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Yun S, Kang SH, Ryu J, Kim K, Lee KY, Lee JJ, Hong JY, Son GH. The Role of Beta-Defensin 2 in Preventing Preterm Birth with Chorioamnionitis: Insights into Inflammatory Responses and Epithelial Barrier Protection. Int J Mol Sci 2025; 26:2127. [PMID: 40076749 PMCID: PMC11900102 DOI: 10.3390/ijms26052127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 02/13/2025] [Accepted: 02/25/2025] [Indexed: 03/14/2025] Open
Abstract
Antimicrobial peptides, such as beta-defensin 2 (BD2), are vital in controlling infections and immune responses. In this study, we investigated the expression and role of BD2 in the amniotic membrane and human amniotic epithelial cells (hAECs) from patients with preterm birth and chorioamnionitis, focusing on its regulation of inflammatory cytokines and its protective effect on the epithelial barrier. Our results show increased BD2 expression in chorioamnionitis, and Lipopolysaccharide (LPS)-induced inflammation increased BD2 release from hAECs in a dose- and time-dependent manner. BD2 treatment effectively modulated the inflammatory response by reducing pro-inflammatory cytokines (IL-6, IL-1β) and enhancing the release of the anti-inflammatory cytokine IL-10. Additionally, BD2 helps preserve epithelial barrier integrity by restoring E-cadherin expression and reducing Snail expression in inflamed hAECs. In an LPS-induced preterm birth mouse model, BD2 treatment delayed preterm delivery and reduced inflammatory cytokine levels. These results suggest that BD2 plays a protective role in preventing preterm birth by regulating inflammation and maintaining epithelial barrier function, highlighting its therapeutic potential for inflammation-related preterm birth.
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Affiliation(s)
- Sangho Yun
- Institute of New Frontier Research Team, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea; (S.Y.); (S.-H.K.); (J.J.L.)
| | - Shin-Hae Kang
- Institute of New Frontier Research Team, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea; (S.Y.); (S.-H.K.); (J.J.L.)
| | - Jiwon Ryu
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Hallym University College of Medicine, Kangnam Sacred Heart Hospital, Seoul 07441, Republic of Korea; (J.R.); (K.K.); (K.-Y.L.)
| | - Kyoungseon Kim
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Hallym University College of Medicine, Kangnam Sacred Heart Hospital, Seoul 07441, Republic of Korea; (J.R.); (K.K.); (K.-Y.L.)
| | - Keun-Young Lee
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Hallym University College of Medicine, Kangnam Sacred Heart Hospital, Seoul 07441, Republic of Korea; (J.R.); (K.K.); (K.-Y.L.)
| | - Jae Jun Lee
- Institute of New Frontier Research Team, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea; (S.Y.); (S.-H.K.); (J.J.L.)
- Departments of Anesthesiology and Pain Medicine, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea
| | - Ji Young Hong
- Institute of New Frontier Research Team, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea; (S.Y.); (S.-H.K.); (J.J.L.)
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Sacred Heart Hospital, Hallym University Medical Center, Chuncheon 24253, Republic of Korea
| | - Ga-Hyun Son
- Institute of New Frontier Research Team, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea; (S.Y.); (S.-H.K.); (J.J.L.)
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Hallym University College of Medicine, Kangnam Sacred Heart Hospital, Seoul 07441, Republic of Korea; (J.R.); (K.K.); (K.-Y.L.)
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Fernández-Torres J, Zamudio-Cuevas Y, Martínez-Flores K. Polymorphic variation of the DEFB1 gene might contribute to the development of ankylosing spondylitis: a preliminary study. Mol Biol Rep 2024; 51:1051. [PMID: 39395079 DOI: 10.1007/s11033-024-09985-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 10/05/2024] [Indexed: 10/14/2024]
Abstract
BACKGROUND Ankylosing spondylitis (AS) is an inflammatory disease that affects the spine and can cause peripheral arthritis, enthesitis, and dactylitis, as well as extra-articular manifestations such as uveitis and inflammatory bowel disease. β-Defensins are antimicrobial peptides involved in the activation and regulation of several immune cell types that may influence the inflammatory response in AS. The aim was to analyze the association and interaction of two functional variants of the DEFB1 gene in AS patients, and their role with inflammatory markers. METHODS AND RESULTS The rs11362 and rs1800972 variants were genotyped using TaqMan probes in Mexican AS patients and controls. C-reactive protein (CRP) levels and erythrocyte sedimentation rate (ESR) were quantified. SPSS software was used for statistical analysis and multifactor dimensionality reduction (MDR) for interactions. The AA and GG genotypes were associated with AS risk in the age- and sex-adjusted model (OR = 6.89, P = 0.008 and OR = 3.43, P = 0.046, respectively); furthermore, the A-G haplotype showed a significant association with AS risk (OR = 2.94, P = 0.012). ESR and CRP were elevated in carriers of the AA genotype compared to the GA and GG genotypes of the rs11362 variant (20.89 ± 9.78 vs. 5.63 ± 4.61 and 4.10 ± 2.65 mm/h, P < 0.0001; and 10.92 ± 14.09 vs. 2.14 ± 2.02 and 2.15 ± 2.13 mg/L, P < 0.001, respectively). Using the MDR method, strong interactions of the rs11362 variant with sex were identified in the adjusted and unadjusted models. CONCLUSIONS These results suggest that the DEFB1 gene may play a key role in AS pathogenesis.
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Affiliation(s)
- Javier Fernández-Torres
- Laboratorio de Líquido Sinovial, Instituto Nacional de Rehabilitación "Luis Guillermo Ibarra Ibarra", Mexico City, Mexico.
| | - Yessica Zamudio-Cuevas
- Laboratorio de Líquido Sinovial, Instituto Nacional de Rehabilitación "Luis Guillermo Ibarra Ibarra", Mexico City, Mexico
| | - Karina Martínez-Flores
- Laboratorio de Líquido Sinovial, Instituto Nacional de Rehabilitación "Luis Guillermo Ibarra Ibarra", Mexico City, Mexico
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Alula KM, Dowdell AS, LeBere B, Lee JS, Levens CL, Kuhn KA, Kaipparettu BA, Thompson WE, Blumberg RS, Colgan SP, Theiss AL. Interplay of gut microbiota and host epithelial mitochondrial dysfunction is necessary for the development of spontaneous intestinal inflammation in mice. MICROBIOME 2023; 11:256. [PMID: 37978573 PMCID: PMC10655390 DOI: 10.1186/s40168-023-01686-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 09/30/2023] [Indexed: 11/19/2023]
Abstract
BACKGROUND Intestinal epithelial cell (IEC) mitochondrial dysfunction involvement in inflammatory bowel diseases (IBD), including Crohn's disease affecting the small intestine, is emerging in recent studies. As the interface between the self and the gut microbiota, IECs serve as hubs of bidirectional cross-talk between host and luminal microbiota. However, the role of mitochondrial-microbiota interaction in the ileum is largely unexplored. Prohibitin 1 (PHB1), a chaperone protein of the inner mitochondrial membrane required for optimal electron transport chain function, is decreased during IBD. We previously demonstrated that mice deficient in PHB1 specifically in IECs (Phb1i∆IEC) exhibited mitochondrial impairment, Paneth cell defects, gut microbiota dysbiosis, and spontaneous inflammation in the ileum (ileitis). Mice deficient in PHB1 in Paneth cells (epithelial secretory cells of the small intestine; Phb1∆PC) also exhibited mitochondrial impairment, Paneth cell defects, and spontaneous ileitis. Here, we determined whether this phenotype is driven by Phb1 deficiency-associated ileal microbiota alterations or direct effects of loss of PHB1 in host IECs. RESULTS Depletion of gut microbiota by broad-spectrum antibiotic treatment in Phb1∆PC or Phb1i∆IEC mice revealed a necessary role of microbiota to cause ileitis. Using germ-free mice colonized with ileal microbiota from Phb1-deficient mice, we show that this microbiota could not independently induce ileitis without host mitochondrial dysfunction. The luminal microbiota phenotype of Phb1i∆IEC mice included a loss of the short-chain fatty acid butyrate. Supplementation of butyrate in Phb1-deficient mice ameliorated Paneth cell abnormalities and ileitis. Phb1-deficient ileal enteroid models suggest deleterious epithelial-intrinsic responses to ileal microbiota that were protected by butyrate. CONCLUSIONS These results suggest a mutual and essential reinforcing interplay of gut microbiota and host IEC, including Paneth cell, mitochondrial health in influencing ileitis. Restoration of butyrate is a potential therapeutic option in Crohn's disease patients harboring epithelial cell mitochondrial dysfunction. Video Abstract.
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Affiliation(s)
- Kibrom M Alula
- Division of Gastroenterology & Hepatology, University of Colorado Anschutz Medical Campus, 12700 East 19Th Avenue, RC2 Campus Box BB158 HSC, Aurora, CO, 80045, USA
| | - Alexander S Dowdell
- Division of Gastroenterology & Hepatology, University of Colorado Anschutz Medical Campus, 12700 East 19Th Avenue, RC2 Campus Box BB158 HSC, Aurora, CO, 80045, USA
| | - Brittany LeBere
- Division of Gastroenterology & Hepatology, University of Colorado Anschutz Medical Campus, 12700 East 19Th Avenue, RC2 Campus Box BB158 HSC, Aurora, CO, 80045, USA
| | - J Scott Lee
- Division of Gastroenterology & Hepatology, University of Colorado Anschutz Medical Campus, 12700 East 19Th Avenue, RC2 Campus Box BB158 HSC, Aurora, CO, 80045, USA
| | - Cassandra L Levens
- Division of Rheumatology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Kristine A Kuhn
- Division of Rheumatology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Benny A Kaipparettu
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Winston E Thompson
- Department of Obstetrics and Gynecology, Morehouse School of Medicine, Atlanta, GA, USA
| | - Richard S Blumberg
- Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Sean P Colgan
- Division of Gastroenterology & Hepatology, University of Colorado Anschutz Medical Campus, 12700 East 19Th Avenue, RC2 Campus Box BB158 HSC, Aurora, CO, 80045, USA
| | - Arianne L Theiss
- Division of Gastroenterology & Hepatology, University of Colorado Anschutz Medical Campus, 12700 East 19Th Avenue, RC2 Campus Box BB158 HSC, Aurora, CO, 80045, USA.
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Rizzi A, Di Gioacchino M, Gammeri L, Inchingolo R, Chini R, Santilli F, Nucera E, Gangemi S. The Emerging Role of Innate Lymphoid Cells (ILCs) and Alarmins in Celiac Disease: An Update on Pathophysiological Insights, Potential Use as Disease Biomarkers, and Therapeutic Implications. Cells 2023; 12:1910. [PMID: 37508573 PMCID: PMC10378400 DOI: 10.3390/cells12141910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 07/16/2023] [Accepted: 07/19/2023] [Indexed: 07/30/2023] Open
Abstract
Celiac disease (CD) is an intestinal disease that develops in genetically predisposed individuals and is triggered by the ingestion of gluten. CD was considered a Th1-disease. Today, the role of Th17, IL-21, and IL-17A lymphocytes is well known. Inflammation is regulated by the activity of gluten-specific CD4+ T lymphocytes that produce pro-inflammatory cytokines, including IFN-γ, TNF-α, and IL-21, perpetuating the Th1 response. These cytokines determine an inflammatory state of the small intestine, with consequent epithelial infiltration of lymphocytes and an alteration of the architecture of the duodenal mucosa. B cells produce antibodies against tissue transglutaminase and against deamidated gliadin. Although the role of the adaptive immune response is currently known, the evidence about the role of innate immunity cells is still poorly understood. Epithelial damage determines the release of damage-associated molecular patterns (DAMPs), also known as alarmins. Together with the intestinal epithelial cells and the type 1 innate lymphoid cells (ILC1s), alarmins like TSLP, IL-33, and HMGB1 could have a fundamental role in the genesis and maintenance of inflammation. Our study aims to evaluate the evidence in the literature about the role of ILCs and alarmins in celiac disease, evaluating the possible future diagnostic and therapeutic implications.
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Affiliation(s)
- Angela Rizzi
- UOSD Allergologia e Immunologia Clinica, Dipartimento di Scienze Mediche e Chirurgiche Addominali ed Endocrino Metaboliche, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (A.R.); (R.C.); (E.N.)
| | - Mario Di Gioacchino
- Institute for Clinical Immunotherapy and Advanced Biological Treatments, 65100 Pescara, Italy
- Center for Advanced Studies and Technology, G. d’Annunzio University, 66100 Chieti, Italy;
| | - Luca Gammeri
- Department of Clinical and Experimental Medicine, School and Operative Unit of Allergy and Clinical Immunology, University of Messina, 98125 Messina, Italy; (L.G.); (S.G.)
| | - Riccardo Inchingolo
- Pulmonary Medicine Unit, Department of Neurosciences, Sense Organs and Thorax, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy;
| | - Raffaella Chini
- UOSD Allergologia e Immunologia Clinica, Dipartimento di Scienze Mediche e Chirurgiche Addominali ed Endocrino Metaboliche, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (A.R.); (R.C.); (E.N.)
| | - Francesca Santilli
- Center for Advanced Studies and Technology, G. d’Annunzio University, 66100 Chieti, Italy;
| | - Eleonora Nucera
- UOSD Allergologia e Immunologia Clinica, Dipartimento di Scienze Mediche e Chirurgiche Addominali ed Endocrino Metaboliche, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (A.R.); (R.C.); (E.N.)
- Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Sebastiano Gangemi
- Department of Clinical and Experimental Medicine, School and Operative Unit of Allergy and Clinical Immunology, University of Messina, 98125 Messina, Italy; (L.G.); (S.G.)
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Kamada M, Miyazaki M, Nakashima A, Yamada Y, Nakano T, Hagiwara D, Komiya Y, Matsuo K, Imakyure O. Characteristics of Patients With Inflammatory Bowel Disease Who Develop Bloodstream Infection. J Clin Med Res 2023; 15:262-267. [PMID: 37303468 PMCID: PMC10251698 DOI: 10.14740/jocmr4920] [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: 04/11/2023] [Accepted: 05/29/2023] [Indexed: 06/13/2023] Open
Abstract
Background The causative microorganisms of bloodstream infections (BSIs) in patients with inflammatory bowel disease (IBD) and the clinical characteristics of these patients have not yet been fully identified. Therefore, this study investigated IBD patients who developed BSI to determine their clinical characteristics and identify the BSI-causing bacteria. Methods The subjects were IBD patients who developed bacteremia between 2015 and 2019 at Fukuoka University Chikushi Hospital. The patients were divided into two groups according to IBD type (Crohn's disease (CD) or ulcerative colitis (UC)). The medical records of the patients were reviewed to determine their clinical backgrounds and identify the BSI-causing bacteria. Results In total 95 patients, 68 CD and 27 UC patients were included in this study. The detection rates of Pseudomonas aeruginosa (P. aeruginosa) and Klebsiella pneumoniae (K. pneumoniae) were higher in the UC group than in the CD group (18.5% vs. 2.9%, P = 0.021; 11.1% vs. 0%, P = 0.019, respectively). Immunosuppressive drugs use was higher in the CD group than in the UC group (57.4% vs. 11.1%, P = 0.00003). Hospital stay length was longer in the UC group than in the CD group (15 vs. 9 days; P = 0.045). Conclusions The causative bacteria of BSI and clinical backgrounds differed between patients with CD and UC. This study showed that P. aeruginosa and K. pneumoniae had higher abundance in UC patients at the onset of BSI. Furthermore, long-term hospitalized patients with UC required antimicrobial therapy against P. aeruginosa and K. pneumoniae.
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Affiliation(s)
- Mitsuhiro Kamada
- Department of Pharmacy, Fukuoka University Chikushi Hospital, Fukuoka 818-8502, Japan
- These authors contributed equally to this work
| | - Motoyasu Miyazaki
- Department of Pharmacy, Fukuoka University Chikushi Hospital, Fukuoka 818-8502, Japan
- These authors contributed equally to this work
| | - Akio Nakashima
- Department of Pharmacy, Fukuoka University Chikushi Hospital, Fukuoka 818-8502, Japan
| | - Yota Yamada
- Department of Pharmacy, Fukuoka University Chikushi Hospital, Fukuoka 818-8502, Japan
| | - Takafumi Nakano
- Department of Pharmacy, Fukuoka University Hospital, Fukuoka 814-0180, Japan
| | - Daiki Hagiwara
- Department of Pharmacy, Fukuoka University Hospital, Fukuoka 814-0180, Japan
| | - Yukie Komiya
- Department of Clinical Laboratory, Fukuoka University Chikushi Hospital, Fukuoka 818-8502, Japan
| | - Koichi Matsuo
- Department of Pharmacy, Fukuoka University Chikushi Hospital, Fukuoka 818-8502, Japan
| | - Osamu Imakyure
- Department of Pharmacy, Fukuoka University Chikushi Hospital, Fukuoka 818-8502, Japan
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Ai LS, Yu YB. Role of Paneth cells-associated Crohn’s disease susceptibility genes in development of Crohn’s disease. Shijie Huaren Xiaohua Zazhi 2022; 30:1009-1015. [DOI: 10.11569/wcjd.v30.i23.1009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022] Open
Affiliation(s)
- Li-Si Ai
- Qilu Hospital of Shandong University (First Clinical College), Jinan 250012, Shandong Province, China
| | - Yan-Bo Yu
- Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
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Selvakumar D, Evans D, Coyte KZ, McLaughlin J, Brass A, Hancock L, Cruickshank S. Understanding the development and function of the gut microbiota in health and inflammation. Frontline Gastroenterol 2022; 13:e13-e21. [PMID: 35812026 PMCID: PMC9234741 DOI: 10.1136/flgastro-2022-102119] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 04/29/2022] [Indexed: 02/04/2023] Open
Abstract
The gut microbiota is known to play an important role in maintaining gut health through a symbiotic relationship with the host. Altered gut microbiota is a common feature of several diseases of the gastrointestinal tract; however, the causal relationship between microbiota and disease pathogenesis is poorly understood. Necrotising enterocolitis (NEC) and inflammatory bowel disease (IBD) are both severe inflammatory diseases affecting the gastrointestinal tract. Although they affect very different patient populations, with NEC primarily being a disease of prematurity and IBD predominantly affecting adults although children can be affected, they both demonstrate common features of gut microbial dysbiosis and a dysregulated host immune response. By comparing and contrasting the changes in gut microbiota, host immune response and function, we aim to highlight common features in diseases that may seem clinically unrelated. Key areas of interest are the role of pattern recognition receptors in altered recognition and responses to the gut microbiota by the host immune system and the associated dysfunctional gut epithelial barrier. The challenge of identifying causal relationships between microbiota and disease is ever-present; however, considering a disease-agnostic approach may help to identify mechanistic pathways shared across several clinical diseases.
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Affiliation(s)
- Deepak Selvakumar
- Department of Colorectal Surgery, Manchester University NHS Foundation Trust, Manchester, UK,Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, UK
| | - Dolan Evans
- Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, UK
| | - Katharine Z Coyte
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - John McLaughlin
- Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, UK,Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK,Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
| | - Andy Brass
- Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, UK,Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Laura Hancock
- Department of Colorectal Surgery, Manchester University NHS Foundation Trust, Manchester, UK,Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
| | - Sheena Cruickshank
- Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, UK,Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
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Son GH, Lee JJ, Kim Y, Lee KY. The Role of Antimicrobial Peptides in Preterm Birth. Int J Mol Sci 2021; 22:ijms22168905. [PMID: 34445608 PMCID: PMC8396209 DOI: 10.3390/ijms22168905] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 08/13/2021] [Accepted: 08/16/2021] [Indexed: 12/12/2022] Open
Abstract
Antimicrobial peptides (AMPs) are short cationic amphipathic peptides with a wide range of antimicrobial properties and play an important role in the maintenance of immune homeostasis by modulating immune responses in the reproductive tract. As intra-amniotic infection and microbial dysbiosis emerge as common causes of preterm births (PTBs), a better understanding of the AMPs involved in the development of PTB is essential. The altered expression of AMPs has been reported in PTB-related clinical presentations, such as preterm labor, intra-amniotic infection/inflammation, premature rupture of membranes, and cervical insufficiency. Moreover, it was previously reported that dysregulation of AMPs may affect the pregnancy prognosis. This review aims to describe the expression of AMPs associated with PTBs and to provide new perspectives on the role of AMPs in PTB.
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Affiliation(s)
- Ga-Hyun Son
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Hallym University College of Medicine, Kangnam Sacred Heart Hospital, Seoul 07441, Korea;
- Institute of New Frontier Research Team, College of Medicine, Hallym University, Chuncheon 24523, Korea; (J.-J.L.); (Y.K.)
- Correspondence: ; Tel.: +82-2-6960-1205
| | - Jae-Jun Lee
- Institute of New Frontier Research Team, College of Medicine, Hallym University, Chuncheon 24523, Korea; (J.-J.L.); (Y.K.)
- Departments of Anesthesiology and Pain Medicine, College of Medicine, Hallym University, Chuncheon 24523, Korea
| | - Youngmi Kim
- Institute of New Frontier Research Team, College of Medicine, Hallym University, Chuncheon 24523, Korea; (J.-J.L.); (Y.K.)
| | - Keun-Young Lee
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Hallym University College of Medicine, Kangnam Sacred Heart Hospital, Seoul 07441, Korea;
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Alkaissi LY, Winberg ME, Heil SDS, Haapaniemi S, Myrelid P, Stange EF, Söderholm JD, Keita ÅV. Antagonism of Adherent Invasive E. coli LF82 With Human α-defensin 5 in the Follicle-associated Epithelium of Patients With Ileal Crohn's Disease. Inflamm Bowel Dis 2021; 27:1116-1127. [PMID: 33336693 PMCID: PMC8205628 DOI: 10.1093/ibd/izaa315] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND The first visible signs of Crohn's disease (CD) are microscopic erosions over the follicle-associated epithelium (FAE). The aim of the study was to investigate the effects of human α-defensin 5 (HD5) on adherent-invasive Escherichia coli LF82 translocation and HD5 secretion after LF82 exposure in an in vitro model of human FAE and in human FAE ex vivo. METHODS An in vitro FAE-model was set up by the coculture of Raji B cells and Caco-2-cl1 cells. Ileal FAE from patients with CD and controls were mounted in Ussing chambers. The effect of HD5 on LF82 translocation was studied by LF82 exposure to the cells or tissues with or without incubation with HD5. The HD5 secretion was measured in human FAE exposed to LF82 or Salmonella typhimurium. The HD5 levels were evaluated by immunofluorescence, immunoblotting, and ELISA. RESULTS There was an increased LF82 translocation across the FAE-model compared with Caco-2-cl1 (P < 0.05). Incubation of cell/tissues with HD5 before LF82 exposure reduced bacterial passage in both models. Human FAE showed increased LF82 translocation in CD compared with controls and attenuated passage after incubation with sublethal HD5 in both CD and controls (P < 0.05). LF82 exposure resulted in a lower HD5 secretion in CD FAE compared with controls (P < 0.05), whereas Salmonella exposure caused equal secretion on CD and controls. There were significantly lower HD5 levels in CD tissues compared with controls. CONCLUSIONS Sublethal HD5 reduces the ability of LF82 to translocate through FAE. The HD5 is secreted less in CD in response to LF82, despite a normal response to Salmonella. This further implicates the integrated role of antimicrobial factors and barrier function in CD pathogenesis.
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Affiliation(s)
- Lina Y Alkaissi
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Martin E Winberg
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Stéphanie D S Heil
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Staffan Haapaniemi
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Department of Surgery, Vrinnevi Hospital, Norrköping, Sweden
| | - Pär Myrelid
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Department of Surgery, Linköping University, Linköping, Sweden
| | - Eduard F Stange
- Department of Gastroenterology, Dept. Internal Medicine I, University of Tübingen, 72076 Tübingen, Germany
| | - Johan D Söderholm
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Department of Surgery, Linköping University, Linköping, Sweden
| | - Åsa V Keita
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
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The Association between Early-Life Gut Microbiota and Long-Term Health and Diseases. J Clin Med 2021; 10:jcm10030459. [PMID: 33504109 PMCID: PMC7865818 DOI: 10.3390/jcm10030459] [Citation(s) in RCA: 120] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 01/12/2021] [Accepted: 01/21/2021] [Indexed: 12/14/2022] Open
Abstract
Early life gut microbiota have been increasingly recognized as major contributors to short and/or long-term human health and diseases. Numerous studies have demonstrated that human gut microbial colonization begins at birth, but continues to develop a succession of taxonomic abundances for two to three years until the gut microbiota reaches adult-like diversity and proportions. Several factors, including gestational age (GA), delivery mode, birth weight, feeding types, antibiotic exposure, maternal microbiome, and diet, influence the diversity, abundance, and function of early life gut microbiota. Gut microbial life is essential for assisting with the digestion of food substances to release nutrients, exerting control over pathogens, stimulating or modulating the immune system, and influencing many systems such as the liver, brain, and endocrine system. Microbial metabolites play multiple roles in these interactions. Furthermore, studies provide evidence supporting that imbalances of the gut microbiota in early life, referred to as dysbiosis, are associated with specific childhood or adult disease outcomes, such as asthma, atopic dermatitis, diabetes, allergic diseases, obesity, cardiovascular diseases (CVD), and neurological disorders. These findings support that the human gut microbiota may play a fundamental role in the risk of acquiring diseases that may be programmed during early life. In fact, it is critical to explore the role of the human gut microbiota in early life.
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11
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Zhang Y, Thanou M, Vllasaliu D. Exploiting disease-induced changes for targeted oral delivery of biologics and nanomedicines in inflammatory bowel disease. Eur J Pharm Biopharm 2020; 155:128-138. [PMID: 32853696 DOI: 10.1016/j.ejpb.2020.08.017] [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: 06/18/2020] [Revised: 07/21/2020] [Accepted: 08/18/2020] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel disease (IBD) is a chronic and progressive disorder with destructive inflammation in the gastrointestinal tract (GIT). Biologics have changed the management of IBD, but have serious limitations, which is associated with their systemic administration via injection. Oral administration is the most accepted route of drug administration. However, the physiological barriers of the GIT pose significant challenges for oral administration of biologics, making this route of administration currently unavailable. The status of tissue barriers to oral drug delivery is altered in IBD. This may bring more challenges, but also present opportunities for oral delivery of biologics. This article provides an overview of disease-induced alterations of GIT barriers in IBD and discusses challenges, opportunities and commonly-utilised strategies for oral delivery of complex therapeutics, including biologics and nanomedicines.
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Affiliation(s)
- Yunyue Zhang
- Institute of Pharmaceutical Science, School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, London SE1 9NH, United Kingdom.
| | - Maya Thanou
- Institute of Pharmaceutical Science, School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, London SE1 9NH, United Kingdom.
| | - Driton Vllasaliu
- Institute of Pharmaceutical Science, School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, London SE1 9NH, United Kingdom.
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12
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Mookherjee N, Anderson MA, Haagsman HP, Davidson DJ. Antimicrobial host defence peptides: functions and clinical potential. Nat Rev Drug Discov 2020; 19:311-332. [DOI: 10.1038/s41573-019-0058-8] [Citation(s) in RCA: 425] [Impact Index Per Article: 85.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/18/2019] [Indexed: 12/18/2022]
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13
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Chen W, Zhuo M, Lu X, Xia X, Zhao Y, Huang Z, Xu J, Li W, Yu C. SRC-3 protects intestine from DSS-induced colitis by inhibiting inflammation and promoting goblet cell differentiation through enhancement of KLF4 expression. Int J Biol Sci 2018; 14:2051-2064. [PMID: 30585268 PMCID: PMC6299374 DOI: 10.7150/ijbs.28576] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Accepted: 10/03/2018] [Indexed: 02/06/2023] Open
Abstract
Goblet cell loss, which leads to the reduction of mucin secretion, is a hallmark of ulcerative colitis (UC). We previously reported that steroid receptor coactivator 3 (SRC-3), a transcriptional coactivator, contributes to host defense against Citrobacter rodentium by recruiting neutrophils, suggesting a role of SRC-3 in intestine homeostasis. However, the biological role of SRC-3 in UC remains unclear. Here, we showed that SRC-3-/- mice were more susceptible to dextran sulfate sodium (DSS)-induced colitis compared with wild-type mice after oral administration of 2% DSS dissolved in drinking water. After oral administration of 2% DSS, SRC-3-/- mice displayed higher mortality rate, significant body weight loss, and higher clinical symptom scores compared to wild-type mice. SRC-3-/- mice suffered a severe loss of mature colonic goblet cells, leading to more severe histopathology and more proinflammatory cytokine production. Mechanistically, SRC-3-/- mice exhibited a decreased expression of transcription factor KLF4 in the colons, which is responsible for colonic goblet cell differentiation and maturation. At the molecular level, SRC-3 cooperated with c-Fos to promote KLF4 expression at the transcriptional level. These results demonstrate that SRC-3 can ameliorate DSS-induced colitis by inhibiting inflammation and promoting colonic goblet cell differentiation and maturation through enhancing the expression of transcriptional factor KLF4, which is responsible for colonic goblet cell differentiation and maturation.
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Affiliation(s)
- Wenbo Chen
- Department of Cardiology, The First Affiliated Hospital of Xiamen University, Xiamen, China.,State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Minghui Zhuo
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Xuqiang Lu
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Xiaochun Xia
- Xiamen Medical College, Xiamen Fujian 361023,China
| | - Yang Zhao
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Zhengrong Huang
- Department of Cardiology, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Jianming Xu
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
| | - Weihua Li
- Department of Cardiology, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Chundong Yu
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China
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14
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Ponce de León-Rodríguez MDC, Guyot JP, Laurent-Babot C. Intestinal in vitro cell culture models and their potential to study the effect of food components on intestinal inflammation. Crit Rev Food Sci Nutr 2018; 59:3648-3666. [DOI: 10.1080/10408398.2018.1506734] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
| | - Jean-Pierre Guyot
- NUTRIPASS—University of Montpellier, IRD, Montpellier SupAgro, Montpellier, France
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15
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Dias Bastos PA, Lara Santos L, Pinheiro Vitorino RM. How are the expression patterns of gut antimicrobial peptides modulated by human gastrointestinal diseases? A bridge between infectious, inflammatory, and malignant diseases. J Pept Sci 2018. [PMID: 29542263 DOI: 10.1002/psc.3071] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The human gut barrier is the tissue exposed to the highest load of microorganisms, harbouring 100 trillion bacteria. In addition, the gut's renewal rate outruns that of any other human tissue. Antimicrobial peptides (AMPs) are highly optimized defense molecules in the intestinal barrier optimized to maintain gastrointestinal homeostasis. Alterations in AMPs activity can lead to or result from human gastrointestinal diseases. In this review, unique, conserved, or otherwise regular alterations in the expression patterns of human AMPs across gastrointestinal inflammatory and infectious diseases were analyzed for pattern elucidation. Human gastrointestinal diseases are associated with alterations in gut AMPs' expression patterns in a peptide-specific, disease-specific, and pathogen-specific way, modulating human gastrointestinal functioning. Across diseases, there is a (i) marked reduction in otherwise constitutively expressed AMPs, leading to increased disease susceptibility, and a (ii) significant increase in the expression of inducible AMPs, leading to tissue damage and disease severity. Infections and inflammatory conditions are associated with altered gene expression in the gut, whose patterns may favour cellular metaplasia, mucosal dysfunction, and disease states. Altered expression of AMPs can thus thrive disease severity and evolution since its early stages. Nevertheless, the modulation of AMP expression patterns unveils promising therapeutic targets.
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Affiliation(s)
| | - Lúcio Lara Santos
- Experimental Pathology and Therapeutics Group - Research Center, Portuguese Oncology Institute - Porto (IPO-Porto), Porto, Portugal.,Department of Surgical Oncology, Portuguese Oncology Institute - Porto (IPO-Porto), Porto, Portugal
| | - Rui Miguel Pinheiro Vitorino
- iBiMED, Institute for Biomedicine, Department of Medical Sciences, University of Aveiro, Aveiro, Portugal.,Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal
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16
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Howell K, de Leeuw E. Cell adhesion properties of human defensins. Biochem Biophys Res Commun 2018; 502:238-242. [PMID: 29800568 DOI: 10.1016/j.bbrc.2018.05.150] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 05/20/2018] [Indexed: 10/16/2022]
Abstract
Effector peptides of innate immunity play an important role in host defense. They act directly by inactivating microbes but also link innate to adaptive immunity. A variety of innate immune functions has been described for these peptides, including chemoattraction and cytokine release. In this study, we describe the effect on cell morphology and cell adhesion of human defensins. We find that Human Defensin 5, the major product of specialized gut epithelial cells, causes changes in cell morphology. HD-5 induces cell adhesion, binds to fibronectin and facilitates binding of T cells to intestinal epithelial cells. These effects were found also for a second prominent defensing, termed Human Neutrophil peptide-1, but not for other human defensins.
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Affiliation(s)
- Katie Howell
- Integrated Biotherapeutics, Inc., Rockville, MD 20850, USA
| | - Erik de Leeuw
- Institute of Human Virology of the University of Maryland Baltimore School of Medicine, 725 West Lombard Street, Baltimore, MD 21201, USA.
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17
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Wang SL, Shao BZ, Zhao SB, Fang J, Gu L, Miao CY, Li ZS, Bai Y. Impact of Paneth Cell Autophagy on Inflammatory Bowel Disease. Front Immunol 2018; 9:693. [PMID: 29675025 PMCID: PMC5895641 DOI: 10.3389/fimmu.2018.00693] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 03/21/2018] [Indexed: 12/19/2022] Open
Abstract
Intestinal mucosal barrier, mainly consisting of the mucus layer and epithelium, functions in absorbing nutrition as well as prevention of the invasion of pathogenic microorganisms. Paneth cell, an important component of mucosal barrier, plays a vital role in maintaining the intestinal homeostasis by producing antimicrobial materials and controlling the host-commensal balance. Current evidence shows that the dysfunction of intestinal mucosal barrier, especially Paneth cell, participates in the onset and progression of inflammatory bowel disease (IBD). Autophagy, a cellular stress response, involves various physiological processes, such as secretion of proteins, production of antimicrobial peptides, and degradation of aberrant organelles or proteins. In the recent years, the roles of autophagy in the pathogenesis of IBD have been increasingly studied. Here in this review, we mainly focus on describing the roles of Paneth cell autophagy in IBD as well as several popular autophagy-related genetic variants in Penath cell and the related therapeutic strategies against IBD.
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Affiliation(s)
- Shu-Ling Wang
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University and Naval Medical University, Shanghai, China
| | - Bo-Zong Shao
- Department of Pharmocology, Second Military Medical University and Naval Medical University, Shanghai, China
| | - Sheng-Bing Zhao
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University and Naval Medical University, Shanghai, China
| | - Jun Fang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Lun Gu
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University and Naval Medical University, Shanghai, China
| | - Chao-Yu Miao
- Department of Pharmocology, Second Military Medical University and Naval Medical University, Shanghai, China
| | - Zhao-Shen Li
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University and Naval Medical University, Shanghai, China
| | - Yu Bai
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University and Naval Medical University, Shanghai, China
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18
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Meijnikman AS, Gerdes VE, Nieuwdorp M, Herrema H. Evaluating Causality of Gut Microbiota in Obesity and Diabetes in Humans. Endocr Rev 2018; 39:133-153. [PMID: 29309555 DOI: 10.1210/er.2017-00192] [Citation(s) in RCA: 189] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2017] [Accepted: 12/19/2017] [Indexed: 02/06/2023]
Abstract
The pathophysiology of obesity and obesity-related diseases such as type 2 diabetes mellitus (T2DM) is complex and driven by many factors. One of the most recently identified factors in development of these metabolic pathologies is the gut microbiota. The introduction of affordable, high-throughput sequencing technologies has substantially expanded our understanding of the role of the gut microbiome in modulation of host metabolism and (cardio)metabolic disease development. Nevertheless, evidence for a role of the gut microbiome as a causal, driving factor in disease development mainly originates from studies in mouse models: data showing causality in humans are scarce. In this review, we will discuss the quality of evidence supporting a causal role for the gut microbiome in the development of obesity and diabetes, in particular T2DM, in humans. Considering overlap in potential mechanisms, the role of the gut microbiome in type 1 diabetes mellitus will also be addressed. We will elaborate on factors that drive microbiome composition in humans and discuss how alterations in microbial composition or microbial metabolite production contribute to disease development. Challenging aspects in determining causality in humans will be postulated together with strategies that might hold potential to overcome these challenges. Furthermore, we will discuss means to modify gut microbiome composition in humans to help establish causality and discuss systems biology approaches that might hold the key to unravelling the role of the gut microbiome in obesity and T2DM.
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Affiliation(s)
- Abraham S Meijnikman
- Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands.,Department of Internal Medicine, MC Slotervaart, Amsterdam, Netherlands
| | - Victor E Gerdes
- Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands.,Department of Internal Medicine, MC Slotervaart, Amsterdam, Netherlands
| | - Max Nieuwdorp
- Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands.,Wallenberg Laboratory, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.,Department of Internal Medicine, Academic Medical Center, Amsterdam, Netherlands.,Diabetes Center, Department of Internal medicine, VU University Medical Center, Amsterdam, Netherlands.,ICAR, VU University Medical Center, Amsterdam, Netherlands
| | - Hilde Herrema
- Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands
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19
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Pucci Molineris M, Gonzalez Polo V, Perez F, Ramisch D, Rumbo M, Gondolesi GE, Meier D. Paneth and intestinal stem cells preserve their functional integrity during worsening of acute cellular rejection in small bowel transplantation. Am J Transplant 2018; 18:1007-1015. [PMID: 29139621 DOI: 10.1111/ajt.14592] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 11/01/2017] [Accepted: 11/05/2017] [Indexed: 01/25/2023]
Abstract
Graft survival after small bowel transplantation remains impaired due to acute cellular rejection (ACR), the leading cause of graft loss. Although it was shown that the number of enteroendocrine progenitor cells in intestinal crypts was reduced during mild ACR, no results of Paneth and intestinal stem cells localized at the crypt bottom have been shown so far. Therefore, we wanted to elucidate integrity and functionality of the Paneth and stem cells during different degrees of ACR, and to assess whether these cells are the primary targets of the rejection process. We compared biopsies from ITx patients with no, mild, or moderate ACR by immunohistochemistry and quantitative PCR. Our results show that numbers of Paneth and stem cells remain constant in all study groups, whereas the transit-amplifying zone is the most impaired zone during ACR. We detected an unchanged level of antimicrobial peptides in Paneth cells and similar numbers of Ki-67+ IL-22R+ stem cells revealing cell functionality in moderate ACR samples. We conclude that Paneth and stem cells are not primary target cells during ACR. IL-22R+ Ki-67+ stem cells might be an interesting target cell population for protection and regeneration of the epithelial monolayer during/after a severe ACR in ITx patients.
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Affiliation(s)
- M Pucci Molineris
- Laboratorio de Investigación Traslacional e Inmunología Asociada al Trasplante, Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMeTTyB), Universidad Favaloro-CONICET, Buenos Aires, Argentina.,Instituto de Trasplante Multiórganico, Hospital Universitario Fundación Favaloro, Buenos Aires, Argentina
| | - V Gonzalez Polo
- Laboratorio de Investigación Traslacional e Inmunología Asociada al Trasplante, Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMeTTyB), Universidad Favaloro-CONICET, Buenos Aires, Argentina.,Instituto de Trasplante Multiórganico, Hospital Universitario Fundación Favaloro, Buenos Aires, Argentina
| | - F Perez
- Instituto de Estudios Inmunológicos y Fisiopatológicos, UNLP-CONICET, La Plata, Argentina
| | - D Ramisch
- Instituto de Trasplante Multiórganico, Hospital Universitario Fundación Favaloro, Buenos Aires, Argentina
| | - M Rumbo
- Instituto de Estudios Inmunológicos y Fisiopatológicos, UNLP-CONICET, La Plata, Argentina
| | - G E Gondolesi
- Laboratorio de Investigación Traslacional e Inmunología Asociada al Trasplante, Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMeTTyB), Universidad Favaloro-CONICET, Buenos Aires, Argentina.,Instituto de Trasplante Multiórganico, Hospital Universitario Fundación Favaloro, Buenos Aires, Argentina
| | - D Meier
- Laboratorio de Investigación Traslacional e Inmunología Asociada al Trasplante, Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMeTTyB), Universidad Favaloro-CONICET, Buenos Aires, Argentina.,Instituto de Trasplante Multiórganico, Hospital Universitario Fundación Favaloro, Buenos Aires, Argentina
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20
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The Interplay between Defensins and Microbiota in Crohn's Disease. Mediators Inflamm 2017; 2017:8392523. [PMID: 28246439 PMCID: PMC5299173 DOI: 10.1155/2017/8392523] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Revised: 12/16/2016] [Accepted: 01/04/2017] [Indexed: 02/08/2023] Open
Abstract
Crohn's disease (CD) is a chronic inflammation of the intestinal mucosa, characterized by periods of acute recurrence and remission. Depending on the specific region affected, CD is classified as ileal CD or colonic CD. It is largely accepted that the intestinal microbiota is involved in the onset of the pathology. Indeed, a reduced immune tolerance to components of the intestinal commensal microbiota and inflammation of the intestinal barrier typifies patients with CD. Several studies have shown defective expression of intestinal antimicrobial peptides (AMPs) in patients with CD compared to controls, particularly defensins. A reduction in α-defensins is observed in ileal CD, while β-defensins are increased in colonic CD. In addition to an immunological basis, the disease is frequently associated with genetic alterations including mutations of NOD2 gene. Several therapeutic strategies to circumvent the dysfunction observed in CD are currently under investigation. These include the use of delivery systems to administer endogenous AMPs and the engineering of peptidomimetics that could ameliorate the severity of CD. In this review, the role defensins play in CD and the strategies aimed at overcoming bacterial resistance will be discussed.
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21
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Bastos P, Trindade F, da Costa J, Ferreira R, Vitorino R. Human Antimicrobial Peptides in Bodily Fluids: Current Knowledge and Therapeutic Perspectives in the Postantibiotic Era. Med Res Rev 2017; 38:101-146. [PMID: 28094448 PMCID: PMC7168463 DOI: 10.1002/med.21435] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Revised: 11/04/2016] [Accepted: 11/14/2016] [Indexed: 12/12/2022]
Abstract
Antimicrobial peptides (AMPs) are an integral part of the innate immune defense mechanism of many organisms. Due to the alarming increase of resistance to antimicrobial therapeutics, a growing interest in alternative antimicrobial agents has led to the exploitation of AMPs, both synthetic and isolated from natural sources. Thus, many peptide-based drugs have been the focus of increasing attention by many researchers not only in identifying novel AMPs, but in defining mechanisms of antimicrobial peptide activity as well. Herein, we review the available strategies for the identification of AMPs in human body fluids and their mechanism(s) of action. In addition, an overview of the distribution of AMPs across different human body fluids is provided, as well as its relation with microorganisms and infectious conditions.
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Affiliation(s)
- Paulo Bastos
- Department of Medical Sciences, iBiMED-Institute for Research in Biomedicine, University of Aveiro, Aveiro, Portugal
| | - Fábio Trindade
- Department of Medical Sciences, iBiMED-Institute for Research in Biomedicine, University of Aveiro, Aveiro, Portugal.,Unidade de Investigação Cardiovascular, Departamento de Cirurgia e Fisiologia, Faculdade de Medicina, Universidade do Porto, Porto, Portugal
| | - João da Costa
- Department of Chemistry, CESAM, University of Aveiro, Aveiro, Portugal
| | - Rita Ferreira
- Department of Chemistry, QOPNA, Mass Spectrometry Center, University of Aveiro, Aveiro, Portugal
| | - Rui Vitorino
- Department of Medical Sciences, iBiMED-Institute for Research in Biomedicine, University of Aveiro, Aveiro, Portugal.,Unidade de Investigação Cardiovascular, Departamento de Cirurgia e Fisiologia, Faculdade de Medicina, Universidade do Porto, Porto, Portugal
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22
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Alexander DB, Iigo M, Abdelgied M, Ozeki K, Tanida S, Joh T, Takahashi S, Tsuda H. Bovine lactoferrin and Crohn's disease: a case study. Biochem Cell Biol 2016; 95:133-141. [PMID: 28165294 DOI: 10.1139/bcb-2016-0107] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
A 22-year-old male suffering from abdominal pain, repeated diarrhea, and weight loss visited the Digestive Disease Department of Nagoya City University Hospital on 19 December 2011. He was hospitalized and diagnosed with Crohn's colitis. His Crohn's Disease Activity Index (CDAI) was 415. Treatment by granulocyte apheresis, mesalazine, and adalimumab was started. His CDAI was 314 on 30 December and 215 on 5 January. A colonoscopic examination on 19 January showed almost complete remission in the transverse colon and marked remission in the rectum. Mesalazine therapy was stopped on 28 February, and the patient was instructed to self-inject 40 mg of adalimumab every other week. His CDAI was 50 on 10 April, indicating clinical remission. His last self-injection of adalimumab was on 24 April 2012, and he started taking 1 g of bovine lactoferrin (bLF) daily. His CDAI was 35 on 8 January 2013. He continued taking 1 g of bLF daily without any other treatment for Crohn's disease. Laboratory blood tests on 7 September 2015 showed no sign of disease recurrence, and a colonoscopic examination on 23 October 2015 showed almost complete mucosal healing. This case indicates that ingestion of bLF to maintain Crohn's disease in a remissive state should be further explored.
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Affiliation(s)
| | - Masaaki Iigo
- a Nanotoxicology Project, Nagoya City University, Nagoya, Japan
| | - Mohamed Abdelgied
- a Nanotoxicology Project, Nagoya City University, Nagoya, Japan.,b Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.,c Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef, Egypt
| | - Keiji Ozeki
- d Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Satoshi Tanida
- d Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Takashi Joh
- d Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Satoru Takahashi
- b Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Hiroyuki Tsuda
- a Nanotoxicology Project, Nagoya City University, Nagoya, Japan
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23
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Sidiq T, Yoshihama S, Downs I, Kobayashi KS. Nod2: A Critical Regulator of Ileal Microbiota and Crohn's Disease. Front Immunol 2016; 7:367. [PMID: 27703457 PMCID: PMC5028879 DOI: 10.3389/fimmu.2016.00367] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Accepted: 09/06/2016] [Indexed: 12/19/2022] Open
Abstract
The human intestinal tract harbors large bacterial community consisting of commensal, symbiotic, and pathogenic strains, which are constantly interacting with the intestinal immune system. This interaction elicits a non-pathological basal level of immune responses and contributes to shaping both the intestinal immune system and bacterial community. Recent studies on human microbiota are revealing the critical role of intestinal bacterial community in the pathogenesis of both systemic and intestinal diseases, including Crohn’s disease (CD). NOD2 plays a key role in the regulation of microbiota in the small intestine. NOD2 is highly expressed in ileal Paneth cells that provide critical mechanism for the regulation of ileal microbiota through the secretion of anti-bacterial compounds. Genome mapping of CD patients revealed that loss of function mutations in NOD2 are associated with ileal CD. Genome-wide association studies further demonstrated that NOD2 is one of the most critical genetic factor linked to ileal CD. The bacterial community in the ileum is indeed dysregulated in Nod2-deficient mice. Nod2-deficient ileal epithelia exhibit impaired ability of killing bacteria. Thus, altered interactions between ileal microbiota and mucosal immunity through NOD2 mutations play significant roles in the disease susceptibility and pathogenesis in CD patients, thereby depicting NOD2 as a critical regulator of ileal microbiota and CD.
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Affiliation(s)
- Tabasum Sidiq
- Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M University , College Station, TX , USA
| | - Sayuri Yoshihama
- Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M University , College Station, TX , USA
| | - Isaac Downs
- Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M University , College Station, TX , USA
| | - Koichi S Kobayashi
- Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M University , College Station, TX , USA
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24
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Liu X, Cao G, Wang Q, Yao X, Fang B. The effect of Bacillus coagulans-fermented and nonfermented Ginkgo biloba on the immunity status of broiler chickens. J Anim Sci 2016; 93:3384-94. [PMID: 26440007 DOI: 10.2527/jas.2015-8902] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
To evaluate and compare the effects of Bacillus coagulans-fermented Ginkgo biloba (FG) and nonfermented Ginkgo biloba (NFG) on the immunity status of broiler chickens, 180 1-d-old female Arbor Acres chicks were divided into 3 groups and fed either a basal diet, a basal diet supplemented with 0.3% NFG, or a basal diet supplemented with 0.3% FG. Blood samples were taken on the seventh (before vaccination), 14th, 21st, 28th and 35th day for the assessment of serum IL-18 and interferon γ (IFN-γ) levels by ELISA. In addition, Newcastle disease antibody titer analysis was made via hemagglutination and hemagglutination inhibition test methods. On d 35, 6 chickens from each group were sacrificed and the thymus, liver, spleen, small intestine (jejunum segment), cecum, and bursa of Fabricius from each chicken were removed for analysis. RNA was isolated for defensin expression detection by real-time PCR (q-PCR). The results showed that serum IL-18 and IFN-γ levels decreased after treatment with NFG and FG compared with untreated control chickens. The ND antibody titers did not differ significantly between the 3 groups on the seventh, 14th, 21st and 28th day; however, on the 35th day, the ND antibody titers of the NFG and FG chickens were both significantly higher than those of control group chickens. Defensin RNA expression levels were inhibited by NFG; however, they were induced by FG. In conclusion, fermentation of Ginkgo biloba with Bacillus coagulans can promote the beneficial effect of Gingko biloba on the immunity status of broiler chickens.
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Intestinal barrier dysfunction: implications for chronic inflammatory conditions of the bowel. Nutr Res Rev 2016; 29:40-59. [DOI: 10.1017/s0954422416000019] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
AbstractThe intestinal epithelium of adult humans acts as a differentially permeable barrier that separates the potentially harmful contents of the lumen from the underlying tissues. Any dysfunction of this boundary layer that disturbs the homeostatic equilibrium between the internal and external environments may initiate and sustain a biochemical cascade that results in inflammation of the intestine. Key to such dysfunction are genetic, microbial and other environmental factors that, singularly or in combination, result in chronic inflammation that is symptomatic of inflammatory bowel disease (IBD). The aim of the present review is to assess the scientific evidence to support the hypothesis that defective transepithelial transport mechanisms and the heightened absorption of intact antigenic proinflammatory oligopeptides are important contributing factors in the pathogenesis of IBD.
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Crosstalk between microbiota, pathogens and the innate immune responses. Int J Med Microbiol 2016; 306:257-265. [PMID: 26996809 DOI: 10.1016/j.ijmm.2016.03.003] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Revised: 03/02/2016] [Accepted: 03/03/2016] [Indexed: 02/07/2023] Open
Abstract
Research in the last decade has convincingly demonstrated that the microbiota is crucial in order to prime and orchestrate innate and adaptive immune responses of their host and influence barrier function as well as multiple developmental and metabolic parameters of the host. Reciprocally, host reactions and immune responses instruct the composition of the microbiota. This review summarizes recent evidence from experimental and human studies which supports these arms of mutual relationship and crosstalk between host and resident microbiota, with a focus on innate immune responses in the gut, the role of cell death pathways and antimicrobial peptides. We also provide some recent examples on how dysbiosis and pathogens can act in concert to promote intestinal infection, inflammatory pathologies and cancer. The future perspectives of these combined research efforts include the discovery of protective species within the microbiota and specific traits and factors of microbes that weaken or enforce host intestinal homeostasis.
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Zhao A, Lu W, de Leeuw E. Functional synergism of Human Defensin 5 and Human Defensin 6. Biochem Biophys Res Commun 2015; 467:967-72. [DOI: 10.1016/j.bbrc.2015.10.035] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Accepted: 10/07/2015] [Indexed: 12/18/2022]
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Keskin M, Zeidán-Chuliá F, Gursoy M, Könönen E, Rautava J, Gursoy UK. Two Cheers for Crohn's Disease and Periodontitis: Beta-Defensin-2 as an Actionable Target to Intervene on Two Clinically Distinct Diseases. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2015; 19:443-50. [DOI: 10.1089/omi.2015.0077] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Mutlu Keskin
- Department of Periodontology, Institute of Dentistry, University of Turku, Turku, Finland
- İstanbul Kemerburgaz University, Vocational School of Health Services, Istanbul, Turkey
| | - Fares Zeidán-Chuliá
- Department of Periodontology, Institute of Dentistry, University of Turku, Turku, Finland
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Mervi Gursoy
- Department of Periodontology, Institute of Dentistry, University of Turku, Turku, Finland
| | - Eija Könönen
- Department of Periodontology, Institute of Dentistry, University of Turku, Turku, Finland
- Oral Health Care, Welfare Division, City of Turku, Turku, Finland
| | - Jaana Rautava
- Department of Oral Pathology, Institute of Dentistry, University of Turku, Turku, Finland
| | - Ulvi Kahraman Gursoy
- Department of Periodontology, Institute of Dentistry, University of Turku, Turku, Finland
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Habil N, Abate W, Beal J, Foey AD. Heat-killed probiotic bacteria differentially regulate colonic epithelial cell production of human β-defensin-2: dependence on inflammatory cytokines. Benef Microbes 2015; 5:483-95. [PMID: 25116382 DOI: 10.3920/bm2013.0061] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The inducible antimicrobial peptide human β-defensin-2 (hBD-2) stimulated by pro-inflammatory cytokines and bacterial products is essential to antipathogen responses of gut epithelial cells. Commensal and probiotic bacteria can augment such mucosal defences. Probiotic use in the treatment of inflammatory bowel disease, however, may have adverse effects, boosting inflammatory responses. The aim of this investigation was to determine the effect of selected probiotic strains on hBD-2 production by epithelial cells induced by pathologically relevant pro-inflammatory cytokines and the role of cytokine modulators in controlling hBD-2. Caco-2 colonic intestinal epithelial cells were pre-incubated with heat-killed probiotics, i.e. Lactobacillus casei strain Shirota (LcS) or Lactobacillus fermentum strain MS15 (LF), followed by stimulation of hBD-2 by interleukin (IL)-1β and tumour necrosis factor alpha (TNF-α) in the absence or presence of exogenous IL-10 or anti-IL-10 neutralising antibody. Cytokines and hBD-2 mRNA and protein were analysed by real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. LcS augmented IL-1β-induced hBD-2, whereas LF enhanced TNF-α- and suppressed IL-1β-induced hBD-2. LF enhanced TNF-α-induced TNF-α and suppressed IL-10, whereas augmented IL-1β-induced IL-10. LcS upregulated IL-1β-induced TNF-α mRNA and suppressed IL-10. Endogenous IL-10 differentially regulated hBD-2; neutralisation of IL-10 augmented TNF-α- and suppressed IL-1β-induced hBD-2. Exogenous IL-10, however, suppressed both TNF-α- and IL-1β-induced hBD-2; LcS partially rescued suppression in TNF-α- and IL-1β-stimulation, whereas LF further suppressed IL-1β-induced hBD-2. It can be concluded that probiotic strains differentially regulate hBD-2 mRNA expression and protein secretion, modulation being dictated by inflammatory stimulus and resulting cytokine environment.
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Affiliation(s)
- N Habil
- School of Biomedical & Healthcare Sciences, University of Plymouth, Drake Circus, Plymouth PL4 8AA, United Kingdom Foundation of Technical Education (FTE), Alnakabat Street, 55555 Baghdad, Iraq
| | - W Abate
- School of Biomedical & Healthcare Sciences, University of Plymouth, Drake Circus, Plymouth PL4 8AA, United Kingdom
| | - J Beal
- School of Biomedical & Healthcare Sciences, University of Plymouth, Drake Circus, Plymouth PL4 8AA, United Kingdom
| | - A D Foey
- School of Biomedical & Healthcare Sciences, University of Plymouth, Drake Circus, Plymouth PL4 8AA, United Kingdom
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30
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Sharma H, Nagaraj R. Human β-defensin 4 with non-native disulfide bridges exhibit antimicrobial activity. PLoS One 2015; 10:e0119525. [PMID: 25785690 PMCID: PMC4364940 DOI: 10.1371/journal.pone.0119525] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2014] [Accepted: 01/14/2015] [Indexed: 01/05/2023] Open
Abstract
Human defensins play multiple roles in innate immunity including direct antimicrobial killing and immunomodulatory activity. They have three disulfide bridges which contribute to the stability of three anti-parallel β-strands. The exact role of disulfide bridges and canonical β-structure in the antimicrobial action is not yet fully understood. In this study, we have explored the antimicrobial activity of human β-defensin 4 (HBD4) analogs that differ in the number and connectivity of disulfide bridges. The cysteine framework was similar to the disulfide bridges present in μ-conotoxins, an unrelated class of peptide toxins. All the analogs possessed enhanced antimicrobial potency as compared to native HBD4. Among the analogs, the single disulfide bridged peptide showed maximum potency. However, there were no marked differences in the secondary structure of the analogs. Subtle variations were observed in the localization and membrane interaction of the analogs with bacteria and Candida albicans, suggesting a role for disulfide bridges in modulating their antimicrobial action. All analogs accumulated in the cytosol where they can bind to anionic molecules such as nucleic acids which would affect several cellular processes leading to cell death. Our study strongly suggests that native disulfide bridges or the canonical β-strands in defensins have not evolved for maximal activity but they play important roles in determining their antimicrobial potency.
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Affiliation(s)
- Himanshu Sharma
- CSIR-Centre for Cellular and Molecular Biology, Hyderabad, Telangana, India
| | - Ramakrishnan Nagaraj
- CSIR-Centre for Cellular and Molecular Biology, Hyderabad, Telangana, India
- * E-mail:
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Kostic AD, Gevers D, Siljander H, Vatanen T, Hyötyläinen T, Hämäläinen AM, Peet A, Tillmann V, Pöhö P, Mattila I, Lähdesmäki H, Franzosa EA, Vaarala O, de Goffau M, Harmsen H, Ilonen J, Virtanen SM, Clish CB, Orešič M, Huttenhower C, Knip M, Xavier RJ. The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes. Cell Host Microbe 2015; 17:260-73. [PMID: 25662751 DOI: 10.1016/j.chom.2015.01.001] [Citation(s) in RCA: 836] [Impact Index Per Article: 83.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2014] [Revised: 11/05/2014] [Accepted: 12/23/2014] [Indexed: 12/12/2022]
Abstract
Colonization of the fetal and infant gut microbiome results in dynamic changes in diversity, which can impact disease susceptibility. To examine the relationship between human gut microbiome dynamics throughout infancy and type 1 diabetes (T1D), we examined a cohort of 33 infants genetically predisposed to T1D. Modeling trajectories of microbial abundances through infancy revealed a subset of microbial relationships shared across most subjects. Although strain composition of a given species was highly variable between individuals, it was stable within individuals throughout infancy. Metabolic composition and metabolic pathway abundance remained constant across time. A marked drop in alpha-diversity was observed in T1D progressors in the time window between seroconversion and T1D diagnosis, accompanied by spikes in inflammation-favoring organisms, gene functions, and serum and stool metabolites. This work identifies trends in the development of the human infant gut microbiome along with specific alterations that precede T1D onset and distinguish T1D progressors from nonprogressors.
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Affiliation(s)
- Aleksandar D Kostic
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA
| | - Dirk Gevers
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Heli Siljander
- Children's Hospital, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, Finland; Research Program Unit, Diabetes and Obesity, University of Helsinki, 00290 Helsinki, Finland
| | - Tommi Vatanen
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Information and Computer Science, Aalto University School of Science, 02150 Espoo, Finland
| | - Tuulia Hyötyläinen
- Steno Diabetes Center, 2820 Gentofte, Denmark; VTT Technical Research Centre of Finland, 02044 Espoo, Finland
| | | | - Aleksandr Peet
- Department of Pediatrics, University of Tartu, Estonia and Tartu University Hospital, 51014 Tartu, Estonia
| | - Vallo Tillmann
- Department of Pediatrics, University of Tartu, Estonia and Tartu University Hospital, 51014 Tartu, Estonia
| | - Päivi Pöhö
- Faculty of Pharmacy, University of Helsinki, 00290 Helsinki, Finland; VTT Technical Research Centre of Finland, 02044 Espoo, Finland
| | - Ismo Mattila
- Steno Diabetes Center, 2820 Gentofte, Denmark; VTT Technical Research Centre of Finland, 02044 Espoo, Finland
| | - Harri Lähdesmäki
- Department of Information and Computer Science, Aalto University School of Science, 02150 Espoo, Finland
| | - Eric A Franzosa
- Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA
| | - Outi Vaarala
- Research Program Unit, Diabetes and Obesity, University of Helsinki, 00290 Helsinki, Finland
| | - Marcus de Goffau
- Department of Medical Microbiology, University Medical Center Groningen and University of Groningen, 9713 GZ Groningen, the Netherlands
| | - Hermie Harmsen
- Department of Medical Microbiology, University Medical Center Groningen and University of Groningen, 9713 GZ Groningen, the Netherlands
| | - Jorma Ilonen
- Immunogenetics Laboratory, University of Turku, 20520 Turku, Finland; Department of Clinical Microbiology, University of Eastern Finland, 70211 Kuopio, Finland
| | - Suvi M Virtanen
- Department of Lifestyle and Participation, National Institute for Health and Welfare, 00271 Helsinki, Finland; School of Health Sciences, University of Tampere, 33014 Tampere, Finland; Science Centre, Pirkanmaa Hospital District, 33521 Tampere, Finland
| | - Clary B Clish
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Matej Orešič
- Steno Diabetes Center, 2820 Gentofte, Denmark; VTT Technical Research Centre of Finland, 02044 Espoo, Finland
| | - Curtis Huttenhower
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA
| | - Mikael Knip
- Children's Hospital, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, Finland; Research Program Unit, Diabetes and Obesity, University of Helsinki, 00290 Helsinki, Finland; Folkhälsan Research Center, 00290 Helsinki, Finland; Department of Pediatrics, Tampere University Hospital, 33521 Tampere, Finland
| | | | - Ramnik J Xavier
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
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Pelissier-Rota MA, Chartier NT, Jacquier-Sarlin MR. Dynamic Regulation of Adherens Junctions: Implication in Cell Differentiation and Tumor Development. INTERCELLULAR COMMUNICATION IN CANCER 2015:53-149. [DOI: 10.1007/978-94-017-7380-5_4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Coskun M. Intestinal epithelium in inflammatory bowel disease. Front Med (Lausanne) 2014; 1:24. [PMID: 25593900 PMCID: PMC4292184 DOI: 10.3389/fmed.2014.00024] [Citation(s) in RCA: 122] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Accepted: 08/11/2014] [Indexed: 12/20/2022] Open
Abstract
The intestinal epithelium has a strategic position as a protective physical barrier to luminal microbiota and actively contributes to the mucosal immune system. This barrier is mainly formed by a monolayer of specialized intestinal epithelial cells (IECs) that are crucial in maintaining intestinal homeostasis. Therefore, dysregulation within the epithelial layer can increase intestinal permeability, lead to abnormalities in interactions between IECs and immune cells in underlying lamina propria, and disturb the intestinal immune homeostasis, all of which are linked to the clinical disease course of inflammatory bowel disease (IBD). Understanding the role of the intestinal epithelium in IBD pathogenesis might contribute to an improved knowledge of the inflammatory processes and the identification of potential therapeutic targets.
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Affiliation(s)
- Mehmet Coskun
- Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen , Herlev , Denmark
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34
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Chronic mucosal inflammation/inflammatory bowel disease-like inflammation after intestinal transplantation: where are we now? Curr Opin Organ Transplant 2014; 19:276-80. [PMID: 24752065 DOI: 10.1097/mot.0000000000000077] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW The purpose of this review is to highlight the similarities between inflammatory bowel disease and the state of the intestine allograft after transplantation. RECENT FINDINGS The mutant nucleotide-binding oligomerization protein 2 (NOD2) gene, which encodes for an intracellular protein that serves as an innate immune system microbial sensor in macrophages, dendritic cells, and certain intestinal epithelial cells, has been recognized as a risk factor in Crohn's disease. Similarly, recent studies have also highlighted the contribution the NOD2 mutation may have on intestinal failure itself. More specifically, in intestinal transplant recipients with the NOD2 mutation, the discovery of the reduced ability to prevent bacterial clearance, increased enterocyte stress response, and failure of key downstream expression of important cytokines and growth factors have been implicated as major factors in intestinal transplant outcomes, namely graft loss and septic death. Treatment strategies with anti tumor necrosis factor (TNF) α, similar to inflammatory bowel disease, have been employed in intestinal transplantation with promising results. SUMMARY In intestinal transplantation, there is evidence that the classical alloimmunity pathways that lead toward graft dysfunction and eventual graft loss may, in fact, be working in concert with a disordered innate immune system to produce a state of chronic inflammation not unlike that seen in inflammatory bowel disease.
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Beck-Broichsitter BE, Dau H, Moest T, Jochens A, Stockmann P, Wiltfang J, Becker ST. Immunohistological expression of human ß-defensin-1 and human ß-defensin-2 in exacerbation of acute and secondary chronic osteomyelitis of the mandible. J Oral Pathol Med 2014; 44:88-93. [DOI: 10.1111/jop.12202] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/07/2014] [Indexed: 12/01/2022]
Affiliation(s)
| | - Heino Dau
- Department of Oral and Maxillofacial Surgery; Schleswig-Holstein University Hospital; Kiel Germany
| | - Tobias Moest
- Department of Oral and Maxillofacial Surgery; University Hospital Erlangen-Nürnberg; Erlangen Germany
| | - Arne Jochens
- Institute of Medical Informatics and Statistics; Schleswig-Holstein University Hospital; Kiel Germany
| | - Philipp Stockmann
- Department of Oral and Maxillofacial Surgery; University Hospital Erlangen-Nürnberg; Erlangen Germany
| | - Jörg Wiltfang
- Department of Oral and Maxillofacial Surgery; Schleswig-Holstein University Hospital; Kiel Germany
| | - Stephan T. Becker
- Department of Oral and Maxillofacial Surgery; Schleswig-Holstein University Hospital; Kiel Germany
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36
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Lu W, de Leeuw E. Functional intersection of Human Defensin 5 with the TNF receptor pathway. FEBS Lett 2014; 588:1906-12. [PMID: 24681099 DOI: 10.1016/j.febslet.2014.03.028] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Revised: 03/06/2014] [Accepted: 03/14/2014] [Indexed: 12/21/2022]
Abstract
Defensins are cationic antimicrobial peptides that contribute to regulation of host cell function also. Here, we report on the regulation of cell death by Human Defensin 5, the major antimicrobial peptide of ileal Paneth cells. We find that Human Defensin 5-mediated cellular effects depend on functional expression of Tumor Necrosis Factor receptors and downstream mediators of TNF signaling. Our data indicate the involvement of interactions between Human Defensin 5 and the extra-cellular domain of Tumor Necrosis Factor receptor 1. Human Defensin-5 also induces apoptosis intrinsically by targeting the mitochondrial membrane.
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Affiliation(s)
- Wuyuan Lu
- Institute of Human Virology, University of Maryland Baltimore School of Medicine, 725 West Lombard Street, Baltimore, MD 21201, USA
| | - Erik de Leeuw
- Institute of Human Virology, University of Maryland Baltimore School of Medicine, 725 West Lombard Street, Baltimore, MD 21201, USA.
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37
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Dietrich DE, Martin AD, Brogden KA. Human β-defensin HBD3 binds to immobilized Bla g2 from the German cockroach (Blattella germanica). Peptides 2014; 53:265-9. [PMID: 24495736 PMCID: PMC3992933 DOI: 10.1016/j.peptides.2014.01.017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2013] [Revised: 01/21/2014] [Accepted: 01/21/2014] [Indexed: 01/28/2023]
Abstract
Human β-defensin 3 (HBD3) is a small, well-characterized peptide in mucosal secretions with broad antimicrobial activities and diverse innate immune functions. Among these functions is the ability of HBD3 to bind to antigens. In this study, we hypothesize that HBD3 binds to the allergen Bla g2 from the German cockroach (Blattella germanica). The ability of HBD1 (used as a control β-defensin) and HBD3 to bind to Bla g2 and human serum albumin (HSA, used as a control ligand) was assessed using the SensíQ Pioneer surface plasmon resonance (SPR) spectroscopy biosensor system. HBD1 was observed to bind weakly to Bla g2, while HBD3 demonstrated a stronger affinity for the allergen. HBD3 was assessed under two buffer conditions using 0.15 M and 0.3 M NaCl to control the electrostatic attraction of the peptide to the chip surface. The apparent K(D) of HBD3 binding Bla g2 was 5.9±2.1 μM and for binding HSA was 4.2±0.7 μM, respectively. Thus, HBD3, found in mucosal secretions has the ability to bind to allergens like Bla g2 possibly by electrostatic interaction, and may alter the ability of Bla g2 to induce localized allergic and/or inflammatory mucosal responses.
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Affiliation(s)
- Deborah E Dietrich
- Dows Institute for Dental Research, College of Dentistry, The University of Iowa, Iowa City, IA 52242, USA
| | - Aaron D Martin
- SensíQ Technologies Inc., 800 Research Parkway, Suite 100, Oklahoma City, OK 73104, USA
| | - Kim A Brogden
- Dows Institute for Dental Research, College of Dentistry, The University of Iowa, Iowa City, IA 52242, USA; Department of Periodontics and Dows Institute for Dental Research, N423 DSB, College of Dentistry, The University of Iowa, 801 Newton Road, Iowa City, IA 52242, USA.
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Antoni L, Nuding S, Wehkamp J, Stange EF. Intestinal barrier in inflammatory bowel disease. World J Gastroenterol 2014; 20:1165-1179. [PMID: 24574793 PMCID: PMC3921501 DOI: 10.3748/wjg.v20.i5.1165] [Citation(s) in RCA: 293] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 11/08/2013] [Accepted: 12/13/2013] [Indexed: 02/06/2023] Open
Abstract
A complex mucosal barrier protects as the first line of defense the surface of the healthy intestinal tract from adhesion and invasion by luminal microorganisms. In this review, we provide an overview about the major components of this protective system as for example an intact epithelium, the synthesis of various antimicrobial peptides (AMPs) and the formation of the mucus layer. We highlight the crucial importance of their correct functioning for the maintenance of a proper intestinal function and the prevention of dysbiosis and disease. Barrier disturbances including a defective production of AMPs, alterations in thickness or composition of the intestinal mucus layer, alterations of pattern-recognition receptors, defects in the process of autophagy as well as unresolved endoplasmic reticulum stress result in an inadequate host protection and are thought to play a crucial role in the pathogenesis of the inflammatory bowel diseases Crohn’s disease and ulcerative colitis.
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Biasi F, Leonarduzzi G, Oteiza PI, Poli G. Inflammatory bowel disease: mechanisms, redox considerations, and therapeutic targets. Antioxid Redox Signal 2013; 19:1711-47. [PMID: 23305298 PMCID: PMC3809610 DOI: 10.1089/ars.2012.4530] [Citation(s) in RCA: 215] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Oxidative stress is thought to play a key role in the development of intestinal damage in inflammatory bowel disease (IBD), because of its primary involvement in intestinal cells' aberrant immune and inflammatory responses to dietary antigens and to the commensal bacteria. During the active disease phase, activated leukocytes generate not only a wide spectrum of pro-inflammatory cytokines, but also excess oxidative reactions, which markedly alter the redox equilibrium within the gut mucosa, and maintain inflammation by inducing redox-sensitive signaling pathways and transcription factors. Moreover, several inflammatory molecules generate further oxidation products, leading to a self-sustaining and auto-amplifying vicious circle, which eventually impairs the gut barrier. The current treatment of IBD consists of long-term conventional anti-inflammatory therapy and often leads to drug refractoriness or intolerance, limiting patients' quality of life. Immune modulators or anti-tumor necrosis factor α antibodies have recently been used, but all carry the risk of significant side effects and a poor treatment response. Recent developments in molecular medicine point to the possibility of treating the oxidative stress associated with IBD, by designing a proper supplementation of specific lipids to induce local production of anti-inflammatory derivatives, as well as by developing biological therapies that target selective molecules (i.e., nuclear factor-κB, NADPH oxidase, prohibitins, or inflammasomes) involved in redox signaling. The clinical significance of oxidative stress in IBD is now becoming clear, and may soon lead to important new therapeutic options to lessen intestinal damage in this disease.
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Affiliation(s)
- Fiorella Biasi
- 1 Department of Clinical and Biological Sciences, University of Turin , San Luigi Gonzaga Hospital, Orbassano, Italy
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Østvik AE, Granlund AVB, Torp SH, Flatberg A, Beisvåg V, Waldum HL, Flo TH, Espevik T, Damås JK, Sandvik AK. Expression of Toll-like receptor-3 is enhanced in active inflammatory bowel disease and mediates the excessive release of lipocalin 2. Clin Exp Immunol 2013; 173:502-11. [PMID: 23668802 DOI: 10.1111/cei.12136] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/08/2013] [Indexed: 12/11/2022] Open
Abstract
Anti-microbial peptides might influence the pathogenesis and course of inflammatory bowel disease (IBD). We sought to clarify the role of the anti-microbial glycoprotein lipocalin 2 (LCN2) in the colon by determining its localization and regulation in IBD. Following a microarray gene expression study of colonic biopsies from a large IBD population (n = 133), LCN2 was localized using immunohistochemistry and in-situ hybridization. Moreover, we examined the regulation of LCN2 in HT-29 cells with a panel of pattern recognition receptors (PRRs) and sought evidence by immunohistochemistry that the most relevant PRR, the Toll-like receptor (TLR)-3, was indeed expressed in colonic epithelium in IBD. LCN2 was among the 10 most up-regulated genes in both active ulcerative colitis (UCa) and active Crohn's disease (CDa) versus healthy controls. LCN2 protein was found in both epithelial cells and infiltrating neutrophils, while mRNA synthesis was located solely to epithelial cells, indicating that de-novo synthesis and thus regulation of LCN2 as measured in the gene expression analysis takes place in the mucosal epithelial cells. LCN2 is a putative biomarker in faeces for intestinal inflammation, different from calprotectin due to its epithelial site of synthesis. LCN2 release from the colonic epithelial cell line HT-29 was enhanced by both interleukin (IL)-1β and the TLR-3 ligand poly(I:C), and TLR-3 was shown to be expressed constitutively in colonic epithelial cells and markedly increased during inflammation.
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Affiliation(s)
- A E Østvik
- Centre of Molecular Inflammation Research, Department of Cancer Research, Norwegian University of Science and Technology, Trondheim, Norway
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Pastorelli L, De Salvo C, Mercado JR, Vecchi M, Pizarro TT. Central role of the gut epithelial barrier in the pathogenesis of chronic intestinal inflammation: lessons learned from animal models and human genetics. Front Immunol 2013; 4:280. [PMID: 24062746 PMCID: PMC3775315 DOI: 10.3389/fimmu.2013.00280] [Citation(s) in RCA: 327] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2013] [Accepted: 08/29/2013] [Indexed: 12/12/2022] Open
Abstract
The gut mucosa is constantly challenged by a bombardment of foreign antigens and environmental microorganisms. As such, the precise regulation of the intestinal barrier allows the maintenance of mucosal immune homeostasis and prevents the onset of uncontrolled inflammation. In support of this concept, emerging evidence points to defects in components of the epithelial barrier as etiologic factors in the pathogenesis of inflammatory bowel diseases (IBDs). In fact, the integrity of the intestinal barrier relies on different elements, including robust innate immune responses, epithelial paracellular permeability, epithelial cell integrity, as well as the production of mucus. The purpose of this review is to systematically evaluate how alterations in the aforementioned epithelial components can lead to the disruption of intestinal immune homeostasis, and subsequent inflammation. In this regard, the wealth of data from mouse models of intestinal inflammation and human genetics are pivotal in understanding pathogenic pathways, for example, that are initiated from the specific loss of function of a single protein leading to the onset of intestinal disease. On the other hand, several recently proposed therapeutic approaches to treat human IBD are targeted at enhancing different elements of gut barrier function, further supporting a primary role of the epithelium in the pathogenesis of chronic intestinal inflammation and emphasizing the importance of maintaining a healthy and effective intestinal barrier.
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Affiliation(s)
- Luca Pastorelli
- Department of Pathology, Case Western Reserve University School of Medicine , Cleveland, OH , USA ; Department of Biomedical Sciences for Health, University of Milan , Milan , Italy ; Gastroenterology and Digestive Endoscopy Unit, IRCCS Policlinico San Donato , San Donato Milanese , Italy
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Wilson TJ, Jobim M, Segat L, Bianco AM, Salim PH, Portela P, Jobim LF, Damin DC, Schwartsmann G, Roesler R, Crovella S. DEFB1 gene 5′ untranslated region (UTR) polymorphisms are marginally involved in inflammatory bowel disease in south Brazilians. Int J Immunogenet 2013; 41:138-42. [DOI: 10.1111/iji.12089] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2013] [Revised: 07/24/2013] [Accepted: 08/10/2013] [Indexed: 12/19/2022]
Affiliation(s)
- T. J. Wilson
- Department of Immunology; Hospital de Clínicas; Porto Alegre Brazil
| | - M. Jobim
- Department of Immunology; Hospital de Clínicas; Porto Alegre Brazil
| | - L. Segat
- Institute for Maternal and Child Health-IRCCS ‘‘Burlo Garofolo’’; Trieste Italy
| | - A. M. Bianco
- Institute for Maternal and Child Health-IRCCS ‘‘Burlo Garofolo’’; Trieste Italy
| | - P. H. Salim
- Department of Immunology; Hospital de Clínicas; Porto Alegre Brazil
| | - P. Portela
- Department of Immunology; Hospital de Clínicas; Porto Alegre Brazil
| | - L. F. Jobim
- Department of Immunology; Hospital de Clínicas; Porto Alegre Brazil
- Department of Internal Medicine; Faculty of Medicine; Federal University of Rio Grande do Sul; Porto Alegre Brazil
| | - D. C. Damin
- Division of Coloproctology; Hospital de Clinicas de Porto Alegre; Porto Alegre Brazil
- Department of Surgery; Federal University of Rio Grande do Sul; Porto Alegre Brazil
| | - G. Schwartsmann
- Department of Internal Medicine; Faculty of Medicine; Federal University of Rio Grande do Sul; Porto Alegre Brazil
- Cancer Research Laboratory; University Hospital Research Center (CPE-HCPA); Porto Alegre Brazil
- National Institute for Translational Medicine; Porto Alegre Brazil
| | - R. Roesler
- Cancer Research Laboratory; University Hospital Research Center (CPE-HCPA); Porto Alegre Brazil
- National Institute for Translational Medicine; Porto Alegre Brazil
- Laboratory of Neuropharmacology and Neural Tumor Biology; Department of Pharmacology; Institute for Basic Health Sciences; Federal University of Rio Grande do Sul; Porto Alegre Brazil
| | - S. Crovella
- Department of Genetics; federal University of Pernambuco; Recife Brazil
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Lu W, de Leeuw E. Pro-inflammatory and pro-apoptotic properties of Human Defensin 5. Biochem Biophys Res Commun 2013; 436:557-62. [PMID: 23770364 DOI: 10.1016/j.bbrc.2013.06.015] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2013] [Accepted: 06/05/2013] [Indexed: 12/15/2022]
Abstract
Defensins are cationic antimicrobial peptides that play an important role in innate immunity by primarily acting against microbes. Their antimicrobial properties have been widely studied and are well understood. Defensins contribute to regulation of host immunity also. Their effects on cells of the host however are less well understood. Here, we report on the pro-inflammatory and apoptotic properties of Human Defensin 5, the major antimicrobial peptide of ileal Paneth cells. We find that HD-5 up-regulates expression of genes involved in cell survival and inflammation in a NF-kB-dependent fashion in epithelial cells. Further, we find that HD-5 has pro-apoptotic effects on intestinal epithelial cells as well as primary CD4+ T cells.
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Affiliation(s)
- Wuyuan Lu
- Institute of Human Virology of the University of Maryland Baltimore School of Medicine, 725 West Lombard Street, Baltimore, MD 21201, USA
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Meisch JP, Nishimura M, Vogel RM, Sung HC, Bednarchik BA, Ghosh SK, Fu P, McCormick T, Weinberg A, Levine AD. Human β-defensin 3 peptide is increased and redistributed in Crohn's ileitis. Inflamm Bowel Dis 2013; 19:942-53. [PMID: 23511030 PMCID: PMC3746836 DOI: 10.1097/mib.0b013e318280b11a] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND Antimicrobial peptides (AMPs) maintain a sterile environment in intestinal crypts, limiting microbial colonization and invasion. Decreased AMP expression is proposed to increase the risk for inflammatory bowel disease. Expression and function of inducible AMPs, human β-defensin 2 and 3 (hBD-2 and hBD-3), remain poorly characterized in healthy and chronically inflamed intestine. METHODS Peptide concentrations of hBD-2 and hBD-3 in serum and intestinal biopsies of subjects with ulcerative colitis and Crohn's disease (CD), and those of healthy subjects were measured by ELISA. Messenger RNA of hBD-2 and hBD-3 was quantified by quantitative PCR in biopsies from the terminal ileum (TI) of patients with CD and healthy controls. Peptide localization of hBD-3 in the TI was visualized by confocal microscopy. RESULTS Immunoreactive hBD-3 peptide is present in the TI and colon in healthy subjects. In the TI of patients with CD, hBD-3, but not hBD-2 peptide, is increased 4-fold, whereas hBD-2 peptide is elevated in the serum. Messenger RNA of hBD-3 in the CD TI remains unchanged and does not correlate with hBD-3 peptide expression. However, hBD-3 is localized to Paneth cell granules and the apical surface of the healthy columnar epithelium. In CD, hBD-3 peptide location switches to the basolateral surface of the columnar epithelium and is diffusely distributed within the lamina propria. CONCLUSION The peptide hBD-3 throughout the healthy gastrointestinal tract suggests a role in maintaining balance between host defenses and commensal microbiota. Increased and relocalized secretion of hBD-3 toward the lamina propria in the CD TI indicates possible local immunomodulation during chronic inflammation, whereas increased serum hBD-2 in CD implicates its systemic antimicrobial and immunomodulatory role.
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Affiliation(s)
- Jeffrey P. Meisch
- Department of Medicine, 10900 Euclid Avenue, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106
| | - Michiko Nishimura
- Department of Biological Sciences, Case Western Reserve University School of Dental Medicine, Cleveland, Ohio 44106
| | - Ryan M. Vogel
- Department of Medicine, 10900 Euclid Avenue, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106
| | - Hannah C. Sung
- Department of Medicine, 10900 Euclid Avenue, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106
| | - Beth A. Bednarchik
- Department of Medicine, 10900 Euclid Avenue, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106
| | - Santosh K. Ghosh
- Department of Biological Sciences, Case Western Reserve University School of Dental Medicine, Cleveland, Ohio 44106
| | - Pingfu Fu
- Department of Biostatistics, 10900 Euclid Avenue, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106
| | - Thomas McCormick
- Department of Dermatology, 10900 Euclid Avenue, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106
| | - Aaron Weinberg
- Department of Biological Sciences, Case Western Reserve University School of Dental Medicine, Cleveland, Ohio 44106
| | - Alan D. Levine
- Department of Medicine, 10900 Euclid Avenue, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106,Department of Pathology, Pharmacology, the Case Comprehensive Cancer Center, 10900 Euclid Avenue, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106,Address correspondence to: Alan D. Levine Ph.D., Department of Medicine, Case Western Reserve University School of Medicine BRB 525, 10900 Euclid Avenue, Cleveland, Ohio, 44106-4952. Phone: (216) 368-0342, Fax: (216) 368-0647,
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de Oca EPM. Antimicrobial peptide elicitors: New hope for the post-antibiotic era. Innate Immun 2012; 19:227-41. [DOI: 10.1177/1753425912460708] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Antimicrobial peptides or host defense peptides are fundamental components of human innate immunity. Recent and growing evidence suggests they have a role in a broad range of diseases, including cancer, allergies and susceptibility to infection, including HIV/AIDS. Antimicrobial peptide elicitors (APEs) are physical, biological or chemical agents that boost human antimicrobial peptide expression. The current knowledge of APEs and their potential use in the treatment of human infectious diseases are reviewed, and a classification system for APEs is proposed. The efficient use of APEs in clinical practice could mark the beginning of the urgently needed post-antibiotic era, but further trials assessing their efficacy and safety are required.
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Affiliation(s)
- Ernesto Prado Montes de Oca
- Molecular Biology Laboratory, Biosecurity Area, CIATEJ – National Council of Science and Technology, Guadalajara, Jalisco, Mexico
- In silico Laboratory, Pharmaceutical and Medical Biotechnology Unit, CIATEJ – National Council of Science and Technology, Guadalajara, Jalisco, Mexico
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Troge A, Scheppach W, Schroeder BO, Rund SA, Heuner K, Wehkamp J, Stange EF, Oelschlaeger TA. More than a marine propeller--the flagellum of the probiotic Escherichia coli strain Nissle 1917 is the major adhesin mediating binding to human mucus. Int J Med Microbiol 2012; 302:304-14. [PMID: 23131416 DOI: 10.1016/j.ijmm.2012.09.004] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2012] [Revised: 09/14/2012] [Accepted: 09/16/2012] [Indexed: 12/12/2022] Open
Abstract
The flagellum of the probiotic Escherichia coli strain Nissle 1917 (EcN) is not just responsible for motility, but also for EcN's ability to induce the production of human β-defensin 2. Here, we report a third function of this EcN organell. In this study we investigated the role of the EcN flagellum in adhesion to different host tissues by ex vivo and in vitro studies. Ex vivo studies with cryosections of human gut biopsies revealed that the flagellum of EcN is most likely important for efficient adhesion to the human intestinal tract. These results and in vitro studies with different epithelial cells indicated that the presence of mucus is important for efficient mediation of adhesion by the flagellum of EcN. We observed direct interaction between isolated flagella from EcN wild type and porcine mucin 2 as well as human mucus. However, we could not observe any interaction of the flagella with murine mucus. For the first time, we identified the mucus component gluconate as one receptor for the binding of flagella from EcN and were able to exclude the flagellin domain D3 as a responsible interaction partner. We propose that the flagellum of EcN is its major adhesin in vivo, which enables this probiotic strain to compete efficiently for binding sites on host tissue with several bacterial pathogens.
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Affiliation(s)
- Anja Troge
- Institute for Molecular Infection Biology, University of Wuerzburg, Wuerzburg, Germany
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47
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Olfactomedin-4 is a glycoprotein secreted into mucus in active IBD. J Crohns Colitis 2012; 6:425-34. [PMID: 22398066 DOI: 10.1016/j.crohns.2011.09.013] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2011] [Revised: 09/28/2011] [Accepted: 09/28/2011] [Indexed: 02/08/2023]
Abstract
BACKGROUND Olfactomedin-4 (OLFM4) is a glycoprotein characteristic of intestinal stem cells and apparently involved in mucosal defense of the stomach and colon. Here we studied its expression, regulation and function in IBD. METHODS The expression of OLFM4, mucins Muc1 and Muc2, the goblet cell differentiation factor Hath1 and the proinflammatory cytokine IL-8 was measured in inflamed or noninflamed colon in IBD patients and controls. OLFM4 protein was located by immunohistochemistry, quantified by Dot Blot and its binding capacity to defensins HBD1-3 was investigated. The influence of bacteria with or without the Notch blocker dibenzazepine (DBZ) and of several cytokines on OLFM4 expression was determined in LS174T cells. RESULTS OLFM4 mRNA and protein were significantly upregulated in inflamed CD (4.3 and 1.7-fold) and even more pronounced in UC (24.8 and 3.7-fold). OLFM4 expression was correlated to IL-8 but not to Hath1. In controls immunostaining was restricted to the lower crypts but in inflamed IBD it expanded up to the epithelial surface including the mucus. OLFM4 bound to HBD1-3 without profoundly inactivating these defensins. In LS174T-cells OLFM4 mRNA was significantly augmented after incubation with Escherichia coli K12, Escherichia coli Nissle and Bacteroides vulgatus. DBZ downregulated OLFM4 expression and blocked bacterial induction whereas IL-22 but not TNF-α was stimulatory. CONCLUSIONS OLFM4 is overexpressed in active IBD and secreted into mucus. The induction is triggered by bacteria through the Notch pathway and also by the cytokine IL-22. OLFM4 seems to be of functional relevance in IBD as a mucus component, possibly by binding defensins.
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Abstract
The pathogenetic mechanisms that cause the two types of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC), are still under investigation. Nevertheless, there is broad agreement that luminal microbes are of particular relevance in the development of these conditions. In recent years, increasing evidence has shown that defects in the innate immunity are at the centre of both types of IBD. The innate intestinal barrier is provided by the epithelium which secretes antimicrobial peptides (so-called defensins) that are retained in the mucus layer. In ileal CD, the alpha-defensins are lacking owing to several Paneth cell defects. In colonic CD, the expression of beta-defensins is inadequate. This may be related to downregulation of the transcription factor peroxisome proliferator-activated receptor-gamma and in some cohorts is associated with a reduced HBD2 gene copy number. In UC, the mucus layer, which protects the host from the enormous amounts of luminal microbes, is defective. This is accompanied by an insufficient differentiation from intestinal stem cells towards goblet cells. All these disturbances in the gut barrier shift the balance from epithelial defence towards bacterial offence. The current treatment for CD and UC is based on suppression of this secondary inflammatory process. In future, patients may benefit from new therapeutic approaches stimulating the protective innate immune system.
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Affiliation(s)
- M Gersemann
- Department of Internal Medicine I, Robert Bosch Hospital, Stuttgart Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart
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Lough D, Abdo J, Guerra-Castro JF, Matsumoto C, Kaufman S, Shetty K, Kwon YK, Zasloff M, Fishbein TM. Abnormal CX3CR1⁺ lamina propria myeloid cells from intestinal transplant recipients with NOD2 mutations. Am J Transplant 2012; 12:992-1003. [PMID: 22233287 DOI: 10.1111/j.1600-6143.2011.03897.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Although progress has been made in intestinal transplantation, chronic inflammation remains a challenge. We have reported that the risk of immunological graft loss is almost 100-fold greater in recipients who carry any of the prevalent NOD2 polymorphisms associated with Crohn's disease, and have shown that the normal levels of a key antimicrobial peptide produced by the Paneth cells of the allograft, fall as the graft becomes repopulated by hematopoietic cells of the NOD2 mutant recipient. These studies are extended in this report. Within several months following engraftment into a NOD2 mutant recipient the allograft loses its capacity to prevent adherence of lumenal microbes. Despite the significantly increased expression of CX3CL1, a stress protein produced by the injured enterocyte, NOD2 mutant CX3CR1(+) myeloid cells within the lamina propria fail to exhibit the characteristic morphological phenotype, and fail to express key genes required expressed by NOD2 wild-type cells, including Wnt 5a. We propose that the CX3CR1(+) myeloid cell within the lamina propria supports normal Paneth cell function through expression of Wnt 5a, and that this function is impaired in the setting of intestinal transplantation into a NOD2 mutant recipient. The therapeutic value of Wnt 5a administration in this setting is proposed.
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Affiliation(s)
- D Lough
- Department of Surgery, Transplant Institute, Georgetown University Medical Center, Washington, DC, USA
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