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1
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Jans M, Vereecke L. A guide to germ-free and gnotobiotic mouse technology to study health and disease. FEBS J 2025; 292:1228-1251. [PMID: 38523409 DOI: 10.1111/febs.17124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 01/17/2024] [Accepted: 03/11/2024] [Indexed: 03/26/2024]
Abstract
The intestinal microbiota has major influence on human physiology and modulates health and disease. Complex host-microbe interactions regulate various homeostatic processes, including metabolism and immune function, while disturbances in microbiota composition (dysbiosis) are associated with a plethora of human diseases and are believed to modulate disease initiation, progression and therapy response. The vast complexity of the human microbiota and its metabolic output represents a great challenge in unraveling the molecular basis of host-microbe interactions in specific physiological contexts. To increase our understanding of these interactions, functional microbiota research using animal models in a reductionistic setting are essential. In the dynamic landscape of gut microbiota research, the use of germ-free and gnotobiotic mouse technology, in which causal disease-driving mechanisms can be dissected, represents a pivotal investigative tool for functional microbiota research in health and disease, in which causal disease-driving mechanisms can be dissected. A better understanding of the health-modulating functions of the microbiota opens perspectives for improved therapies in many diseases. In this review, we discuss practical considerations for the design and execution of germ-free and gnotobiotic experiments, including considerations around germ-free rederivation and housing conditions, route and timing of microbial administration, and dosing protocols. This comprehensive overview aims to provide researchers with valuable insights for improved experimental design in the field of functional microbiota research.
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Affiliation(s)
- Maude Jans
- VIB Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Belgium
| | - Lars Vereecke
- VIB Center for Inflammation Research, Ghent, Belgium
- Department of Internal Medicine and Pediatrics, Ghent University, Belgium
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2
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Lao J, Yan S, Yong Y, Li Y, Wen Z, Zhang X, Ju X, Li Y. Lacticaseibacillus casei IB1 Alleviates DSS-Induced Inflammatory Bowel Disease by Regulating the Microbiota and Restoring the Intestinal Epithelial Barrier. Microorganisms 2024; 12:1379. [PMID: 39065147 PMCID: PMC11278699 DOI: 10.3390/microorganisms12071379] [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: 04/26/2024] [Revised: 06/18/2024] [Accepted: 07/04/2024] [Indexed: 07/28/2024] Open
Abstract
Inflammatory bowel disease (IBD) is becoming an increasingly serious health problem in humans and animals. Probiotics can inhibit the development of IBD. Due to the specificity of the strains, the function and mechanism of action of different strains are still unclear. Here, a DSS-induced colitis mouse model was utilized to investigate the ability and mechanism by which Lacticaseibacillus casei IB1 alleviates colitis. Treatment with L. casei IB1 improved DSS-induced colitis in mice, as indicated by increased body weight, colon length, and goblet cell numbers and decreased disease activity index (DAI), proinflammatory factor (TNF-α, IL-1β, and IL-6) levels, and histopathological scores after intake of IB1. IB1 supplementation also improved the expression of tight junction proteins and inhibited the activation of the MAPK and NF-κB signaling pathways to alleviate intestinal inflammation. In addition, IB1 rebalanced the intestinal microbial composition of colitis mice by increasing the abundance of Faecalibaculum and Alistipes and decreasing the abundance of Bacteroides and Escherichia_Shigella. In summary, L. casei IB1 showed great potential for relieving colitis by regulating the microbiota and restoring the epithelial barrier. It can be used as a potential probiotic for the prevention and treatment of UC in the future.
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Affiliation(s)
- Jianlong Lao
- College of Coastal Agricultural Sciences, Guangdong Ocean University, Zhanjiang 524088, China; (J.L.); (S.Y.); (Y.Y.); (Y.L.); (Z.W.); (X.Z.)
- Marine Medical Research and Development Centre, Shenzhen Institute of Guangdong Ocean University, Shenzhen 518120, China
| | - Shuping Yan
- College of Coastal Agricultural Sciences, Guangdong Ocean University, Zhanjiang 524088, China; (J.L.); (S.Y.); (Y.Y.); (Y.L.); (Z.W.); (X.Z.)
| | - Yanhong Yong
- College of Coastal Agricultural Sciences, Guangdong Ocean University, Zhanjiang 524088, China; (J.L.); (S.Y.); (Y.Y.); (Y.L.); (Z.W.); (X.Z.)
| | - Yin Li
- College of Coastal Agricultural Sciences, Guangdong Ocean University, Zhanjiang 524088, China; (J.L.); (S.Y.); (Y.Y.); (Y.L.); (Z.W.); (X.Z.)
| | - Zhaohai Wen
- College of Coastal Agricultural Sciences, Guangdong Ocean University, Zhanjiang 524088, China; (J.L.); (S.Y.); (Y.Y.); (Y.L.); (Z.W.); (X.Z.)
| | - Xiaoyong Zhang
- College of Coastal Agricultural Sciences, Guangdong Ocean University, Zhanjiang 524088, China; (J.L.); (S.Y.); (Y.Y.); (Y.L.); (Z.W.); (X.Z.)
| | - Xianghong Ju
- College of Coastal Agricultural Sciences, Guangdong Ocean University, Zhanjiang 524088, China; (J.L.); (S.Y.); (Y.Y.); (Y.L.); (Z.W.); (X.Z.)
- Marine Medical Research and Development Centre, Shenzhen Institute of Guangdong Ocean University, Shenzhen 518120, China
| | - Youquan Li
- College of Coastal Agricultural Sciences, Guangdong Ocean University, Zhanjiang 524088, China; (J.L.); (S.Y.); (Y.Y.); (Y.L.); (Z.W.); (X.Z.)
- Marine Medical Research and Development Centre, Shenzhen Institute of Guangdong Ocean University, Shenzhen 518120, China
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Shaosan Z, Zhao T, Wang Y, Mi J, Liu J, Fan X, Niu R, Sun Z. Intestinal microbiota regulates colonic inflammation in fluorosis mice by TLR/NF-κB pathway through short-chain fatty acids. Food Chem Toxicol 2023:113866. [PMID: 37269894 DOI: 10.1016/j.fct.2023.113866] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 05/20/2023] [Accepted: 05/31/2023] [Indexed: 06/05/2023]
Abstract
Intestinal inflammation and microbial dysbiosis are found simultaneously in patients with fluorosis. However, whether the inflammation derived from fluoride exposure only or intestinal microbial disorders has not been clarified. In this study, 100 mg/L NaF exposure for 90 days significantly elevated the expressions of inflammatory factors (TNF-α, IL-1β, IL-6, IFN-γ, TGF-β, and IL-10), and the levels of TLR4, TRAF6, Myd88, IKKβ, and NF-κB P65 in mouse colon, while the above factors were reduced in pseudo germ-free mice with fluorosis, hinting that disordered microbiota might play a more direct role in the development of colonic inflammation than fluoride. Fecal microbiota transplantation (FMT) lowered the levels of inflammatory factors and inactivated the TLR/NF-κB pathway in fluoride-exposed mice. In addition, supplementing short-chain fatty acids (SCFAs) exhibited the identical effects to the model of FMT. In summary, intestinal microbiota may alleviate the colonic inflammatory of mice with fluorosis by regulating TLR/NF-κB pathway through SCFAs.
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Affiliation(s)
- Zhang Shaosan
- Shanxi Key Laboratory of Ecological Animal Science and Environmental Veterinary Medicine, College of Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, 030801, China
| | - Taotao Zhao
- Shanxi Key Laboratory of Ecological Animal Science and Environmental Veterinary Medicine, College of Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, 030801, China
| | - Yu Wang
- Shanxi Key Laboratory of Ecological Animal Science and Environmental Veterinary Medicine, College of Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, 030801, China
| | - Jiahui Mi
- Shanxi Key Laboratory of Ecological Animal Science and Environmental Veterinary Medicine, College of Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, 030801, China
| | - Jie Liu
- Shanxi Key Laboratory of Ecological Animal Science and Environmental Veterinary Medicine, College of Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, 030801, China
| | - Xinyu Fan
- Shanxi Key Laboratory of Ecological Animal Science and Environmental Veterinary Medicine, College of Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, 030801, China
| | - Ruiyan Niu
- Shanxi Key Laboratory of Ecological Animal Science and Environmental Veterinary Medicine, College of Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, 030801, China.
| | - Zilong Sun
- Shanxi Key Laboratory of Ecological Animal Science and Environmental Veterinary Medicine, College of Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, 030801, China.
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Eswaran S, Babbar A, Drescher HK, Hitch TCA, Clavel T, Muschaweck M, Ritz T, Kroy DC, Trautwein C, Wagner N, Schippers A. Upregulation of Anti-Oxidative Stress Response Improves Metabolic Changes in L-Selectin-Deficient Mice but Does Not Prevent NAFLD Progression or Fecal Microbiota Shifts. Int J Mol Sci 2021; 22:ijms22147314. [PMID: 34298930 PMCID: PMC8306675 DOI: 10.3390/ijms22147314] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/29/2021] [Accepted: 07/04/2021] [Indexed: 12/12/2022] Open
Abstract
(1) Background: Non-alcoholic fatty liver disease (NAFLD) is a growing global health problem. NAFLD progression involves a complex interplay of imbalanced inflammatory cell populations and inflammatory signals such as reactive oxygen species and cytokines. These signals can derive from the liver itself but also from adipose tissue or be mediated via changes in the gut microbiome. We analyzed the effects of a simultaneous migration blockade caused by L-selectin-deficiency and an enhancement of the anti-oxidative stress response triggered by hepatocytic Kelch-like ECH-associated protein 1 (Keap1) deletion on NAFLD progression. (2) Methods: L-selectin-deficient mice (Lsel−/−Keap1flx/flx) and littermates with selective hepatic Keap1 deletion (Lsel−/−Keap1Δhepa) were compared in a 24-week Western-style diet (WD) model. (3) Results: Lsel−/−Keap1Δhepa mice exhibited increased expression of erythroid 2-related factor 2 (Nrf2) target genes in the liver, decreased body weight, reduced epidydimal white adipose tissue with decreased immune cell frequencies, and improved glucose response when compared to their Lsel−/−Keap1flx/flx littermates. Although WD feeding caused drastic changes in fecal microbiota profiles with decreased microbial diversity, no genotype-dependent shifts were observed. (4) Conclusions: Upregulation of the anti-oxidative stress response improves metabolic changes in L-selectin-deficient mice but does not prevent NAFLD progression and shifts in the gut microbiota.
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Affiliation(s)
- Sreepradha Eswaran
- Department of Pediatrics, Faculty of Medicine, RWTH Aachen University, D-52074 Aachen, Germany; (S.E.); (A.B.); (M.M.)
| | - Anshu Babbar
- Department of Pediatrics, Faculty of Medicine, RWTH Aachen University, D-52074 Aachen, Germany; (S.E.); (A.B.); (M.M.)
- Production Animal Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Hannah K. Drescher
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA;
| | - Thomas C. A. Hitch
- Functional Microbiome Research Group, Faculty of Medicine, RWTH Aachen University, D-52074 Aachen, Germany; (T.C.A.H.); (T.C.)
| | - Thomas Clavel
- Functional Microbiome Research Group, Faculty of Medicine, RWTH Aachen University, D-52074 Aachen, Germany; (T.C.A.H.); (T.C.)
| | - Moritz Muschaweck
- Department of Pediatrics, Faculty of Medicine, RWTH Aachen University, D-52074 Aachen, Germany; (S.E.); (A.B.); (M.M.)
| | - Thomas Ritz
- Institute of Pathology, Ruprecht-Karls-University Heidelberg, D-69117 Heidelberg, Germany;
| | - Daniela C. Kroy
- Department of Internal Medicine III, University Hospital, RWTH Aachen, D-52074 Aachen, Germany; (D.C.K.); (C.T.)
| | - Christian Trautwein
- Department of Internal Medicine III, University Hospital, RWTH Aachen, D-52074 Aachen, Germany; (D.C.K.); (C.T.)
| | - Norbert Wagner
- Department of Pediatrics, Faculty of Medicine, RWTH Aachen University, D-52074 Aachen, Germany; (S.E.); (A.B.); (M.M.)
- Correspondence: (N.W.); (A.S.)
| | - Angela Schippers
- Department of Pediatrics, Faculty of Medicine, RWTH Aachen University, D-52074 Aachen, Germany; (S.E.); (A.B.); (M.M.)
- Correspondence: (N.W.); (A.S.)
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5
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Ashaolu TJ, Fernández-Tomé S. Gut mucosal and adipose tissues as health targets of the immunomodulatory mechanisms of probiotics. Trends Food Sci Technol 2021. [DOI: 10.1016/j.tifs.2021.04.040] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Poletti M, Arnauts K, Ferrante M, Korcsmaros T. Organoid-based Models to Study the Role of Host-microbiota Interactions in IBD. J Crohns Colitis 2020; 15:1222-1235. [PMID: 33341879 PMCID: PMC8256633 DOI: 10.1093/ecco-jcc/jjaa257] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The gut microbiota appears to play a central role in health, and alterations in the gut microbiota are observed in both forms of inflammatory bowel disease [IBD], namely Crohn's disease and ulcerative colitis. Yet, the mechanisms behind host-microbiota interactions in IBD, especially at the intestinal epithelial cell level, are not yet fully understood. Dissecting the role of host-microbiota interactions in disease onset and progression is pivotal, and requires representative models mimicking the gastrointestinal ecosystem, including the intestinal epithelium, the gut microbiota, and immune cells. New advancements in organoid microfluidics technology are facilitating the study of IBD-related microbial-epithelial cross-talk, and the discovery of novel microbial therapies. Here, we review different organoid-based ex vivo models that are currently available, and benchmark their suitability and limitations for specific research questions. Organoid applications, such as patient-derived organoid biobanks for microbial screening and 'omics technologies, are discussed, highlighting their potential to gain better mechanistic insights into disease mechanisms and eventually allow personalised medicine.
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Affiliation(s)
- Martina Poletti
- Earlham Institute, Norwich Research Park, Norwich, UK,Quadram Institute, Norwich Research Park, Norwich, UK
| | - Kaline Arnauts
- Department of Chronic Diseases, Metabolism and Ageing [CHROMETA], Translational Research Center for Gastrointestinal Disorders [TARGID], KU Leuven, Leuven, Belgium,Department of Development and Regeneration, Stem Cell Institute Leuven [SCIL], KU Leuven, Leuven, Belgium
| | - Marc Ferrante
- Department of Chronic Diseases, Metabolism and Ageing [CHROMETA], Translational Research Center for Gastrointestinal Disorders [TARGID], KU Leuven, Leuven, Belgium,Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium,Corresponding author: Marc Ferrante, MD, PhD, Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Herestraat 49, 3000 Leuven, Belgium. Tel.: +32 16 344225;
| | - Tamas Korcsmaros
- Earlham Institute, Norwich Research Park, Norwich, UK,Quadram Institute, Norwich Research Park, Norwich, UK
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7
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Schippers A, Hübel J, Heymann F, Clahsen T, Eswaran S, Schlepütz S, Püllen R, Gaßler N, Tenbrock K, Tacke F, Wagner N. MAdCAM-1/α4β7 Integrin-Mediated Lymphocyte/Endothelium Interactions Exacerbate Acute Immune-Mediated Hepatitis in Mice. Cell Mol Gastroenterol Hepatol 2020; 11:1227-1250.e1. [PMID: 33316453 PMCID: PMC8053699 DOI: 10.1016/j.jcmgh.2020.12.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 12/03/2020] [Accepted: 12/04/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Aberrant lymphocyte homing could potentially link inflammatory processes in the intestine and the liver, as distinct hepatobiliary diseases frequently develop as extra-intestinal manifestations in inflammatory bowel disease. In this study, we examined the role of the gut-tropic leukocyte adhesion molecule β7 integrin and its endothelial ligand mucosal addressin cell-adhesion molecule-1 (MAdCAM-1) in immune-mediated hepatitis in mice. METHODS Wild-type (WT) mice, MAdCAM-1-deficient mice, β7 integrin-deficient mice, RAG-2-deficient mice, RAG-2/MAdCAM-1 double-deficient mice, and RAG-2/β7 integrin double-deficient mice were subjected to concanavalin A (ConA)-induced hepatitis. The degree of hepatitis was evaluated by histology, flow cytometry, and expression analysis of inflammatory mediators. The motility of lymphocytes in progressive liver damage was assessed by intravital laser scanning multiphoton microscopy. RESULTS Ablation of MAdCAM-1 or β7 integrin ameliorated ConA-induced hepatitis in mice. β7 integrin-deficient lymphocytes caused less liver damage than WT lymphocytes in ConA-treated RAG-2-deficient mice. Moreover, WT lymphocytes caused less liver damage in ConA-treated RAG-2/β7 integrin double-deficient mice than in similarly treated RAG-2-deficient mice, indicating that β7 integrin expression contributes significantly to the liver damage mediated by innate immune cells. MAdCAM-1 expression was dependent on β7 integrin expression on adaptive and innate immune cells. Most importantly, lymphocytes in ConA-treated MAdCAM-1-deficient mice displayed more motility and less adhesion in the liver sinusoids in vivo, than lymphocytes in similarly treated WT mice. CONCLUSIONS These data suggest that β7 integrin expression on lymphocytes and innate immune cells contributes to MAdCAM-1 upregulation and liver damage in acute immune-mediated hepatitis, most likely by facilitating lymphocyte/sinusoidal endothelial cell interactions.
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Affiliation(s)
- Angela Schippers
- Department of Pediatrics, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Jessica Hübel
- Department of Pediatrics, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Felix Heymann
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany
| | - Thomas Clahsen
- Department of Pediatrics, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Sreepradha Eswaran
- Department of Pediatrics, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Sarah Schlepütz
- Department of Pediatrics, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Robin Püllen
- Department of Pediatrics, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Nikolaus Gaßler
- Institute of Forensic Medicine, Section of Pathology, Jena University Hospital, Jena, Germany
| | - Klaus Tenbrock
- Department of Pediatrics, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany
| | - Norbert Wagner
- Department of Pediatrics, Medical Faculty, RWTH Aachen University, Aachen, Germany.
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8
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Hurtubise R, Audiger C, Dominguez-Punaro MC, Chabot-Roy G, Chognard G, Raymond-Marchand L, Coderre L, Chemtob S, Michnick SW, Rioux JD, Lesage S. Induced and spontaneous colitis mouse models reveal complex interactions between IL-10 and IL-12/IL-23 pathways. Cytokine 2019; 121:154738. [DOI: 10.1016/j.cyto.2019.154738] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Revised: 05/13/2019] [Accepted: 05/28/2019] [Indexed: 02/08/2023]
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9
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Khan I, Ullah N, Zha L, Bai Y, Khan A, Zhao T, Che T, Zhang C. Alteration of Gut Microbiota in Inflammatory Bowel Disease (IBD): Cause or Consequence? IBD Treatment Targeting the Gut Microbiome. Pathogens 2019; 8:pathogens8030126. [PMID: 31412603 PMCID: PMC6789542 DOI: 10.3390/pathogens8030126] [Citation(s) in RCA: 491] [Impact Index Per Article: 81.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 08/03/2019] [Accepted: 08/05/2019] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic complex inflammatory gut pathological condition, examples of which include Crohn’s disease (CD) and ulcerative colitis (UC), which is associated with significant morbidity. Although the etiology of IBD is unknown, gut microbiota alteration (dysbiosis) is considered a novel factor involved in the pathogenesis of IBD. The gut microbiota acts as a metabolic organ and contributes to human health by performing various physiological functions; deviation in the gut flora composition is involved in various disease pathologies, including IBD. This review aims to summarize the current knowledge of gut microbiota alteration in IBD and how this contributes to intestinal inflammation, as well as explore the potential role of gut microbiota-based treatment approaches for the prevention and treatment of IBD. The current literature has clearly demonstrated a perturbation of the gut microbiota in IBD patients and mice colitis models, but a clear causal link of cause and effect has not yet been presented. In addition, gut microbiota-based therapeutic approaches have also shown good evidence of their effects in the amelioration of colitis in animal models (mice) and IBD patients, which indicates that gut flora might be a new promising therapeutic target for the treatment of IBD. However, insufficient data and confusing results from previous studies have led to a failure to define a core microbiome associated with IBD and the hidden mechanism of pathogenesis, which suggests that well-designed randomized control trials and mouse models are required for further research. In addition, a better understanding of this ecosystem will also determine the role of prebiotics and probiotics as therapeutic agents in the management of IBD.
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Affiliation(s)
- Israr Khan
- School of Life Sciences, Lanzhou University, Lanzhou 730000, China
- Key Laboratory of Cell Activities and Stress Adaptations, Ministry of Education, Lanzhou University, Lanzhou 730000, China
- Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, Lanzhou University, Lanzhou 730000, China
| | - Naeem Ullah
- School of Life Sciences, Lanzhou University, Lanzhou 730000, China
- Key Laboratory of Cell Activities and Stress Adaptations, Ministry of Education, Lanzhou University, Lanzhou 730000, China
- Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, Lanzhou University, Lanzhou 730000, China
| | - Lajia Zha
- School of Life Sciences, Lanzhou University, Lanzhou 730000, China
- Key Laboratory of Cell Activities and Stress Adaptations, Ministry of Education, Lanzhou University, Lanzhou 730000, China
- Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, Lanzhou University, Lanzhou 730000, China
| | - Yanrui Bai
- School of Life Sciences, Lanzhou University, Lanzhou 730000, China
- Key Laboratory of Cell Activities and Stress Adaptations, Ministry of Education, Lanzhou University, Lanzhou 730000, China
- Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, Lanzhou University, Lanzhou 730000, China
| | - Ashiq Khan
- School of Life Sciences, Lanzhou University, Lanzhou 730000, China
- Probiotics and Biological Feed Research Center, Lanzhou University, Lanzhou 730000, China
| | - Tang Zhao
- School of Life Sciences, Lanzhou University, Lanzhou 730000, China
- Key Laboratory of Cell Activities and Stress Adaptations, Ministry of Education, Lanzhou University, Lanzhou 730000, China
- Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, Lanzhou University, Lanzhou 730000, China
| | - Tuanjie Che
- Gansu Key Laboratory of Functional Genomics and Molecular Diagnosis, Lanzhou 730000, China
| | - Chunjiang Zhang
- School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
- Key Laboratory of Cell Activities and Stress Adaptations, Ministry of Education, Lanzhou University, Lanzhou 730000, China.
- Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, Lanzhou University, Lanzhou 730000, China.
- Gansu Key Laboratory of Functional Genomics and Molecular Diagnosis, Lanzhou 730000, China.
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10
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Geesala R, Schanz W, Biggs M, Dixit G, Skurski J, Gurung P, Meyerholz DK, Elliott D, Issuree PD, Maretzky T. Loss of RHBDF2 results in an early-onset spontaneous murine colitis. J Leukoc Biol 2019; 105:767-781. [PMID: 30694569 DOI: 10.1002/jlb.4a0718-283rr] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Revised: 01/16/2019] [Accepted: 01/17/2019] [Indexed: 12/16/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a heterogeneous group of inflammation-mediated pathologies that include Crohn's disease and ulcerative colitis and primarily affects the colon and small intestine. Previous studies have shown that a disintegrin and metalloprotease (ADAM) 17, a membrane-bound sheddase, capable of cleaving the proinflammatory cytokine TNF and epidermal growth factor receptor ligands, plays a critical role in maintaining gut homeostasis and modulating intestinal inflammation during IBD. Rhomboid 5 homolog 2 (RHBDF2), a catalytically inactive member of the rhomboid family of intramembrane serine proteases, was recently identified as a crucial regulator of ADAM17. Here, we assessed the role of RHBDF2 in the development of colitis in the context of IL10 deficiency. Il10-/- /Rhbdf2-/- mice developed spontaneous colitis and experienced severe weight loss starting at 8 wk of age, without the need for exogenous triggers. Severity of disease pathology in Il10-/- /Rhbdf2-/- mice correlated with a dysbiotic gut microbiota and elevated Th1-associated immune responses with increased interferon gamma and IL2 production. In addition, Il10-/- /Rhbdf2-/- mice failed to maintain their epithelial cell homeostasis, although the intestinal epithelial barrier of Rhbdf2-/- mice is intact and loss of Rhbdf2 did not significantly exacerbate sensitivity to dextran sulfate sodium-induced colitis, suggesting differences in the underlying disease pathway of intestinal inflammation in this model. Taken together, our results demonstrate a critical regulatory role for RHBDF2 in the maintenance of the unique homeostasis between intestinal microbiota and host immune responses in the gut that is dysregulated during the pathogenesis of IBD.
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Affiliation(s)
- Ramasatyaveni Geesala
- Inflammation Program, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa, USA.,Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa, USA
| | - Willow Schanz
- Inflammation Program, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa, USA.,Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa, USA
| | - Mikayla Biggs
- Inflammation Program, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa, USA.,Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa, USA
| | - Garima Dixit
- Inflammation Program, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa, USA.,Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa, USA
| | - Joseph Skurski
- Inflammation Program, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa, USA.,Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa, USA.,Immunology Graduate Program, Iowa City, Iowa, USA
| | - Prajwal Gurung
- Inflammation Program, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa, USA.,Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa, USA.,Immunology Graduate Program, Iowa City, Iowa, USA
| | - David K Meyerholz
- Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA
| | - David Elliott
- Department of Veterans Affairs Medical Center, Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA
| | - Priya D Issuree
- Inflammation Program, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa, USA.,Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa, USA
| | - Thorsten Maretzky
- Inflammation Program, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa, USA.,Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa, USA.,Immunology Graduate Program, Iowa City, Iowa, USA.,Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa, USA
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11
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Zhu JF, Xu Y, Zhao J, Li X, Meng X, Wang TQ, Zou BY, Zhao PY, Liu Q, Lu CL, Zheng FL, Liu HS. IL-33 Protects Mice against DSS-Induced Chronic Colitis by Increasing Both Regulatory B Cell and Regulatory T Cell Responses as Well as Decreasing Th17 Cell Response. J Immunol Res 2018; 2018:1827901. [PMID: 30539029 PMCID: PMC6260543 DOI: 10.1155/2018/1827901] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Revised: 08/21/2018] [Accepted: 08/27/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Previously, we have reported that IL-33 functioned as a protective modulator in dextran sulfate sodium- (DSS-) induced chronic colitis by suppressing Th17 cell response in colon lamina propria and IL-33 induced both regulatory B cells (Bregs) and regulatory T cells (Tregs) in mesenteric lymph nodes (MLNs) of mice with DSS-induced acute colitis. Moreover, we speculated that IL-33 would promote the Treg or Breg responses leading to the attenuation of DSS-induced chronic colitis. So, we investigated the role of IL-33 on Bregs and Tregs in the MLN of DSS-induced chronic colitis mice. METHODS IL-33 was administered by intraperitoneal injection to mice with DSS-induced chronic colitis. Clinical symptoms, colon length, and histological changes were determined. The production of cytokines was measured by ELISA. The T and B cell subsets were measured by flow cytometry. The expression of mRNA of transcription factors was measured by quantitative real-time PCR. RESULTS We show that IL-33 treatment increases both Breg and Treg responses in the MLN of mice with DSS-induced chronic colitis. Moreover, IL-33 treatment also decreases Th17 cell response in the MLN of mice with DSS-induced chronic colitis. CONCLUSION Our data provide clear evidence that IL-33 plays a protective role in DSS-induced chronic colitis, which is closely related to increasing Breg and Treg responses in the MLN of mice as well as suppressing Th17 cell responses.
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Affiliation(s)
- Jun-feng Zhu
- Life Science School, Liaoning University, Shenyang 110036, China
| | - Ying Xu
- Life Science School, Liaoning University, Shenyang 110036, China
| | - Jian Zhao
- Life Science School, Liaoning University, Shenyang 110036, China
- Engineering Laboratory for Molecular Simulation and Designing of Drug Molecules of Liaoning, Shenyang 110036, China
| | - Xue Li
- Life Science School, Liaoning University, Shenyang 110036, China
| | - Xinrui Meng
- Life Science School, Liaoning University, Shenyang 110036, China
| | - Tian-qi Wang
- Life Science School, Liaoning University, Shenyang 110036, China
| | - Ben-yao Zou
- Life Science School, Liaoning University, Shenyang 110036, China
| | - Peng-yan Zhao
- Life Science School, Liaoning University, Shenyang 110036, China
| | - Qi Liu
- Life Science School, Liaoning University, Shenyang 110036, China
| | - Chang-long Lu
- Department of Immunology, China Medical University, Shenyang 110013, China
| | - Fang-liang Zheng
- Life Science School, Liaoning University, Shenyang 110036, China
| | - Hong-sheng Liu
- Life Science School, Liaoning University, Shenyang 110036, China
- Engineering Laboratory for Molecular Simulation and Designing of Drug Molecules of Liaoning, Shenyang 110036, China
- Research Center for Computer Simulating and Information Processing of Bio-Macromolecules of Liaoning, Shenyang 110036, China
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12
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Ohl K, Fragoulis A, Klemm P, Baumeister J, Klock W, Verjans E, Böll S, Möllmann J, Lehrke M, Costa I, Denecke B, Schippers A, Roth J, Wagner N, Wruck C, Tenbrock K. Nrf2 Is a Central Regulator of Metabolic Reprogramming of Myeloid-Derived Suppressor Cells in Steady State and Sepsis. Front Immunol 2018; 9:1552. [PMID: 30034396 PMCID: PMC6043652 DOI: 10.3389/fimmu.2018.01552] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2018] [Accepted: 06/22/2018] [Indexed: 12/18/2022] Open
Abstract
Arising in inflammatory conditions, myeloid-derived suppressor cells (MDSCs) are constantly confronted with intracellular and extracellular reactive oxygen species molecules and oxidative stress. Generating mice with a constitutive activation of Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) we show a pivotal role of the antioxidant stress defense for development of these immune-modulatory cells. These mice are characterized by a massive increase of splenic CD11b+Gr-1+ cells, which exhibit typical suppressive characteristics of MDSCs. Whole transcriptome analysis revealed Nrf2-dependent activation of cell cycle and metabolic pathways, which resemble pathways in CD11b+Gr-1+ MDSCs expanded by in vivo LPS exposure. Constitutive Nrf2 activation thereby regulates activation and balance between glycolysis and mitochondrial metabolism and hence expansion of highly suppressive MDSCs, which mediate protection in LPS-induced sepsis. Our study establishes Nrf2 as key regulator of MDSCs and acquired tolerance against LPS-induced sepsis.
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Affiliation(s)
- Kim Ohl
- Department of Pediatrics, Medical Faculty, RWTH Aachen, Aachen, Germany
| | - Athanassios Fragoulis
- Department of Anatomy and Cell Biology, Medical Faculty, RWTH Aachen, Aachen, Germany.,Department of General Visceral and Transplantation Surgery, Molecular Tumor Biology, Medical Faculty, RWTH Aachen, Aachen, Germany
| | - Patricia Klemm
- Department of Pediatrics, Medical Faculty, RWTH Aachen, Aachen, Germany
| | - Julian Baumeister
- Department of Pediatrics, Medical Faculty, RWTH Aachen, Aachen, Germany
| | - Wiebke Klock
- Department of Pediatrics, Medical Faculty, RWTH Aachen, Aachen, Germany
| | - Eva Verjans
- Department of Pediatrics, Medical Faculty, RWTH Aachen, Aachen, Germany.,Institute of Pharmacology and Toxicology, RWTH Aachen, Aachen, Germany
| | - Svenja Böll
- Department of Pediatrics, Medical Faculty, RWTH Aachen, Aachen, Germany.,Institute of Pharmacology and Toxicology, RWTH Aachen, Aachen, Germany
| | - Julia Möllmann
- Department of Medicine I, Medical Faculty, RWTH Aachen, Aachen, Germany
| | - Michael Lehrke
- Department of Medicine I, Medical Faculty, RWTH Aachen, Aachen, Germany
| | - Ivan Costa
- Interdisciplinary Centre for Clinical Research (IZKF) Aachen, Medical Faculty, RWTH Aachen, Aachen, Germany
| | - Bernd Denecke
- Interdisciplinary Centre for Clinical Research (IZKF) Aachen, Medical Faculty, RWTH Aachen, Aachen, Germany
| | - Angela Schippers
- Department of Pediatrics, Medical Faculty, RWTH Aachen, Aachen, Germany
| | - Johannes Roth
- Institute of Immunology, University of Münster, Münster, Germany
| | - Norbert Wagner
- Department of Pediatrics, Medical Faculty, RWTH Aachen, Aachen, Germany
| | - Christoph Wruck
- Department of Anatomy and Cell Biology, Medical Faculty, RWTH Aachen, Aachen, Germany
| | - Klaus Tenbrock
- Department of Pediatrics, Medical Faculty, RWTH Aachen, Aachen, Germany
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13
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Roychowdhury S, Cadnum J, Glueck B, Obrenovich M, Donskey C, Cresci GAM. Faecalibacterium prausnitzii and a Prebiotic Protect Intestinal Health in a Mouse Model of Antibiotic and Clostridium difficile Exposure. JPEN J Parenter Enteral Nutr 2018; 42:1156-1167. [PMID: 29385239 DOI: 10.1002/jpen.1053] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 11/07/2017] [Accepted: 11/08/2017] [Indexed: 01/20/2023]
Abstract
BACKGROUND Clostridium difficile (CD) infection (CDI) increases patient morbidity, mortality and healthcare costs. Antibiotic treatment induces gut dysbiosis and is both a major risk factor for CD colonization and treatment of CDI. Probiotics have been trialed to support commensal gut microbiota and reduce CDI. This study investigated commensal microbe Faecalibacterium prausnitzii (FP) and a prebiotic, both known to yield butyrate and be anti-inflammatory and immunomodulatory, on CD colonization and gut integrity in mice. METHODS Mice were randomly grouped and supplemented daily with FP, prebiotic, FP + prebiotic, FP/prebiotic supernatant, or saline throughout the entire study. Following treatment with clindamycin for 3 days, mice were exposed to CD. Feces were collected at baseline, the day after antibiotic, and 1, 3, and 5 days after CD exposure and cultured for bacterial overgrowth and CD colonization. On days 1 and 5 after CD exposure, mice were randomly euthanized, and proximal colon was dissected for histological analysis and preparation of RNA for analysis of proinflammatory and anti-inflammatory cytokines. RESULTS Although all mice exhibited bacterial overgrowth and CD colonization, bacterial burden resolved quicker in the FP + prebiotic group. This was associated with induction and resolution of innate immune responses, anion exchanger, and tight junction protein preservation in proximal colon. CD toxin virulence potential was questionable as expression of CD toxin B receptor was depleted in the FP + prebiotic group. CONCLUSION Supplementation with anti-inflammatory butyrate-supporting commensal bacteria and prebiotic may support innate immune responses and minimize bacterial burden and negative effects during antibiotic and CD exposure.
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Affiliation(s)
- Sanjoy Roychowdhury
- Lerner Research Institute, Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio, USA
| | - Jennifer Cadnum
- Research Service, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio, USA
| | - Bryan Glueck
- Lerner Research Institute, Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio, USA
| | - Mark Obrenovich
- Research Service, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio, USA
| | - Curtis Donskey
- Research Service, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio, USA.,Department of Medicine, Division of Infectious Diseases, Case Western Reserve University, Cleveland, Ohio, USA
| | - Gail A M Cresci
- Lerner Research Institute, Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio, USA.,Pediatric Institute, Department of Gastroenterology, Cleveland Clinic, Cleveland, Ohio, USA.,Digestive Disease & Surgery Institute, Department of Gastroenterology & Hepatology, Cleveland Clinic, Cleveland, Ohio, USA
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14
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Indrelid S, Kleiveland C, Holst R, Jacobsen M, Lea T. The Soil Bacterium Methylococcus capsulatus Bath Interacts with Human Dendritic Cells to Modulate Immune Function. Front Microbiol 2017; 8:320. [PMID: 28293233 PMCID: PMC5329024 DOI: 10.3389/fmicb.2017.00320] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Accepted: 02/15/2017] [Indexed: 01/09/2023] Open
Abstract
The prevalence of inflammatory bowel disease (IBD) has increased in Western countries during the course of the twentieth century, and is evolving to be a global disease. Recently we showed that a bacterial meal of a non-commensal, non-pathogenic methanotrophic soil bacterium, Methylococcus capsulatus Bath prevents experimentally induced colitis in a murine model of IBD. The mechanism behind the effect has this far not been identified. Here, for the first time we show that M. capsulatus, a soil bacterium adheres specifically to human dendritic cells, influencing DC maturation, cytokine production, and subsequent T cell activation, proliferation and differentiation. We characterize the immune modulatory properties of M. capsulatus and compare its immunological properties to those of another Gram-negative gammaproteobacterium, the commensal Escherichia coli K12, and the immune modulatory Gram-positive probiotic bacterium, Lactobacillus rhamnosus GG in vitro. M. capsulatus induces intermediate phenotypic and functional DC maturation. In a mixed lymphocyte reaction M. capsulatus-primed monocyte-derived dendritic cells (MoDCs) enhance T cell expression of CD25, the γ-chain of the high affinity IL-2 receptor, supports cell proliferation, and induce a T cell cytokine profile different from both E. coli K12 and Lactobacillus rhamnosus GG. M. capsulatus Bath thus interacts specifically with MoDC, affecting MoDC maturation, cytokine profile, and subsequent MoDC directed T cell polarization.
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Affiliation(s)
- Stine Indrelid
- Research and Innovation, Østfold Hospital TrustKalnes, Norway; Department of Chemistry, Biotechnology and Food Science, Norwegian University of Life SciencesAas, Norway
| | - Charlotte Kleiveland
- Department of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences Aas, Norway
| | - René Holst
- Research and Innovation, Østfold Hospital Trust Kalnes, Norway
| | - Morten Jacobsen
- Research and Innovation, Østfold Hospital TrustKalnes, Norway; Department of Chemistry, Biotechnology and Food Science, Norwegian University of Life SciencesAas, Norway
| | - Tor Lea
- Department of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences Aas, Norway
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15
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Ohl K, Wiener A, Lippe R, Schippers A, Zorn C, Roth J, Wagner N, Tenbrock K. CREM Alpha Enhances IL-21 Production in T Cells In Vivo and In Vitro. Front Immunol 2016; 7:618. [PMID: 28066428 PMCID: PMC5165720 DOI: 10.3389/fimmu.2016.00618] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2016] [Accepted: 12/06/2016] [Indexed: 12/16/2022] Open
Abstract
The cAMP-responsive element modulator alpha (CREMα) plays a role in autoimmunity and, in particular, in systemic lupus erythematosus. CREMα negatively regulates IL-2 transcription and activates IL-17 expression by direct transcriptional mechanisms. To understand the role of CREM in autoimmunity, we recently generated a mouse with a transgenic overexpression of CREMα selectively in T cells. This mouse is characterized by enhanced IL-17 and IL-21 expression. We, herein, dissect the transcriptional mechanisms of enhanced IL-21 transcription in these mice. T cells of CREMα transgenic mice display an enhanced binding of CREMα to the CD3ζ chain promoter resulting in decreased CD3ζ chain expression. This is accompanied by a decreased excitation threshold and enhanced Ca2+ influx, which is known to induce IL-21 expression via NFATc2 activation. However, CREMα directly binds to cAMP-response element (CRE) half-site within the Il-21 promoter, which results in enhanced promoter activity shown by promoter reporter assays. CREMα-induced IL-21 transcription is not abrogated in the presence of cyclosporine A but depends on an intact CRE site within the IL-21 promoter, which suggests that CREM largely enhances IL-21 expression by direct transcriptional regulation. IL-21 transcription is critical for IL-17 generation in these mice, since IL-21 receptor blockade downregulates IL-17 transcription to wild-type levels. Finally, this is of functional relevance since CREMα transgenic mice display enhanced disease activity in dextran sodium sulfate-induced colitis accompanied by higher local IL-21 expression. Thus, we describe two novel mechanisms of CREMα-dependent IL-21 transcription. Since T cells of systemic lupus erythematosus patients are characterized by enhanced IL-21 transcription, this might also be of functional relevance in humans.
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Affiliation(s)
- Kim Ohl
- Pediatric Immunology, Department of Pediatrics, RWTH Aachen University , Aachen , Germany
| | - Anastasia Wiener
- Pediatric Immunology, Department of Pediatrics, RWTH Aachen University , Aachen , Germany
| | - Ralph Lippe
- Institute of Immunology, University of Münster , Münster , Germany
| | - Angela Schippers
- Pediatric Immunology, Department of Pediatrics, RWTH Aachen University , Aachen , Germany
| | - Carolin Zorn
- Institute of Biochemistry and Molecular Immunology, RWTH Aachen University , Aachen , Germany
| | - Johannes Roth
- Institute of Immunology, University of Münster , Münster , Germany
| | - Norbert Wagner
- Pediatric Immunology, Department of Pediatrics, RWTH Aachen University , Aachen , Germany
| | - Klaus Tenbrock
- Pediatric Immunology, Department of Pediatrics, RWTH Aachen University , Aachen , Germany
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16
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Mingomataj EÇ, Bakiri AH. Regulator Versus Effector Paradigm: Interleukin-10 as Indicator of the Switching Response. Clin Rev Allergy Immunol 2016; 50:97-113. [PMID: 26450621 DOI: 10.1007/s12016-015-8514-7] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The interleukin-10 (IL-10) is generally considered as the most important cytokine with anti-inflammatory properties and one of the key cytokines preventing inflammation-mediated tissue damage. In this respect, IL-10 producing cells play a crucial role in the outcome of infections, allergy, autoimmune reactions, tumor development, and transplant tolerance. Based on recent findings with regard to the mentioned clinical conditions, this review attempts to shed some light on the IL-10 functions, considering this cytokine as inherent inducer of the switching immunity. While acute infections and vaccinations are associated by IL-10 enhanced during few weeks, chronic parasitoses, tumor diseases, allergen-specific immunotherapy, transplants, and use of immune-suppressor drugs show an increased IL-10 level along months or years. With regard to autoimmune pathologies, the IL-10 increase is prevalently observed during early stages, whereas the successive stages are characterized by reaching of immune equilibrium independently to disease's activity. Together, these findings indicate that IL-10 is mainly produced during transient immune conditions and the persistent IL-10-related effect is the indication/prediction (and maybe effectuation) of the switching immunity. Actual knowledge emphasizes that any manipulation of the IL-10 response for treatment purposes should be considered very cautiously due to its potential hazards to the immune system. Probably, the IL-10 as potential switcher of immunity response should be used in association with co-stimulatory immune effectors that are necessary to determine the appropriate deviation during treatment of respective pathologies. Hopefully, further findings would open new avenues to study the biology of this "master switch" cytokine and its therapeutic potential.
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Affiliation(s)
- Ervin Ç Mingomataj
- Department of Allergy & Clinical Immunology, "Mother Theresa" School of Medicine, Tirana, Albania. .,Faculty of Technical Medical Sciences, Department of Preclinical Disciplines, University of Medicine, Tirana, Albania.
| | - Alketa H Bakiri
- Hygeia Hospital Tirana, Outpatients Service, Allergology Consulting Room, Tirana, Albania.,Faculty of Medical Sciences, Department of Preclinical Disciplines, Albanian University, Tirana, Albania
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17
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Hernández-Chirlaque C, Aranda CJ, Ocón B, Capitán-Cañadas F, Ortega-González M, Carrero JJ, Suárez MD, Zarzuelo A, Sánchez de Medina F, Martínez-Augustin O. Germ-free and Antibiotic-treated Mice are Highly Susceptible to Epithelial Injury in DSS Colitis. J Crohns Colitis 2016; 10:1324-1335. [PMID: 27117829 DOI: 10.1093/ecco-jcc/jjw096] [Citation(s) in RCA: 189] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Accepted: 04/22/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Intestinal microbiota is required to maintain immune homeostasis and intestinal barrier function. At the same time, intraluminal bacteria are considered to be involved in inflammatory bowel disease and are required for colitis induction in animal models, with the possible exception of dextran sulphate sodium [DSS] colitis. This study was carried out to ascertain the mechanism underlying the induction of colitis by DSS in the absence of bacteria. METHODS Conventional and germ-free [GF] Naval Medical Research Institute [NMRI] mice were used, plus conventional mice treated with an antibiotic cocktail to deplete the intestinal microbiota ['pseudo-GF' or PGF mice]. The differential response to DSS was assessed. RESULTS Conventional mice developed DSS-induced colitis normally, whereas GF mice showed only minimal inflammation [no colonic thickening, lower myeloperoxidase activity, IL-6, IL-17, TNF-α, and IFN-γ secretion by splenocytes and mesenteric cell cultures, etc.]. However, these mice suffered enhanced haemorrhage, epithelial injury and mortality as a consequence of a weakened intestinal barrier, as shown by lower occludin, claudin 4, TFF3, MUC3, and IL-22. In contrast, PGF mice had a relatively normal, albeit attenuated, inflammatory response, but were less prone to haemorrhage and epithelial injury than GF mice. This was correlated with an increased expression of IL-10 and Foxp3 and preservation barrier-related markers. CONCLUSIONS We conclude that enteric bacteria are essential for the development of normal DSS-induced colitis. The absence of microbiota reduces DSS colonic inflammation dramatically but it also impairs barrier function, whereas subtotal microbiota depletion has intermediate effects at both levels.
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Affiliation(s)
- Cristina Hernández-Chirlaque
- Department of Biochemistry and Molecular Biology II, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBERehd], University of Granada, Granada, Spain
| | - Carlos J Aranda
- Department of Biochemistry and Molecular Biology II, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBERehd], University of Granada, Granada, Spain
| | - Borja Ocón
- Department of Pharmacology, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBERehd], University of Granada, Granada, Spain
| | - Fermín Capitán-Cañadas
- Department of Biochemistry and Molecular Biology II, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBERehd], University of Granada, Granada, Spain
| | - Mercedes Ortega-González
- Department of Biochemistry and Molecular Biology II, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBERehd], University of Granada, Granada, Spain
| | | | - María Dolores Suárez
- Department of Biochemistry and Molecular Biology II, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBERehd], University of Granada, Granada, Spain
| | - Antonio Zarzuelo
- Department of Pharmacology, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBERehd], University of Granada, Granada, Spain
| | - Fermín Sánchez de Medina
- Department of Pharmacology, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBERehd], University of Granada, Granada, Spain
| | - Olga Martínez-Augustin
- Department of Biochemistry and Molecular Biology II, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBERehd], University of Granada, Granada, Spain
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18
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Wang Y, Jiang X, Zhu J, Dan Yue, Zhang X, Wang X, You Y, Wang B, Xu Y, Lu C, Sun X, Yoshikai Y. IL-21/IL-21R signaling suppresses intestinal inflammation induced by DSS through regulation of Th responses in lamina propria in mice. Sci Rep 2016; 6:31881. [PMID: 27545302 PMCID: PMC4992961 DOI: 10.1038/srep31881] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 07/28/2016] [Indexed: 12/15/2022] Open
Abstract
Serum level of IL-21 is increased in patients with inflammatory bowel diseases (IBD), suggesting that IL-21/IL-21 receptor (IL-21R) signaling may be involved in the pathogenesis of IBD. However, the role of IL-21/IL-21 receptor signaling plays in the pathogenesis of IBD is not very clear. In this study, using IL-21R.KO mice, we tested the role of IL-21/IL-21R signaling in the regulation of T helper cell responses during intestinal inflammation. Here we found that IL-21R.KO mice were more susceptible to DSS-induced colitis as compared with C57BL/6 mice. The spontaneous inflammatory cytokines released by macrophages in LP of colon were significantly increased, and Th2, Th17 and Treg responses were down-regulated markedly. However, Th1 responses were significantly up-regulated in IL-21R.KO mice. Meanwhile, the population of CD8(+)CD44(+)IFN-γ(+) T cells was markedly elevated in LP of inflammatory intestine of IL-21RKO mice. In vivo, after disease onset, DSS-induced intestinal inflammation was ameliorated in C57BL/6 mice treated with rIL-21. Our results demonstrate that IL-21/IL-21R signaling contributes to protection against DSS-induced acute colitis through suppression of Th1 and activation of Th2, Th17 and Treg responses in mice. Therefore, therapeutic manipulation of IL-21/IL-21R activity may allow improved immunotherapy for IBD and other inflammatory diseases associated with Th cell responses.
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Affiliation(s)
- Yuanyuan Wang
- Department of anesthesiology, The Fourth Affiliated Hospital, China Medical University, Shenyang, China
| | - Xuefeng Jiang
- Department of Immunology, China Medical University, Shenyang, China
| | - Junfeng Zhu
- Life Science School, Liaoning University, Shenyang, China
| | - Dan Yue
- Department of Immunology, China Medical University, Shenyang, China
- Laboratory Medicine Department, Sheng Jing Hospital of China Medical University, Shenyang, China
| | - Xiaoqing Zhang
- Department of Immunology, China Medical University, Shenyang, China
| | - Xiao Wang
- Department of Immunology, China Medical University, Shenyang, China
| | - Yong You
- Department of Immunology, China Medical University, Shenyang, China
| | - Biao Wang
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences of China Medical University, Shenyang, China
| | - Ying Xu
- Northeast Pharmaceutical Group Co., Ltd, Shenyang, China
| | - Changlong Lu
- Department of Immunology, China Medical University, Shenyang, China
| | - Xun Sun
- Department of Immunology, China Medical University, Shenyang, China
| | - Yasunobu Yoshikai
- Division of Host Defense, Center for Prevention of Infectious Disease, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
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19
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Hörmannsperger G, Schaubeck M, Haller D. Intestinal Microbiota in Animal Models of Inflammatory Diseases. ILAR J 2016; 56:179-91. [PMID: 26323628 DOI: 10.1093/ilar/ilv019] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
The intestinal microbiota has long been known to play an important role in the maintenance of health. In addition, alterations of the intestinal microbiota have recently been associated with a range of immune-mediated and metabolic disorders. Characterizing the composition and functionality of the intestinal microbiota, unravelling relevant microbe-host interactions, and identifying disease-relevant microbes are therefore currently of major interest in scientific and medical communities. Experimental animal models for the respective diseases of interest are pivotal in order to address functional questions on microbe-host interaction and to clarify the clinical relevance of microbiome alterations associated with disease initiation and development. This review presents an overview of the outcomes of highly sophisticated experimental studies on microbe-host interaction in animal models of inflammatory diseases, with a focus on inflammatory bowel disease (IBD). We will address the advantages and drawbacks of analyzing microbe-host interaction in complex colonized animal models compared with gnotobiotic animal models using monoassociation, simplified microbial consortia (SMC), or microbial humanization.
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Affiliation(s)
- G Hörmannsperger
- Gabriele Hörmannsperger, PhD, is a molecular biologist researcher, Monika Schaubeck, MSc, is a PhD student, and Dirk Haller, PhD, is full professor and head of the Chair of Nutrition and Immunology at the Technische Universität München, Freising-Weihenstephan, Germany
| | - M Schaubeck
- Gabriele Hörmannsperger, PhD, is a molecular biologist researcher, Monika Schaubeck, MSc, is a PhD student, and Dirk Haller, PhD, is full professor and head of the Chair of Nutrition and Immunology at the Technische Universität München, Freising-Weihenstephan, Germany
| | - D Haller
- Gabriele Hörmannsperger, PhD, is a molecular biologist researcher, Monika Schaubeck, MSc, is a PhD student, and Dirk Haller, PhD, is full professor and head of the Chair of Nutrition and Immunology at the Technische Universität München, Freising-Weihenstephan, Germany
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Schippers A, Muschaweck M, Clahsen T, Tautorat S, Grieb L, Tenbrock K, Gaßler N, Wagner N. β7-Integrin exacerbates experimental DSS-induced colitis in mice by directing inflammatory monocytes into the colon. Mucosal Immunol 2016; 9:527-538. [PMID: 26349655 PMCID: PMC4801899 DOI: 10.1038/mi.2015.82] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Accepted: 08/06/2015] [Indexed: 02/04/2023]
Abstract
Leukocyte recruitment is pivotal for the initiation and perpetuation of inflammatory bowel disease (IBD) and controlled by the specificity and interactions of chemokines and adhesion molecules. Interactions of the adhesion molecules α4β7-integrin and mucosal addressin cell-adhesion molecule-1 (MAdCAM-1) promote the accumulation of pathogenic T-cell populations in the inflamed intestine. We aimed to elucidate the significance of β7-integrin expression on innate immune cells for the pathogenesis of IBD. We demonstrate that β7-integrin deficiency protects recombination-activating gene-2 (RAG-2)-deficient mice from dextran sodium sulfate (DSS)-induced colitis and coincides with decreased numbers of colonic effector monocytes. We also show that β7-integrin is expressed on most CD11b(+)CD64(low)Ly6C(+) bone marrow progenitors and contributes to colonic recruitment of these proinflammatory monocytes. Importantly, adoptive transfer of CD115(+) wild-type (WT) monocytes partially restored the susceptibility of RAG-2/β7-integrin double-deficient mice to DSS-induced colitis, thereby demonstrating the functional importance of β7-integrin-expressing monocytes for the development of DSS colitis. We also reveal that genetic ablation of MAdCAM-1 ameliorates experimental colitis in RAG-2-deficient mice as well. In summary, we demonstrate a previously unknown role of α4β7-integrin-MAdCAM-1 interactions as drivers of colitis by directing inflammatory monocytes into the colon.
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Affiliation(s)
- A Schippers
- Department of Pediatrics, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - M Muschaweck
- Department of Pediatrics, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - T Clahsen
- Department of Pediatrics, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - S Tautorat
- Department of Pediatrics, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - L Grieb
- Department of Pediatrics, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - K Tenbrock
- Department of Pediatrics, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - N Gaßler
- Institute of Pathology, Klinikum Braunschweig, Braunschweig, Germany
| | - N Wagner
- Department of Pediatrics, Medical Faculty, RWTH Aachen University, Aachen, Germany
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Abstract
Complex mechanisms are pulling the strings to initiate the development of inflammatory bowel disease. Current evidence indicates that an interaction of genetic susceptibilities (polymorphisms), environmental factors, and the host microbiota leads to a dysregulation of the mucosal immune system. In the past decades, the interleukin-10-deficient mouse has served as an excellent model to mirror the multifactorial nature of this disease. Here, we want to review in detail the interplay of the genetic factors, immune aspects, and especially summarize and discuss the role of the microbiota contributing to colitis development in the interleukin-10-deficient mouse model of inflammatory bowel disease as a multihit model.
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Abstract
BACKGROUND Interleukin 10-deficient mice (IL-10(-/-)) are a popular model used to dissect the mechanisms underlying inflammatory bowel diseases. The role of complement, a host defense mechanism that bridges the innate and adaptive immune systems, has not been described in this model. We therefore studied the effect of deficiency of properdin, a positive regulator of complement, on colitis in mice with the IL-10(-/-) background. METHODS For acute colitis, IL-10(-/-) and IL-10/properdin double knockout (DKO) or radiation bone marrow-reconstituted chimeric mice, had piroxicam added to their powdered chow for 14 days. For chronic colitis, 2.5% dextran sodium sulfate was added to the animals' water for 4 days then the mice were killed 8 weeks later. Colons were assessed for inflammation, cell infiltration, and cytokine and complement measurements. Bacterial translocation was measured by cultivating bacteria from organs on Luria broth agar plates. RESULTS C3a and C5a levels and C9 deposition were all increased in piroxicam-fed IL-10(-/-) mice compared with mice not fed piroxicam. Piroxicam-fed DKO mice lacked increased C5a and C9 deposition combined with exacerbated colitis, reduced numbers of infiltrating neutrophils, and markedly higher local and systemic bacterial numbers compared with IL-10(-/-) mice. Bone marrow cells from IL-10(-/-) mice were sufficient to restore protection against the heightened colitis in piroxicam-fed DKO mice. CONCLUSIONS Complement is activated in the IL-10(-/-) mouse mucosa in a properdin-dependent manner. In the absence of terminal complement activation, the inflammation is heightened, likely due to a lack of neutrophil control over microbes escaping from the intestines.
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Abstract
The intestine contains the largest pool of macrophages in the body which are essential for maintaining mucosal homeostasis in the face of the microbiota and the constant need for epithelial renewal but are also important components of protective immunity and are involved in the pathology of inflammatory bowel disease (IBD). However, defining the biological roles of intestinal macrophages has been impeded by problems in defining the phenotype and origins of different populations of myeloid cells in the mucosa. Here, we discuss how multiple parameters can be used in combination to discriminate between functionally distinct myeloid cells and discuss the roles of macrophages during homeostasis and how these may change when inflammation ensues. We also discuss the evidence that intestinal macrophages do not fit the current paradigm that tissue-resident macrophages are derived from embryonic precursors that self-renew in situ, but require constant replenishment by blood monocytes. We describe our recent work demonstrating that classical monocytes constantly enter the intestinal mucosa and how the environment dictates their subsequent fate. We believe that understanding the factors that drive intestinal macrophage development in the steady state and how these may change in response to pathogens or inflammation could provide important insights into the treatment of IBD.
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Affiliation(s)
- Calum C Bain
- Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
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Abstract
The intestine contains the largest pool of macrophages in the body which are essential for maintaining mucosal homeostasis in the face of the microbiota and the constant need for epithelial renewal but are also important components of protective immunity and are involved in the pathology of inflammatory bowel disease (IBD). However, defining the biological roles of intestinal macrophages has been impeded by problems in defining the phenotype and origins of different populations of myeloid cells in the mucosa. Here, we discuss how multiple parameters can be used in combination to discriminate between functionally distinct myeloid cells and discuss the roles of macrophages during homeostasis and how these may change when inflammation ensues. We also discuss the evidence that intestinal macrophages do not fit the current paradigm that tissue-resident macrophages are derived from embryonic precursors that self-renew in situ, but require constant replenishment by blood monocytes. We describe our recent work demonstrating that classical monocytes constantly enter the intestinal mucosa and how the environment dictates their subsequent fate. We believe that understanding the factors that drive intestinal macrophage development in the steady state and how these may change in response to pathogens or inflammation could provide important insights into the treatment of IBD.
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Affiliation(s)
- Calum C Bain
- Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
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Hansen AK, Hansen CHF, Krych L, Nielsen DS. Impact of the gut microbiota on rodent models of human disease. World J Gastroenterol 2014; 20:17727-17736. [PMID: 25548471 PMCID: PMC4273123 DOI: 10.3748/wjg.v20.i47.17727] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Revised: 09/30/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
Traditionally bacteria have been considered as either pathogens, commensals or symbionts. The mammal gut harbors 1014 organisms dispersed on approximately 1000 different species. Today, diagnostics, in contrast to previous cultivation techniques, allow the identification of close to 100% of bacterial species. This has revealed that a range of animal models within different research areas, such as diabetes, obesity, cancer, allergy, behavior and colitis, are affected by their gut microbiota. Correlation studies may for some diseases show correlation between gut microbiota composition and disease parameters higher than 70%. Some disease phenotypes may be transferred when recolonizing germ free mice. The mechanistic aspects are not clear, but some examples on how gut bacteria stimulate receptors, metabolism, and immune responses are discussed. A more deeper understanding of the impact of microbiota has its origin in the overall composition of the microbiota and in some newly recognized species, such as Akkermansia muciniphila, Segmented filamentous bacteria and Faecalibacterium prausnitzii, which seem to have an impact on more or less severe disease in specific models. Thus, the impact of the microbiota on animal models is of a magnitude that cannot be ignored in future research. Therefore, either models with specific microbiota must be developed, or the microbiota must be characterized in individual studies and incorporated into data evaluation.
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Mazagova M, Wang L, Anfora AT, Wissmueller M, Lesley SA, Miyamoto Y, Eckmann L, Dhungana S, Pathmasiri W, Sumner S, Westwater C, Brenner DA, Schnabl B. Commensal microbiota is hepatoprotective and prevents liver fibrosis in mice. FASEB J 2014; 29:1043-55. [PMID: 25466902 DOI: 10.1096/fj.14-259515] [Citation(s) in RCA: 129] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Translocation of bacteria and their products across the intestinal barrier is common in patients with liver disease, and there is evidence that experimental liver fibrosis depends on bacterial translocation. The purpose of our study was to investigate liver fibrosis in conventional and germ-free (GF) C57BL/6 mice. Chronic liver injury was induced by administration of thioacetamide (TAA) in the drinking water for 21 wk or by repeated intraperitoneal injections of carbon tetrachloride (CCl4). Increased liver fibrosis was observed in GF mice compared with conventional mice. Hepatocytes showed more toxin-induced oxidative stress and cell death. This was accompanied by increased activation of hepatic stellate cells, but hepatic mediators of inflammation were not significantly different. Similarly, a genetic model using Myd88/Trif-deficient mice, which lack downstream innate immunity signaling, had more severe fibrosis than wild-type mice. Isolated Myd88/Trif-deficient hepatocytes were more susceptible to toxin-induced cell death in culture. In conclusion, the commensal microbiota prevents fibrosis upon chronic liver injury in mice. This is the first study describing a beneficial role of the commensal microbiota in maintaining liver homeostasis and preventing liver fibrosis.
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Affiliation(s)
- Magdalena Mazagova
- *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Lirui Wang
- *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Andrew T Anfora
- *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Max Wissmueller
- *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Scott A Lesley
- *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Yukiko Miyamoto
- *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Lars Eckmann
- *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Suraj Dhungana
- *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Wimal Pathmasiri
- *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Susan Sumner
- *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Caroline Westwater
- *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
| | - David A Brenner
- *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Bernd Schnabl
- *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
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Műzes G, Sipos F, Fűri I, Constantinovits M, Spisák S, Wichmann B, Valcz G, Tulassay Z, Molnár B. Preconditioning with intravenous colitic cell-free DNA prevents DSS-colitis by altering TLR9-associated gene expression profile. Dig Dis Sci 2014; 59:2935-2946. [PMID: 25217236 DOI: 10.1007/s10620-014-3325-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Accepted: 08/07/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND Presence of cell-free-circulating DNA (fcDNA) sequences in sera of patients with inflammatory bowel diseases (IBD) is a well-established phenomenon. Potential roles of fcDNA in diagnosis, prognosis and therapy monitoring of chronic inflammatory colonic disorders have already been examined, albeit its actual biological function still remains unclear. AIMS AND METHODS In the present experiment, we studied the immunobiological effects of isolated fcDNA of normal and inflammatory origin administered intravenously to mice prior to induction of dextran sulfate sodium (DSS)-colitis. In addition to evaluate the current disease and histological activity, changes of the gene expression profile in isolated lamina propria cells upon TLR9 ligation were assayed. RESULTS A single intravenous dose of fcDNA pretreatment with colitic fcDNA exhibited beneficial response concerning the clinical and histological severity of DSS-colitis as compared to effects of normal fcDNA. Pretreatment with colitic fcDNA substantially altered the expression of several TLR9-related and inflammatory cytokine genes in a clinically favorable manner. CONCLUSIONS During the process of acute colitis, the subsequent inflammatory environment presumably results in changes of fcDNA with the potential to facilitate the downregulation of inflammation and improvement of regeneration. Thus, preconditioning of mice with colitis-derived fcDNA via TLR9 signaling could exert a tissue-protective effect and influence beneficially the course of DSS-colitis. Elucidating mechanisms of immune response alterations by nucleic acids may provide further insight into the etiology of IBD and develop the basis of novel immunotherapies.
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Affiliation(s)
- Györgyi Műzes
- 2nd Department of Internal Medicine, Semmelweis University, Szentkirályi Street 46, Budapest, 1088, Hungary,
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Serotonin 5-HT7 receptor is critically involved in acute and chronic inflammation of the gastrointestinal tract. Inflamm Bowel Dis 2014; 20:1516-29. [PMID: 25072499 DOI: 10.1097/mib.0000000000000150] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Intestinal inflammation is often associated with an increased level of serotonin (5-HT), an important gastrointestinal signaling molecule involved in gut homeostasis through stimulation of specific receptors. In this study, we investigated the role of 5-HT7 receptor (5-HT7R) in the induction and development of intestinal inflammation using a mouse model of acute and chronic colitis and human patients with Crohn's disease (CD). METHODS Acute colitis was induced through administration of dextran sodium sulfate to wild-type, 5-HT7R-deficient mice and hematopoietic bone marrow chimera. Chronic colitis was induced in interleukin 10-deficient mice. The role of 5-HT7R in gut inflammation was assessed using agonist/antagonist treatment. We investigated expression and distribution of 5-HT7R, extent of gut inflammation with magnetic resonance imaging and histological analysis, survival rate, and disease activity index. Finally, biopsies from the large intestine of patients with CD were analyzed. RESULTS Under basal conditions, 5-HT7R is expressed both in enteric neurons and CD11c cells of the large intestine. Expression of 5-HT7R significantly increased after induction of colitis in mice and in inflamed intestinal regions of patients with CD in CD11c/CD86 double-positive cells. Pharmacological blockade or genetic ablation of 5-HT7R resulted in increased severity of both acute and chronic dextran sodium sulfate-induced colitis, whereas receptor stimulation showed an anti-inflammatory effect. Analysis of bone marrow chimera indicated importance of 5-HT7R expressed by hematopoietic cells in intestinal inflammation. CONCLUSIONS The 5-HT7R expressed on CD11c/CD86-positive myeloid cells modulates the severity of intestinal inflammation in an acute and chronic colitis and thus represents a potential therapeutic target for the treatment of inflammatory disorders such as CD.
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Jones-Hall YL, Grisham MB. Immunopathological characterization of selected mouse models of inflammatory bowel disease: Comparison to human disease. ACTA ACUST UNITED AC 2014; 21:267-88. [PMID: 24935242 DOI: 10.1016/j.pathophys.2014.05.002] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2014] [Revised: 05/16/2014] [Accepted: 05/17/2014] [Indexed: 12/19/2022]
Abstract
Inflammatory bowel diseases (IBD) are chronic, relapsing conditions of multifactorial etiology. The two primary diseases of IBD are Crohn's disease (CD) and ulcerative colitis (UC). Both entities are hypothesized to occur in genetically susceptible individuals due to microbial alterations and environmental contributions. The exact etiopathogenesis, however, is not known for either disease. A variety of mouse models of CD and UC have been developed to investigate the pathogenesis of these diseases and evaluate treatment modalities. Broadly speaking, the mouse models can be divided into 4 categories: genetically engineered, immune manipulated, spontaneous and erosive/chemically induced. No one mouse model completely recapitulates the immunopathology of CD or UC, however each model possesses particular similarities to human IBD and offers advantageous for specific details of IBD pathogenesis. Here we discuss the more commonly used models in each category and critically evaluate how the immunopathology induced compares to CD or UC, as well as the advantages and disadvantages associated with each model.
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Affiliation(s)
- Yava L Jones-Hall
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47906, United States.
| | - Matthew B Grisham
- Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, United States
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Zigmond E, Bernshtein B, Friedlander G, Walker CR, Yona S, Kim KW, Brenner O, Krauthgamer R, Varol C, Müller W, Jung S. Macrophage-restricted interleukin-10 receptor deficiency, but not IL-10 deficiency, causes severe spontaneous colitis. Immunity 2014; 40:720-33. [PMID: 24792913 DOI: 10.1016/j.immuni.2014.03.012] [Citation(s) in RCA: 441] [Impact Index Per Article: 40.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2013] [Accepted: 03/18/2014] [Indexed: 02/07/2023]
Abstract
Interleukin-10 (IL-10) is a pleiotropic anti-inflammatory cytokine produced and sensed by most hematopoietic cells. Genome-wide association studies and experimental animal models point at a central role of the IL-10 axis in inflammatory bowel diseases. Here we investigated the importance of intestinal macrophage production of IL-10 and their IL-10 exposure, as well as the existence of an IL-10-based autocrine regulatory loop in the gut. Specifically, we generated mice harboring IL-10 or IL-10 receptor (IL-10Rα) mutations in intestinal lamina propria-resident chemokine receptor CX3CR1-expressing macrophages. We found macrophage-derived IL-10 dispensable for gut homeostasis and maintenance of colonic T regulatory cells. In contrast, loss of IL-10 receptor expression impaired the critical conditioning of these monocyte-derived macrophages and resulted in spontaneous development of severe colitis. Collectively, our results highlight IL-10 as a critical homeostatic macrophage-conditioning agent in the colon and define intestinal CX3CR1(hi) macrophages as a decisive factor that determines gut health or inflammation.
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Affiliation(s)
- Ehud Zigmond
- Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel; The Research Center for Digestive Tract and Liver Diseases, Tel Aviv-Sourasky Medical Center and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel
| | - Biana Bernshtein
- Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Gilgi Friedlander
- Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Catherine R Walker
- Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK
| | - Simon Yona
- Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Ki-Wook Kim
- Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Ori Brenner
- Department of Veterinary Resources, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Rita Krauthgamer
- Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Chen Varol
- The Research Center for Digestive Tract and Liver Diseases, Tel Aviv-Sourasky Medical Center and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel
| | - Werner Müller
- Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK
| | - Steffen Jung
- Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
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Attenuation of intestinal inflammation in interleukin-10-deficient mice infected with Citrobacter rodentium. Infect Immun 2014; 82:1949-58. [PMID: 24566625 DOI: 10.1128/iai.00066-14] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Interleukin-10 (IL-10) curtails immune responses to microbial infection and autoantigens and contributes to intestinal immune homeostasis, yet administration of IL-10 has not been effective at attenuating chronic intestinal inflammatory conditions, suggesting that its immune functions may be context dependent. To gain a broader understanding of the importance of IL-10 in controlling mucosal immune responses to infectious challenges, we employed the murine attaching and effacing pathogen Citrobacter rodentium, which colonizes primarily the surfaces of the cecum and colon and causes transient mucosal inflammation driven by Th17 and Th1 T helper cells. Infection induced macrophage and dendritic cell production of IL-10, which diminished antibacterial host defenses, because IL-10-deficient mice cleared infection faster than wild-type controls. In parallel, the mice had less acute infection-associated colitis and resolved it more rapidly than controls. Importantly, transient C. rodentium infection protected IL-10-deficient mice against the later development of spontaneous colitis that normally occurs with aging in these mice. Genome-wide expression studies revealed that IL-10 deficiency was associated with downregulation of proinflammatory pathways but increased expression of the anti-inflammatory cytokine IL-27 in response to infection. IL-27 was found to suppress in vitro Th17 and, to a lesser degree, Th1 differentiation independent of IL-10. Furthermore, neutralization of IL-27 resulted in more severe colitis in infected IL-10-deficient mice. Together, these findings indicate that IL-10 is dispensable for resolving C. rodentium-associated colitis and further suggest that IL-27 may be a critical factor for controlling intestinal inflammation and Th17 and Th1 development by IL-10-independent mechanisms.
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Foster A, Jacobson K. Changing incidence of inflammatory bowel disease: environmental influences and lessons learnt from the South asian population. Front Pediatr 2013; 1:34. [PMID: 24400280 PMCID: PMC3864265 DOI: 10.3389/fped.2013.00034] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2013] [Accepted: 10/21/2013] [Indexed: 12/13/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disorder of the gastrointestinal tract associated with significant morbidity. While IBD occurs in genetically susceptible individuals, the etiology is multifactorial, involving environmental influences, intestinal dysbiosis, and altered immune responses. The rising incidence of IBD in industrialized countries and the emergence of IBD in countries with traditionally low prevalence underscore the importance of environmental influences in the pathobiology of the disease. Moreover the high incidence of IBD observed in the South Asian immigrant population in the United Kingdom and Canada further supports the influence of environmental factors.
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Affiliation(s)
- Alice Foster
- Division of Gastroenterology, Hepatology and Nutrition, University of British Columbia , Vancouver, BC , Canada
| | - Kevan Jacobson
- Division of Gastroenterology, Hepatology and Nutrition, University of British Columbia , Vancouver, BC , Canada ; Child and Family Research Institute, University of British Columbia , Vancouver, BC , Canada ; Department of Cellular and Physiological Sciences, BC Children's Hospital, University of British Columbia , Vancouver, BC , Canada
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Zhan Y, Chen PJ, Sadler WD, Wang F, Poe S, Núñez G, Eaton KA, Chen GY. Gut microbiota protects against gastrointestinal tumorigenesis caused by epithelial injury. Cancer Res 2013; 73:7199-210. [PMID: 24165160 DOI: 10.1158/0008-5472.can-13-0827] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Inflammation is a critical player in the development of both colitis-associated and sporadic colon cancers. Several studies suggest that the microbiota contribute to inflammation and tumorigenesis; however, studies to understand the role of the microbiota in colon tumor development in germ-free (GF) mice are limited. We therefore studied the effects of the microbiota on the development of inflammation and tumors in GF and conventionally raised specific pathogen-free (SPF) mice treated with azoxymethane (AOM) and dextran sulfate sodium (DSS). We discovered that GF mice developed significantly more and larger tumors compared with that in SPF mice after AOM and DSS treatment despite the lack of early acute inflammation in response to chemically induced injury by DSS. Although the extent of intestinal epithelial damage and apoptosis was not significantly different in GF and SPF mice, there was a delay in intestinal epithelial repair to DSS-induced injury in GF mice resulting in a late onset of proinflammatory and protumorigenic responses and increased epithelial proliferation and microadenoma formation. Recolonization of GF mice with commensal bacteria or administration of lipopolysaccharide reduced tumorigenesis. Thus, although commensal bacteria are capable of driving chronic inflammation and tumorigenesis, the gut microbiota also have important roles in limiting chemically induced injury and proliferative responses that lead to tumor development.
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Affiliation(s)
- Yu Zhan
- Authors' Affiliations: Division of Hematology and Oncology, Department of Internal Medicine, Department of Pathology, Comprehensive Cancer Center, Unit for Laboratory Animal Medicine, and Department of Microbiology and Immunology, University of Michigan Medical School, University of Michigan, Ann Arbor, Michigan
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Elinav E, Peer D. Harnessing nanomedicine for mucosal theranostics--a silver bullet at last? ACS NANO 2013; 7:2883-2890. [PMID: 23570555 DOI: 10.1021/nn400885b] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
Inflammatory bowel disease (IBD) has been extensively studied in the last four decades both in animal models and humans. The treatment options remain disappointing, nonspecific, and associated with multiple systemic adverse effects. In this Perspective, we highlight issues related to emerging nanotechnologies designed particularly for treatment and disease management of IBD and discuss potential therapeutic target options with novel molecular imaging modalities.
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Affiliation(s)
- Eran Elinav
- Department of Immunology, Weizmann Institute of Sciences, Rehovot 76100, Israel.
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Moise L, Gutierrez AH, Bailey-Kellogg C, Terry F, Leng Q, Abdel Hady KM, VerBerkmoes NC, Sztein MB, Losikoff PT, Martin WD, Rothman AL, De Groot AS. The two-faced T cell epitope: examining the host-microbe interface with JanusMatrix. Hum Vaccin Immunother 2013; 9:1577-86. [PMID: 23584251 PMCID: PMC3974887 DOI: 10.4161/hv.24615] [Citation(s) in RCA: 77] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Advances in the field of T cell immunology have contributed to the understanding that cross-reactivity is an intrinsic characteristic of the T cell receptor (TCR), and that each TCR can potentially interact with many different T cell epitopes. To better define the potential for TCR cross-reactivity between epitopes derived from the human genome, the human microbiome, and human pathogens, we developed a new immunoinformatics tool, JanusMatrix, that represents an extension of the validated T cell epitope mapping tool, EpiMatrix. Initial explorations, summarized in this synopsis, have uncovered what appear to be important differences in the TCR cross-reactivity of selected regulatory and effector T cell epitopes with other epitopes in the human genome, human microbiome, and selected human pathogens. In addition to exploring the T cell epitope relationships between human self, commensal and pathogen, JanusMatrix may also be useful to explore some aspects of heterologous immunity and to examine T cell epitope relatedness between pathogens to which humans are exposed (Dengue serotypes, or HCV and Influenza, for example). In Hand-Foot-Mouth disease (HFMD) for example, extensive enterovirus and human microbiome cross-reactivity (and limited cross-reactivity with the human genome) seemingly predicts immunodominance. In contrast, more extensive cross-reactivity with proteins contained in the human genome as compared to the human microbiome was observed for selected Treg epitopes. While it may be impossible to predict all immune response influences, the availability of sequence data from the human genome, the human microbiome, and an array of human pathogens and vaccines has made computationally–driven exploration of the effects of T cell epitope cross-reactivity now possible. This is the first description of JanusMatrix, an algorithm that assesses TCR cross-reactivity that may contribute to a means of predicting the phenotype of T cells responding to selected T cell epitopes. Whether used for explorations of T cell phenotype or for evaluating cross-conservation between related viral strains at the TCR face of viral epitopes, further JanusMatrix studies may contribute to developing safer, more effective vaccines.
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Affiliation(s)
- Leonard Moise
- Institute for Immunology and Informatics; University of Rhode Island; Providence, RI, USA; EpiVax Inc.; Providence, RI USA
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Host-microbe interactions: the difficult yet peaceful coexistence of the microbiota and the intestinal mucosa. Br J Nutr 2013; 109 Suppl 2:S12-20. [PMID: 23360876 DOI: 10.1017/s0007114512004035] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The immune system has evolved to live in a collaborative relationship with the microbiota, while still serving its seminal function to fight off invasive pathogenic bacteria. The mechanisms that rule the interactions between the intestinal microbiota and the intestinal immune system are the focus of intense research. Here, we describe how the innate immunity is, to a great extent, in charge of the control of the microbiota in the intestine and relies on non-specific receptors called pathogen-recognition receptors. While the microbiota has a well-defined effect on the host immune homoeostasis, it has become clear that the opposite is also true, i.e., the mucosal immune system has the capacity to shape the microbial population. The mechanisms that rule the reciprocal regulation between host immunity and commensal bacteria (including specific bacteria) are currently being elucidated and will be described here. A better knowledge of how the host and bacteria interact and how the intestinal microbiota and the immune system are co-regulated will provide the basis for a better understanding of intestinal and systemic immunopathologies and for the development of new therapeutic approaches.
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Winter SE, Winter MG, Xavier MN, Thiennimitr P, Poon V, Keestra AM, Laughlin RC, Gomez G, Wu J, Lawhon SD, Popova IE, Parikh SJ, Adams LG, Tsolis RM, Stewart VJ, Bäumler AJ. Host-derived nitrate boosts growth of E. coli in the inflamed gut. Science 2013; 339:708-11. [PMID: 23393266 DOI: 10.1126/science.1232467] [Citation(s) in RCA: 732] [Impact Index Per Article: 61.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Changes in the microbial community structure are observed in individuals with intestinal inflammatory disorders. These changes are often characterized by a depletion of obligate anaerobic bacteria, whereas the relative abundance of facultative anaerobic Enterobacteriaceae increases. The mechanisms by which the host response shapes the microbial community structure, however, remain unknown. We show that nitrate generated as a by-product of the inflammatory response conferred a growth advantage to the commensal bacterium Escherichia coli in the large intestine of mice. Mice deficient in inducible nitric oxide synthase did not support the growth of E. coli by nitrate respiration, suggesting that the nitrate generated during inflammation was host-derived. Thus, the inflammatory host response selectively enhances the growth of commensal Enterobacteriaceae by generating electron acceptors for anaerobic respiration.
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Affiliation(s)
- Sebastian E Winter
- Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, One Shields Avenue, Davis, CA, USA
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IL-10 high producing genotype predisposes HIV infected individuals to TB infection. Hum Immunol 2012; 73:605-11. [DOI: 10.1016/j.humimm.2012.03.012] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2011] [Revised: 03/05/2012] [Accepted: 03/19/2012] [Indexed: 11/21/2022]
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Bleich A, Hansen AK. Time to include the gut microbiota in the hygienic standardisation of laboratory rodents. Comp Immunol Microbiol Infect Dis 2012; 35:81-92. [PMID: 22257867 DOI: 10.1016/j.cimid.2011.12.006] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2011] [Revised: 11/17/2011] [Accepted: 12/19/2011] [Indexed: 02/06/2023]
Abstract
The gut microbiota (GM) composition and its impact on animal experiments has become currently dramatically relevant in our days: (1) recent progress in metagenomic technologies, (2) the availability of large scale quantitative analyses to characterize even subtle phenotypes, (3) the limited diversity of laboratory rodent GM due to strict barriers at laboratory animal vendors, and (4) the availability of up to 300.000 different transgenic mouse strains from different sources displaying a huge variety in their GM composition. In this review the GM is described as a variable in animal experiments which need to be reduced for scientific as well as ethical reasons, and strategies how to implement this in routine diagnostic procedures are proposed. We conclude that we have both enough information available to state that the GM has an essential impact on animal models, as well as the methods available to start dealing with these impacts.
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Affiliation(s)
- André Bleich
- Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany, Hannover, Germany.
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Skyberg JA, Robison A, Golden S, Rollins MF, Callis G, Huarte E, Kochetkova I, Jutila MA, Pascual DW. Apple polyphenols require T cells to ameliorate dextran sulfate sodium-induced colitis and dampen proinflammatory cytokine expression. J Leukoc Biol 2011; 90:1043-54. [PMID: 21693591 DOI: 10.1189/jlb.0311168] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Human IBD, including UC and Crohn's disease, is characterized by a chronic, relapsing, and remitting condition that exhibits various features of immunological inflammation and affects at least one/1000 people in Western countries. Polyphenol extracts from a variety of plants have been shown to have immunomodulatory and anti-inflammatory effects. In this study, treatment with APP was investigated to ameliorate chemically induced colitis. Oral but not peritoneal administration of APP during colitis induction significantly protected C57BL/6 mice against disease, as evidenced by the lack of weight loss, colonic inflammation, and shortening of the colon. APP administration dampened the mRNA expression of IL-1β, TNF-α, IL-6, IL-17, IL-22, CXCL9, CXCL10, CXCL11, and IFN-γ in the colons of mice with colitis. APP-mediated protection requires T cells, as protection was abated in Rag-1(-/-) or TCRα(-/-) mice but not in IL-10(-/-), IRF-1(-/-), μMT, or TCRδ(-/-) mice. Administration of APP during colitis to TCRα(-/-) mice actually enhanced proinflammatory cytokine expression, further demonstrating a requirement for TCRαβ cells in APP-mediated protection. APP treatment also inhibited CXCR3 expression by TCRαβ cells, but not B or NK cells, in the colons of mice with colitis; however, depletion of CD4(+) or CD8(+) T cells alone did not abolish APP-mediated protection. Collectively, these results show that oral administration of APP protects against experimental colitis and diminishes proinflammatory cytokine expression via T cells.
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Affiliation(s)
- Jerod A Skyberg
- Department of Immunology and Infectious Diseases, Montana State University, Bozeman, Montana, USA
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