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Zhang K, Xie N, Ye H, Miao J, Xia B, Yang Y, Peng H, Xu S, Wu T, Tao C, Ruan J, Wang Y, Yang S. Glucose restriction enhances oxidative fiber formation: A multi-omic signal network involving AMPK and CaMK2. iScience 2024; 27:108590. [PMID: 38161415 PMCID: PMC10755363 DOI: 10.1016/j.isci.2023.108590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 10/23/2023] [Accepted: 11/27/2023] [Indexed: 01/03/2024] Open
Abstract
Skeletal muscle is a highly plastic organ that adapts to different metabolic states or functional demands. This study explored the impact of permanent glucose restriction (GR) on skeletal muscle composition and metabolism. Using Glut4m mice with defective glucose transporter 4, we conducted multi-omics analyses at different ages and after low-intensity treadmill training. The oxidative fibers were significantly increased in Glut4m muscles. Mechanistically, GR activated AMPK pathway, promoting mitochondrial function and beneficial myokine expression, and facilitated slow fiber formation via CaMK2 pathway. Phosphorylation-activated Perm1 may synergize AMPK and CaMK2 signaling. Besides, MAPK and CDK kinases were also implicated in skeletal muscle protein phosphorylation during GR response. This study provides a comprehensive signaling network demonstrating how GR influences muscle fiber types and metabolic patterns. These insights offer valuable data for understanding oxidative fiber formation mechanisms and identifying clinical targets for metabolic diseases.
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Affiliation(s)
- Kaiyi Zhang
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100193, China
- Precision Livestock and Nutrition Unit, Gembloux Agro-Bio Tech, TERRA Teaching and Research Centre, Liège University, 5030 Gembloux, Belgium
| | - Ning Xie
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100193, China
| | - Huaqiong Ye
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100193, China
| | - Jiakun Miao
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100193, China
| | - Boce Xia
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100193, China
| | - Yu Yang
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100193, China
| | - Huanqi Peng
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100193, China
| | - Shuang Xu
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100193, China
| | - Tianwen Wu
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100193, China
| | - Cong Tao
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100193, China
| | - Jinxue Ruan
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education & Key Lab of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan 430070, China
| | - Yanfang Wang
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100193, China
| | - Shulin Yang
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100193, China
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Muhammad B, Li H, Gu Y, Xue S, Gao Y, Xu Z, Fang X, Ding H, Wu F, Geng D, Niu H. IL-1β/IL-1R1 signaling is involved in the propagation of α-synuclein pathology of the gastrointestinal tract to the brain. J Neurochem 2023; 166:830-846. [PMID: 37434423 DOI: 10.1111/jnc.15886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 06/03/2023] [Accepted: 06/07/2023] [Indexed: 07/13/2023]
Abstract
The pathological hallmark of Parkinson's disease (PD) is the intraneuronal accumulation of misfolded alpha-synuclein (termed Lewy bodies) in dopaminergic neurons of substantia nigra par compacta (SNc). It is assumed that the α-syn pathology is induced by gastrointestinal inflammation and then transfers to the brain by the gut-brain axis. Therefore, the relationship between gastrointestinal inflammation and α-syn pathology leading to PD remains to be investigated. In our study, rotenone (ROT) oral administration induces gastrointestinal tract (GIT) inflammation in mice. In addition, we used pseudorabies virus (PRV) for tracing studies and performed behavioral testing. We observed that ROT treatments enhance macrophage activation, inflammatory mediator expression, and α-syn pathology in the GIT 6-week post-treatment (P6). Moreover, pathological α-syn was localized with IL-1R1 positive neural cells in GIT. In line with these findings, we also find pS129-α-syn signals in the dorsal motor nucleus of the vagus (DMV) and tyrosine hydroxylase in the nigral-striatum dynamically change from 3-week post-treatment (P3) to P6. Following that, pS129-α-syn was dominant in the enteric neural cell, DMV, and SNc, accompanied by microglial activation, and these phenotypes were absent in IL-1R1r/r mice. These data suggest that IL-1β/IL-1R1-dependent inflammation of GIT can induce α-syn pathology, which then propagates to the DMV and SNc, resulting in PD.
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Affiliation(s)
- Bilal Muhammad
- Department of Neurology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Haiying Li
- Department of Pathology, Xuzhou Medical University, Xuzhou, China
| | - Yunlu Gu
- Department of Neuroscience, Xuzhou Medical University, Xuzhou, China
| | - Senlin Xue
- Department of Post-Graduation, Xuzhou Medical University, Xuzhou, China
| | - Yao Gao
- Department of Post-Graduation, Xuzhou Medical University, Xuzhou, China
| | - Zhou Xu
- Department of Post-Graduation, Xuzhou Medical University, Xuzhou, China
| | - Xiaoli Fang
- Department of Neurology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Haohan Ding
- Department of Neuroscience, Xuzhou Medical University, Xuzhou, China
| | - Fang Wu
- Department of Neuroscience, Xuzhou Medical University, Xuzhou, China
| | - Deqin Geng
- Department of Neurology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Haichen Niu
- Department of Genetics, Xuzhou Medical University, Xuzhou, China
- Public Experimental Research Center of Xuzhou Medical University, Xuzhou, China
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Alves JL, Lemos L, Rodrigues NM, Pereira VB, Barros PAV, Canesso MCC, Guimarães MAF, Cara DC, Miyoshi A, Azevedo VA, Maioli TU, Gomes-Santos AC, Faria AMC. Immunomodulatory effects of different strains of Lactococcus lactis in DSS-induced colitis. Braz J Microbiol 2023; 54:1203-1215. [PMID: 36821043 PMCID: PMC10234881 DOI: 10.1007/s42770-023-00928-0] [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: 12/12/2021] [Accepted: 02/10/2023] [Indexed: 02/24/2023] Open
Abstract
Inflammatory bowel diseases (IBD) are gastrointestinal disorders characterized by a breakdown in intestinal homeostasis by inflammatory immune responses to luminal antigens. Novel strategies for ameliorating IBD have been proposed in many studies using animal models. Our group has demonstrated that administration of Lactococcus lactis NCDO 2118 can improve clinical parameters of colitis induced by oral administration of dextran sulphate sodium (DSS). However, it is not clear whether other strains of L. lactis can yield the same effect. The objective of present study was to analyze the effects of three different L. lactis strains (NCDO2118, IL1403 and MG1363) in the development of DSS-induced colitis in C57BL/6 mice. Acute colitis was induced in C57/BL6 mice by the administration of 2% DSS during 7 consecutive days. Body weight loss and shortening of colon length were observed in DSS-treated mice, and none of L. lactis strains had an impact in these clinical signs of colitis. On the other hand, all strains improved the global macroscopical disease index and prevented goblet cells depletion as well as the increase of intestinal permeability. TNF-α production was reduced in gut mucosa of L. lactis DSS-treated mice indicating a modulation of a critical pro-inflammatory response by all strains tested. However, only L. lactis NCDO2118 and MG1363 induced a higher frequency of CD11c+CD11b-CD103+ tolerogenic dendritic cells in lymphoid organs of mice at steady state. We conclude that all tested strains of L. lactis improved the clinical scores and parameters of colitis, which confirm their anti-inflammatory properties in this model of colitis.
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Affiliation(s)
- Juliana Lima Alves
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil.
| | - Luisa Lemos
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - Nubia Morais Rodrigues
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - Vanessa Bastos Pereira
- Departamento de Genética, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Ecologia E Evolução, Belo Horizonte, MG, Brazil
| | - Patrícia A Vieira Barros
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - Maria Cecília Campos Canesso
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - Mauro A F Guimarães
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - Denise Carmona Cara
- Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - Anderson Miyoshi
- Departamento de Genética, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Ecologia E Evolução, Belo Horizonte, MG, Brazil
| | - Vasco Ariston Azevedo
- Departamento de Genética, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Ecologia E Evolução, Belo Horizonte, MG, Brazil
| | - Tatiani Uceli Maioli
- Departamento de Nutrição, Escola de Enfermagem, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - Ana Cristina Gomes-Santos
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - Ana Maria Caetano Faria
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil.
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Sex differences in pain-related behaviors and clinical progression of disease in mouse models of colonic pain. Pain 2023; 164:197-215. [PMID: 35559931 PMCID: PMC9756435 DOI: 10.1097/j.pain.0000000000002683] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 04/28/2022] [Indexed: 01/09/2023]
Abstract
ABSTRACT Previous studies have reported sex differences in patients with irritable bowel syndrome and inflammatory bowel disease, including differences in visceral pain perception. Despite this, sex differences in behavioral manifestations of visceral pain and underlying pathology of the gastrointestinal tract have been largely understudied in preclinical research. In this study, we evaluated potential sex differences in spontaneous nociceptive responses, referred abdominal hypersensitivity, disease progression, and bowel pathology in mouse models of acute and persistent colon inflammation. Our experiments show that females exhibit more nociceptive responses and referred abdominal hypersensitivity than males in the context of acute but not persistent colon inflammation. We further demonstrate that, after acute and persistent colon inflammation, pain-related behavioral responses in females and males are distinct, with increases in licking of the abdomen only observed in females and increases in abdominal contractions only seen in males. During persistent colon inflammation, males exhibit worse disease progression than females, which is manifested as worse physical appearance and higher weight loss. However, no measurable sex differences were observed in persistent inflammation-induced bowel pathology, stool consistency, or fecal blood. Overall, our findings demonstrate sex differences in pain-related behaviors and disease progression in the context of acute and persistent colon inflammation, highlighting the importance of considering sex as a biological variable in future mechanistic studies of visceral pain as well as in the development of diagnostics and therapeutic options for chronic gastrointestinal diseases.
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Peek CT, Ford CA, Eichelberger KR, Jacobse J, Torres TP, Maseda D, Latour YL, Piazuelo MB, Johnson JR, Byndloss MX, Wilson KT, Rathmell JC, Goettel JA, Cassat JE. Intestinal Inflammation Promotes MDL-1 + Osteoclast Precursor Expansion to Trigger Osteoclastogenesis and Bone Loss. Cell Mol Gastroenterol Hepatol 2022; 14:731-750. [PMID: 35835390 PMCID: PMC9420375 DOI: 10.1016/j.jcmgh.2022.07.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 07/01/2022] [Accepted: 07/05/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Inflammatory bowel disease (IBD) is characterized by severe gastrointestinal inflammation, but many patients experience extra-intestinal disease. Bone loss is one common extra-intestinal manifestation of IBD that occurs through dysregulated interactions between osteoclasts and osteoblasts. Systemic inflammation has been postulated to contribute to bone loss, but the specific pathologic mechanisms have not yet been fully elucidated. We hypothesized that intestinal inflammation leads to bone loss through increased abundance and altered function of osteoclast progenitors. METHODS We used chemical, T cell driven, and infectious models of intestinal inflammation to determine the impact of intestinal inflammation on bone volume, the skeletal cytokine environment, and the cellular changes to pre-osteoclast populations within bone marrow. Additionally, we evaluated the potential for monoclonal antibody treatment against an inflammation-induced osteoclast co-receptor, myeloid DNAX activation protein 12-associating lectin-1 (MDL-1) to reduce bone loss during colitis. RESULTS We observed significant bone loss across all models of intestinal inflammation. Bone loss was associated with an increase in pro-osteoclastogenic cytokines within the bone and an expansion of a specific Cd11b-/loLy6Chi osteoclast precursor (OCP) population. Intestinal inflammation led to altered OCP expression of surface receptors involved in osteoclast differentiation and function, including the pro-osteoclastogenic co-receptor MDL-1. OCPs isolated from mice with intestinal inflammation demonstrated enhanced osteoclast differentiation ex vivo compared to controls, which was abrogated by anti-MDL-1 antibody treatment. Importantly, in vivo anti-MDL-1 antibody treatment ameliorated bone loss during intestinal inflammation. CONCLUSIONS Collectively, these data implicate the pathologic expansion and altered function of OCPs expressing MDL-1 in bone loss during IBD.
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Affiliation(s)
- Christopher T Peek
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Caleb A Ford
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
| | - Kara R Eichelberger
- Department of Pediatrics, Division of Pediatric Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Justin Jacobse
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee; Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Teresa P Torres
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Damian Maseda
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Yvonne L Latour
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - M Blanca Piazuelo
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Joshua R Johnson
- Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Mariana X Byndloss
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Keith T Wilson
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee; Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee; Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee; Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee
| | - Jeffrey C Rathmell
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee; Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jeremy A Goettel
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee; Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee; Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee
| | - James E Cassat
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee; Department of Pediatrics, Division of Pediatric Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee; Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, Tennessee.
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T-Cell-Specific CerS4 Depletion Prolonged Inflammation and Enhanced Tumor Burden in the AOM/DSS-Induced CAC Model. Int J Mol Sci 2022; 23:ijms23031866. [PMID: 35163788 PMCID: PMC8837088 DOI: 10.3390/ijms23031866] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 01/31/2022] [Accepted: 02/04/2022] [Indexed: 12/12/2022] Open
Abstract
To better understand the role of sphingolipids in the multifactorial process of inflammatory bowel disease (IBD), we elucidated the role of CerS4 in colitis and colitis-associated cancer (CAC). For this, we utilized the azoxymethane/dextran sodium sulphate (AOM/DSS)-induced colitis model in global CerS4 knockout (CerS4 KO), intestinal epithelial (CerS4 Vil/Cre), or T-cell restricted knockout (CerS4 LCK/Cre) mice. CerS4 KO mice were highly sensitive to the toxic effect of AOM/DSS, leading to a high mortality rate. CerS4 Vil/Cre mice had smaller tumors than WT mice. In contrast, CerS4 LCK/Cre mice frequently suffered from pancolitis and developed more colon tumors. In vitro, CerS4-depleted CD8+ T-cells isolated from the thymi of CerS4 LCK/Cre mice showed impaired proliferation and prolonged cytokine production after stimulation in comparison with T-cells from WT mice. Depletion of CerS4 in human Jurkat T-cells led to a constitutively activated T-cell receptor and NF-κB signaling pathway. In conclusion, the deficiency of CerS4 in T-cells led to an enduring active status of these cells and prevents the resolution of inflammation, leading to a higher tumor burden in the CAC mouse model. In contrast, CerS4 deficiency in epithelial cells resulted in smaller colon tumors and seemed to be beneficial. The higher tumor incidence in CerS4 LCK/Cre mice and the toxic effect of AOM/DSS in CerS4 KO mice exhibited the importance of CerS4 in other tissues and revealed the complexity of general targeting CerS4.
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Anti-inflammatory properties and gut microbiota modulation of an alkali-soluble polysaccharide from purple sweet potato in DSS-induced colitis mice. Int J Biol Macromol 2020; 153:708-722. [DOI: 10.1016/j.ijbiomac.2020.03.053] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 03/08/2020] [Accepted: 03/09/2020] [Indexed: 12/19/2022]
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The impact of Clonorchis sinensis infection on immune response in mice with type II collagen-induced arthritis. BMC Immunol 2020; 21:7. [PMID: 32066378 PMCID: PMC7027077 DOI: 10.1186/s12865-020-0336-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 02/12/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Clonorchis sinensis infection could trigger strong immune responses in mice and humans. However, whether the C.sinensis infection has an impact on arthritis is unknown. Here we investigated the effect of C.sinensis infection on type II collagen-induced arthritis in BALB/c mice. RESULTS The mice were firstly infected with 45 C.sinensis metacercariae by oral gavage. Four weeks later, arthritis in mice was induced by type II collagen. Joint inflammation with severe redness and swelling in hind paws was observed in type II collagen-induced arthritis (CIA) mice. Besides, the physical activity was significantly reduced, but the respiratory exchange ratio was increased in CIA mice. Compared with CIA mice, C.sinensis infection could increase the severity of arthritis in CIA mice, based on the results of disease score and pathological changes. Compared to CIA mice, increased neutrophils and Ly6Chi monocytes, decreased B cells and CD4+T cells, were found in C.sinensis infected CIA mice. Besides these, C.sinensis infected mice also displayed significantly higher levels of serum IL-4 and IL-17 than those in CIA mice. CONCLUSIONS Taken together, our data suggest that C.sinensis infection have a bad effect on arthritis, and could induce the abnormality of the immune response in mice with CIA.
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Early life nutrition influences susceptibility to chronic inflammatory colitis in later life. Sci Rep 2019; 9:18111. [PMID: 31792267 PMCID: PMC6889478 DOI: 10.1038/s41598-019-54308-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Accepted: 11/08/2019] [Indexed: 12/21/2022] Open
Abstract
The first thousand days of life are a critical time of development in humans during which the risk profile for diseases in later life can be modified. Nevertheless, long-term consequences of early environment on susceptibility to intestinal diseases have not yet been assessed. Using a mouse model of postnatal growth restriction (PNGR), we showed that early life nutrition influences intestinal maturation and gut health in later life. PNGR induced an alteration of the intestinal barrier in pups at weaning, resulting in increased intestinal permeability, and affected gut bacterial colonization. Specifically, pups with PNGR harbored a decreased bacterial diversity, higher Enterococcus spp., Staphylococcus spp., and Escherichia-Shigella spp., and lower Odoribacter spp. and several members of the Lachnospiraceae family. The lack of an efficient intestinal barrier in early life and the dysbiosis induced by PNGR were associated with a higher susceptibility to chronic colitis in adulthood.
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Chiabai MJ, Almeida JF, de Azevedo MGD, Fernandes SS, Pereira VB, de Castro RJA, Jerônimo MS, Sousa IG, de Souza Vianna LM, Miyoshi A, Bocca AL, Maranhão AQ, Brigido MM. Mucosal delivery of Lactococcus lactis carrying an anti-TNF scFv expression vector ameliorates experimental colitis in mice. BMC Biotechnol 2019; 19:38. [PMID: 31238939 PMCID: PMC6593574 DOI: 10.1186/s12896-019-0518-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Accepted: 04/25/2019] [Indexed: 02/06/2023] Open
Abstract
Background Anti-Tumor Necrosis Factor-alpha therapy has become clinically important for treating inflammatory bowel disease. However, the use of conventional immunotherapy requires a systemic exposure of patients and collateral side effects. Lactic acid bacteria have been shown to be effective as mucosal delivering system for cytokine and single domain antibodies, and it is amenable to clinical purposes. Therefore, lactic acid bacteria may function as vehicles for delivery of therapeutic antibodies molecules to the gastrointestinal tract restricting the pharmacological effect towards the gut. Here, we use the mucosal delivery of Lactococcus lactis carrying an anti-TNFα scFv expression plasmid on a DSS-induced colitis model in mice. Results Experimental colitis was induced with DSS administered in drinking water. L. lactis carrying the scFv expression vector was introduced by gavage. After four days of treatment, animals showed a significant improvement in histological score and disease activity index compared to those of untreated animals. Moreover, treated mice display IL-6, IL17A, IL1β, IL10 and FOXP3 mRNA levels similar to health control mice. Therefore, morphological and molecular markers suggest amelioration of the experimentally induced colitis. Conclusion These results provide evidence for the use of this alternative system for delivering therapeutic biopharmaceuticals in loco for treating inflammatory bowel disease, paving the way for a novel low-cost and site-specific biotechnological route for the treatment of inflammatory disorders. Electronic supplementary material The online version of this article (10.1186/s12896-019-0518-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Maria José Chiabai
- Laboratório de Imunologia Molecular, Departamento de Biologia Molecular, Universidade de Brasília, Brasília, Distrito Federal, Brazil
| | - Juliana Franco Almeida
- Centro de Biotecnologia, Departamento de Biologia Celular e Molecular, Universidade Federal da Paraíba, João Pessoa, Paraíba, Brazil
| | | | - Suelen Soares Fernandes
- Laboratório de Imunologia Molecular, Departamento de Biologia Molecular, Universidade de Brasília, Brasília, Distrito Federal, Brazil
| | - Vanessa Bastos Pereira
- Laboratório de Tecnologia Genética, Departamento de Biologia Geral, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Raffael Júnio Araújo de Castro
- Laboratório de Imunologia Aplicada, Departamento de Biologia Celular, Universidade de Brasília, Brasília, Distrito Federal, Brazil
| | - Márcio Sousa Jerônimo
- Laboratório de Imunologia Aplicada, Departamento de Biologia Celular, Universidade de Brasília, Brasília, Distrito Federal, Brazil
| | - Isabel Garcia Sousa
- Laboratório de Imunologia Molecular, Departamento de Biologia Molecular, Universidade de Brasília, Brasília, Distrito Federal, Brazil
| | | | - Anderson Miyoshi
- Laboratório de Tecnologia Genética, Departamento de Biologia Geral, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Anamelia Lorenzetti Bocca
- Laboratório de Imunologia Aplicada, Departamento de Biologia Celular, Universidade de Brasília, Brasília, Distrito Federal, Brazil
| | - Andrea Queiroz Maranhão
- Laboratório de Imunologia Molecular, Departamento de Biologia Molecular, Universidade de Brasília, Brasília, Distrito Federal, Brazil.,Instituto Nacional de Investigação em Imunologia, INCTii, Brasília, Distrito Federal, Brazil
| | - Marcelo Macedo Brigido
- Laboratório de Imunologia Molecular, Departamento de Biologia Molecular, Universidade de Brasília, Brasília, Distrito Federal, Brazil. .,Instituto Nacional de Investigação em Imunologia, INCTii, Brasília, Distrito Federal, Brazil.
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Yu W, Hwa LS, Makhijani VH, Besheer J, Kash TL. Chronic inflammatory pain drives alcohol drinking in a sex-dependent manner for C57BL/6J mice. Alcohol 2019; 77:135-145. [PMID: 30300665 DOI: 10.1016/j.alcohol.2018.10.002] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 10/01/2018] [Accepted: 10/01/2018] [Indexed: 12/31/2022]
Abstract
Sex differences in chronic pain and alcohol abuse are not well understood. The development of rodent models is imperative for investigating the underlying changes behind these pathological states. In the present study, we investigated whether hind paw treatment with the inflammatory agent Complete Freund's Adjuvant (CFA) could generate hyperalgesia and alter alcohol consumption in male and female C57BL/6J mice. CFA treatment led to greater nociceptive sensitivity for both sexes in the Hargreaves test, and increased alcohol drinking for males in a continuous-access two-bottle choice (CA2BC) paradigm. Regardless of treatment, female mice exhibited greater alcohol drinking than males. Following a 2-h terminal drinking session, CFA treatment failed to produce changes in alcohol drinking, blood ethanol concentration (BEC), and plasma corticosterone (CORT) for both sexes. Two-hour alcohol consumption and CORT was higher in females than males, regardless of CFA treatment. Taken together, these findings have established that male mice are more susceptible to escalations in alcohol drinking when undergoing pain, despite higher levels of total alcohol drinking and CORT in females. Furthermore, the exposure of CFA-treated C57BL/6J mice to the CA2BC drinking paradigm has proven to be a useful model for studying the relationship between chronic pain and alcohol abuse. Future applications of the CFA/CA2BC model should incorporate manipulations of stress signaling and other related biological systems to improve our mechanistic understanding of pain and alcohol interactions.
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12
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Peng Y, Yan Y, Wan P, Chen D, Ding Y, Ran L, Mi J, Lu L, Zhang Z, Li X, Zeng X, Cao Y. Gut microbiota modulation and anti-inflammatory properties of anthocyanins from the fruits of Lycium ruthenicum Murray in dextran sodium sulfate-induced colitis in mice. Free Radic Biol Med 2019; 136:96-108. [PMID: 30959170 DOI: 10.1016/j.freeradbiomed.2019.04.005] [Citation(s) in RCA: 280] [Impact Index Per Article: 46.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 04/02/2019] [Accepted: 04/02/2019] [Indexed: 02/07/2023]
Abstract
In the present study, the therapeutic effects of crude anthocyanins (ACN) from the fruits of Lycium ruthenicum Murray and the main monomer of ACN, petunidin 3-O-[rhamnopyranosyl-(trans-p-coumaroyl)]-5-O-[β-d-glucopyranoside] (P3G), on the dextran sodium sulfate (DSS)-induced colitis in mice were investigated. Both ACN and P3G showed intestinal anti-inflammatory effects, evidenced by restoration of various physical signs (body weight, feed quantity, solid fecal weight and colon length were increased, and DAI score was decreased), reduction of the expression of proinflammatory cytokines and related mRNA (such as TNF-α, IL-6, IL-1β and IFN-γ), and promotion of the intestinal barrier function by histological and immunofluorescence analysis (proteins such as ZO-1, occludin and claudin-1 were increased). Furthermore, the effects on gut microbiota community of DSS-induced colitis in mice have been investigated. It was found that Porphyromonadaceae, Helicobacter, Parasutterella, Parabacteroides, Oscillibacter and Lachnospiraceae were the key bacteria associated with inflammatory bowel disease. Taken together, P3G and ACN ameliorated DSS-induced colitis in mice through three aspects including blocking proinflammatory cytokines, increasing tight junction protein and modulating gut microbiota. What's more, P3G showed better anti-inflammatory effects than ACN.
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Affiliation(s)
- Yujia Peng
- College of Food Science and Technology, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, China
| | - Yamei Yan
- National Wolfberry Engineering Research Center, Yinchuan, 750002, Ningxia, China
| | - Peng Wan
- College of Food Science and Technology, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, China
| | - Dan Chen
- College of Food Science and Technology, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, China
| | - Yu Ding
- College of Food Science and Technology, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, China
| | - Linwu Ran
- Laboratory Animal Center, Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Jia Mi
- National Wolfberry Engineering Research Center, Yinchuan, 750002, Ningxia, China
| | - Lu Lu
- National Wolfberry Engineering Research Center, Yinchuan, 750002, Ningxia, China
| | - Zhijuan Zhang
- National Wolfberry Engineering Research Center, Yinchuan, 750002, Ningxia, China
| | - Xiaoying Li
- National Wolfberry Engineering Research Center, Yinchuan, 750002, Ningxia, China
| | - Xiaoxiong Zeng
- College of Food Science and Technology, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, China.
| | - Youlong Cao
- National Wolfberry Engineering Research Center, Yinchuan, 750002, Ningxia, China.
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13
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Moreira TG, Gomes-Santos AC, Horta LS, Goncalves MC, Santiago AF, Lauar JG, Dos Reis DS, Castro-Junior AB, Lemos L, Guimarães M, Aguilar EC, Pap A, Amaral JF, Alvarez-Leite JI, Cara DC, Rezende RM, Nagy L, Faria AMC, Maioli TU. Consumption of conjugated linoleic acid (CLA)-supplemented diet during colitis development ameliorates gut inflammation without causing steatosis in mice. J Nutr Biochem 2018; 57:238-245. [PMID: 29800810 DOI: 10.1016/j.jnutbio.2018.04.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Revised: 03/06/2018] [Accepted: 04/13/2018] [Indexed: 12/25/2022]
Abstract
Dietary supplementation with conjugated linoleic acid (CLA) has been proposed for weight management and to prevent gut inflammation. However, some animal studies suggest that supplementation with CLA leads to the development of nonalcoholic fatty liver disease. The aims of this study were to test the efficiency of CLA in preventing dextran sulfate sodium (DSS)-induced colitis, to analyze the effects of CLA in the liver function, and to access putative liver alterations upon CLA supplementation during colitis. So, C57BL/6 mice were supplemented for 3 weeks with either control diet (AIN-G) or 1% CLA-supplemented diet. CLA content in the diet and in the liver of mice fed CLA containing diet were accessed by gas chromatography. On the first day of the third week of dietary treatment, mice received ad libitum a 1.5%-2.5% DSS solution for 7 days. Disease activity index score was evaluated; colon and liver samples were stained by hematoxylin and eosin for histopathology analysis and lamina propria cells were extracted to access the profile of innate cell infiltrate. Metabolic alterations before and after colitis induction were accessed by an open calorimetric circuit. Serum glucose, cholesterol, triglycerides and alanine aminotransaminase were measured; the content of fat in liver and feces was also accessed. CLA prevented weight loss, histopathologic and macroscopic signs of colitis, and inflammatory infiltration. Mice fed CLA-supplemented without colitis induction diet developed steatosis, which was prevented in mice with colitis probably due to the higher lipid consumption as energy during gut inflammation. This result suggests that CLA is safe for use during gut inflammation but not at steady-state conditions.
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Affiliation(s)
- Thais Garcias Moreira
- Departamento de Ciência de Alimentos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Ana Cristina Gomes-Santos
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Laila Sampaio Horta
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Mariana Camila Goncalves
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Andrezza Fernanda Santiago
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Juliana Gonçalves Lauar
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Daniela Silva Dos Reis
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Archimedes Barbosa Castro-Junior
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Luisa Lemos
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Mauro Guimarães
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Edenil Costa Aguilar
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Attila Pap
- Department of Biochemistry and Molecular Biology, University of Debrecen, Medical and Health Science Center, Debrecen, Hungary
| | - Joana Ferreira Amaral
- Escola de Nutrição e Núcleo de Pesquisa em Biologia, Universidade Federal de Ouro Preto, Ouro Preto, MG, Brazil
| | - Jacqueline I Alvarez-Leite
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Denise Carmona Cara
- Departamento de Morfologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Rafael Machado Rezende
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Laszlo Nagy
- Department of Biochemistry and Molecular Biology, University of Debrecen, Medical and Health Science Center, Debrecen, Hungary; Diabetes and Obesity Research Center, Sanford Burnham Medical Research Institute, Lake Nona, Orlando, FL, USA
| | - Ana Maria Caetano Faria
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
| | - Tatiani Uceli Maioli
- Departamento de Nutrição, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
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14
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Jiminez JA, Uwiera TC, Abbott DW, Uwiera RRE, Inglis GD. Impacts of resistant starch and wheat bran consumption on enteric inflammation in relation to colonic bacterial community structures and short-chain fatty acid concentrations in mice. Gut Pathog 2016; 8:67. [PMID: 28031748 PMCID: PMC5178079 DOI: 10.1186/s13099-016-0149-6] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Accepted: 12/05/2016] [Indexed: 02/07/2023] Open
Abstract
Background
Identifying the connection among diet, the intestinal microbiome, and host health is currently an area of intensive research, but the potential of dietary fiber (DF) consumption to ameliorate intestinal inflammation has not been extensively studied. We examined the impacts of the DFs, wheat bran (WB) and resistant starch (RS) on host enteric health. A murine model of acute Th1/Th17 colitis (i.e. incited by Citrobacter rodentium) was used. Results Diets enriched with RS increased weight gain in mice inoculated with C. rodentium compared to mice consuming a conventional control (CN) diet. Short-chain fatty acid (SCFA) quantities in the cecum and distal colon were higher in mice consuming DFs, and these mice exhibited higher butyrate concentrations in the distal colon during inflammation. Histopathologic scores of inflammation in the proximal colon on day 14 post-inoculation (p.i.) (peak infection) and 21 p.i. (late infection) were lower in mice consuming DF-enriched diets compared to the CN diet. Consumption of WB reduced the expression of Th1/Th17 cytokines. As well, the expression of bacterial recognition and response genes such as Relmβ, RegIIIγ, and Tlr4 increased in mice consuming the RS-enriched diets. Furthermore, each diet generated a region-specific bacterial community, suggesting a link between selection for specific bacterial communities, SCFA concentrations, and inflammation in the murine colon. Conclusions Collectively, data indicated that the consumption of DF-rich diets ameliorates the effects of C. rodentium-induced enteritis by modifying the host microbiota to increase SCFA production, and bacterial recognition and response mechanisms to promote host health.
Electronic supplementary material The online version of this article (doi:10.1186/s13099-016-0149-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Janelle A Jiminez
- Agriculture and Agri-Food Canada, 5403-1st Avenue South, Lethbridge, AB T1J 4B1 Canada.,Department of Agricultural Food and Nutritional Science, University of Alberta, 410 Agriculture/Forestry Centre, Edmonton, AB T6G 2P5 Canada
| | - Trina C Uwiera
- Divisions of Pediatric Surgery, Department of Surgery, University of Alberta, 2C3.82 Walter C. Mackenzie Health Sciences Center, 8440-112th Street, Edmonton, AB T6G 2B7 Canada
| | - D Wade Abbott
- Agriculture and Agri-Food Canada, 5403-1st Avenue South, Lethbridge, AB T1J 4B1 Canada
| | - Richard R E Uwiera
- Department of Agricultural Food and Nutritional Science, University of Alberta, 410 Agriculture/Forestry Centre, Edmonton, AB T6G 2P5 Canada
| | - G Douglas Inglis
- Agriculture and Agri-Food Canada, 5403-1st Avenue South, Lethbridge, AB T1J 4B1 Canada
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15
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Brooks L, Viardot A, Tsakmaki A, Stolarczyk E, Howard JK, Cani PD, Everard A, Sleeth ML, Psichas A, Anastasovskaj J, Bell JD, Bell-Anderson K, Mackay CR, Ghatei MA, Bloom SR, Frost G, Bewick GA. Fermentable carbohydrate stimulates FFAR2-dependent colonic PYY cell expansion to increase satiety. Mol Metab 2016; 6:48-60. [PMID: 28123937 PMCID: PMC5220466 DOI: 10.1016/j.molmet.2016.10.011] [Citation(s) in RCA: 185] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Revised: 10/27/2016] [Accepted: 10/28/2016] [Indexed: 12/24/2022] Open
Abstract
Objective Dietary supplementation with fermentable carbohydrate protects against body weight gain. Fermentation by the resident gut microbiota produces short-chain fatty acids, which act at free fatty acid receptor 2 (FFAR2). Our aim was to test the hypothesis that FFAR2 is important in regulating the beneficial effects of fermentable carbohydrate on body weight and to understand the role of gut hormones PYY and GLP-1. Methods Wild-type or Ffar2−/− mice were fed an inulin supplemented or control diet. Mice were metabolically characterized and gut hormone concentrations, enteroendocrine cell density measurements were carried out. Intestinal organoids and colonic cultures were utilized to substantiate the in vivo findings. Results We provide new mechanistic insight into how fermentable carbohydrate regulates metabolism. Using mice that lack FFAR2, we demonstrate that the fermentable carbohydrate inulin acts via this receptor to drive an 87% increase in the density of cells that produce the appetite-suppressing hormone peptide YY (PYY), reduce food intake, and prevent diet-induced obesity. Conclusion Our results demonstrate that FFAR2 is predominantly involved in regulating the effects of fermentable carbohydrate on metabolism and does so, in part, by enhancing PYY cell density and release. This highlights the potential for targeting enteroendocrine cell differentiation to treat obesity.
Fermentable carbohydrate protects against diet-induced obesity via FFAR2. Fermentable carbohydrate increases GLP-1 cell density independently of FFAR2. FFAR2 signaling increases PYY cell density and circulating PYY concentration.
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Affiliation(s)
- Lucy Brooks
- Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, W12 0NN, UK
| | - Alexander Viardot
- Diabetes & Metabolism Division, Garvan Institute of Medical Research, Sydney-Darlinghurst, NSW, 2010, Australia
| | - Anastasia Tsakmaki
- Division of Diabetes and Nutritional Sciences, King's College London, London, SE1 9RT, UK
| | - Emilie Stolarczyk
- Division of Diabetes and Nutritional Sciences, King's College London, London, SE1 9RT, UK
| | - Jane K Howard
- Division of Diabetes and Nutritional Sciences, King's College London, London, SE1 9RT, UK
| | - Patrice D Cani
- Louvain Drug Research Institute, Metabolism and Nutrition Research Group, WELBIO (Walloon Excellence in Life sciences and BIOtechnology), Université catholique de Louvain, B-1200, Brussels, Belgium
| | - Amandine Everard
- Louvain Drug Research Institute, Metabolism and Nutrition Research Group, WELBIO (Walloon Excellence in Life sciences and BIOtechnology), Université catholique de Louvain, B-1200, Brussels, Belgium
| | - Michelle L Sleeth
- Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, W12 0NN, UK
| | - Arianna Psichas
- Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, W12 0NN, UK
| | - Jelena Anastasovskaj
- Metabolic and Molecular Imaging Group, MRC Clinical Science Centre, Imperial College London, London, W12 0NN, UK
| | - Jimmy D Bell
- Metabolic and Molecular Imaging Group, MRC Clinical Science Centre, Imperial College London, London, W12 0NN, UK
| | - Kim Bell-Anderson
- School of Molecular Bioscience, University of Sydney, Sydney, NSW, 2006, Australia
| | - Charles R Mackay
- Charles Perkins Centre, Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia; Department of Immunology, Monash University, Clayton, VIC, 3800, Australia
| | - Mohammad A Ghatei
- Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, W12 0NN, UK
| | - Stephen R Bloom
- Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, W12 0NN, UK
| | - Gary Frost
- Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, W12 0NN, UK.
| | - Gavin A Bewick
- Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, W12 0NN, UK; Division of Diabetes and Nutritional Sciences, King's College London, London, SE1 9RT, UK.
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16
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Kamdar K, Khakpour S, Chen J, Leone V, Brulc J, Mangatu T, Antonopoulos DA, Chang EB, Kahn SA, Kirschner BS, Young G, DePaolo RW. Genetic and Metabolic Signals during Acute Enteric Bacterial Infection Alter the Microbiota and Drive Progression to Chronic Inflammatory Disease. Cell Host Microbe 2016; 19:21-31. [PMID: 26764594 DOI: 10.1016/j.chom.2015.12.006] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Revised: 11/20/2015] [Accepted: 12/21/2015] [Indexed: 12/18/2022]
Abstract
Chronic inflammatory disorders are thought to arise due to an interplay between predisposing host genetics and environmental factors. For example, the onset of inflammatory bowel disease is associated with enteric proteobacterial infection, yet the mechanistic basis for this association is unclear. We have shown previously that genetic defiency in TLR1 promotes acute enteric infection by the proteobacteria Yersinia enterocolitica. Examining that model further, we uncovered an altered cellular immune response that promotes the recruitment of neutrophils which in turn increases metabolism of the respiratory electron acceptor tetrathionate by Yersinia. These events drive permanent alterations in anti-commensal immunity, microbiota composition, and chronic inflammation, which persist long after Yersinia clearence. Deletion of the bacterial genes involved in tetrathionate respiration or treatment using targeted probiotics could prevent microbiota alterations and inflammation. Thus, acute infection can drive long term immune and microbiota alterations leading to chronic inflammatory disease in genetically predisposed individuals.
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Affiliation(s)
- Karishma Kamdar
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90089, USA
| | - Samira Khakpour
- Department of Medicine, Section of Gastroenterology, University of Chicago, Chicago, IL 60637, USA
| | - Jingyu Chen
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China; Department of Food Science and Technology, University of California, Davis, Davis, CA 95616, USA
| | - Vanessa Leone
- Department of Medicine, Section of Gastroenterology, University of Chicago, Chicago, IL 60637, USA
| | | | - Thomas Mangatu
- Department of Medicine, Section of Gastroenterology, University of Chicago, Chicago, IL 60637, USA; Department of Pediatrics Section of Pediatric Gastroenterology, Hepatology, & Nutrition, University of Chicago, Chicago, IL 60637, USA
| | - Dionysios A Antonopoulos
- Department of Medicine, Section of Gastroenterology, University of Chicago, Chicago, IL 60637, USA; Argonne National Laboratory, Argonne, IL 60439, USA
| | - Eugene B Chang
- Department of Medicine, Section of Gastroenterology, University of Chicago, Chicago, IL 60637, USA
| | - Stacy A Kahn
- Department of Medicine, Section of Gastroenterology, University of Chicago, Chicago, IL 60637, USA; Department of Pediatrics Section of Pediatric Gastroenterology, Hepatology, & Nutrition, University of Chicago, Chicago, IL 60637, USA
| | - Barbara S Kirschner
- Department of Medicine, Section of Gastroenterology, University of Chicago, Chicago, IL 60637, USA; Department of Pediatrics Section of Pediatric Gastroenterology, Hepatology, & Nutrition, University of Chicago, Chicago, IL 60637, USA
| | - Glenn Young
- Department of Food Science and Technology, University of California, Davis, Davis, CA 95616, USA
| | - R William DePaolo
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90089, USA.
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17
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Irwin R, Raehtz S, Parameswaran N, McCabe LR. Intestinal inflammation without weight loss decreases bone density and growth. Am J Physiol Regul Integr Comp Physiol 2016; 311:R1149-R1157. [PMID: 27733383 DOI: 10.1152/ajpregu.00051.2016] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Revised: 09/05/2016] [Accepted: 09/19/2016] [Indexed: 02/07/2023]
Abstract
Increasing evidence indicates a strong link between intestinal health and bone health. For example, inflammatory bowel disease can cause systemic inflammation, weight loss, and extra-intestinal manifestations, such as decreased bone growth and density. However, the effects of moderate intestinal inflammation without weight loss on bone health have never been directly examined; yet this condition is relevant not only to IBD but to conditions of increased intestinal permeability and inflammation, as seen with ingestion of high-fat diets, intestinal dysbiosis, irritable bowel syndrome, metabolic syndrome, and food allergies. Here, we induced moderate intestinal inflammation without weight loss in young male mice by treating with a low dose of dextran sodium sulfate (1%) for 15 days. The mice displayed systemic changes marked by significant bone loss and a redistribution of fat from subcutaneous to visceral fat pad stores. Bone loss was caused by reduced osteoblast activity, characterized by decreased expression of osteoblast markers (runx2, osteocalcin), histomorphometry, and dynamic measures of bone formation. In addition, we observed a reduction in growth plate thickness and hypertrophic chondrocyte matrix components (collagen X). Correlation analyses indicate a link between gut inflammation and disease score, but more importantly, we observed that bone density measures negatively correlated with intestinal disease score, as well as colon and bone TNF-α levels. These studies demonstrate that colitis-induced bone loss is not dependent upon weight loss and support a role for inflammation in the link between gut and bone health, an important area for future therapeutic development.
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Affiliation(s)
- Regina Irwin
- Department of Physiology, Michigan State University, East Lansing, Michigan
| | - Sandi Raehtz
- Department of Physiology, Michigan State University, East Lansing, Michigan
| | | | - Laura R McCabe
- Department of Physiology, Michigan State University, East Lansing, Michigan; .,Department of Radiology, Michigan State University, East Lansing, Michigan; and.,Biomedical Imaging Research Center, Michigan State University, East Lansing, Michigan
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18
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Agollah GD, Wu G, Peng HL, Kwon S. Dextran sulfate sodium-induced acute colitis impairs dermal lymphatic function in mice. World J Gastroenterol 2015; 21:12767-12777. [PMID: 26668501 PMCID: PMC4671032 DOI: 10.3748/wjg.v21.i45.12767] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2015] [Revised: 07/10/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate whether dermal lymphatic function and architecture are systemically altered in dextran sulfate sodium (DSS)-induced acute colitis.
METHODS: Balb/c mice were administered 4% DSS in lieu of drinking water ad libitum for 7 d and monitored to assess disease activity including body weight, diarrhea severity, and fecal bleeding. Control mice received standard drinking water with no DSS. Changes in mesenteric lymphatics were assessed following oral administration of a fluorescently-labelled fatty acid analogue, while dermal lymphatic function and architecture was longitudinally characterized using dynamic near-infrared fluorescence (NIRF) imaging following intradermal injection of indocyanine green (ICG) at the base of the tail or to the dorsal aspect of the left paw prior to, 4, and 7 d after DSS administration. We also measured dye clearance rate after injection of Alexa680-bovine serum albumin (BSA). NIRF imaging data was analyzed to reveal lymphatic contractile activity after selecting fixed regions of interest (ROIs) of the same size in fluorescent lymphatic vessels on fluorescence images. The averaged fluorescence intensity within the ROI of each fluorescence image was plotted as a function of imaging time and the lymphatic contraction frequency was computed by assessing the number of fluorescent pulses arriving at a ROI.
RESULTS: Mice treated with DSS developed acute inflammation with clinical symptoms of loss of body weight, loose feces/watery diarrhea, and fecal blood, all of which were aggravated as disease progressed to 7 d. Histological examination of colons of DSS-treated mice confirmed acute inflammation, characterized by segmental to complete loss of colonic mucosa with an associated chronic inflammatory cell infiltrate that extended into the deeper layers of the wall of the colon, compared to control mice. In situ intravital imaging revealed that mice with acute colitis showed significantly fewer fluorescent mesenteric lymphatic vessels, indicating impaired uptake of a lipid tracer within mesenteric lymphatics. Our in vivo NIRF imaging data demonstrated dilated dermal lymphatic vessels, which were confirmed by immunohistochemical staining of lymphatic vessels, and significantly reduced lymphatic contractile function in the skin of mice with DSS-induced acute colitis. Quantification of the fluorescent intensity remaining in the depot as a function of time showed that there was significantly higher Alexa680-BSA fluorescence in mice with DSS-induced acute colitis compared to pre-treatment with DSS, indicative of impaired lymphatic drainage.
CONCLUSION: The lymphatics are locally and systemically altered in acute colitis, and functional NIRF imaging is useful for noninvasively monitoring systemic lymphatic changes during inflammation.
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19
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Myrelid P, Salim SY, Darby T, Almer S, Melgar S, Andersson P, Söderholm JD. Effects of anti-inflammatory therapy on bursting pressure of colonic anastomosis in murine dextran sulfate sodium induced colitis. Scand J Gastroenterol 2015; 50:991-1001. [PMID: 25861827 DOI: 10.3109/00365521.2014.964760] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND The aim of this study was to examine the effect of colitis and anti-inflammatory therapies on the healing of colonic anastomoses in mice. METHODS Female C57BL/6 mice were randomized into eight groups; four groups receiving plain tap-water and four groups receiving dextran sulfate sodium. Intra-peritoneal treatment was given therapeutically for 14 days with placebo, prednisolone, azathioprine, or infliximab (IFX). Colonic anastomoses were performed and bursting pressure (BP) measurements were recorded and the inflammation evaluated with histology and zymography. RESULTS The mice with colitis had a more active inflammation based on histology and bowel weight compared with the tap water group, 8.3 (7.6-9.5) mg/mm and 5.5 (4.8-6.2) mg/mm respectively (p < 0.0001). Similarly mice with colitis receiving placebo had a more active inflammation, 12.8 (10.6-15.0) mg/mm, which differed significantly from all the other therapy arms among the colitic mice; prednisolone 8.1 (7.5-9.1) mg/mm (p = 0.014), azathioprine 8.2 (7.0-8.5) mg/mm (p = 0.0046), IFX 6.7 (6.4-7.9) mg/mm (p = 0.0055). BP for the placebo group was 90.0 (71.5-102.8) mmHg and did not differ from azathioprine or IFX groups, 84.4 (70.5-112.5) and 92.3 (75.8-122.3) mmHg respectively. In contrast BP for the prednisolone group was significantly decreased compared to placebo, 55.5 (42.8-73.0) mmHg (p = 0.0004). CONCLUSIONS All therapies had a beneficial effect on the colitis. An impaired BP of colonic anastomoses was noted after preoperative steroids but not after azathioprine or IFX in this model.
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Affiliation(s)
- Pär Myrelid
- Department of Surgery and Department of Clinical and Experimental Medicine, Linköping University , Linköping , Sweden
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Zurita-Turk M, Del Carmen S, Santos ACG, Pereira VB, Cara DC, Leclercq SY, de LeBlanc ADM, Azevedo V, Chatel JM, LeBlanc JG, Miyoshi A. Lactococcus lactis carrying the pValac DNA expression vector coding for IL-10 reduces inflammation in a murine model of experimental colitis. BMC Biotechnol 2014; 14:73. [PMID: 25106058 PMCID: PMC4129430 DOI: 10.1186/1472-6750-14-73] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2014] [Accepted: 08/04/2014] [Indexed: 12/20/2022] Open
Abstract
Background Inflammatory bowel diseases (IBD) are intestinal disorders characterized by inflammation in the gastrointestinal tract. Interleukin-10 is one of the most important anti-inflammatory cytokines involved in the intestinal immune system and because of its role in downregulating inflammatory cascades, its potential for IBD therapy is under study. We previously presented the development of an invasive strain of Lactococcus lactis (L. lactis) producing Fibronectin Binding Protein A (FnBPA) which was capable of delivering, directly to host cells, a eukaryotic DNA expression vector coding for IL-10 of Mus musculus (pValac:il-10) and diminish inflammation in a trinitrobenzene sulfonic acid (TNBS)-induced mouse model of intestinal inflammation. As a new therapeutic strategy against IBD, the aim of this work was to evaluate the therapeutic effect of two L. lactis strains (the same invasive strain evaluated previously and the wild-type strain) carrying the therapeutic pValac:il-10 plasmid in the prevention of inflammation in a dextran sodium sulphate (DSS)-induced mouse model. Results Results obtained showed that not only delivery of the pValac:il-10 plasmid by the invasive strain L. lactis MG1363 FnBPA+, but also by the wild-type strain L. lactis MG1363, was effective at diminishing intestinal inflammation (lower inflammation scores and higher IL-10 levels in the intestinal tissues, accompanied by decrease of IL-6) in the DSS-induced IBD mouse model. Conclusions Administration of both L. lactis strains carrying the pValac:il-10 plasmid was effective at diminishing inflammation in this murine model of experimental colitis, showing their potential for therapeutic intervention of IBD.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Anderson Miyoshi
- Department of General Biology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil.
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Zarepoor L, Lu JT, Zhang C, Wu W, Lepp D, Robinson L, Wanasundara J, Cui S, Villeneuve S, Fofana B, Tsao R, Wood GA, Power KA. Dietary flaxseed intake exacerbates acute colonic mucosal injury and inflammation induced by dextran sodium sulfate. Am J Physiol Gastrointest Liver Physiol 2014; 306:G1042-55. [PMID: 24763556 DOI: 10.1152/ajpgi.00253.2013] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Flaxseed (FS), a dietary oilseed, contains a variety of anti-inflammatory bioactives, including fermentable fiber, phenolic compounds (lignans), and the n-3 polyunsaturated fatty acid (PUFA) α-linolenic acid. The objective of this study was to determine the effects of FS and its n-3 PUFA-rich kernel or lignan- and soluble fiber-rich hull on colitis severity in a mouse model of acute colonic inflammation. C57BL/6 male mice were fed a basal diet (negative control) or a basal diet supplemented with 10% FS, 6% kernel, or 4% hull for 3 wk prior to and during colitis induction via 5 days of 2% (wt/vol) dextran sodium sulfate (DSS) in their drinking water (n = 12/group). An increase in anti-inflammatory metabolites (hepatic n-3 PUFAs, serum mammalian lignans, and cecal short-chain fatty acids) was associated with consumption of all FS-based diets, but not with anti-inflammatory effects in DSS-exposed mice. Dietary FS exacerbated DSS-induced acute colitis, as indicated by a heightened disease activity index and an increase in colonic injury and inflammatory biomarkers [histological damage, apoptosis, myeloperoxidase, inflammatory cytokines (IL-6 and IL-1β), and NF-κB signaling-related genes (Nfkb1, Ccl5, Bcl2a1a, Egfr, Relb, Birc3, and Atf1)]. Additionally, the adverse effect of the FS diet was extended systemically, as serum cytokines (IL-6, IFNγ, and IL-1β) and hepatic cholesterol levels were increased. The adverse effects of FS were not associated with alterations in fecal microbial load or systemic bacterial translocation (endotoxemia). Collectively, this study demonstrates that although consumption of a 10% FS diet enhanced the levels of n-3 PUFAs, short-chain polyunsaturated fatty acids, and lignans in mice, it exacerbated DSS-induced colonic injury and inflammation.
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Affiliation(s)
- Leila Zarepoor
- Guelph Food Research Centre, Agriculture and Agri-Food Canada (AAFC), Guelph, Ontario, Canada; Department of Human Health and Nutritional Science, University of Guelph, Guelph, Ontario, Canada
| | - Jenifer T Lu
- Guelph Food Research Centre, Agriculture and Agri-Food Canada (AAFC), Guelph, Ontario, Canada; Department of Human Health and Nutritional Science, University of Guelph, Guelph, Ontario, Canada
| | - Claire Zhang
- Guelph Food Research Centre, Agriculture and Agri-Food Canada (AAFC), Guelph, Ontario, Canada; Department of Human Health and Nutritional Science, University of Guelph, Guelph, Ontario, Canada
| | - Wenqing Wu
- Guelph Food Research Centre, Agriculture and Agri-Food Canada (AAFC), Guelph, Ontario, Canada
| | - Dion Lepp
- Guelph Food Research Centre, Agriculture and Agri-Food Canada (AAFC), Guelph, Ontario, Canada
| | - Lindsay Robinson
- Department of Human Health and Nutritional Science, University of Guelph, Guelph, Ontario, Canada
| | | | - Steve Cui
- Guelph Food Research Centre, Agriculture and Agri-Food Canada (AAFC), Guelph, Ontario, Canada
| | | | - Bourlaye Fofana
- Crops and Livestock Research Centre, AAFC, Charlottetown, Prince Edward Island, Canada; and
| | - Rong Tsao
- Guelph Food Research Centre, Agriculture and Agri-Food Canada (AAFC), Guelph, Ontario, Canada
| | - Geoffrey A Wood
- Department of Pathobiology, University of Guelph, Guelph, Ontario, Canada
| | - Krista A Power
- Guelph Food Research Centre, Agriculture and Agri-Food Canada (AAFC), Guelph, Ontario, Canada; Department of Human Health and Nutritional Science, University of Guelph, Guelph, Ontario, Canada;
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Olivier I, Theodorou V, Valet P, Castan-Laurell I, Ferrier L, Eutamène H. Modifications of mesenteric adipose tissue during moderate experimental colitis in mice. Life Sci 2014; 94:1-7. [DOI: 10.1016/j.lfs.2013.09.028] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2013] [Revised: 07/26/2013] [Accepted: 09/25/2013] [Indexed: 01/29/2023]
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Reciprocal interference of experimental dyslipidemia and food allergy in the evolution of both diseases. ISRN ALLERGY 2013; 2013:545184. [PMID: 23840965 PMCID: PMC3690233 DOI: 10.1155/2013/545184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/23/2013] [Accepted: 05/19/2013] [Indexed: 11/17/2022]
Abstract
Background. Food allergies have been shown to reduce serum triacylglycerol, glucose, cholesterol, and free fatty acid levels in mice. In turn, dyslipidemias, especially dyslipidemias presenting with low levels of HDL cholesterol, are important risk factors for the development of atherosclerosis. However, the consequences of food allergies on dyslipidemia and atherosclerosis have not been fully investigated. Methods. Food allergy was induced using an egg white solution (EWS) in ovalbumin- (OVA-) sensitized C57BL/6 and low-density lipoprotein receptor knockout mice (LDLr−/−) for 5 weeks and was confirmed by the high production of anti-OVA IgE and IgG1 antibodies in both mouse strains. Results. The allergic C57BL/6 mice exhibited EWS aversion that was associated with less visceral fat and high levels of anti-Ova IgE antibodies after 5 weeks of EWS intake compared to controls. However, LDLr−/− allergic mice showed reduced anti-Ova IgE levels that were similar to the nonsensitized group. The LDLr−/− allergic mice also demonstrated a reversal of food aversion and sustained visceral fat after 5 weeks of allergy. Although HDL cholesterol levels were reduced in both sensitized mouse strains, lipid deposition in thoracic and abdominal aorta as well as area and composition of atherosclerotic plaques as unaffected by chronic ingestion of EWS. Conclusion. LDLr−/− mice develop an attenuated food allergy, as they showed a reversal of food aversion and lower IgE production after 5 weeks of induced allergy. The development of atherosclerosis, in turn, was not accelerated in the allergic LDLr−/− group despite the more atherogenic lipid profile.
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Karp NA, Segonds-Pichon A, Gerdin AKB, Ramírez-Solis R, White JK. The fallacy of ratio correction to address confounding factors. Lab Anim 2012; 46:245-52. [PMID: 22829707 PMCID: PMC4152922 DOI: 10.1258/la.2012.012003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Scientists aspire to measure cause and effect. Unfortunately confounding variables, ones that are associated with both the probable cause and the outcome, can lead to an association that is true but potentially misleading. For example, altered body weight is often observed in a gene knockout; however, many other variables, such as lean mass, will also change as the body weight changes. This leaves the researcher asking whether the change in that variable is expected for that change in weight. Ratio correction, which is often referred to as normalization, is a method used commonly to remove the effect of a confounding variable. Although ratio correction is used widely in biological research, it is not the method recommended in the statistical literature to address confounding factors; instead regression methods such as the analysis of covariance (ANCOVA) are proposed. This method examines the difference in means after adjusting for the confounding relationship. Using real data, this manuscript demonstrates how the ratio correction approach is flawed and can result in erroneous calls of significance leading to inappropriate biological conclusions. This arises as some of the underlying assumptions are not met. The manuscript goes on to demonstrate that researchers should use ANCOVA, and discusses how graphical tools can be used readily to judge the robustness of this method. This study is therefore a clear example of why assumption testing is an important component of a study and thus why it is included in the Animal Research: Reporting of In Vivo Experiment (ARRIVE) guidelines.
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Affiliation(s)
- Natasha A Karp
- Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK. Tel: +44 (0)1223 834244, Fax: +44 (0)1223 494919
| | - Anne Segonds-Pichon
- The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK. Tel: +44 (0)1223 496000, Fax: +44 (0)1223 496002
| | - Anna-Karin B Gerdin
- Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK. Tel: +44 (0)1223 834244, Fax: +44 (0)1223 494919
| | - Ramiro Ramírez-Solis
- Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK. Tel: +44 (0)1223 834244, Fax: +44 (0)1223 494919
| | - Jacqueline K White
- Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK. Tel: +44 (0)1223 834244, Fax: +44 (0)1223 494919
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Hardenberg G, Yao Y, Piccirillo CA, Levings MK, Steiner TS. Toll-like receptor 5 deficiency protects from wasting disease in a T cell transfer colitis model in T cell receptor-β-deficient mice. Inflamm Bowel Dis 2012; 18:85-93. [PMID: 22038840 DOI: 10.1002/ibd.21738] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2011] [Accepted: 03/19/2011] [Indexed: 12/13/2022]
Abstract
BACKGROUND Toll-like receptor 5 (TLR5) is implicated in the innate and adaptive immune responses that are associated with inflammatory bowel disease (IBD). In humans TLR5 is expressed on CD4(+) T cells and costimulation with flagellin potentiates effector and regulatory T cell responses. The aim of this study was to determine the role of TLR5 in CD4(+) T cell subsets versus other cells in induction of disease in a model of T cell-dependent colitis. METHODS TLR5 expression on CD4(+) T cells was assessed by real-time reverse-transcriptase polymerase chain reaction (RT-PCR). Wildtype (WT) or TLR5-deficient (5-/-) CD4(+) T conventional cells (Tconv) and T regulatory cells (Treg) were compared for their ability to induce and suppress T cell transfer colitis, respectively. In addition, the role of TLR5 expression in recipient mice was analyzed. RESULTS TLR5 is preferentially expressed on mouse Treg compared to Tconv, although expression levels were low. The colitogenic capacity of WT and 5-/- Tconv was found to be similar and Treg from WT or 5-/- donor animals both prevented T cell transfer colitis in TLR-competent hosts. TLR5 deficiency in recipient mice, however, did affect the disease process, as T cell receptor-β (TCRβ) 5-/- recipients had decreased weight loss compared to TCRβ recipient mice when WT Tconv were used. CONCLUSIONS TLR5 expression on T cells is not required for induction of or protection from T cell-dependent colitis. Expression of TLR5 in non-T cells has a pathogenic role, since TLR5 deficiency in recipient mice protects against weight loss induced by WT T cells.
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Affiliation(s)
- Gijs Hardenberg
- Department of Surgery, University of British Columbia and Immunity in Health & Disease, Child and Family Research Institute, British Columbia Children's Hospital, Vancouver, Canada
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Patel M, Patel M, Shah G. Investigation of Possible Role of the PAR-2 Receptor in Intestinal Inflammation. J Young Pharm 2011; 2:54-8. [PMID: 21331192 PMCID: PMC3035886 DOI: 10.4103/0975-1483.62214] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
The present study was undertaken to study the role of PAR-2 receptor activation in pathophysiology of intestinal inflammation. Inflammatory bowel disease was induced in Wistar albino rats by intrarectal administration of 2, 4, 6 trinitrobenzenesulfonic acid (TNBS, 0.25 ml 120 mg/ml in 50% ethanol intrarectally, on 1st day only). Trypsin (500 μg/kg, 1 mg/kg, 5 mg/kg, intrarectal) was given from the same day up to 20 days. Various physical parameters including body weight, food and water intake were measured on 1st and 20th days. At end of the experiment, colon weight and various histopathological indexes were assessed. The colon homogenate malondialdehyde (MDA), myeloperoxidase (MPO), and superoxide dismutase (SOD) and % mast cell protection in mesentery were also measured. Trypsin at higher dose (5 mg/kg) showed the higher level of oxidative enzymes and lower level of protective enzymes as compared to the animals treated with only TNBS. Trypsin treatment produced significantly more mast cell degranulation. Finally in the histopathology, there was increased in severity of the disease in trypsin-treated animals. The role of PAR-2 (protease activated receptor-2) receptor in gut is pro-inflammatory and thus appears as a new potential therapeutic target for inflammatory bowel disease treatments.
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Affiliation(s)
- Mb Patel
- Department of Pharmacology, Shree Sarvajanik Pharmacy College, Mahesana, India
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Schicho R, Nazyrova A, Shaykhutdinov R, Duggan G, Vogel HJ, Storr M. Quantitative metabolomic profiling of serum and urine in DSS-induced ulcerative colitis of mice by (1)H NMR spectroscopy. J Proteome Res 2010; 9:6265-73. [PMID: 20886908 DOI: 10.1021/pr100547y] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Quantitative profiling of a large number of metabolic compounds is a promising method to detect biomarkers in inflammatory bowel diseases (IBD), such as ulcerative colitis (UC). We induced an experimental form of UC in mice by treatment with dextran sulfate sodium (DSS) and characterized 53 serum and 69 urine metabolites by use of (1)H NMR spectroscopy and quantitative ("targeted") analysis to distinguish between diseased and healthy animals. Hierarchical multivariate orthogonal partial least-squares (OPLS) models were developed to detect and predict separation of control and DSS-treated mice. DSS treatment resulted in weight loss, colonic inflammation, and increase in myeloperoxidase activity. Metabolomic patterns generated from the OPLS data clearly separated DSS-treated from control mice with a slightly higher predictive power (Q(2)) for serum (0.73) than urine (0.71). During DSS colitis, creatine, carnitine, and methylamines increased in urine while in serum, maximal increases were observed for ketone bodies, hypoxanthine, and tryptophan. Antioxidant metabolites decreased in urine whereas in serum, glucose and Krebs cycle intermediates decreased strongly. Quantitative metabolic profiling of serum and urine thus discriminates between healthy and DSS-treated mice. Analysis of serum or urine seems to be equally powerful for detecting experimental colitis, and a combined analysis offers only a minor improvement.
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Affiliation(s)
- Rudolf Schicho
- Department of Medicine, Division of Gastroenterology, Snyder Institute of Infection, Immunity and Inflammation, University of Calgary, Alberta, Canada.
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Berglund M, Melgar S, Kobayashi KS, Flavell RA, Hörnquist EH, Hultgren OH. IL-1 receptor-associated kinase M downregulates DSS-induced colitis. Inflamm Bowel Dis 2010; 16:1778-86. [PMID: 20848470 DOI: 10.1002/ibd.21287] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Ulcerative colitis is associated with increased colon permeability resulting in bacterial translocation into the lamina propria. We investigate the importance of the Toll-like receptor (TLR) regulating protein IL-1 receptor-associated kinase M (IRAK-M) using the erosive dextran sulfate sodium (DSS)-induced model of colitis. METHODS IRAK-M-competent and -incompetent mice were treated with 3% DSS for 5 days followed by 2 days of regular drinking water. Clinical signs of disease were followed for 7 days. At day 7 the mice were sacrificed and plasma and tissue were collected for histopathological examination and analyses of the production of cytokines and chemokines as well as expression of T-cell transcription factors. RESULTS At day 7 IRAK-M-deficient mice display a reduced total body weight (77.1 ± 2.1 versus 88.5 ± 2.0, *P = 0.002) and an increased macroscopical (2.7 ± 0.2 versus 1.6 ± 0.1, *P = 0.002) and histopathological (6.0 ± 0 versus 3.3 ± 0.5, *P = < 0.001) colon score compared to wildtype mice. Furthermore, IRAK-M-deficient mice have increased colon mRNA expression of proinflammatory cytokines and increased tumor necrosis factor concentrations (41.1 ± 13.5 versus 12.8 ± 2.0 pg/mL, *P = 0.010) in plasma. CONCLUSIONS This is the first report examining the role of IRAK-M in colitis. We find that IRAK-M is of critical importance in downregulating induction and progression of DSS colitis, and thereby suggesting that IRAK-M might be a target for future interventional therapies.
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Affiliation(s)
- Martin Berglund
- Department of Microbiology and Immunology, Institute of Biomedicine, The Sahlgrenska Academy at Göteborg University, Sweden.
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Patel MA, Patel PK, Patel MB. Aqueous Extract of Ficus bengalensis Linn. Bark for Inflammatory Bowel Disease. J Young Pharm 2010; 2:130-6. [PMID: 21264114 PMCID: PMC3021686 DOI: 10.4103/0975-1483.63149] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
The present study was designed to evaluate the effects of aqueous extract of Ficus bengalensis Linn. bark (AEFB) on inflammatory bowel disease (IBD). Effects of AEFB were studied on 2, 4, 6-trinitrobenzenesulfonic acid (TNBS, 0.25 ml 120 mg/ml in 50% ethanol intrarectally, on first day only)-induced IBD in rats. Effects of co-administration of prednisolone (2 mg/kg) and AEFB (250, 500 mg/kg) for 21 days were also evaluated. Various physical parameters including body weight, food, and water intake measured on 1st and 21st days. At end of the experiment, various histopathological indexes are assessed. The colon homogenate malondialdehyde (MDA), myeloperoxidase (MPO), superoxide dismutase (SOD), and nitric oxide (NO) levels and % mast cell protection in mesentery were also measured. In our study, we found that AEFB has a significant protective effect in the inflammatory bowel disease as compared to prednisolone in rats.
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Affiliation(s)
- MA Patel
- Department of Pharmacology, C. K. Pithawala Institute of Pharmaceutical Sciences and Research, Surat-395 007, Gujarat, India
| | - PK Patel
- Department of Pharmacology, C. K. Pithawala Institute of Pharmaceutical Sciences and Research, Surat-395 007, Gujarat, India
| | - MB Patel
- Department of Pharmacology, Shri Sarvajanik College of Pharmacy, Mahesana, Gujarat, India
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Harris L, Senagore P, Young VB, McCabe LR. Inflammatory bowel disease causes reversible suppression of osteoblast and chondrocyte function in mice. Am J Physiol Gastrointest Liver Physiol 2009; 296:G1020-9. [PMID: 19299577 PMCID: PMC4059386 DOI: 10.1152/ajpgi.90696.2008] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Decreased bone density and stature can occur in pediatric patients with inflammatory bowel disease (IBD). Little is known about how IBD broadly impacts the skeleton. To evaluate the influence of an acute episode of IBD on growing bone, 4-wk-old mice were administered 5% dextran sodium sulfate (DSS) for 5 days to induce colitis and their recovery was monitored. During active disease and early recovery, trabecular bone mineral density, bone volume, and thickness were decreased. Cortical bone thickness, outer perimeter, and density were also decreased, whereas inner perimeter and marrow area were increased. These changes appear to maintain bone strength since measures of moments of inertia were similar between DSS-treated and control mice. Histological (static and dynamic), serum, and RNA analyses indicate that a decrease in osteoblast maturation and function account for changes in bone density. Unlike some conditions of bone loss, marrow adiposity did not increase. Similar to reports in humans, bone length decreased and correlated with decreases in growth plate thickness and chondrocyte marker expression. During disease recovery, mice experienced a growth spurt that led to their achieving final body weights and bone length, density, and gene expression similar to healthy controls. Increased TNF-alpha and decreased IGF-I serum levels were observed with active disease and returned to normal with recovery. Changes in serum TNF-alpha (increased) and IGF-I (decreased) paralleled changes in bone parameters and returned to normal values with recovery, suggesting a potential role in the skeletal response.
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Shakya A, Cooksey R, Cox JE, Wang V, McClain DA, Tantin D. Oct1 loss of function induces a coordinate metabolic shift that opposes tumorigenicity. Nat Cell Biol 2009; 11:320-7. [PMID: 19219035 DOI: 10.1038/ncb1840] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2008] [Accepted: 12/10/2008] [Indexed: 01/08/2023]
Abstract
Cancer cells frequently undergo a shift from oxidative to glycolytic metabolism. Although there is interest in targeting metabolism as a form of cancer therapy, this area still remains in its infancy. Using cells, embryos and adult animals, we show here that loss of the widely expressed transcription factor Oct1 induces a coordinated metabolic shift: mitochondrial activity and amino acid oxidation are increased, while glucose metabolism is reduced. Altered expression of direct Oct1 targets encoding metabolic regulators provides a mechanistic underpinning to these results. We show that these metabolic changes directly oppose tumorigenicity. Collectively, our findings show that Oct1, the genes it regulates and the pathways these genes affect could be used as targets for new modes of cancer therapy.
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Affiliation(s)
- Arvind Shakya
- Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA
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Li H, Lelliott C, Håkansson P, Ploj K, Tuneld A, Verolin-Johansson M, Benthem L, Carlsson B, Storlien L, Michaëlsson E. Intestinal, adipose, and liver inflammation in diet-induced obese mice. Metabolism 2008; 57:1704-10. [PMID: 19013294 DOI: 10.1016/j.metabol.2008.07.029] [Citation(s) in RCA: 85] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2007] [Accepted: 07/03/2008] [Indexed: 12/23/2022]
Abstract
Chronic inflammation and increased visceral adipose tissue (VAT) are key elements of the metabolic syndrome. Both are considered to play a pathogenic role in the development of liver steatosis and insulin resistance. The aim of the present study was to investigate the hypothesis that an inflamed intestine, induced both by diet and chemical irritation, could induce persistent inflammation in VAT. Female C57BL/6JOlaHsd mice were used. In study I, groups of mice (n = 6 per group) were given an obesity-inducing cafeteria diet (diet-induced obesity) or regular chow only (control) for 14 weeks. In study II, colitis in mice (n = 8) was induced by 3% dextran sulfate sodium in tap water for 5 days followed by 21 days of tap water alone. Healthy control mice (n = 8) had tap water only. At the end of the studies, all mice were killed; and blood and tissues were sampled and processed for analysis. Body weight of diet-induced obese mice was greatly increased, with evidence of systemic inflammation, insulin resistance, and liver steatosis. Tissue inflammation indexed by proinflammatory cytokine expression was recorded in liver, mesenteric fat, and proximal colon/distal ileum, but not in subcutaneous or perigonadal fat. In dextran sulfate sodium-induced colitis mice, mesenteric fat was even more inflamed than the colon, whereas a much milder inflammation was seen in liver and subcutaneous fat. The studies showed both diet- and colitis-initiated inflammation in mesenteric fat. Fat depots contiguous with intestine and their capacity for exaggerated inflammatory responses to conditions of impaired gut barrier function may account for the particularly pathogenic role of VAT in obesity-induced metabolic disorders.
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MESH Headings
- Animals
- Body Weight/physiology
- Cytokines/blood
- Cytokines/metabolism
- Diet, Atherogenic
- Female
- Gastroenteritis/blood
- Gastroenteritis/complications
- Gastroenteritis/pathology
- Gastroenteritis/veterinary
- Hepatitis, Animal/blood
- Hepatitis, Animal/complications
- Hepatitis, Animal/pathology
- Intestinal Mucosa/metabolism
- Intestines/pathology
- Intra-Abdominal Fat/metabolism
- Intra-Abdominal Fat/pathology
- Liver/metabolism
- Liver/pathology
- Mice
- Mice, Inbred C57BL
- Mice, Obese
- Obesity/complications
- Obesity/etiology
- Obesity/pathology
- Obesity/veterinary
- Organ Size
- Panniculitis, Peritoneal/blood
- Panniculitis, Peritoneal/complications
- Panniculitis, Peritoneal/pathology
- Panniculitis, Peritoneal/veterinary
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Affiliation(s)
- Hong Li
- Department of Integrative Pharmacology, AstraZeneca R&D Mölndal, S-431 83 Mölndal, Sweden
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33
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Hamdani G, Gabet Y, Rachmilewitz D, Karmeli F, Bab I, Dresner-Pollak R. Dextran sodium sulfate-induced colitis causes rapid bone loss in mice. Bone 2008; 43:945-50. [PMID: 18675386 DOI: 10.1016/j.bone.2008.06.018] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2008] [Revised: 06/17/2008] [Accepted: 06/25/2008] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Osteopenia is a common complication of human inflammatory bowel disease (IBD). We evaluated the contribution of colonic inflammation to osteopenia and its mechanism in a murine colitis model. METHODS Colitis was induced by adding dextran sodium sulfate (DSS) to the drinking water for 2 weeks to nine-week-old Balb/C male mice. 5% DSS was added on the first week and was reduced to 2.5% on the second week. Age- and sex-matched Balb/C mice served as the control group. Indices of femoral bone mass and architecture were determined by micro computed tomography (muCT). Bone formation parameters and osteoclast number were determined by dynamic histomorphometry. The degree of colonic inflammation was assessed by a clinical disease activity index, and colonic mucosal myeloperoxidase activity. RESULTS DSS-treated mice exhibited a significantly lower bone mass compared to controls as indicated by decreased trabecular bone volume (BV/TV) of 32%. This reduction was accompanied by decreased trabecular number (23%) and connectivity density (37%) compared to the controls. No changes were observed in cortical bone indices. Osteopenia resulted from suppressed bone formation, as indicated by decreased trabecular double-labeled surface (dL%) of 90%, mineralizing surface (MS) of 62%, and bone formation rate (BFR) of 67%, and increased bone resorption as indicated by a 34% increase in osteoclast number in DSS-treated mice compared to the controls. Myeloperoxidase activity inversely correlated with trabecular BV/TV (r=-0.67, p=0.02), trabecular number (r=-0.86, p=0.0008) and connectivity density (r=-0.63, p=0.03). Myeloperoxidase activity inversely correlated with the bone formation indices: dL%, MS, and BFR (r=-0.79, p=0.007, r=-0.84, p=0.002, r=-0.83, p=0.003, respectively). CONCLUSIONS DSS-induced colitis is associated with reduced femoral bone mass and altered micro architecture, which results from suppressed bone formation and increased bone resorption. The decrease in indices of bone mass, structure and formation are directly linked to the degree of colonic mucosal inflammation. DSS-induced colitis can be used to study pharmacological interventions for bone loss in colitis.
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Affiliation(s)
- Gilad Hamdani
- Hebrew University-Hadassah School of Medicine, Jerusalem, Israel
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34
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Martínez-Augustin O, Merlos M, Zarzuelo A, Suárez MD, de Medina FS. Disturbances in metabolic, transport and structural genes in experimental colonic inflammation in the rat: a longitudinal genomic analysis. BMC Genomics 2008; 9:490. [PMID: 18928539 PMCID: PMC2577662 DOI: 10.1186/1471-2164-9-490] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2008] [Accepted: 10/17/2008] [Indexed: 12/26/2022] Open
Abstract
Background Trinitrobenzenesulphonic acid (TNBS) induced rat colitis is one of the most widely used models of inflammatory bowel disease (IBD), a condition whose aetiology and pathophysiology are incompletely understood. We have characterized this model at the genomic level using a longitudinal approach. Six control rats were compared with colitic animals at 2, 5, 7 and 14 days after TNBS administration (n = 3). The Affymetrix Rat Expression Array 230 2.0 system was used. Results TNBS-induced colitis had a profound impact on the gene expression profile, which was maximal 5 and 7 days post-induction. Most genes were affected at more than one time point. They were related to a number of biological functions, not only inflammation/immunity but also transport, metabolism, signal transduction, tissue remodeling and angiogenesis. Gene changes generally correlated with the severity of colitis. The results were successfully validated in a subset of genes by real-time PCR. Conclusion The TNBS model of rat colitis has been described in detail at the transcriptome level. The changes observed correlate with pathophysiological disturbances such as tissue remodelling and alterations in ion transport, which are characteristic of both this model and IBD.
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Affiliation(s)
- Olga Martínez-Augustin
- Department of Biochemistry and Molecular Biology II, CIBEREHD, School of Pharmacy, University of Granada, Granada, Spain.
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35
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Karlsson A, Jägervall A, Pettersson M, Andersson AK, Gillberg PG, Melgar S. Dextran sulphate sodium induces acute colitis and alters hepatic function in hamsters. Int Immunopharmacol 2007; 8:20-7. [PMID: 18068096 DOI: 10.1016/j.intimp.2007.10.007] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2007] [Revised: 10/01/2007] [Accepted: 10/01/2007] [Indexed: 10/22/2022]
Abstract
Dextran sulphate sodium (DSS)-induced colitis in rodents is an experimental model for human inflammatory bowel disease (IBD). The aim of this study was to characterize the effect of DSS in hamster colon and liver. DSS (2-5%) was administrated in the drinking water for 4-6 days. Clinical symptoms were recorded daily, inflammatory and fatty acid-related metabolic markers were assessed in plasma, colon and liver. Six days of 3 or 5% DSS induced a severe wasting disease, whereas 2.5% DSS induced a colonic inflammation without severe systemic adverse effects. The systemic inflammatory response was characterized by an inverse production of albumin and the acute phase protein haptoglobin. The colonic inflammatory response was confined to the proximal colon, manifested by a high macroscopic inflammatory score, increased colon weight and expression of IL-1beta, IL-6 and iNOS, infiltration of inflammatory cells and epithelial disruption. In contrast, only a low/mild inflammatory response was observed in the distal colon of DSS-exposed hamsters. Significant hepatic-related metabolic alterations were also observed, with elevation of plasma triglycerides and increased liver expression of lipoprotein lipase and reduced expression of acyl-CoA oxidase and cytochrome P450A. Although liver weight was significantly reduced, no histopathological signs of inflammation or tissue damage were observed. In summary, hamsters exposed to 2.5% DSS for 6 days develop acute colitis resembling murine DSS-induced colitis. In addition, DSS-exposed hamster showed alterations in hepatic fatty acids metabolism resembling human IBD, suggesting that the model can potentially be used for target discovery and validation of hepatic-related metabolic alterations.
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Affiliation(s)
- Agneta Karlsson
- Department of Integrative Pharmacology, AstraZeneca R&D Mölndal, Sweden
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36
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Fritsch Fredin M, Elgbratt K, Svensson D, Jansson L, Melgar S, Hultgren Hörnquist E. Dextran sulfate sodium-induced colitis generates a transient thymic involution--impact on thymocyte subsets. Scand J Immunol 2007; 65:421-9. [PMID: 17444952 DOI: 10.1111/j.1365-3083.2007.01923.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
One of the most widely used animal models for inflammatory bowel disease (IBD) is the dextran sulfate sodium (DSS)-induced colitis. We have previously reported that 5 days administration of DSS in C57Bl/6J mice induces a colonic inflammation that progresses into chronicity after DSS removal, whereas in BALB/cJ mice the inflammation resolves within 4 weeks post-DSS. Here we show that both thymic size and thymocyte numbers dramatically decreased in the acute phase of inflammation in C57Bl/6 mice, 7 days after DSS withdrawal. Mature, CD4(+) and CD8(+) single positive (SP) CD69(lo) CD62L(hi) thymocytes were enriched in these mice, accompanied by a major decrease in the number of immature double positive (DP) thymocytes. However, the different maturation stages within the DP thymocyte subset were unchanged between healthy and inflamed C57Bl/6J mice. Interestingly, as the inflammation progressed into the chronic phase, the thymus recovered and 2 weeks after the acute inflammatory phase all the thymic parameters investigated in this study were restored to normal. In contrast, BALB/cJ mice only develop mild thymic alterations. Nevertheless, we found that within the double negative (DN) thymocytes an increased frequency and also total numbers of CD44(+) CD25(-) (DN1) cells correlated with the severity of colitis, and that the frequency of CD44(-) CD25(-) (DN4) thymocytes decreased proportionally in the acute phase in BALB/cJ mice. Our observations suggest that the thymic effects are intimately connected to the intestinal inflammatory response in colitis regardless of the inflammatory stimuli.
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Affiliation(s)
- M Fritsch Fredin
- Department of Integrative Pharmacology, AstraZeneca R&D Mölndal, Mölndal, Sweden
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