|
1
|
Zhu F, Zou D, Shi P, Tang L, Wu D, Hu X, Yin F, Liu J. Dipeptidyl peptidase 4: A predictor of ferroptosis in ulcerative colitis. J Gene Med 2024; 26:e3742. [PMID: 39343840 DOI: 10.1002/jgm.3742] [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: 04/25/2024] [Revised: 08/06/2024] [Accepted: 09/12/2024] [Indexed: 10/01/2024] Open
Abstract
BACKGROUND With its rapidly increasing incidence and prevalence, ulcerative colitis (UC) has become a major global health challenge. Recent evidence suggests that ferroptosis plays a significant role in the development of UC. However, the relationship between ferroptosis and the progression of UC needs to be extensively studied. METHODS The differentially expressed genes in UC patients were screened from the GEO database. The ferroptosis-related genes were obtained from FErrDB and GeneCards. The UC subtypes were identified with the R package "CancerSubtype" and evaluated with consensus clustering (CC) to identify gene expression patterns in patients with UC. The key genes were detected with qRT-PCR, Western blot, and immunohistochemistry in vitro and in vivo models. Ferroptosis was identified with western blotting on ferrotic-associated proteins and staining on Fe2+ with commercial FerroOrange kits. RESULTS Dipeptidyl peptidase 4 (DPP4), also known as CD26, is a potential biomarker for ferroptosis in UC patients. Transcriptome sequencing data showed a positive correlation between decreased DPP4 expression and proinflammatory cytokines such as TNF-α, IL-6, and IL-β, as well as immune cell infiltration in the colon tissues of UC patients. Furthermore, DPP4 was strongly associated with ferroptosis biomarkers, particularly in Subtype 2 of UC. Interestingly, our study also found that DPP4 expression was significantly reduced in RSL3-treated ferroptotic intestinal epithelial cells, more so than in LPS-treated cell models. Inhibition of DPP4 had a significant impact on the expression of ferroptotic biomarkers. Additionally, DPP4 expression was decreased in the colon tissues of DSS-treated mice, and the ferroptosis inhibitor Ferritin-1 effectively counteracted the effects of DSS on immune cell infiltration, colon length, and DPP4 expression. CONCLUSIONS DPP4 can serve as a biomarker for ferroptosis in the diagnosis and management of UC.
Collapse
Affiliation(s)
- Fuyun Zhu
- College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
| | - Dezeng Zou
- College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
| | - Ping Shi
- College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
| | - Lianhua Tang
- College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
| | - Dan Wu
- College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
| | - Xiaoxue Hu
- College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
| | - Fei Yin
- College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
- Chongqing Key Laboratory of Target-Based Drug Discovery and Research, Chongqing, China
| | - Jianhui Liu
- College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
- Chongqing Key Laboratory of Target-Based Drug Discovery and Research, Chongqing, China
| |
Collapse
|
|
2
|
Mashtoub S, Howarth GS. Emu Oil and zinc monoglycerolate independently reduce disease severity in a rat model of ulcerative colitis. Biometals 2023; 36:1331-1345. [PMID: 37402926 PMCID: PMC10684413 DOI: 10.1007/s10534-023-00521-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: 02/12/2023] [Accepted: 06/21/2023] [Indexed: 07/06/2023]
Abstract
Ulcerative colitis is characterized by colonic inflammation. Previously, Emu Oil protected the intestine against experimentally-induced inflammatory intestinal disorders. Zinc monoglycerolate (ZMG) polymer, formed by heating zinc oxide with glycerol, demonstrated anti-inflammatory and wound healing properties. We aimed to determine whether ZMG, alone or in combination with Emu Oil, could reduce acute colitis severity in rats. Male Sprague Dawley rats (n = 8/group) were orally-administered either vehicle, ZMG, Emu Oil (EO) or ZMG combined with EO (ZMG/EO) daily. Rats were provided ad libitum access to drinking water (Groups 1-4) or dextran sulphate sodium (DSS; 2%w/v; Groups 5-8) throughout the trial (days 0-5) before euthanasia on day 6. Disease activity index, crypt depth, degranulated mast cells (DMCs) and myeloperoxidase (MPO) activity were assessed. p < 0.05 was considered significant. DSS increased disease severity (days 3-6) compared to normal controls (p < 0.05). Importantly, in DSS-administered rats, ZMG/EO (day 3) and ZMG (day 6) reduced disease activity index compared to controls (p < 0.05). Following DSS consumption, distal colonic crypts lengthened (p < 0.01), occurring to a greater extent with EO compared to ZMG and ZMG/EO (p < 0.001). DSS increased colonic DMC numbers compared to normal controls (p < 0.001); an effect decreased only by EO (p < 0.05). Colonic MPO activity increased following DSS consumption (p < 0.05); notably, ZMG, EO and ZMG/EO treatments decreased MPO activity compared to DSS controls (p < 0.001). EO, ZMG and ZMG/EO did not impact any parameter in normal animals. Emu Oil and ZMG independently decreased selected indicators of colitic disease severity in rats; however, the combination did not reveal any additional benefit.
Collapse
Affiliation(s)
- Suzanne Mashtoub
- Department of Gastroenterology, Women's and Children's Hospital, 72 King William Road, North Adelaide, SA, 5006, Australia.
- Discipline of Physiology, School of Biomedicine, The University of Adelaide, Adelaide, SA, Australia.
- School of Medicine, The University of Western Australia, Perth, WA, Australia.
| | - Gordon S Howarth
- Department of Gastroenterology, Women's and Children's Hospital, 72 King William Road, North Adelaide, SA, 5006, Australia
- Discipline of Physiology, School of Biomedicine, The University of Adelaide, Adelaide, SA, Australia
- School of Animal and Veterinary Sciences, The University of Adelaide Roseworthy Campus, Roseworthy, SA, Australia
| |
Collapse
|
|
3
|
Melo FJ, Pinto-Lopes P, Estevinho MM, Magro F. The Role of Dipeptidyl Peptidase 4 as a Therapeutic Target and Serum Biomarker in Inflammatory Bowel Disease: A Systematic Review. Inflamm Bowel Dis 2021; 27:1153-1165. [PMID: 33295607 DOI: 10.1093/ibd/izaa324] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND The roles dipeptidyl peptidase 4 (DPP4), aminopeptidase N (APN), and their substrates in autoimmune diseases are being increasingly recognized. However, their significance in inflammatory bowel diseases (IBD) is not entirely understood. This systematic review aims to discuss the pathophysiological processes related to these ectopeptidases while comparing findings from preclinical and clinical settings. METHODS This review was conducted according to the PRISMA guidelines. We performed a literature search in PubMed, SCOPUS, and Web of Science to identify all reports from inception until February 2020. The search included validated animal models of intestinal inflammation and studies in IBD patients. Quality assessment was performed using SYRCLE's risk of bias tool and CASP qualitative and cohort checklists. RESULTS From the 45 included studies, 36 were performed in animal models and 12 in humans (3 reports included both). Overall, the methodological quality of preclinical studies was acceptable. In animal models, DPP4 and APN inhibition significantly improved intestinal inflammation.Glucagon-like peptide (GLP)-1 and GLP-2 analogs and GLP-2-relase-inducing drugs also showed significant benefits in recovery from inflammatory damage. A nonsignificant trend toward disease remission with the GLP-2 analog teduglutide was observed in the sole interventional human study. All human studies reported an inverse correlation between soluble DPP4/CD26 levels and disease severity, in accordance with the proposal of DPP4 as a biomarker for IBD. CONCLUSIONS The use of DPP4 inhibitors and analogs of its substrates has clear benefits in the treatment of experimentally induced intestinal inflammation. Further research is warranted to validate their potential diagnostic and therapeutic applications in IBD patients.
Collapse
Affiliation(s)
- Francisco Jorge Melo
- Department of Biomedicine, Unity of Pharmacology and Therapeutics, Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Pedro Pinto-Lopes
- Department of Biomedicine, Unity of Pharmacology and Therapeutics, Faculty of Medicine of the University of Porto, Porto, Portugal.,Department of Internal Medicine, Tâmega e Sousa Hospital Center, Padre Américo Hospital, Penafiel, Portugal
| | - Maria Manuela Estevinho
- Department of Biomedicine, Unity of Pharmacology and Therapeutics, Faculty of Medicine of the University of Porto, Porto, Portugal.,Department of Gastroenterology, Vila Nova de Gaia/Espinho Hospital Center, Vila Nova de Gaia, Portugal
| | - Fernando Magro
- Department of Biomedicine, Unity of Pharmacology and Therapeutics, Faculty of Medicine of the University of Porto, Porto, Portugal.,Unit of Clinical Pharmacology, São João Hospital Center, Porto, Portugal
| |
Collapse
|
|
4
|
Bilski J, Wojcik D, Danielak A, Mazur-Bialy A, Magierowski M, Tønnesen K, Brzozowski B, Surmiak M, Magierowska K, Pajdo R, Ptak-Belowska A, Brzozowski T. Alternative Therapy in the Prevention of Experimental and Clinical Inflammatory Bowel Disease. Impact of Regular Physical Activity, Intestinal Alkaline Phosphatase and Herbal Products. Curr Pharm Des 2020; 26:2936-2950. [PMID: 32338209 DOI: 10.2174/1381612826666200427090127] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 04/18/2020] [Indexed: 02/06/2023]
Abstract
Inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn's disease, are multifactorial, chronic, disabling, and progressive diseases characterised by cyclical nature, alternating between active and quiescent states. While the aetiology of IBD is not fully understood, this complex of diseases involve a combination of factors including the genetic predisposition and changes in microbiome as well as environmental risk factors such as high-fat and low-fibre diets, reduced physical activity, air pollution and exposure to various toxins and drugs such as antibiotics. The prevalence of both IBD and obesity is increasing in parallel, undoubtedly proving the existing interactions between these risk factors common to both disorders to unravel poorly recognized cell signaling and molecular alterations leading to human IBD. Therefore, there is still a significant and unmet need for supportive and adjunctive therapy for IBD patients directed against the negative consequences of visceral obesity and bacterial dysbiosis. Among the alternative therapies, a moderate-intensity exercise can benefit the health and well-being of IBD patients and improve both the healing of human IBD and experimental animal colitis. Intestinal alkaline phosphatase (IAP) plays an essential role in the maintenance of intestinal homeostasis intestinal and the mechanism of mucosal defence. The administration of exogenous IAP could be recommended as a therapeutic strategy for the cure of diseases resulting from the intestinal barrier dysfunction such as IBD. Curcumin, a natural anti-inflammatory agent, which is capable of stimulating the synthesis of endogenous IAP, represents another alternative approach in the treatment of IBD. This review was designed to discuss potential “nonpharmacological” alternative and supplementary therapeutic approaches taking into account epidemiological and pathophysiological links between obesity and IBD, including changes in the functional parameters of the intestinal mucosa and alterations in the intestinal microbiome.
Collapse
Affiliation(s)
- Jan Bilski
- Department of Ergonomics and Exercise Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, Cracow, Poland
| | - Dagmara Wojcik
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Aleksandra Danielak
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Agnieszka Mazur-Bialy
- Department of Ergonomics and Exercise Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, Cracow, Poland
| | - Marcin Magierowski
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Katherine Tønnesen
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Bartosz Brzozowski
- Gastroenterology and Hepatology Clinic, Jagiellonian University Medical College, Cracow, Poland
| | - Marcin Surmiak
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Katarzyna Magierowska
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Robert Pajdo
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Agata Ptak-Belowska
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Tomasz Brzozowski
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland
| |
Collapse
|
|
5
|
Olivares M, Schüppel V, Hassan AM, Beaumont M, Neyrinck AM, Bindels LB, Benítez-Páez A, Sanz Y, Haller D, Holzer P, Delzenne NM. The Potential Role of the Dipeptidyl Peptidase-4-Like Activity From the Gut Microbiota on the Host Health. Front Microbiol 2018; 9:1900. [PMID: 30186247 PMCID: PMC6113382 DOI: 10.3389/fmicb.2018.01900] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 07/27/2018] [Indexed: 12/16/2022] Open
Abstract
The Dipeptidyl peptidase-4 (DPP-4) activity influences metabolic, behavioral and intestinal disorders through the cleavage of key hormones and peptides. Some studies describe the existence of human DPP-4 homologs in commensal bacteria, for instance in Prevotella or Lactobacillus. However, the role of the gut microbiota as a source of DPP-4-like activity has never been investigated. Through the comparison of the DPP-4 activity in the cecal content of germ-free mice (GFM) and gnotobiotic mice colonized with the gut microbiota of a healthy subject, we bring the proof of concept that a significant DPP-4-like activity occurs in the microbiota. By analyzing the existing literature, we propose that DPP-4-like activity encoded by the intestinal microbiome could constitute a novel mechanism to modulate protein digestion as well as host metabolism and behavior.
Collapse
Affiliation(s)
- Marta Olivares
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
| | - Valentina Schüppel
- ZIEL Institute for Food and Health, Technical University of Munich, Freising-Weihenstephan, Germany.,Chair of Nutrition and Immunology, Technical University of Munich, Freising-Weihenstephan, Germany
| | - Ahmed M Hassan
- Research Unit of Translational Neurogastroenterology, Pharmacology Section, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Martin Beaumont
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
| | - Audrey M Neyrinck
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
| | - Laure B Bindels
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
| | - Alfonso Benítez-Páez
- Microbial Ecology, Nutrition and Health Research Unit, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), Valencia, Spain
| | - Yolanda Sanz
- Microbial Ecology, Nutrition and Health Research Unit, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), Valencia, Spain
| | - Dirk Haller
- ZIEL Institute for Food and Health, Technical University of Munich, Freising-Weihenstephan, Germany.,Chair of Nutrition and Immunology, Technical University of Munich, Freising-Weihenstephan, Germany
| | - Peter Holzer
- Research Unit of Translational Neurogastroenterology, Pharmacology Section, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Nathalie M Delzenne
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
| |
Collapse
|
|
6
|
Stone DAJ, Bellgrove EJ, Forder REA, Howarth GS, Bansemer MS. Inducing Subacute Enteritis in Yellowtail Kingfish Seriola lalandi: the Effect of Dietary Inclusion of Soybean Meal and Grape Seed Extract on Hindgut Morphology and Inflammation. NORTH AMERICAN JOURNAL OF AQUACULTURE 2018; 80:59-68. [DOI: 10.1002/naaq.10002] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 09/25/2017] [Indexed: 02/09/2025]
Abstract
Abstract
In this 42-d trial, grape seed extract (GSE) was evaluated as a potential treatment for subacute enteritis in Yellowtail Kingfish Seriola lalandi induced by soybean meal (SBM) at winter water temperatures (12–15°C). Four diets were investigated: a fish meal control diet (46% fish meal, 0% SBM), a SBM diet (30% SBM with 0 mg/kg GSE), and two 30% SBM diets containing either 20 mg/kg or 40 mg/kg GSE. Yellowtail Kingfish growth performance was significantly reduced when fed 30% SBM. Fish fed 30% SBM exhibited a significant enlargement of the lamina propria, a sign of subacute enteritis, and a significant decrease in myeloperoxidase (MPO) activity, compared with those fish fed the control diet. Dietary inclusions of GSE did not affect growth performance, intestinal morphology, or MPO activity. We recommend that SBM be excluded from Yellowtail Kingfish diets. We also recommend future studies investigate higher dietary GSE inclusions, other potential dietary additives, or more refined soy products, to alleviate subacute enteritis in Yellowtail Kingfish.
Collapse
Affiliation(s)
- David A J Stone
- South Australian Research and Development Institute, Marine Innovation Southern Australia, South Australian Aquatic Sciences Centre, Aquaculture Nutrition and Feed Technology Subprogram, West Beach, South Australia 5024, Australia; School of Animal and Veterinary Sciences, University of Adelaide, Roseworthy Campus, Roseworthy, South Australia 5371, Australia; and School of Biological Sciences, Flinders University, Adelaide, South Australia 5001, Australia
| | - Emma J Bellgrove
- School of Animal and Veterinary Sciences, University of Adelaide, Roseworthy Campus, Roseworthy, South Australia, 5371, Australia
| | - Rebecca E A Forder
- School of Animal and Veterinary Sciences, University of Adelaide, Roseworthy Campus, Roseworthy, South Australia, 5371, Australia
| | - Gordon S Howarth
- School of Animal and Veterinary Sciences, University of Adelaide, Roseworthy Campus, Roseworthy, South Australia 5371, Australia; and Women’s and Children’s Hospital, Gastroenterology Department, North Adelaide, South Australia 5006, Australia
| | - Matthew S Bansemer
- South Australian Research and Development Institute, Marine Innovation Southern Australia, South Australian Aquatic Sciences Centre, Aquaculture Nutrition and Feed Technology Subprogram, West Beach, South Australia, 5024, Australia
| |
Collapse
|
|
7
|
Bilski J, Mazur-Bialy A, Brzozowski B, Magierowski M, Zahradnik-Bilska J, Wójcik D, Magierowska K, Kwiecien S, Mach T, Brzozowski T. Can exercise affect the course of inflammatory bowel disease? Experimental and clinical evidence. Pharmacol Rep 2016; 68:827-836. [PMID: 27255494 DOI: 10.1016/j.pharep.2016.04.009] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Revised: 04/17/2016] [Accepted: 04/19/2016] [Indexed: 02/07/2023]
Abstract
The inflammatory bowel disease (IBD) consisting of Crohn's disease (CD) and ulcerative colitis (UC) are defined as idiopathic, chronic and relapsing intestinal disorders occurring in genetically predisposed individuals exposed to environmental risk factors such as diet and microbiome changes. Since conventional drug therapy is expensive and not fully efficient, there is a need for alternative remedies that can improve the outcome in patients suffering from IBD. Whether exercise, which has been proposed as adjunct therapy in IBD, can be beneficial in patients with IBD remains an intriguing question. In this review, we provide an overview of the effects of exercise on human IBD and experimental colitis in animal models that mimic human disease, although the information on exercise in human IBD are sparse and poorly understood. Moderate exercise can exert a beneficial ameliorating effect on IBD and improve the healing of experimental animal colitis due to the activity of protective myokines such as irisin released from working skeletal muscles. CD patients with higher levels of exercise were significantly less likely to develop active disease at six months. Moreover, voluntary exercise has been shown to exert a positive effect on IBD patients' mood, weight maintenance and osteoporosis. On the other hand, depending on its intensity and duration, exercise can evoke transient mild systemic inflammation and enhances pro-inflammatory cytokine release, thereby exacerbating the gastrointestinal symptoms. We discuss recent advances in the mechanism of voluntary and strenuous exercise affecting the outcome of IBD in patients and experimental animal models.
Collapse
Affiliation(s)
- Jan Bilski
- Department of Ergonomics and Exercise Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, Kraków, Poland
| | - Agnieszka Mazur-Bialy
- Department of Ergonomics and Exercise Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, Kraków, Poland
| | - Bartosz Brzozowski
- Gastroenterology and Hepatology Clinic, The University Hospital, Jagiellonian University Medical College, Kraków, Poland
| | - Marcin Magierowski
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland
| | - Janina Zahradnik-Bilska
- Gastroenterology and Hepatology Clinic, The University Hospital, Jagiellonian University Medical College, Kraków, Poland
| | - Dagmara Wójcik
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland
| | - Katarzyna Magierowska
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland
| | - Slawomir Kwiecien
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland
| | - Tomasz Mach
- Gastroenterology and Hepatology Clinic, The University Hospital, Jagiellonian University Medical College, Kraków, Poland
| | - Tomasz Brzozowski
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland.
| |
Collapse
|
|
8
|
Klemann C, Wagner L, Stephan M, von Hörsten S. Cut to the chase: a review of CD26/dipeptidyl peptidase-4's (DPP4) entanglement in the immune system. Clin Exp Immunol 2016; 185:1-21. [PMID: 26919392 DOI: 10.1111/cei.12781] [Citation(s) in RCA: 317] [Impact Index Per Article: 35.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Revised: 02/14/2016] [Accepted: 02/21/2016] [Indexed: 12/11/2022] Open
Abstract
CD26/DPP4 (dipeptidyl peptidase 4/DP4/DPPIV) is a surface T cell activation antigen and has been shown to have DPP4 enzymatic activity, cleaving-off amino-terminal dipeptides with either L-proline or L-alanine at the penultimate position. It plays a major role in glucose metabolism by N-terminal truncation and inactivation of the incretins glucagon-like peptide-1 (GLP) and gastric inhibitory protein (GIP). In 2006, DPP4 inhibitors have been introduced to clinics and have been demonstrated to efficiently enhance the endogenous insulin secretion via prolongation of the half-life of GLP-1 and GIP in patients. However, a large number of studies demonstrate clearly that CD26/DPP4 also plays an integral role in the immune system, particularly in T cell activation. Therefore, inhibition of DPP4 might represent a double-edged sword. Apart from the metabolic benefit, the associated immunological effects of long term DPP4 inhibition on regulatory processes such as T cell homeostasis, maturation and activation are not understood fully at this stage. The current data point to an important role for CD26/DPP4 in maintaining lymphocyte composition and function, T cell activation and co-stimulation, memory T cell generation and thymic emigration patterns during immune-senescence. In rodents, critical immune changes occur at baseline levels as well as after in-vitro and in-vivo challenge. In patients receiving DPP4 inhibitors, evidence of immunological side effects also became apparent. The scope of this review is to recapitulate the role of CD26/DPP4 in the immune system regarding its pharmacological inhibition and T cell-dependent immune regulation.
Collapse
Affiliation(s)
- C Klemann
- Center of Pediatric Surgery, Hannover Medical School, Hannover.,Center of Chronic Immunodeficiency, University Medical Center Freiburg, University Medical Center Freiburg
| | - L Wagner
- Deutschsprachige Selbsthilfegruppe für Alkaptonurie (DSAKU) e.V.,Department for Experimental Therapy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - M Stephan
- Clinic for Psychosomatics and Psychotherapy, Hannover Medical School, Hannover
| | - S von Hörsten
- Department for Experimental Therapy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| |
Collapse
|
|
9
|
Detel D, Buljevic S, Pucar LB, Kucic N, Pugel EP, Varljen J. Influence of CD26/dipeptidyl peptidase IV deficiency on immunophenotypic changes during colitis development and resolution. J Physiol Biochem 2016; 72:405-19. [DOI: 10.1007/s13105-016-0491-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Accepted: 04/20/2016] [Indexed: 01/01/2023]
|
|
10
|
Sakanaka T, Inoue T, Yorifuji N, Iguchi M, Fujiwara K, Narabayashi K, Kakimoto K, Nouda S, Okada T, Kuramoto T, Ishida K, Abe Y, Takeuchi T, Umegaki E, Akiba Y, Kaunitz JD, Higuchi K. The effects of a TGR5 agonist and a dipeptidyl peptidase IV inhibitor on dextran sulfate sodium-induced colitis in mice. J Gastroenterol Hepatol 2015; 30 Suppl 1:60-5. [PMID: 25827806 PMCID: PMC4874188 DOI: 10.1111/jgh.12740] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/08/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Luminal nutrients stimulate enteroendocrine L cells to release gut hormones, including intestinotrophic glucagon-like peptide-2 (GLP-2). Because L cells express the bile acid receptor TGR5 and dipeptidyl peptidase-IV (DPPIV) rapidly degrades GLPs, we hypothesized that luminal TGR5 activation may attenuate intestinal injury via GLP-2 release, which is enhanced by DPPIV inhibition. METHODS Intestinal injury was induced in mice by administration of dextran sulfate sodium (DSS) in drinking water (free access to water containing 5% DSS for 7 days). The selective TGR5 agonist betulinic acid (BTA) and the DPPIV inhibitor sitagliptin phosphate monohydrate (STG) were administered orally for 7 days. Male C57BL/6 mice (6-7 weeks old) were divided into five groups: normal control group, disease control group, BTA low group (drinking water containing 15 mg/L BTA), BTA high group (50 mg/L BTA), and BTA high + STG (3 mg/kg, i.g.) group. RESULTS The selective TGR5 agonist BTA dose-dependently suppressed disease activity index and mRNA expression of the pro-inflammatory cytokines interleukin (IL)-1β, IL-6, and tumor necrosis factor-α in the colon. Nevertheless, STG administration had little additive effect on BTA-induced protection. Fibroblast activation protein mRNA expression, but not expression of other DPP family members, was increased in the colon of DSS-treated mice with increased mucosal DPPIV. Co-administration of the selective GLP-2 antagonist GLP-2 (3-33) reversed the effect of BTA. CONCLUSION The selective TGR5 agonist BTA ameliorated DSS-induced colitis in mice via the GLP-2 pathway with no effect of DPPIV inhibition, suggesting that other DPP enzymatic activity is involved in GLP-2 degradation.
Collapse
Affiliation(s)
- Taisuke Sakanaka
- Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka, Japan
| | - Takuya Inoue
- Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka, Japan
| | - Naoki Yorifuji
- Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka, Japan
| | - Munetaka Iguchi
- Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka, Japan
| | - Kaori Fujiwara
- Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka, Japan
| | - Ken Narabayashi
- Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka, Japan
| | - Kazuki Kakimoto
- Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka, Japan
| | - Sadaharu Nouda
- Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka, Japan
| | - Toshihiko Okada
- Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka, Japan
| | - Takanori Kuramoto
- Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka, Japan
| | - Kumi Ishida
- Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka, Japan
| | - Yosuke Abe
- Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka, Japan
| | - Toshihisa Takeuchi
- Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka, Japan
| | - Eiji Umegaki
- Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka, Japan
| | - Yasutada Akiba
- Greater Los Angeles Veterans Affairs Healthcare System, University of California, Los Angeles, California, USA
| | - Jonathan D. Kaunitz
- Greater Los Angeles Veterans Affairs Healthcare System, University of California, Los Angeles, California, USA
| | - Kazuhide Higuchi
- Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka, Japan
| |
Collapse
|
|
11
|
Fujiwara K, Inoue T, Yorifuji N, Iguchi M, Sakanaka T, Narabayashi K, Kakimoto K, Nouda S, Okada T, Ishida K, Abe Y, Masuda D, Takeuchi T, Fukunishi S, Umegaki E, Akiba Y, Kaunitz JD, Higuchi K. Combined treatment with dipeptidyl peptidase 4 (DPP4) inhibitor sitagliptin and elemental diets reduced indomethacin-induced intestinal injury in rats via the increase of mucosal glucagon-like peptide-2 concentration. J Clin Biochem Nutr 2015; 56:155-62. [PMID: 25759522 PMCID: PMC4345177 DOI: 10.3164/jcbn.14-111] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Accepted: 10/06/2014] [Indexed: 12/31/2022] Open
Abstract
The gut incretin glucagon-like peptide-1 (GLP-1) and the intestinotropic hormone GLP-2 are released from enteroendocrine L cells in response to ingested nutrients. Treatment with an exogenous GLP-2 analogue increases intestinal villous mass and prevents intestinal injury. Since GLP-2 is rapidly degraded by dipeptidyl peptidase 4 (DPP4), DPP4 inhibition may be an effective treatment for intestinal ulcers. We measured mRNA expression and DPP enzymatic activity in intestinal segments. Mucosal DPP activity and GLP concentrations were measured after administration of the DPP4 inhibitor sitagliptin (STG). Small intestinal ulcers were induced by indomethacin (IM) injection. STG was given before IM treatment, or orally administered after IM treatment with or without an elemental diet (ED). DPP4 mRNA expression and enzymatic activity were high in the jejunum and ileum. STG dose-dependently suppressed ileal mucosal enzyme activity. Treatment with STG prior to IM reduced small intestinal ulcer scores. Combined treatment with STG and ED accelerated intestinal ulcer healing, accompanied by increased mucosal GLP-2 concentrations. The reduction of ulcers by ED and STG was reversed by co-administration of the GLP-2 receptor antagonist. DPP4 inhibition combined with luminal nutrients, which up-regulate mucosal concentrations of GLP-2, may be an effective therapy for the treatment of small intestinal ulcers.
Collapse
Affiliation(s)
- Kaori Fujiwara
- Second Department of Internal Medicine, Osaka Medical College, 2-7 Daigakumachi, Takatsuki City, Osaka 569-8686, Japan
| | - Takuya Inoue
- Second Department of Internal Medicine, Osaka Medical College, 2-7 Daigakumachi, Takatsuki City, Osaka 569-8686, Japan
| | - Naoki Yorifuji
- Second Department of Internal Medicine, Osaka Medical College, 2-7 Daigakumachi, Takatsuki City, Osaka 569-8686, Japan
| | - Munetaka Iguchi
- Second Department of Internal Medicine, Osaka Medical College, 2-7 Daigakumachi, Takatsuki City, Osaka 569-8686, Japan
| | - Taisuke Sakanaka
- Second Department of Internal Medicine, Osaka Medical College, 2-7 Daigakumachi, Takatsuki City, Osaka 569-8686, Japan
| | - Ken Narabayashi
- Second Department of Internal Medicine, Osaka Medical College, 2-7 Daigakumachi, Takatsuki City, Osaka 569-8686, Japan
| | - Kazuki Kakimoto
- Second Department of Internal Medicine, Osaka Medical College, 2-7 Daigakumachi, Takatsuki City, Osaka 569-8686, Japan
| | - Sadaharu Nouda
- Second Department of Internal Medicine, Osaka Medical College, 2-7 Daigakumachi, Takatsuki City, Osaka 569-8686, Japan
| | - Toshihiko Okada
- Second Department of Internal Medicine, Osaka Medical College, 2-7 Daigakumachi, Takatsuki City, Osaka 569-8686, Japan
| | - Kumi Ishida
- Second Department of Internal Medicine, Osaka Medical College, 2-7 Daigakumachi, Takatsuki City, Osaka 569-8686, Japan
| | - Yosuke Abe
- Second Department of Internal Medicine, Osaka Medical College, 2-7 Daigakumachi, Takatsuki City, Osaka 569-8686, Japan
| | - Daisuke Masuda
- Second Department of Internal Medicine, Osaka Medical College, 2-7 Daigakumachi, Takatsuki City, Osaka 569-8686, Japan
| | - Toshihisa Takeuchi
- Second Department of Internal Medicine, Osaka Medical College, 2-7 Daigakumachi, Takatsuki City, Osaka 569-8686, Japan
| | - Shinya Fukunishi
- Second Department of Internal Medicine, Osaka Medical College, 2-7 Daigakumachi, Takatsuki City, Osaka 569-8686, Japan
| | - Eiji Umegaki
- Second Department of Internal Medicine, Osaka Medical College, 2-7 Daigakumachi, Takatsuki City, Osaka 569-8686, Japan
| | - Yasutada Akiba
- Greater Los Angeles Veterans Affairs Healthcare System and School of Medicine, Department of Medicine, University of California, Los Angeles, California, USA
| | - Jonathan D Kaunitz
- Greater Los Angeles Veterans Affairs Healthcare System and School of Medicine, Department of Medicine, University of California, Los Angeles, California, USA ; Greater Los Angeles Veterans Affairs Healthcare System and School of Medicine, Department of Surgery, University of California, Los Angeles, California, USA
| | - Kazuhide Higuchi
- Second Department of Internal Medicine, Osaka Medical College, 2-7 Daigakumachi, Takatsuki City, Osaka 569-8686, Japan
| |
Collapse
|
|
12
|
Huang CH, Hou YC, Yeh CL, Yeh SL. A soybean and fish oil mixture with different n-6/n-3 PUFA ratios modulates the inflammatory reaction in mice with dextran sulfate sodium-induced acute colitis. Clin Nutr 2014; 34:1018-24. [PMID: 25434577 DOI: 10.1016/j.clnu.2014.11.008] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2014] [Revised: 10/22/2014] [Accepted: 11/09/2014] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Inflammatory bowel disease is a recurrent disease of the gastrointestinal tract. n-3 polyunsaturated fatty acids (PUFAs) are proved to have anti-inflammatory and immunomodulatory properties. This study evaluated the effects of different dietary n-6/n-3 PUFA ratios on the mechanism of alleviating the inflammatory response in mice with dextran sulfate sodium (DSS)-induced colitis. METHODS Mice were randomly assigned to 6 groups including 3 non-colitis groups (C, LF, and HF) and 3 colitis groups (DC, DLF, and DHF). Mice in the C and DC groups were fed a common semipurified diet with soybean oil as the fat source. The other groups received an identical component except that part of the soybean oil was replaced by different amounts of fish oil. The n-6/n-3 PUFA ratio of the LF and DLF groups was 4:1, the ratio of the HF and DHF groups was 2:1. After feeding the respective diets for 2 weeks, the colitis groups were given distilled water containing 2% DSS, while the non-colitis groups were given distilled water for 5 days. After that, all mice were sacrificed at the recovery phase after drinking distilled water for another 5 days. RESULTS Colitis resulted in higher expressions of colonic inflammatory mediators in colon tissues and colon lavage fluid. Also, colonic peroxisome proliferator-activated receptor (PPAR)-γ and the IκBα/nuclear factor (NF)-κB p65 ratio were lower than those of the non-colitis groups. Compared to the DC group, fish oil-enriched colitis groups had lower inflammatory mediator expressions and higher PPAR-γ protein levels and IκBα/NF-κB p65 ratios in colon tissues. The DHF group had even lower colonic inflammatory gene and higher PPAR-γ protein expressions than did the DLF group. CONCLUSIONS These findings suggest that diets enriched with fish oil upregulated PPAR-γ and decreased NF-κB activation that may consequently have reduced luminal inflammatory mediator production. Compared to a n-6/n-3 PUFA ratio 4:1, a ratio of 2:1 was more effective in reducing inflammatory reactions in DSS-induced colitis.
Collapse
Affiliation(s)
- Cyoung-Huei Huang
- School of Nutrition and Health Sciences, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan
| | - Yu-Chen Hou
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Chiu-Li Yeh
- Department of Nutrition and Health Science, Chinese Culture University, Taipei, Taiwan
| | - Sung-Ling Yeh
- School of Nutrition and Health Sciences, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan.
| |
Collapse
|
|
13
|
Bilski J, Brzozowski B, Mazur-Bialy A, Sliwowski Z, Brzozowski T. The role of physical exercise in inflammatory bowel disease. BIOMED RESEARCH INTERNATIONAL 2014; 2014:429031. [PMID: 24877092 PMCID: PMC4022156 DOI: 10.1155/2014/429031] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/01/2014] [Revised: 02/25/2014] [Accepted: 03/05/2014] [Indexed: 12/20/2022]
Abstract
We reviewed and analyzed the relationship between physical exercise and inflammatory bowel disease (IBD) which covers a group of chronic, relapsing, and remitting intestinal disorders including Crohn's disease (CD) and ulcerative colitis. The etiology of IBD likely involves a combination of genetic predisposition and environmental risk factors. Physical training has been suggested to be protective against the onset of IBD, but there are inconsistencies in the findings of the published literature. Hypertrophy of the mesenteric white adipose tissue (mWAT) is recognized as a characteristic feature of CD, but its importance for the perpetuation of onset of this intestinal disease is unknown. Adipocytes synthesize proinflammatory and anti-inflammatory cytokines. Hypertrophy of mWAT could play a role as a barrier to the inflammatory process, but recent data suggest that deregulation of adipokine secretion is involved in the pathogenesis of CD. Adipocytokines and macrophage mediators perpetuate the intestinal inflammatory process, leading to mucosal ulcerations along the mesenteric border, a typical feature of CD. Contracting skeletal muscles release biologically active myokines, known to exert the direct anti-inflammatory effects, and inhibit the release of proinflammatory mediators from visceral fat. Further research is required to confirm these observations and establish exercise regimes for IBD patients.
Collapse
Affiliation(s)
- Jan Bilski
- Department of Ergonomics and Exercise Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, 31-531 Cracow, Poland
| | - Bartosz Brzozowski
- Gastroenterology Clinic, Jagiellonian University Medical College, 31-501 Cracow, Poland
| | - Agnieszka Mazur-Bialy
- Department of Ergonomics and Exercise Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, 31-531 Cracow, Poland
| | - Zbigniew Sliwowski
- Department of Physiology, Faculty of Medicine Jagiellonian University Medical College, 31-531 Cracow, Poland
| | - Tomasz Brzozowski
- Department of Physiology, Faculty of Medicine Jagiellonian University Medical College, 31-531 Cracow, Poland
| |
Collapse
|
|
14
|
Mashtoub S, Hoang BV, Vu M, Lymn KA, Feinle-Bisset C, Howarth GS. Clinical and structural effects of traditional Chinese medicine and the herbal preparation, Iberogast, in a rat model of ulcerative colitis. J Evid Based Complementary Altern Med 2014; 19:10-19. [PMID: 24647374 DOI: 10.1177/2156587213503660] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Plant-sourced formulations such as Iberogast and the traditional Chinese medicine formulation, Cmed, purportedly possess anti-inflammatory and radical scavenging properties. We investigated Iberogast and Cmed, independently, for their potential to decrease the severity of the large bowel inflammatory disorder, ulcerative colitis. Sprague Dawley rats (n = 8/group) received daily 1 mL gavages (days 0-13) of water, Iberogast (100 μL/200 μL), or Cmed (10 mg/20 mg). Rats ingested 2% dextran sulfate sodium or water ad libitum for 7 days commencing on day 5. Dextran sulfate sodium administration increased disease activity index scores from days 6 to 12, compared with water controls (P < .05). On day 10, 200 μL Iberogast decreased disease activity index scores in colitic rats compared with colitic controls (P < .05). Neither Iberogast nor Cmed achieved statistical significance for daily metabolic parameters or colonic crypt depth. The therapeutic effects of Iberogast and Cmed were minimal in the colitis setting. Further studies of plant extracts are required investigating greater concentrations and alternative delivery systems.
Collapse
Affiliation(s)
- Suzanne Mashtoub
- The University of Adelaide, Adelaide, South Australia, Australia
| | | | | | | | | | | |
Collapse
|
|
15
|
Inhibition of proteases as a novel therapeutic strategy in the treatment of metabolic, inflammatory and functional diseases of the gastrointestinal tract. Drug Discov Today 2013; 18:708-15. [DOI: 10.1016/j.drudis.2013.03.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2013] [Revised: 03/19/2013] [Accepted: 03/28/2013] [Indexed: 12/14/2022]
|
|
16
|
Cheah KY, Bastian SEP, Acott TMV, Abimosleh SM, Lymn KA, Howarth GS. Grape seed extract reduces the severity of selected disease markers in the proximal colon of dextran sulphate sodium-induced colitis in rats. Dig Dis Sci 2013; 58:970-977. [PMID: 23143736 DOI: 10.1007/s10620-012-2464-1] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2012] [Accepted: 10/10/2012] [Indexed: 12/12/2022]
Abstract
BACKGROUND Grape seed extract (GSE) constitutes a rich source of procyanidins. GSE has been demonstrated to exert encouraging anti-inflammatory and anti-ulcer properties in experimental settings, although its effects on inflammation of the colon remain undefined. AIM To determine the effects of GSE in a rat model of dextran sulphate sodium (DSS) for ulcerative colitis. METHODS Male Sprague-Dawley rats were gavaged daily (days 0-10) with GSE (400 mg/kg). Ulcerative colitis was induced by substituting DSS (2 % w/v) for drinking water from days 5-10. A sucrose breath test was performed on day 11 to determine small bowel function and intestinal tissues were collected for histological analyses. Statistical analysis was by one-way or repeated-measures ANOVA and p < 0.05 was considered significant. RESULTS Compared to DSS-treated controls, GSE significantly decreased ileal villus height (14 %; p < 0.01) and mucosal thickness (13 %; p < 0.01) towards the values of normal controls. GSE reduced qualitative histological severity score (p < 0.05) in the proximal colon, although no significant effect was evident in the distal colon. However, GSE failed to prevent DSS-induced damage to the crypts of both colonic regions. Administration of GSE did not negatively impact metabolic parameters, nor did it induce any deleterious gastrointestinal side effects in healthy animals. CONCLUSIONS GSE decreased the severity of selected markers of DSS-induced colitis in the distal ileum and proximal colon, suggesting the potential as an adjuvant therapy for the treatment of ulcerative colitis. Future studies of GSE should investigate alternative delivery methods and treatment regimens, further seeking to identify the individual bioactive factors.
Collapse
Affiliation(s)
- Ker Y Cheah
- Wine Science and Business Group School of Agriculture, Food and Wine, Waite Campus, The University of Adelaide, PMB 1, Glen Osmond, SA 5064, Australia
| | | | | | | | | | | |
Collapse
|
|
17
|
Abstract
Gastrointestinal diseases characterized by inflammation, including the inflammatory bowel diseases, chemotherapy-induced mucositis and non-steroidal anti-inflammatory drug-induced enteropathy, currently have variably effective treatment options, highlighting the need for novel therapeutic approaches. Recently, naturally-sourced agents including prebiotics, probiotics, plant-extracts and marine-derived oils known to possess anti-inflammatory and anti-oxidant properties have been investigated in vitro and in vivo. However, animal-derived oils are yet to be extensively tested. Emu Oil is extracted from the subcutaneous and retroperitoneal fat of the Emu, a flightless bird native to Australia, and predominantly comprises fatty acids. Despite the limited rigorous scientific studies conducted to date, with largely anecdotal claims, Emu Oil, when administered topically and orally, has been shown to possess significant anti-inflammatory properties in vivo. These include a CD-1 mouse model of croton oil-induced auricular inflammation, experimentally-induced polyarthritis and dextran sulfate sodium-induced colitis. Recently, Emu Oil has been demonstrated to endow partial protection against chemotherapy-induced mucositis, with early indications of improved intestinal repair. Emu Oil could therefore form the basis of an adjunct to conventional treatment approaches for inflammatory disorders affecting the gastrointestinal system.
Collapse
Affiliation(s)
- Suzanne M Abimosleh
- Department of Gastroenterology, Women's and Children's Hospital, North Adelaide, South Australia, Australia
| | | | | |
Collapse
|
|
18
|
Yazbeck R, Howarth GS, Butler RN, Geier MS, Abbott CA. Biochemical and histological changes in the small intestine of mice with dextran sulfate sodium colitis. J Cell Physiol 2011; 226:3219-3224. [PMID: 21351101 DOI: 10.1002/jcp.22682] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The dextran sulfate sodium (DSS) model of colitis has been commonly utilized in mice to assess novel treatments for ulcerative colitis. Recent studies have indicated that morphological and biochemical changes extend to the small intestine (SI). This study aimed to characterize histological and biochemical changes in the SI during DSS colitis in wild-type (WT) and DPIV knock-out (DPIV(-/-) ) mice treated with saline or the DPIV inhibitors, Ile-Pyrr-(2-CN)*TFA or Ile-Thia. Groups (n = 10) of DPIV(-/-) and WT mice were orally gavaged twice daily with saline, Ile-Pyrr-(2-CN)*TFA or Ile-Thia. Mice consumed 2% DSS in drinking water for 6 days to induce colitis. Small intestinal tissue was assessed for histological changes, sucrase, and DPIV activity and neutrophil infiltration. Jejunal villus length was increased in all groups after 6 days DSS consumption (P < 0.05). Jejunal DPIV activity was significantly lower by 35% in WT mice receiving Ile-Pyrr-(2-CN)*TFA compared to saline controls. Jejunal MPO activity was significantly increased in the WT + saline and DPIV(-/-) + saline groups following DSS consumption, compared to WT and DPIV(-/-) controls at day 0. Increased sucrase activity was apparent at day 0 in DPIV(-/-) compared to WT mice (P < 0.05). We conclude that DSS-induced damage is not restricted to the colon, but also extends to the small intestine. Furthermore, reduced or absent DPIV activity resulted in functional adaptations to brush border enzyme activity. DPIV inhibitors are now a recognized therapy for type-II diabetes. The work presented here highlights the need to delineate any long-term effects of DPIV inhibitors on SI function, to further validate their safety and tolerability.
Collapse
Affiliation(s)
- Roger Yazbeck
- School of Biological Sciences, Flinders University, Adelaide, South Australia, Australia.
| | | | | | | | | |
Collapse
|
|
19
|
Detel D, Pugel EP, Pucar LB, Buljevic S, Varljen J. Development and resolution of colitis in mice with target deletion of dipeptidyl peptidase IV. Exp Physiol 2011; 97:486-96. [PMID: 22125312 DOI: 10.1113/expphysiol.2011.061143] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
A role for dipeptidyl peptidase IV (DPP IV/CD26) in the pathogenesis of inflammatory bowel disease has been proposed owing to its involvement in immune regulation via its expression on immune cells and ability to cleave biologically active molecules. The aim of this study was to investigate the influence of DPP IV/CD26 deficiency on development and resolution of dextran sulfate sodium-induced colitis in CD26-deficient (CD26(-/-)) and wild-type (C57BL/6) mice. Colitis was characterized by clinical and histological changes and infiltration of immune cells in the colonic mucosa. In the acute phase of colitis, loss of body mass and disease activity in C57BL/6 mice was more intensive than in CD26(-/-) mice, in spite of similar histopathological changes at the local level. Although acute inflammation induced a significant increase in the number of macrophages and dendritic cells in both mouse strains, in CD26(-/-) mice the increase of macrophages was twice that in C57BL/6 animals (18.0 ± 4.5 versus 41.3 ± 5.8), whereas the increase in dendritic cells was more pronounced in C57BL/6 mice. In the acute phase of colitis, colonic DPP IV/CD26 activity was significantly decreased in C57BL/6 mice compared with healthy animals. The results of our study reveal that DPP IV/CD26 deficiency affects the onset of clinical symptoms and the specific cells infiltrating at the site of inflammation in CD26(-/-) animals, suggesting a pathophysiological role of DPP IV/CD26 and providing new insights into the nature of the immune response activated during the development of colitis.
Collapse
Affiliation(s)
- Dijana Detel
- Department of Chemistry and Biochemistry, School of Medicine, University of Rijeka, Bráce Branchetta 20, 51000 Rijeka, Croatia
| | | | | | | | | |
Collapse
|
|
20
|
Abstract
CD26 is a 110-kDa surface glycoprotein with intrinsic dipeptidyl peptidase IV (DPPIV) activity that is expressed on various cell types and has many biological functions. An important aspect of CD26 biology is its peptidase activity and its functional and physical association with molecules with key roles in human immunological programs. CD26 role in immune regulation has been extensively characterized, with recent findings elucidating its link age with signaling pathways and structures involved in T cell activation a well as antigen-presenting cell-T cell interaction, being a marker of diseas behavior clinically as well as playing an important role in autoimmune pathogenesis and development. Through the use of various experimental approaches and agents to influence CD26/DPPIV expression and activity, such as anti-CD26 antibodies, CD26/DPPIV chemical inhibitors, siRNAs to inhibit CD26 expression, overexpressing CD26 transfectants, soluble CD26 molecules and proteomic approach, we have shown that CD26 interacts with structures with essential cellular functions in T cell responses. We will review emerging data that suggest CD26 may be an appropriate therapeutic target for the treatment of selected immune disorders.
Collapse
Affiliation(s)
- Kei Ohnuma
- Division of Rheumatology and Allergy, Research Hospital, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan
| | | | | | | |
Collapse
|
|
21
|
Jin NS, Dong Z, Fu JM, Zeng FX. DPP-4 inhibitors and inflammatory bowel disease. Shijie Huaren Xiaohua Zazhi 2010; 18:3215-3219. [DOI: 10.11569/wcjd.v18.i30.3215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic, debilitating disease associated with severe damage to the intestinal mucosa whose etiology is still unknown. The two most common forms of IBD are ulcerative colitis (UC) and Crohn's disease (CD). DPP-4 inhibitors are a new class of agents developed for treatment of diabetes. However, recent studies have indicated that DPP-4 inhibitors have therapeutic effects against IBD in animal models. This may provide a new avenue to cure IBD.
Collapse
|
|
22
|
Yazbeck R, Sulda ML, Howarth GS, Bleich A, Raber K, von Hörsten S, Holst JJ, Abbott CA. Dipeptidyl peptidase expression during experimental colitis in mice. Inflamm Bowel Dis 2010; 16:1340-1351. [PMID: 20186930 DOI: 10.1002/ibd.21241] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND We have previously demonstrated that inhibition of dipeptidyl peptidase (DP) activity partially attenuates dextran sulfate sodium (DSS) colitis in mice. The aim of this study was to further investigate the mechanisms of this protection. MATERIALS AND METHODS Wildtype (WT) and DPIV(-/-) mice consumed 2% DSS in drinking water for 6 days to induce colitis. Mice were treated with saline or the DP inhibitors Ile-Pyrr-(2-CN)*TFA or Ile-Thia. DP mRNA and enzyme levels were measured in the colon. Glucagon-like peptide (GLP)-2 and GLP-1 concentrations were determined by radioimmunoassay, regulatory T-cells (Tregs) by fluorescence activated cell sorting (FACS) on FOXp3+T cells in blood, and neutrophil infiltration assessed by myeloperoxidase (MPO) assay. RESULTS DP8 and DP2 mRNA levels were increased (P < 0.05) in WT+saline mice compared to untreated WT mice with colitis. Cytoplasmic DP enzyme activity was increased (P < 0.05) in DPIV(-/-) mice at day 6 of DSS, while DP2 activity was increased (P < 0.05) in WT mice with colitis. GLP-1 (63%) and GLP-2 (50%) concentrations increased in WT+Ile-Pyrr-(2-CN)*TFA mice compared to day-0 controls. MPO activity was lower in WT+Ile-Thia and WT+Ile-Pyrr-(2-CN)*TFA treated mice compared to WT+saline (P < 0.001) at day 6 colitis. CONCLUSIONS DP expression and activity are differentially regulated during DSS colitis, suggesting a pathophysiological role for these enzymes in human inflammatory bowel disease (IBD). DP inhibitors impaired neutrophil recruitment and maintenance of the Treg population during DSS-colitis, providing further preclinical evidence for the potential therapeutic use of these inhibitors in IBD. Finally, DPIV appears to play a critical role in mediating the protective effect of DP inhibitors.
Collapse
Affiliation(s)
- Roger Yazbeck
- School of Biological Sciences, Flinders University, Adelaide, South Australia, Australia
| | | | | | | | | | | | | | | |
Collapse
|
|
23
|
Håkansson A, Bränning C, Adawi D, Molin G, Nyman M, Jeppsson B, Ahrné S. Blueberry husks, rye bran and multi-strain probiotics affect the severity of colitis induced by dextran sulphate sodium. Scand J Gastroenterol 2010; 44:1213-25. [PMID: 19670079 DOI: 10.1080/00365520903171268] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE The enteric microbiota is a pivotal factor in the development of intestinal inflammation in humans but probiotics, dietary fibres and phytochemicals can have anti-inflammatory effects. The aim of this study was to evaluate the therapeutic effect of multi-strain probiotics and two conceivable prebiotics in an experimental colitis model. MATERIAL AND METHODS Sprague-Dawley rats were fed a fibre-free diet alone or in combination with Lactobacillus crispatus DSM 16743, L. gasseri DSM 16737 and Bifidobacterium infantis DSM 15158 and/or rye bran and blueberry husks. Colitis was induced by 5% dextran sulphate sodium (DSS) given by oro-gastric tube. Colitis severity, inflammatory markers, gut-load of lactobacilli and Enterobacteriaceae, bacterial translocation and formation of carboxylic acids (CAs) were analysed. RESULTS The disease activity index (DAI) was lower in all treatment groups. Viable counts of Enterobacteriaceae were reduced and correlated positively with colitis severity, while DAI was negatively correlated with several CAs, e.g. butyric acid. The addition of probiotics to blueberry husks lowered the level of caecal acetic acid and increased that of propionic acid, while rye bran in combination with probiotics increased caecal CA levels and decreased distal colonic levels. Blueberry husks with probiotics reduced the incidence of bacterial translocation to the liver, colonic levels of myeloperoxidase, malondialdehyde and serum interleukin-12. Acetic and butyric acids in colonic content correlated negatively to malondialdehyde. CONCLUSIONS A combination of probiotics and blueberry husks or rye bran enhanced the anti-inflammatory effects compared with probiotics or dietary fibres alone. These combinations can be used as a preventive or therapeutic approach to dietary amelioration of intestinal inflammation.
Collapse
|
|
24
|
A label-free nano-liquid chromatography-mass spectrometry approach for quantitative serum peptidomics in Crohn's disease patients. J Chromatogr B Analyt Technol Biomed Life Sci 2009; 877:3127-36. [PMID: 19683480 DOI: 10.1016/j.jchromb.2009.08.003] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2009] [Revised: 07/18/2009] [Accepted: 08/03/2009] [Indexed: 12/28/2022]
Abstract
The identification of serum biomarkers for the diagnosis of inflammatory bowel diseases able to reduce the need for invasive tests represents a major goal in their therapy and follow-up. We report here a methodological approach for the evaluation of specific changes in the serum peptides abundance in healthy (H) and Crohn's disease (CD) subjects, based on a label-free LC ESI/Q-TOF differential mass spectrometry (MS) approach combined with targeted MS/MS analysis. The low molecular weight serum proteins were separated by RP nano-LC ESI/Q-TOF MS and the resulting datasets were aligned with msInspect software. The differently abundant peptides, evaluated using Proteios Software Environment, were identified by MS/MS analysis and database search. The identification of clusters of peptides resulting from proteins (such as fibrinogen-alpha) commonly involved in physiological processes lead to the evaluation of a possible role in CD of specific serum exoproteases. An assay based on synthetic peptides spiked into H, CD and ulcerative colitis (UC) serum samples as substrate, followed by MALDI MS and chemometric analysis of the metabolite patterns has been developed achieving a 100% discrimination between CD, UC and H subjects. The results are promising for the application of this approach as a simple tool for diagnostic aims and biomarker discovery in CD.
Collapse
|
|
25
|
Geier MS, Smith CL, Butler RN, Howarth GS. Small-intestinal manifestations of dextran sulfate sodium consumption in rats and assessment of the effects of Lactobacillus fermentum BR11. Dig Dis Sci 2009; 54:1222-1228. [PMID: 19005763 DOI: 10.1007/s10620-008-0495-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2008] [Accepted: 08/22/2008] [Indexed: 12/13/2022]
Abstract
The dextran sulfate sodium (DSS) colitis model has been utilized to screen for novel therapeutics for ulcerative colitis. Evidence suggests the small intestine may also be affected by DSS. We characterized the effects of DSS on the small intestine and assessed the potential for Lactobacillus fermentum BR11 to modify or normalize DSS-induced changes. Rats were allocated to three groups, Water + Vehicle, DSS + Vehicle, and DSS + L. fermentum BR11. BR11 was administered twice daily for 14 days. DSS (2%) was provided from days 7 to 14. Small-intestinal tissue was analyzed for sucrase activity, histology, and crypt cell proliferation. Increased ileum crypt depth and cell proliferation was observed in DSS-treated rats compared to controls (P < 0.05). BR11 normalized these parameters. While DSS predominantly induces colonic damage, minor morphological alterations were also detected in the distal small intestine. L. fermentum BR11 normalized these features.
Collapse
Affiliation(s)
- Mark S Geier
- Centre for Paediatric and Adolescent Gastroenterology, Children, Youth and Women's Health Service, North Adelaide, Adelaide, SA, Australia
| | | | | | | |
Collapse
|
|
26
|
Yazbeck R, Howarth GS, Abbott CA. Growth factor based therapies and intestinal disease: is glucagon-like peptide-2 the new way forward? Cytokine Growth Factor Rev 2009; 20:175-184. [PMID: 19324585 DOI: 10.1016/j.cytogfr.2009.02.008] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Inflammatory bowel disease (IBD) is a chronic, debilitating disease associated with severe damage to the intestinal mucosa. Glucagon-like peptide-2 (GLP-2) is a potent and specific gastrointestinal growth factor that is demonstrating therapeutic potential for the prevention or treatment of an expanding number of intestinal diseases, including short bowel syndrome (SBS), small bowel enteritis and IBD. The biological activity of GLP-2 is limited due to proteolytic inactivation by the protease dipeptidyl peptidase (DP)IV. Inhibitors of DPIV activity may represent a novel strategy to prolong the growth promoting actions of GLP-2. This review outlines evidence for the clinical application of GLP-2, its degradation resistant analogue, Teduglutide, and novel DPIV inhibitors in efficacy studies utilizing pre-clinical models of intestinal damage, in particular IBD.
Collapse
Affiliation(s)
- Roger Yazbeck
- School of Biological Sciences, Flinders University, Adelaide, South Australia, Australia.
| | | | | |
Collapse
|
|
27
|
Howarth GS, Lindsay RJ, Butler RN, Geier MS. Can emu oil ameliorate inflammatory disorders affecting the gastrointestinal system? AUSTRALIAN JOURNAL OF EXPERIMENTAL AGRICULTURE 2008; 48:1276. [DOI: 10.1071/ea08139] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2025]
Abstract
Emu oil possesses significant anti-inflammatory properties in vivo, primarily when applied topically. However, to date, the evidence supporting its therapeutic application has been largely anecdotal, and significant batch-to-batch variations in potency have been reported. Nevertheless, the anti-inflammatory properties of emu oil suggest therapeutic promise for the adjunctive treatment of a range of disparate gastrointestinal diseases and disorders characterised by inflammatory processes. These include the idiopathic condition inflammatory bowel disease, chemotherapy-induced mucositis, non-steroidal anti-inflammatory drug enteropathy and the various infective enteritides (i.e. fungal, bacterial and viral gastroenteritis). Although rigorous scientific investigations are in their infancy, the evidence for emu oil efficacy in extra-intestinal disorders, supported by limited in vivo investigations of other naturally sourced oils, identifies emu oil as a possible adjunct to conventional treatment approaches for inflammatory disorders affecting the gastrointestinal system.
Collapse
|
|
28
|
Tran CD, Ball JM, Sundar S, Coyle P, Howarth GS. The role of zinc and metallothionein in the dextran sulfate sodium-induced colitis mouse model. Dig Dis Sci 2007; 52:2113-2121. [PMID: 17410436 DOI: 10.1007/s10620-007-9765-9] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2006] [Accepted: 01/04/2007] [Indexed: 12/15/2022]
Abstract
Zinc (Zn) and its binding protein metallothionein (MT) have been proposed to suppress the disease activity in ulcerative colitis. To determine the role of Zn and MT in the dextran sulfate sodium (DSS)-induced model of colitis in mice, a DSS dose-response study was conducted in male C57BL/6 wild-type (MT+/+) and MT-null (MT-/-) mice by supplementing 2%, 3%, and 4% DSS in the drinking water for 6 days. In the intervention study, colitis was induced with 2% DSS, Zn (24 mg/ml as ZnO) was gavaged (0.1 ml) daily, concurrent with DSS administration, and the disease activity index (DAI) was scored daily. Histology, MT levels, and myeloperoxidase (MPO) activity were determined. DAI was increased (P<0.05) by 16% and 21% with 3% and 4% concentrations of DSS, respectively, compared to 2%, evident after 5 days of DSS administration. MPO activity was increased in MT+/+ compared to MT-/- mice and those receiving DSS. Zn administration had a 50% (P<0.05) lower DAI compared to DSS alone. Zn partially prevented the distal colon of MT+/+ by 47% from DSS-induced damage compared to MT-/- mice. MT did not prevent DSS-induced colitis and Zn was partially effective in amelioration of DSS-induced colitis.
Collapse
Affiliation(s)
- C D Tran
- Gastroenterology Unit, Children, Youth and Women's Health Service, 72 King William Road, North Adelaide, SA 5006, Australia.
| | | | | | | | | |
Collapse
|
|
29
|
Geier MS, Butler RN, Giffard PM, Howarth GS. Prebiotic and synbiotic fructooligosaccharide administration fails to reduce the severity of experimental colitis in rats. Dis Colon Rectum 2007; 50:1061-1069. [PMID: 17429712 DOI: 10.1007/s10350-007-0213-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Opposing effects of the prebiotic, fructooligosaccharide, have been reported in experimental colitis. We compared the effects of the prebiotic, fructooligosaccharide, alone and in synbiotic combination with Lactobacillus fermentum BR11, on the development of dextran sulfate sodium-induced colitis in rats. Rats consumed an 18 percent casein-based diet or diet supplemented with 6 percent fructooligosaccharide or maltodextrin for 14 days. The synbiotic group was gavaged 1 ml of L. fermentum BR11 (1x10(9) cfu/ml) twice daily. From Days 7 to 14, colitis was induced via 3 percent dextran sulfate sodium in drinking water. Disease activity was assessed daily, and at killing, gastrointestinal organs were measured, weighed, and examined by quantitative histology, proliferating cell nuclear antigen immunohistochemistry, and colonic myeloperoxidase activity. Administration of dextran sulfate sodium resulted in an increased colitic disease activity, and an increased colon and cecum weight compared with normal controls. Colon and cecum weights were further increased in dextran sulfate sodium+fructooligosaccharide (colon: 19 percent; cecum: 48 percent) and dextran sulfate sodium+fructooligosaccharide/L. fermentum BR11-treated rats (16 and 62 percent) compared with dextran sulfate sodium+vehicle-treatment. Dextran sulfate sodium+fructooligosaccharide-treated rats displayed an 81 percent increase in colonic myeloperoxidase activity compared with dextran sulfate sodium-treated controls. Histologic damage severity scores increased in dextran sulfate sodium+vehicle, dextran sulfate sodium+fructooligosaccharide, and dextran sulfate sodium+fructooligosaccharide/L. fermentum BR11-treated rats compared with normal controls (P<0.05). Crypt depth increased in all treatments compared with normal controls (P<0.01). No protection from dextran sulfate sodium-colitis was accorded by fructooligosaccharide alone or in synbiotic combination with L. fermentum BR11, whereas fructooligosaccharide actually increased some indicators of colonic injury.
Collapse
Affiliation(s)
- Mark S Geier
- Centre for Paediatric and Adolescent Gastroenterology, Children, Youth and Women's Health Service, 72 King William Road, North Adelaide, South Australia, Australia.
| | | | | | | |
Collapse
|
|
30
|
Kamil R, Geier MS, Butler RN, Howarth GS. Lactobacillus rhamnosus GG exacerbates intestinal ulceration in a model of indomethacin-induced enteropathy. Dig Dis Sci 2007; 52:1247-1252. [PMID: 17357841 DOI: 10.1007/s10620-006-9443-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2006] [Accepted: 05/12/2006] [Indexed: 01/12/2023]
Abstract
Lactobacillus rhamnosus GG (LGG) and Bifidobacterium lactis Bb12 (Bb12) were assessed for their potential to prevent indomethacin-induced ulceration in the small intestine of Sprague-Dawley rats. Rats were gavaged skim milk, LGG, or Bb12 twice daily for 14 days. Between days 7-14, rats were gavaged indomethacin (Indo; 6 mg/kg). At sacrifice, small intestine was scored for ulceration and sampled for histologic, immunohistochemical, and myeloperoxidase (MPO) analyses. Indo+LGG-treated rats exhibited a 2.3-fold increase in MPO activity and a 9.8-fold increase in ulceration area compared to Indo-treated controls; these parameters did not differ significantly between Indo+Bb12 and Indo-treated controls. Crypt cell apoptosis decreased by 82% in Indo+Bb12-treated and 55% in Indo+LGG-treated rats compared to Indo-treated controls. Proliferation increased by 209% in Indo+LGG-treated animals compared to Indo-treated controls. Bb12 did not reduce indomethacin-induced intestinal ulceration, whereas LGG actually increased some indicators of injury. LGG and Bb12, at the doses tested, cannot alleviate indomethacin-induced intestinal injury.
Collapse
Affiliation(s)
- Rasha Kamil
- entre for Paediatric and Adolescent Gastroenterology, Children, Youth and Women's Health Service, 72 King William Road, North Adelaide, South Australia, Australia
| | | | | | | |
Collapse
|
|
31
|
Geier MS, Butler RN, Giffard PM, Howarth GS. Lactobacillus fermentum BR11, a potential new probiotic, alleviates symptoms of colitis induced by dextran sulfate sodium (DSS) in rats. Int J Food Microbiol 2007; 114:267-274. [PMID: 17150273 DOI: 10.1016/j.ijfoodmicro.2006.09.018] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2006] [Revised: 08/23/2006] [Accepted: 09/26/2006] [Indexed: 12/16/2022]
Abstract
Current treatments for inflammatory bowel disease (IBD) are relatively ineffective. Recently, probiotics have emerged as a potential treatment modality for numerous gastrointestinal disorders, including IBD. Few probiotics, however, have undergone appropriate preclinical screening in vivo. The current study compared the effects of four candidate probiotics on development of dextran sulfate sodium (DSS)-induced colitis in rats. Sprague Dawley rats were gavaged 1 mL of the potential probiotic (1 x 10(10) CFU/mL), or vehicle, twice daily for 14 days. Strains tested were Lactobacillus rhamnosus GG (LGG), Streptococcus thermophilus TH-4 (TH-4), Bifidobacterium lactis Bb12 (Bb12) and Lactobacillus fermentum BR11 (BR11). Colitis was induced from day 7 to 14 via administration of 2% DSS in drinking water. Disease activity index (DAI) was monitored daily until rats were killed at day 14. DAI decreased in DSS+Bb12 and DSS+BR11 compared to DSS+Vehicle. Colon length increased in DSS+BR11 (10%) and DSS+LGG (10%) compared to DSS+Vehicle. DSS+Bb12 and DSS+BR11 prevented the distal colon crypt hyperplasia evident in DSS+Vehicle, DSS+LGG and DSS+TH-4. BR11 was most effective at reducing colitic symptoms. Bb12 had minimal effects, whilst TH-4 did not prevent DSS-colitis and LGG actually exacerbated some indicators of colitis. Further studies into the potential benefits of L. fermentum BR11 are indicated.
Collapse
Affiliation(s)
- Mark S Geier
- Centre for Paediatric and Adolescent Gastroenterology, Children, Youth and Women's Health Service, 72 King William Road, North Adelaide, South Australia, 5006, Australia.
| | | | | | | |
Collapse
|
|
32
|
Mauger CA, Butler RN, Geier MS, Tooley KL, Howarth GS. Probiotic effects on 5-fluorouracil-induced mucositis assessed by the sucrose breath test in rats. Dig Dis Sci 2007; 52:612-619. [PMID: 17237997 DOI: 10.1007/s10620-006-9464-y] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2006] [Accepted: 05/19/2006] [Indexed: 12/21/2022]
Abstract
The sucrose breath test (SBT) was employed to noninvasively assess the efficacy of probiotics in 5-fluorouracil (5-FU)-induced intestinal mucositis. Dark Agouti rats were allocated to 5 groups (n = 10): 5-FU + L. fermentum BR 11, 5-FU + L. rhamnosus GG, 5-FU + B. lactis BB 12, 5-FU + skim milk (SM), and saline + SM. Probiotics were administered by oral gavage for 10 days. Mucositis was induced on day 7 by intraperitoneal injection of 5-FU (150 mg/kg) or vehicle (saline). Rats were sacrificed 72 h after 5-FU injection. The SBT measured breath 13CO2 (expressed as percentage cumulative dose at 90 min; %CD90) on days 0, 7, and 10. %CD90 was significantly lower in 5-FU-treated controls compared with that in saline-treated controls on day 10. 5-FU caused an 83% reduction in sucrase and a 510% increase in MPO activity. The SBT detected damage induced by 5-FU and is a simple, noninvasive indicator of small bowel injury. The probiotics assessed offered no protection from mucositis at the dose tested.
Collapse
Affiliation(s)
- Chad A Mauger
- Centre for Paediatric and Adolescent Gastroenterology, Children, Youth and Women's Health Service, 72 King William Road, North Adelaide, South Australia, Australia
| | | | | | | | | |
Collapse
|
|
33
|
Triggering endogenous immunosuppressive mechanisms by combined targeting of Dipeptidyl peptidase IV (DPIV/CD26) and Aminopeptidase N (APN/ CD13)--a novel approach for the treatment of inflammatory bowel disease. Int Immunopharmacol 2006; 6:1925-34. [PMID: 17161345 DOI: 10.1016/j.intimp.2006.09.014] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2006] [Accepted: 09/15/2006] [Indexed: 12/25/2022]
Abstract
The ectopeptidases Dipeptidylpeptidase IV and Alanyl-Aminopeptidase N, strongly expressed by both, activated and regulatory T cells were shown to co-operate in T cell regulation. Based on the findings that DPIV and APN inhibitors induce the TGF-beta1 and IL-10 production and a suppression of T helper cell proliferation in parallel, and that particularly APN inhibitors amplify the suppressing activity of regulatory T cells, both peptidases represent a promising target complex for treatment of diseases associated with an imbalanced T cell response, such as inflammatory bowel diseases (IBD). The aim of the present study was to analyze the therapeutic potential of DPIV and APN inhibitors in vivo in a mouse model of colitis. Balb/c mice received 3% (w/v) dextran sulphate sodium with the drinking water for 7 days. After onset of colitis symptoms, inhibitor treatment started at day 3. Disease activity index (DAI) was assessed daily, supplemented by histological and immunological analysis. While the DPIV inhibitor Lys-[Z(NO])(2)]-pyrrolidide or the APN-inhibitor Actinonin alone had marked but no significant therapeutic effects, the simultaneous administration of both inhibitors reduced colitis activity in comparison to placebo treated mice, significantly (DAI 4.8 vs. 7.7, p<0.005). A newly developed compound IP12.C6 with inhibitory capacity toward both enzymes significantly attenuated the clinical manifestation of colitis (DAI 3.2 vs. 7.6, p<0.0001). TGF-beta mRNA was found to be up-regulated in colon tissue of inhibitor-treated animals. In summary our results strongly suggest that combined DPIV and APN inhibition by synthetic inhibitors represents a novel and efficient approach for the pharmacological therapy of IBD by triggering endogenous immunosuppressive mechanisms.
Collapse
|
|
34
|
Martin GR, Beck PL, Sigalet DL. Gut hormones, and short bowel syndrome: The enigmatic role of glucagon-like peptide-2 in the regulation of intestinal adaptation. World J Gastroenterol 2006; 12:4117-29. [PMID: 16830359 PMCID: PMC4087358 DOI: 10.3748/wjg.v12.i26.4117] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Short bowel syndrome (SBS) refers to the malabsorption of nutrients, water, and essential vitamins as a result of disease or surgical removal of parts of the small intestine. The most common reasons for removing part of the small intestine are due to surgical intervention for the treatment of either Crohn's disease or necrotizing enterocolitis. Intestinal adaptation following resection may take weeks to months to be achieved, thus nutritional support requires a variety of therapeutic measures, which include parenteral nutrition. Improper nutrition management can leave the SBS patient malnourished and/or dehydrated, which can be life threatening. The development of therapeutic strategies that reduce both the complications and medical costs associated with SBS/long-term parenteral nutrition while enhancing the intestinal adaptive response would be valuable.
Currently, therapeutic options available for the treatment of SBS are limited. There are many potential stimulators of intestinal adaptation including peptide hormones, growth factors, and neuronally-derived components. Glucagon-like peptide-2 (GLP-2) is one potential treatment for gastrointestinal disorders associated with insufficient mucosal function. A significant body of evidence demonstrates that GLP-2 is a trophic hormone that plays an important role in controlling intestinal adaptation. Recent data from clinical trials demonstrate that GLP-2 is safe, well-tolerated, and promotes intestinal growth in SBS patients. However, the mechanism of action and the localization of the glucagon-like peptide-2 receptor (GLP-2R) remains an enigma. This review summarizes the role of a number of mucosal-derived factors that might be involved with intestinal adaptation processes; however, this discussion primarily examines the physiology, mechanism of action, and utility of GLP-2 in the regulation of intestinal mucosal growth.
Collapse
Affiliation(s)
- G-R Martin
- Department of Gastrointestinal Sciences, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW., Calgary, Alberta T2N 4N1, Canada.
| | | | | |
Collapse
|
|
35
|
Cowin AJ, Adams D, Geary SM, Wright MD, Jones JCR, Ashman LK. Wound healing is defective in mice lacking tetraspanin CD151. J Invest Dermatol 2006; 126:680-9. [PMID: 16410781 PMCID: PMC2976039 DOI: 10.1038/sj.jid.5700142] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
The tetraspanin CD151 forms complexes in epithelial cell membranes with laminin-binding integrins alpha6beta4, alpha3beta1, and alpha6beta1, and modifies integrin-mediated cell migration in vitro. We demonstrate in this study that CD151 expression is upregulated in a distinct temporal and spatial pattern during wound healing, particularly in the migrating epidermal tongue at the wound edge, suggesting a role for CD151 in keratinocyte migration. We show that healing is significantly impaired in CD151-null mice, with wounds gaping wider at 7 days post-injury. The rate of re-epithelialization of the CD151-null wounds is adversely affected, with significantly less wound area being covered by migrating epidermal cells. Our studies reveal that although laminin levels are similar in wild-type and CD151-null wounds, the organization of the laminin in the basement membrane is impaired. Furthermore, upregulation of alpha6 and beta4 integrin expression is adversely affected in CD151-null mice wounds. In contrast, we find no significant effect of CD151 gene knockout on alpha3 and beta1 integrin expression in wound repair. We suggest that mice lacking the CD151 gene are defective in wound healing, primarily owing to impairment of the re-epithelialization process. This may be due to defective basement membrane formation and epithelial cell adhesion and migration.
Collapse
Affiliation(s)
- Allison J Cowin
- Child Health Research Institute, North Adelaide, South Australia, Australia.
| | | | | | | | | | | |
Collapse
|
|
36
|
Brandt I, Lambeir AM, Maes MB, Scharpé S, De Meester I. Peptide substrates of dipeptidyl peptidases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2006; 575:3-18. [PMID: 16700503 DOI: 10.1007/0-387-32824-6_1] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Affiliation(s)
- Inger Brandt
- Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium
| | | | | | | | | |
Collapse
|
|
37
|
Abbott CA, Yazbeck R, Geier MS, Demuth HU, Howarth GS. Dipeptidyl peptidases and inflammatory bowel disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2006; 575:155-62. [PMID: 16700518 DOI: 10.1007/0-387-32824-6_16] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Catherine A Abbott
- School of Biological Sciences, Flinders University, Adelaide, SA, Australia
| | | | | | | | | |
Collapse
|