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Qiao T, Wen XH. Exploring gut microbiota as a novel therapeutic target in Crohn's disease: Insights and emerging strategies. World J Gastroenterol 2025; 31:100827. [PMID: 39811502 PMCID: PMC11684203 DOI: 10.3748/wjg.v31.i2.100827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 09/30/2024] [Accepted: 11/15/2024] [Indexed: 12/18/2024] Open
Abstract
Extensive research has investigated the etiology of Crohn's disease (CD), encompassing genetic predisposition, lifestyle factors, and environmental triggers. Recently, the gut microbiome, recognized as the human body's second-largest gene pool, has garnered significant attention for its crucial role in the pathogenesis of CD. This paper investigates the mechanisms underlying CD, focusing on the role of 'creeping fat' in disease progression and exploring emerging therapeutic strategies, including fecal microbiota transplantation, enteral nutrition, and therapeutic diets. Creeping fat has been identified as a unique pathological feature of CD and has recently been found to be associated with dysbiosis of the gut microbiome. We characterize this dysbiotic state by identifying key microbiome-bacteria, fungi, viruses, and archaea, and their contributions to CD pathogenesis. Additionally, this paper reviews contemporary therapies, emphasizing the potential of biological therapies like fecal microbiota transplantation and dietary interventions. By elucidating the complex interactions between host-microbiome dynamics and CD pathology, this article aims to advance our understanding of the disease and guide the development of more effective therapeutic strategies for managing CD.
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Affiliation(s)
- Tong Qiao
- Department of Clinical Medicine, Jinan University, Guangzhou 510632, Guangdong Province, China
| | - Xian-Hui Wen
- College of Life Science and Technology, Jinan University, Guangzhou 510632, Guangdong Province, China
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2
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Mohyeldin RH, Abdelzaher WY, Sharata EE, Mohamed HMA, Ahmed MYM, Attia JZ, Atta M, Saleh RK, Ghallab EA, Marey H, Elrehany MA, Rofaeil RR. Aprepitant boasted a protective effect against olanzapine-induced metabolic syndrome and its subsequent hepatic, renal, and ovarian dysfunction; Role of IGF 1/p-AKT/FOXO 1 and NFκB/IL-1β/TNF-α signaling pathways in female Wistar albino rats. Biochem Pharmacol 2024; 221:116020. [PMID: 38237301 DOI: 10.1016/j.bcp.2024.116020] [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: 10/02/2023] [Revised: 12/28/2023] [Accepted: 01/11/2024] [Indexed: 03/03/2024]
Abstract
Olanzapine-induced metabolic syndrome (MS) is a primary risk factor for insulin resistance, hepatorenal damage, and polycystic ovarian syndrome. The objective of the current study was to assess the protective effects of aprepitant (AP) against MS caused by olanzapine and the associated ovarian, renal, and liver dysfunction via modulation of IGF1/p-AKT/FOXO1 and NFκB/IL-1β/TNF-α signaling pathways. AP mitigated all biochemical and histopathological abnormalities induced by olanzapine and resulted in a significant reduction of serum HOMA-IR, lipid profile parameters, and a substantial decrease in hepatic, renal, and ovarian MDA, IL-6, IL-1β, TNF-α, NFκB, and caspase 3. Serum AST, ALT, urea, creatinine, FSH, LH, and testosterone also decreased significantly by AP administration. The FOXO 1 signaling pathway was downregulated in the AP-treated group, while GSH, SOD, and HDL cholesterol levels were elevated.
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Affiliation(s)
- Reham H Mohyeldin
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Deraya University, Minia 61111, Egypt.
| | - Walaa Yehia Abdelzaher
- Department of Medical Pharmacology, Faculty of Medicine, Minia University, Minia 61519, Egypt.
| | - Ehab E Sharata
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Deraya University, Minia 61111, Egypt.
| | - Hamza M A Mohamed
- Department of Obstetrics and Gynecology, Faculty of Medicine, Minia University, Minia 61519, Egypt
| | - Mohamed Y M Ahmed
- Department of Obstetrics and Gynecology, Faculty of Medicine, Minia University, Minia 61519, Egypt
| | - Josef Zekry Attia
- Department of Anesthesia and I.C.U, Faculty of Medicine, Minia University, Minia 61519, Egypt
| | - Medhat Atta
- Department of Anatomy, Faculty of Medicine, Minia University, Minia 61519, Egypt
| | - Rabeh Khairy Saleh
- Department of Pathology, Faculty of Medicine, Minia University, Minia 61519, Egypt.
| | - Elshimaa A Ghallab
- Department of Biochemistry, Faculty of Pharmacy, Deraya University, Minia 61111, Egypt.
| | - Heba Marey
- Department of Biochemistry, Faculty of Medicine, Minia University, Minia 61519, Egypt.
| | - Mahmoud A Elrehany
- Department of Biochemistry, Faculty of Pharmacy, Deraya University, Minia 61111, Egypt.
| | - Remon Roshdy Rofaeil
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Deraya University, Minia 61111, Egypt; Department of Medical Pharmacology, Faculty of Medicine, Minia University, Minia 61519, Egypt.
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Mishra G, Townsend KL. Sensory nerve and neuropeptide diversity in adipose tissues. Mol Cells 2024; 47:100030. [PMID: 38364960 PMCID: PMC10960112 DOI: 10.1016/j.mocell.2024.100030] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 02/06/2024] [Accepted: 02/06/2024] [Indexed: 02/18/2024] Open
Abstract
Both brown and white adipose tissues (BAT/WAT) are innervated by the peripheral nervous system, including efferent sympathetic nerves that communicate from the brain/central nervous system out to the tissue, and afferent sensory nerves that communicate from the tissue back to the brain and locally release neuropeptides to the tissue upon stimulation. This bidirectional neural communication is important for energy balance and metabolic control, as well as maintaining adipose tissue health through processes like browning (development of metabolically healthy brown adipocytes in WAT), thermogenesis, lipolysis, and adipogenesis. Decades of sensory nerve denervation studies have demonstrated the particular importance of adipose sensory nerves for brown adipose tissue and WAT functions, but far less is known about the tissue's sensory innervation compared to the better-studied sympathetic nerves and their neurotransmitter norepinephrine. In this review, we cover what is known and not yet known about sensory nerve activities in adipose, focusing on their effector neuropeptide actions in the tissue.
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Affiliation(s)
- Gargi Mishra
- Department of Neurological Surgery, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Kristy L Townsend
- Department of Neurological Surgery, College of Medicine, The Ohio State University, Columbus, OH, USA.
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Tsounis EP, Aggeletopoulou I, Mouzaki A, Triantos C. Creeping Fat in the Pathogenesis of Crohn's Disease: An Orchestrator or a Silent Bystander? Inflamm Bowel Dis 2023; 29:1826-1836. [PMID: 37260352 DOI: 10.1093/ibd/izad095] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Indexed: 06/02/2023]
Abstract
Although the phenomenon of hypertrophied adipose tissue surrounding inflamed bowel segments in Crohn's disease has been described since 1932, the mechanisms mediating the creeping fat formation and its role in the pathogenesis of the disease have not been fully unraveled. Recent advances demonstrating the multiple actions of adipose tissue beyond energy storage have brought creeping fat to the forefront of scientific research. In Crohn's disease, dysbiosis and transmural injury compromise the integrity of the intestinal barrier, resulting in an excessive influx of intraluminal microbiota and xenobiotics. The gut and peri-intestinal fat are in close anatomic relationship, implying a direct reciprocal immunologic relationship, whereas adipocytes are equipped with an arsenal of innate immunity sensors that respond to invading stimuli. As a result, adipocytes and their progenitor cells undergo profound immunophenotypic changes, leading to adipose tissue remodeling and eventual formation of creeping fat. Indeed, creeping fat is an immunologically active organ that synthesizes various pro- and anti-inflammatory cytokines, profibrotic mediators, and adipokines that serve as paracrine/autocrine signals and regulate immune responses. Therefore, creeping fat appears to be involved in inflammatory signaling, which explains why it has been associated with a higher severity or complicated phenotype of Crohn's disease. Interestingly, there is growing evidence for an alternative immunomodulatory function of creeping fat as a second barrier that prevents an abnormal systemic inflammatory response at the expense of an increasingly proliferating profibrotic environment. Further studies are needed to clarify how this modified adipose tissue exerts its antithetic effect during the course of Crohn's disease.
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Affiliation(s)
- Efthymios P Tsounis
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras 26504, Greece
| | - Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras 26504, Greece
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Athanasia Mouzaki
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras 26504, Greece
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Wu HX, Lin X, Cheng CL, Jiang HL, Iqbal J, Liu J, Zhou HD. Fat distribution measurements by chemical shift-encoded transition region extraction predict the risk of hyperglycaemia, dyslipidaemia and metabolic syndrome in mice. NMR IN BIOMEDICINE 2023; 36:e4985. [PMID: 37283179 DOI: 10.1002/nbm.4985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 04/27/2023] [Accepted: 05/16/2023] [Indexed: 06/08/2023]
Abstract
Metabolically healthy or unhealthy obesity is closely related to metabolic syndrome (MetS). To validate a more accurate diagnostic method for obesity that reflects the risk of metabolic disorders in a pre-clinical mouse model, C57BL/6J mice were fed high-sucrose-high-fat and chow diets for 12 weeks to induce obesity. MRI was performed and analysed by chemical shift-encoded fat-water separation based on the transition region extraction method. Abdominal fat was divided into upper and lower abdominal regions at the horizontal lower border of the liver. Blood samples were collected, and the glucose level, lipid profile, liver function, HbA1c and insulin were tested. k-means clustering and stepwise logistic regression were applied to validate the diagnosis of hyperglycaemia, dyslipidaemia and MetS, and to ascertain the predictive effect of MRI-derived parameters to the metabolic disorders. Pearson or Spearman correlation was used to assess the relationship between MRI-derived parameters and metabolic traits. The receiver-operating characteristic curve was used to evaluate the diagnostic effect of each logistic regression model. A two-sided p value less than 0.05 was considered to indicate statistical significance for all tests. We made the precise diagnosis of obesity, dyslipidaemia, hyperglycaemia and MetS in mice. In all, 14 mice could be diagnosed as having MetS, and the levels of body weight, HbA1c, triglyceride, total cholesterol and low-density lipoprotein cholesterol were significantly higher than in the normal group. Upper abdominal fat better predicted dyslipidaemia (odds ratio, OR = 2.673; area under the receiver-operating characteristic curve, AUCROC = 0.9153) and hyperglycaemia (OR = 2.456; AUCROC = 0.9454), and the abdominal visceral adipose tissue (VAT) was better for predicting MetS risk (OR = 1.187; AUCROC = 0.9619). We identified the predictive effect of fat volume and distribution in dyslipidaemia, hyperglycaemia and MetS. The upper abdominal fat played a better predictive role for the risk of dyslipidaemia and hyperglycaemia, and the abdominal VAT played a better predictive role for the risk of MetS.
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Affiliation(s)
- Hui-Xuan Wu
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Xiao Lin
- Clinical Research Center for Medical Imaging in Hunan Province, Department of Radiology Quality Control Center in Hunan Province, Department of Radiology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Chuan-Li Cheng
- Paul C. Lauterbur Research Center for Biomedical Imaging, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China
| | - Hong-Li Jiang
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Junaid Iqbal
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Jun Liu
- Clinical Research Center for Medical Imaging in Hunan Province, Department of Radiology Quality Control Center in Hunan Province, Department of Radiology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Hou-De Zhou
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
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Aggeletopoulou I, Tsounis EP, Mouzaki A, Triantos C. Creeping Fat in Crohn's Disease-Surgical, Histological, and Radiological Approaches. J Pers Med 2023; 13:1029. [PMID: 37511642 PMCID: PMC10381426 DOI: 10.3390/jpm13071029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 06/16/2023] [Accepted: 06/19/2023] [Indexed: 07/30/2023] Open
Abstract
During the course of Crohn's disease, the response of mesenteric adipose tissue to the production of inflammatory mediators and bacterial invasion through the intestinal mucosa results in the formation of creeping fat. Creeping fat describes the arresting finger-like projections that surround the inflamed bowel. In this review, the microscopic and macroscopic features of creeping fat and histological evidence for the importance of this tissue are discussed. Moreover, the most recent insights into the radiological assessment of creeping fat in patients with Crohn's disease are reported. Advances in imaging techniques have revolutionized the possibility of visualization and quantification of adipose tissue depots with excellent accuracy. Visceral fat has been significantly correlated with various Crohn's-disease-related outcomes. Despite the difficulties in distinguishing physiologic perienteric fat from creeping fat, the growing interest in fat-wrapping in Crohn's disease has rejuvenated radiologic research. With regard to the noninvasive fat-wrapping assessment, a novel CT enterography-based mesenteric creeping fat index has been developed for the mitigation of the confounding effect of normal retroperitoneal and perienteric adipose tissue. Research on machine learning algorithms and computational radiomics in conjunction with mechanistic studies may be the key for the elucidation of the complex role of creeping fat in Crohn's disease.
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Affiliation(s)
- Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (I.A.); (E.P.T.)
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, 26504 Patras, Greece;
| | - Efthymios P. Tsounis
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (I.A.); (E.P.T.)
| | - Athanasia Mouzaki
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, 26504 Patras, Greece;
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (I.A.); (E.P.T.)
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Kokabi F, Ebrahimi S, Mirzavi F, Ghiasi Nooghabi N, Hashemi SF, Hashemy SI. The neuropeptide substance P/neurokinin-1 receptor system and diabetes: From mechanism to therapy. Biofactors 2023. [PMID: 36651605 DOI: 10.1002/biof.1935] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 12/22/2022] [Indexed: 01/19/2023]
Abstract
Diabetes is a significant public health issue known as the world's fastest-growing disease condition. It is characterized by persistent hyperglycemia and subsequent chronic complications leading to organ dysfunction and, ultimately, the failure of target organs. Substance P (SP) is an undecapeptide that belongs to the family of tachykinin (TK) peptides. The SP-mediated activation of the neurokinin 1 receptor (NK1R) regulates many pathophysiological processes in the body. There is also a relation between the SP/NK1R system and diabetic processes. Importantly, deregulated expression of SP has been reported in diabetes and diabetes-associated chronic complications. SP can induce both diabetogenic and antidiabetogenic effects and thus affect the pathology of diabetes destructively or protectively. Here, we review the current knowledge of the functional relevance of the SP/NK1R system in diabetes pathogenesis and its exploitation for diabetes therapy. A comprehensive understanding of the role of the SP/NK1R system in diabetes is expected to shed further light on developing new therapeutic possibilities for diabetes and its associated chronic conditions.
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Affiliation(s)
- Fariba Kokabi
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Safieh Ebrahimi
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Farshad Mirzavi
- Cardiovascular Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | | | | | - Seyed Isaac Hashemy
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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8
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Ullah R, Rauf N, Nabi G, Yi S, Yu-Dong Z, Fu J. Mechanistic insight into high-fat diet-induced metabolic inflammation in the arcuate nucleus of the hypothalamus. Biomed Pharmacother 2021; 142:112012. [PMID: 34388531 DOI: 10.1016/j.biopha.2021.112012] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 07/31/2021] [Accepted: 08/03/2021] [Indexed: 12/16/2022] Open
Abstract
A high-fat diet (HFD) is linked with cytokines production by non-neuronal cells within the hypothalamus, which mediates metabolic inflammation. These cytokines then activate different inflammatory mediators in the arcuate nucleus of the hypothalamus (ARC), a primary hypothalamic area accommodating proopiomelanocortin (POMC) and agouti-related peptide (AGRP) neurons, first-order neurons that sense and integrate peripheral metabolic signals and then respond accordingly. These mediators, such as inhibitor of κB kinase-β (IKKβ), suppression of cytokine signaling 3 (SOCS3), c-Jun N-terminal kinases (JNKs), protein kinase C (PKC), etc., cause insulin and leptin resistance in POMC and AGRP neurons and support obesity and related metabolic complications. On the other hand, inhibition of these mediators has been shown to counteract the impaired metabolism. Therefore, it is important to discuss the contribution of neuronal and non-neuronal cells in HFD-induced hypothalamic inflammation. Furthermore, understanding few other questions, such as the diets causing hypothalamic inflammation, the gender disparity in response to HFD feeding, and how hypothalamic inflammation affects ARC neurons to cause impaired metabolism, will be helpful for the development of therapeutic approaches to prevent or treat HFD-induced obesity.
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Affiliation(s)
- Rahim Ullah
- Department of Endocrinology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China; Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, China
| | - Naveed Rauf
- Department of Endocrinology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China
| | - Ghulam Nabi
- Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Shijiazhuang 050024, Hebei Province, China; Department of Life Sciences, School of Science, University of Management and Technology (UMT), Lahore, Pakistan
| | - Shen Yi
- Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, China.
| | - Zhou Yu-Dong
- Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, China.
| | - Junfen Fu
- Department of Endocrinology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China; National Clinical Research Center for Child Health, Hangzhou 310052, China; National Children's Regional Medical Center, Hangzhou 310052, China.
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Basson AR, Chen C, Sagl F, Trotter A, Bederman I, Gomez-Nguyen A, Sundrud MS, Ilic S, Cominelli F, Rodriguez-Palacios A. Regulation of Intestinal Inflammation by Dietary Fats. Front Immunol 2021; 11:604989. [PMID: 33603741 PMCID: PMC7884479 DOI: 10.3389/fimmu.2020.604989] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 12/11/2020] [Indexed: 12/12/2022] Open
Abstract
With the epidemic of human obesity, dietary fats have increasingly become a focal point of biomedical research. Epidemiological studies indicate that high-fat diets (HFDs), especially those rich in long-chain saturated fatty acids (e.g., Western Diet, National Health Examination survey; NHANES 'What We Eat in America' report) have multi-organ pro-inflammatory effects. Experimental studies have confirmed some of these disease associations, and have begun to elaborate mechanisms of disease induction. However, many of the observed effects from epidemiological studies appear to be an over-simplification of the mechanistic complexity that depends on dynamic interactions between the host, the particular fatty acid, and the rather personalized genetics and variability of the gut microbiota. Of interest, experimental studies have shown that certain saturated fats (e.g., lauric and myristic fatty acid-rich coconut oil) could exert the opposite effect; that is, desirable anti-inflammatory and protective mechanisms promoting gut health by unanticipated pathways. Owing to the experimental advantages of laboratory animals for the study of mechanisms under well-controlled dietary settings, we focus this review on the current understanding of how dietary fatty acids impact intestinal biology. We center this discussion on studies from mice and rats, with validation in cell culture systems or human studies. We provide a scoping overview of the most studied diseases mechanisms associated with the induction or prevention of Inflammatory Bowel Disease in rodent models relevant to Crohn's Disease and Ulcerative Colitis after feeding either high-fat diet (HFD) or feed containing specific fatty acid or other target dietary molecule. Finally, we provide a general outlook on areas that have been largely or scarcely studied, and assess the effects of HFDs on acute and chronic forms of intestinal inflammation.
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Affiliation(s)
- Abigail R. Basson
- Division of Gastroenterology and Liver Diseases, School of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, United States
- Digestive Health Research Institute, School of Medicine, Case Western Reserve University, Cleveland, OH, United States
- Cleveland Digestive Diseases Research Core, School of Medicine, Case Western Reserve University, Cleveland, OH, United States
- Digestive Health Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, United States
| | - Christy Chen
- Digestive Health Research Institute, School of Medicine, Case Western Reserve University, Cleveland, OH, United States
| | - Filip Sagl
- Digestive Health Research Institute, School of Medicine, Case Western Reserve University, Cleveland, OH, United States
| | - Ashley Trotter
- Division of Gastroenterology and Liver Diseases, School of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, United States
- Digestive Health Research Institute, School of Medicine, Case Western Reserve University, Cleveland, OH, United States
- Department of Hospital Medicine, Pritzker School of Medicine, NorthShore University Health System, Chicago, IL, United States
| | - Ilya Bederman
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, United States
| | - Adrian Gomez-Nguyen
- Division of Gastroenterology and Liver Diseases, School of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, United States
- Digestive Health Research Institute, School of Medicine, Case Western Reserve University, Cleveland, OH, United States
- Cleveland Digestive Diseases Research Core, School of Medicine, Case Western Reserve University, Cleveland, OH, United States
| | - Mark S. Sundrud
- Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, United States
| | - Sanja Ilic
- Department of Human Sciences, Human Nutrition, College of Education and Human Ecology, The Ohio State University, Columbus, OH, United States
| | - Fabio Cominelli
- Division of Gastroenterology and Liver Diseases, School of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, United States
- Digestive Health Research Institute, School of Medicine, Case Western Reserve University, Cleveland, OH, United States
- Cleveland Digestive Diseases Research Core, School of Medicine, Case Western Reserve University, Cleveland, OH, United States
- Digestive Health Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, United States
| | - Alex Rodriguez-Palacios
- Division of Gastroenterology and Liver Diseases, School of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, United States
- Digestive Health Research Institute, School of Medicine, Case Western Reserve University, Cleveland, OH, United States
- Cleveland Digestive Diseases Research Core, School of Medicine, Case Western Reserve University, Cleveland, OH, United States
- Digestive Health Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, United States
- University Hospitals Research and Education Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, United States
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10
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Matsumura S, Kurashima Y, Murasaki S, Morimoto M, Arai F, Saito Y, Katayama N, Kim D, Inagaki Y, Kudo T, Ernst PB, Shimizu T, Kiyono H. Stratified layer analysis reveals intrinsic leptin stimulates cryptal mesenchymal cells for controlling mucosal inflammation. Sci Rep 2020; 10:18351. [PMID: 33110098 PMCID: PMC7591933 DOI: 10.1038/s41598-020-75186-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 10/07/2020] [Indexed: 12/30/2022] Open
Abstract
Mesenchymal cells in the crypt play indispensable roles in the maintenance of intestinal epithelial homeostasis through their contribution to the preservation of stem cells. However, the acquisition properties of the production of stem cell niche factors by the mesenchymal cells have not been well elucidated, due to technical limitations regarding the isolation and subsequent molecular and cellular analyses of cryptal mesenchymal cells. To evaluate the function of mesenchymal cells located at the large intestinal crypt, we established a novel method through which cells are harvested according to the histologic layers of mouse colon, and we compared cellular properties between microenvironmental niches, the luminal mucosa and crypts. The gene expression pattern in the cryptal mesenchymal cells showed that receptors of the hormone/cytokine leptin were highly expressed, and we found a decrease in Wnt2b expression under conditions of leptin receptor deficiency, which also induced a delay in cryptal epithelial proliferation. Our novel stratified layer isolation strategies thus revealed new microenvironmental characteristics of colonic mesenchymal cells, including the intrinsic involvement of leptin in the control of mucosal homeostasis.
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Affiliation(s)
- Seiichi Matsumura
- Department of Innovative Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba, 260-8670, Japan.,Department of Mucosal Immunology, The University of Tokyo Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.,Department of Pediatrics, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Yosuke Kurashima
- Department of Innovative Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba, 260-8670, Japan. .,Department of Mucosal Immunology, The University of Tokyo Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan. .,International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan. .,Division of Gastroenterology, Department of Medicine, CU-UCSD Center for Mucosal Immunology, Allergy and Vaccines (CU-UCSD cMAV), University of California, San Diego, CA, 92093-0956, USA. .,Division of Comparative Pathology and Medicine, Department of Pathology, University of California San Diego, San Diego, CA, 92093-0956, USA.
| | - Sayuri Murasaki
- Department of Mucosal Immunology, The University of Tokyo Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan
| | - Masako Morimoto
- Department of Innovative Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba, 260-8670, Japan
| | - Fujimi Arai
- Department of Mucosal Immunology, The University of Tokyo Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan
| | - Yukari Saito
- Department of Innovative Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba, 260-8670, Japan
| | - Nana Katayama
- Department of Mucosal Immunology, The University of Tokyo Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan
| | - Dayoung Kim
- Department of Mucosal Immunology, The University of Tokyo Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan
| | - Yutaka Inagaki
- Center for Matrix Biology and Medicine, Graduate School of Medicine, Tokai University, Kanagawa, Japan
| | - Takahiro Kudo
- Department of Pediatrics, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Peter B Ernst
- Division of Gastroenterology, Department of Medicine, CU-UCSD Center for Mucosal Immunology, Allergy and Vaccines (CU-UCSD cMAV), University of California, San Diego, CA, 92093-0956, USA.,Division of Comparative Pathology and Medicine, Department of Pathology, University of California San Diego, San Diego, CA, 92093-0956, USA.,Center for Veterinary Sciences and Comparative Medicine, University of California, San Diego, CA, 92093-0956, USA
| | - Toshiaki Shimizu
- Department of Pediatrics, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Hiroshi Kiyono
- Department of Mucosal Immunology, The University of Tokyo Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.,International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.,Division of Gastroenterology, Department of Medicine, CU-UCSD Center for Mucosal Immunology, Allergy and Vaccines (CU-UCSD cMAV), University of California, San Diego, CA, 92093-0956, USA
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11
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Role of Obesity, Mesenteric Adipose Tissue, and Adipokines in Inflammatory Bowel Diseases. Biomolecules 2019; 9:biom9120780. [PMID: 31779136 PMCID: PMC6995528 DOI: 10.3390/biom9120780] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 11/14/2019] [Accepted: 11/15/2019] [Indexed: 12/11/2022] Open
Abstract
Inflammatory bowel diseases (IBDs) are a group of disorders which include ulcerative colitis and Crohn's disease. Obesity is becoming increasingly more common among patients with inflammatory bowel disease and plays a role in the development and course of the disease. This is especially true in the case of Crohn's disease. The recent results indicate a special role of visceral adipose tissue and particularly mesenteric adipose tissue, also known as "creeping fat", in pathomechanism, leading to intestinal inflammation. The involvement of altered adipocyte function and the deregulated production of adipokines, such as leptin and adiponectin, has been suggested in pathogenesis of IBD. In this review, we discuss the epidemiology and pathophysiology of obesity in IBD, the influence of a Western diet on the course of Crohn's disease and colitis in IBD patients and animal's models, and the potential role of adipokines in these disorders. Since altered body composition, decrease of skeletal muscle mass, and development of pathologically changed mesenteric white adipose tissue are well-known features of IBD and especially of Crohn's disease, we discuss the possible crosstalk between adipokines and myokines released from skeletal muscle during exercise with moderate or forced intensity. The emerging role of microbiota and the antioxidative and anti-inflammatory enzymes such as intestinal alkaline phosphatase is also discussed, in order to open new avenues for the therapy against intestinal perturbations associated with IBD.
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Rahmani J, Kord-Varkaneh H, Hekmatdoost A, Thompson J, Clark C, Salehisahlabadi A, Day AS, Jacobson K. Body mass index and risk of inflammatory bowel disease: A systematic review and dose-response meta-analysis of cohort studies of over a million participants. Obes Rev 2019; 20:1312-1320. [PMID: 31190427 DOI: 10.1111/obr.12875] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 03/25/2019] [Accepted: 04/10/2019] [Indexed: 12/28/2022]
Abstract
The relationship between body mass index (BMI) and risk of inflammatory bowel disease (IBD) is controversial. We performed a dose-response meta-analysis to investigate the association between BMI and risk of incident ulcerative colitis (UC) and Crohn's disease (CD) using prospective cohort studies. A systematic search was conducted in MEDLINE/PubMed, SCOPUS, Cochrane, and Web of Science databases from inception to January 2019. DerSimonian and Laird random-effects model was used to estimate combined hazard ratios (HRs). Overall, 882 articles were screened, and 42 full-text articles were reviewed for inclusion using the study eligibility criteria. Five studies evaluated the association between BMI and IBD with 1 044 517 participants. Pooled results showed a significant association between participants affected by obesity and risk of CD (HR: 1.42, 95% CI: 1.18-1.71, I2 : 0.00). There was a significant nonlinear association between BMI and risk of CD (P = .01, coeff = 0.5024). Pooled results did not show any significant association between being underweight and risk of UC (HR: 1.07, 95% CI: 0.96-1.19, I2 : 0.00) or CD (HR: 1.11, 95% CI: 0.93-1.31, I2 : 12.8). There was no difference in the risk for UC among participants affected by obesity compared with participants categorized as having normal BMI (HR: 0.96, 95% CI: 0.80-1.14, I2 : 8.0). This systematic review and meta-analysis identified significant dose-response relationship between being affected by obesity, as a risk factor, and incidence of CD.
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Affiliation(s)
- Jamal Rahmani
- Department of Community Nutrition, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamed Kord-Varkaneh
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Azita Hekmatdoost
- Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, Canada
| | - Jacqueline Thompson
- Nuffield Department of Orthopaedics, Rheumatology & Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Cain Clark
- School of Life Sciences, Coventry University, Coventry, UK
| | - Ammar Salehisahlabadi
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Andrew S Day
- Department of Paediatrics, University of Otago, Christchurch, New Zealand
| | - Kevan Jacobson
- Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, Canada
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13
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Silva Rischiteli AB, Neto NIP, Gascho K, Carnier M, de Miranda DA, Silva FP, Boldarine VT, Seelaender M, Ribeiro EB, Oyama LM, Oller do Nascimento CM. A diet including xanthan gum triggers a pro-inflammatory response in Wistar rats inoculated with Walker 256 cells. PLoS One 2019; 14:e0218567. [PMID: 31211796 PMCID: PMC6581265 DOI: 10.1371/journal.pone.0218567] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Accepted: 06/04/2019] [Indexed: 12/31/2022] Open
Abstract
Objective The aim of this study was to evaluate the effect of adding xanthan gum to the diet of rats on the production of cytokines and pro-inflammatory factors and on tumor development in rats inoculated with Walker 256 tumor cells. Methods Fifty-six rats were divided into 4 groups: control diet (C), control diet with tumor (TC), xanthan gum diet (XG), xanthan gum diet with tumor (TXG). Results The ingestion of xanthan gum promotes changes in cytokine content: increasing IL-6 TNF-α and IL-10 in retroperitoneal adipose tissue compared to the control group; and increasing TNF-α in the mesenteric adipose tissue compared to the C and TXG groups. On the contrary, the addition of xanthan gum to the diet did not affect the development of Walker 256 tumors in rats. Conclusion The continuous use of xanthan gum triggered a pro-inflammatory response, promoting an increase in pro-inflammatory cytokines in the adipose tissue, but it did not have an effect on the tumor development in the animals inoculated with Walker 256 tumor cells.
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Affiliation(s)
| | - Nelson I. P. Neto
- Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Fisiologia, São Paulo, Brasil
| | - Karina Gascho
- Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Fisiologia, São Paulo, Brasil
| | - Marcela Carnier
- Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Fisiologia, São Paulo, Brasil
| | - Danielle A. de Miranda
- Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Fisiologia, São Paulo, Brasil
| | - Fernanda P. Silva
- Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Fisiologia, São Paulo, Brasil
| | - Valter T. Boldarine
- Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Fisiologia, São Paulo, Brasil
| | - Marília Seelaender
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo (SP), Brasil
| | - Eliane B. Ribeiro
- Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Fisiologia, São Paulo, Brasil
| | - Lila M. Oyama
- Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Fisiologia, São Paulo, Brasil
- * E-mail:
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14
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Zalecki M. Gastric ulcer induced changes in substance P and Nk1, Nk2, Nk3 receptors expression in different stomach localizations with regard to intrinsic neuronal system. Histochem Cell Biol 2018; 151:29-42. [PMID: 30155561 PMCID: PMC6328524 DOI: 10.1007/s00418-018-1715-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/23/2018] [Indexed: 12/22/2022]
Abstract
Gastric ulceration, a focal tissue damage accompanied by inflammation, can influence other parts of the stomach. Substance P and its receptors are strongly involved in regulation of gastrointestinal motility, secretion and inflammation. The enteric nervous system is one of the regulators of gastrointestinal functioning and contributes to tissue response to the pathology. The pig, an omnivorous animal, is a valuable species for gastrointestinal experiments. Thus, the objective of the study was to verify whether the antral ulceration induces changes in the expression of substance P and tachykinin receptors in the neighboring (antrum) and distanced (corpus, pylorus) porcine gastric tissues and therein localized myenteric and submucosal perikarya as well as in the intrinsic descending neurons supplying pyloric sphincter. The experiment was performed on healthy pigs and pigs with experimentally induced gastric ulcers. Stomach samples from the corpus, antrum (adjacent to the ulcer in experimental pigs) and pylorus were analyzed by: (1) double immunofluorescence for changes in the number of SP-positive myenteric and submucosal neurons (2) Real-Time PCR for changes in expression of mRNA encoding SP and Nk1, Nk2, Nk3 receptors. Additionally, gastric descending neurons supplying pyloric sphincter were immunostained for SP. In experimental animals, only the number of SP-positive myenteric perikarya significantly increased in all stomach localizations studied. Q-PCR revealed increased expression for: SP, Nk1, Nk3 in the corpus; Nk2 and Nk3 in the pylorus; In the antrum, expression of Nk3 was increased but Nk2-decreased. Antral ulcers induced significant changes in the expression of SP and tachykinin receptors in the wide stomach area indicating sophisticated tissue reaction.
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Affiliation(s)
- Michal Zalecki
- Department of Animal Anatomy, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Oczapowskiego 13 str., 10-719, Olsztyn, Poland.
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15
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A peculiar case of Campylobacter jejuni attenuated aspartate chemosensory mutant, able to cause pathology and inflammation in avian and murine model animals. Sci Rep 2018; 8:12594. [PMID: 30135522 PMCID: PMC6105663 DOI: 10.1038/s41598-018-30604-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Accepted: 08/01/2018] [Indexed: 01/25/2023] Open
Abstract
An attenuated Campylobacter jejuni aspartate chemoreceptor ccaA mutant caused gross pathological changes despite reduced colonisation ability in animal models. In chickens, the pathological changes included connective tissue and thickening of the mesenteric fat, as well as the disintegration of the villus tips in the large intestine, whereas in mice, hepatomegaly occurred between 48–72 hours post infection and persisted for the six days of the time course. In addition, there was a significant change in the levels of IL-12p70 in mice infected with the C. jejuni ccaA mutant. CcaA isogenic mutant was hyper-invasive in cell culture and microscopic examination revealed that it had a “run” bias in its “run-and-tumble” chemotactic behaviour. The mutant cells also exhibited lower level of binding to fucosylated and higher binding to sialylated glycan structures in glycan array analysis. This study highlights the importance of investigating phenotypic changes in C. jejuni, as we have shown that specific mutants can cause pathological changes in the host, despite reduction in colonisation potential.
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Hoffman JM, Sideri A, Ruiz JJ, Stavrakis D, Shih DQ, Turner JR, Pothoulakis C, Karagiannides I. Mesenteric Adipose-derived Stromal Cells From Crohn's Disease Patients Induce Protective Effects in Colonic Epithelial Cells and Mice With Colitis. Cell Mol Gastroenterol Hepatol 2018; 6:1-16. [PMID: 29928668 PMCID: PMC6008259 DOI: 10.1016/j.jcmgh.2018.02.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Accepted: 02/01/2018] [Indexed: 12/14/2022]
Abstract
Mesenteric adipose tissue hyperplasia is a hallmark of Crohn's disease (CD). Recently, we showed that mesenteric adipose-derived stromal cells (ADSCs) from CD, ulcerative colitis, and control patients synthesize and release adipokines in a disease-dependent manner. Here we examined the expression profiles of CD and control patient-derived mesenteric ADSCs and studied the effects of their extracellular mediators on colonocyte signaling in vitro and experimental colitis in vivo. ADSCs were isolated from mesenteric fat of control and CD patients. Microarray profiling and network analysis were performed in ADSCs and human colonocytes treated with conditioned media from cultured ADSCs. Mice with acute colitis received daily injections of conditioned media from patient-derived ADSCs, vehicle, or apolactoferrin. Proliferative responses were evaluated in conditioned media-treated colonocytes and mouse colonic epithelium. Total protein was isolated from cultured colonocytes after treatment with apolactoferrin for Western blot analysis of phosphorylated intracellular signaling kinases. Microarray profiling revealed differential mRNA expression in CD patient-derived ADSCs compared with controls, including lactoferrin. Administration of CD patient-derived medium or apolactoferrin increased colonocyte proliferation compared with controls. Conditioned media from CD patient-derived ADSCs or apolactoferrin attenuated colitis severity in mice and enhanced colonocyte proliferation in vivo. ADSCs from control and CD patients show disease-dependent inflammatory responses and alter colonic epithelial cell signaling in vitro and in vivo. Furthermore, we demonstrate lactoferrin production by adipose tissue, specifically mesenteric ADSCs. We suggest that mesenteric ADSC-derived lactoferrin may mediate protective effects and participate in the pathophysiology of CD by promoting colonocyte proliferation and the resolution of inflammation.
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Key Words
- ADSC, adipose-derived stromal cell
- CD, Crohn’s disease
- DSS, dextran sodium sulfate
- IBD, inflammatory bowel disease
- IBS, irritable bowel syndrome
- IL, interleukin
- Inflammatory Bowel Disease
- Intestinal Epithelium
- Mesenteric Adipose Tissue
- PCR, polymerase chain reaction
- Preadipocytes
- RT, reverse-transcriptase
- TNBS, trinitrobenzenesulfonic acid
- VEGF, vascular endothelial growth factor
- i.c., intracolonic
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Affiliation(s)
- Jill M. Hoffman
- Center for Inflammatory Bowel Diseases, Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California,Jill Hoffman, PhD, Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, 675 Charles E. Young Drive South, MRL Building 1220, Los Angeles, California 90095. fax: (310) 825-3542
| | - Aristea Sideri
- Center for Inflammatory Bowel Diseases, Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
| | - Jonathan J. Ruiz
- Center for Inflammatory Bowel Diseases, Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
| | - Dimitris Stavrakis
- Center for Inflammatory Bowel Diseases, Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
| | - David Q. Shih
- Inflammatory Bowel and Immunobiology Research Institute, Cedars Sinai Medical Center, Los Angeles, California
| | - Jerrold R. Turner
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts,Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Charalabos Pothoulakis
- Center for Inflammatory Bowel Diseases, Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
| | - Iordanes Karagiannides
- Center for Inflammatory Bowel Diseases, Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California,Correspondence Address correspondence to: Iordanes Karagiannides, PhD, Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, 675 Charles E. Young Drive South, MRL Building 1220, Los Angeles, California 90095. fax: (310) 825-3542.
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17
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Fang K, Law IKM, Padua D, Sideri A, Huang V, Kevil CG, Iliopoulos D, Pothoulakis C. MicroRNA-31-3p Is Involved in Substance P (SP)-Associated Inflammation in Human Colonic Epithelial Cells and Experimental Colitis. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 188:586-599. [PMID: 29253460 DOI: 10.1016/j.ajpath.2017.10.023] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Revised: 10/24/2017] [Accepted: 10/30/2017] [Indexed: 02/08/2023]
Abstract
Substance P (SP) mediates colitis. SP signaling regulates the expression of several miRNAs, including miR-31-3p, in human colonocytes. However, the role of miR-31-3p in colitis and the underlying mechanisms has not been elucidated. We performed real-time PCR analysis of miR-31-3p expression in human colonic epithelial cells overexpressing neurokinin-1 receptor (NCM460 NK-1R) in response to SP stimulation and in NCM460 cells after IL-6, IL8, tumor necrosis factor (TNF)-α, and interferon-γ exposure. Functions of miR-31-3p were tested in NCM460-NK-1R cells and the trinitrobenzene sulfonic acid (TNBS) and dextran sodium sulfate (DSS) models of colitis. Targets of miRNA-31-3p were confirmed by Western blot analysis and luciferase reporter assay. Jun N-terminal kinase inhibition decreased SP-induced miR-31-3p expression. miR-31-3p expression was increased in both TNBS- and DSS-induced colitis and human colonic biopsies from ulcerative colitis, compared with controls. Intracolonic administration of a miR-31-3p chemical inhibitor exacerbated TNBS- and DSS-induced colitis and increased colonic TNF-α, CXCL10, and chemokine (C-C motif) ligand 2 (CCL2) mRNA expression. Conversely, overexpression of miR-31-3p ameliorated the severity of DSS-induced colitis. Bioinformatic, luciferase reporter assay, and Western blot analyses identified RhoA as a target of miR-31-3p in NCM460 cells. Constitutive activation of RhoA led to increased expression of CCL2, IL6, TNF-α, and CXCL10 in NCM460-NK-1R cells on SP stimulation. Our results reveal a novel SP-miR-31-3p-RhoA pathway that protects from colitis. The use of miR-31-3p mimics may be a promising approach for colitis treatment.
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Affiliation(s)
- Kai Fang
- Inflammatory Bowel Disease Center, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California
| | - Ivy Ka Man Law
- Inflammatory Bowel Disease Center, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California
| | - David Padua
- Inflammatory Bowel Disease Center, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California
| | - Aristea Sideri
- Inflammatory Bowel Disease Center, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California
| | - Vanessa Huang
- Inflammatory Bowel Disease Center, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California
| | - Christopher G Kevil
- Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, Louisiana
| | - Dimitrios Iliopoulos
- Center for Systems Biomedicine, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California
| | - Charalabos Pothoulakis
- Inflammatory Bowel Disease Center, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California.
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TRPV1: A Potential Therapeutic Target in Type 2 Diabetes and Comorbidities? Trends Mol Med 2017; 23:1002-1013. [DOI: 10.1016/j.molmed.2017.09.005] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 09/07/2017] [Accepted: 09/14/2017] [Indexed: 12/14/2022]
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Reciprocal Inflammatory Signaling Between Intestinal Epithelial Cells and Adipocytes in the Absence of Immune Cells. EBioMedicine 2017; 23:34-45. [PMID: 28789943 PMCID: PMC5605307 DOI: 10.1016/j.ebiom.2017.07.027] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 07/31/2017] [Accepted: 07/31/2017] [Indexed: 12/19/2022] Open
Abstract
Visceral fat accumulation as observed in Crohn's disease and obesity is linked to chronic gut inflammation, suggesting that accumulation of gut adipocytes can trigger local inflammatory signaling. However, direct interactions between intestinal epithelial cells (IECs) and adipocytes have not been investigated, in part because IEC physiology is difficult to replicate in culture. In this study, we originally prepared intact, polarized, and cytokine responsive IEC monolayers from primary or induced pluripotent stem cell-derived intestinal organoids by simple and repeatable methods. When these physiological IECs were co-cultured with differentiated adipocytes in Transwell, pro-inflammatory genes were induced in both cell types, suggesting reciprocal inflammatory activation in the absence of immunocompetent cells. These inflammatory responses were blocked by nuclear factor-κB or signal transducer and activator of transcription 3 inhibition and by anti-tumor necrosis factor- or anti-interleukin-6-neutralizing antibodies. Our results highlight the utility of these monolayers for investigating IEC biology. Furthermore, this system recapitulates the intestinal epithelium-mesenteric fat signals that potentially trigger or worsen inflammatory disorders such as Crohn's disease and obesity-related enterocolitis.
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20
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Mazur-Bialy AI, Bilski J, Wojcik D, Brzozowski B, Surmiak M, Hubalewska-Mazgaj M, Chmura A, Magierowski M, Magierowska K, Mach T, Brzozowski T. Beneficial Effect of Voluntary Exercise on Experimental Colitis in Mice Fed a High-Fat Diet: The Role of Irisin, Adiponectin and Proinflammatory Biomarkers. Nutrients 2017; 9:410. [PMID: 28425943 PMCID: PMC5409749 DOI: 10.3390/nu9040410] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Revised: 04/12/2017] [Accepted: 04/14/2017] [Indexed: 12/18/2022] Open
Abstract
Inflammatory bowel diseases (IBDs) are a heterogeneous group of disorders exhibited by two major phenotypic forms: Crohn's disease and ulcerative colitis. Although the aetiology of IBD is unknown, several factors coming from the adipose tissue and skeletal muscles, such as cytokines, adipokines and myokines, were suggested in the pathogenesis of ulcerative colitis; however, it has not been extensively studied whether voluntary exercise can ameliorate that disorder. We explored the effect of moderate exercise (i.e., voluntary wheel running) on the disease activity index (DAI), colonic blood flow (CBF), plasma irisin and adiponectin levels and real-time PCR expression of proinflammatory markers in mesenteric fat in mice with 2,4,6-trinitrobenzenesulfonic acid (TNBS) colitis fed a high-fat diet (HFD) compared to those on a standard chow diet (SD). Macroscopic and microscopic colitis in sedentary SD mice was accompanied by a significant fall in CBF, some increase in colonic tissue weight and a significant increase in the plasma levels of tumour necrosis factor-alpha (TNF-α), IL-6, monocyte chemotactic protein 1 (MCP-1) and IL-13 (p < 0.05). In sedentary HFD mice, colonic lesions were aggravated, colonic tissue weight increased and the plasma TNF-α, IL-6, MCP-1, IL-1β and leptin levels significantly increased. Simultaneously, a significant decrease in the plasma irisin and adiponectin levels was observed in comparison with SD mice (p < 0.05). Exercise significantly decreased macroscopic and microscopic colitis, substantially increased CBF and attenuated the plasma TNF-α, IL-6, MCP-1, IL-1β and leptin levels while raising the plasma irisin and the plasma and WAT concentrations of adiponectin in HFD mice (p < 0.05). We conclude that: (1) experimental colitis is exacerbated in HFD mice, possibly due to a fall in colonic microcirculation and an increase in the plasma and mesenteric fat content of proinflammatory biomarkers; and (2) voluntary physical activity can attenuate the severity of colonic damage in mice fed a HFD through the release of protective irisin and restoration of plasma adiponectin.
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Affiliation(s)
- Agnieszka Irena Mazur-Bialy
- Department of Ergonomics and Exercise Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, 20 Grzegorzecka Street, 31-531 Cracow, Poland.
| | - Jan Bilski
- Department of Ergonomics and Exercise Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, 20 Grzegorzecka Street, 31-531 Cracow, Poland.
| | - Dagmara Wojcik
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland.
| | - Bartosz Brzozowski
- Gastroenterology and Hepatology Clinic, Jagiellonian University Medical College, 5 Sniadeckich Street, 31-531 Cracow, Poland.
| | - Marcin Surmiak
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland.
| | - Magdalena Hubalewska-Mazgaj
- Department of Genetic Research and Nutrigenomics, Malopolska Centre of Biotechnology, Jagiellonian University, 7A Gronostajowa Street, 30-387 Cracow, Poland.
| | - Anna Chmura
- Department of Ergonomics and Exercise Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, 20 Grzegorzecka Street, 31-531 Cracow, Poland.
| | - Marcin Magierowski
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland.
| | - Katarzyna Magierowska
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland.
| | - Tomasz Mach
- Gastroenterology and Hepatology Clinic, Jagiellonian University Medical College, 5 Sniadeckich Street, 31-531 Cracow, Poland.
| | - Tomasz Brzozowski
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland.
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Karrasch T, Schaeffler A. Adipokines and the role of visceral adipose tissue in inflammatory bowel disease. Ann Gastroenterol 2016; 29:424-438. [PMID: 27708507 PMCID: PMC5049548 DOI: 10.20524/aog.2016.0077] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Accepted: 07/22/2016] [Indexed: 12/20/2022] Open
Abstract
Recently, adipocytes have been recognized as actively participating in local and systemic immune responses via the secretion of peptides detectable in relevant levels in the systemic circulation, the so-called "adipo(cyto)kines". Multiple studies appearing within the last 10-15 years have focused on the possible impact of adipose tissue depots on inflammatory bowel disease (IBD). Consequently, various hypotheses regarding the role of different adipokines in inflammatory diseases in general and in intestinal inflammatory processes in particular have been developed and have been further refined in recent years. After a focused summary of the data reported concerning the impact of visceral adipose tissue on IBD, such as Crohn's disease and ulcerative colitis, our review focuses on recent developments indicating that adipocytes as part of the innate immune system actively participate in antimicrobial host defenses in the context of intestinal bacterial translocation, which are of utmost importance for the homeostasis of the whole organism. Modulators of adipose tissue function and regulators of adipokine secretion, as well as modifiers of adipocytic pattern recognition molecules, might represent future potential drug targets in IBD.
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Affiliation(s)
- Thomas Karrasch
- Department of Internal Medicine III, Giessen University Hospital, Germany
| | - Andreas Schaeffler
- Department of Internal Medicine III, Giessen University Hospital, Germany
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22
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Bilski J, Mazur-Bialy A, Brzozowski B, Magierowski M, Zahradnik-Bilska J, Wójcik D, Magierowska K, Kwiecien S, Mach T, Brzozowski T. Can exercise affect the course of inflammatory bowel disease? Experimental and clinical evidence. Pharmacol Rep 2016; 68:827-836. [PMID: 27255494 DOI: 10.1016/j.pharep.2016.04.009] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Revised: 04/17/2016] [Accepted: 04/19/2016] [Indexed: 02/07/2023]
Abstract
The inflammatory bowel disease (IBD) consisting of Crohn's disease (CD) and ulcerative colitis (UC) are defined as idiopathic, chronic and relapsing intestinal disorders occurring in genetically predisposed individuals exposed to environmental risk factors such as diet and microbiome changes. Since conventional drug therapy is expensive and not fully efficient, there is a need for alternative remedies that can improve the outcome in patients suffering from IBD. Whether exercise, which has been proposed as adjunct therapy in IBD, can be beneficial in patients with IBD remains an intriguing question. In this review, we provide an overview of the effects of exercise on human IBD and experimental colitis in animal models that mimic human disease, although the information on exercise in human IBD are sparse and poorly understood. Moderate exercise can exert a beneficial ameliorating effect on IBD and improve the healing of experimental animal colitis due to the activity of protective myokines such as irisin released from working skeletal muscles. CD patients with higher levels of exercise were significantly less likely to develop active disease at six months. Moreover, voluntary exercise has been shown to exert a positive effect on IBD patients' mood, weight maintenance and osteoporosis. On the other hand, depending on its intensity and duration, exercise can evoke transient mild systemic inflammation and enhances pro-inflammatory cytokine release, thereby exacerbating the gastrointestinal symptoms. We discuss recent advances in the mechanism of voluntary and strenuous exercise affecting the outcome of IBD in patients and experimental animal models.
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Affiliation(s)
- Jan Bilski
- Department of Ergonomics and Exercise Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, Kraków, Poland
| | - Agnieszka Mazur-Bialy
- Department of Ergonomics and Exercise Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, Kraków, Poland
| | - Bartosz Brzozowski
- Gastroenterology and Hepatology Clinic, The University Hospital, Jagiellonian University Medical College, Kraków, Poland
| | - Marcin Magierowski
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland
| | - Janina Zahradnik-Bilska
- Gastroenterology and Hepatology Clinic, The University Hospital, Jagiellonian University Medical College, Kraków, Poland
| | - Dagmara Wójcik
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland
| | - Katarzyna Magierowska
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland
| | - Slawomir Kwiecien
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland
| | - Tomasz Mach
- Gastroenterology and Hepatology Clinic, The University Hospital, Jagiellonian University Medical College, Kraków, Poland
| | - Tomasz Brzozowski
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland.
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Cathelicidin suppresses lipid accumulation and hepatic steatosis by inhibition of the CD36 receptor. Int J Obes (Lond) 2016; 40:1424-34. [PMID: 27163748 PMCID: PMC5014693 DOI: 10.1038/ijo.2016.90] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Revised: 04/27/2016] [Accepted: 04/30/2016] [Indexed: 01/29/2023]
Abstract
BACKGROUND AND OBJECTIVES Obesity is a global epidemic which increases the risk of the metabolic syndrome. Cathelicidin (LL-37 and mCRAMP) is an antimicrobial peptide with an unknown role in obesity. We hypothesize that cathelicidin expression correlates with obesity and modulates fat mass and hepatic steatosis. MATERIALS AND METHODS Male C57BL/6 J mice were fed a high-fat diet. Streptozotocin was injected into mice to induce diabetes. Experimental groups were injected with cathelicidin and CD36 overexpressing lentiviruses. Human mesenteric fat adipocytes, mouse 3T3-L1 differentiated adipocytes and human HepG2 hepatocytes were used in the in vitro experiments. Cathelicidin levels in non-diabetic, prediabetic and type II diabetic patients were measured by enzyme-linked immunosorbent assay. RESULTS Lentiviral cathelicidin overexpression reduced hepatic steatosis and decreased the fat mass of high-fat diet-treated diabetic mice. Cathelicidin overexpression reduced mesenteric fat and hepatic fatty acid translocase (CD36) expression that was reversed by lentiviral CD36 overexpression. Exposure of adipocytes and hepatocytes to cathelicidin significantly inhibited CD36 expression and reduced lipid accumulation. Serum cathelicidin protein levels were significantly increased in non-diabetic and prediabetic patients with obesity, compared with non-diabetic patients with normal body mass index (BMI) values. Prediabetic patients had lower serum cathelicidin protein levels than non-diabetic subjects. CONCLUSIONS Cathelicidin inhibits the CD36 fat receptor and lipid accumulation in adipocytes and hepatocytes, leading to a reduction of fat mass and hepatic steatosis in vivo. Circulating cathelicidin levels are associated with increased BMI. Our results demonstrate that cathelicidin modulates the development of obesity.
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Fang K, Sideri A, Law IKM, Bakirtzi K, Polytarchou C, Iliopoulos D, Pothoulakis C. Identification of a novel substance P (SP)-neurokinin-1 receptor (NK-1R) microRNA-221-5p inflammatory network in human colonic epithelial cells. Cell Mol Gastroenterol Hepatol 2015; 1:503-515. [PMID: 26645045 PMCID: PMC4669978 DOI: 10.1016/j.jcmgh.2015.06.008] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Substance P (SP), a neuropeptide member of the tachykinin family, plays a critical role in colitis. MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression. However, whether SP modulates expression of microRNAs in human colonic epithelial cells remains unknown. METHODS We performed microRNA profiling analysis of SP-stimulated human colonic epithelial NCM460 cells overexpressing neurokinin-1 receptor (NCM460-NK-1R). Targets of SP-regulated microRNAs were validated by real time polymerase chain reaction (RT-PCR). Functions of miRNAs were tested in NCM460-NK-1R cells and the TNBS and DSS models of colitis. RESULTS SP stimulated differential expression of 29 microRNAs, including miR-221-5p, the highest up regulated miR (by 12.6-fold) upon SP stimulation. Bioinformatic and luciferase reporter analyses identified interleukin 6 receptor (IL-6R) mRNA as a direct target of miR-221-5p in NCM460 cells. Accordingly, SP exposure of NCM460-NK-1R cells increased IL-6R mRNA expression, while overexpression of miR-221-5p reduced IL-6R expression. NF-κB and JNK inhibition decreased SP-induced miR-221-5p expression. MiR-221-5p expression was increased in both TNBS- and DSS-induced colitis and colonic biopsies from Ulcerative Colitis, but not Crohn's Disease subjects, compared to controls. In mice, intracolonic administration of a miR-221-5p chemical inhibitor, exacerbated TNBS-and DSS-induced colitis, and increased colonic TNF-α, Cxcl10, and Col2 α 1 mRNA expression. In situ hybridization in TNBS-and DSS-exposed colons revealed increased miR-221-5p expression primarily in colonocytes. CONCLUSIONS Our results reveal a novel NK-1R-miR-221-5p-IL-6R network that protects from colitis. The use of miR-221-5p mimics may be a promising approach for colitis treatment.
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Affiliation(s)
- Kai Fang
- Inflammatory Bowel Disease Center, David Geffen School of Medicine, University of California, Los Angeles, California
| | - Aristea Sideri
- Inflammatory Bowel Disease Center, David Geffen School of Medicine, University of California, Los Angeles, California
| | - Ivy Ka Man Law
- Inflammatory Bowel Disease Center, David Geffen School of Medicine, University of California, Los Angeles, California
| | - Kyriaki Bakirtzi
- Inflammatory Bowel Disease Center, David Geffen School of Medicine, University of California, Los Angeles, California
| | - Christos Polytarchou
- Center for Systems Biomedicine, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, California
| | - Dimitrios Iliopoulos
- Center for Systems Biomedicine, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, California
| | - Charalabos Pothoulakis
- Inflammatory Bowel Disease Center, David Geffen School of Medicine, University of California, Los Angeles, California,Correspondence Address correspondence to: Charalabos Pothoulakis, MD, Division of Digestive Diseases, Inflammatory Bowel Disease Center, David Geffen School of Medicine, University of California at Los Angeles, 675 Charles E. Young Drive, South MRL Building 1240, Los Angeles, California 90095.
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Sideri A, Stavrakis D, Bowe C, Shih DQ, Fleshner P, Arsenescu V, Arsenescu R, Turner JR, Pothoulakis C, Karagiannides I. Effects of obesity on severity of colitis and cytokine expression in mouse mesenteric fat. Potential role of adiponectin receptor 1. Am J Physiol Gastrointest Liver Physiol 2015; 308:G591-604. [PMID: 25591865 PMCID: PMC4385897 DOI: 10.1152/ajpgi.00269.2014] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Accepted: 01/08/2015] [Indexed: 01/31/2023]
Abstract
In inflammatory bowel disease (IBD), obesity is associated with worsening of the course of disease. Here, we examined the role of obesity in the development of colitis and studied mesenteric fat-epithelial cell interactions in patients with IBD. We combined the diet-induce obesity with the trinitrobenzene sulfonic acid (TNBS) colitis mouse model to create groups with obesity, colitis, and their combination. Changes in the mesenteric fat and intestine were assessed by histology, myeloperoxidase assay, and cytokine mRNA expression by real-time PCR. Medium from human mesenteric fat and cultured preadipocytes was obtained from obese patients and those with IBD. Histological analysis showed inflammatory cell infiltrate and increased histological damage in the intestine and mesenteric fat of obese mice with colitis compared with all other groups. Obesity also increased the expression of proinflammatory cytokines including IL-1β, TNF-α, monocyte chemoattractant protein 1, and keratinocyte-derived chemokine, while it decreased the TNBS-induced increases in IL-2 and IFN-γ in mesenteric adipose and intestinal tissues. Human mesenteric fat isolated from obese patients and those with and IBD demonstrated differential release of adipokines and growth factors compared with controls. Fat-conditioned media reduced adiponectin receptor 1 (AdipoR1) expression in human NCM460 colonic epithelial cells. AdipoR1 intracolonic silencing in mice exacerbated TNBS-induced colitis. In conclusion, obesity worsens the outcome of experimental colitis, and obesity- and IBD-associated changes in adipose tissue promote differential mediator release in mesenteric fat that modulates colonocyte responses and may affect the course of colitis. Our results also suggest an important role for AdipoR1 for the fat-intestinal axis in the regulation of inflammation during colitis.
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Affiliation(s)
- Aristea Sideri
- 1Inflammatory Bowel Disease Center, and Neuroendocrine Assay Core, Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, California; ,7Postgraduate Program: Molecular Medicine, University of Crete, Medical School, Crete, Greece
| | - Dimitris Stavrakis
- 1Inflammatory Bowel Disease Center, and Neuroendocrine Assay Core, Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, California;
| | - Collin Bowe
- 1Inflammatory Bowel Disease Center, and Neuroendocrine Assay Core, Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, California;
| | - David Q. Shih
- 2Inflammatory Bowel and Immunobiology Research Institute, Cedars Sinai Medical Center, Los Angeles, California;
| | - Phillip Fleshner
- 2Inflammatory Bowel and Immunobiology Research Institute, Cedars Sinai Medical Center, Los Angeles, California;
| | - Violeta Arsenescu
- 3Inflammatory Bowel Diseases Center, Division of Gastroenterology, Hepatology and Nutrition, Wexner Medical Center, Ohio State University, Columbus, Ohio;
| | - Razvan Arsenescu
- 4Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, Wexner Medical Center, Ohio State University, Columbus, Ohio;
| | - Jerrold R. Turner
- 5Department of Pathology, The University of Chicago, Chicago, Illinois; ,6Department of Medicine, The University of Chicago, Chicago, Illinois;
| | - Charalabos Pothoulakis
- 1Inflammatory Bowel Disease Center, and Neuroendocrine Assay Core, Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, California;
| | - Iordanes Karagiannides
- Inflammatory Bowel Disease Center, and Neuroendocrine Assay Core, Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, California;
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Substance P mediates pro-inflammatory cytokine release form mesenteric adipocytes in Inflammatory Bowel Disease patients. Cell Mol Gastroenterol Hepatol 2015; 1:420-432. [PMID: 26543894 PMCID: PMC4629258 DOI: 10.1016/j.jcmgh.2015.03.003] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Substance P (SP), neurokinin-1 receptors (NK-1Rs) are expressed in mesenteric preadipocytes and SP binding activates proinflammatory signalling in these cells. We evaluated the expression levels of SP (Tac-1), NK-1R (Tacr-1), and NK-2R (Tacr-2) mRNA in preadipocytes isolated from patients with Inflammatory Bowel Disease (IBD) and examined their responsiveness to SP compared to control human mesenteric preadipocytes. The Aim of our study is to investigate the effects of the neuropeptide SP on cytokine expression in preadipocytes of IBD vs control patients and evaluate the potential effects of these cells on IBD pathophysiology via SP-NK-R interactions. METHODS Mesenteric fat was collected from control, Ulcerative colitis (UC) and Crohn's disease (CD) patients (n=10-11 per group). Preadipocytes were isolated, expanded in culture and exposed to substance P. Colon biopsies were obtained from control and IBD patients. RESULTS Tacr-1 and -2 mRNA were increased in IBD preadipocytes compared to controls, while Tac-1 mRNA was increased only in UC preadipocytes. SP differentially regulated the expression of inflammatory mediators in IBD preadipocytes compared to controls. Disease-dependent responses to SP were also observed between UC and CD preadipocytes. IL-17A mRNA expression and release increased after SP treatment in both CD and UC preadipocytes, while IL-17RA mRNA increased in colon biopsies from IBD patients. CONCLUSIONS Preadipocyte SP-NK-1R interactions during IBD may participate in IBD pathophysiology. The ability of human preadipocytes to release IL-17A in response to SP together with increased IL-17A receptor in IBD colon opens the possibility of a fat-colonic mucosa inflammatory loop that may be active during IBD.
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Abstract
Epidemiological studies show that both the incidence of inflammatory bowel disease (IBD) and the proportion of people with obesity and/or obesity-associated metabolic syndrome increased markedly in developed countries during the past half century. Obesity is also associated with the development of more active IBD and requirement for hospitalization and with a decrease in the time span between diagnosis and surgery. Patients with IBD, especially Crohn's disease, present fat-wrapping or "creeping fat," which corresponds to ectopic adipose tissue extending from the mesenteric attachment and covering the majority of the small and large intestinal surface. Mesenteric adipose tissue in patients with IBD presents several morphological and functional alterations, e.g., it is more infiltrated with immune cells such as macrophages and T cells. All these lines of evidence clearly show an association between obesity, adipose tissue, and functional bowel disorders. In this review, we will show that the mesenteric adipose tissue and creeping fat are not innocent by standers but actively contribute to the intestinal and systemic inflammatory responses in patients with IBD. More specifically, we will review evidence showing that adipose tissue in IBD is associated with major alterations in the secretion of cytokines and adipokines involved in inflammatory process, in adipose tissue mesenchymal stem cells and adipogenesis, and in the interaction between adipose tissue and other intestinal components (immune, lymphatic, neuroendocrine, and intestinal epithelial systems). Collectively, these studies underline the importance of adipose tissue for the identification of novel therapeutic approaches for IBD.
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Tardif N, Salles J, Guillet C, Tordjman J, Reggio S, Landrier J, Giraudet C, Patrac V, Bertrand‐Michel J, Migne C, Collin M, Chardigny J, Boirie Y, Walrand S. Muscle ectopic fat deposition contributes to anabolic resistance in obese sarcopenic old rats through eIF2α activation. Aging Cell 2014; 13:1001-11. [PMID: 25139155 PMCID: PMC4326920 DOI: 10.1111/acel.12263] [Citation(s) in RCA: 132] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/19/2014] [Indexed: 12/25/2022] Open
Abstract
Obesity and aging are characterized by decreased insulin sensitivity (IS) and muscle protein synthesis. Intramuscular ceramide accumulation has been implicated in insulin resistance during obesity. We aimed to measure IS, muscle ceramide level, protein synthesis, and activation of intracellular signaling pathways involved in translation initiation in male Wistar young (YR, 6-month) and old (OR, 25-month) rats receiving a low- (LFD) or a high-fat diet (HFD) for 10 weeks. A corresponding cellular approach using C2C12 myotubes treated with palmitate to induce intracellular ceramide deposition was taken. A decreased ability of adipose tissue to store lipids together with a reduced adipocyte diameter and a development of fibrosis were observed in OR after the HFD. Consequently, OR fed the HFD were insulin resistant, showed a strong increase in intramuscular ceramide level and a decrease in muscle protein synthesis associated with increased eIF2α phosphorylation. The accumulation of intramuscular lipids placed a lipid burden on mitochondria and created a disconnect between metabolic and regulating pathways in skeletal muscles of OR. In C2C12 cells, palmitate-induced ceramide accumulation was associated with a decreased protein synthesis together with upregulated eIF2α phosphorylation. In conclusion, a reduced ability to expand adipose tissues was found in OR, reflecting a lower lipid buffering capacity. Muscle mitochondrial activity was affected in OR conferring a reduced ability to oxidize fatty acids entering the muscle cell. Hence, OR were more prone to ectopic muscle lipid accumulation than YR, leading to decreased muscle protein anabolism. This metabolic change is a potential therapeutic target to counter sarcopenic obesity.
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Affiliation(s)
- Nicolas Tardif
- Clermont Université Université d'Auvergne Unité de Nutrition Humaine BP 10448Clermont‐Ferrand F‐63000France
- INRA UMR 1019 UNH CRNH Auvergne Clermont‐Ferrand F‐63000 France
| | - Jérôme Salles
- Clermont Université Université d'Auvergne Unité de Nutrition Humaine BP 10448Clermont‐Ferrand F‐63000France
- INRA UMR 1019 UNH CRNH Auvergne Clermont‐Ferrand F‐63000 France
| | - Christelle Guillet
- Clermont Université Université d'Auvergne Unité de Nutrition Humaine BP 10448Clermont‐Ferrand F‐63000France
- INRA UMR 1019 UNH CRNH Auvergne Clermont‐Ferrand F‐63000 France
| | - Joan Tordjman
- UPMC Inserm U872 Equipe 7 Centre de Recherche des Cordeliers Paris F‐75006France
| | - Sophie Reggio
- UPMC Inserm U872 Equipe 7 Centre de Recherche des Cordeliers Paris F‐75006France
| | | | - Christophe Giraudet
- Clermont Université Université d'Auvergne Unité de Nutrition Humaine BP 10448Clermont‐Ferrand F‐63000France
- INRA UMR 1019 UNH CRNH Auvergne Clermont‐Ferrand F‐63000 France
| | - Véronique Patrac
- Clermont Université Université d'Auvergne Unité de Nutrition Humaine BP 10448Clermont‐Ferrand F‐63000France
- INRA UMR 1019 UNH CRNH Auvergne Clermont‐Ferrand F‐63000 France
| | | | - Carole Migne
- Clermont Université Université d'Auvergne Unité de Nutrition Humaine BP 10448Clermont‐Ferrand F‐63000France
- INRA UMR 1019 UNH CRNH Auvergne Clermont‐Ferrand F‐63000 France
| | - Marie‐Laure Collin
- Clermont Université Université d'Auvergne Unité de Nutrition Humaine BP 10448Clermont‐Ferrand F‐63000France
- INRA UMR 1019 UNH CRNH Auvergne Clermont‐Ferrand F‐63000 France
| | - Jean‐Michel Chardigny
- Clermont Université Université d'Auvergne Unité de Nutrition Humaine BP 10448Clermont‐Ferrand F‐63000France
- INRA UMR 1019 UNH CRNH Auvergne Clermont‐Ferrand F‐63000 France
| | - Yves Boirie
- Clermont Université Université d'Auvergne Unité de Nutrition Humaine BP 10448Clermont‐Ferrand F‐63000France
- INRA UMR 1019 UNH CRNH Auvergne Clermont‐Ferrand F‐63000 France
- CHU Clermont‐Ferrand Service de Nutrition Clinique Clermont‐Ferrand F‐63003France
| | - Stéphane Walrand
- Clermont Université Université d'Auvergne Unité de Nutrition Humaine BP 10448Clermont‐Ferrand F‐63000France
- INRA UMR 1019 UNH CRNH Auvergne Clermont‐Ferrand F‐63000 France
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Steinhoff MS, von Mentzer B, Geppetti P, Pothoulakis C, Bunnett NW. Tachykinins and their receptors: contributions to physiological control and the mechanisms of disease. Physiol Rev 2014; 94:265-301. [PMID: 24382888 DOI: 10.1152/physrev.00031.2013] [Citation(s) in RCA: 457] [Impact Index Per Article: 41.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
The tachykinins, exemplified by substance P, are one of the most intensively studied neuropeptide families. They comprise a series of structurally related peptides that derive from alternate processing of three Tac genes and are expressed throughout the nervous and immune systems. Tachykinins interact with three neurokinin G protein-coupled receptors. The signaling, trafficking, and regulation of neurokinin receptors have also been topics of intense study. Tachykinins participate in important physiological processes in the nervous, immune, gastrointestinal, respiratory, urogenital, and dermal systems, including inflammation, nociception, smooth muscle contractility, epithelial secretion, and proliferation. They contribute to multiple diseases processes, including acute and chronic inflammation and pain, fibrosis, affective and addictive disorders, functional disorders of the intestine and urinary bladder, infection, and cancer. Neurokinin receptor antagonists are selective, potent, and show efficacy in models of disease. In clinical trials there is a singular success: neurokinin 1 receptor antagonists to treat nausea and vomiting. New information about the involvement of tachykinins in infection, fibrosis, and pruritus justifies further trials. A deeper understanding of disease mechanisms is required for the development of more predictive experimental models, and for the design and interpretation of clinical trials. Knowledge of neurokinin receptor structure, and the development of targeting strategies to disrupt disease-relevant subcellular signaling of neurokinin receptors, may refine the next generation of neurokinin receptor antagonists.
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Kruis T, Batra A, Siegmund B. Bacterial translocation - impact on the adipocyte compartment. Front Immunol 2014; 4:510. [PMID: 24432024 PMCID: PMC3881001 DOI: 10.3389/fimmu.2013.00510] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Accepted: 12/24/2013] [Indexed: 12/29/2022] Open
Abstract
Over the last decade it became broadly recognized that adipokines and thus the fat tissue compartment exert a regulatory function on the immune system. Our own group described the pro-inflammatory function of the adipokine leptin within intestinal inflammation in a variety of animal models. Following-up on this initial work, the aim was to reveal stimuli and mechanisms involved in the activation of the fat tissue compartment and the subsequent release of adipokines and other mediators paralleled by the infiltration of immune cells. This review will summarize the current literature on the possible role of the mesenteric fat tissue in intestinal inflammation with a focus on Crohn’s disease (CD). CD is of particular interest in this context since the transmural intestinal inflammation has been associated with a characteristic hypertrophy of the mesenteric fat, a phenomenon called “creeping fat.” The review will address three consecutive questions: (i) What is inducing adipocyte activation, (ii) which factors are released after activation and what are the consequences for the local fat tissue compartment and infiltrating cells; (iii) do the answers generated before allow for an explanation of the role of the mesenteric fat tissue within intestinal inflammation? With this review we will provide a working model indicating a close interaction in between bacterial translocation, activation of the adipocytes, and subsequent direction of the infiltrating immune cells. In summary, the models system mesenteric fat indicates a unique way how adipocytes can directly interact with the immune system.
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Affiliation(s)
- Tassilo Kruis
- Department of Medicine I (Gastroenterology, Rheumatology, Infectious Diseases), Charité - Universitätsmedizin Berlin , Berlin , Germany
| | - Arvind Batra
- Department of Medicine I (Gastroenterology, Rheumatology, Infectious Diseases), Charité - Universitätsmedizin Berlin , Berlin , Germany
| | - Britta Siegmund
- Department of Medicine I (Gastroenterology, Rheumatology, Infectious Diseases), Charité - Universitätsmedizin Berlin , Berlin , Germany
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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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Mustain WC, Starr ME, Valentino JD, Cohen DA, Okamura D, Wang C, Evers BM, Saito H. Inflammatory cytokine gene expression in mesenteric adipose tissue during acute experimental colitis. PLoS One 2013; 8:e83693. [PMID: 24386254 PMCID: PMC3873328 DOI: 10.1371/journal.pone.0083693] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Accepted: 11/15/2013] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Production of inflammatory cytokines by mesenteric adipose tissue (MAT) has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Animal models of colitis have demonstrated inflammatory changes within MAT, but it is unclear if these changes occur in isolation or as part of a systemic adipose tissue response. It is also unknown what cell types are responsible for cytokine production within MAT. The present study was designed to determine whether cytokine production by MAT during experimental colitis is depot-specific, and also to identify the source of cytokine production within MAT. METHODS Experimental colitis was induced in 6-month-old C57BL/6 mice by administration of dextran sulfate sodium (2% in drinking water) for up to 5 days. The induction of cytokine mRNA within various adipose tissues, including mesenteric, epididymal, and subcutaneous, was analyzed by qRT-PCR. These adipose tissues were also examined for histological evidence of inflammation. The level of cytokine mRNA during acute colitis was compared between mature mesenteric adipocytes, mesenteric stromal vascular fraction (SVF), and mesenteric lymph nodes. RESULTS During acute colitis, MAT exhibited an increased presence of infiltrating mononuclear cells and fibrotic structures, as well as decreased adipocyte size. The mRNA levels of TNF-α, IL-1β, and IL-6 were significantly increased in MAT but not other adipose tissue depots. Within the MAT, induction of these cytokines was observed mainly in the SVF. CONCLUSIONS Acute experimental colitis causes a strong site-specific inflammatory response within MAT, which is mediated by cells of the SVF, rather than mature adipocytes or mesenteric lymph nodes.
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Affiliation(s)
- W. Conan Mustain
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky, United States of America
- Department of Surgery, University of Kentucky, Lexington, Kentucky, United States of America
| | - Marlene E. Starr
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky, United States of America
- Department of Surgery, University of Kentucky, Lexington, Kentucky, United States of America
| | - Joseph D. Valentino
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky, United States of America
- Department of Surgery, University of Kentucky, Lexington, Kentucky, United States of America
| | - Donald A. Cohen
- Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, Kentucky, United States of America
| | - Daiki Okamura
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky, United States of America
- Department of Surgery, University of Kentucky, Lexington, Kentucky, United States of America
| | - Chi Wang
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky, United States of America
- Department of Biostatistics, University of Kentucky, Lexington, Kentucky, United States of America
| | - B. Mark Evers
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky, United States of America
- Department of Surgery, University of Kentucky, Lexington, Kentucky, United States of America
| | - Hiroshi Saito
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky, United States of America
- Department of Surgery, University of Kentucky, Lexington, Kentucky, United States of America
- Department of Physiology, University of Kentucky, Lexington, Kentucky, United States of America
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Yang Y, Yan M, Zhang H, Wang X. Substance P participates in immune-mediated hepatic injury induced by concanavalin A in mice and stimulates cytokine synthesis in Kupffer cells. Exp Ther Med 2013; 6:459-464. [PMID: 24137208 PMCID: PMC3786810 DOI: 10.3892/etm.2013.1152] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2013] [Accepted: 05/17/2013] [Indexed: 12/14/2022] Open
Abstract
Studies have indicated that the immune system plays a pivotal role in hepatitis. Substance P (SP) has been shown to modulate the immune response. In order to investigate the role of SP in liver injury and to determine whether it leads to pro-inflammatory signaling, we established a mouse model of hepatic injury induced by concanavalin A (ConA). We also exposed mouse Kupffer cells (KCs) to SP in vitro. Cytokine and SP levels in liver homogenates were detected using enzyme-linked immunosorbent assay (ELISA) and the protective effects of L-703,606 were evaluated through serological and histological assessments. Neurokinin-1 receptor (NK-1R) expression was evaluated by immunofluorescence and quantitative polymerase chain reaction (PCR). The levels of SP, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were significantly increased in the ConA-treated mice and the levels of ALT and AST were markedly reduced by L-703,606-pretreatment. Liver injury was significantly reduced by treatment with L-703,606. The mouse KCs expressed NK-1R and SP increased NK-1R mRNA expression. Furthermore, NK-1R blockade eliminated the effect of SP on NK-1R mRNA expression. The cytokine levels exhibited a substantial increase in the SP-pretreated KCs compared with the KCs that were cultured in control medium. The inter-leukin (IL)-6 and tumor necrosis factor (TNF)-α levels in the L-703,606-pretreated KCs were significantly lower compared with those in the SP-pretreated KCs. Our study suggests that neurogenic inflammation induced by SP plays an important role in hepatitis. Mouse KCs express NK-1R and SP increases NK-1R mRNA expression. SP enhances IL-6 and TNF-α secretion and an NK-1R antagonist inhibits this secretion.
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Affiliation(s)
- Yan Yang
- Health Examination Center, Qilu Hospital of Shandong University, Jinan, Shandong 250012
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Tchkonia T, Thomou T, Zhu Y, Karagiannides I, Pothoulakis C, Jensen MD, Kirkland JL. Mechanisms and metabolic implications of regional differences among fat depots. Cell Metab 2013; 17:644-656. [PMID: 23583168 PMCID: PMC3942783 DOI: 10.1016/j.cmet.2013.03.008] [Citation(s) in RCA: 495] [Impact Index Per Article: 41.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Fat distribution is closely linked to metabolic disease risk. Distribution varies with sex, genetic background, disease state, certain drugs and hormones, development, and aging. Preadipocyte replication and differentiation, developmental gene expression, susceptibility to apoptosis and cellular senescence, vascularity, inflammatory cell infiltration, and adipokine secretion vary among depots, as do fatty-acid handling and mechanisms of enlargement with positive-energy and loss with negative-energy balance. How interdepot differences in these molecular, cellular, and pathophysiological properties are related is incompletely understood. Whether fat redistribution causes metabolic disease or whether it is a marker of underlying processes that are primarily responsible is an open question.
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Affiliation(s)
| | - Thomas Thomou
- Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
| | - Yi Zhu
- Robert and Arlene Kogod Center on Aging
| | - Iordanes Karagiannides
- Inflammatory Bowel Disease Center, Division of Digestive Diseases, Department of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA
| | - Charalabos Pothoulakis
- Inflammatory Bowel Disease Center, Division of Digestive Diseases, Department of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA
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Kanauchi O, Mitsuyama K, Andoh A. The new prophylactic strategy for colon cancer in inflammatory bowel disease by modulating microbiota. Scand J Gastroenterol 2013; 48:387-400. [PMID: 23249220 DOI: 10.3109/00365521.2012.741617] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
It is well understood that intestinal microbiota play an important role in the pathogenesis of inflammatory bowel disease (IBD). In addition, IBD patients are well known to have a higher risk of developing colon cancer due to chronic inflammation. Recent evidence suggests that manipulation of microbiota improves the clinical outcome of patients with IBD and may reduce onset of colon cancer without obvious toxicity. This review summarizes the current experimental and clinical knowledge about the role of intestinal microbiota in IBD and colon cancer, and the nutraceutical therapy for colon cancer.
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Affiliation(s)
- Osamu Kanauchi
- Strategic Research and Development Department Kirin Holdings Co., Ltd., Chuo-ku, Tokyo, Japan. kanauchio@kirin,co.jp
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Miegueu P, St-Pierre DH, Lapointe M, Poursharifi P, Lu H, Gupta A, Cianflone K. Substance P decreases fat storage and increases adipocytokine production in 3T3-L1 adipocytes. Am J Physiol Gastrointest Liver Physiol 2013; 304:G420-G427. [PMID: 23257919 DOI: 10.1152/ajpgi.00162.2012] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Obesity, inflammation, and insulin resistance are closely linked. Substance P (SP), via its neurokinin 1 receptor (NK1R), mediates inflammatory and, possibly, neuroendocrine processes. We examined SP effects on lipid storage and cytokine production in 3T3-L1 adipocytes and adipose tissues. 3T3-L1 adipocytes and preadipocytes express NK1R, and 8 days of SP supplementation during differentiation to 3T3-L1 preadipocytes decreased lipid droplet accumulation. SP (10 nM, 24 h) increased lipolysis in primary adipocytes (138 ± 7%, P < 0.05) and reduced fatty acid uptake (-31 ± 7%, P < 0.05) and mRNA expression of the differentiation-related transcription factors peroxisome proliferator-activated receptor-γ type 2 (-64 ± 2%, P < 0.001) and CCAAT enhancer-binding protein (CEBP)-α (-65 ± 2%, P < 0.001) and the lipid storage genes fatty acid-binding protein type 4 (-59 ± 2%, P < 0.001) and diacylglycerol O-acyltransferase-1 (-45 ± 2%, P < 0.01) in 3T3-L1 adipocytes, while CD36, a fatty acid transporter (+82 ± 19%, P < 0.01), was augmented. SP increased secretion of complement C3 (148 ± 15%, P < 0.04), monocyte chemoattractant protein-1 (156 ± 16%, P < 0.03), and keratinocyte-derived chemokine (148 ± 18%, P = 0.045) in 3T3-L1 adipocytes and monocyte chemoattractant protein-1 (496 ± 142%, P < 0.02) and complement C3 (152 ± 25%, P < 0.04) in adipose tissue and primary adipocytes, respectively. These SP effects were accompanied by downregulation of insulin receptor substrate 1 (-82 ± 2%, P < 0.01) and GLUT4 (-76 ± 2%, P < 0.01) mRNA expression, and SP acutely blocked insulin-mediated stimulation of fatty acid uptake and Akt phosphorylation. Although adiponectin secretion was unchanged, mRNA expression was decreased (-86 ± 8%, P < 0.001). In humans, NK1R expression correlates positively with plasma insulin, fatty acid, and complement C3 and negatively with adiponectin, CEBPα, CEBPβ, and peroxisome proliferator-activated receptor-γ mRNA expression in omental, but not subcutaneous, adipose tissue. Our results suggest that, beyond its neuroendocrine and inflammatory effects, SP could also be involved in targeting adipose tissue and influencing insulin resistance.
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Affiliation(s)
- Pierre Miegueu
- Centre de Recherche Institut Universitaire de Cardiologie and Pneumologie de Quebec and Department of Medicine, Université Laval, Quebec, Quebec, Canada
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Ramalho R, Almeida J, Beltrão M, Pirraco A, Costa R, Sokhatska O, Guardão L, Palmares C, Guimarães JT, Delgado L, Moreira A, Soares R. Substance P antagonist improves both obesity and asthma in a mouse model. Allergy 2013; 68:48-54. [PMID: 23176443 DOI: 10.1111/all.12052] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/20/2012] [Indexed: 11/30/2022]
Abstract
BACKGROUND Evidence suggests a causal relationship between obesity and asthma; however, the underlying mechanisms remain unknown. Substance P (SP), involved in neurogenic inflammation by acting through its receptor NK1-R, seems to participate in obese-asthma phenotype in mice. OBJECTIVES To evaluate the effect of a selective substance P receptor antagonist on a mouse model of diet-induced obesity and asthma. METHODS Diet-induced obese Balb/c mice were sensitized and challenged with ovalbumin (OVA) and treated with a selective NK1-R antagonist or placebo. Serum glucose, insulin, IL-6, resistin, and OVA-specific IgE levels were quantified. A score for peribronchial inflammation in lung histology was used. Cells were counted in bronchoalveolar lavage fluid. Adipocyte sizes were measured. RESULTS Ovalbumin-obese mice treated with NK1-R antagonist had lower weight (P = 0.0002), reduced daily food intake (P = 0.0021), reduced daily energy intake (P = 0.0021), reduced surface adipocyte areas (P < 0.0001), lower serum glucose (P = 0.04), lower serum insulin (P = 0.03), lower serum IL-(P = 0.0022), lower serum resistin (P = 0.0043), lower serum OVA-specific IgE (P = 0.035), and lower peribronchial inflammation score (P < 0.0001) than nontreated OVA-obese mice. We observed an interaction between obesity, allergen sensitization, and treatment with NK1-R antagonist for metabolic and systemic biomarkers, and for allergen sensitization and bronchial inflammation, showing a synergy between these variables. CONCLUSION & CLINICAL RELEVANCE In an experimental model of obesity and asthma in mice, NK1-R blockade improved metabolic and systemic biomarkers, as well as allergen sensitization and bronchial inflammation. These positive effects support a common pathway in the obese-asthma phenotype and highlight SP as a target with potential clinical interest in the obese-asthma epidemics.
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Affiliation(s)
- R. Ramalho
- Immunology; Faculty of Medicine; University of Porto; Porto; Portugal
| | - J. Almeida
- Ciências Químicas e das Biomoléculas; Escola Superior de Tecnologia da Saúde do Porto; Instituto Politécnico do Porto; Porto; Portugal
| | - M. Beltrão
- Immunology; Faculty of Medicine; University of Porto; Porto; Portugal
| | - A. Pirraco
- Biochemistry (U38-FCT); Faculty of Medicine; University of Porto; Porto; Portugal
| | - R. Costa
- Biochemistry (U38-FCT); Faculty of Medicine; University of Porto; Porto; Portugal
| | - O. Sokhatska
- Immunology; Faculty of Medicine; University of Porto; Porto; Portugal
| | - L. Guardão
- Animal House Unit; Faculty of Medicine; University of Porto; Porto; Portugal
| | - C. Palmares
- Immunology; Faculty of Medicine; University of Porto; Porto; Portugal
| | | | | | | | - R. Soares
- Biochemistry (U38-FCT); Faculty of Medicine; University of Porto; Porto; Portugal
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Ortuño Sahagún D, Márquez-Aguirre AL, Quintero-Fabián S, López-Roa RI, Rojas-Mayorquín AE. Modulation of PPAR-γ by Nutraceutics as Complementary Treatment for Obesity-Related Disorders and Inflammatory Diseases. PPAR Res 2012; 2012:318613. [PMID: 23251142 PMCID: PMC3515933 DOI: 10.1155/2012/318613] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2012] [Revised: 10/03/2012] [Accepted: 10/23/2012] [Indexed: 12/16/2022] Open
Abstract
A direct correlation between adequate nutrition and health is a universally accepted truth. The Western lifestyle, with a high intake of simple sugars, saturated fat, and physical inactivity, promotes pathologic conditions. The main adverse consequences range from cardiovascular disease, type 2 diabetes, and metabolic syndrome to several cancers. Dietary components influence tissue homeostasis in multiple ways and many different functional foods have been associated with various health benefits when consumed. Natural products are an important and promising source for drug discovery. Many anti-inflammatory natural products activate peroxisome proliferator-activated receptors (PPAR); therefore, compounds that activate or modulate PPAR-gamma (PPAR-γ) may help to fight all of these pathological conditions. Consequently, the discovery and optimization of novel PPAR-γ agonists and modulators that would display reduced side effects is of great interest. In this paper, we present some of the main naturally derived products studied that exert an influence on metabolism through the activation or modulation of PPAR-γ, and we also present PPAR-γ-related diseases that can be complementarily treated with nutraceutics from functional foods.
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Affiliation(s)
- D. Ortuño Sahagún
- Laboratorio de Desarrollo y Regeneración Neural, Instituto de Neurobiología, Departamento de Biología Celular y Molecular, CUCBA, Universidad de Guadalajara, camino Ing. R. Padilla Sánchez 2100, Las Agujas, 44600 Zapopan JAL, Mexico
| | - A. L. Márquez-Aguirre
- Unidad de Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco A.C., 44270 Guadalajara, JAL, Mexico
| | - S. Quintero-Fabián
- Laboratorio de Desarrollo y Regeneración Neural, Instituto de Neurobiología, Departamento de Biología Celular y Molecular, CUCBA, Universidad de Guadalajara, camino Ing. R. Padilla Sánchez 2100, Las Agujas, 44600 Zapopan JAL, Mexico
- Departamento de Farmacobiología, CUCEI, Universidad de Guadalajara, Boulevard Marcelino García Barragán, 44430 Tlaquepaque, JAL, Mexico
| | - R. I. López-Roa
- Departamento de Farmacobiología, CUCEI, Universidad de Guadalajara, Boulevard Marcelino García Barragán, 44430 Tlaquepaque, JAL, Mexico
| | - A. E. Rojas-Mayorquín
- Departamento de Ciencias Ambientales, Instituto de Neurociencias, CUCBA, Universidad de Guadalajara, 45100, JAL, Mexico
- Departamento de Investigación Básica, Instituto Nacional de Geriatría (INGER), Periférico Sur No. 2767, Col, San Jerónimo Lídice, Delegación Magdalena Contreras 10200, México DF, Mexico
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Fink C, Karagiannides I, Bakirtzi K, Pothoulakis C. Adipose tissue and inflammatory bowel disease pathogenesis. Inflamm Bowel Dis 2012; 18:1550-7. [PMID: 22407798 PMCID: PMC3374883 DOI: 10.1002/ibd.22893] [Citation(s) in RCA: 102] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2011] [Accepted: 01/04/2012] [Indexed: 12/17/2022]
Abstract
Creeping fat has long been recognized as an indicator of Crohn's disease (CD) activity. Although most patients with CD have normal or low body mass index (BMI), the ratio of intraabdominal fat to total abdominal fat is far greater than that of controls. The obesity epidemic has instructed us on the inflammatory nature of hypertrophic adipose tissue and similarities between mesenteric depots in obese and CD patients can be drawn. However, several important physiological differences exist between these two depots as well. While the molecular basis of the crosstalk between mesenteric adipose and the inflamed intestine in CD is largely unknown, novel evidence implicates neuropeptides along with adipocyte-derived paracrine mediators (adipokines) as potential targets for future investigations and highlight adipose tissue physiology as a potential important determinant in the course of IBD.
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Affiliation(s)
- Christopher Fink
- Inflammatory Bowel Disease Center, Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles
,Division of Pediatric Gastroenterology, Department of Pediatrics David Geffen School of Medicine, University of California at Los Angeles
| | - Iordanes Karagiannides
- Inflammatory Bowel Disease Center, Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles
| | - Kyriaki Bakirtzi
- Inflammatory Bowel Disease Center, Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles
| | - Charalabos Pothoulakis
- Inflammatory Bowel Disease Center, Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles
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40
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41
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Chang L, Adeyemo M, Karagiannides I, Videlock EJ, Bowe C, Shih W, Presson AP, Yuan PQ, Cortina G, Gong H, Singh S, Licudine A, Mayer M, Tache Y, Pothoulakis C, Mayer EA, Mayer EA. Serum and colonic mucosal immune markers in irritable bowel syndrome. Am J Gastroenterol 2012; 107:262-72. [PMID: 22158028 PMCID: PMC3297737 DOI: 10.1038/ajg.2011.423] [Citation(s) in RCA: 122] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Low-grade colonic mucosal inflammation has been postulated to have an important role in the pathophysiology of irritable bowel syndrome (IBS). The objectives of this study were (i) to identify serum and tissue-based immunological and neuroendocrine markers associated with mucosal inflammation in male (M) and female (F) patients with non-post-infectious IBS (non-PI-IBS) compared with healthy controls and (ii) to assess possible correlations of such markers with IBS symptoms. METHODS Sigmoid mucosal biopsies were obtained from 45 Rome II positive IBS patients without a history of PI-IBS (26 F, 35.5% IBS-C, 33.3% IBS-D, 31.1% IBS-A/M) and 41 healthy controls (22 F) in order to measure immunological markers (serum cytokine levels, colonic mucosal mRNA levels of cytokines, mucosal immune cell counts) and neuroendocrine markers associated with mucosal inflammation (corticotropin releasing factor- and neurokinin (NK)-related ligands and receptors, enterochromaffin cells). Symptoms were measured using validated questionnaires. RESULTS Of all the serum and mucosal cytokines measured, only interleukin-10 (IL-10) mRNA expression showed a group difference, with female, but not male, patients showing lower levels compared with female controls (18.0±2.9 vs. 29.5±4.0, P=0.006). Mucosal mRNA expression of NK-1 receptor was significantly lower (1.15±0.19 vs. 2.66±0.56, P=0.008) in female, but not male, patients compared with healthy controls. No other significant differences were observed. CONCLUSIONS Immune cell counts and levels of cytokines and neuropeptides that are associated with inflammation were not significantly elevated in the colonic mucosa of non-PI-IBS patients, and did not correlate with symptoms. Thus, these findings do not support that colonic mucosal inflammation consistently has a primary role in these patients. However, the finding of decreased IL-10 mRNA expression may be a possible biomarker of IBS and warrants further investigation.
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Affiliation(s)
- Lin Chang
- Center for Neurobiology of Stress, University of California, Los Angeles, California, USA,Department of Medicine, University of California, Los Angeles, California, USA
| | - Mopelola Adeyemo
- Center for Neurobiology of Stress, University of California, Los Angeles, California, USA,Department of Medicine, University of California, Los Angeles, California, USA
| | - Iordanis Karagiannides
- Department of Medicine, University of California, Los Angeles, California, USA,Inflammatory Bowel Disease Center, Department of Medicine, University of California, Los Angeles, California, USA
| | - Elizabeth J. Videlock
- Center for Neurobiology of Stress, University of California, Los Angeles, California, USA,Department of Medicine, University of California, Los Angeles, California, USA
| | - Collin Bowe
- Department of Medicine, University of California, Los Angeles, California, USA,Inflammatory Bowel Disease Center, Department of Medicine, University of California, Los Angeles, California, USA
| | - Wendy Shih
- Department of Biostatistics, University of California, Los Angeles, California, USA
| | - Angela P. Presson
- Department of Biostatistics, University of California, Los Angeles, California, USA
| | - Pu-Qing Yuan
- Center for Neurobiology of Stress, University of California, Los Angeles, California, USA,Inflammatory Bowel Disease Center, Department of Medicine, University of California, Los Angeles, California, USA,VA GLA Healthcare System, Los Angeles, California, USA
| | - Galen Cortina
- Department of Pathology, University of California, Los Angeles, California, USA
| | - Hua Gong
- Prometheus Laboratories, San Diego, California, USA
| | - Sharat Singh
- Prometheus Laboratories, San Diego, California, USA
| | - Arlene Licudine
- Center for Neurobiology of Stress, University of California, Los Angeles, California, USA,Department of Medicine, University of California, Los Angeles, California, USA
| | - Minou Mayer
- Center for Neurobiology of Stress, University of California, Los Angeles, California, USA,Department of Medicine, University of California, Los Angeles, California, USA
| | - Yvette Tache
- Center for Neurobiology of Stress, University of California, Los Angeles, California, USA,Inflammatory Bowel Disease Center, Department of Medicine, University of California, Los Angeles, California, USA,VA GLA Healthcare System, Los Angeles, California, USA
| | - Charalabos Pothoulakis
- Department of Medicine, University of California, Los Angeles, California, USA,Inflammatory Bowel Disease Center, Department of Medicine, University of California, Los Angeles, California, USA
| | - Emeran A. Mayer
- Center for Neurobiology of Stress, University of California, Los Angeles, California, USA,Department of Medicine, University of California, Los Angeles, California, USA,Department of Physiology, University of California, Los Angeles, California, USA,Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, California, USA,Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, California, USA
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Karagiannides I, Bakirtzi K, Kokkotou E, Stavrakis D, Margolis KG, Thomou T, Giorgadze N, Kirkland JL, Pothoulakis C. Role of substance P in the regulation of glucose metabolism via insulin signaling-associated pathways. Endocrinology 2011; 152:4571-80. [PMID: 22009727 PMCID: PMC3230056 DOI: 10.1210/en.2011-1170] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Substance P (SP), encoded by the tachykinin 1 (Tac1) gene, is the most potent tachykinin ligand for the high-affinity neurokinin-1 receptor (NK-1R). We previously reported that NK-1R-deficient mice show less weight gain and reduced circulating levels of leptin and insulin in response to a high-fat diet (HFD) and demonstrated the presence of functional NK-1R in isolated human preadipocytes. Here we assessed the effects of SP on weight gain in response to HFD and determined glucose metabolism in Tac1-deficient (Tac1(-/-)) mice. The effect of SP on the expression of molecules that may predispose to reduced glucose uptake was also determined in isolated human mesenteric, omental, and sc preadipocytes. We show that although weight accumulation in response to HFD was similar between Tac1(-/-) mice and wild-type littermates, Tac1(-/-) mice demonstrated lower glucose and leptin and increased adiponectin blood levels and showed improved responses to insulin challenge after HFD. SP stimulated phosphorylation of c-Jun N-terminal kinase, protein kinase C, mammalian target of rapamycin, and inhibitory serine insulin receptor substrate-1 phosphorylation in human preadipocytes in vitro. Preincubation of human mesenteric preadipocytes with the protein kinase C pseudosubstrate inhibitor reduced insulin receptor substrate 1 phosphorylation in response to SP. Lastly, SP also induced insulin receptor substrate-1 phosphorylation in mature human sc adipocytes. Our results demonstrate an important role for SP in adipose tissue responses and obesity-associated pathologies. These novel SP effects on molecules that enhance insulin resistance at the adipocyte level may reflect an important role for this peptide in the pathophysiology of type 2 diabetes.
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Affiliation(s)
- Iordanes Karagiannides
- Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, 675 Charles E. Young Drive, Los Angeles, CA 90095, USA
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Mencarelli A, Distrutti E, Renga B, D'Amore C, Cipriani S, Palladino G, Donini A, Ricci P, Fiorucci S. Probiotics modulate intestinal expression of nuclear receptor and provide counter-regulatory signals to inflammation-driven adipose tissue activation. PLoS One 2011; 6:e22978. [PMID: 21829567 PMCID: PMC3146529 DOI: 10.1371/journal.pone.0022978] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2011] [Accepted: 07/04/2011] [Indexed: 12/16/2022] Open
Abstract
Background Adipocytes from mesenteric white adipose tissue amplify the inflammatory response and participate in inflammation-driven immune dysfunction in Crohn's disease by releasing proinflammatory mediators. Peroxisome proliferator-activated receptors (PPAR)-α and -γ, pregnane x receptor (PXR), farnesoid x receptor (FXR) and liver x-receptor (LXR) are ligand-activated nuclear receptor that provide counter-regulatory signals to dysregulated immunity and modulates adipose tissue. Aims To investigate the expression and function of nuclear receptors in intestinal and adipose tissues in a rodent model of colitis and mesenteric fat from Crohn's patients and to investigate their modulation by probiotics. Methods Colitis was induced by TNBS administration. Mice were administered vehicle or VSL#3, daily for 10 days. Abdominal fat explants obtained at surgery from five Crohn's disease patients and five patients with colon cancer were cultured with VSL#3 medium. Results Probiotic administration attenuated development of signs and symptoms of colitis, reduced colonic expression of TNFα, IL-6 and IFNγ and reserved colonic downregulation of PPARγ, PXR and FXR caused by TNBS. Mesenteric fat depots isolated from TNBS-treated animals had increased expression of inflammatory mediators along with PPARγ, FXR, leptin and adiponectin. These changes were prevented by VSL#3. Creeping fat and mesenteric adipose tissue from Crohn's patients showed a differential expression of PPARγ and FXR with both tissue expressing high levels of leptin. Exposure of these tissues to VSL#3 medium abrogates leptin release. Conclusions Mesenteric adipose tissue from rodent colitis and Crohn's disease is metabolically active and shows inflammation-driven regulation of PPARγ, FXR and leptin. Probiotics correct the inflammation-driven metabolic dysfunction.
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Affiliation(s)
- Andrea Mencarelli
- Dipartimento di Medicina Clinica e Sperimentale, University of Perugia, Facoltà di Medicina e Chirurgia, Via Gerardo Dottori n° 1 S. Andrea delle Fratte, Perugia, Italy
| | - Eleonora Distrutti
- Azienda Ospedaliera di Perugia, Ospedale Santa Maria della Misericordia, S. Andrea delle Fratte, Perugia, Italy
| | - Barbara Renga
- Dipartimento di Medicina Clinica e Sperimentale, University of Perugia, Facoltà di Medicina e Chirurgia, Via Gerardo Dottori n° 1 S. Andrea delle Fratte, Perugia, Italy
| | - Claudio D'Amore
- Dipartimento di Medicina Clinica e Sperimentale, University of Perugia, Facoltà di Medicina e Chirurgia, Via Gerardo Dottori n° 1 S. Andrea delle Fratte, Perugia, Italy
| | - Sabrina Cipriani
- Dipartimento di Medicina Clinica e Sperimentale, University of Perugia, Facoltà di Medicina e Chirurgia, Via Gerardo Dottori n° 1 S. Andrea delle Fratte, Perugia, Italy
| | - Giuseppe Palladino
- Dipartimento di Medicina Clinica e Sperimentale, University of Perugia, Facoltà di Medicina e Chirurgia, Via Gerardo Dottori n° 1 S. Andrea delle Fratte, Perugia, Italy
| | - Annibale Donini
- Dipartimento di Scienze Chirurgiche, Radiologiche e Odontostomatologiche, Nuova Facoltà di Medicina e Chirurgia Sant' Andrea delle Fratte, Perugia, Italy
| | - Patrizia Ricci
- Dipartimento di Scienze Chirurgiche, Radiologiche e Odontostomatologiche, Nuova Facoltà di Medicina e Chirurgia Sant' Andrea delle Fratte, Perugia, Italy
| | - Stefano Fiorucci
- Dipartimento di Medicina Clinica e Sperimentale, University of Perugia, Facoltà di Medicina e Chirurgia, Via Gerardo Dottori n° 1 S. Andrea delle Fratte, Perugia, Italy
- * E-mail:
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Karagiannides I, Stavrakis D, Bakirtzi K, Kokkotou E, Pirtskhalava T, Nayeb-Hashemi H, Bowe C, Bugni JM, Nuño M, Lu B, Gerard NP, Leeman SE, Kirkland JL, Pothoulakis C. Substance P (SP)-neurokinin-1 receptor (NK-1R) alters adipose tissue responses to high-fat diet and insulin action. Endocrinology 2011; 152:2197-205. [PMID: 21467195 PMCID: PMC3100617 DOI: 10.1210/en.2010-1345] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Peripheral administration of a specific neurokinin-1 receptor (NK-1R) antagonist to mice leads to reduced weight gain and circulating levels of insulin and leptin after high-fat diet (HFD). Here, we assessed the contribution of substance P (SP) and NK-1R in diet-induced obesity using NK-1R deficient [knockout (KO)] mice and extended our previous findings to show the effects of SP-NK-1R interactions on adipose tissue-associated insulin signaling and glucose metabolic responses. NK-1R KO and wild-type (WT) littermates were fed a HFD for 3 wk, and obesity-associated responses were determined. Compared with WT, NK-1 KO mice show reduced weight gain and circulating levels of leptin and insulin in response to HFD. Adiponectin receptor mRNA levels are higher in mesenteric fat and liver in NK-1 KO animals compared with WT, after HFD. Mesenteric fat from NK-1R KO mice fed with HFD has reduced stress-activated protein kinase/c-Jun N-terminal kinase and protein kinase C activation compared with WT mice. After glucose challenge, NK-1R KO mice remove glucose from the circulation more efficiently than WT and pair-fed controls, suggesting an additional peripheral effect of NK-1R-mediated signaling on glucose metabolism. Glucose uptake experiments in isolated rat adipocytes showed that SP directly inhibits insulin-mediated glucose uptake. Our results further establish a role for SP-NK-1R interactions in adipose tissue responses, specifically as they relate to obesity-associated pathologies such as glucose intolerance and insulin resistance. Our results highlight this pathway as an important therapeutic approach for type 2 diabetes.
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Affiliation(s)
- Iordanes Karagiannides
- Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, South MacDonald Research Laboratories Building 1240, Los Angeles, California 90095-7019, USA.
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Mendall MA, Gunasekera AV, John BJ, Kumar D. Is obesity a risk factor for Crohn's disease? Dig Dis Sci 2011; 56:837-44. [PMID: 21221790 DOI: 10.1007/s10620-010-1541-6] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2009] [Accepted: 12/18/2010] [Indexed: 12/18/2022]
Abstract
BACKGROUND Obesity is associated with a proinflammatory state. AIM To determine whether obesity at diagnosis is a risk factor for Crohn's disease vs. ulcerative colitis and also vs. community controls and whether there is a U-shaped relationship between body mass index at diagnosis and risk of Crohn's disease versus ulcerative colitis. METHODS A total of 524 consecutive inflammatory bowel disease patients attending gastroenterology clinics were administered a questionnaire inquiring about weight at diagnosis and height as well as other risk factors for inflammatory bowel disease. An opportunistic control group of 480 community controls aged 50-70 were randomly selected from the registers of four local general practices as part of another study. RESULTS Obesity at diagnosis was more common in subjects with Crohn's disease versus ulcerative colitis odds ratio 2.02 (1.18-3.43) p = 0.0096 and also Crohn's disease versus community controls in the 50-70 year age group (odds ratio 3.22 (1.59-6.52) p = 0.001). There was evidence of a 'dose response' with increasing degrees of obesity associated with increased risk. Low BMI at diagnosis was also associated with risk of Crohn's disease versus ulcerative colitis. A U-shaped relationship between BMI and risk of Crohn's was supported by the strong inverse association of BMI at diagnosis (p = 0.0001) and positive association of BMI at diagnosis squared (p = 0.0002) when they were fitted together into the model. CONCLUSIONS Obesity may play a role in the pathogenesis of Crohn's disease and it may be that obesity-related enteropathy is a distinct entity or a sub-type of Crohn's disease.
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Olivier I, Théodorou V, Valet P, Castan-Laurell I, Guillou H, Bertrand-Michel J, Cartier C, Bezirard V, Ducroc R, Segain JP, Portier G, Kirzin S, Moreau J, Duffas JP, Ferrier L, Eutamène H. Is Crohn's creeping fat an adipose tissue? Inflamm Bowel Dis 2011; 17:747-57. [PMID: 20684014 DOI: 10.1002/ibd.21413] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND In human pathology, the "creeping fat" (CF) of the mesentery is unique to Crohn's disease (CD). CF is usually referred to as an ectopic extension of mesenteric adipose tissue (MAT). However, since no animal model developing CF has ever been established, very little is known about this type of fat-depot expansion and its role in the development of the disease. METHODS We developed and standardized an experimental protocol in mice that reproducibly induces CF development when a severe colonic inflammation is obtained by intracolonic instillation of DNBS. RESULTS Macro-microscopic observations revealed a fatty appearance of CF. Yet when compared to MAT from the same animals, CF contains very little triglycerides, few adipocytes, and we observed a very low expression and protein levels of both adipose markers (hormone-sensitive lipase, perilipin) and adipocytokines (leptin, adiponectin). The decreased expression of perilipin in CF was also observed by immunohistochemistry. Conversely, the expression of proinflammatory and fibrous markers (Pref-1) was much higher in CF than in MAT. These observations were fully consistent with those made on CF recovered from five CD patients and compared with subcutaneous and mesenteric fat from the same patients. CONCLUSIONS Altogether, this work reports an original experimental mice model of CF. In this model we establish for the first time that CF only occurs in severe colonic inflammation and shows an inflammatory, fibrous but not an adipose pattern.
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Affiliation(s)
- Isabelle Olivier
- INRA, UMR 1054, Neuro-Gastroenterology & Nutrition Unit, Toulouse, France
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Tchkonia T, Morbeck DE, Von Zglinicki T, Van Deursen J, Lustgarten J, Scrable H, Khosla S, Jensen MD, Kirkland JL. Fat tissue, aging, and cellular senescence. Aging Cell 2010; 9:667-84. [PMID: 20701600 PMCID: PMC2941545 DOI: 10.1111/j.1474-9726.2010.00608.x] [Citation(s) in RCA: 790] [Impact Index Per Article: 52.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/26/2010] [Indexed: 12/13/2022] Open
Abstract
Fat tissue, frequently the largest organ in humans, is at the nexus of mechanisms involved in longevity and age-related metabolic dysfunction. Fat distribution and function change dramatically throughout life. Obesity is associated with accelerated onset of diseases common in old age, while fat ablation and certain mutations affecting fat increase life span. Fat cells turn over throughout the life span. Fat cell progenitors, preadipocytes, are abundant, closely related to macrophages, and dysdifferentiate in old age, switching into a pro-inflammatory, tissue-remodeling, senescent-like state. Other mesenchymal progenitors also can acquire a pro-inflammatory, adipocyte-like phenotype with aging. We propose a hypothetical model in which cellular stress and preadipocyte overutilization with aging induce cellular senescence, leading to impaired adipogenesis, failure to sequester lipotoxic fatty acids, inflammatory cytokine and chemokine generation, and innate and adaptive immune response activation. These pro-inflammatory processes may amplify each other and have systemic consequences. This model is consistent with recent concepts about cellular senescence as a stress-responsive, adaptive phenotype that develops through multiple stages, including major metabolic and secretory readjustments, which can spread from cell to cell and can occur at any point during life. Senescence could be an alternative cell fate that develops in response to injury or metabolic dysfunction and might occur in nondividing as well as dividing cells. Consistent with this, a senescent-like state can develop in preadipocytes and fat cells from young obese individuals. Senescent, pro-inflammatory cells in fat could have profound clinical consequences because of the large size of the fat organ and its central metabolic role.
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Affiliation(s)
- Tamara Tchkonia
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA
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Hegde A, Koh YH, Moochhala SM, Bhatia M. Neurokinin-1 receptor antagonist treatment in polymicrobial sepsis: molecular insights. Int J Inflam 2010; 2010:601098. [PMID: 21188216 PMCID: PMC3003979 DOI: 10.4061/2010/601098] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2010] [Revised: 06/25/2010] [Accepted: 08/04/2010] [Indexed: 01/04/2023] Open
Abstract
Neurokinin-1 receptor blocking has been shown to be beneficial against lung injury in polymicrobial sepsis. In this paper, we evaluated the possible mediators and the mechanism involved. Mice were subjected to cecal ligation and puncture (CLP-) induced sepsis or sham surgery. Vehicle or SR140333 [1 mg/kg; subcutaneous (s.c.)] was administered to septic mice either 30 min before or 1 h after the surgery. Lung tissue was collected 8 h after surgery and further analyzed. CLP alone caused a significant increase in the activation of the transcription factors, protein kinase C-α, extracellular signal regulated kinases, neurokinin receptors, and substance P levels in lung when compared to sham-operated mice. SR140333 injected pre- and post surgery significantly attenuated the activation of transcription factors and protein kinase C-α and the plasma levels of substance P compared to CLP-operated mice injected with the vehicle. In addition, GR159897 (0.12 mg/kg; s.c.), a neurokinin-2 receptor antagonist, failed to show beneficial effects. We conclude that substance P acting via neurokinin-1 receptor in sepsis initiated signaling cascade mediated mainly by protein kinase C-α, led to NF-κB and activator protein-1 activation, and further modulated proinflammatory mediators.
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Affiliation(s)
- Akhil Hegde
- Cardiovascular Biology Program, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, MD 11, No. 05-09, 10 Medical Drive, Singapore 117597
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Silva AFD, Schieferdecker MEM, Rocco CS, Amarante HMBDS. Relação entre estado nutricional e atividade inflamatória em pacientes com doença inflamatória intestinal. ABCD-ARQUIVOS BRASILEIROS DE CIRURGIA DIGESTIVA 2010. [DOI: 10.1590/s0102-67202010000300005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
RACIONAL: As doenças inflamatórias intestinais caracterizam-se por diversos sintomas que afetam o aparelho digestório e, consequentemente, podem interferir sobre o estado nutricional. OBJETIVO: Avaliar o estado nutricional de pacientes com doença inflamatória intestinal em diferentes estágios de atividade inflamatória. MÉTODOS: Foram avaliados 55 pacientes com doença inflamatória intestinal, por meio de dados antropométricos, com aferição de peso, altura, circunferência do braço e prega cutânea do tríceps e tiveram sua composição corporal determinada por impedância bioelétrica. Para determinação de atividade inflamatória da doença foram utilizados os níveis séricos de proteína C reativa e o índice de Harvey e Bradshaw. Para comparação de médias foi usado o teste t não pareado, e para as médias não paramétricas, o teste de Mann-Whitney, considerando nível de significância valor de p<0,05. RESULTADOS: Entre os pacientes avaliados, 28 apresentavam doença de Crohn e 27 retocolite ulcerativa inespecífica, com idade entre 19 e 63 anos e tempo de diagnóstico de 1 a 22 anos. Não houve diferença nas medidas antropométricas e na composição corporal dos pacientes cuja doença inflamatória estava em atividade ou em remissão. Os que usaram glicocorticóides nos seis meses anteriores à avaliação apresentaram percentual de gordura corporal de 23,4±8,2%, enquanto para os que não usaram o percentual foi de 30,7±11,3 (p<0,0199). Os sintomas gastrintestinais mais comuns foram distensão abdominal (41%), diarréia (18%), náusea (13%), obstipação (12%), inapetência (11%) e vômito (5%). Todos os sintomas foram mais frequentes nos pacientes com maior índice de massa corporal e de gordura corporal. CONCLUSÃO: Houve maior número de pacientes com excesso de peso e de gordura corporal, sendo que esses pacientes foram mais sintomáticos e apresentaram maiores valores de proteína C reativa.
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Abstract
PURPOSE OF REVIEW Increasing evidence indicates that adipose tissue is an active endocrine organ involved in metabolic syndrome and regulation of inflammation. Visceral fat accumulation is a hallmark of both obesity and Crohn's disease. Here, we present recent data describing the immune properties of intra-abdominal adipose tissue that could link the innate immune response to obesity-related disorders and gut inflammation. RECENT FINDINGS Innate immune properties of adipocytes have become well characterized since recent studies described the Toll-like receptor (TLR) expression repertoire and specific TLR ligand responses of adipocytes. Adipokine secretion profiles have also been elucidated both in obese patients, when they may be involved in obesity-associated metabolic disease, and in Crohn's disease. Whereas mesenteric fat hypertrophy and fat wrapping of the bowel are characteristic of Crohn's disease, there exists a paucity of information concerning this important pathophysiological aspect. Our current classical animal models are of limited interest when investigating the role of mesenteric fat in gut inflammation. Recent new alternative disease paradigms could help to design more specific models for elucidating chronic transmural inflammation of the gut. SUMMARY Obesity and Crohn's disease share common features with the development of mesenteric fat that may be involved in gut inflammation. Further studies are required to clearly assess the origin and influence of intestinal fat deposits upon gut inflammation, notably during Crohn's disease development.
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