|
1
|
Magen-Rimon R, Cohen M, Rosen I, Spector-Cohen I, Garah J, Weiss R, Shaoul R. Adipokine Profiles and Their Association with Body Composition and Disease Activity in Pediatric Crohn's Disease. Dig Dis Sci 2025:10.1007/s10620-025-08941-z. [PMID: 40299289 DOI: 10.1007/s10620-025-08941-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 02/18/2025] [Indexed: 04/30/2025]
Abstract
OBJECTIVES Emerging evidence implicates an important role for visceral fat, particularly "creeping fat," in the pathogeneses and progression of inflammatory bowel diseases (IBD), specifically Crohn's disease (CD). In this study, we aimed to explore the association between body composition, adipocytokine profiles, and disease activity in pediatric CD patients. METHODS We recruited patients with active and quiescent CD, aged 6-18, along with age matched healthy controls. Body composition was analyzed via bio-impedance analysis, and adipocytokines were assessed by ELISA-multiplex. RESULTS Patients with active CD exhibited significantly elevated levels of adiponectin and resistin compared to healthy controls and patients in remission even upon adjustment for body composition indices. Leptin correlated only with body composition and not with disease activity. Patients with active CD had relatively higher percentage of body fat and total body fat than the other groups. CONCLUSIONS This study underscores the complex interactions between adipocytokine profiles and disease activity in CD. Further studies are needed to investigate the potential mechanistic role of adiponectin and resistin in CD pathogenesis.
Collapse
Affiliation(s)
- Ramit Magen-Rimon
- Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel.
- Pediatric Gastroenterology & Nutrition Institute, Ruth Children's Hospital, Rambam Medical Center, Haifa, Israel.
| | - Michal Cohen
- Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel
- Pediatric Endocrinology Institute, Ruth Children's Hospital, Rambam Medical Center, Haifa, Israel
| | - Irit Rosen
- Pediatric Gastroenterology & Nutrition Institute, Ruth Children's Hospital, Rambam Medical Center, Haifa, Israel
| | - Inna Spector-Cohen
- Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel
- Pediatric Gastroenterology & Nutrition Institute, Ruth Children's Hospital, Rambam Medical Center, Haifa, Israel
| | - Jamal Garah
- Pediatric Gastroenterology & Nutrition Institute, Ruth Children's Hospital, Rambam Medical Center, Haifa, Israel
| | - Ram Weiss
- Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel
- Department of Pediatrics, Ruth Children's Hospital, Rambam Medical Center, Haifa, Israel
| | - Ron Shaoul
- Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel
- Pediatric Gastroenterology & Nutrition Institute, Ruth Children's Hospital, Rambam Medical Center, Haifa, Israel
| |
Collapse
|
|
2
|
Mori R, Ogino T, Murakami M, Kayama H, Okuzaki D, Ikeda A, Sekido Y, Hata T, Hamabe A, Takahashi H, Miyoshi N, Uemura M, Ikeuchi H, Takeda K, Mizushima T, Doki Y, Eguchi H. Group 1 innate lymphoid cells and inflammatory macrophages exacerbate fibrosis in creeping fat through IFN-γ secretion. J Gastroenterol 2025:10.1007/s00535-025-02243-x. [PMID: 40158049 DOI: 10.1007/s00535-025-02243-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 03/11/2025] [Indexed: 04/01/2025]
Abstract
BACKGROUND Creeping fat is a characteristic of Crohn's disease and impacts the disease course. We evaluated creeping fat formation, focusing on innate lymphoid cell-mediated fibrogenesis and its clinical significance. METHODS Patients with inflammatory lesions in the ileum (the most commonly affected area), who underwent surgical resection at Osaka University or Hyogo Medical University (n = 34), were included. The ileum and mesentery were obtained from three sites: the control, non-creeping fat part, and creeping fat part. The distribution and properties of the innate lymphoid cells were analyzed by cell isolation. Furthermore, the correlation between macrophages and their effects on adipose tissue and clinical course were also investigated in a prospective cohort study. RESULTS Group 1 innate lymphoid cells in creeping fat were increased, correlating with inflammatory macrophages in the mesentery and showing higher interferon-γ expression. Co-culture experiment involving stromal vascular fraction from the control mesentery and Group 1 innate lymphoid cells from creeping fat revealed increased mRNA expression of fibrosis-related genes and inflammatory markers of macrophages, although these changes were nullified by interferon-γ-neutralizing antibody. Next, we examined the clinical importance of Group 1 innate lymphoid cells and identified their high frequency in creeping fat as a risk factor for early recurrence (P = 0.008, odds ratio: 1.19). Furthermore, the higher Group 1 innate lymphoid cell frequency group (≥ 80%) had shorter relapse-free survival (P = 0.03). CONCLUSIONS Group 1 innate lymphoid cells and inflammatory macrophages contribute to creeping fat formation via interferon-γ secretion, affecting post-surgery intestinal outcomes.
Collapse
Affiliation(s)
- Ryota Mori
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Takayuki Ogino
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
- Department of Therapeutics for Inflammatory Bowel Diseases, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Mari Murakami
- Immunology Frontier Research Center, Osaka University, Osaka, Japan
- Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Hisako Kayama
- Immunology Frontier Research Center, Osaka University, Osaka, Japan
- Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan
- Institute for Advanced Co-Creation Studies, Osaka University, Osaka, Japan
| | - Daisuke Okuzaki
- Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Atsuyo Ikeda
- Laboratory of Innate Immunity, Department of Microbiology, Infectious Diseases and Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Yuki Sekido
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Tsuyoshi Hata
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Atsushi Hamabe
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hidekazu Takahashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
- Department of Surgery, Dokkyo Medical University, Tochigi, Japan
| | - Norikatsu Miyoshi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Mamoru Uemura
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hiroki Ikeuchi
- Division of Inflammatory Bowel Disease Surgery, Department of Gastroenterological Surgery, Hyogo Medical University, Hyogo, Japan
| | - Kiyoshi Takeda
- Immunology Frontier Research Center, Osaka University, Osaka, Japan
- Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Tsunekazu Mizushima
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
- Department of Therapeutics for Inflammatory Bowel Diseases, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
- Department of Surgery, Dokkyo Medical University, Tochigi, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| |
Collapse
|
|
3
|
Gao Y, Chen C, Huang X, Liu Y, Zhou Z, Pan Y. Omentin-1, a Protective Adipokine for Irritable Bowel Syndrome. J Inflamm Res 2025; 18:1689-1701. [PMID: 39925934 PMCID: PMC11806724 DOI: 10.2147/jir.s499613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 01/25/2025] [Indexed: 02/11/2025] Open
Abstract
Introduction Irritable bowel syndrome (IBS) is characterized by patients' high level of suffering. There is increasing evidence for involvement of the immune system in this disease. Adipokines have been reported to be critical immunoregulators in many clinical conditions, including gastrointestinal (GI) inflammatory diseases. Our study aimed to investigate associations of omentin-1 (a newly discovered adipokine) with IBS. Methods In the current study, serum levels of omentin-1 were measured in 209 patients with IBS (including three subtypes) and 188 healthy controls by enzyme-linked immunosorbent assay (ELISA). The somatic symptoms of IBS were determined by the 5-item IBS symptoms severity score (IBS-SSS), quality of life (QOL) by 34-item IBS-QOL questionnaire, and psychological disorders by Patient Health Questionnaire (PHQ-9), Hospital Anxiety and Depression Scale (HADS), Visceral Sensitivity Index (VSI). Therapeutic effect of omentin-1 for IBS was investigated in a 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced IBS mouse model. Results We found that serum levels of omentin-1 were significantly decreased in patients with the diarrhea-predominant IBS (IBS-D) subtype (not the constipation or alternating subtype) compared to those in healthy subjects. Patients with lower serum omentin-1 levels suffered from higher severity of somatic symptoms (abdominal pain and distention, flatulence, rumbling), lower QOL, and worse psychological status. In a one-year follow-up, serum omentin-1 levels showed potential to reflect the disease progression. Additionally, lower omentin-1 levels were found to be accompanied with higher levels of serum pro-inflammatory cytokine concentrations in patients with IBS-D. Supplement of omentin-1 was protective against visceral hypersensitivity and mucosal inflammation in an IBS mouse model. Discussion Our findings highlight the potential value of serum omentin-1 levels as an innovative biomarker in IBS, emphasizing its significance in improving clinical treatment and management of the disease.
Collapse
Affiliation(s)
- Yanping Gao
- Department of Gastroenterology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China
| | - Chen Chen
- Department of Gastroenterology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China
| | - Xijing Huang
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China
| | - Ya Liu
- Department of Gastroenterology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China
| | - Zhou Zhou
- Department of Gastroenterology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China
| | - Yan Pan
- Department of Gastroenterology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China
| |
Collapse
|
|
4
|
Boumitri C. Use of Glucagon-Like Peptide-1 Receptor Agonists in Patients With Inflammatory Bowel Disease. Gastroenterol Hepatol (N Y) 2025; 21:59-61. [PMID: 39897342 PMCID: PMC11784567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Affiliation(s)
- Christine Boumitri
- Assistant Professor Feinberg School of Medicine Northwestern Medicine Chicago, Illinois
| |
Collapse
|
|
5
|
Geryk M, Kucerova V, Velganova-Veghova M, Foltenova H, Bouchalova K, Karasek D, Radvansky M, Karaskova E. Association of selected adipokines with vitamin D deficiency in children with inflammatory bowel disease. BMC Pediatr 2024; 24:426. [PMID: 38961351 PMCID: PMC11223338 DOI: 10.1186/s12887-024-04890-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 06/19/2024] [Indexed: 07/05/2024] Open
Abstract
BACKGROUND Adipose tissue is significantly involved in inflammatory bowel disease (IBD). Vitamin D can affect both adipogenesis and inflammation. The aim of this study was to compare the production of selected adipokines, potentially involved in the pathogenesis of IBD - adiponectin, resistin, retinol binding protein 4 (RBP-4), adipocyte fatty acid binding protein and nesfatin-1 in children with IBD according to the presence of 25-hydroxyvitamin D (25(OH)D) deficiency. METHODS The study was conducted as a case-control study in pediatric patients with IBD and healthy children of the same sex and age. In addition to adipokines and 25(OH)D, anthropometric parameters, markers of inflammation and disease activity were assessed in all participants. RESULTS Children with IBD had significantly higher resistin levels regardless of 25(OH)D levels. IBD patients with 25(OH)D deficiency only had significantly lower RBP-4 compared to healthy controls and also compared to IBD patients without 25(OH)D deficiency. No other significant differences in adipokines were found in children with IBD with or without 25(OH)D deficiency. 25(OH)D levels in IBD patients corelated with RBP-4 only, and did not correlate with other adipokines. CONCLUSIONS Whether the lower RBP-4 levels in the 25(OH)D-deficient group of IBD patients directly reflect vitamin D deficiency remains uncertain. The production of other adipokines does not appear to be directly related to vitamin D deficiency.
Collapse
Affiliation(s)
- Milos Geryk
- Department of Pediatrics, University Hospital Olomouc, Faculty of Medicine and Dentistry Palacky University Olomouc, Olomouc, Czech Republic
| | - Veronika Kucerova
- Department of Clinical Biochemistry, University Hospital Olomouc, Olomouc, Czech Republic
| | - Maria Velganova-Veghova
- Department of Pediatrics, University Hospital Olomouc, Faculty of Medicine and Dentistry Palacky University Olomouc, Olomouc, Czech Republic
| | - Hana Foltenova
- Department of Pediatrics, University Hospital Olomouc, Faculty of Medicine and Dentistry Palacky University Olomouc, Olomouc, Czech Republic
| | - Katerina Bouchalova
- Department of Pediatrics, University Hospital Olomouc, Faculty of Medicine and Dentistry Palacky University Olomouc, Olomouc, Czech Republic
| | - David Karasek
- 3rd Department of Internal Medicine - Nephrology, Rheumatology and Endocrinology, University Hospital Olomouc, Faculty of Medicine and Dentistry, Palacky University Olomouc, Olomouc, Czech Republic
| | - Martin Radvansky
- Department of Computer Science, Faculty of Electrical Engineering and Computer Science, VSB-Technical University of Ostrava, Ostrava - Poruba, Czech Republic
| | - Eva Karaskova
- Department of Pediatrics, University Hospital Olomouc, Faculty of Medicine and Dentistry Palacky University Olomouc, Olomouc, Czech Republic.
| |
Collapse
|
|
6
|
Kreienbuehl AS, Rogler G, Emanuel B, Biedermann L, Meier C, Juillerat P, Restellini S, Hruz P, Vavricka SR, Aeberli D, Seibold F. Bone health in patients with inflammatory bowel disease. Swiss Med Wkly 2024; 154:3407. [PMID: 38875461 DOI: 10.57187/s.3407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2024] Open
Abstract
Patients with inflammatory bowel disease (IBD) are prone to reduced bone mineral density and elevated overall fracture risk. Osteopenia affects up to 40% of patients with IBD (high regional variability). Besides disease activity, IBD specialists must consider possible side effects of medication and the presence of associated diseases and extraintestinal manifestations. Osteopenia and osteoporosis remain frequent problems in patients with IBD and are often underestimated because of widely differing screening and treatment practices. Malnutrition, chronic intestinal inflammation and corticosteroid intake are the major pathophysiological factors contributing to osteoporosis. Patients with IBD are screened for osteoporosis using dual-energy X-ray absorptiometry (DXA), which is recommended for all patients with a prolonged disease course of more than three months, with repeated corticosteroid administration, aged >40 years with a high FRAX risk score or aged <40 years with multiple risk factors. From a therapeutic perspective, besides good disease control, vitamin D supplementation and glucocorticoid sparing, several specific osteological options are available: bisphosphonates, receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors (denosumab), parathyroid hormone (PTH) analogues and selective estrogen receptor modulators. This review provides an overview of the pathophysiology, diagnosis, prevention and treatment of IBD-associated bone loss.
Collapse
Affiliation(s)
- Andrea S Kreienbuehl
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Burri Emanuel
- Gastroenterology and Hepatology, University Medical Clinic, Kantonsspital Baselland, Liestal, Switzerland
| | - Luc Biedermann
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Christian Meier
- Gastroenterology and Hepatology, University Medical Clinic, Kantonsspital Baselland, Liestal, Switzerland
| | - Pascal Juillerat
- Crohn's and Colitis Center, Gastroenterologie Beaulieu, Lausanne, Switzerland
- Gastroenterology, Clinic for Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Sophie Restellini
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Hôpital de la Tour, Geneva, Switzerland
- Faculty of Medicine, University of Geneva, Switzerland
- McGill University Health Center, McGill University, Montréal, Québec, Canada
| | - Peter Hruz
- Clarunis, University Center for Gastrointestinal and Liver Diseases, Basel, Switzerland
| | - Stefan R Vavricka
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Daniel Aeberli
- Department of Rheumatology and Immunology, University Hospital Bern, Bern, Switzerland
- Department of Internal Medicine, Spital Emmental, Burgdorf, Switzerland
| | - Frank Seibold
- Intesto, Gastroenterologische Praxis, Crohn-Colitis-Zentrum Bern, Bern, Switzerland
- University of Fribourg, Switzerland
| |
Collapse
|
|
7
|
Nagao I, Ambrosini YM. High-fat diet enhances cell proliferation and compromises intestinal permeability in a translational canine intestinal organoid model. BMC Mol Cell Biol 2024; 25:14. [PMID: 38689222 PMCID: PMC11059635 DOI: 10.1186/s12860-024-00512-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 04/26/2024] [Indexed: 05/02/2024] Open
Abstract
BACKGROUND Emerging evidence underscores the responsiveness of the mammalian intestine to dietary cues, notably through the involvement of LGR5 + intestinal stem cells in orchestrating responses to diet-driven signals. However, the effects of high-fat diet (HFD) on these cellular dynamics and their impact on gut integrity remain insufficiently understood. Our study aims to assess the multifaceted interactions between palmitic acid (PA), cell proliferation, and the intestinal epithelial barrier using a canine colonoid model. Canine models, due to their relevance in simulating human intestinal diseases, offer a unique platform to explore the molecular mechanisms underlying HFD derived intestinal dysfunction. RESULTS Canine colonoids were subjected to PA exposure, a surrogate for the effects of HFD. This intervention revealed a remarkable augmentation of cell proliferative activity. Furthermore, we observed a parallel reduction in transepithelial electrical resistance (TEER), indicating altered epithelium barrier integrity. While E-cadherin exhibited consistency, ZO-1 displayed a noteworthy reduction in fluorescence intensity within the PA-exposed group. CONCLUSIONS By employing canine intestinal organoid systems, we provide compelling insights into the impact of PA on intestinal physiology. These findings underscore the importance of considering both cell proliferative activity and epithelial integrity in comprehending the repercussions of HFDs on intestinal health. Our study contributes to a deeper understanding of the consequences of HFD on intestinal homeostasis, utilizing valuable translational in vitro models derived from dogs.
Collapse
Affiliation(s)
- Itsuma Nagao
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA, USA
- Department of Veterinary Internal Medicine, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Yoko M Ambrosini
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA, USA.
| |
Collapse
|
|
8
|
Behnoush AH, Maroufi SP, Reshadmanesh T, Mohtasham Kia Y, Norouzi M, Mohammadi SM, Klisic A, Khalaji A. Circulatory resistin levels in inflammatory bowel disease: a systematic review and meta-analysis. BMC Gastroenterol 2024; 24:107. [PMID: 38486190 PMCID: PMC10941394 DOI: 10.1186/s12876-024-03199-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 03/11/2024] [Indexed: 03/17/2024] Open
Abstract
BACKGROUND Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a chronic relapsing-remitting systemic disease of the gastrointestinal tract with rising incidence. Studies have shown that adipocytes play a crucial role in patients with IBD by actively participating in systemic immune responses. The present study was designed to investigate the correlation between the circulatory levels of resistin, as an adipokine, and active and remission phases of IBD in comparison with healthy controls. METHODS Relevant articles were retrieved from PubMed, Embase, the Web of Science, and Scopus from inception until June 2023. Estimation of the standardized mean difference (SMD) and 95% confidence interval (CI) for comparison of plasma/serum resistin levels between IBD patients, patients in remission, and healthy controls were conducted through random-effect meta-analysis. RESULTS A total of 19 studies were included, assessing 1836 cases. Meta-analysis indicated that generally, serum/plasma resistin levels were higher in IBD patients in comparison with healthy controls (SMD 1.33, 95% CI 0.58 to 2.08, p-value < 0.01). This was true for each of the UC and CD separate analyses, as well. Moreover, it was shown that higher serum/plasma resistin levels were detected in the active phase of IBD than in the remission phase (SMD 1.04, 95% CI 0.65 to 1.42, p-value = 0.01). Finally, higher serum/plasma resistin levels were found in the remission phase compared to healthy controls (SMD 0.60, 95% CI 0.15 to 1.06, p-value < 0.01). CONCLUSION The results of this systematic review and meta-analysis support the conclusion that circulating resistin levels are increased in IBD (both UC and CD). Also, higher resistin levels were recorded in the remission phase of IBD in comparison with healthy controls. This indicates that further studies may provide valuable insights into the role of resistin in the pathogenesis of IBD.
Collapse
Affiliation(s)
- Amir Hossein Behnoush
- School of Medicine, Tehran University of Medical Sciences, Poursina St., Keshavarz Blvd, 1417613151, Tehran, Iran.
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Seyede Parmis Maroufi
- Neurosurgical Research Network, Universal Scientific Education and Research Network, Tehran University of Medical Sciences, Tehran, Iran
| | - Tara Reshadmanesh
- Student Research Center, School of Medicine, Zanjan University of Medical Science, Zanjan, Iran
| | | | - Mitra Norouzi
- Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | | | - Aleksandra Klisic
- Faculty of Medicine, University of Montenegro, Podgorica, Montenegro
- Center for Laboratory Diagnostics, Primary Health Care Center, Podgorica, Montenegro
| | - Amirmohammad Khalaji
- School of Medicine, Tehran University of Medical Sciences, Poursina St., Keshavarz Blvd, 1417613151, Tehran, Iran
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
9
|
Tschurtschenthaler M, Verstockt B. Targeting a Hallmark of Crohn's Disease: Browning of the Hypertrophic Mesenteric Adipose Tissue as a Novel Strategy to Reduce Inflammation? J Crohns Colitis 2023; 17:1177-1178. [PMID: 37099722 DOI: 10.1093/ecco-jcc/jjad059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/28/2023]
Affiliation(s)
- Markus Tschurtschenthaler
- Division of Translational Cancer Research, German Cancer Research Center [DKFZ] and German Cancer Consortium [DKTK], Heidelberg, Germany
- Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
- Center for Translational Cancer Research [TranslaTUM], School of Medicine, Technical University of Munich, Munich, Germany
| | - Bram Verstockt
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
- Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| |
Collapse
|
|
10
|
Kwon HJ, Chun SY, Lee EH, Yoon B, Han MH, Chung JW, Ha YS, Lee JN, Kim HT, Kim DH, Kwon TG, Kim BS, Lee SO, Jang BI. Protaetia Brevitarsis-Derived Protein Hydrolysate Reduces Obesity-Related Colitis Induced by High-Fat Diet in Mice through Anti-Inflammatory Pathways. Int J Mol Sci 2023; 24:12333. [PMID: 37569708 PMCID: PMC10418620 DOI: 10.3390/ijms241512333] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 07/26/2023] [Accepted: 07/31/2023] [Indexed: 08/13/2023] Open
Abstract
Ulcerative colitis is an inflammatory bowel disease characterized by inflammation in the mucosal and submucosal layers of the colon. Obesity is closely related to the occurrence and progression of colitis. The most plausible mechanism linking obesity and colitis is an excessive adipogenesis-related inflammatory response, which causes mucosal dysfunction. Obesity and colitis are linked by several etiologic mechanisms, including excessive adipogenesis, lipotoxicity, pro-inflammatory adipokines/cytokines, macrophage polarization, oxidative stress, endoplasmic reticulum (ER) stress, and gut microbiota. These low-grade enteric inflammations cause mucosal layer damage, especially goblet cell dysfunction through mucin 2 (MUC2) misfolding, ultimately leading to colitis. Inhibiting the inflammatory response can be the most effective approach for treating obesity-related colitis. We focused on the anti-inflammatory effects of polyphenols in Protaectia brevitas larvae. The P. brevitas was prepared as a low molecular protein hydrolysate (PHPB) to increase the concentration of anti-inflammatory molecules. In the current study, we investigated the anti-inflammatory effect of PHPB in an obesity-induced colitis mouse model. Compared with the high-fat diet (HFD) group, the group treated with PHPB exhibited reduced body/organ/fat weight, appetite/food intake inhibition, hypolipidemic effect on ectopic fat, and anti-adipogenic mechanism through the AMPK signaling pathway. Furthermore, we observed attenuated expression of PPARγ and C/EBPα, inhibition of pro-inflammatory molecules, stimulation of anti-inflammatory molecules, probiotic-like effect against obesogenic gut microbiota, inhibition of macrophage polarization into M1, suppression of oxidative/ER stress, and reduction of Muc2 protein misfolding in colon. These diverse anti-inflammatory responses caused histological and functional recovery of goblet cells, eventually improving colitis. Therefore, our findings suggest that the protein hydrolysate of Protaetia brevitarsis can improve obesity-related colitis through its anti-inflammatory activities.
Collapse
Affiliation(s)
- Hyung Jun Kwon
- Department of Surgery, School of Medicine, Kyungpook National University, Daegu 41566, Republic of Korea;
| | - So Young Chun
- BioMedical Research Institute, Kyungpook National University Hospital, Daegu 41944, Republic of Korea
| | - Eun Hye Lee
- Joint Institute for Regenerative Medicine, Kyungpook National University, Daegu 41566, Republic of Korea
| | - BoHyun Yoon
- Joint Institute for Regenerative Medicine, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Man-Hoon Han
- Department of Pathology, School of Medicine, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Jae-Wook Chung
- Department of Urology, School of Medicine, Kyungpook National University, Daegu 41566, Republic of Korea; (J.-W.C.); (J.N.L.); (T.G.K.); (B.S.K.)
| | - Yun-Sok Ha
- Department of Urology, School of Medicine, Kyungpook National University, Daegu 41566, Republic of Korea; (J.-W.C.); (J.N.L.); (T.G.K.); (B.S.K.)
| | - Jun Nyung Lee
- Department of Urology, School of Medicine, Kyungpook National University, Daegu 41566, Republic of Korea; (J.-W.C.); (J.N.L.); (T.G.K.); (B.S.K.)
| | - Hyun Tae Kim
- Department of Urology, School of Medicine, Kyungpook National University, Daegu 41566, Republic of Korea; (J.-W.C.); (J.N.L.); (T.G.K.); (B.S.K.)
| | - Dae Hwan Kim
- Department of Laboratory Animal Research Support Team, Yeungnam University Medical Center, Daegu 42415, Republic of Korea;
| | - Tae Gyun Kwon
- Department of Urology, School of Medicine, Kyungpook National University, Daegu 41566, Republic of Korea; (J.-W.C.); (J.N.L.); (T.G.K.); (B.S.K.)
| | - Bum Soo Kim
- Department of Urology, School of Medicine, Kyungpook National University, Daegu 41566, Republic of Korea; (J.-W.C.); (J.N.L.); (T.G.K.); (B.S.K.)
| | - Syng-Ook Lee
- Department of Food Science and Technology, Keimyung University, Daegu 42601, Republic of Korea
| | - Byung Ik Jang
- Department of Internal Medicine, School of Medicine, Yeungnam University, Daegu 42415, Republic of Korea
| |
Collapse
|
|
11
|
Campbell I, Glinka M, Shaban F, Kirkwood KJ, Nadalin F, Adams D, Papatheodorou I, Burger A, Baldock RA, Arends MJ, Din S. The Promise of Single-Cell RNA Sequencing to Redefine the Understanding of Crohn's Disease Fibrosis Mechanisms. J Clin Med 2023; 12:3884. [PMID: 37373578 PMCID: PMC10299644 DOI: 10.3390/jcm12123884] [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: 05/08/2023] [Revised: 06/03/2023] [Accepted: 06/05/2023] [Indexed: 06/29/2023] Open
Abstract
Crohn's disease (CD) is a chronic inflammatory bowel disease with a high prevalence throughout the world. The development of Crohn's-related fibrosis, which leads to strictures in the gastrointestinal tract, presents a particular challenge and is associated with significant morbidity. There are currently no specific anti-fibrotic therapies available, and so treatment is aimed at managing the stricturing complications of fibrosis once it is established. This often requires invasive and repeated endoscopic or surgical intervention. The advent of single-cell sequencing has led to significant advances in our understanding of CD at a cellular level, and this has presented opportunities to develop new therapeutic agents with the aim of preventing or reversing fibrosis. In this paper, we discuss the current understanding of CD fibrosis pathogenesis, summarise current management strategies, and present the promise of single-cell sequencing as a tool for the development of effective anti-fibrotic therapies.
Collapse
Affiliation(s)
- Iona Campbell
- Edinburgh Inflammatory Bowel Disease Unit, Western General Hospital, NHS Lothian, Edinburgh EH4 2XU, UK
| | - Michael Glinka
- Edinburgh Pathology, Centre for Comparative Pathology, Cancer Research UK Scotland Centre, Institute of Cancer and Genetics, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK
| | - Fadlo Shaban
- Edinburgh Colorectal Unit, Western General Hospital, NHS Lothian, Edinburgh EH4 2XU, UK
| | - Kathryn J. Kirkwood
- Department of Pathology, Western General Hospital, NHS Lothian, Edinburgh EH4 2XU, UK
| | - Francesca Nadalin
- European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Hinxton, Cambridge CB10 1SD, UK
| | - David Adams
- Experimental Cancer Genetics, Wellcome Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
| | - Irene Papatheodorou
- European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Hinxton, Cambridge CB10 1SD, UK
| | - Albert Burger
- Department of Computer Science, School of Mathematical and Computer Sciences, Heriot-Watt University, Edinburgh EH14 4AS, UK;
| | - Richard A. Baldock
- Edinburgh Pathology, Centre for Comparative Pathology, Cancer Research UK Scotland Centre, Institute of Cancer and Genetics, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK
| | - Mark J. Arends
- Edinburgh Pathology, Centre for Comparative Pathology, Cancer Research UK Scotland Centre, Institute of Cancer and Genetics, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK
| | - Shahida Din
- Edinburgh Inflammatory Bowel Disease Unit, Western General Hospital, NHS Lothian, Edinburgh EH4 2XU, UK
| |
Collapse
|
|
12
|
Świątkiewicz I, Wróblewski M, Nuszkiewicz J, Sutkowy P, Wróblewska J, Woźniak A. The Role of Oxidative Stress Enhanced by Adiposity in Cardiometabolic Diseases. Int J Mol Sci 2023; 24:ijms24076382. [PMID: 37047352 PMCID: PMC10094567 DOI: 10.3390/ijms24076382] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Revised: 03/23/2023] [Accepted: 03/24/2023] [Indexed: 03/31/2023] Open
Abstract
Cardiometabolic diseases (CMDs), including cardiovascular disease (CVD), metabolic syndrome (MetS), and type 2 diabetes (T2D), are associated with increased morbidity and mortality. The growing prevalence of CVD is mostly attributed to the aging population and common occurrence of risk factors, such as high systolic blood pressure, elevated plasma glucose, and increased body mass index, which led to a global epidemic of obesity, MetS, and T2D. Oxidant–antioxidant balance disorders largely contribute to the pathogenesis and outcomes of CMDs, such as systemic essential hypertension, coronary artery disease, stroke, and MetS. Enhanced and disturbed generation of reactive oxygen species in excess adipose tissue during obesity may lead to increased oxidative stress. Understanding the interplay between adiposity, oxidative stress, and cardiometabolic risks can have translational impacts, leading to the identification of novel effective strategies for reducing the CMDs burden. The present review article is based on extant results from basic and clinical studies and specifically addresses the various aspects associated with oxidant–antioxidant balance disorders in the course of CMDs in subjects with excess adipose tissue accumulation. We aim at giving a comprehensive overview of existing knowledge, knowledge gaps, and future perspectives for further basic and clinical research. We provide insights into both the mechanisms and clinical implications of effects related to the interplay between adiposity and oxidative stress for treating and preventing CMDs. Future basic research and clinical trials are needed to further examine the mechanisms of adiposity-enhanced oxidative stress in CMDs and the efficacy of antioxidant therapies for reducing risk and improving outcome of patients with CMDs.
Collapse
|
|
13
|
Richter FC, Friedrich M, Kampschulte N, Piletic K, Alsaleh G, Zummach R, Hecker J, Pohin M, Ilott N, Guschina I, Wideman SK, Johnson E, Borsa M, Hahn P, Morriseau C, Hammock BD, Schipper HS, Edwards CM, Zechner R, Siegmund B, Weidinger C, Schebb NH, Powrie F, Simon AK. Adipocyte autophagy limits gut inflammation by controlling oxylipin and IL-10. EMBO J 2023; 42:e112202. [PMID: 36795015 PMCID: PMC10015370 DOI: 10.15252/embj.2022112202] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 01/15/2023] [Accepted: 01/17/2023] [Indexed: 02/17/2023] Open
Abstract
Lipids play a major role in inflammatory diseases by altering inflammatory cell functions, either through their function as energy substrates or as lipid mediators such as oxylipins. Autophagy, a lysosomal degradation pathway that limits inflammation, is known to impact on lipid availability, however, whether this controls inflammation remains unexplored. We found that upon intestinal inflammation visceral adipocytes upregulate autophagy and that adipocyte-specific loss of the autophagy gene Atg7 exacerbates inflammation. While autophagy decreased lipolytic release of free fatty acids, loss of the major lipolytic enzyme Pnpla2/Atgl in adipocytes did not alter intestinal inflammation, ruling out free fatty acids as anti-inflammatory energy substrates. Instead, Atg7-deficient adipose tissues exhibited an oxylipin imbalance, driven through an NRF2-mediated upregulation of Ephx1. This shift reduced secretion of IL-10 from adipose tissues, which was dependent on the cytochrome P450-EPHX pathway, and lowered circulating levels of IL-10 to exacerbate intestinal inflammation. These results suggest an underappreciated fat-gut crosstalk through an autophagy-dependent regulation of anti-inflammatory oxylipins via the cytochrome P450-EPHX pathway, indicating a protective effect of adipose tissues for distant inflammation.
Collapse
Affiliation(s)
| | - Matthias Friedrich
- Kennedy Institute of RheumatologyUniversity of OxfordOxfordUK
- Translational Gastroenterology Unit, Nuffield Department of Medicine, John Radcliffe HospitalUniversity of OxfordOxfordUK
| | - Nadja Kampschulte
- Faculty of Mathematics and Natural SciencesUniversity of WuppertalWuppertalGermany
| | - Klara Piletic
- Kennedy Institute of RheumatologyUniversity of OxfordOxfordUK
| | - Ghada Alsaleh
- Kennedy Institute of RheumatologyUniversity of OxfordOxfordUK
| | | | - Julia Hecker
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt‐Universität zu Berlin and Berlin Institute of HealthBerlinGermany
- Department of Gastroenterology, Infectious Diseases and RheumatologyCampus Benjamin FranklinBerlinGermany
| | - Mathilde Pohin
- Kennedy Institute of RheumatologyUniversity of OxfordOxfordUK
| | - Nicholas Ilott
- Kennedy Institute of RheumatologyUniversity of OxfordOxfordUK
| | | | - Sarah Karin Wideman
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe HospitalUniversity of OxfordOxfordUK
| | - Errin Johnson
- The Dunn School of PathologyUniversity of OxfordOxfordUK
| | - Mariana Borsa
- Kennedy Institute of RheumatologyUniversity of OxfordOxfordUK
| | - Paula Hahn
- Kennedy Institute of RheumatologyUniversity of OxfordOxfordUK
| | - Christophe Morriseau
- Department of Entomology and Nematology, UC Davis Comprehensive Cancer CenterUniversity of CaliforniaDavisCAUSA
| | - Bruce D Hammock
- Department of Entomology and Nematology, UC Davis Comprehensive Cancer CenterUniversity of CaliforniaDavisCAUSA
| | - Henk Simon Schipper
- Kennedy Institute of RheumatologyUniversity of OxfordOxfordUK
- Center for Translational ImmunologyUniversity Medical Center UtrechtUtrechtThe Netherlands
| | - Claire M Edwards
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research CentreUniversity of OxfordOxfordUK
- Nuffield Department of Surgical Sciences, Botnar Research CentreUniversity of OxfordOxfordUK
| | - Rudolf Zechner
- Institute of Molecular BiosciencesUniversity of GrazGrazAustria
| | - Britta Siegmund
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt‐Universität zu Berlin and Berlin Institute of HealthBerlinGermany
- Department of Gastroenterology, Infectious Diseases and RheumatologyCampus Benjamin FranklinBerlinGermany
| | - Carl Weidinger
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt‐Universität zu Berlin and Berlin Institute of HealthBerlinGermany
- Department of Gastroenterology, Infectious Diseases and RheumatologyCampus Benjamin FranklinBerlinGermany
| | - Nils Helge Schebb
- Faculty of Mathematics and Natural SciencesUniversity of WuppertalWuppertalGermany
| | - Fiona Powrie
- Kennedy Institute of RheumatologyUniversity of OxfordOxfordUK
| | - Anna Katharina Simon
- Kennedy Institute of RheumatologyUniversity of OxfordOxfordUK
- Max Delbrück CenterBerlinGermany
| |
Collapse
|
|
14
|
Xia Q, Li M, Xu M, Chen S, Xie X, Chen Y. Measurement of the stiffness of the normal terminal ileum mesentery using shear-wave elastography. Eur J Radiol 2023; 163:110807. [PMID: 37030100 DOI: 10.1016/j.ejrad.2023.110807] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 03/23/2023] [Accepted: 03/27/2023] [Indexed: 03/31/2023]
Abstract
OBJECTIVE To investigate the feasibility of using shear-wave elastography (SWE) to measure the stiffness of the normal terminal ileum mesentery, and to establish its normal reference range. METHODS Ninety-five normal subjects and 22 patients with mesentery-related disease were included. The average Young's modulus of the normal terminal ileal mesentery was measured by SWE ultrasound. The thickness and the extent to which mesenteric fat extended around the intestinal circumference of the normal terminal ileum were also recorded. The normal reference range was established and the SWE values of normal and diseased subjects were compared. RESULTS Transabdominal SWE examination of the terminal ileum mesentery was successfully performed on 91 subjects (95.8 %). The mean extent range, thickness, and SWE value of the normal terminal ileum mesentery were 1/4 (1/5-1/3), 6.8 ± 2.4 mm, and 4.3 ± 2.1 kPa, respectively. These parameters did not differ significantly between genders, and across age and body mass index groups (all P > 0.05). The intra- and inter-operator consistencies were excellent for the replicated SWE measurements (0.801 [95 % confidence interval: 0.560-0.916] and 0.751 (95 % confidence interval: 0.388-0.900], respectively). The mean mesenteric elasticity in diseased subjects was 21.9 ± 10.7 kPa, which was significantly higher than that in normal subjects (P < 0.001). The cut-off value for mesenteric elasticity was 9.3 kPa, with a sensitivity of 90 % and a specificity of 100 % (P < 0.001). CONCLUSION SWE can be used to reliably evaluate the stiffness of the terminal ileum mesentery in normal subjects.
Collapse
Affiliation(s)
- Qingqing Xia
- Department of Medical Ultrasonics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Manying Li
- Department of Medical Ultrasonics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Ming Xu
- Department of Medical Ultrasonics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Shuling Chen
- Department of Medical Ultrasonics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiaoyan Xie
- Department of Medical Ultrasonics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yujun Chen
- Department of Medical Ultrasonics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
| |
Collapse
|
|
15
|
De S, Paul S, Manna A, Majumder C, Pal K, Casarcia N, Mondal A, Banerjee S, Nelson VK, Ghosh S, Hazra J, Bhattacharjee A, Mandal SC, Pal M, Bishayee A. Phenolic Phytochemicals for Prevention and Treatment of Colorectal Cancer: A Critical Evaluation of In Vivo Studies. Cancers (Basel) 2023; 15:993. [PMID: 36765950 PMCID: PMC9913554 DOI: 10.3390/cancers15030993] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/30/2023] [Accepted: 01/30/2023] [Indexed: 02/08/2023] Open
Abstract
Colorectal cancer (CRC) is the third most diagnosed and second leading cause of cancer-related death worldwide. Limitations with existing treatment regimens have demanded the search for better treatment options. Different phytochemicals with promising anti-CRC activities have been reported, with the molecular mechanism of actions still emerging. This review aims to summarize recent progress on the study of natural phenolic compounds in ameliorating CRC using in vivo models. This review followed the guidelines of the Preferred Reporting Items for Systematic Reporting and Meta-Analysis. Information on the relevant topic was gathered by searching the PubMed, Scopus, ScienceDirect, and Web of Science databases using keywords, such as "colorectal cancer" AND "phenolic compounds", "colorectal cancer" AND "polyphenol", "colorectal cancer" AND "phenolic acids", "colorectal cancer" AND "flavonoids", "colorectal cancer" AND "stilbene", and "colorectal cancer" AND "lignan" from the reputed peer-reviewed journals published over the last 20 years. Publications that incorporated in vivo experimental designs and produced statistically significant results were considered for this review. Many of these polyphenols demonstrate anti-CRC activities by inhibiting key cellular factors. This inhibition has been demonstrated by antiapoptotic effects, antiproliferative effects, or by upregulating factors responsible for cell cycle arrest or cell death in various in vivo CRC models. Numerous studies from independent laboratories have highlighted different plant phenolic compounds for their anti-CRC activities. While promising anti-CRC activity in many of these agents has created interest in this area, in-depth mechanistic and well-designed clinical studies are needed to support the therapeutic use of these compounds for the prevention and treatment of CRC.
Collapse
Affiliation(s)
- Samhita De
- Division of Molecular Medicine, Bose Institute, Kolkata 700 054, India
| | - Sourav Paul
- Department of Biotechnology, National Institute of Technology, Durgapur 713 209, India
| | - Anirban Manna
- Division of Molecular Medicine, Bose Institute, Kolkata 700 054, India
| | | | - Koustav Pal
- Jawaharlal Institute Post Graduate Medical Education and Research, Puducherry 605 006, India
| | - Nicolette Casarcia
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA
| | - Arijit Mondal
- Department of Pharmaceutical Chemistry, M.R. College of Pharmaceutical Sciences and Research, Balisha 743 234, India
| | - Sabyasachi Banerjee
- Department of Pharmaceutical Chemistry, Gupta College of Technological Sciences, Asansol 713 301, India
| | - Vinod Kumar Nelson
- Department of Pharmacology, Raghavendra Institute of Pharmaceutical Education and Research, Anantapur 515 721, India
| | - Suvranil Ghosh
- Division of Molecular Medicine, Bose Institute, Kolkata 700 054, India
| | - Joyita Hazra
- Department of Biotechnology, Indian Institute of Technology, Chennai 600 036, India
| | - Ashish Bhattacharjee
- Department of Biotechnology, National Institute of Technology, Durgapur 713 209, India
| | | | - Mahadeb Pal
- Division of Molecular Medicine, Bose Institute, Kolkata 700 054, India
| | - Anupam Bishayee
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA
| |
Collapse
|
|
16
|
Yao H, Tang G. Macrophages in intestinal fibrosis and regression. Cell Immunol 2022; 381:104614. [PMID: 36182587 DOI: 10.1016/j.cellimm.2022.104614] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 09/14/2022] [Accepted: 09/20/2022] [Indexed: 11/03/2022]
Abstract
Intestinal macrophages are heterogenous cell populations with different developmental ontogeny and tissue anatomy. The concerted actions of intestinal macrophage subsets are critical to maintaining tissue homeostasis. However, the dysregulation of macrophages following tissue injury or chronic inflammation could also lead to intestinal fibrosis, with few treatment options in the clinic. In this review, we will characterize the features of intestinal macrophages in light of the latest advances in lineage tracing and single-cell sequencing technology. The roles of macrophages in distinct stages of intestinal fibrosis would be also elaborated. Finally, based on the reciprocal interaction between macrophages and intestinal fibrosis, we will propose the potential macrophage targeting anti-intestinal fibrosis therapies.
Collapse
Affiliation(s)
- Hui Yao
- Department of Oral Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; College of Stomatology, Shanghai Jiao Tong University, Shanghai 200011, China; National Center for Stomatology, Shanghai 200011, China; National Clinical Research Center for Oral Diseases, Shanghai 200011, China; Shanghai Key Laboratory of Stomatology, Shanghai 200011, China
| | - Guoyao Tang
- Department of Oral Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; College of Stomatology, Shanghai Jiao Tong University, Shanghai 200011, China; National Center for Stomatology, Shanghai 200011, China; National Clinical Research Center for Oral Diseases, Shanghai 200011, China; Shanghai Key Laboratory of Stomatology, Shanghai 200011, China.
| |
Collapse
|
|
17
|
Michalak A, Kasztelan-Szczerbińska B, Cichoż-Lach H. Impact of Obesity on the Course of Management of Inflammatory Bowel Disease-A Review. Nutrients 2022; 14:3983. [PMID: 36235636 PMCID: PMC9573343 DOI: 10.3390/nu14193983] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 09/16/2022] [Accepted: 09/19/2022] [Indexed: 11/16/2022] Open
Abstract
It is already well-known that visceral adipose tissue is inseparably related to the pathogenesis, activity, and general outcome of inflammatory bowel disease (IBD). We are getting closer and closer to the molecular background of this loop, finding certain relationships between activated mesenteric tissue and inflammation within the lumen of the gastrointestinal tract. Recently, relatively new data have been uncovered, indicating a direct impact of body fat on the pattern of pharmacological treatment in the course of IBD. On the other hand, ileal and colonic types of Crohn's disease and ulcerative colitis appear to be more diversified than it was thought in the past. However, the question arises whether at this stage we are able to translate this knowledge into the practical management of IBD patients or we are still exploring the scientific background of this pathology, having no specific tools to be used directly in patients. Our review explores IBD in the context of obesity and associated disorders, focusing on adipokines, creeping fat, and possible relationships between these disorders and the treatment of IBD patients.
Collapse
Affiliation(s)
| | | | - Halina Cichoż-Lach
- Department of Gastroenterology, Medical University of Lublin, Jaczewski St 8, 20-954 Lublin, Poland
| |
Collapse
|
|
18
|
Xiong S, Tan J, Wang Y, He J, Hu F, Wu X, Liu Z, Lin S, Li X, Chen Z, Mao R. Fibrosis in fat: From other diseases to Crohn’s disease. Front Immunol 2022; 13:935275. [PMID: 36091035 PMCID: PMC9453038 DOI: 10.3389/fimmu.2022.935275] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 08/03/2022] [Indexed: 11/17/2022] Open
Abstract
Creeping fat is a specific feature of Crohn’s disease (CD) and is characterized by mesenteric fat wrapping around the intestine. It highly correlates with intestinal transmural inflammation, muscular hypertrophy, fibrosis, and stricture formation. However, the pathogenesis of creeping fat remains unclear. Molecular crosstalk exists between mesenteric fat and the intestine. Indeed, creeping fat contains different types of cells, including adipocytes and immune cells. These cell types can produce various cytokines, fatty acids, and growth factors, which affect the mesenteric fat function and modulate intestinal inflammation and immunity. Moreover, adipocyte progenitors can produce extracellular matrix to adapt to fat expansion. Previous studies have shown that fat fibrosis is an important feature of adipose tissue malfunction and exists in other diseases, including metabolic disorders, cancer, atrial fibrillation, and osteoarthritis. Furthermore, histological sections of CD showed fibrosis in the creeping fat. However, the role of fibrosis in the mesenteric fat of CD is not well understood. In this review, we summarized the possible mechanisms of fat fibrosis and its impact on other diseases. More specifically, we illustrated the role of various cells (adipocyte progenitors, macrophages, mast cells, and group 1 innate lymphoid cells) and molecules (including hypoxia-inducible factor 1-alpha, transforming growth factor-beta, platelet-derived growth factor, and peroxisome proliferator-activated receptor-gamma) in the pathogenesis of fat fibrosis in other diseases to understand the role of creeping fat fibrosis in CD pathogenesis. Future research will provide key information to decipher the role of fat fibrosis in creeping fat formation and intestinal damage, thereby helping us identify novel targets for the diagnosis and treatment of CD.
Collapse
Affiliation(s)
- Shanshan Xiong
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jinyu Tan
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yu Wang
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jinshen He
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Fan Hu
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiaomin Wu
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zishan Liu
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Sinan Lin
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xuehua Li
- Department of Radiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zhihui Chen
- Gastrointestinal Surgery Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- *Correspondence: Ren Mao, ; Zhihui Chen,
| | - Ren Mao
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Department of Gastroenterology, Huidong People’s Hospital, Huizhou, China
- *Correspondence: Ren Mao, ; Zhihui Chen,
| |
Collapse
|
|
19
|
Ribeiro FM, Silva MA, Lyssa V, Marques G, Lima HK, Franco OL, Petriz B. The molecular signaling of exercise and obesity in the microbiota-gut-brain axis. Front Endocrinol (Lausanne) 2022; 13:927170. [PMID: 35966101 PMCID: PMC9365995 DOI: 10.3389/fendo.2022.927170] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Accepted: 07/05/2022] [Indexed: 11/13/2022] Open
Abstract
Obesity is one of the major pandemics of the 21st century. Due to its multifactorial etiology, its treatment requires several actions, including dietary intervention and physical exercise. Excessive fat accumulation leads to several health problems involving alteration in the gut-microbiota-brain axis. This axis is characterized by multiple biological systems generating a network that allows bidirectional communication between intestinal bacteria and brain. This mutual communication maintains the homeostasis of the gastrointestinal, central nervous and microbial systems of animals. Moreover, this axis involves inflammatory, neural, and endocrine mechanisms, contributes to obesity pathogenesis. The axis also acts in appetite and satiety control and synthesizing hormones that participate in gastrointestinal functions. Exercise is a nonpharmacologic agent commonly used to prevent and treat obesity and other chronic degenerative diseases. Besides increasing energy expenditure, exercise induces the synthesis and liberation of several muscle-derived myokines and neuroendocrine peptides such as neuropeptide Y, peptide YY, ghrelin, and leptin, which act directly on the gut-microbiota-brain axis. Thus, exercise may serve as a rebalancing agent of the gut-microbiota-brain axis under the stimulus of chronic low-grade inflammation induced by obesity. So far, there is little evidence of modification of the gut-brain axis as a whole, and this narrative review aims to address the molecular pathways through which exercise may act in the context of disorders of the gut-brain axis due to obesity.
Collapse
Affiliation(s)
- Filipe M. Ribeiro
- Post-Graduation Program in Physical Education, Catholic University of Brasilia, Brasilia, Brazil
- Center for Proteomic and Biochemical Analysis, Post-Graduation in Genomic and Biotechnology Sciences, Catholic University of Brasilia, Brasília, Brazil
- Laboratory of Molecular Exercise Physiology - University Center of the Federal District - UDF, Brasilia, Brazil
| | - Maycon A. Silva
- Center for Proteomic and Biochemical Analysis, Post-Graduation in Genomic and Biotechnology Sciences, Catholic University of Brasilia, Brasília, Brazil
| | - Victória Lyssa
- Laboratory of Molecular Analysis, Graduate Program of Sciences and Technology of Health, University of Brasilia, Brasilia, Brazil
| | - Gabriel Marques
- Laboratory of Molecular Exercise Physiology - University Center of the Federal District - UDF, Brasilia, Brazil
| | - Henny K. Lima
- Center for Proteomic and Biochemical Analysis, Post-Graduation in Genomic and Biotechnology Sciences, Catholic University of Brasilia, Brasília, Brazil
| | - Octavio L. Franco
- Post-Graduation Program in Physical Education, Catholic University of Brasilia, Brasilia, Brazil
- Center for Proteomic and Biochemical Analysis, Post-Graduation in Genomic and Biotechnology Sciences, Catholic University of Brasilia, Brasília, Brazil
- S-Inova Biotech, Catholic University Dom Bosco, Biotechnology Program, Campo Grande, Brazil
| | - Bernardo Petriz
- Center for Proteomic and Biochemical Analysis, Post-Graduation in Genomic and Biotechnology Sciences, Catholic University of Brasilia, Brasília, Brazil
- Laboratory of Molecular Exercise Physiology - University Center of the Federal District - UDF, Brasilia, Brazil
- Postgraduate Program in Rehabilitation Sciences - University of Brasília, Brasília, Brazil
| |
Collapse
|
|
20
|
Montero-Calle A, Gómez de Cedrón M, Quijada-Freire A, Solís-Fernández G, López-Alonso V, Espinosa-Salinas I, Peláez-García A, Fernández-Aceñero MJ, Ramírez de Molina A, Barderas R. Metabolic Reprogramming Helps to Define Different Metastatic Tropisms in Colorectal Cancer. Front Oncol 2022; 12:903033. [PMID: 35957902 PMCID: PMC9358964 DOI: 10.3389/fonc.2022.903033] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 06/09/2022] [Indexed: 12/02/2022] Open
Abstract
Approximately 25% of colorectal cancer (CRC) patients experience systemic metastases, with the most frequent target organs being the liver and lung. Metabolic reprogramming has been recognized as one of the hallmarks of cancer. Here, metabolic and functional differences between two CRC cells with different metastatic organotropisms (metastatic KM12SM CRC cells to the liver and KM12L4a to the lung when injected in the spleen and in the tail vein of mice) were analysed in comparison to their parental non-metastatic isogenic KM12C cells, for a subsequent investigation of identified metabolic targets in CRC patients. Meta-analysis from proteomic and transcriptomic data deposited in databases, qPCR, WB, in vitro cell-based assays, and in vivo experiments were used to survey for metabolic alterations contributing to their different organotropism and for the subsequent analysis of identified metabolic markers in CRC patients. Although no changes in cell proliferation were observed between metastatic cells, KM12SM cells were highly dependent on oxidative phosphorylation at mitochondria, whereas KM12L4a cells were characterized by being more energetically efficient with lower basal respiration levels and a better redox management. Lipid metabolism-related targets were found altered in both cell lines, including LDLR, CD36, FABP4, SCD, AGPAT1, and FASN, which were also associated with the prognosis of CRC patients. Moreover, CD36 association with lung metastatic tropism of CRC cells was validated in vivo. Altogether, our results suggest that LDLR, CD36, FABP4, SCD, FASN, LPL, and APOA1 metabolic targets are associated with CRC metastatic tropism to the liver or lung. These features exemplify specific metabolic adaptations for invasive cancer cells which stem at the primary tumour.
Collapse
Affiliation(s)
- Ana Montero-Calle
- Functional Proteomics Unit, Chronic Disease Programme, UFIEC, Instituto de Salud Carlos III, Madrid, Spain
| | - Marta Gómez de Cedrón
- Precision Nutrition and Cancer Program, Molecular Oncology Group, IMDEA Food Institute, Campus of International Excellence (CEI) University Autonomous of Madrid (UAM) + Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
| | - Adriana Quijada-Freire
- Precision Nutrition and Cancer Program, Molecular Oncology Group, IMDEA Food Institute, Campus of International Excellence (CEI) University Autonomous of Madrid (UAM) + Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
| | - Guillermo Solís-Fernández
- Molecular Imaging and Photonics Division, Chemistry Department, Faculty of Sciences, KU Leuven, Leuven, Belgium
| | - Victoria López-Alonso
- Unidad de Biología Computacional, Chronic Disease Programme, UFIEC, Instituto de Salud Carlos III, Madrid, Spain
| | - Isabel Espinosa-Salinas
- Platform for Clinical Trials in Nutrition and Health (GENYAL), IMDEA Food Institute, Campus of International Excellence (CEI) University Autonomous of Madrid (UAM) + Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
| | - Alberto Peláez-García
- Molecular Pathology and Therapeutic Targets Group, La Paz University Hospital (IdiPAZ), Madrid, Spain
| | - María Jesús Fernández-Aceñero
- Servicio de Anatomía Patológica Hospital Clínico San Carlos, Departamento de Anatomía Patológica, Facultad de Medicina, Complutense University of Madrid, Madrid, Spain
| | - Ana Ramírez de Molina
- Precision Nutrition and Cancer Program, Molecular Oncology Group, IMDEA Food Institute, Campus of International Excellence (CEI) University Autonomous of Madrid (UAM) + Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
| | - Rodrigo Barderas
- Functional Proteomics Unit, Chronic Disease Programme, UFIEC, Instituto de Salud Carlos III, Madrid, Spain
| |
Collapse
|
|
21
|
Xie M, Xiong Z, Yin S, Xiong J, Li X, Jin L, Zhang F, Chen H, Lan P, Lian L. Adiponectin Alleviates Intestinal Fibrosis by Enhancing AMP-Activated Protein Kinase Phosphorylation. Dig Dis Sci 2022; 67:2232-2243. [PMID: 34009553 DOI: 10.1007/s10620-021-07015-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 04/15/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND Intestinal fibrosis is a common complication of Crohn's disease (CD). Adiponectin reportedly exerts anti-inflammatory effects in various disease models, including colitis models. AIMS In this study, we aimed to determine the effects of adiponectin on intestinal fibrosis and the underlying mechanisms. METHODS A murine model of intestinal fibrosis was established by administering increasing doses of 2,4,6-trinitrobenzene sulfonic acid to Balb/c mice via enema for 7 weeks. Primary human fibroblasts were isolated from the colon tissues of patients with CD. The fibroblasts were incubated with transforming growth factor (TGF)-β1 to establish a fibrosis model in vitro. Pathway inhibitors were used to verify the potential signaling pathways involved in the anti-fibrogenic effect of adiponectin. RESULTS Compared with the normal mesentery, adiponectin expression was significantly increased in the hypertrophic mesentery of patients with CD. Intraperitoneal injection of adiponectin significantly decreased the activity of myeloperoxidase and the expression of pro-inflammatory cytokines (tumor necrosis factor α and interleukin 6) in the colon of fibrosis model mice, whereas the expression of the anti-inflammatory cytokine interleukin 10 was substantially increased. Moreover, adiponectin treatment inhibited colon shortening, decreased colon weight, and reduced fibrotic protein deposition in the model mice. Adiponectin reduced the phosphorylation of Smad2 and collagen deposition induced by TGF-β1 in primary human intestinal fibroblasts, with an increase in AMP-activated protein kinase (AMPK) phosphorylation. Furthermore, this phenomenon was reversed by the AMPK inhibitor. CONCLUSIONS Adiponectin can protect against intestinal fibrosis by enhancing the phosphorylation of AMPK and inhibiting the activity of the TGF-β1/Smad signaling pathway.
Collapse
Affiliation(s)
- Minghao Xie
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26 Yuancun Er Heng Rd., Guangzhou, 510655, Guangdong, People's Republic of China.,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, People's Republic of China
| | - Zhizhong Xiong
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26 Yuancun Er Heng Rd., Guangzhou, 510655, Guangdong, People's Republic of China.,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, People's Republic of China
| | - Shi Yin
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26 Yuancun Er Heng Rd., Guangzhou, 510655, Guangdong, People's Republic of China.,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, People's Republic of China
| | - Jiaqing Xiong
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26 Yuancun Er Heng Rd., Guangzhou, 510655, Guangdong, People's Republic of China.,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, People's Republic of China
| | - Xianzhe Li
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26 Yuancun Er Heng Rd., Guangzhou, 510655, Guangdong, People's Republic of China.,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, People's Republic of China
| | - Longyang Jin
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26 Yuancun Er Heng Rd., Guangzhou, 510655, Guangdong, People's Republic of China.,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, People's Republic of China
| | - Fengxiang Zhang
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26 Yuancun Er Heng Rd., Guangzhou, 510655, Guangdong, People's Republic of China.,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, People's Republic of China
| | - Huaxian Chen
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26 Yuancun Er Heng Rd., Guangzhou, 510655, Guangdong, People's Republic of China.,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, People's Republic of China
| | - Ping Lan
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26 Yuancun Er Heng Rd., Guangzhou, 510655, Guangdong, People's Republic of China.,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, People's Republic of China
| | - Lei Lian
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, 26 Yuancun Er Heng Rd., Guangzhou, 510655, Guangdong, People's Republic of China. .,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, People's Republic of China.
| |
Collapse
|
|
22
|
Chuck W, Shadbolt BF, Nordin F, Subramaniam K. BMI is important in predicting the loss of response in inflammatory bowel disease patients on tumour necrosis factor-α inhibitors. Eur J Gastroenterol Hepatol 2022; 34:622-629. [PMID: 35352694 DOI: 10.1097/meg.0000000000002371] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
INTRODUCTION Obesity is an emerging phenomenon among patients with inflammatory bowel disease (IBD). This study aims to evaluate whether the response to tumour necrosis factor-α (TNF-α) inhibitors (infliximab and adalimumab) could be influenced by BMI in IBD. METHODS We identified a cohort of 181 IBD patients attending a single-tertiary centre, naive to biologic therapy and stratified them according to their BMI. The primary outcome is the first occurrence of loss of response (LOR). RESULTS The median BMI was 26 kg/m2 (15-63 kg/m2). Approximately 68% of patients had LOR on both adalimumab (ADA) (n = 52) and infliximab (IFX) (n = 71). However, 83% on ADA with BMI ≥30 kg/m2 had LOR compared to 61% on IFX with BMI ≥30 kg/m2. For patients on ADA, Cox regression analysis revealed that after accounting for age, sex, disease type, duration of disease, fistulising disease, smoking status, haemoglobin, C-reactive protein, albumin and platelet levels, there were statistically significant associations between BMI (≥30 kg/m2 vs. <30 kg/m2) and LOR [P = 0.010; hazard ratio (HR) 3.2; confidence interval (CI), 1.3-7.6]. However, for patients on IFX, after accounting for the same factors, the only significant factor was the association of lower rate of LOR with higher albumin levels (P = 0.024; HR 0.95; CI, 0.91-0.99). There was an increased accelerated time to LOR for patients on ADA with BMI ≥30 kg/m2 compared to BMI <30 kg/m2 (P = 0.026). However, there was no difference in time to LOR for patients on IFX (P = 0.177). CONCLUSION BMI is important in predicting the LOR among IBD patients on TNF-α inhibitors, especially among patients receiving ADA.
Collapse
Affiliation(s)
- Winnie Chuck
- Gastroenterology and Hepatology Unit, Canberra Hospital
| | | | - Fariza Nordin
- Gastroenterology and Hepatology Unit, Canberra Hospital
| | - Kavitha Subramaniam
- Gastroenterology and Hepatology Unit, Canberra Hospital
- ANU Medical School, Australian National University, Canberra, Australian Capital Territory, Australia
| |
Collapse
|
|
23
|
Karaskova E, Kubickova V, Velganova-Veghova M, Geryk M, Foltenova H, Karasek D. Circulating Levels of WISP-1 (Wnt1-Inducible Signaling Pathway Protein 1) and Other Selected Adipokines in Children With Inflammatory Bowel Disease. Physiol Res 2022; 71:275-284. [DOI: 10.33549/physiolres.934854] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Wnt1 inducible protein-1 signaling pathway (WISP-1) is a relatively new adipokine involved in many cellular processes, including epithelial mucosa healing. The aim of the study was to compare circulating levels of WISP-1 and other selected adipokines [adiponectin, resistin and retinol-binding protein 4 (RBP-4)] in children with inflammatory bowel disease (IBD) with healthy controls and to investigate possible differences between Crohn's disease patients. (CD) or ulcerative colitis (UC). The study was performed as a case-control study. In addition to adipokines, anthropometric, lipid parameters, markers of inflammation or disease activity were evaluated in all participants. Compared to healthy controls (n=20), significantly lower levels of adiponectin and higher levels of resistin and WISP-1 were found in patients with IBD (n=58). Elevation of WISP-1 was detected only in the CD group (n=31). There were no differences in RBP-4 levels between the groups. Adiponectin, WISP-1 and RBP-4 were independently associated with body mass index only, resistin levels were associated with C-reactive protein levels and leukocyte counts. Adverse adipokines production reflects presence of dysfunctional fat tissue in IBD patients. Higher levels of WISP-1 in CD compared to patients with UC may indicate a specific role for mesenteric adipose tissue in WISP-1 production.
Collapse
|
|
24
|
Abstract
AbstractCrohn's disease (CD) is a chronic relapsing inflammatory bowel disease with unknown etiology. Up to 80% of patients will eventually require surgery throughout their lifetime, and often repeated resections are required for disease recurrence. Observations of “creeping fat” surrounding the diseased intestine renewed interest in the mesentery, recently defined as an organ with endocrine and immune functions. According to the inside-out model, the mesentery may be primarily affected in CD and subsequent cause alterations in the mucosa. Recently, lower surgical recurrence rates have been reported with en-bloc excision of the mesentery adjoining the diseased intestine. Results of ongoing randomized controlled trials may clarify the role of the mesentery in CD and possibly lead to its adoption as standard during surgery for Crohn's disease.
Collapse
|
|
25
|
Role of Obesity, Physical Exercise, Adipose Tissue-Skeletal Muscle Crosstalk and Molecular Advances in Barrett's Esophagus and Esophageal Adenocarcinoma. Int J Mol Sci 2022; 23:ijms23073942. [PMID: 35409299 PMCID: PMC8999972 DOI: 10.3390/ijms23073942] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/28/2022] [Accepted: 03/30/2022] [Indexed: 02/07/2023] Open
Abstract
Both obesity and esophageal adenocarcinoma (EAC) rates have increased sharply in the United States and Western Europe in recent years. EAC is a classic example of obesity-related cancer where the risk of EAC increases with increasing body mass index. Pathologically altered visceral fat in obesity appears to play a key role in this process. Visceral obesity may promote EAC by directly affecting gastroesophageal reflux disease and Barrett’s esophagus (BE), as well as a less reflux-dependent effect, including the release of pro-inflammatory adipokines and insulin resistance. Deregulation of adipokine production, such as the shift to an increased amount of leptin relative to “protective” adiponectin, has been implicated in the pathogenesis of BE and EAC. This review discusses not only the epidemiology and pathophysiology of obesity in BE and EAC, but also molecular alterations at the level of mRNA and proteins associated with these esophageal pathologies and the potential role of adipokines and myokines in these disorders. Particular attention is given to discussing the possible crosstalk of adipokines and myokines during exercise. It is concluded that lifestyle interventions to increase regular physical activity could be helpful as a promising strategy for preventing the development of BE and EAC.
Collapse
|
|
26
|
Ferraz LF, Caria CREP, Santos RDC, Ribeiro ML, Gambero A. Effects of systemic inflammation due to hepatic ischemia-reperfusion injury upon lean or obese visceral adipose tissue. Acta Cir Bras 2022; 37:e370105. [PMID: 35293942 PMCID: PMC8923565 DOI: 10.1590/acb370105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 12/12/2021] [Indexed: 11/22/2022] Open
Abstract
Purpose: To evaluate how the induction of liver damage by ischemia and reperfusion
affects the adipose tissue of lean and obese mice. Methods: Lean and diet-induced obese mice were subjected to liver ischemia (30 min)
followed by 6 h of reperfusion. The vascular stromal fraction of visceral
adipose tissue was analyzed by cytometry, and gene expression was evaluated
by an Array assay and by RT-qPCR. Intestinal permeability was assessed by
oral administration of fluorescein isothiocyanate (FITC)-dextran and
endotoxemia by serum endotoxin measurements using a limulus amebocyte lysate
assay. Results: It was found that, after liver ischemia and reperfusion, there is an
infiltration of neutrophils, monocytes, and lymphocytes, as well as an
increase in the gene expression that encode cytokines, chemokines and their
receptors in the visceral adipose tissue of lean mice. This inflammatory
response was associated with the presence of endotoxemia in lean mice.
However, these changes were not observed in the visceral adipose tissue of
obese mice. Conclusions: Liver ischemia and reperfusion induce an acute inflammatory response in
adipose tissue of lean mice characterized by an intense chemokine induction
and leukocyte infiltration; however, inflammatory alterations are already
present at baseline in the obese adipose tissue and liver ischemia and
reperfusion do not injure further.
Collapse
|
|
27
|
Suau R, Pardina E, Domènech E, Lorén V, Manyé J. The Complex Relationship Between Microbiota, Immune Response and Creeping Fat in Crohn's Disease. J Crohns Colitis 2022; 16:472-489. [PMID: 34528668 DOI: 10.1093/ecco-jcc/jjab159] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
In the last decade, there has been growing interest in the pathological involvement of hypertrophic mesenteric fat attached to the serosa of the inflamed intestinal segments involved in Crohn's disease [CD], known as creeping fat. In spite of its protective nature, creeping fat harbours an aberrant inflammatory activity which, in an already inflamed intestine, may explain why creeping fat is associated with a greater severity of CD. The transmural inflammation of CD facilitates the interaction of mesenteric fat with translocated intestinal microorganisms, contributing to activation of the immune response. This may be not the only way in which microorganisms alter the homeostasis of this fatty tissue: intestinal dysbiosis may also impair xenobiotic metabolism. All these CD-related alterations have a functional impact on nuclear receptors such as the farnesoid X receptor or the peroxisome proliferator-activated receptor γ, which are implicated in regulation of the immune response, adipogenesis and the maintenance of barrier function, as well as on creeping fat production of inflammatory-associated cells such as adipokines. The dysfunction of creeping fat worsens the inflammatory course of CD and may favour intestinal fibrosis and fistulizing complications. However, our current knowledge of the pathophysiology and pathogenic role of creeping fat is controversial and a better understanding might provide new therapeutic targets for CD. Here we aim to review and update the key cellular and molecular alterations involved in this inflammatory process that link the pathological components of CD with the development of creeping fat.
Collapse
Affiliation(s)
- Roger Suau
- IBD Research Group, 'Germans Trias i Pujol' Research Institute (IGTP), Badalona (Catalonia), Spain.,Centro de Investigación Biomédica en Red (CIBER), Madrid, Spain
| | - Eva Pardina
- Biochemistry and Molecular Biomedicine Department, University of Barcelona, Barcelona (Catalonia), Spain
| | - Eugeni Domènech
- IBD Research Group, 'Germans Trias i Pujol' Research Institute (IGTP), Badalona (Catalonia), Spain.,Centro de Investigación Biomédica en Red (CIBER), Madrid, Spain.,Gastroenterology Department, 'Germans Trias i Pujol' University Hospital, Badalona (Catalonia), Spain
| | - Violeta Lorén
- IBD Research Group, 'Germans Trias i Pujol' Research Institute (IGTP), Badalona (Catalonia), Spain.,Centro de Investigación Biomédica en Red (CIBER), Madrid, Spain
| | - Josep Manyé
- IBD Research Group, 'Germans Trias i Pujol' Research Institute (IGTP), Badalona (Catalonia), Spain.,Centro de Investigación Biomédica en Red (CIBER), Madrid, Spain
| |
Collapse
|
|
28
|
Zheng Z, Wu L, Li Z, Jaspers RT, Huang H, Zhang Q, Li Z, Pathak JL, Wu G, Li H. Local administration of low doses of exogenous BMP2 and leptin promotes ectopic bone regeneration in leptin-deficient mice. Biomed Mater Eng 2022; 33:303-313. [PMID: 35147528 DOI: 10.3233/bme-211323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Obesity and leptin deficiency are associated with compromised bone regeneration. OBJECTIVE This study aims to investigate the role of locally administrated low-dose BMP2+leptin on bone regeneration in leptin-deficient obese (ob/ob) mice. METHODS Wildtype (WT) and ob/ob mice were divided into 3 groups (4 mice/group): BMP2 (5 μg) group, BMP2+low-dose leptin (1 μg) group, and BMP2+high-dose leptin (2.5 μg) group. WT mice were used as control mice. An equal size absorbable collagen sponge was prepared by loading the BMP2 or/and leptin and implanted subcutaneously. After 19 days, samples were collected and analyzed by micro-CT and H&E staining. RESULTS No significant difference in bone regeneration among the three groups in WT mice. Quantification of newly formed bone parameters from micro-CT and H&E staining showed that low-dose BMP2 treatment formed less new bone in ob/ob mice compared to WT. BMP2+low-dose leptin treatment substantially rescued the compromised bone regeneration in ob/ob mice up to the level in WT mice. However, the BMP2 and high dose of leptin failed to rescue the compromised bone regeneration in ob/ob mice. CONCLUSION Our findings suggest that a combination of the low-dose BMP2 and leptin could be a strategy to promote osteogenesis in obese populations with leptin deficiency.
Collapse
Affiliation(s)
- Zhichao Zheng
- Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, China.,Laboratory for Myology, Faculty of Behavioral and Movement Sciences, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Lihong Wu
- Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, China
| | - Zhicong Li
- Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, China
| | - Richard T Jaspers
- Laboratory for Myology, Faculty of Behavioral and Movement Sciences, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Hairong Huang
- Department of Oral Implantology and Prosthetic Dentistry, Academic Centre for Dentistry Amsterdam (ACTA), Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Qing Zhang
- Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, China
| | - Zhengmao Li
- Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, China
| | - Janak L Pathak
- Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, China
| | - Gang Wu
- Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, China.,Department of Oral Implantology and Prosthetic Dentistry, Academic Centre for Dentistry Amsterdam (ACTA), Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Hongtao Li
- State Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| |
Collapse
|
|
29
|
Bilski J, Pierzchalski P, Szczepanik M, Bonior J, Zoladz JA. Multifactorial Mechanism of Sarcopenia and Sarcopenic Obesity. Role of Physical Exercise, Microbiota and Myokines. Cells 2022; 11:cells11010160. [PMID: 35011721 PMCID: PMC8750433 DOI: 10.3390/cells11010160] [Citation(s) in RCA: 105] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/27/2021] [Accepted: 12/31/2021] [Indexed: 02/07/2023] Open
Abstract
Obesity and ageing place a tremendous strain on the global healthcare system. Age-related sarcopenia is characterized by decreased muscular strength, decreased muscle quantity, quality, and decreased functional performance. Sarcopenic obesity (SO) is a condition that combines sarcopenia and obesity and has a substantial influence on the older adults’ health. Because of the complicated pathophysiology, there are disagreements and challenges in identifying and diagnosing SO. Recently, it has become clear that dysbiosis may play a role in the onset and progression of sarcopenia and SO. Skeletal muscle secretes myokines during contraction, which play an important role in controlling muscle growth, function, and metabolic balance. Myokine dysfunction can cause and aggravate obesity, sarcopenia, and SO. The only ways to prevent and slow the progression of sarcopenia, particularly sarcopenic obesity, are physical activity and correct nutritional support. While exercise cannot completely prevent sarcopenia and age-related loss in muscular function, it can certainly delay development and slow down the rate of sarcopenia. The purpose of this review was to discuss potential pathways to muscle deterioration in obese individuals. We also want to present the current understanding of the role of various factors, including microbiota and myokines, in the process of sarcopenia and SO.
Collapse
Affiliation(s)
- Jan Bilski
- Department of Biomechanics and Kinesiology, Chair of Biomedical Sciences, Faculty of Health Sciences, Institute of Physiotherapy, Jagiellonian University Medical College, 31-008 Krakow, Poland
- Correspondence: ; Tel.: +48-12-421-93-51
| | - Piotr Pierzchalski
- Department of Medical Physiology, Chair of Biomedical Sciences, Faculty of Health Sciences, Institute of Physiotherapy, Jagiellonian University Medical College, 31-126 Krakow, Poland; (P.P.); (J.B.)
| | - Marian Szczepanik
- Department of Medical Biology, Chair of Biomedical Sciences, Faculty of Health Sciences, Institute of Physiotherapy, Jagiellonian University Medical College, 31-034 Krakow, Poland;
| | - Joanna Bonior
- Department of Medical Physiology, Chair of Biomedical Sciences, Faculty of Health Sciences, Institute of Physiotherapy, Jagiellonian University Medical College, 31-126 Krakow, Poland; (P.P.); (J.B.)
| | - Jerzy A. Zoladz
- Chair of Exercise Physiology and Muscle Bioenergetics, Faculty of Health Sciences, Jagiellonian University Medical College, 31-066 Krakow, Poland;
| |
Collapse
|
|
30
|
Yin Y, Zhu ZX, Li Z, Chen YS, Zhu WM. Role of mesenteric component in Crohn’s disease: A friend or foe? World J Gastrointest Surg 2021; 13:1536-1549. [PMID: 35070062 PMCID: PMC8727179 DOI: 10.4240/wjgs.v13.i12.1536] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 08/01/2021] [Accepted: 11/25/2021] [Indexed: 02/06/2023] Open
Abstract
Crohn’s disease (CD) is a complex and relapsing gastrointestinal disease with mesenteric alterations. The mesenteric neural, vascular, and endocrine systems actively take part in the gut dysbiosis-adaptive immunity-mesentery-body axis, and this axis has been proven to be bidirectional. The abnormalities of morphology and function of the mesenteric component are associated with intestinal inflammation and disease progress of CD via responses to afferent signals, neuropeptides, lymphatic drainage, adipokines, and functional cytokines. The hypertrophy of mesenteric adipose tissue plays important roles in the pathogenesis of CD by secreting large amounts of adipokines and representing a rich source of proinflammatory or profibrotic cytokines. The vascular alteration, including angiogenesis and lymphangiogenesis, is concomitant in the disease course of CD. Of note, the enlarged and obstructed lymphatic vessels, which have been described in CD patients, are likely related to the early onset submucosa edema and being a cause of CD. The function of mesenteric lymphatics is influenced by endocrine of mesenteric nerves and adipocytes. Meanwhile, the structure of the mesenteric lymphatic vessels in hypertrophic mesenteric adipose tissue is mispatterned and ruptured, which can lead to lymph leakage. Leaky lymph factors can in turn stimulate adipose tissue to proliferate and effectively elicit an immune response. The identification of the role of mesentery and the crosstalk between mesenteric tissues in intestinal inflammation may shed light on understanding the underlying mechanism of CD and help explore new therapeutic targets.
Collapse
Affiliation(s)
- Yi Yin
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Zhen-Xing Zhu
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Zhun Li
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Yu-Sheng Chen
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Wei-Ming Zhu
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
| |
Collapse
|
|
31
|
Hyun CK. Molecular and Pathophysiological Links between Metabolic Disorders and Inflammatory Bowel Diseases. Int J Mol Sci 2021; 22:ijms22179139. [PMID: 34502047 PMCID: PMC8430512 DOI: 10.3390/ijms22179139] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 08/21/2021] [Accepted: 08/22/2021] [Indexed: 02/07/2023] Open
Abstract
Despite considerable epidemiological evidence indicating comorbidity between metabolic disorders, such as obesity, type 2 diabetes, and non-alcoholic fatty liver disease, and inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis, as well as common pathophysiological features shared by these two categories of diseases, the relationship between their pathogenesis at molecular levels are not well described. Intestinal barrier dysfunction is a characteristic pathological feature of IBD, which also plays causal roles in the pathogenesis of chronic inflammatory metabolic disorders. Increased intestinal permeability is associated with a pro-inflammatory response of the intestinal immune system, possibly leading to the development of both diseases. In addition, dysregulated interactions between the gut microbiota and the host immunity have been found to contribute to immune-mediated disorders including the two diseases. In connection with disrupted gut microbial composition, alterations in gut microbiota-derived metabolites have also been shown to be closely related to the pathogeneses of both diseases. Focusing on these prominent pathophysiological features observed in both metabolic disorders and IBD, this review highlights and summarizes the molecular risk factors that may link between the pathogeneses of the two diseases, which is aimed at providing a comprehensive understanding of molecular mechanisms underlying their comorbidity.
Collapse
Affiliation(s)
- Chang-Kee Hyun
- School of Life Science, Handong Global University, Pohang 37554, Gyungbuk, Korea
| |
Collapse
|
|
32
|
Adipose stem cell niche reprograms the colorectal cancer stem cell metastatic machinery. Nat Commun 2021; 12:5006. [PMID: 34408135 PMCID: PMC8373975 DOI: 10.1038/s41467-021-25333-9] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 08/03/2021] [Indexed: 12/30/2022] Open
Abstract
Obesity is a strong risk factor for cancer progression, posing obesity-related cancer as one of the leading causes of death. Nevertheless, the molecular mechanisms that endow cancer cells with metastatic properties in patients affected by obesity remain unexplored. Here, we show that IL-6 and HGF, secreted by tumor neighboring visceral adipose stromal cells (V-ASCs), expand the metastatic colorectal (CR) cancer cell compartment (CD44v6 + ), which in turn secretes neurotrophins such as NGF and NT-3, and recruits adipose stem cells within tumor mass. Visceral adipose-derived factors promote vasculogenesis and the onset of metastatic dissemination by activation of STAT3, which inhibits miR-200a and enhances ZEB2 expression, effectively reprogramming CRC cells into a highly metastatic phenotype. Notably, obesity-associated tumor microenvironment provokes a transition in the transcriptomic expression profile of cells derived from the epithelial consensus molecular subtype (CMS2) CRC patients towards a mesenchymal subtype (CMS4). STAT3 pathway inhibition reduces ZEB2 expression and abrogates the metastatic growth sustained by adipose-released proteins. Together, our data suggest that targeting adipose factors in colorectal cancer patients with obesity may represent a therapeutic strategy for preventing metastatic disease. Obesity is a major risk factor for cancer related death. Here, the authors show that visceral adipose-derived factors promote vasculogenesis and metastatic dissemination by activation of STAT3, which inhibits miR-200a and enhances ZEB2 expression, effectively reprogramming colorectal cancer cells into a highly metastatic phenotype.
Collapse
|
|
33
|
Zeng MS, Yu WD, Wang HX, Xu PP, Liu JY. Puerarin reduces impairment of intestinal and adipose immune responses to influenza virus infection in mice. Arch Virol 2021; 166:2387-2397. [PMID: 34114139 PMCID: PMC8191723 DOI: 10.1007/s00705-021-05112-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 04/05/2021] [Indexed: 11/07/2022]
Abstract
Influenza is an acute viral respiratory disease that can also cause gastroenteritis-like symptoms, such as abdominal pain, nausea, vomiting, and diarrhea. Immune dysfunction of adipose tissue is involved in the occurrence and prognosis of influenza viral pneumonia. In this study, we analyzed intestinal and adipose immune responses in mice infected with influenza virus and found that the impairment of intestinal and adipose immunity to influenza virus infection could be reversed by treatment with puerarin, a medicinal compound isolated from Pueraria lobata (called “gegen” in Chinese). We found that the lungs, small intestines (duodenum, ileum, jejunum) and large intestines (colon and rectum) of infected mice showed obvious inflammatory lesions, with significantly increased levels of virus, inflammatory cytokines (interleukin [IL]-6, IL-17, and tumor necrosis factor-α), Toll-like receptors 3, 4, and 9, and integrin αvβ3 and α4, and a decreased level of secreted IgA compared to the normal control group (NC) (P < 0.05-0.001). Influenza virus infected mesenteric lymph nodes and adipose tissue, and adipokines (leptin, visfatin, “chemerin”, and adiponectin) of lung and mesenteric adipose tissue were dysregulated. Puerarin treatment reversed the impairment of the intestinal and adipose immune responses in mice infected with influenza virus. Our findings suggest that influenza virus can infect adipose tissue and lead to intestinal adipose immune dysfunction in normal-weight mice and that the impairment of the intestinal and adipose immune response to influenza virus infection can be reversed by puerarin treatment.
Collapse
Affiliation(s)
- Mao-Seng Zeng
- Institute of Tropical Medicine, Guangzhou University of Chinese Medicine, 12 Jichang Rd., San Yuanli St., Bai Yun Dist., Guangzhou, 510405, Guangdong, People's Republic of China
| | - Wen-Di Yu
- Institute of Tropical Medicine, Guangzhou University of Chinese Medicine, 12 Jichang Rd., San Yuanli St., Bai Yun Dist., Guangzhou, 510405, Guangdong, People's Republic of China
| | - Hui-Xian Wang
- Institute of Tropical Medicine, Guangzhou University of Chinese Medicine, 12 Jichang Rd., San Yuanli St., Bai Yun Dist., Guangzhou, 510405, Guangdong, People's Republic of China
| | - Pei-Ping Xu
- Institute of Tropical Medicine, Guangzhou University of Chinese Medicine, 12 Jichang Rd., San Yuanli St., Bai Yun Dist., Guangzhou, 510405, Guangdong, People's Republic of China.
| | - Jin-Yuan Liu
- Basic Medical College, Guangzhou University of Chinese Medicine, 12 Jichang Rd., San Yuanli St., Bai Yun Dist., Guangzhou, 510405, Guangdong, People's Republic of China.
| |
Collapse
|
|
34
|
Heap RE, Marín-Rubio JL, Peltier J, Heunis T, Dannoura A, Moore A, Trost M. Proteomics characterisation of the L929 cell supernatant and its role in BMDM differentiation. Life Sci Alliance 2021; 4:e202000957. [PMID: 33853969 PMCID: PMC8091624 DOI: 10.26508/lsa.202000957] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 03/31/2021] [Accepted: 04/07/2021] [Indexed: 01/02/2023] Open
Abstract
BMDMs are a key model system to study macrophage biology in vitro. Commonly used methods to differentiate macrophages from BM are treatment with either recombinant M-CSF or the supernatant of L929 cells, which secrete M-CSF. However, little is known about the composition of L929 cell-conditioned media (LCCM) and how it affects the BMDM phenotype. Here, we used quantitative mass spectrometry to characterise the kinetics of protein secretion from L929 cells over a 2-wk period, identifying 2,193 proteins. Whereas M-CSF is very abundant in LCCM, we identified several other immune-regulatory proteins such as macrophage migration inhibitory factor (MIF), osteopontin, and chemokines such as Ccl2 and Ccl7 at surprisingly high abundance levels. We therefore further characterised the proteomes of BMDMs after differentiation with M-CSF, M-CSF + MIF, or LCCM, respectively. Interestingly, macrophages differentiated with LCCM induced a stronger anti-inflammatory M1 phenotype that those differentiated with M-CSF. This resource will be valuable to all researchers using LCCM for the differentiation of BMDMs.
Collapse
Affiliation(s)
- Rachel E Heap
- Laboratory for Biological Mass Spectrometry, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - José Luis Marín-Rubio
- Laboratory for Biological Mass Spectrometry, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Julien Peltier
- Laboratory for Biological Mass Spectrometry, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Tiaan Heunis
- Laboratory for Biological Mass Spectrometry, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Abeer Dannoura
- Laboratory for Biological Mass Spectrometry, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Adam Moore
- Laboratory for Biological Mass Spectrometry, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Matthias Trost
- Laboratory for Biological Mass Spectrometry, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| |
Collapse
|
|
35
|
Abstract
Several non-redundant features of the tumour microenvironment facilitate immunosuppression and limit anticancer immune responses. These include physical barriers to immune infiltration, the recruitment of suppressive immune cells and the upregulation of ligands on tumour cells that bind to inhibitory receptors on immune cells. Recent insights into the importance of the metabolic restrictions imposed by the tumour microenvironment on antitumour T cells have begun to inform immunotherapeutic anticancer strategies. Therapeutics that target metabolic restrictions, such as low glucose levels, a low pH, hypoxia and the generation of suppressive metabolites, have shown promise as combination therapies for different types of cancer. In this Review, we discuss the metabolic aspects of the antitumour T cell response in the context of immune checkpoint blockade, adoptive cell therapy and treatment with oncolytic viruses, and discuss emerging combination strategies.
Collapse
|
|
36
|
Karaskova E, Velganova-Veghova M, Geryk M, Foltenova H, Kucerova V, Karasek D. Role of Adipose Tissue in Inflammatory Bowel Disease. Int J Mol Sci 2021; 22:4226. [PMID: 33921758 PMCID: PMC8073530 DOI: 10.3390/ijms22084226] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 04/05/2021] [Accepted: 04/16/2021] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel diseases (IBDs), chronic inflammatory disorders affecting the gastrointestinal tract, include Crohn's disease and ulcerative colitis. There are increasing clinical and experimental data showing that obesity, especially visceral adiposity, plays a substantial role in the pathogenesis of IBD. Obesity seems to be an important risk factor also for IBD disease severity and clinical outcomes. Visceral adipose tissue is an active multifunctional metabolic organ involved in lipid storage and immunological and endocrine activity. Bowel inflammation penetrates the surrounding adipose tissue along the mesentery. Mesenteric fat serves as a barrier to inflammation and controls immune responses to the translocation of gut bacteria. At the same time, mesenteric adipose tissue may be the principal source of cytokines and adipokines responsible for inflammatory processes associated with IBD. This review is particularly focusing on the potential role of adipokines in IBD pathogenesis and their possible use as promising therapeutic targets.
Collapse
Affiliation(s)
- Eva Karaskova
- Department of Pediatrics, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, 77900 Olomouc, Czech Republic; (M.V.-V.); (M.G.); (H.F.)
| | - Maria Velganova-Veghova
- Department of Pediatrics, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, 77900 Olomouc, Czech Republic; (M.V.-V.); (M.G.); (H.F.)
| | - Milos Geryk
- Department of Pediatrics, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, 77900 Olomouc, Czech Republic; (M.V.-V.); (M.G.); (H.F.)
| | - Hana Foltenova
- Department of Pediatrics, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, 77900 Olomouc, Czech Republic; (M.V.-V.); (M.G.); (H.F.)
| | - Veronika Kucerova
- Department of Clinical Biochemistry, University Hospital Olomouc, 77900 Olomouc, Czech Republic;
| | - David Karasek
- Third Department of Internal Medicine—Nephrology, Rheumatology and Endocrinology, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, 77900 Olomouc, Czech Republic;
| |
Collapse
|
|
37
|
Ambroszkiewicz J, Gajewska J, Chełchowska M, Rowicka G. Assessment of Inflammatory Markers in Children with Cow's Milk Allergy Treated with a Milk-Free Diet. Nutrients 2021; 13:nu13041057. [PMID: 33805091 PMCID: PMC8064076 DOI: 10.3390/nu13041057] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/19/2021] [Accepted: 03/21/2021] [Indexed: 12/20/2022] Open
Abstract
Background: The aim of the study was to establish whether the use of a strict milk-free diet in children with cow’s milk allergy, resulting in the resolution of clinical symptoms of the disease, also extinguishes the inflammatory reaction induced by the allergy. Methods: We examined 64 children (aged 3–6 years) with a diagnosed cow’s milk allergy who had been treated with an elimination diet for at least six months and showed remission of the disease’s clinical symptoms as a result of the treatment. The control group consisted of 30 healthy children of the same age following an unrestricted age-appropriate diet. Concentrations of cytokines, calprotectin, and adipokines (leptin, resistin, chemerin, neutrophilic lipocalin associated with gelatinase—NGAL) were determined in the serum samples obtained from the studied children by immunoenzymatic assays. Results: Patients with CMA had significantly higher median values of serum IL-6, TNF-α, resistin, chemerin and NGAL in comparison to the healthy children (p < 0.05, p < 0.001, p < 0.05, p < 0.01, p < 0.001, respectively). Serum concentrations of IL-10, leptin, calprotectin and CRP as well as in WBC count were in the same range in both studied groups. We observed direct statistically significant correlations between levels of IL-10 and CRP (p = 0.005), IL-10 and WBC (p = 0.045), TNF-α and WBC (p = 0.038), calprotectin and WBC (p < 0.001), chemerin and CRP (p < 0.001) as well as between NGAL and WBC (p = 0.002) in children with CMA. Conclusion: The use of a strict milk-free diet by children with CMA, resulting in the resolution of clinical symptoms of the disease, does not seem to extinguish the inflammation induced by the allergy. The findings of this study—elevated IL-6, TNF-α, resistin, chemerin and NGAL levels in patients with CMA—suggest that these parameters seem to be involved in the generation of a low-grade proinflammatory environment observed in cow‘s milk allergy and could be used to monitor the effectiveness of treatment.
Collapse
Affiliation(s)
- Jadwiga Ambroszkiewicz
- Department of Screening Tests and Metabolic Diagnostics, Institute of Mother and Child, Kasprzaka 17A, 01-211 Warsaw, Poland; (J.G.); (M.C.)
- Correspondence: ; Tel.: +48-22-327-7260
| | - Joanna Gajewska
- Department of Screening Tests and Metabolic Diagnostics, Institute of Mother and Child, Kasprzaka 17A, 01-211 Warsaw, Poland; (J.G.); (M.C.)
| | - Magdalena Chełchowska
- Department of Screening Tests and Metabolic Diagnostics, Institute of Mother and Child, Kasprzaka 17A, 01-211 Warsaw, Poland; (J.G.); (M.C.)
| | - Grażyna Rowicka
- Department of Nutrition, Institute of Mother and Child, Kasprzaka 17A, 01-211 Warsaw, Poland;
| |
Collapse
|
|
38
|
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.
Collapse
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
| |
Collapse
|
|
39
|
Soták M, Casselbrant A, Rath E, Zietek T, Strömstedt M, Adingupu DD, Karlsson D, Fritsch Fredin M, Ergang P, Pácha J, Batorsky A, Alpers CE, Börgeson E, Hansen PBL, Ericsson A, Björnson Granqvist A, Wallenius V, Fändriks L, Unwin RJ. Intestinal sodium/glucose cotransporter 3 expression is epithelial and downregulated in obesity. Life Sci 2020; 267:118974. [PMID: 33385407 DOI: 10.1016/j.lfs.2020.118974] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 12/11/2020] [Accepted: 12/20/2020] [Indexed: 12/12/2022]
Abstract
AIM We aimed to determine whether the sodium/glucose cotransporter family member SGLT3, a proposed glucose sensor, is expressed in the intestine and/or kidney, and if its expression is altered in mouse models of obesity and in humans before and after weight-loss surgery. MAIN METHODS We used in-situ hybridization and quantitative PCR to determine whether the Sglt3 isoforms 3a and 3b were expressed in the intestine and kidney of C57, leptin-deficient ob/ob, and diabetic BTBR ob/ob mice. Western blotting and immunohistochemistry were also used to assess SGLT3 protein levels in jejunal biopsies from obese patients before and after weight-loss Roux-en-Y gastric bypass surgery (RYGB), and in lean healthy controls. KEY FINDINGS Sglt3a/3b mRNA was detected in the small intestine (duodenum, jejunum and ileum), but not in the large intestine or kidneys of mice. Both isoforms were detected in epithelial cells (confirmed using intestinal organoids). Expression of Sglt3a/3b mRNA in duodenum and jejunum was significantly lower in ob/ob and BTBR ob/ob mice than in normal-weight littermates. Jejunal SGLT3 protein levels in aged obese patients before RYGB were lower than in lean individuals, but substantially upregulated 6 months post-RYGB. SIGNIFICANCE Our study shows that Sglt3a/3b is expressed primarily in epithelial cells of the small intestine in mice. Furthermore, we observed an association between intestinal mRNA Sglt3a/3b expression and obesity in mice, and between jejunal SGLT3 protein levels and obesity in humans. Further studies are required to determine the possible role of SGLT3 in obesity.
Collapse
Affiliation(s)
- Matúš Soták
- Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, University of Gothenburg, Sweden; Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Sweden.
| | - Anna Casselbrant
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Eva Rath
- Chair of Nutrition and Immunology, Technische Universität München, Freising, Germany
| | - Tamara Zietek
- Department of Nutritional Physiology, Technische Universität München, Freising, Germany
| | - Maria Strömstedt
- Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Damilola D Adingupu
- Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Daniel Karlsson
- Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Maria Fritsch Fredin
- Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Peter Ergang
- Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic
| | - Jiří Pácha
- Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic
| | - Anna Batorsky
- Department of Pathology, University of Washington School of Medicine, Seattle, USA
| | - Charles E Alpers
- Department of Pathology, University of Washington School of Medicine, Seattle, USA
| | - Emma Börgeson
- Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, University of Gothenburg, Sweden; Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Sweden; Department of Clinical Physiology, Sahlgrenska University Hospital, Sweden
| | - Pernille B L Hansen
- Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Sweden
| | - Anette Ericsson
- Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Anna Björnson Granqvist
- Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Ville Wallenius
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Lars Fändriks
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Robert J Unwin
- Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Department of Renal Medicine, Division of Medicine, University College London, UK
| |
Collapse
|
|
40
|
Tsai YW, Fu SH, Dong JL, Chien MW, Liu YW, Hsu CY, Sytwu HK. Adipokine-Modulated Immunological Homeostasis Shapes the Pathophysiology of Inflammatory Bowel Disease. Int J Mol Sci 2020; 21:ijms21249564. [PMID: 33334069 PMCID: PMC7765468 DOI: 10.3390/ijms21249564] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 12/07/2020] [Accepted: 12/13/2020] [Indexed: 12/11/2022] Open
Abstract
Inflammatory colon diseases, which are a global health concern, include a variety of gastrointestinal tract disorders, such as inflammatory bowel disease and colon cancer. The pathogenesis of these colon disorders involves immune alterations with the pronounced infiltration of innate and adaptive immune cells into the intestines and the augmented expression of mucosal pro-inflammatory cytokines stimulated by commensal microbiota. Epidemiological studies during the past half century have shown that the proportion of obese people in a population is associated with the incidence and pathogenesis of gastrointestinal tract disorders. The advancement of understanding of the immunological basis of colon disease has shown that adipocyte-derived biologically active substances (adipokines) modulate the role of innate and adaptive immune cells in the progress of intestinal inflammation. The biomedical significance in immunological homeostasis of adipokines, including adiponectin, leptin, apelin and resistin, is clear. In this review, we highlight the existing literature on the effect and contribution of adipokines to the regulation of immunological homeostasis in inflammatory colon diseases and discuss their crucial roles in disease etiology and pathogenesis, as well as the implications of these results for new therapies in these disorders.
Collapse
Affiliation(s)
- Yi-Wen Tsai
- Department of Family Medicine, Chang Gung Memorial Hospital, Keelung, No. 222, Maijin Road, Keelung 204, Taiwan;
- College of Medicine, Chang-Gung University, No. 259, Wenhua 1st Rd., Guishan Dist., Taoyuan City 333, Taiwan
- Graduate Institute of Medical Sciences, National Defense Medical Center, No. 161, Section 6, Min Chuan East Road, Neihu, Taipei 114, Taiwan
| | - Shin-Huei Fu
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, No. 161, Section 6, Min Chuan East Road, Neihu, Taipei 114, Taiwan; (S.-H.F.); (M.-W.C.)
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, No. 35, Keyan Road, Zhunan, Miaoli 350, Taiwan; (J.-L.D.); (Y.-W.L.)
| | - Jia-Ling Dong
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, No. 35, Keyan Road, Zhunan, Miaoli 350, Taiwan; (J.-L.D.); (Y.-W.L.)
| | - Ming-Wei Chien
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, No. 161, Section 6, Min Chuan East Road, Neihu, Taipei 114, Taiwan; (S.-H.F.); (M.-W.C.)
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, No. 35, Keyan Road, Zhunan, Miaoli 350, Taiwan; (J.-L.D.); (Y.-W.L.)
| | - Yu-Wen Liu
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, No. 35, Keyan Road, Zhunan, Miaoli 350, Taiwan; (J.-L.D.); (Y.-W.L.)
- Graduate Institute of Life Sciences, National Defense Medical Center, No. 161, Section 6, Min Chuan East Road, Neihu, Taipei 114, Taiwan
- Molecular Cell Biology, Taiwan International Graduate Program, No. 128, Academia Road, Section 2, Nankang, Taipei 115, Taiwan
| | - Chao-Yuan Hsu
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, No. 161, Section 6, Min Chuan East Road, Neihu, Taipei 114, Taiwan; (S.-H.F.); (M.-W.C.)
- Graduate Institute of Life Sciences, National Defense Medical Center, No. 161, Section 6, Min Chuan East Road, Neihu, Taipei 114, Taiwan
- Correspondence: (C.-Y.H.); (H.-K.S.)
| | - Huey-Kang Sytwu
- Graduate Institute of Medical Sciences, National Defense Medical Center, No. 161, Section 6, Min Chuan East Road, Neihu, Taipei 114, Taiwan
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, No. 161, Section 6, Min Chuan East Road, Neihu, Taipei 114, Taiwan; (S.-H.F.); (M.-W.C.)
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, No. 35, Keyan Road, Zhunan, Miaoli 350, Taiwan; (J.-L.D.); (Y.-W.L.)
- Graduate Institute of Life Sciences, National Defense Medical Center, No. 161, Section 6, Min Chuan East Road, Neihu, Taipei 114, Taiwan
- Correspondence: (C.-Y.H.); (H.-K.S.)
| |
Collapse
|
|
41
|
Hoffmann P, Jung V, Behnisch R, Gauss A. Prevalence and risk factors of nonalcoholic fatty liver disease in patients with inflammatory bowel diseases: A cross-sectional and longitudinal analysis. World J Gastroenterol 2020; 26:7367-7381. [PMID: 33362390 PMCID: PMC7739163 DOI: 10.3748/wjg.v26.i46.7367] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 11/03/2020] [Accepted: 11/21/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is common in the German population, with an even higher prevalence in inflammatory bowel disease patients.
AIM To investigate the risk factors for NAFLD in inflammatory bowel disease patients.
METHODS This monocentric retrospective study with a cross-sectional and a longitudinal part included 694 patients. Inclusion criteria were diagnosed inflammatory bowel disease, age ≥ 18 years, availability of at least one abdominal ultrasound. Patients with infectious or suspected alcoholic fatty liver disease were excluded. NAFLD was defined by increased echogenicity at liver ultrasound. Demographic characteristics, disease activity and medications were analyzed as potential risk factors. Parameters influencing the course of NAFLD were identified by a generalized linear mixed model.
RESULTS Forty-eight percent of Crohn’s disease (CD) patients and 44% of ulcerative colitis patients suffered from NAFLD. Its occurrence was associated with greater age, hypertension and body mass index (BMI) in both groups, and with higher disease activity and dyslipidemia in CD. 2467 ultrasound results were included in the longitudinal analysis. Risk factors for NAFLD were age, BMI, higher disease activity, bowel resection(s), endoscopic activity and azathioprine use in CD; and BMI and endoscopic activity in ulcerative colitis.
CONCLUSION NAFLD was highly prevalent in this cohort of German inflammatory bowel disease patients. Its risk increased mainly with rising age and BMI. This analysis provides a rationale for non-invasive liver screening in inflammatory bowel disease patients.
Collapse
Affiliation(s)
- Peter Hoffmann
- Department of Gastroenterology and Hepatology, University Hospital Heidelberg, Heidelberg 69120, Germany
| | - Victoria Jung
- Department of Gastroenterology and Hepatology, University Hospital Heidelberg, Heidelberg 69120, Germany
| | - Rouven Behnisch
- Institute of Medical Biometry and Informatics, University Hospital Heidelberg, Heidelberg 69120, Germany
| | - Annika Gauss
- Department of Gastroenterology and Hepatology, University Hospital Heidelberg, Heidelberg 69120, Germany
| |
Collapse
|
|
42
|
Yoshikawa M, Asaba K, Nakayama T. The APLNR gene polymorphism rs7119375 is associated with an increased risk of development of essential hypertension in the Chinese population: A meta-analysis. Medicine (Baltimore) 2020; 99:e22418. [PMID: 33327224 PMCID: PMC7738041 DOI: 10.1097/md.0000000000022418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Hypertension (HT) has recently been defined as a systolic blood pressure (BP) of ≥130 mm Hg and/or a diastolic BP of ≥80 mm Hg. It is important to further understand the pathophysiology of essential HT as its proportion is larger among most of the diagnosed HT cases. The apelin and apelin receptor (APLNR) are known to play roles in regulating BP, but the putative associations of single nucleotide polymorphisms in the APLNR gene with the risk of development of essential HT have not yet been fully investigated. Herein, we conducted a meta-analysis to investigate the relationship between single nucleotide polymorphisms in the APLNR gene and the risk of essential HT.We conducted a search in the PubMed and Web of Science databases for eligible studies. The pooled odds ratios (ORs) with their 95% confidence intervals (CI) were calculated using random-effects models when heterogeneity was expected across the studies. Otherwise, fixed-effect models were used.Regarding the SNP rs7119375, 5 studies were analyzed, which included a total of 3567 essential HT patients and 3256 healthy controls. Four of the 5 studies were from China and 1 was from Mexico. The meta-analysis showed the existence of a significant association between the AA genotype of rs7119375 and the risk of developing essential HT in the Chinese population, as determined using additive and recessive models (OR, 2.11; 95% CI, 1.12-3.96; I = 86% for AA vs GG. OR, 1.53; 95% CI, 1.21-1.94; I = 28% for AA vs AG. OR, 1.88; 95% CI, 1.13-3.12; I = 79% for AA vs AG + GG).Our study showed, for the first time, the existence of an association between rs7119375 and the risk of development of essential HT in the Chinese population, although the sample size was small and there was considerable population heterogeneity. The apelin/APLNR system could be a novel therapeutic target for the treatment of essential HT, and more studies are warranted to further investigate the association.
Collapse
Affiliation(s)
- Masahiro Yoshikawa
- Division of Laboratory Medicine, Department of Pathology and Microbiology, Nihon University School of Medicine
| | - Kensuke Asaba
- Department of Computational Diagnostic Radiology and Preventive Medicine, The University of Tokyo Hospital, Tokyo, Japan
| | - Tomohiro Nakayama
- Division of Laboratory Medicine, Department of Pathology and Microbiology, Nihon University School of Medicine
| |
Collapse
|
|
43
|
Chang ML, Yang Z, Yang SS. Roles of Adipokines in Digestive Diseases: Markers of Inflammation, Metabolic Alteration and Disease Progression. Int J Mol Sci 2020; 21:E8308. [PMID: 33167521 PMCID: PMC7663948 DOI: 10.3390/ijms21218308] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 10/30/2020] [Accepted: 11/01/2020] [Indexed: 12/13/2022] Open
Abstract
Adipose tissue is a highly dynamic endocrine tissue and constitutes a central node in the interorgan crosstalk network through adipokines, which cause pleiotropic effects, including the modulation of angiogenesis, metabolism, and inflammation. Specifically, digestive cancers grow anatomically near adipose tissue. During their interaction with cancer cells, adipocytes are reprogrammed into cancer-associated adipocytes and secrete adipokines to affect tumor cells. Moreover, the liver is the central metabolic hub. Adipose tissue and the liver cooperatively regulate whole-body energy homeostasis via adipokines. Obesity, the excessive accumulation of adipose tissue due to hyperplasia and hypertrophy, is currently considered a global epidemic and is related to low-grade systemic inflammation characterized by altered adipokine regulation. Obesity-related digestive diseases, including gastroesophageal reflux disease, Barrett's esophagus, esophageal cancer, colon polyps and cancer, non-alcoholic fatty liver disease, viral hepatitis-related diseases, cholelithiasis, gallbladder cancer, cholangiocarcinoma, pancreatic cancer, and diabetes, might cause specific alterations in adipokine profiles. These patterns and associated bases potentially contribute to the identification of prognostic biomarkers and therapeutic approaches for the associated digestive diseases. This review highlights important findings about altered adipokine profiles relevant to digestive diseases, including hepatic, pancreatic, gastrointestinal, and biliary tract diseases, with a perspective on clinical implications and mechanistic explorations.
Collapse
Affiliation(s)
- Ming-Ling Chang
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 33305, Taiwan
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Zinger Yang
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA;
| | - Sien-Sing Yang
- Liver Center, Cathay General Hospital Medical Center, Taipei 10630, Taiwan;
| |
Collapse
|
|
44
|
Uzzan M, Corcos O, Martin JC, Treton X, Bouhnik Y. Why is SARS-CoV-2 infection more severe in obese men? The gut lymphatics - Lung axis hypothesis. Med Hypotheses 2020; 144:110023. [PMID: 32593832 PMCID: PMC7308746 DOI: 10.1016/j.mehy.2020.110023] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 06/19/2020] [Indexed: 02/07/2023]
Abstract
Consistent observations report increased severity of SARS-CoV-2 infection in overweight men with cardiovascular factors. As the visceral fat possesses an intense immune activity, is involved in metabolic syndrome and is at the crossroad between the intestines, the systemic circulation and the lung, we hypothesized that it plays a major role in severe forms of SARS-CoV-2 infection. SARS-CoV2 presents the ability to infect epithelial cells of the respiratory tract as well as the intestinal tract. Several factors may increase intestinal permeability including direct enterocyte damage by SARS-CoV2, systemic inflammatory response syndrome (SIRS) and epithelial ischemia secondary to SARS-CoV2- associated endothelial dysfunction. This increase permeability further leads to translocation of microbial components such as MAMPs (microbial-associated molecular pattern), triggering an inflammatory immune response by TLR-expressing cells of the mesentery fat (mostly macrophages and adipocytes). The pro-inflammatory cytokines produced by the mesentery fat mediates systemic inflammation and aggravate acute respiratory distress syndrome (ARDS) through the mesenteric lymph drainage.
Collapse
Affiliation(s)
- Mathieu Uzzan
- Department of Gastroenterology, IBD and Nutritional Support, CHU Paris Nord-Val de Seine, Beaujon Hospital, Clichy, France.
| | - Olivier Corcos
- Department of Gastroenterology, IBD and Nutritional Support, CHU Paris Nord-Val de Seine, Beaujon Hospital, Clichy, France
| | - Jerome C Martin
- Université de Nantes, Inserm, CHU Nantes, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, F-44000 Nantes, France; CHU Nantes, Laboratoire d'Immunologie, Center for Immuno Monitoring Nantes-Atlantique (CIMNA), F-44000 Nantes, France
| | - Xavier Treton
- Department of Gastroenterology, IBD and Nutritional Support, CHU Paris Nord-Val de Seine, Beaujon Hospital, Clichy, France
| | - Yoram Bouhnik
- Department of Gastroenterology, IBD and Nutritional Support, CHU Paris Nord-Val de Seine, Beaujon Hospital, Clichy, France
| |
Collapse
|
|
45
|
Gholamrezayi A, Mohamadinarab M, Rahbarinejad P, Fallah S, Barez SR, Setayesh L, Moradi N, Fadaei R, Chamani E, Tavakoli T. Characterization of the serum levels of Meteorin-like in patients with inflammatory bowel disease and its association with inflammatory cytokines. Lipids Health Dis 2020; 19:230. [PMID: 33126870 PMCID: PMC7602304 DOI: 10.1186/s12944-020-01404-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 10/19/2020] [Indexed: 02/07/2023] Open
Abstract
Background Meteorin-like (Metrnl) is an adipokine with insulin sensitizing and anti-inflammatory properties that has been discovered recently. The relation among Metrnl, Inflammatory Bowel Disease (IBD), and obesity has been unexplored yet. Methods The present study was conducted on 54 healthy control, 42 Ulcerative Colitis (UC), and 43 Crohn’s disease (CD) patients who were diagnosed by pathological examination. In all participants, serum levels of adiponectin, Metrnl, interleukin (IL)-6, and Tumor necrosis factor (TNF-α) were measured using ELISA kits. Results Metrnl concentration was considerably lower in both UC (85.25 ± 36.55 pg/mL) and CD (76.93 ± 27.92 pg/mL) patients in comparison to control (107.52 ± 35.33 pg/mL). In addition, it was seen that both patient groups have a decreased level of adiponectin compared to the controls. Besides that, the level of IL-6 and TNF-α were significantly greater in the patient groups. Moreover, the result showed that the level of Metrnl is inversely correlated with body mass index (BMI) in the controls and the patients. Metrnl levels are also inversely associated with IL-6, and TNF-α in both of the patient groups. Conclusions The current study is the first one reporting the decreased levels of Metrnl in serum among patients with IBD, which is inversely related with BMI, TNF-α, and IL-6. These results suggested a possible relation of Metrnl with the pathogenesis of IBD, particularly through inflammatory process, although further studies are warranted to dissect the possible mechanism.
Collapse
Affiliation(s)
- Afsane Gholamrezayi
- Department of Nutrition, School of Public Health-International Campus, Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Mohamadinarab
- Department of Nutrition, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Pegah Rahbarinejad
- Department of Nutrition, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Soudabeh Fallah
- Department of Clinical Biochemistry, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Shekufe Rezghi Barez
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Leila Setayesh
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Nariman Moradi
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Reza Fadaei
- Sleep Disorders Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Elham Chamani
- Cardiovascular Diseases Research Center, Department of Clinical Biochemistry, Birjand University of Medical Sciences, Birjand, Iran.
| | - Tahmine Tavakoli
- Cardiovascular Diseases Research Center, Department of Internal Medicine, Gastroenterology Section, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran.
| |
Collapse
|
|
46
|
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.
Collapse
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
| |
Collapse
|
|
47
|
Hu JCE, Bojarski C, Branchi F, Fromm M, Krug SM. Leptin Downregulates Angulin-1 in Active Crohn's Disease via STAT3. Int J Mol Sci 2020; 21:ijms21217824. [PMID: 33105684 PMCID: PMC7672602 DOI: 10.3390/ijms21217824] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 10/19/2020] [Accepted: 10/20/2020] [Indexed: 12/15/2022] Open
Abstract
Crohn’s disease (CD) has an altered intestinal barrier function, yet the underlying mechanisms remain to be disclosed. The tricellular tight junction protein tricellulin is involved in the maintenance of the paracellular macromolecule barrier and features an unchanged expression level in CD but a shifted localization. As angulins are known to regulate the localization of tricellulin, we hypothesized the involvement of angulins in CD. Using human biopsies, we found angulin-1 was downregulated in active CD compared with both controls and CD in remission. In T84 and Caco-2 monolayers, leptin, a cytokine secreted by fat tissue and affected in CD, decreased angulin-1 expression. This effect was completely blocked by STAT3 inhibitors, Stattic and WP1066, but only partially by JAK2 inhibitor AG490. The effect of leptin was also seen at a functional level as we observed in Caco-2 cells an increased permeability for FITC-dextran 4 kDa indicating an impaired barrier against macromolecule uptake. In conclusion, we were able to show that in active CD angulin-1 expression is downregulated, which leads to increased macromolecule permeability and is inducible by leptin via STAT3. This suggests that angulin-1 and leptin secretion are potential targets for intervention in CD to restore the impaired intestinal barrier.
Collapse
Affiliation(s)
- Jia-Chen E. Hu
- Institute of Clinical Physiology/Nutritional Medicine, Charité—Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany
| | - Christian Bojarski
- Department of Gastroenterology, Rheumatology and Infectious Diseases, Charité—Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany
| | - Federica Branchi
- Department of Gastroenterology, Rheumatology and Infectious Diseases, Charité—Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany
| | - Michael Fromm
- Institute of Clinical Physiology/Nutritional Medicine, Charité—Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany
| | - Susanne M. Krug
- Institute of Clinical Physiology/Nutritional Medicine, Charité—Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany
- Correspondence:
| |
Collapse
|
|
48
|
Martínez-Sánchez N. There and Back Again: Leptin Actions in White Adipose Tissue. Int J Mol Sci 2020; 21:ijms21176039. [PMID: 32839413 PMCID: PMC7503240 DOI: 10.3390/ijms21176039] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 08/17/2020] [Accepted: 08/18/2020] [Indexed: 12/13/2022] Open
Abstract
Leptin is a hormone discovered almost 30 years ago with important implications in metabolism. It is primarily produced by white adipose tissue (WAT) in proportion to the amount of fat. The discovery of leptin was a turning point for two principle reasons: on one hand, it generated promising expectations for the treatment of the obesity, and on the other, it changed the classical concept that white adipose tissue was simply an inert storage organ. Thus, adipocytes in WAT produce the majority of leptin and, although its primary role is the regulation of fat stores by controlling lipolysis and lipogenesis, this hormone also has implications in other physiological processes within WAT, such as apoptosis, browning and inflammation. Although a massive number of questions related to leptin actions have been answered, the necessity for further clarification facilitates constantly renewing interest in this hormone and its pathways. In this review, leptin actions in white adipose tissue will be summarized in the context of obesity.
Collapse
|
|
49
|
Johnson AM, Loftus EV. Impact of Obesity on the Management of Inflammatory Bowel Disease. Gastroenterol Hepatol (N Y) 2020; 16:350-359. [PMID: 34035739 PMCID: PMC8132647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
The worldwide prevalence of obesity has reached staggering proportions, and the inflammatory bowel disease (IBD) population has not been immune to this trend, with obesity rates estimated to be between 15% and 40%. With the concurrent rise in incidence of IBD itself, there are biologically plausible mechanisms that suggest a potential role of obesity in the pathogenesis of IBD, although epidemiologic data on this issue are conflicting. Similarly, studies exploring the impact that obesity may have on the natural history of disease have produced inconsistent results. Some studies suggest higher and others lower rates of surgery in obese Crohn's disease patients, other studies suggest a higher risk of surgery in obese ulcerative colitis patients, and yet other studies reveal no difference in outcomes regarding hospitalization or surgery for either group. Regardless of its impact on the pathogenesis or natural history of IBD, the rising prevalence of obesity in this population results in a need to better understand the effect it has on IBD management. Although pharmacologic data suggest that obesity may influence the absorption, distribution, and clearance of the available therapeutic agents, the actual clinical consequences that these differences have on disease management are less clear. Finally, it is possible that weight loss interventions for obesity could have an impact on the clinical course of IBD.
Collapse
Affiliation(s)
- Amanda M Johnson
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Mayo Clinic, Rochester, Minnesota
| | - Edward V Loftus
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Mayo Clinic, Rochester, Minnesota
| |
Collapse
|
|
50
|
Abstract
BACKGROUND Adiponectin is the most abundant adipokines that plays critical roles in the maintenance of energy homeostasis as well as inflammation regulation. The half-life of adiponectin is very short and the small-molecule adiponectin receptor agonist has been synthesized recently. In the present study, the potential roles of AdipoRon, an adiponectin receptor agonist, in a mouse model of lipopolysaccharide (LPS)/D-galactosamine (D-Gal)-induced acute hepatitis was explored. METHODS BALB/c mice (n = 144, male) were divided into three sets. In set 1, 32 mice were randomized into four groups: the control group, the AdipoRon group, the LPS/D-Gal group, and the AdipoRon + LPS/D-Gal group. The mice in set 1 were sacrificed after LPS/D-Gal treatment, and the plasma samples were collected for detection of tumor necrosis factor-alpha (TNF-α). In set 2, the 32 mice were also divided into four groups similar to that of set 1. The mice were sacrificed 6 h after LPS/D-Gal injection and plasma samples and liver were collected. In set 3, 80 mice (divided into four groups, n = 20) were used for survival observation. The survival rate, plasma aminotransferases, histopathological damage were measured and compared between these four groups. RESULTS AdipoRon suppressed the elevation of plasma aminotransferases (from 2106.3 ± 781.9 to 286.8 ± 133.1 U/L for alanine aminotransferase, P < 0.01; from 566.5 ± 243.4 to 180.1 ± 153.3 U/L for aspartate aminotransferase, P < 0.01), attenuated histopathological damage and improved the survival rate (from 10% to 60%) in mice with LPS/D-Gal-induced acute hepatitis. Additionally, AdipoRon down-regulated the production of TNF-α (from 328.6 ± 121.2 to 213.4 ± 52.2 pg/mL, P < 0.01), inhibited the activation of caspase-3 (from 2.04-fold to 1.34-fold of the control), caspase-8 (from 2.03-fold to 1.31-fold of the control), and caspase-9 (from 2.14-fold to 1.43-fold of the control), and decreased the level of cleaved caspase-3 (0.28-fold to that of the LPS/D-Gal group). The number of terminal deoxynucleotidyl transferase-mediated nucleotide nick-end labeling-positive apoptotic hepatocytes in LPS/D-Gal-exposed mice also reduced. CONCLUSIONS These data indicated that LPS/D-Gal-induced acute hepatitis was effectively attenuated by the adiponectin receptor agonist AdipoRon, implying that AdipoRon might become a new reagent for treatment of acute hepatitis.
Collapse
|