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Tang YT, Yin SG, Peng CF, Tang JY, Jia G, Che LQ, Liu GM, Tian G, Chen XL, Cai JY, Kang B, Zhao H. Compound bioengineering protein supplementation improves intestinal health and growth performance of broilers. Poult Sci 2023; 102:103037. [PMID: 37657250 PMCID: PMC10480649 DOI: 10.1016/j.psj.2023.103037] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Revised: 08/06/2023] [Accepted: 08/11/2023] [Indexed: 09/03/2023] Open
Abstract
Currently, antimicrobial peptides (AMPs) are of growing interest as potential substitutes for antibiotic growth promoters in animal production. The present study was conducted to evaluate the effects of dietary supplementation of bioengineering artificial Parasin I protein (API) and artificial plectasin protein (APL) (named as compound bioengineering protein, CBP) on growth performance and intestinal health of broilers. A total of 450 one-day-old Arbor Acres male healthy broilers were randomly allotted to 5 dietary groups with 10 replicates of 9 individuals in each replicate and supplemented with 0, 250, 500, 750, and 1,000 mg/kg CBP for 6 wk. Dietary CBP supplementation increased (P < 0.01) body weight (6 wk), average daily gain (0-6 wk), and average daily feed intake (3-6 wk and 0-6 wk). CBP addition enhanced antioxidant capacity, which was accompanied by the higher (P < 0.05) activity of serum total antioxidant capacity (T-AOC) (750 mg/kg), jejunal glutathione peroxidase (750 mg/kg), and T-AOC (500 and 1,000 mg/kg). Dietary CBP addition improved intestinal health, reflecting by the increased (P < 0.05) villus height to crypt depth ratio in the duodenum, the upregulated (P < 0.01) mRNA levels of claudin-1 (500 and 750 mg/kg) in the ileum, the downregulated (P < 0.01) mRNA expression of occludin (500 mg/kg) in the duodenum and claudin-1 (500 mg/kg) and occludin (500 and 750 mg/kg) in the jejunum, and the upregulated mRNA expression of (P < 0.01) mucin2 (MUC2) (1,000 mg/kg) in the duodenum. In addition, CBP upregulated (P < 0.01) IL-10 (1,000 mg/kg) in duodenum and ileum, and downregulated (P < 0.05) the mRNA expression of IL-6 (750 and 1,000 mg/kg), interferon-γ (1,000 mg/kg) in the jejunum and TNF-α (250 mg/kg) in the ileum. Furthermore, dietary CBP increased (P < 0.01) the abundance of total bacteria and Lactobacillus (500 and 750 mg/kg), and reduced (P < 0.05) the abundance of Escherichia coli (750 mg/kg) in the cecum. In conclusion, CBP supplementation enhances the antioxidant capacity, intestinal health, immune function, and ameliorates the gut microflora population, thus improving the growth performance of broilers. Dietary supplementation of 750 mg/kg CBP exhibits a better beneficial effect.
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Affiliation(s)
- Y T Tang
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education of China, Ministry of Agriculture and Rural Affairs of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, Sichuan, China
| | - S G Yin
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education of China, Ministry of Agriculture and Rural Affairs of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, Sichuan, China
| | - C F Peng
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education of China, Ministry of Agriculture and Rural Affairs of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, Sichuan, China
| | - J Y Tang
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education of China, Ministry of Agriculture and Rural Affairs of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, Sichuan, China
| | - G Jia
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education of China, Ministry of Agriculture and Rural Affairs of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, Sichuan, China
| | - L Q Che
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education of China, Ministry of Agriculture and Rural Affairs of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, Sichuan, China
| | - G M Liu
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education of China, Ministry of Agriculture and Rural Affairs of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, Sichuan, China
| | - G Tian
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education of China, Ministry of Agriculture and Rural Affairs of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, Sichuan, China
| | - X L Chen
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education of China, Ministry of Agriculture and Rural Affairs of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, Sichuan, China
| | - J Y Cai
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education of China, Ministry of Agriculture and Rural Affairs of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, Sichuan, China
| | - B Kang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, Sichuan, China
| | - H Zhao
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education of China, Ministry of Agriculture and Rural Affairs of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.
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Shih CC, Liao WC, Ke HY, Kuo CW, Tsao CM, Tsai WC, Chiu YL, Huang HC, Wu CC. Antimicrobial peptide cathelicidin LL-37 preserves intestinal barrier and organ function in rats with heat stroke. Biomed Pharmacother 2023; 161:114565. [PMID: 36958193 DOI: 10.1016/j.biopha.2023.114565] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 03/14/2023] [Accepted: 03/16/2023] [Indexed: 03/25/2023] Open
Abstract
Global warming increases the incidence of heat stroke (HS) and HS causes the reduction of visceral blood flow during hyperthermia, leading to intestinal barrier disruption, microbial translocation, systemic inflammation and multiple organ failure. Cathelicidin LL-37 exhibits antimicrobial activities, helps innate immunity within the gut to maintain intestinal homeostasis, and augments intestinal wound healing and barrier function. Thus, we evaluated the effects and possible mechanisms of cathelicidin LL-37 on HS. Wistar rats were placed in a heating-chamber of 42 ̊C to induce HS. Changes in rectal temperature, hemodynamic parameters, and survival rate were measured during the experimental period. Blood samples and ilea were collected to analyze the effects of LL-37 on systemic inflammation, multiple organ dysfunction, and intestinal injury. Furthermore, LS174T and HT-29 cells were used to assess the underlying mechanisms. Our data showed cathelicidin LL-37 ameliorated the damage of intestinal cells induced by HS. Intestinal injury, systemic inflammation, and nitrosative stress (high nitric oxide level) caused by continuous hyperthermia were attenuated in HS rats treated with cathelicidin LL-37, and hence, improved multiple organ dysfunction, coagulopathy, and survival rate. These beneficial effects of cathelicidin LL-37 were attributed to the protection of intestinal goblet cells (by increasing transepithelial resistance, mucin-2 and Nrf2 expression) and the improvement of intestinal barrier function (less cyclooxygenase-2 expression and FITC-dextran translocation). Interestingly, high cathelicidin expression in the ileal samples of inflammatory bowel disease patients was associated with better clinical outcome. These results suggest that cathelicidin LL-37 could prevent heat stress-induced intestinal damage and heat-related illnesses.
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Affiliation(s)
- Chih-Chin Shih
- Department and Graduate Institute of Pharmacology, National Defense Medical Center, Taipei, Taiwan, ROC.
| | - Wei-Chieh Liao
- Department and Graduate Institute of Pharmacology, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Hung-Yen Ke
- Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Chia-Wen Kuo
- Department of Nephrology, Taichung Armed Forces General Hospital, Taichung, Taiwan, ROC
| | - Cheng-Ming Tsao
- Department of Anesthesiology, Taipei Veterans General Hospital and National Yang-Ming Chiao-Tung University, Taipei, Taiwan, ROC
| | - Wen-Chiuan Tsai
- Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Yi-Lin Chiu
- Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Hsieh-Chou Huang
- Department of Anesthesiology, Cheng-Hsin General Hospital, Taipei, Taiwan, ROC
| | - Chin-Chen Wu
- Department and Graduate Institute of Pharmacology, National Defense Medical Center, Taipei, Taiwan, ROC.
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Gubatan J, Holman DR, Puntasecca CJ, Polevoi D, Rubin SJS, Rogalla S. Antimicrobial peptides and the gut microbiome in inflammatory bowel disease. World J Gastroenterol 2021; 27:7402-7422. [PMID: 34887639 PMCID: PMC8613745 DOI: 10.3748/wjg.v27.i43.7402] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 05/13/2021] [Accepted: 11/15/2021] [Indexed: 02/06/2023] Open
Abstract
Antimicrobial peptides (AMP) are highly diverse and dynamic molecules that are expressed by specific intestinal epithelial cells, Paneth cells, as well as immune cells in the gastrointestinal (GI) tract. They play critical roles in maintaining tolerance to gut microbiota and protecting against enteric infections. Given that disruptions in tolerance to commensal microbiota and loss of barrier function play major roles in the pathogenesis of inflammatory bowel disease (IBD) and converge on the function of AMP, the significance of AMP as potential biomarkers and novel therapeutic targets in IBD have been increasingly recognized in recent years. In this frontier article, we discuss the function and mechanisms of AMP in the GI tract, examine the interaction of AMP with the gut microbiome, explore the role of AMP in the pathogenesis of IBD, and review translational applications of AMP in patients with IBD.
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Affiliation(s)
- John Gubatan
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Redwood City, CA 94063, United States
| | - Derek R Holman
- Department of Radiology, Molecular Imaging Program at Stanford , Stanford University, Stanford , CA 94305, United States
| | | | - Danielle Polevoi
- Stanford University School of Medicine, Stanford University, Stanford, CA 94063, United States
| | - Samuel JS Rubin
- Stanford University School of Medicine, Stanford University, Stanford, CA 94063, United States
| | - Stephan Rogalla
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Redwood City, CA 94063, United States
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Gong T, Fu J, Shi L, Chen X, Zong X. Antimicrobial Peptides in Gut Health: A Review. Front Nutr 2021; 8:751010. [PMID: 34660671 PMCID: PMC8514777 DOI: 10.3389/fnut.2021.751010] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 09/03/2021] [Indexed: 12/15/2022] Open
Abstract
Animal antimicrobial peptides (AMPs), known as broad-spectrum and high-efficiency antibacterial activity, are important effector molecules in innate immune system. AMPs not only have antimicrobial, antiviral and antitumor effects but also exhibit important effects in vivo, such as anti-inflammatory response, recruiting immune cells, promoting epithelial damage repair, and promoting phagocytosis of bacteria. However, research on the application of AMPs is incomplete and controversial. This review mainly introduces the classification of AMPs, biological functions, as well as the mechanisms of action, expression rules, and nutrition regulation from three perspectives, aiming to provide important information for the application of AMPs.
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Affiliation(s)
- Tao Gong
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Jie Fu
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Lexuan Shi
- Guangzhou Dublin International College of Life Sciences and Technology, South China Agricultural University, Guangzhou, China
| | - Xin Chen
- School of Medicine, Foshan University, Foshan, China
| | - Xin Zong
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou, China.,Key Laboratory of Animal Nutrition and Feed Science in Eastern China, Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou, China
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Pan LL, Zhang M, Li Z, Li B, Pan X, Chen X, Yang B, Zhang H, Chen W, Zhang L, Sun J. CRAMP-encoding Lactobacillus plantarum FCQHC24 attenuates experimental colitis in mice. FOOD BIOSCI 2021. [DOI: 10.1016/j.fbio.2021.101111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Rolando M, Barabino S. Are there Clinical Ways to Assess Inflammation in Dry Eye Disease? Ocul Immunol Inflamm 2021; 29:1183-1189. [PMID: 34227903 DOI: 10.1080/09273948.2021.1916540] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
In the diagnostic process of dry eye disease, the detection of inflammatory activity is critical in order to evaluate the risk of progression and immunologic shift of the disease, to predict patient response to treatment, and to design an efficient therapeutic strategy, including artificial tear replacement, punctal occlusion or anti-inflammatory therapy.Even if it is difficult to quantify, some indicators of the presence of inflammation are collectible during the examination of the ocular surface in a first-line clinical setting. This review presents and critically discusses the assessment of inflammation in dry eye disease in clinical practice.
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Affiliation(s)
- Maurizio Rolando
- Ocular Surface and Dry Eye Clinic, ISPRE Ophthalmica, Genoa, Italy
| | - Stefano Barabino
- Ocular Surface and Dry Eye Center, ASST Fatebenefratelli-Sacco, Sacco Hospital-University of Milan, Milan, Italy
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The role of the microbiome in gastrointestinal inflammation. Biosci Rep 2021; 41:228872. [PMID: 34076695 PMCID: PMC8201460 DOI: 10.1042/bsr20203850] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/27/2021] [Accepted: 06/02/2021] [Indexed: 12/12/2022] Open
Abstract
The microbiome plays an important role in maintaining human health. Despite multiple factors being attributed to the shaping of the human microbiome, extrinsic factors such diet and use of medications including antibiotics appear to dominate. Mucosal surfaces, particularly in the gut, are highly adapted to be able to tolerate a large population of microorganisms whilst still being able to produce a rapid and effective immune response against infection. The intestinal microbiome is not functionally independent from the host mucosa and can, through presentation of microbe-associated molecular patterns (MAMPs) and generation of microbe-derived metabolites, fundamentally influence mucosal barrier integrity and modulate host immunity. In a healthy gut there is an abundance of beneficial bacteria that help to preserve intestinal homoeostasis, promote protective immune responses, and limit excessive inflammation. The importance of the microbiome is further highlighted during dysbiosis where a loss of this finely balanced microbial population can lead to mucosal barrier dysfunction, aberrant immune responses, and chronic inflammation that increases the risk of disease development. Improvements in our understanding of the microbiome are providing opportunities to harness members of a healthy microbiota to help reverse dysbiosis, reduce inflammation, and ultimately prevent disease progression.
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Chen K, Yoshimura T, Yao X, Gong W, Huang J, Dzutsev AK, McCulloch J, O'hUigin C, Bian XW, Trinchieri G, Wang JM. Distinct contributions of cathelin-related antimicrobial peptide (CRAMP) derived from epithelial cells and macrophages to colon mucosal homeostasis. J Pathol 2021; 253:339-350. [PMID: 33104252 PMCID: PMC7898386 DOI: 10.1002/path.5572] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Revised: 10/16/2020] [Accepted: 10/21/2020] [Indexed: 12/14/2022]
Abstract
The cathelin‐related antimicrobial peptide CRAMP protects the mouse colon from inflammation, inflammation‐associated carcinogenesis, and disrupted microbiome balance, as shown in systemic Cnlp−/− mice (also known as Camp−/− mice). However, the mechanistic basis for the role and the cellular source of CRAMP in colon pathophysiology are ill defined. This study, using either epithelial or myeloid conditional Cnlp−/−mice, demonstrated that epithelial cell‐derived CRAMP played a major role in supporting normal development of colon crypts, mucus production, and repair of injured mucosa. On the other hand, myeloid cell‐derived CRAMP potently supported colon epithelial resistance to bacterial invasion during acute inflammation with exacerbated mucosal damage and higher rate of mouse mortality. Therefore, a well concerted cooperation of epithelial‐ and myeloid‐derived CRAMP is essential for colon mucosal homeostasis. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Keqiang Chen
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA.,Laboratory of Cancer and Immunometabolism, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA
| | - Teizo Yoshimura
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Xiaohong Yao
- Institute of Pathology and Southwest Cancer Center, Third Military Medical University, Chongqing, PR China
| | - Wanghua Gong
- Basic Research Program, Leidos Biomedical Research, Inc, Frederick, MD, USA
| | - Jiaqiang Huang
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA.,College of Life Sciences, Beijing Jiaotong University, Beijing, PR China
| | - Amiran K Dzutsev
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA
| | - John McCulloch
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA
| | - Colm O'hUigin
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA
| | - Xiu-Wu Bian
- Institute of Pathology and Southwest Cancer Center, Third Military Medical University, Chongqing, PR China
| | - Giorgio Trinchieri
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA
| | - Ji Ming Wang
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA.,Laboratory of Cancer and Immunometabolism, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA
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Fabisiak N, Fabisiak A, Chmielowiec-Korzeniowska A, Tymczyna L, Kamysz W, Kordek R, Bauer M, Kamysz E, Fichna J. Anti-inflammatory and antibacterial effects of human cathelicidin active fragment KR-12 in the mouse models of colitis: a novel potential therapy of inflammatory bowel diseases. Pharmacol Rep 2020; 73:163-171. [PMID: 33219923 PMCID: PMC7862075 DOI: 10.1007/s43440-020-00190-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 10/31/2020] [Accepted: 11/03/2020] [Indexed: 12/11/2022]
Abstract
Introduction Inflammatory bowel diseases (IBD) are a group of chronic gastrointestinal tract disorders with complex etiology, with intestinal dysbiosis as the most prominent factor. In this study, we assessed the anti-inflammatory and antibacterial actions of the human cathelicidin LL-37 and its shortest active fragment, KR-12 in the mouse models of colitis. Materials and methods Mouse models of colitis induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) and dextran sulfate sodium (DSS) were used in the study. The extent of inflammation was evaluated based on the macro- and microscopic scores, quantification of myeloperoxidase (MPO) activity and microbiological analysis of stool samples. Results A preliminary study with LL-37 and KR-12 (1 mg/kg, ip, twice daily) showed a decrease in macroscopic and ulcer scores in the acute TNBS-induced model of colitis. We observed that KR-12 (5 mg/kg, ip, twice daily) reduced microscopic and ulcer scores in the semi-chronic and chronic TNBS-induced models of colitis compared with inflamed mice. Furthermore, qualitative and quantitative changes in colonic microbiota were observed: KR-12 (5 mg/kg, ip, twice daily) decreased the overall number of bacteria, Escherichia coli and coli group bacteria. In the semi-chronic DSS-induced model, KR-12 attenuated intestinal inflammation as demonstrated by a reduction in macroscopic score and colon damage score and MPO activity. Conclusions We demonstrated that KR-12 alleviates inflammation in four different mouse models of colitis what suggests KR-12 and cathelicidins as a whole are worth being considered as a potential therapeutic option in the treatment of IBD.
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Affiliation(s)
- Natalia Fabisiak
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland
- Department of Gastroenterology, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Adam Fabisiak
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland
- Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | | | - Leszek Tymczyna
- Department of Animal Hygiene and Environment, University of Agriculture in Lublin, Lublin, Poland
| | - Wojciech Kamysz
- Department of Inorganic Chemistry, Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland
| | - Radzisław Kordek
- Department of Pathology, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Marta Bauer
- Department of Inorganic Chemistry, Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland
| | - Elżbieta Kamysz
- Department of Molecular Biotechnology, Faculty of Chemistry, University of Gdansk, Gdansk, Poland
| | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland.
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10
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Blyth GAD, Connors L, Fodor C, Cobo ER. The Network of Colonic Host Defense Peptides as an Innate Immune Defense Against Enteropathogenic Bacteria. Front Immunol 2020; 11:965. [PMID: 32508838 PMCID: PMC7251035 DOI: 10.3389/fimmu.2020.00965] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 04/24/2020] [Indexed: 12/11/2022] Open
Abstract
Host defense peptides, abundantly secreted by colonic epithelial cells and leukocytes, are proposed to be critical components of an innate immune response in the colon against enteropathogenic bacteria, including Shigella spp., Salmonella spp., Clostridium difficile, and attaching and effacing Escherichia coli and Citrobacter rodentium. These short cationic peptides are bactericidal against both Gram-positive and -negative enteric pathogens, but may also exert killing effects on intestinal luminal microbiota. Simultaneously, these peptides modulate numerous cellular responses crucial for gut defenses, including leukocyte chemotaxis and migration, wound healing, cytokine production, cell proliferation, and pathogen sensing. This review discusses recent advances in our understanding of expression, mechanisms of action and microbicidal and immunomodulatory functions of major colonic host defense peptides, namely cathelicidins, β-defensins, and members of the Regenerating islet-derived protein III (RegIII) and Resistin-like molecule (RELM) families. In a theoretical framework where these peptides work synergistically, aspects of pathogenesis of infectious colitis reviewed herein uncover roles of host defense peptides aimed to promote epithelial defenses and prevent pathogen colonization, mediated through a combination of direct antimicrobial function and fine-tuning of host immune response and inflammation. This interactive host defense peptide network may decode how the intestinal immune system functions to quickly clear infections, restore homeostasis and avoid damaging inflammation associated with pathogen persistence during infectious colitis. This information is of interest in development of host defense peptides (either alone or in combination with reduced doses of antibiotics) as antimicrobial and immunomodulatory therapeutics for controlling infectious colitis.
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Affiliation(s)
- Graham A D Blyth
- Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Liam Connors
- Bachelor of Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Cristina Fodor
- Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Eduardo R Cobo
- Department of Production Animal Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
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Pothuraju R, Krishn SR, Gautam SK, Pai P, Ganguly K, Chaudhary S, Rachagani S, Kaur S, Batra SK. Mechanistic and Functional Shades of Mucins and Associated Glycans in Colon Cancer. Cancers (Basel) 2020; 12:E649. [PMID: 32168759 PMCID: PMC7139953 DOI: 10.3390/cancers12030649] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 02/28/2020] [Accepted: 03/02/2020] [Indexed: 02/08/2023] Open
Abstract
Mucus serves as the chief protective barrier against pathogenic and mechanical insults in respiratory, gastrointestinal, and urogenital tracts. Altered mucin expression, the major component of mucus, in conjunction with differential glycosylation has been strongly associated with both benign and malignant pathologies of colon. Mucins and their associated glycans arbitrate their impact sterically as well as mechanically by altering molecular and microbial spectrum during pathogenesis. Mucin expression in normal and pathological conditions is regulated by nonspecific (dietary factors and gut microbiota) and specific (epigenetic and transcriptional) modulators. Further, recent studies highlight the impact of altering mucin glycome (cancer-associated carbohydrate antigens including Tn, Sialyl-Tn, Sialyl-Lew A, and Sialyl-Lewis X) on host immunomodulation, antitumor immunity, as well as gut microbiota. In light of emerging literature, the present review article digs into the impact of structural organization and of expressional and glycosylation alteration of mucin family members on benign and malignant pathologies of colorectal cancer.
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Affiliation(s)
- Ramesh Pothuraju
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; (R.P.); (S.R.K.); (S.K.G.); (P.P.); (K.G.); (S.C.); (S.R.); (S.K.)
| | - Shiv Ram Krishn
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; (R.P.); (S.R.K.); (S.K.G.); (P.P.); (K.G.); (S.C.); (S.R.); (S.K.)
| | - Shailendra K. Gautam
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; (R.P.); (S.R.K.); (S.K.G.); (P.P.); (K.G.); (S.C.); (S.R.); (S.K.)
| | - Priya Pai
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; (R.P.); (S.R.K.); (S.K.G.); (P.P.); (K.G.); (S.C.); (S.R.); (S.K.)
| | - Koelina Ganguly
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; (R.P.); (S.R.K.); (S.K.G.); (P.P.); (K.G.); (S.C.); (S.R.); (S.K.)
| | - Sanjib Chaudhary
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; (R.P.); (S.R.K.); (S.K.G.); (P.P.); (K.G.); (S.C.); (S.R.); (S.K.)
| | - Satyanarayana Rachagani
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; (R.P.); (S.R.K.); (S.K.G.); (P.P.); (K.G.); (S.C.); (S.R.); (S.K.)
| | - Sukhwinder Kaur
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; (R.P.); (S.R.K.); (S.K.G.); (P.P.); (K.G.); (S.C.); (S.R.); (S.K.)
| | - Surinder K. Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; (R.P.); (S.R.K.); (S.K.G.); (P.P.); (K.G.); (S.C.); (S.R.); (S.K.)
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68105, USA
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
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12
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Yoo JH, Donowitz M. Intestinal enteroids/organoids: A novel platform for drug discovery in inflammatory bowel diseases. World J Gastroenterol 2019; 25:4125-4147. [PMID: 31435168 PMCID: PMC6700704 DOI: 10.3748/wjg.v25.i30.4125] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 06/14/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
The introduction of biologics such as anti-tumor necrosis factor (TNF) monoclonal antibodies followed by anti-integrins has dramatically changed the therapeutic paradigm of inflammatory bowel diseases (IBD). Furthermore, a newly developed anti-p40 subunit of interleukin (IL)-12 and IL-23 (ustekinumab) has been recently approved in the United States for patients with moderate to severe Crohn’s disease who have failed treatment with anti-TNFs. However, these immunosuppressive therapeutics which focus on anti-inflammatory mechanisms or immune cells still fail to achieve long-term remission in a significant percentage of patients. This strongly underlines the need to identify novel treatment targets beyond immune suppression to treat IBD. Recent studies have revealed the critical role of intestinal epithelial cells (IECs) in the pathogenesis of IBD. Physical, biochemical and immunologic driven barrier dysfunctions of epithelial cells contribute to the development of IBD. In addition, the recent establishment of adult stem cell-derived intestinal enteroid/organoid culture technology has allowed an exciting opportunity to study human IECs comprising all normal epithelial cells. This long-term epithelial culture model can be generated from endoscopic biopsies or surgical resections and recapitulates the tissue of origin, representing a promising platform for novel drug discovery in IBD. This review describes the advantages of intestinal enteroids/organoids as a research tool for intestinal diseases, introduces studies with these models in IBD, and gives a description of the current status of therapeutic approaches in IBD. Finally, we provide an overview of the current endeavors to identify a novel drug target for IBD therapy based on studies with human enteroids/organoids and describe the challenges in using enteroids/organoids as an IBD model.
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Affiliation(s)
- Jun-Hwan Yoo
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, Seongnam 13496, South Korea
| | - Mark Donowitz
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
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13
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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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14
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Cuperus T, Kraaij MD, Zomer AL, van Dijk A, Haagsman HP. Immunomodulation and effects on microbiota after in ovo administration of chicken cathelicidin-2. PLoS One 2018; 13:e0198188. [PMID: 29870564 PMCID: PMC5988267 DOI: 10.1371/journal.pone.0198188] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Accepted: 05/15/2018] [Indexed: 01/06/2023] Open
Abstract
Host Defense Peptides (HDPs) such as cathelicidins are multifunctional effectors of the innate immune system with both antimicrobial and pleiotropic immunomodulatory functions. Chicken cathelicidin-2 (CATH-2) has multiple immunomodulatory effects in vitro and the D-amino acid analog of this peptide has been shown to partially protect young chicks from a bacterial infection. However, the mechanisms responsible for CATH-2 mediated in vivo protection have not been investigated so far. In this study, D-CATH-2 was administered in ovo and the immune status and microbiota of the chicks were investigated at 7 days posthatch to elucidate the in vivo mechanisms of the peptide. In three consecutive studies, no effects on numbers and functions of immune cells were found and only small changes were seen in gene expression of Peripheral Blood Mononuclear Cells (PBMCs). In two studies, intestinal microbiota composition was determined which was highly variable, suggesting that it was strongly influenced by environmental factors. In both studies, in ovo D-CATH-2 treatment caused significant reduction of Ruminococcaceae and Butyricicoccus in the cecum and Escherichia/Shigella in both ileum and cecum. In conclusion, this study shows that, in the absence of an infectious stimulus, in ovo administration of a CATH-2 analog alters the microbiota composition but does not affect the chicks' immune system posthatch.
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Affiliation(s)
- Tryntsje Cuperus
- Division of Molecular Host Defence, Department of Infectious Diseases & Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Marina D. Kraaij
- Division of Molecular Host Defence, Department of Infectious Diseases & Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Aldert L. Zomer
- Division Clinical Infectiology, Department of Infectious Diseases & Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Albert van Dijk
- Division of Molecular Host Defence, Department of Infectious Diseases & Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Henk P. Haagsman
- Division of Molecular Host Defence, Department of Infectious Diseases & Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
- * E-mail:
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15
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Shen J, Xiao Z. Cathelicidin in Gastrointestinal Disorders. ANTIMICROBIAL PEPTIDES IN GASTROINTESTINAL DISEASES 2018:61-76. [DOI: 10.1016/b978-0-12-814319-3.00004-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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16
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Li Y, Chu X, Liu C, Huang W, Yao Y, Xia Y, Sun P, Long Q, Feng X, Li K, Yang X, Bai H, Sun W, Ma Y. Exogenous murine antimicrobial peptide CRAMP significantly exacerbates Ovalbumin-induced airway inflammation but ameliorates oxazolone-induced intestinal colitis in BALB/c mice. Hum Vaccin Immunother 2017; 14:146-158. [PMID: 29049008 DOI: 10.1080/21645515.2017.1386823] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Cathelicidin has been reported to be multifunctional. The current study aimed to investigate the influences of exogenous cathelicidin-related antimicrobial peptide (CRAMP) on inflammatory responses in different disease models. In OVA-induced allergic airway inflammation, CRAMP significantly enhanced the infiltration of inflammatory cells and accumulation of proinflammatory Th2 cytokine IL-13 and IL-33 in bronchial alveolar lavage fluid (BALF), exacerbated lung tissue inflammation and airway goblet cell hyperplasia, and elevated OVA-specific IgE level in serum. In oxazolone-induced intestinal colitis, the expression levels of CRAMP and its receptor FPR2 significantly increased in comparison with those of TNBS-induced mice, vesicle and normal controls. Exogenous CRAMP significantly prevented the development of ulcerative colitis, evidenced by improved body weight regain, decreased colons weight/length ratio, elevated epithelial integrity, and ameliorated colon tissue inflammation. In addition, pro-inflammatory cytokines TNF-α, IL-1β, IL-4 and IL-13, as well as chemokines CXCL2 and CXCL5 for neutrophils recruitment were significantly decreased in CRAMP-treated mice, and epithelial repair-related factors MUC2 and Claudin1 were increased, determined by real time-PCR and ELISAs. The results indicated that although CRAMP has pro-inflammatory effects in airway, local application of exogenous CRAMP might be a potential approach for the treatment of ulcerative colitis.
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Affiliation(s)
- Yang Li
- a Laboratory of Molecular Immunology , Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Diseases , Kunming , China
| | - Xiaojie Chu
- a Laboratory of Molecular Immunology , Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Diseases , Kunming , China
| | - Cunbao Liu
- a Laboratory of Molecular Immunology , Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Diseases , Kunming , China
| | - Weiwei Huang
- a Laboratory of Molecular Immunology , Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Diseases , Kunming , China
| | - Yufeng Yao
- a Laboratory of Molecular Immunology , Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Diseases , Kunming , China
| | - Ye Xia
- a Laboratory of Molecular Immunology , Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Diseases , Kunming , China
| | - Pengyan Sun
- a Laboratory of Molecular Immunology , Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Diseases , Kunming , China
| | - Qiong Long
- a Laboratory of Molecular Immunology , Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Diseases , Kunming , China
| | - Xuejun Feng
- a Laboratory of Molecular Immunology , Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Diseases , Kunming , China
| | - Kui Li
- a Laboratory of Molecular Immunology , Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Diseases , Kunming , China
| | - Xu Yang
- a Laboratory of Molecular Immunology , Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Diseases , Kunming , China
| | - Hongmei Bai
- a Laboratory of Molecular Immunology , Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Diseases , Kunming , China
| | - Wenjia Sun
- a Laboratory of Molecular Immunology , Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Diseases , Kunming , China
| | - Yanbing Ma
- a Laboratory of Molecular Immunology , Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Diseases , Kunming , China
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17
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Paparo L, Aitoro R, Nocerino R, Fierro C, Bruno C, Canani RB. Direct effects of fermented cow's milk product with Lactobacillus paracasei CBA L74 on human enterocytes. Benef Microbes 2017; 9:165-172. [PMID: 29065709 DOI: 10.3920/bm2017.0038] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Cow's milk fermented with Lactobacillus paracasei CBA L74 (FM-CBAL74) exerts a preventive effect against infectious diseases in children. We evaluated if this effect is at least in part related to a direct modulation of non-immune and immune defence mechanisms in human enterocytes. Human enterocytes (Caco-2) were stimulated for 48 h with FM-CBAL74 at different concentrations. Cell growth was assessed by colorimetric assay; cell differentiation (assessed by lactase expression), tight junction proteins (zonula occludens1 and occludin), mucin 2, and toll-like receptor (TRL) pathways were analysed by real-time PCR; innate immunity peptide synthesis, beta-defensin-2 (HBD-2) and cathelicidin (LL-37) were evaluated by ELISA. Mucus layer thickness was analysed by histochemistry. FMCBA L74 stimulated cell growth and differentiation, tight junction proteins and mucin 2 expression, and mucus layer thickness in a dose-dependent fashion. A significant stimulation of HBD-2 and LL-37 synthesis, associated with a modulation of TLR pathway, was also observed. FM-CBAL74 regulates non-immune and immune defence mechanisms through a direct interaction with the enterocytes. These effects could be involved in the preventive action against infectious diseases demonstrated by this fermented product in children.
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Affiliation(s)
- L Paparo
- 1 Department of Translational Medical Science, University of Naples 'Federico II', via S. Pansini 5, 80131 Naples, Italy
| | - R Aitoro
- 1 Department of Translational Medical Science, University of Naples 'Federico II', via S. Pansini 5, 80131 Naples, Italy
| | - R Nocerino
- 1 Department of Translational Medical Science, University of Naples 'Federico II', via S. Pansini 5, 80131 Naples, Italy
| | - C Fierro
- 1 Department of Translational Medical Science, University of Naples 'Federico II', via S. Pansini 5, 80131 Naples, Italy
| | - C Bruno
- 1 Department of Translational Medical Science, University of Naples 'Federico II', via S. Pansini 5, 80131 Naples, Italy
| | - R Berni Canani
- 1 Department of Translational Medical Science, University of Naples 'Federico II', via S. Pansini 5, 80131 Naples, Italy.,2 European Laboratory for the Investigation of Food-Induced Diseases, University of Naples 'Federico II', via S. Pansini 5, 80131 Naples, Italy.,3 CEINGE Advanced Biotechnologies, University of Naples 'Federico II', via S. Pansini 5, 80131 Naples, Italy
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18
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Wong CCM, Zhang L, Wu WKK, Shen J, Chan RLY, Lu L, Hu W, Li MX, Li LF, Ren SX, Li YF, Li J, Cho CH. Cathelicidin-encoding Lactococcus lactis promotes mucosal repair in murine experimental colitis. J Gastroenterol Hepatol 2017; 32:609-619. [PMID: 27470075 DOI: 10.1111/jgh.13499] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Revised: 06/22/2016] [Accepted: 07/08/2016] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIM The preventive effect of intrarectal administration of mouse cathelicidin (mCRAMP) and oral administration of mCRAMP-encoding Lactococcus lactis (N4I) has been shown in murine experimental colitis. It is pivotal to understand the ability of N4I whether it can promote mucosal repair in existing colitis. METHODS Mice with dextran sulfate sodium-induced ulcerative colitis (UC) were treated orally with L. lactis or its transformed strain with or without nisin induction. The body weight, clinical symptoms, and histological changes of colonic tissues were determined. Sulfasalazine was used as a reference drug. Young adult mouse colon cells were used to further elucidate the direct action and possible mechanisms of mCRAMP to promote colonic wound repair. RESULTS Results showed that N4I could improve the clinical symptoms, maintain crypt integrity and preserve mucus-secreting layer in colitis animals. The preparation also could prevent cell death and promote cell proliferation. In contrast, effective dose of sulfasalazine only alleviated clinical symptoms but not the mucosal damage and repair in the colon. In vitro study further showed that mCRAMP could directly promote wound repair by accelerating cell migration but not cell proliferation through the GPCR/MAPK pathway. CONCLUSIONS mCRAMP-encoding L. lactis could be a potential therapeutic preparation better than the traditional anti-inflammatory agent in the treatment of UC.
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Affiliation(s)
- Clover C M Wong
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Lin Zhang
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.,Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, China.,Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - William K K Wu
- Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, China.,Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Ruby L Y Chan
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Lan Lu
- Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu, China
| | - Wei Hu
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Ming X Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Long F Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Shun X Ren
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Yi F Li
- Central Laboratory, Affiliated Nanshan Hospital, Guangdong Medical College, Shenzhen, Guangdong, 518052, China
| | - Jiang Li
- Department of Clinical Laboratory, Affiliated Nanshan Hospital, Guangdong Medical College, Shenzhen, Guangdong, 518052, China
| | - Chi H Cho
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
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19
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MUC2 Mucin and Butyrate Contribute to the Synthesis of the Antimicrobial Peptide Cathelicidin in Response to Entamoeba histolytica- and Dextran Sodium Sulfate-Induced Colitis. Infect Immun 2017; 85:IAI.00905-16. [PMID: 28069814 DOI: 10.1128/iai.00905-16] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Accepted: 12/21/2016] [Indexed: 12/14/2022] Open
Abstract
Embedded in the colonic mucus are cathelicidins, small cationic peptides secreted by colonic epithelial cells. Humans and mice have one cathelicidin-related antimicrobial peptide (CRAMP) each, LL-37/hCAP-18 and Cramp, respectively, with related structure and functions. Altered production of MUC2 mucin and antimicrobial peptides is characteristic of intestinal amebiasis. The interactions between MUC2 mucin and cathelicidins in conferring innate immunity against Entamoeba histolytica are not well characterized. In this study, we quantified whether MUC2 expression and release could regulate the expression and secretion of cathelicidin LL-37 in colonic epithelial cells and in the colon. The synthesis of LL-37 was enhanced with butyrate (a product of bacterial fermentation) and interleukin-1β (IL-1β) (a proinflammatory cytokine in colitis) in the presence of exogenously added purified MUC2. The LL-37 responses to butyrate and IL-1β were higher in high-MUC2-producing cells than in lentivirus short hairpin RNA (shRNA) MUC2-silenced cells. Activation of cyclic adenylyl cyclase (AMP) and mitogen-activated protein kinase (MAPK) signaling pathways was necessary for the simultaneous expression of MUC2 and cathelicidins. In Muc2 mucin-deficient (Muc2-/-) mice, murine cathelicidin (Cramp) was significantly reduced compared to that in Muc2+/- and Muc2+/+ littermates. E. histolytica-induced acute inflammation in colonic loops stimulated high levels of cathelicidin in Muc2+/+ but not in Muc2-/- littermates. In dextran sodium sulfate (DSS)-induced colitis in Muc2+/+ mice, which depletes the mucus barrier and goblet cell mucin, Cramp expression was significantly enhanced during restitution. These studies demonstrate regulatory mechanisms between MUC2 and cathelicidins in the colonic mucosa where an intact mucus barrier is essential for expression and secretion of cathelicidins in response to E. histolytica- and DSS-induced colitis.
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20
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Novel peptides derived from α s1 -casein with opioid activity and mucin stimulatory effect on HT29-MTX cells. J Funct Foods 2016. [DOI: 10.1016/j.jff.2016.06.023] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
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21
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Abstract
Human cathelicidin LL-37, the only member of the cathelicidin family of host defense peptides expressed in humans, plays a crucial role in host defense against pathogen invasion, as well as in regulating the functions of anti-inflammation, antitumorigenesis, and tissue repair. It is primarily produced by phagocytic leukocytes and epithelial cells, and mediates a wide range of biological responses. Emerging evidence from several studies indicates that LL-37 plays a prominent and complex role in inflammatory bowel disease (IBD). Although overexpression of LL-37 has been implicated in the inflamed and noninflamed colon mucosa in patients with ulcerative colitis, LL-37 expression was not changed in the inflamed or noninflamed colon or ileal mucosa in patients with Crohn's disease. Furthermore, studies in animal models and human patients further characterized the protective effect of cathelicidins both in ulcerative colitis and Crohn's disease. These data suggest the intricate functions of LL-37 in IBD. They will also create many strategies and opportunities for therapeutic intervention in IBD in the future. This review aims to elucidate the structure and bioactivity of LL-37 and also discuss the recent progress in understanding the relationship between LL-37 and IBD.
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22
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Abstract
Research in the past decade has greatly expanded our understanding of the pathogenesis of inflammatory bowel disease, which includes Crohn's disease and ulcerative colitis. In addition to the sophisticated network of immune response, the epithelial layer lining the mucosa has emerged as an essential player in the development and persistence of intestinal inflammation. As the frontline of numerous environmental insults in the gut, the intestinal epithelial cells are subject to various cellular stresses. In eukaryotic cells, disturbance of endoplasmic reticulum homeostasis may lead to the accumulation of unfolded and misfolded proteins in the ER lumen, a condition called ER stress. This cellular process activates the unfolded protein response, which functions to enhance the ER protein folding capacity, alleviates the burden of protein synthesis and maturation, and activates ER-associated protein degradation. Paneth and goblet cells, 2 secretory epithelial populations in the gut, are particularly sensitive to ER stress on environmental or genetic disturbances. Recent studies suggested that epithelial ER stress may contribute to the pathogenesis of Crohn's disease and ulcerative colitis by compromising protein secretion, inducing epithelial cell apoptosis and activating proinflammatory response in the gut. Our knowledge of ER stress in intestinal epithelial function may open avenue to new inflammatory bowel disease therapies by targeting the ER protein folding homeostasis in the cells lining the intestinal mucosa.
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Abstract
The large number of intestinal microorganisms, which exceeds the total number of human cells by ten folds, alludes to a significant contribution to human health. This is vivid in enteric and some systemic diseases emanating from disruption of the microbiota. As life style keeps shifting towards disruption of the microbiota in most societies worldwide, interest in the contribution of the microbiota to gut health has grown enormously. Many studies have been conducted to elucidate the exact contribution of the microbiota to human health. The knowledge gained from these studies indicates that the microbiota interacts with the intestinal milieu to maintain gut health. In this review, the crosstalk of microbiota with the intestinal physicochemical barrier pivotal to the gut innate immunity is highlighted. In particular, the review focuses on the role of the microbiota on competitive exclusion of pathogens, intestinal pH, epithelial mechanical barrier integrity, apical actin cytoskeleton, antimicrobial peptides, and the mucus layer. Understanding this microbe-host relationship will provide useful insight into overcoming some diseases related to the disruption of the host microbiota.
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Affiliation(s)
- J J Malago
- Department of Veterinary Pathology, Faculty of Veterinary Medicine, Sokoine University of Agriculture, P.O. Box 3203, Chuo Kikuu, Morogoro, Tanzania
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24
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Zhang L, Wu WKK, Gallo RL, Fang EF, Hu W, Ling TKW, Shen J, Chan RLY, Lu L, Luo XM, Li MX, Chan KM, Yu J, Wong VWS, Ng SC, Wong SH, Chan FKL, Sung JJY, Chan MTV, Cho CH. Critical Role of Antimicrobial Peptide Cathelicidin for Controlling Helicobacter pylori Survival and Infection. THE JOURNAL OF IMMUNOLOGY 2016; 196:1799-1809. [DOI: 10.4049/jimmunol.1500021] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Abstract
Abstract
The antimicrobial peptide cathelicidin is critical for protection against different kinds of microbial infection. This study sought to elucidate the protective action of cathelicidin against Helicobacter pylori infection and its associated gastritis. Exogenous cathelicidin was found to inhibit H. pylori growth, destroy the bacteria biofilm, and induce morphological alterations in H. pylori membrane. Additionally, knockdown of endogenous cathelicidin in human gastric epithelial HFE-145 cells markedly increased the intracellular survival of H. pylori. Consistently, cathelicidin knockout mice exhibited stronger H. pylori colonization, higher expression of proinflammatory cytokines IL-6, IL-1β, and ICAM1, and lower expression of the anti-inflammatory cytokine IL-10 in the gastric mucosa upon H. pylori infection. In wild-type mice, H. pylori infection also stimulated gastric epithelium-derived cathelicidin production. Importantly, pretreatment with bioengineered Lactococcus lactis that actively secretes cathelicidin significantly increased mucosal cathelicidin levels and reduced H. pylori infection and the associated inflammation. Moreover, cathelicidin strengthened the barrier function of gastric mucosa by stimulating mucus synthesis. Collectively, these findings indicate that cathelicidin plays a significant role as a potential natural antibiotic for H. pylori clearance and a therapeutic agent for chronic gastritis.
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Affiliation(s)
- Lin Zhang
- *Institute of Digestive Diseases and State Key Laboratory of Digestive Diseases, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China
- †Department of Medicine and Therapeutics, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China
- ‡CUHK Shenzhen Research Institute, Shenzhen 518057, China
| | - William K. K. Wu
- *Institute of Digestive Diseases and State Key Laboratory of Digestive Diseases, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China
- ‡CUHK Shenzhen Research Institute, Shenzhen 518057, China
- §Department of Anesthesia and Intensive Care, Chinese University of Hong Kong, Hong Kong, China
| | - Richard L. Gallo
- ¶Division of Dermatology, University of California, San Diego, La Jolla, CA 92093
| | - Evandro F. Fang
- ‖Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224
| | - Wei Hu
- #School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China; and
| | - Thomas K. W. Ling
- **Department of Microbiology, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, China
| | - Jing Shen
- #School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China; and
| | - Ruby L. Y. Chan
- #School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China; and
| | - Lan Lu
- #School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China; and
| | - Xiao M. Luo
- #School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China; and
| | - Ming X. Li
- #School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China; and
| | - Kam M. Chan
- #School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China; and
| | - Jun Yu
- *Institute of Digestive Diseases and State Key Laboratory of Digestive Diseases, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China
- †Department of Medicine and Therapeutics, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China
- ‡CUHK Shenzhen Research Institute, Shenzhen 518057, China
| | - Vincent W. S. Wong
- *Institute of Digestive Diseases and State Key Laboratory of Digestive Diseases, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China
- †Department of Medicine and Therapeutics, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China
| | - Siew C. Ng
- *Institute of Digestive Diseases and State Key Laboratory of Digestive Diseases, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China
- †Department of Medicine and Therapeutics, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China
| | - Sunny H. Wong
- *Institute of Digestive Diseases and State Key Laboratory of Digestive Diseases, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China
- †Department of Medicine and Therapeutics, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China
- ‡CUHK Shenzhen Research Institute, Shenzhen 518057, China
| | - Francis K. L. Chan
- *Institute of Digestive Diseases and State Key Laboratory of Digestive Diseases, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China
- †Department of Medicine and Therapeutics, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China
- ‡CUHK Shenzhen Research Institute, Shenzhen 518057, China
| | - Joseph J. Y. Sung
- *Institute of Digestive Diseases and State Key Laboratory of Digestive Diseases, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China
- †Department of Medicine and Therapeutics, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China
- ‡CUHK Shenzhen Research Institute, Shenzhen 518057, China
| | - Matthew T. V. Chan
- §Department of Anesthesia and Intensive Care, Chinese University of Hong Kong, Hong Kong, China
| | - Chi H. Cho
- #School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China; and
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Sharifi A, Hosseinzadeh-Attar MJ, Vahedi H, Nedjat S. A randomized controlled trial on the effect of vitamin D3 on inflammation and cathelicidin gene expression in ulcerative colitis patients. Saudi J Gastroenterol 2016; 22:316-23. [PMID: 27488327 PMCID: PMC4991203 DOI: 10.4103/1319-3767.187606] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is an intestinal chronic inflammatory condition and includes Crohn's disease (CD) and ulcerative colitis (UC). It has been proposed that Vitamin D supplementation may have a beneficial role in IBD. AIM To characterize the effects of Vitamin D on cathelicidin (hCAP/LL37) gene expression, ESR, and serum hs-CRP levels. MATERIALS AND METHODS Ninety UC patients on remission were randomized to receive 300,000 IU intramuscular Vitamin D or 1 mL normal saline as placebo, respectively. Before and 90 days after intervention, serum levels of 25 (OH)-Vitamin D3, PTH, Calcium, ESR, and hs-CRP were measured. Cathelicidin gene expression was also quantified using qRT-PCR. RESULTS Baseline serum 25-OH-Vitamin D3 levels were not different between the two groups and after intervention, increased only in Vitamin D group (P < 0.001). Hs-CRP levels were lower in Vitamin D group after intervention (Before: 3.43 ± 3.47 vs 3.86 ± 3.55 mg/L, P = 0.56; after: 2.31 ± 2.25 vs 3.90 ± 3.97 mg/L, P= 0.023). ESR decreased significantly in Vitamin D group (Before: 12.4 ± 6.1 vs 12.1 ± 5.3 mm/h, P= 0.77; after: 6.7 ± 4.5 vs 11.4 ± 5.5 mm/h, P< 0.001). The mean fold change in hCAP18 gene expression in Vitamin D group was significantly higher than placebo group. (Mean ± SD: 3.13 ± 2.56 vs 1.09 ± 0.56; median ± interquartile range: 2.17 ± 3.81 vs 0.87 ± 0.53, P< 0.001). CONCLUSION Decreases in ESR and hs-CRP levels and increase in LL37 gene expression support the hypothesis that Vitamin D supplementation may have a beneficial role in UC patients.
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Affiliation(s)
- Amrollah Sharifi
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Javad Hosseinzadeh-Attar
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran,Address for correspondence: Dr. Mohammad Javad Hosseinzadeh-Attar, No: 44, Hojjat-dost Alley, Naderi St., Keshavarz Blvd, Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran. E-mail:
| | - Homayoon Vahedi
- Digestive Disease Research Center, Digestive Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Saharnaz Nedjat
- Department of Epidemiology and Biostatistics, School of Public Health, Knowledge Utilization Research Center, Tehran University of Medical Sciences, Tehran, Iran
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Robinson K, Deng Z, Hou Y, Zhang G. Regulation of the Intestinal Barrier Function by Host Defense Peptides. Front Vet Sci 2015; 2:57. [PMID: 26664984 PMCID: PMC4672242 DOI: 10.3389/fvets.2015.00057] [Citation(s) in RCA: 106] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Accepted: 11/02/2015] [Indexed: 12/17/2022] Open
Abstract
Intestinal barrier function is achieved primarily through regulating the synthesis of mucins and tight junction (TJ) proteins, which are critical for maintaining optimal gut health and animal performance. An aberrant expression of TJ proteins results in increased paracellular permeability, leading to intestinal and systemic disorders. As an essential component of innate immunity, host defense peptides (HDPs) play a critical role in mucosal defense. Besides broad-spectrum antimicrobial activities, HDPs promotes inflammation resolution, endotoxin neutralization, wound healing, and the development of adaptive immune response. Accumulating evidence has also indicated an emerging role of HDPs in barrier function and intestinal homeostasis. HDP deficiency in the intestinal tract is associated with barrier dysfunction and dysbiosis. Several HDPs were recently shown to enhance mucosal barrier function by directly inducing the expression of multiple mucins and TJ proteins. Consistently, dietary supplementation of HDPs often leads to an improvement in intestinal morphology, production performance, and feed efficiency in livestock animals. This review summarizes current advances on the regulation of epithelial integrity and homeostasis by HDPs. Major signaling pathways mediating HDP-induced mucin and TJ protein synthesis are also discussed. As an alternative strategy to antibiotics, supplementation of exogenous HDPs or modulation of endogenous HDP synthesis may have potential to improve intestinal barrier function and animal health and productivity.
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Affiliation(s)
- Kelsy Robinson
- Department of Animal Science, Oklahoma State University , Stillwater, OK , USA
| | - Zhuo Deng
- Department of Animal Science, Oklahoma State University , Stillwater, OK , USA
| | - Yongqing Hou
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University , Wuhan , China
| | - Guolong Zhang
- Department of Animal Science, Oklahoma State University , Stillwater, OK , USA ; Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University , Wuhan , China
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Guo FF, Fang JY. Antimicrobial peptide LL-37 and gastrointestinal diseases. Shijie Huaren Xiaohua Zazhi 2014; 22:5454-5459. [DOI: 10.11569/wcjd.v22.i35.5454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Host defense antimicrobial peptides are key components of the human innate immunity that plays an indispensable role in human health. Cathelicidins are a family of antimicrobial peptides in mammals. LL-37, the only cathelicidin described so far in humans, plays a critical role in host defense against pathogen invasion, as well as regulating the functions of anti-inflammation, anti-tumorigenesis and tissue repair. Emerging evidence suggests that LL-37 is related to several kinds of gastrointestinal diseases, and its application to the diagnosis and treatment of gastrointestinal diseases has become a growing concern. This review aims to elucidate the structure and biological activity of LL-37 and discuss the recent progress in understanding the relationship between LL-37 and gastrointestinal diseases.
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Heimlich DR, Harrison A, Mason KM. Host Antimicrobial Peptides in Bacterial Homeostasis and Pathogenesis of Disease. Antibiotics (Basel) 2014; 3:645-76. [PMID: 26029470 PMCID: PMC4448142 DOI: 10.3390/antibiotics3040645] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2014] [Revised: 11/05/2014] [Accepted: 11/05/2014] [Indexed: 01/10/2023] Open
Abstract
Innate immune responses function as a first line of host defense against the development of bacterial infection, and in some cases to preserve the sterility of privileged sites in the human host. Bacteria that enter these sites must counter host responses for colonization. From the host's perspective, the innate immune system works expeditiously to minimize the bacterial threat before colonization and subsequent dysbiosis. The multifactorial nature of disease further challenges predictions of how each independent variable influences bacterial pathogenesis. From bacterial colonization to infection and through disease, the microenvironments of the host are in constant flux as bacterial and host factors contribute to changes at the host-pathogen interface, with the host attempting to eradicate bacteria and the bacteria fighting to maintain residency. A key component of this innate host response towards bacterial infection is the production of antimicrobial peptides (AMPs). As an early component of the host response, AMPs modulate bacterial load and prevent establishment of infection. Under quiescent conditions, some AMPs are constitutively expressed by the epithelium. Bacterial infection can subsequently induce production of other AMPs in an effort to maintain sterility, or to restrict colonization. As demonstrated in various studies, the absence of a single AMP can influence pathogenesis, highlighting the importance of AMP concentration in maintaining homeostasis. Yet, AMPs can increase bacterial virulence through the co-opting of the peptides or alteration of bacterial virulence gene expression. Further, bacterial factors used to subvert AMPs can modify host microenvironments and alter colonization of the residential flora that principally maintain homeostasis. Thus, the dynamic interplay between host defense peptides and bacterial factors produced to quell peptide activity play a critical role in the progression and outcome of disease.
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Affiliation(s)
- Derek R. Heimlich
- The Research Institute at Nationwide Children’s Center for Microbial Pathogenesis, Columbus, OH 43205, USA; E-Mails: (D.R.H.); (A.H.)
| | - Alistair Harrison
- The Research Institute at Nationwide Children’s Center for Microbial Pathogenesis, Columbus, OH 43205, USA; E-Mails: (D.R.H.); (A.H.)
| | - Kevin M. Mason
- The Research Institute at Nationwide Children’s Center for Microbial Pathogenesis, Columbus, OH 43205, USA; E-Mails: (D.R.H.); (A.H.)
- The Ohio State University College of Medicine, Department of Pediatrics, Columbus, OH 43205, USA
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29
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Yang L, Yan Y. Protein kinases are potential targets to treat inflammatory bowel disease. World J Gastrointest Pharmacol Ther 2014; 5:209-217. [PMID: 25374761 PMCID: PMC4218950 DOI: 10.4292/wjgpt.v5.i4.209] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2013] [Revised: 04/05/2014] [Accepted: 07/29/2014] [Indexed: 02/06/2023] Open
Abstract
Protein kinases play a crucial role in the pathogenesis of inflammatory bowel disease (IBD), the two main forms of which are ulcerative colitis and Crohn’s disease. In this article, we will review the mechanisms of involvement of protein kinases in the pathogenesis of and intervention against IBD, in terms of their effects on genetics, microbiota, mucous layer and tight junction, and the potential of protein kinases as therapeutic targets against IBD.
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30
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Lu L, Chan RLY, Luo XM, Wu WKK, Shin VY, Cho CH. Animal models of gastrointestinal inflammation and cancer. Life Sci 2014; 108:1-6. [PMID: 24825611 DOI: 10.1016/j.lfs.2014.04.036] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Revised: 04/20/2014] [Accepted: 04/29/2014] [Indexed: 02/06/2023]
Abstract
Inflammation and cancer are the two major disorders in the gastrointestinal tract. They are causally related in their pathogenesis. It is important to study animal models' causal relationship and, in particular, to discover new therapeutic agents for such diseases. There are several criteria for these models in order to make them useful in better understanding the etiology and treatment of the said diseases in humans. In this regard, animal models should be similar as possible to human diseases and also be easy to produce and reproducible and also economic to allow a continuous replication in different laboratories. In this review, we summarize the various animal models for inflammatory and cancerous disorders in the upper and lower gastrointestinal tract. Experimental approaches are as simple as by giving a single oral dose of alcohol or other noxious agents or by injections of multiple dosages of ulcer inducing agents or by parenteral administration or in drinking water of carcinogens or by modifying the genetic makeups of animals to produce relatively long-term pathological changes in particular organs. With these methods they could induce consistent inflammatory responses or tumorigenesis in the gastrointestinal mucosa. These animal models are widely used in laboratories in understanding the pathogenesis as well as the mechanisms of action for therapeutic agents in the treatment of gastrointestinal inflammation and cancer.
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Affiliation(s)
- L Lu
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Ruby L Y Chan
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - X M Luo
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - William K K Wu
- Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Vivian Y Shin
- Department of Surgery, Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - C H Cho
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
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31
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Kim JM. Antimicrobial proteins in intestine and inflammatory bowel diseases. Intest Res 2014; 12:20-33. [PMID: 25349560 PMCID: PMC4204685 DOI: 10.5217/ir.2014.12.1.20] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2013] [Revised: 10/29/2013] [Accepted: 10/30/2013] [Indexed: 12/21/2022] Open
Abstract
Mucosal surface of the intestinal tract is continuously exposed to a large number of microorganisms. To manage the substantial microbial exposure, epithelial surfaces produce a diverse arsenal of antimicrobial proteins (AMPs) that directly kill or inhibit the growth of microorganisms. Thus, AMPs are important components of innate immunity in the gut mucosa. They are frequently expressed in response to colonic inflammation and infection. Expression of many AMPs, including human β-defensin 2-4 and cathelicidin, is induced in response to invasion of pathogens or enteric microbiota into the mucosal barrier. In contrast, some AMPs, including human α-defensin 5-6 and human β-defensin 1, are constitutively expressed without microbial contact or invasion. In addition, specific AMPs are reported to be associated with inflammatory bowel disease (IBD) due to altered expression of AMPs or development of autoantibodies against AMPs. The advanced knowledge for AMPs expression in IBD can lead to its potential use as biomarkers for disease activity. Although the administration of exogenous AMPs as therapeutic strategies against IBD is still at an early stage of development, augmented induction of endogenous AMPs may be another interesting future research direction for the protective and therapeutic purposes. This review discusses new advances in our understanding of how intestinal AMPs protect against pathogens and contribute to pathophysiology of IBD.
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Affiliation(s)
- Jung Mogg Kim
- Department of Microbiology, Hanyang University College of Medicine, Seoul, Korea
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32
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Martínez-Maqueda D, Miralles B, Ramos M, Recio I. Effect of β-lactoglobulin hydrolysate and β-lactorphin on intestinal mucin secretion and gene expression in human goblet cells. Food Res Int 2013. [DOI: 10.1016/j.foodres.2012.12.029] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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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: 336] [Impact Index Per Article: 28.0] [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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Saxena A, Baliga MS, Ponemone V, Kaur K, Larsen B, Fletcher E, Greene J, Fayad R. Mucus and adiponectin deficiency: role in chronic inflammation-induced colon cancer. Int J Colorectal Dis 2013; 28:1267-79. [PMID: 23474825 PMCID: PMC3961717 DOI: 10.1007/s00384-013-1664-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/02/2013] [Indexed: 02/04/2023]
Abstract
PURPOSE This study aims to define the role of adiponectin (APN) in preventing goblet cell apoptosis and in differentiation of epithelial cells to goblet cell lineage resulting in greater mucus production and hence greater protection from chronic inflammation-induced colon cancer (CICC). METHODS Six- to eight-week-old male APNKO and C57BL/6 (WT) mice were randomly distributed to three treatment groups: DSS, DMH, DSS + DMH and control. Chronic inflammation was induced in DSS and DSS + DMH group by administrating 2 % DSS in drinking water for 5 days followed by 5 days of normal drinking water and this constitutes one DSS cycle. Three cycles of DSS were administered to induce chronic inflammation. Cancer was induced in both APNKO and WT mice in DMH and DSS + DMH groups by intraperitoneal injections of DMH (20 mg/kg body weight) once for DSS + DMH group and once per week for 12 weeks for DMH group. On day 129, the colon tissue was dissected for mucus thickness measurements and for genomic studies. HT29-C1.16E and Ls174T cells were used for several genomic and siRNA studies. RESULTS APNKO mice have more tumors and tumor area in DSS + DMH group than WT mice. APN deficiency downregulated goblet to epithelial cell ratio and enhanced the colonic mucosal erosion with reduced mucus thickness. APN increases Muc2 production with no affect on Muc1 production. APN abated goblet cell apoptosis, while APN deficiency reduced epithelial to goblet cell differentiation. CONCLUSION APN may be involved in reducing the severity of CICC by preventing goblet cell apoptosis and increasing epithelial to goblet cell differentiation.
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Affiliation(s)
- Arpit Saxena
- Center for Colon Cancer Research, University of South Carolina, Columbia, SC 29208, USA
| | | | | | - Kamaljeet Kaur
- Center for Colon Cancer Research, University of South Carolina, Columbia, SC 29208, USA
| | - Bianca Larsen
- Center for Colon Cancer Research, University of South Carolina, Columbia, SC 29208, USA
| | - Emma Fletcher
- Center for Colon Cancer Research, University of South Carolina, Columbia, SC 29208, USA
| | - Jennifer Greene
- Center for Colon Cancer Research, University of South Carolina, Columbia, SC 29208, USA
| | - Raja Fayad
- Center for Colon Cancer Research, University of South Carolina, Columbia, SC 29208, USA
- Arnold School of Public Health, Applied Physiology Division, University of South Carolina, 921 Assembly St. room 403A, Columbia, SC 29208, USA
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Martínez-Maqueda D, Miralles B, Cruz-Huerta E, Recio I. Casein hydrolysate and derived peptides stimulate mucin secretion and gene expression in human intestinal cells. Int Dairy J 2013. [DOI: 10.1016/j.idairyj.2013.03.010] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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36
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Ho S, Pothoulakis C, Koon HW. Antimicrobial peptides and colitis. Curr Pharm Des 2013; 19:40-7. [PMID: 22950497 DOI: 10.2174/13816128130108] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2012] [Accepted: 07/30/2012] [Indexed: 11/22/2022]
Abstract
Antimicrobial peptides (AMPs) are important components of innate immunity. They are often expressed in response to colonic inflammation and infection. Over the last several years, the roles of several antimicrobial peptides have been explored. Gene expression of many AMPs (beta defensin HBD2-4 and cathelicidin) is induced in response to invasion of gut microbes into the mucosal barrier. Some AMPs are expressed in a constitutive manner (alpha defensin HD 5-6 and beta defensin HBD1), while others (defensin and bactericidal/ permeability increasing protein BPI) are particularly associated with Inflammatory Bowel Disease (IBD) due to altered defensin expression or development of autoantibodies against Bactericidal/permeability increasing protein (BPI). Various AMPs have different spectrum and strength of antimicrobial effects. Some may play important roles in modulating the colitis (cathelicidin) while others (lactoferrin, hepcidin) may represent biomarkers of disease activity. The use of AMPs for therapeutic purposes is still at an early stage of development. A few natural AMPs were shown to be able to modulate colitis when delivered intravenously or intracolonically (cathelicidin, elafin and SLPI) in mouse colitis models. New AMPs (synthetic or artificial non-human peptides) are being developed and may represent new therapeutic approaches against colitis. This review discusses the latest research developments in the AMP field with emphasis in innate immunity and pathophysiology of colitis.
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Affiliation(s)
- Samantha Ho
- Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, The University of California Los Angeles, Los Angeles, CA 90095, USA
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Chow JYC, Li ZJ, Kei WK, Cho CH. Cathelicidin a potential therapeutic peptide for gastrointestinal inflammation and cancer. World J Gastroenterol 2013; 19:2731-2735. [PMID: 23687409 PMCID: PMC3653146 DOI: 10.3748/wjg.v19.i18.2731] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2013] [Accepted: 04/04/2013] [Indexed: 02/06/2023] Open
Abstract
Cathelicidins, are host defense peptides synthesized and stored in circulating leukocytes and numerous types of epithelial tissues in particular the gastrointestinal (GI) tract and skin. They have been known for their antimicrobial activities against a variety of microbes. Recently it was discovered that they have other significant biological functions and produce appealing pharmacological actions against inflammation and cancer in the GI tract through defined mechanisms. Experimental evidence shows that these actions could be tissue and disease specific and concentration dependent. This article reviews some of the physiological functions of cathelicidins and also their therapeutic potential in the treatment of inflammation and cancer and also the delivery system for this peptide as targeted therapy for various disorders in the GI tract both in animals and humans.
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Chromek M, Arvidsson I, Karpman D. The antimicrobial peptide cathelicidin protects mice from Escherichia coli O157:H7-mediated disease. PLoS One 2012; 7:e46476. [PMID: 23077510 PMCID: PMC3471911 DOI: 10.1371/journal.pone.0046476] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2012] [Accepted: 08/30/2012] [Indexed: 12/16/2022] Open
Abstract
This study investigated the role of the antimicrobial peptide cathelicidin in Escherichia coli O157:H7 infection and subsequent renal damage. Mouse and human cathelicidin, CRAMP and LL-37, respectively, killed E. coli O157:H7 in vitro. Intestines from healthy wild-type (129/SvJ) and cathelicidin-knock-out (Camp−/−) mice were investigated, showing that cathelicidin-deficient mice had a thinner colonic mucus layer compared with wild-type mice. Wild-type (n = 11) and cathelicidin-knock-out (n = 11) mice were inoculated with E. coli O157:H7. Cathelicidin-deficient animals exhibited higher fecal counts of E. coli O157:H7 and bacteria penetrated the mucus forming attaching-and-effacing lesions to a much higher extent than in wild-type animals. Cathelicidin knock-out mice developed symptoms (9/11) as well as anemia, thrombocytopenia and extensive renal tubular damage while all cathelicidin-producing mice remained asymptomatic with normal laboratory findings. When injected with Shiga toxin intraperitoneally, both murine strains developed the same degree of renal tubular damage and clinical disease indicating that differences in sensitivity to infection between the murine strains were related to the initial intestinal response. In conclusion, cathelicidin substantially influenced the antimicrobial barrier in the mouse colon mucosa. Cathelicidin deficiency lead to increased susceptibility to E. coli O157:H7 infection and subsequent renal damage. Administration of cathelicidin or stimulation of endogenous production may prove to be novel treatments for E. coli O157:H7-induced hemolytic uremic syndrome.
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Affiliation(s)
| | | | - Diana Karpman
- Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden
- * E-mail:
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39
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Martínez-Maqueda D, Miralles B, De Pascual-Teresa S, Reverón I, Muñoz R, Recio I. Food-derived peptides stimulate mucin secretion and gene expression in intestinal cells. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2012; 60:8600-8605. [PMID: 22916966 DOI: 10.1021/jf301279k] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
In this study, the hypothesis that food-derived opioid peptides besides β-casomorphin 7 might modulate the production of mucin via a direct action on epithelial goblet cells was investigated in HT29-MTX cells used as a model of human colonic epithelium. Seven milk whey or casein peptides, a human milk peptide, and a wheat gluten-derived peptide with proved or probable ability to bind μ- or δ-opioid receptors were tested on the cell culture. Significantly increased secretion of mucins was found after exposure to six of the assayed peptides, besides the previously described β-casomorphin 7, as measured by an enzyme-linked lectin assay (ELLA). Human β-casomorphin 5 and α-lactorphin were selected to study the expression of mucin 5AC gene (MUC5AC), the HT29-MTX major secreted mucin gene. α-Lactorphin showed increased expression of MUC5AC from 4 to 24 h (up to 1.6-fold over basal level expression), although differences were statistically different only after 24 h of exposure. However, this increased expression of MUC5AC did not reach significance after cell treatment with human β-casomorphin 5. In conclusion, six food-derived peptides have been identifed with described or probable opioid activity that induce mucin secretion in HT29-MTX cells. Concretely, α-lactorphin is able to up-regulate the expression of the major secreted mucin gene encoded by these cells.
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Cathelicidins in inflammation and tissue repair: Potential therapeutic applications for gastrointestinal disorders. Acta Pharmacol Sin 2010; 31:1118-22. [PMID: 20676121 DOI: 10.1038/aps.2010.117] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Cathelicidins, a family of host defense peptides, are highly expressed during infection, inflammation and wound healing. These peptides not only have broad-spectrum antimicrobial activities, but also modulate inflammation by altering cytokine response and chemoattraction of inflammatory cells in diseased tissues. In this connection, a mouse cathelicidin has been demonstrated to prevent inflammation in the colon through enhancing mucus production and reducing production of pro-inflammatory cytokines. In addition, cathelicidins promote wound healing through stimulation of re-epithelialization and angiogenesis at injured tissues. In an animal model of gastric ulceration, the rat cathelicidin promotes ulcer healing by inducing proliferation of gastric epithelial cells both in vitro and in vivo. In conclusion, cathelicidins represent an important group of effector molecules in the innate immune system that operates a complex integration of inflammation and tissue repair in the gastrointestinal mucosa and other organs.
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Two atypical enteropathogenic Escherichia coli strains induce the production of secreted and membrane-bound mucins to benefit their own growth at the apical surface of human mucin-secreting intestinal HT29-MTX cells. Infect Immun 2010; 78:927-38. [PMID: 20065027 DOI: 10.1128/iai.01115-09] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
In rabbit ligated ileal loops, two atypical enteropathogenic Escherichia coli (aEPEC) strains, 3991-1 and 0421-1, intimately associated with the cell membrane, forming the characteristic EPEC attachment and effacement lesion of the brush border, induced a mucous hypersecretion, whereas typical EPEC (tEPEC) strain E2348/69 did not. Using cultured human mucin-secreting intestinal HT29-MTX cells, we demonstrate that apically aEPEC infection is followed by increased production of secreted MUC2 and MUC5AC mucins and membrane-bound MUC3 and MUC4 mucins. The transcription of the MUC5AC and MUC4 genes was transiently upregulated after aEPEC infection. We provide evidence that the apically adhering aEPEC cells exploit the mucins' increased production since they grew in the presence of membrane-bound mucins, whereas tEPEC did not. The data described herein report a putative new virulence phenomenon in aEPEC.
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Cathelicidin LL-37: a multitask antimicrobial peptide. Arch Immunol Ther Exp (Warsz) 2010; 58:15-25. [PMID: 20049649 DOI: 10.1007/s00005-009-0057-2] [Citation(s) in RCA: 159] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2009] [Accepted: 04/30/2009] [Indexed: 01/07/2023]
Abstract
The antimicrobial peptide LL-37 is the only known member of the cathelicidin family of peptides expressed in humans. LL-37 is a multifunctional host defense molecule essential for normal immune responses to infection and tissue injury. LL-37 peptide is a potent killer of different microorganisms with the ability to prevent immunostimulatory effects of bacterial wall molecules such as lipopolysaccharide and can therefore protect against lethal endotoxemia. Additional reported activities of LL-37 include chemoattractant function, inhibition of neutrophil apoptosis, and stimulation of angiogenesis, tissue regeneration, and cytokine release (e.g. IL-8). Cellular production of LL-37 is affected by multiple factors, including bacterial products, host cytokines, availability of oxygen, and sun exposure through the activation of CAP-18 gene expression by vitamin D(3). At infection sites, the function of LL-37 can be inhibited by charge-driven interactions with DNA and F-actin released from dead neutrophils and other cells lysed as the result of inflammation. A better understanding of LL-37's biological properties is necessary for its possible therapeutic application for immunomodulatory purposes as well as in treating bacterial infection.
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Effects of the cathelicidin LL-37 on intestinal epithelial barrier integrity. ACTA ACUST UNITED AC 2009; 156:104-17. [PMID: 19328825 DOI: 10.1016/j.regpep.2009.03.009] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2009] [Accepted: 03/20/2009] [Indexed: 01/02/2023]
Abstract
The human cathelicidin LL-37 is involved in innate immune responses, angiogenesis and wound healing. Functions in maintenance and re-establishment of intestinal barrier integrity have not been characterized yet. Following direct and indirect stimulation of human colonic HT-29 and Caco-2 cells with LL-37 the cellular viability, rate of apoptosis, proliferation and wound healing were determined. Expression of mucins and growth factors was quantified by real-time PCR and Western blotting. Direct application of LL-37 stimulated migration in Caco-2 cells expressing the proposed LL-37 receptor P2X7. Intestinal epithelial cell (IEC) proliferation was not altered. Indirectly, LL-37 significantly enhanced IEC migration via release of growth factors from subepithelial fibroblasts and IEC. Furthermore, LL-37 induced the expression of protective mucins in IEC and abated tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induced apoptosis in IEC. LL-37 induced signaling is mediated in part by the P2X7 receptor, the epidermal growth factor receptor and the p38 mitogen-activated protein kinase (MAPK). LL-37 contributes to maintenance and re-establishment of the intestinal barrier integrity via direct and indirect pathways. These features, in addition to its known antimicrobial properties, suggest an important role for this peptide in intestinal homeostasis.
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