relationship between the gastrointestinal tract and respiratory tract. Exacerbations of chronic gut and lung disease have been shown to share key conceptual features with the disorder and dysregulation of the microbial ecosystem. In this review, we discuss the impact of gut and lung microbiota on disease exacerbation and progression, and the recent understanding of the immunological link between the gut and the lung, the gut-lung axis.
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Affiliation(s)
- Yang He
- a Department of Cancer Center, Union Hospital , Tongji Medical College, Huazhong University of Science and Technology , Wuhan , China
| | - Qu Wen
- a Department of Cancer Center, Union Hospital , Tongji Medical College, Huazhong University of Science and Technology , Wuhan , China
| | - Fangfang Yao
- a Department of Cancer Center, Union Hospital , Tongji Medical College, Huazhong University of Science and Technology , Wuhan , China
| | - Dong Xu
- b Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan , China
| | - Yuancheng Huang
- b Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan , China
| | - Junshuai Wang
- c Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan , China
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Chiodini RJ, Dowd SE, Galandiuk S, Davis B, Glassing A. The predominant site of bacterial translocation across the intestinal mucosal barrier occurs at the advancing disease margin in Crohn's disease. MICROBIOLOGY-SGM 2016; 162:1608-1619. [PMID: 27418066 DOI: 10.1099/mic.0.000336] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Crohn's disease is characterized by increased permeability of the intestinal mucosal barriers and an abnormal or dysregulated immune response to specific and/or commensal bacteria arising from the intestinal lumen. To determine the types of bacteria that are transgressing the mucosal barrier and colonizing the intestinal submucosal tissues, we performed 16S rRNA gene microbiota sequencing of the submucosal and mucosal tissues at the advancing disease margin in ileal Crohn's disease. Microbial populations were compared between mucosa and submucosa and non-inflammatory bowel disease (non-IBD) controls, as well as to microbial populations previously found at the centre of the disease lesion. There was no significant increase in bacteria within the submucosa of non-IBD controls at any taxonomic level when compared to the corresponding superjacent mucosa, indicating an effective mucosal barrier within the non-IBD population. In contrast, there was a statistically significant increase in 13 bacterial families and 16 bacterial genera within the submucosa at the advancing disease margin in Crohn's disease when compared to the superjacent mucosa. Major increases within the submucosa included bacteria of the Families Sphingomonadaceae, Alicyclobacillaceae, Methylobacteriaceae, Pseudomonadaceae and Prevotellaceae. Data suggest that the primary site of bacterial translocation across the mucosal barrier occurs at the margin between diseased and normal tissue, the advancing disease margin. The heterogeneity of the bacterial populations penetrating the mucosal barrier and colonizing the submucosal intestinal tissues and, therefore, contributing to the inflammatory processes, suggests that bacterial translocation is secondary to a primary event leading to a breakdown of the mucosal barrier.
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Affiliation(s)
- Rodrick J Chiodini
- St Vincent Healthcare, Sisters of Charity of Leavenworth Health System, Billings, MT, USA.,Department of Biological and Physical Sciences, Montana State University-Billings, Billings, MT, USA
| | - Scot E Dowd
- Molecular Research (Mr. DNA), Shallowater, TX, USA
| | - Susan Galandiuk
- Hiram C. Polk, Jr. MD, Department of Surgery, University of Louisville, Louisville, KY, USA
| | - Brian Davis
- Department of Surgery, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA
| | - Angela Glassing
- Department of Biological and Physical Sciences, Montana State University-Billings, Billings, MT, USA
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Roggenbuck D, Vermeire S, Hoffman I, Reinhold D, Schierack P, Goihl A, von Arnim U, De Hertogh G, Polymeros D, Bogdanos DP, Bossuyt X. Evidence of Crohn's disease-related anti-glycoprotein 2 antibodies in patients with celiac disease. Clin Chem Lab Med 2016; 53:1349-57. [PMID: 25411995 DOI: 10.1515/cclm-2014-0238] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2014] [Accepted: 10/03/2014] [Indexed: 12/13/2022]
Abstract
BACKGROUND Autoantibodies to exocrine-pancreatic glycoprotein 2 (anti-GP2) are Crohn's disease (CD) markers. However, CD-specific antibodies have also been found in celiac-disease (CeD) patients, in which type 1 diabetes-specific autoantibodies against endocrine pancreatic targets can be present. We investigated whether anti-GP2 are also present in CeD, a disease like CD which is also characterised by intestinal mucosal inflammation with barrier impairment. METHODS Antibodies against GP2, tissue transglutaminase (tTG), deamidated gliadin (dGD), glutamic decarboxylase (GAD), and islet antigen-2 (IA2) were tested in sera from 73 CD patients, 90 blood donors (BD), and 79 (58 de novo) CeD patients (2 consecutive sera were available from 40 patients). RESULTS IgA and/or IgG anti-GP2 were found in 15/79 (19.0%) CeD patients on at least one occasion, in 25/73 (34.2%) CD patients, and in 4/90 (4.4%) BD (CeD vs. CD, p=0.042; BD vs. CeD and CD, p<0.001, respectively). Amongst the 58 de novo CeD patients, anti-GP2 IgA and/or IgG were present in 11 (19.0%). Anti-GP2 IgA was significantly less prevalent in CeD compared with CD (p=0.004). Anti-GP2 IgA and IgG in CD patients demonstrated a significantly higher median level compared to patients with CeD (p<0.001, p=0.008, respectively). IgA anti-GP2 levels correlated significantly with IgA anti-tTG and anti-dGD levels in CeD Spearman's coefficient of rank correlation (ρ)=0.42, confidence interval (CI): 0.26-0.56, p<0.001; ρ=0.54, CI 0.39-0.65, p<0.001, respectively. CONCLUSIONS The presence of anti-GP2 in CeD patients supports the notion that loss of tolerance to GP2 can probably be a manifestation of an autoinflammatory process in this intestinal disorder.
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Hondo T, Someya S, Nagasawa Y, Terada S, Watanabe H, Chen X, Watanabe K, Ohwada S, Kitazawa H, Rose MT, Nochi T, Aso H. Cyclophilin A is a new M cell marker of bovine intestinal epithelium. Cell Tissue Res 2016; 364:585-597. [DOI: 10.1007/s00441-015-2342-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2015] [Accepted: 12/03/2015] [Indexed: 12/20/2022]
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Abstract
Inflammation in inflammatory bowel diseases (IBD) has been linked to a loss of tolerance to self-antigens suggesting the existence of autoantibodies in specific disease phenotypes. However, the lack of clearly defined autoantigenic targets has slowed down research. Genome-wide association studies have identified an impressive number of immune-related susceptibility loci for IBD with no clearly discernible pattern among them. Growing evidence supports the hypothesis that innate immune responses to a low-diversity and impaired gut microbiota may be of key importance in initiating and perpetuating chronic inflammation in IBD. Increasing evidence suggests that reduced microbial diversity and microbial-mucosal epithelium interaction (including adhesion and clearance) are critically involved in IBD pathogenesis. Along these lines the discovery of autoantigenic targets in Crohn's disease (CD) has refocused research in IBD on the possible role of autoimmune responses. The identification of the major zymogen granule membrane glycoprotein 2 (GP2) as an autoantigen in CD patients and its proposed role in the sensing of the microbiota lends credence to this trend. Loss of tolerance to GP2 occurs in up to 40% of patients with CD. Corresponding autoantibodies appear to be associated with distinct disease courses (types or phenotypes) in CD. Here, we critically review autoantibodies in CD for their impact on clinical practice and future IBD research. The immunomodulatory role of GP2 in innate and adaptive intestinal immunity is also discussed.
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Zhang S, Wu Z, Luo J, Ding X, Hu C, Li P, Deng C, Zhang F, Qian J, Li Y. Diagnostic Potential of Zymogen Granule Glycoprotein 2 Antibodies as Serologic Biomarkers in Chinese Patients With Crohn Disease. Medicine (Baltimore) 2015; 94:e1654. [PMID: 26496271 PMCID: PMC4620836 DOI: 10.1097/md.0000000000001654] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The need for reliable biomarkers for distinguishing Crohn disease (CD) from ulcerative colitis (UC) is increasing. This study aimed at evaluating the diagnostic potential of anti-GP2 antibodies as a biomarker in Chinese patients with CD. In addition, a variety of autoantibodies, including anti-saccharomyces cerevisiae antibodies (ASCA), perinuclear anti-neutrophil cytoplasmic antibodies (PANCA), anti-intestinal goblet cell autoantibodies (GAB), and anti-pancreatic autoantibodies (PAB), were evaluated.A total of 91 subjects were prospectively enrolled in this study, including 35 patients with CD, 35 patients with UC, 13 patients with non-IBD gastrointestinal diseases as disease controls (non-IBD DC), and 8 healthy controls (HC). The diagnosis of IBD was determined based on the Lennard-Jones criteria, and the clinical phenotypes of the IBD patients were determined based on the Montreal Classification.Anti-GP2 IgG antibodies were significantly elevated in patients with CD, compared with patients with UC (P = 0.0038), HC (P = 0.0055), and non-IBD DC (P = 0.0063). The prevalence of anti-GP2 IgG, anti-GP2 IgA and anti-GP2 IgA, or IgG antibodies in patients with CD was 40.0%, 37.1%, and 54.3%, respectively, which were higher than those in non-IBD DC (anti-GP2 IgG, 15.4%; anti-GP2 IgA, 7.7%; and anti-GP2 IgA or IgG, 23.1%) and those in patients with UC (anti-GP2 IgG, 11.4%; anti-GP2 IgA, 2.9%; and anti-GP2 IgA or IgG, 14.3%). For distinguishing CD from UC, the sensitivity, specificity, positive predictive value (PPV) and positive likelihood ratios (LR+) were 40%, 88.6%, 77.8%, and 3.51 for anti-GP2 IgG, 37.1%, 97.1%, 92.9%, and 13.0 for anti-GP2 IgA, and 54.3%, 85.3%, 79.2%, and 3.69 for anti-GP2 IgA or IgG. For CD diagnosis, the combination of anti-GP2 antibodies with ASCA IgA increased the sensitivity to 68.6% with moderate loss of specificity to 74.3%. Spearman's rank of order revealed a significantly positive correlation of anti-GP2 IgG with ileocolonic location of disease (L3) (P = 0.043) and a negative correlation of anti-GP2 IgA with biologic therapy (P = 0.012).Our findings suggest that anti-GP2 antibodies could serve as a biomarker for distinguishing patients with CD from patients with UC, and the combination of anti-GP2 antibodies with ASCA IgA may improve the predictive power.
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Affiliation(s)
- Shulan Zhang
- From the Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education (SZ, ZW, CH, PL, CD, FZ, YL); Department of Gastroenterology, Peking Union Medical College Hospital, Beijing (JQ); Division of Rheumatology, Department of Medicine, The Second Hospital of Shanxi Medical University, Shanxi (JL); and Clinical Laboratory, General Hospital of CNPC, Jilin, China (XD)
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Sun J, Qiao Y, Qi C, Jiang W, Xiao H, Shi Y, Le GW. High-fat-diet-induced obesity is associated with decreased antiinflammatory Lactobacillus reuteri sensitive to oxidative stress in mouse Peyer's patches. Nutrition 2015; 32:265-72. [PMID: 26620713 DOI: 10.1016/j.nut.2015.08.020] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2015] [Revised: 08/01/2015] [Accepted: 08/22/2015] [Indexed: 12/18/2022]
Abstract
OBJECTIVE Diet-induced inflammation in the small intestine may represent an early event that precedes and predisposes to obesity and insulin resistance. This is related to decrease of lactobacilli in Peyer's patches (PP) revealed in our previous study. The present study aimed to clarify specific changes of PP Lactobacillus on the strain level and related biological activity. METHODS C57 BL/6 J male mice were fed with either low-fat diet (control [CT]; 10% calories from fat) or high-fat diet (HFD; 50% calories from fat) for 25 wk, and the HFD-fed mice were classified into obesity prone (OP) or obesity resistant (OR) on the basis of their body weight gain. Lactobacillus was isolated from PP using a selective medium. Oxidative resistance and cytokine-inducing effect were analyzed in vitro. RESULTS We obtained 52, 18, and 22 isolates from CT, OP, and OR mice, respectively. They belonged to 13 different types according to enterobacterial repetitive intergenic consensus sequence-PCR analysis. Lactobacillus reuteri was the most abundant strain, but its abundance in OP mice was much lower than that in CT and OR mice. This strain includes eight subgroups according to genotyping. L. reuteri L3 and L. reuteri L8 were the specific strains found in CT and OP mice, respectively. Oxidative-resistant L. reuteri was much higher in HFD-fed mice. When co-cultured with PP cells, L8 induced higher production of proinflammatory cytokines such as interleukin (IL)-6, IL-12, and tumor necrosis factor-α, whereas L3 induced higher production of an anti-inflammatory cytokine (IL-10). CONCLUSION HFD may induce oxidative stress that drives strain selection of Lactobacillus strains, resulting in decreased anti-inflammatory response in PP.
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Affiliation(s)
- Jin Sun
- Food Nutrition and Functional Factors Research Center, School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P.R. China; State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P.R. China.
| | - Yi Qiao
- Food Nutrition and Functional Factors Research Center, School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P.R. China
| | - Ce Qi
- Food Nutrition and Functional Factors Research Center, School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P.R. China; State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P.R. China
| | - Wei Jiang
- Food Nutrition and Functional Factors Research Center, School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P.R. China
| | - Hang Xiao
- Department of Food Science, University of Massachusetts, Amherst, Massachusetts, USA
| | - Yonghui Shi
- Food Nutrition and Functional Factors Research Center, School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P.R. China; State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P.R. China
| | - Guo-Wei Le
- Food Nutrition and Functional Factors Research Center, School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P.R. China; State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, P.R. China
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Powell JJ, Thomas-McKay E, Thoree V, Robertson J, Hewitt RE, Skepper JN, Brown A, Hernandez-Garrido JC, Midgley PA, Gomez-Morilla I, Grime GW, Kirkby KJ, Mabbott NA, Donaldson DS, Williams IR, Rios D, Girardin SE, Haas CT, Bruggraber SFA, Laman JD, Tanriver Y, Lombardi G, Lechler R, Thompson RPH, Pele LC. An endogenous nanomineral chaperones luminal antigen and peptidoglycan to intestinal immune cells. NATURE NANOTECHNOLOGY 2015; 10:361-9. [PMID: 25751305 PMCID: PMC4404757 DOI: 10.1038/nnano.2015.19] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Accepted: 01/21/2015] [Indexed: 05/06/2023]
Abstract
In humans and other mammals it is known that calcium and phosphate ions are secreted from the distal small intestine into the lumen. However, why this secretion occurs is unclear. Here, we show that the process leads to the formation of amorphous magnesium-substituted calcium phosphate nanoparticles that trap soluble macromolecules, such as bacterial peptidoglycan and orally fed protein antigens, in the lumen and transport them to immune cells of the intestinal tissue. The macromolecule-containing nanoparticles utilize epithelial M cells to enter Peyer's patches, small areas of the intestine concentrated with particle-scavenging immune cells. In wild-type mice, intestinal immune cells containing these naturally formed nanoparticles expressed the immune tolerance-associated molecule 'programmed death-ligand 1', whereas in NOD1/2 double knockout mice, which cannot recognize peptidoglycan, programmed death-ligand 1 was undetected. Our results explain a role for constitutively formed calcium phosphate nanoparticles in the gut lumen and show how this helps to shape intestinal immune homeostasis.
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Affiliation(s)
- Jonathan J Powell
- Medical Research Council Human Nutrition Research, Elsie Widdowson Laboratory, Fulbourn Road, Cambridge CB1 9NL, UK
| | - Emma Thomas-McKay
- Medical Research Council Human Nutrition Research, Elsie Widdowson Laboratory, Fulbourn Road, Cambridge CB1 9NL, UK
| | - Vinay Thoree
- Medical Research Council Human Nutrition Research, Elsie Widdowson Laboratory, Fulbourn Road, Cambridge CB1 9NL, UK
| | - Jack Robertson
- Medical Research Council Human Nutrition Research, Elsie Widdowson Laboratory, Fulbourn Road, Cambridge CB1 9NL, UK
| | - Rachel E Hewitt
- Medical Research Council Human Nutrition Research, Elsie Widdowson Laboratory, Fulbourn Road, Cambridge CB1 9NL, UK
| | - Jeremy N Skepper
- Cambridge Advanced Imaging Centre, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, UK
| | - Andy Brown
- Institute for Materials Research, SPEME, University of Leeds, Leeds LS2 9JT, UK
| | - Juan Carlos Hernandez-Garrido
- Departamento de Ciencia de los Materiales e Ingenieria Metalúrgica y Química Inorganica, Facultad de Ciencias, Universidad de Cádiz, Campus Universitario Rio San Pedro, Puerto Real (Cádiz) 11.510, Spain
| | - Paul A Midgley
- Department of Materials Science and Metallurgy, University of Cambridge, 27 Charles Babbage Road, Cambridge CB3 0FS, UK
| | - Inmaculada Gomez-Morilla
- Technische Universitaet Dresden, Fakultaet Maschinenwesen, Institut fuer Stroemungsmechanik, Dresden 01062, Germany
| | - Geoffrey W Grime
- Ion Beam Centre, Advanced Technology Institute, Faculty of Engineering and Physical Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK
| | - Karen J Kirkby
- 1] Ion Beam Centre, Advanced Technology Institute, Faculty of Engineering and Physical Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK [2] Institute of Cancer Sciences, The University of Manchester, 27 Palatine Road, Withington, Manchester M20 3LJ, UK
| | - Neil A Mabbott
- The Roslin Institute and Royal (Dick) School of Veterinary Sciences, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, UK
| | - David S Donaldson
- The Roslin Institute and Royal (Dick) School of Veterinary Sciences, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, UK
| | - Ifor R Williams
- Department of Pathology, Emory University School of Medicine, 615 Michael Street, Atlanta, Georgia 30322, USA
| | - Daniel Rios
- Department of Pathology, Emory University School of Medicine, 615 Michael Street, Atlanta, Georgia 30322, USA
| | - Stephen E Girardin
- Department of Laboratory Medicine and Pathobiology, 1 King's College Circle, Toronto M5S 1A8, Canada
| | - Carolin T Haas
- Medical Research Council Human Nutrition Research, Elsie Widdowson Laboratory, Fulbourn Road, Cambridge CB1 9NL, UK
| | - Sylvaine F A Bruggraber
- Medical Research Council Human Nutrition Research, Elsie Widdowson Laboratory, Fulbourn Road, Cambridge CB1 9NL, UK
| | - Jon D Laman
- 1] Department of Immunology, Erasmus MC, University Medical Centre and MS Centre ErasMS, PO Box 2040, Rotterdam 3000 CA, The Netherlands [2] Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Yakup Tanriver
- Department of Internal Medicine IV and Institute of Medical Microbiology and Hygiene, University Medical Center, Freiburg 79106, Germany
| | - Giovanna Lombardi
- Immunoregulation Laboratory, MRC Centre for Transplantation, King's College London, Guys' Hospital, London SE1 9RT, UK
| | - Robert Lechler
- Immunoregulation Laboratory, MRC Centre for Transplantation, King's College London, Guys' Hospital, London SE1 9RT, UK
| | - Richard P H Thompson
- 1] Medical Research Council Human Nutrition Research, Elsie Widdowson Laboratory, Fulbourn Road, Cambridge CB1 9NL, UK [2] Royal College of Physicians, 11 St Andrews Place, Regent's Park, London NW1 4LE, UK
| | - Laetitia C Pele
- Medical Research Council Human Nutrition Research, Elsie Widdowson Laboratory, Fulbourn Road, Cambridge CB1 9NL, UK
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Roggenbuck D, Reinhold D, Schierack P, Bogdanos DP, Conrad K, Laass MW. Crohn's disease specific pancreatic antibodies: clinical and pathophysiological challenges. Clin Chem Lab Med 2015; 52:483-94. [PMID: 24231127 DOI: 10.1515/cclm-2013-0801] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Accepted: 10/22/2013] [Indexed: 12/22/2022]
Abstract
Crohn's disease (CrD) and ulcerative colitis (UC) are the main inflammatory bowel diseases (IBD). IBD-specific humoral markers of autoimmunity in the form of autoantibodies have been reported first in the late 1950s by demonstrating the occurrence of autoimmunity in UC, while humoral autoimmunity in CrD can be traced back to the 1970s. Ever since, the pathophysiological role of autoimmune responses in IBDs has remained poorly understood. Notwithstanding, autoreactive responses play a major role in inflammation leading to overt IBD. In CrD, approximately 40% of patients and <20% of patients with UC demonstrate loss of tolerance to antigens of the exocrine pancreas. Glycoprotein 2 (GP2) has been identified as a major autoantigenic target of the so-called pancreatic antibodies. The previously unsolved contradiction of pancreatic autoreactivity and intestinal inflammation in IBD was elucidated by demonstrating the expression of GP2 at the site thereof. Intriguingly, GP2 has been reported to be a receptor on microfold cells of intestinal Peyer's patches, which are believed to represent the origin of CrD inflammation. The development of immunoassays for the detection of antibodies to GP2 has paved the way to investigate the association of such antibodies with the clinical phenotype in CrD. Given the recently discovered immunomodulating role of GP2 in innate and adaptive intestinal immunity, this association can shed further light on the pathophysiology of IBD. In this context, the association of anti-GP2 autoantibodies as novel CrD-specific markers with the clinical phenotype in CrD will be discussed in this review.
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Understanding host-adherent-invasive Escherichia coli interaction in Crohn's disease: opening up new therapeutic strategies. BIOMED RESEARCH INTERNATIONAL 2014; 2014:567929. [PMID: 25580435 PMCID: PMC4279263 DOI: 10.1155/2014/567929] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 09/16/2014] [Accepted: 09/16/2014] [Indexed: 02/07/2023]
Abstract
A trillion of microorganisms colonize the mammalian intestine. Most of them have coevolved with the host in a symbiotic relationship and some of them have developed strategies to promote their replication in the presence of competing microbiota. Recent evidence suggests that perturbation of the microbial community favors the emergence of opportunistic pathogens, in particular adherent-invasive Escherichia coli (AIEC) that can increase incidence and severity of gut inflammation in the context of Crohn's disease (CD). This review will report the importance of AIEC as triggers of intestinal inflammation, focusing on their impact on epithelial barrier function and stimulation of mucosal inflammation. Beyond manipulation of immune response, restoration of gut microbiota as a new treatment option for CD patients will be discussed.
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Inflammation-associated adherent-invasive Escherichia coli are enriched in pathways for use of propanediol and iron and M-cell translocation. Inflamm Bowel Dis 2014; 20:1919-32. [PMID: 25230163 DOI: 10.1097/mib.0000000000000183] [Citation(s) in RCA: 122] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND Perturbations of the intestinal microbiome, termed dysbiosis, are linked to intestinal inflammation. Isolation of adherent-invasive Escherichia coli (AIEC) from intestines of patients with Crohn's disease (CD), dogs with granulomatous colitis, and mice with acute ileitis suggests these bacteria share pathoadaptive virulence factors that promote inflammation. METHODS To identify genes associated with AIEC, we sequenced the genomes of phylogenetically diverse AIEC strains isolated from people with CD (4), dogs with granulomatous colitis (2), and mice with ileitis (2) and 1 non-AIEC strain from CD ileum and compared them with 38 genome sequences of E. coli and Shigella. We then determined the prevalence of AIEC-associated genes in 49 E. coli strains from patients with CD and controls and correlated genotype with invasion of intestinal epithelial cells, persistence within macrophages, AIEC pathotype, and growth in standardized conditions. RESULTS Genes encoding propanediol utilization (pdu operon) and iron acquisition (yersiniabactin, chu operon) were overrepresented in AIEC relative to nonpathogenic E. coli. PduC (propanediol dehydratase) was enriched in CD-derived AIEC, correlated with increased cellular invasion, and persistence in vitro and was increasingly expressed in fucose-containing media. Growth of AIEC required iron, and the presence of chuA (heme acquisition) correlated with persistence in macrophages. CD-associated AIEC with lpfA 154 (long polar fimbriae) demonstrated increased invasion of epithelial cells and translocation across M cells. CONCLUSIONS Our findings provide novel insights into the genetic basis of the AIEC pathotype, supporting the concept that AIEC are equipped to exploit and promote intestinal inflammation and reveal potential targets for intervention against AIEC and inflammation-associated dysbiosis.
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Tawfik A, Flanagan PK, Campbell BJ. Escherichia coli-host macrophage interactions in the pathogenesis of inflammatory bowel disease. World J Gastroenterol 2014; 20:8751-8763. [PMID: 25083050 PMCID: PMC4112894 DOI: 10.3748/wjg.v20.i27.8751] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Revised: 01/07/2014] [Accepted: 04/03/2014] [Indexed: 02/06/2023] Open
Abstract
Multiple studies have demonstrated alterations in the intestinal microbial community (termed the microbiome) in Crohn’s disease (CD) and several lines of evidence suggest these changes may have a significant role in disease pathogenesis. In active and quiescent disease, both the faecal and mucosa-associated microbiome are discordant with matched controls with reduced biodiversity, changes in dominant organisms and increased temporal variation described. Mucosa-associated adherent, invasive Escherichia coli (E. coli) (AIEC), pro-inflammatory and resistant to killing by mucosal macrophages, appear to be particularly important. AIEC possess several virulence factors which may confer pathogenic potential in CD. Type-1 pili (FimH) allow adherence to intestinal cells via cell-surface carcinoembryonic antigen-related cell adhesion molecules and possession of long polar fimbrae promotes translocation across the intestinal mucosa via microfold (M)-cells of the follicle-associated epithelium. Resistance to stress genes (htrA, dsbA and hfq) and tolerance of an acidic pH may contribute to survival within the phagolysosomal environment. Here we review the current understanding of the role of mucosa-associated E. coli in Crohn’s pathogenesis, the role of the innate immune system, factors which may contribute to prolonged bacterial survival and therapeutic strategies to target intracellular E. coli.
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Haberman Y, Tickle TL, Dexheimer PJ, Kim MO, Tang D, Karns R, Baldassano RN, Noe JD, Rosh J, Markowitz J, Heyman MB, Griffiths AM, Crandall WV, Mack DR, Baker SS, Huttenhower C, Keljo DJ, Hyams JS, Kugathasan S, Walters TD, Aronow B, Xavier RJ, Gevers D, Denson LA. Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature. J Clin Invest 2014; 124:3617-33. [PMID: 25003194 DOI: 10.1172/jci75436] [Citation(s) in RCA: 387] [Impact Index Per Article: 35.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2014] [Accepted: 05/29/2014] [Indexed: 12/13/2022] Open
Abstract
Interactions between the host and gut microbial community likely contribute to Crohn disease (CD) pathogenesis; however, direct evidence for these interactions at the onset of disease is lacking. Here, we characterized the global pattern of ileal gene expression and the ileal microbial community in 359 treatment-naive pediatric patients with CD, patients with ulcerative colitis (UC), and control individuals. We identified core gene expression profiles and microbial communities in the affected CD ilea that are preserved in the unaffected ilea of patients with colon-only CD but not present in those with UC or control individuals; therefore, this signature is specific to CD and independent of clinical inflammation. An abnormal increase of antimicrobial dual oxidase (DUOX2) expression was detected in association with an expansion of Proteobacteria in both UC and CD, while expression of lipoprotein APOA1 gene was downregulated and associated with CD-specific alterations in Firmicutes. The increased DUOX2 and decreased APOA1 gene expression signature favored oxidative stress and Th1 polarization and was maximally altered in patients with more severe mucosal injury. A regression model that included APOA1 gene expression and microbial abundance more accurately predicted month 6 steroid-free remission than a model using clinical factors alone. These CD-specific host and microbe profiles identify the ileum as the primary inductive site for all forms of CD and may direct prognostic and therapeutic approaches.
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Li M, Li W, Wen S, Liu Y, Tang L. Effects of ceftriaxone-induced intestinal dysbacteriosis on dendritic cells of small intestine in mice. Microbiol Immunol 2014; 57:561-8. [PMID: 23650903 DOI: 10.1111/1348-0421.12068] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2012] [Revised: 04/21/2013] [Accepted: 04/26/2013] [Indexed: 12/24/2022]
Abstract
Intestinal microflora plays a pivotal role in the development of the innate immune system and is essential in shaping adaptive immunity. Dysbacteriosis of intestinal microflora induces altered immune responses and results in disease susceptibility. Dendritic cells (DCs), the professional antigen-presenting cells, have gained increasing attention because they connect innate and adaptive immunity. They generate both immunity in response to stimulation by pathogenic bacteria and immune tolerance in the presence of commensal bacteria. However, few studies have examined the effects of intestinal dysbacteriosis on DCs. In this study, changes of DCs in the small intestine of mice under the condition of dysbacteriosis induced by ceftriaxone sodium were investigated. It was found that intragastric administration of ceftriaxone sodium caused severe dysteriosis in mice. Compared with controls, numbers of DCs in mice with dysbacteriosis increased significantly (P = 0.0001). However, the maturity and antigen-presenting ability of DCs were greatly reduced. In addition, there was a significant difference in secretion of IL-10 and IL-12 between DCs from mice with dysbacteriosis and controls. To conclude, ceftriaxone-induced intestinal dysbacteriosis strongly affected the numbers and functions of DCs. The present data suggest that intestinal microflora plays an important role in inducing and maintaining the functions of DCs and thus is essential for the connection between innate and adaptive immune responses.
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Affiliation(s)
- Ming Li
- Department of Microecology, Dalian Medical University, No.9 Western Section, Lvshun South Street, Lvshunkou District, 116044, Dalian, China
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Söderman J, Norén E, Christiansson M, Bragde H, Thiébaut R, Hugot JP, Tysk C, O’Morain CA, Gassull M, Finkel Y, Colombel JF, Lémann M, Almer S. Analysis of single nucleotide polymorphisms in the region of CLDN2-MORC4 in relation to inflammatory bowel disease. World J Gastroenterol 2013; 19:4935-4943. [PMID: 23946598 PMCID: PMC3740423 DOI: 10.3748/wjg.v19.i30.4935] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2012] [Revised: 04/24/2013] [Accepted: 06/05/2013] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate a possible genetic influence of claudin (CLDN)1, CLDN2 and CLDN4 in the etiology of inflammatory bowel disease. METHODS Allelic association between genetic regions of CLDN1, CLDN2 or CLDN4 and patients with inflammatory bowel disease, Crohn's disease (CD) or ulcerative colitis were investigated using both a case-control study approach (one case randomly selected from each of 191 Swedish inflammatory bowel disease families and 333 controls) and a family-based study (463 non-Swedish European inflammatory bowel disease -families). A nonsynonymous coding single nucleotide polymorphism in MORC4, located on the same linkage block as CLDN2, was investigated for association, as were two novel CLDN2 single nucleotide polymorphism markers, identified by resequencing. RESULTS A single nucleotide polymorphism marker (rs12014762) located in the genetic region of CLDN2 was significantly associated to CD (case-control allelic OR = 1.98, 95%CI: 1.17-3.35, P = 0.007). MORC4 was present on the same linkage block as this CD marker. Using the case-control approach, a significant association (case control allelic OR = 1.61, 95%CI: 1.08-2.41, P = 0.018) was found between CD and a nonsynonymous coding single nucleotide polymorphism (rs6622126) in MORC4. The association between the CLDN2 marker and CD was not replicated in the family-based study. Ulcerative colitis was not associated to any of the single nucleotide polymorphism markers. CONCLUSION These findings suggest that a variant of the CLDN2-MORC4 region predisposes to CD in a Swedish population.
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Roggenbuck D, Reinhold D, Werner L, Schierack P, Bogdanos DP, Conrad K. Glycoprotein 2 antibodies in Crohn's disease. Adv Clin Chem 2013; 60:187-208. [PMID: 23724745 DOI: 10.1016/b978-0-12-407681-5.00006-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The pathogenesis of Crohn's disease (CrD) and ulcerative colitis (UC), the two major inflammatory bowel diseases (IBD), remains poorly understood. Autoimmunity is considered to be involved in the triggering and perpetuation of inflammatory processes leading to overt disease. Approximately 30% of CrD patients and less than 8% of UC patients show evidence of humoral autoimmunity to exocrine pancreas, detected by indirect immunofluorescence. Pancreatic autoantibodies (PAB) were described for the first time in 1984, but the autoantigenic target(s) of PABs were identified only in 2009. Utilizing immunoblotting and matrix-assisted laser desorption ionization time-of-flight mass spectrometry, the major zymogen granule membrane glycoprotein 2 (GP2) has been discovered as the main PAB autoantigen. The expression of GP2 has been demonstrated at the site of intestinal inflammation, explaining the previously unaddressed contradiction of pancreatic autoimmunity and intestinal inflammation. Recent data demonstrate GP2 to be a specific receptor on microfold (M) cells of intestinal Peyer's patches, which are considered to be the original site of inflammation in CrD. Novel ELISAs, employing recombinant GP2 as the solid phase antigen, have confirmed the presence of IgA and IgG anti-GP2 PABs in CrD patients and revealed an association of anti-GP2 IgA as well as IgG levels with a specific clinical phenotype in CrD. Also, GP2 plays an important role in modulating innate and acquired intestinal immunity. Its urinary homologue, Tamm-Horsfall protein or uromodulin, has a similar effect in the urinary tract, further indicating that GP2 is not just an epiphenomenon of intestinal destruction. This review discusses the role of anti-GP2 autoantibodies as novel CrD-specific markers, the quantification of which provides the basis for further stratification of IBD patients. Given the association with a disease phenotype and the immunomodulating properties of GP2 itself, an important role for GP2 in the immunopathogenesis of IBD cannot be excluded.
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Affiliation(s)
- Dirk Roggenbuck
- Faculty of Natural Sciences, Lausitz University of Applied Sciences, Senftenberg, Germany.
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des Rieux A, Pourcelle V, Cani PD, Marchand-Brynaert J, Préat V. Targeted nanoparticles with novel non-peptidic ligands for oral delivery. Adv Drug Deliv Rev 2013; 65:833-44. [PMID: 23454185 DOI: 10.1016/j.addr.2013.01.002] [Citation(s) in RCA: 113] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2012] [Revised: 01/12/2013] [Accepted: 01/30/2013] [Indexed: 12/31/2022]
Abstract
Orally administered targeted nanoparticles have a large number of potential biomedical applications and display several putative advantages for oral drug delivery, such as the protection of fragile drugs or modification of drug pharmacokinetics. These advantages notwithstanding, oral drug delivery by nanoparticles remains challenging. The optimization of particle size and surface properties and targeting by ligand grafting have been shown to enhance nanoparticle transport across the intestinal epithelium. Here, different grafting strategies for non-peptidic ligands, e.g., peptidomimetics, lectin mimetics, sugars and vitamins, that are stable in the gastrointestinal tract are discussed. We demonstrate that the grafting of these non-peptidic ligands allows nanoparticles to be targeted to M cells, enterocytes, immune cells or L cells. We show that these grafted nanoparticles could be promising vehicles for oral vaccination by targeting M cells or for the delivery of therapeutic proteins. We suggest that targeting L cells could be useful for the treatment of type 2 diabetes or obesity.
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Somma V, Ababneh H, Ababneh A, Gatti S, Romagnoli V, Bendia E, Conrad K, Bogdanos DP, Roggenbuck D, Ciarrocchi G. The Novel Crohn's Disease Marker Anti-GP2 Antibody Is Associated with Ileocolonic Location of Disease. Gastroenterol Res Pract 2013; 2013:683824. [PMID: 23762038 PMCID: PMC3671301 DOI: 10.1155/2013/683824] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2013] [Accepted: 03/19/2013] [Indexed: 12/19/2022] Open
Abstract
Crohn's disease (CD) is an inflammatory bowel disease (IBD) that can affect the whole gastrointestinal tract. The ileocolonic variant of CD, an inflammation of both the ileum and the large intestine, accounts for up to 50% of the cases with CD, whereas Crohn's ileitis affecting the ileum is diagnosed in about 30%. Crohn's colitis, which is confined to the large intestine and accounts for the remaining 20%, is difficult to distinguish from the large bowel inflammation seen in patients with ulcerative colitis (UC). The pathogenesis of CD is not yet completely understood. Autoimmunity is one factor that can partake in the triggering or modulation of inflammatory processes in IBD. The major zymogen-granule membrane glycoprotein 2 (GP2) has been recently identified as a major autoantigenic target in CD. Interestingly, GP2 is mainly expressed in the pancreas and has also been demonstrated to be a membrane-anchored receptor of microfold cells in the follicle-associated epithelium. Remarkably, GP2 is overexpressed at the site of CD inflammation in contrast to the one in UC. By utilizing novel enzyme-linked immunosorbent assays for the detection of GP2-specific IgA and IgG, the loss of tolerance to GP2 has been associated with a specific clinical phenotype in CD, in particular with the ileocolonic location of the disease.
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Affiliation(s)
| | - Hani Ababneh
- Immunology Department, King Hussein Medical Center, Amman 11855, Jordan
| | | | - Simona Gatti
- Department of Pediatrics, Polytechnic University of Marche, 60123 Ancona, Italy
| | - Vittorio Romagnoli
- Department of Pediatrics, Polytechnic University of Marche, 60123 Ancona, Italy
| | - Emanuele Bendia
- Department of Gastroenterology, “Ospedali Riuniti” University Hospital, 60020 Ancona, Italy
| | - Karsten Conrad
- Institute of Immunology, Technical University, 01307 Dresden, Germany
| | - Dimitrios P. Bogdanos
- Division of Transplantation Immunology and Mucosal Biology, Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, Denmark Hill Campus, London SE5 9RJ, UK
| | - Dirk Roggenbuck
- R/D, Medipan GmbH, 15827 Dahlewitz/Berlin, Germany
- Faculty of Natural Sciences, Lausitz University of Applied Sciences, 01968 Senftenberg, Germany
| | - Gino Ciarrocchi
- Central Analytical Laboratory, “Ospedali Riuniti” University Hospital, 60020 Ancona, Italy
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de Bie CI, Paerregaard A, Kolacek S, Ruemmele FM, Koletzko S, Fell JME, Escher JC. Disease phenotype at diagnosis in pediatric Crohn's disease: 5-year analyses of the EUROKIDS Registry. Inflamm Bowel Dis 2013; 19:378-85. [PMID: 22573581 DOI: 10.1002/ibd.23008] [Citation(s) in RCA: 125] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND It has been speculated that pediatric Crohn's disease (CD) is a distinct disease entity, with probably different disease subtypes. We therefore aimed to accurately phenotype newly diagnosed pediatric CD by using the pediatric modification of the Montreal classification, the Paris classification. METHODS Information was collected from the EUROKIDS registry, a prospective, web-based registry of new-onset pediatric IBD patients in 17 European countries and Israel. When a complete diagnostic workup was performed (ileocolonoscopy, upper gastrointestinal [GI] endoscopy, small bowel imaging), CD patients were evaluated for ileocolonic disease extent, esophagogastroduodenal involvement, and jejunal/proximal ileal involvement. Disease behavior and the occurrence of granulomas were also analyzed. RESULTS In all, 582 pediatric CD patients could be classified according to the Paris classification. Isolated terminal ileal disease (± limited cecal disease) was seen at presentation in 16%, isolated colonic disease in 27%, ileocolonic disease in 53%, and isolated upper GI disease in 4% of patients. In total, 30% had esophagogastroduodenal involvement and 24% jejunal/proximal ileal disease. Patients with L2 disease were less likely to have esophagogastroduodenal involvement or stricturing disease than patients with L1 or L3 disease. Terminal ileal disease and stricturing disease behavior were more common in children diagnosed after 10 years of age than in younger patients. Granulomas were identified in 43% of patients. CONCLUSIONS Accurate phenotyping is essential in pediatric CD, as this affects the management of individual patients. Disease phenotypes differ according to age at disease onset. The Paris classification is a useful tool to capture the variety of phenotypic characteristics of pediatric CD.
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Affiliation(s)
- Charlotte I de Bie
- Department of Pediatric Gastroenterology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands
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Ileal inflammation may trigger the development of GP2-specific pancreatic autoantibodies in patients with Crohn's disease. Clin Dev Immunol 2012; 2012:640835. [PMID: 23118780 PMCID: PMC3483735 DOI: 10.1155/2012/640835] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2012] [Accepted: 09/07/2012] [Indexed: 12/11/2022]
Abstract
Why zymogen glycoprotein 2 (GP2), the Crohn's disease (CD)-specific pancreatic autoantigen, is the major target of humoral autoimmunity in inflammatory bowel diseases (IBD) is uknown. Recent evidence demonstrates that GP2 is also present on the apical surface of microfold (M) intestinal cells. As the colon lacks GP2-rich M cells, we assumed that patients with colonic CD are seronegative for anti-GP2. Anti-GP2 antibodies were tested in 225 CDs, including 45 patients with colonic location (L2), 45 with terminal ileum (L1) and 135 with ileocolonic involvement; 225 patients with ulcerative colitis (UC) were also tested. Anti-GP2 reactivity was detected in 59 (26.2%) CDs and 15 (6.7%) UCs (P < 0.001). Only 5 CDs with L2 had anti-GP2 antibodies, compared to 54/180 (30.0%, P = 0.0128) of the CDs with L1 and L3. Anti-GP2 antibody positive CD patients had higher ASCA titres compared to seronegative cases. Amongst the 128 CD patients with previous surgical intervention, 45 (35.0%) were anti-GP2 antibody positive compared to 14/97 (14.0%) without surgical (P < 0.001). Our data support the assumption that ileal inflammation is required for the development of anti-GP2 antibodies in CD, and suggest that the intestine rather than the pancreatic juice is the antigenic source required for the initiation of anti-GP2 antibodies.
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Abstract
Alum (AlK(SO(4))(2)) is an adjuvant commonly utilized in vaccines, and is a ubiquitous element used extensively in contemporary life. Food, air, water, waste, the earth's surface, and pharmaceuticals all represent pathways of aluminum (Al) exposure. Crohn's disease (CD) is a chronic relapsing intestinal inflammation in genetically susceptible individuals and is caused by yet unidentified environmental factors. Al is a potential factor for the induction of inflammation in CD, and its immune activities share many characteristics with the immune pathology of CD: many luminal bacterial or dietary compounds can be adsorbed to the metal surface and induce Th1 profile cytokines, shared cytokines/chemokines, co-stimulatory molecules, and intracellular pathways and stress-related molecular expression enhancement, affecting intestinal macrobiota, trans-mural granuloma formation, and colitis induction in an animal CD model. The inflammasome plays a central role in Al mode of action and in CD pathophysiology. It is suggested that Al adjuvant activity can fit between the aberrations of innate and adaptive immune responses occurring in CD. The CD mucosa is confronted with numerous inappropriate bacterial components adsorbed on the Al compound surface, constituting a pro-inflammatory supra-adjuvant. Al fits the diagnostic criteria of the newly described autoimmune/inflammatory syndrome induced by adjuvants. If a cause and effect relationship can be established, the consequences will greatly impact public health and CD prevention and management.
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Affiliation(s)
- A Lerner
- Pediatric Gastroenterology and Nutrition Unit, Carmel Medical Center, Haifa, Israel.
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Iwaya H, Maeta K, Hara H, Ishizuka S. Mucosal permeability is an intrinsic factor in susceptibility to dextran sulfate sodium-induced colitis in rats. Exp Biol Med (Maywood) 2012; 237:451-60. [PMID: 22522346 DOI: 10.1258/ebm.2011.011269] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
We investigated differences in the pathogenesis of dextran sulfate sodium (DSS)-induced colitis between two inbred rat strains, Wistar King A Hokkaido (WKAH) and Dark Agouti (DA) rats, to determine the intrinsic factors responsible for the development of colitis. DSS exposure exacerbated the clinical symptoms such as body weight loss, stool consistency and rectal bleeding in DA rats rather than that in WKAH rats. Additionally, the average survival was shorter in DA rats than in WKAH rats. The expression levels of tumor necrosis factor-α, interleukin (IL)-12 p35 and IL-23 p19 increased prominently in the DA rats that were administered DSS, accompanied by severe infiltration of leukocytes into the colon. We also found that colonic permeability was greater in the DA rats than in the WKAH rats. In Ussing chambers, exposure of the isolated colon tissue to DSS enhanced the colonic permeability of both strains. Immunoblot analysis revealed that the expression levels of tight junction (TJ) proteins were modulated during DSS administration. Higher expression levels of claudin-4 and junctional adhesion molecule-A proteins were observed in DA rats than in WKAH rats, even in intact conditions. These results indicated that the expression pattern of TJ proteins determines the colonic permeability of the rats. In conclusion, the intrinsic colonic permeability is one of critical factors responsible for the susceptibility of rats to colitis.
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Affiliation(s)
- Hitoshi Iwaya
- Division of Applied Bioscience, Research Faculty of Agriculture, Hokkaido University, Sapporo 060-8589, Japan
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44
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Bogdanos DP, Rigopoulou EI, Smyk DS, Roggenbuck D, Reinhold D, Forbes A, Laass MW, Conrad K. Diagnostic value, clinical utility and pathogenic significance of reactivity to the molecular targets of Crohn's disease specific-pancreatic autoantibodies. Autoimmun Rev 2011; 11:143-8. [PMID: 21983481 DOI: 10.1016/j.autrev.2011.09.004] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2011] [Accepted: 09/19/2011] [Indexed: 12/22/2022]
Abstract
Pancreatic autoantibodies (PAB) giving characteristic staining patterns of the exocrine pancreas by indirect immunoflourescence appear to be specific markers of Crohn's disease (CrD), being present in approximately 30% of patients with CrD and in less than 5% of patients with ulcerative colitis (UC). Some studies have suggested that PAB are associated with specific disease phenotypes and that their detection may be of clinical significance. Thorough investigation of the role of PAB in the immunopathogenesis of inflammatory bowel diseases (IBD) has been hampered due to the lack of identity of their antigenic targets. The recent identification of the pancreatic zymogen granule protein 2 (GP2) as the major target of PAB has led to the development of an enzyme immunoassay that helps determine the diagnostic and clinical relevance of antigen-specific immune responses. Recent studies have demonstrated that GP2 is expressed on the apical surface of intestinal membranous cells of the follicle-associated epithelium, and is essential for host-microbial interaction and the initiation of bacteria-specific mucosal immune responses. This review critically discusses recent reports investigating the diagnostic and clinical utility of GP2-specific autoantibody responses in patients with IBD. Hints towards a better understanding of the immunogenicity of GP2 are also provided.
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Affiliation(s)
- Dimitrios P Bogdanos
- Institute of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, King's College London School of Medicine at King's College Hospital, London, UK.
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Chassaing B, Darfeuille-Michaud A. Interaction entreEscherichia coliet plaques de Peyer dans la maladie de Crohn. Med Sci (Paris) 2011; 27:572-3. [DOI: 10.1051/medsci/2011276003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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Chassaing B, Rolhion N, de Vallée A, Salim SY, Prorok-Hamon M, Neut C, Campbell BJ, Söderholm JD, Hugot JP, Colombel JF, Darfeuille-Michaud A. Crohn disease--associated adherent-invasive E. coli bacteria target mouse and human Peyer's patches via long polar fimbriae. J Clin Invest 2011; 121:966-75. [PMID: 21339647 DOI: 10.1172/jci44632] [Citation(s) in RCA: 194] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2010] [Accepted: 12/01/2010] [Indexed: 12/13/2022] Open
Abstract
Crohn disease (CD) is a multifactorial disease in which an abnormal immune response in the gastrointestinal (GI) tract leads to chronic inflammation. The small intestine, particularly the ileum, of patients with CD is colonized by adherent-invasive E. coli (AIEC)--a pathogenic group of E. coli able to adhere to and invade intestinal epithelial cells. As the earliest inflammatory lesions are microscopic erosions of the epithelium lining the Peyer's patches (PPs), we investigated the ability of AIEC bacteria to interact with PPs and the virulence factors involved. We found that AIEC bacteria could interact with mouse and human PPs via long polar fimbriae (LPF). An LPF-negative AIEC mutant was highly impaired in its ability to interact with mouse and human PPs and to translocate across monolayers of M cells, specialized epithelial cells at the surface of PPs. The prevalence of AIEC strains harboring the lpf operon was markedly higher in CD patients compared with controls. In addition, increased numbers of AIEC, but not LPF-deficient AIEC, bacteria were found interacting with PPs from Nod2(-/-) mice compared with WT mice. In conclusion, we have identified LPF as a key factor for AIEC to target PPs. This could be the missing link between AIEC colonization and the presence of early lesions in the PPs of CD patients.
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Affiliation(s)
- Benoit Chassaing
- Clermont Université, Université Auvergne, JE2526, USC INRA 2018, Clermont-Ferrand, Auvergne, France
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Salim SY, Söderholm JD. Importance of disrupted intestinal barrier in inflammatory bowel diseases. Inflamm Bowel Dis 2011; 17:362-81. [PMID: 20725949 DOI: 10.1002/ibd.21403] [Citation(s) in RCA: 445] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2010] [Accepted: 06/01/2010] [Indexed: 12/12/2022]
Abstract
The current paradigm of inflammatory bowel diseases (IBD), both Crohn's disease (CD) and ulcerative colitis (UC), involves the interaction between environmental factors in the intestinal lumen and inappropriate host immune responses in genetically predisposed individuals. The intestinal mucosal barrier has evolved to maintain a delicate balance between absorbing essential nutrients while preventing the entry and responding to harmful contents. In IBD, disruptions of essential elements of the intestinal barrier lead to permeability defects. These barrier defects exacerbate the underlying immune system, subsequently resulting in tissue damage. The epithelial phenotype in active IBD is very similar in CD and UC. It is characterized by increased secretion of chloride and water, leading to diarrhea, increased permeability via both the transcellular and paracellular routes, and increased apoptosis of epithelial cells. The main cytokine that seems to drive these changes is tumor necrosis factor alpha in CD, whereas interleukin (IL)-13 may be more important in UC. Therapeutic restoration of the mucosal barrier would provide protection and prevent antigenic overload due to intestinal "leakiness." Here we give an overview of the key players of the intestinal mucosal barrier and review the current literature from studies in humans and human systems on mechanisms underlying mucosal barrier dysfunction in IBD.
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Affiliation(s)
- Sa'ad Y Salim
- Department of Clinical and Experimental Medicine, Division of Surgery and Clinical Oncology, Faculty of Health Sciences, Linköping University, Linköping, Sweden
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48
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Takebayashi K, Koboziev I, Ostanin DV, Gray L, Karlsson F, Robinson-Jackson SA, Kosloski-Davidson M, Dooley AB, Zhang S, Grisham MB. Role of the gut-associated and secondary lymphoid tissue in the induction of chronic colitis. Inflamm Bowel Dis 2011; 17:268-78. [PMID: 20812332 PMCID: PMC3072787 DOI: 10.1002/ibd.21447] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2010] [Accepted: 07/13/2010] [Indexed: 12/13/2022]
Abstract
BACKGROUND It is well known that enteric bacterial antigens drive the development of chronic colitis in a variety of different mouse models of the inflammatory bowel diseases (IBD). The objective of this study was to evaluate the role of gut-associated lymphoid tissue (GALT; Peyer's patches, isolated lymphoid follicles), mesenteric lymph nodes (MLNs) and spleen in the pathogenesis of chronic colitis in mice. METHODS Surgical as well as genetic approaches were used to generate lymphopenic mice devoid of one or more of these lymphoid tissues. For the first series of studies, we subjected recombinase activating gene-1-deficient mice (RAG(-/-) ) to sham surgery (Sham), mesenteric lymphadenectomy (MLNx), splenectomy (Splx) or both (MLNx/Splx). In a second series of studies we intercrossed lymphotoxinβ-deficient (LTβ(-/-) ) mice with RAG(-/-) animals to generate LTβ(-/-) x RAG(-/-) offspring that were anticipated to contain functional MLNs but be devoid of GALT and most peripheral lymph nodes. Flow purified naïve (CD4(+) CD45RB(high) ) T-cells were adoptively transferred into the different groups of RAG(-/-) recipients to induce chronic colitis. RESULTS We found that at 3-5 wks following T-cell transfer, all four of the surgically-manipulated RAG(-/-) groups (Sham, MLNx, Splx and MLNx/Splx) developed chronic colitis that was similar in onset and severity. Flow cytometric analysis revealed no differences among the different groups with respect to surface expression of different gut-homing markers nor were there any differences noted in IFN-γ and IL-17 generation by mononuclear cells isolated among these surgically-manipulated mice. Although we anticipated that LTβ(-/-) x RAG(-/-) mice would contain functional MLNs but be devoid of GALT and peripheral lymph nodes (PLNs), we found that LTβ(-/-) x RAG(-/-) mice were in fact devoid of MLNs as well as GALT and PLNs. Adoptive transfer of CD45RB(high) T-cells into LTβ(-/-) x RAG(-/-) mice or their littermate controls (LTβ(+/+) x RAG(-/-) ) induced rapid and severe colitis in both groups. CONCLUSIONS Taken together, our data demonstrate that: a) neither the GALT, MLNs nor PLNs are required for induction of chronic gut inflammation in this model of IBD and b) T-and/or B-cells may be required for the development of MLNs in LTβ(-/-) mice.
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Affiliation(s)
- Koichi Takebayashi
- Immunology and Inflammation Research Group, LSU Health Sciences Center, Shreveport, Louisiana.,Department of Molecular and Cellular Physiology, LSU Health Sciences Center, Shreveport, Louisiana
| | - Iurii Koboziev
- Immunology and Inflammation Research Group, LSU Health Sciences Center, Shreveport, Louisiana.,Department of Molecular and Cellular Physiology, LSU Health Sciences Center, Shreveport, Louisiana
| | - Dmitry V. Ostanin
- Immunology and Inflammation Research Group, LSU Health Sciences Center, Shreveport, Louisiana.,Department of Medicine, Division of Rheumatology, LSU Health Sciences Center, Shreveport, Louisiana
| | - Laura Gray
- Immunology and Inflammation Research Group, LSU Health Sciences Center, Shreveport, Louisiana.,Department of Molecular and Cellular Physiology, LSU Health Sciences Center, Shreveport, Louisiana
| | - Fridrik Karlsson
- Immunology and Inflammation Research Group, LSU Health Sciences Center, Shreveport, Louisiana.,Department of Molecular and Cellular Physiology, LSU Health Sciences Center, Shreveport, Louisiana
| | - Sherry A. Robinson-Jackson
- Immunology and Inflammation Research Group, LSU Health Sciences Center, Shreveport, Louisiana.,Department of Molecular and Cellular Physiology, LSU Health Sciences Center, Shreveport, Louisiana
| | - Melissa Kosloski-Davidson
- Immunology and Inflammation Research Group, LSU Health Sciences Center, Shreveport, Louisiana.,Department of Molecular and Cellular Physiology, LSU Health Sciences Center, Shreveport, Louisiana
| | - Angela Burrows Dooley
- Immunology and Inflammation Research Group, LSU Health Sciences Center, Shreveport, Louisiana.,Department of Molecular and Cellular Physiology, LSU Health Sciences Center, Shreveport, Louisiana
| | - Songlin Zhang
- Immunology and Inflammation Research Group, LSU Health Sciences Center, Shreveport, Louisiana.,Department of Pathology, LSU Health Sciences Center, Shreveport, Louisiana
| | - Matthew B. Grisham
- Immunology and Inflammation Research Group, LSU Health Sciences Center, Shreveport, Louisiana.,Department of Molecular and Cellular Physiology, LSU Health Sciences Center, Shreveport, Louisiana
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Ping X, Li Y, Li J. Antigen sampling on the Peyer's patches in a murine small bowel transplantation model. Transplant Proc 2010; 42:3803-8. [PMID: 21094860 DOI: 10.1016/j.transproceed.2010.08.057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2010] [Revised: 07/10/2010] [Accepted: 08/20/2010] [Indexed: 10/18/2022]
Abstract
AIM This study investigated changes in the mucosal barrier of transplanted intestines with particular emphasis on antigen sampling by Peyer's patches (PPs). METHODS Heterotopic small bowel transplantation (SBTx) was performed as described previously. C57BL/6 mice were used as donors and BALB/c (allogeneic) or C57BL/6 mice (syngeneic) as recipients. Tacrolimus (FK506) or saline control was administered to the recipients for 2 weeks. Four groups included in this study were: syngeneic with or without immunosuppression (SYN and SYN + FK506, respectively) and allogeneic with or without immunosuppression (ALLO and ALLO + FK506, respectively). Animals were sacrificed weekly after SBTx to evaluate microfold (M) cells within PPs and for routine histology. By the third postoperative week, recipients were subjected to an intestine loop model to examine the uptake of microbeads by M cells as well as expression of Toll-like receptor 2 (TLR2) protein in the PPs with or without a TLR2 agonist challenge. We also measured occludin expression on follicle-associated epithelium (FAE) of PPs in the grafts. RESULTS Transportation of microbeads through the PPs of the grafts increased in the ALLO + FK506 group compared with that in the SYN or SYN + FK506 group. This finding was accompanied by increased expression of TLR2 in the PPs and a gradually increased number of M cells following SBTx. However, occludin expression patterns on the FAE of the PPs in the grafts were similar among SYN, SYN + FK506, and ALLO + FK506 groups. Nevertheless, as transportation of microbeads and TLR2 expression in the PPs of the grafts was enhanced once exposed to Pam3Cys-SKKKK, similar results were not seen in the ALLO + FK506 group. CONCLUSIONS Our study revealed that the mucosal barrier of intestinal grafts is altered under alloreactivity as evidenced by enhanced antigen sampling. Such a change may provide a pathway for translocation of microorganisms in the lumen.
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Affiliation(s)
- X Ping
- Nanjing University School of Medicine, Research Institute of General Surgery, Jinling Hospital, Nanjing, China
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50
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Kalischuk LD, Leggett F, Inglis GD. Campylobacter jejuni induces transcytosis of commensal bacteria across the intestinal epithelium through M-like cells. Gut Pathog 2010. [PMID: 21040540 DOI: 10.1186/1757] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Recent epidemiological analyses have implicated acute Campylobacter enteritis as a factor that may incite or exacerbate inflammatory bowel disease (IBD) in susceptible individuals. We have demonstrated previously that C. jejuni disrupts the intestinal barrier function by rapidly inducing epithelial translocation of non-invasive commensal bacteria via a transcellular lipid raft-mediated mechanism ('transcytosis'). To further characterize this mechanism, the aim of this current study was to elucidate whether C. jejuni utilizes M cells to facilitate transcytosis of commensal intestinal bacteria. RESULTS C. jejuni induced translocation of non-invasive E. coli across confluent Caco-2 epithelial monolayers in the absence of disrupted transepithelial electrical resistance or increased permeability to a 3 kDa dextran probe. C. jejuni-infected monolayers displayed increased numbers of cells expressing the M cell-specific marker, galectin-9, reduced numbers of enterocytes that stained with the absorptive enterocyte marker, Ulex europaeus agglutinin-1, and reduced activities of enzymes typically associated with absorptive enterocytes (namely alkaline phosphatase, lactase, and sucrase). Furthermore, in Campylobacter-infected monolayers, E. coli were observed to be internalized specifically within epithelial cells displaying M-like cell characteristics. CONCLUSION These data indicate that C. jejuni may utilize M cells to promote transcytosis of non-invasive bacteria across the intact intestinal epithelial barrier. This mechanism may contribute to the inflammatory immune responses against commensal intestinal bacteria commonly observed in IBD patients.
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Affiliation(s)
- Lisa D Kalischuk
- Agriculture and Agri-Food Canada, 5403 1st Avenue South, T1J 4B1, Lethbridge, AB, Canada.
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