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Zha H, Zhang H, Zhong J, Wang Y, Liu L, Yu S, Liu Y. Molecular characterization and functional analysis of Collectin-11 from Hexagrammos otakii. FISH & SHELLFISH IMMUNOLOGY 2025; 162:110338. [PMID: 40239931 DOI: 10.1016/j.fsi.2025.110338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Revised: 04/05/2025] [Accepted: 04/14/2025] [Indexed: 04/18/2025]
Abstract
Hexagrammos otakii is an essential economic fish for some coastal cities, but severe and frequent infections have appeared in aquaculture. Previous studies have shown that collectin-11 (CL-11) is a typical soluble pattern recognition receptor capable of recognizing pathogens and initiating the complement cascade by interacting with mannan-binding lectin-associated serine protease-1 (MASP1). Hence, to better understand the functions of CL-11 in Hexagrammos otakii (HoCL-11), we conducted qRT-PCR, LPS and PGN binding, bacterial agglutination, ELISA, and FAR-WESTERN after recombinant expression. As a result, qRT-PCR revealed that the HoCL-11 gene was predominantly expressed in the liver, skin, and ovary tissues of Hexagrammos otakii. Bacterial agglutination and binding assays showed that the recombinant CL-11 protein could recognize various pathogens. ELISA and far-western experiments confirmed that HoCL-11 could bind to MASP1 and MASP2 and may further activate the complement. In conclusion, HoCL-11 is pivotal in teleost Hexagrammos otakii's immune defense, and this study has theoretically supplemented its innate immune mechanism.
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Affiliation(s)
- Haidong Zha
- Marine College, Shandong University (Weihai), Weihai, 264209, China
| | - Haoyue Zhang
- Marine College, Shandong University (Weihai), Weihai, 264209, China
| | - Jinmiao Zhong
- Marine College, Shandong University (Weihai), Weihai, 264209, China
| | - Yujiang Wang
- Weihai Changqing Ocean Science Technology Co., Ltd., Rongcheng, 264300, China
| | - Liyuan Liu
- Weihai Changqing Ocean Science Technology Co., Ltd., Rongcheng, 264300, China
| | - Shanshan Yu
- Marine College, Shandong University (Weihai), Weihai, 264209, China.
| | - Yingying Liu
- Marine College, Shandong University (Weihai), Weihai, 264209, China; Weihai Changqing Ocean Science Technology Co., Ltd., Rongcheng, 264300, China.
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2
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Nguyen PTT, Dinh TT, Tran-Van H. Construction of L-type lectin displaying Saccharomyces cerevisiae for Vibrio parahaemolyticus agglutination. Int Microbiol 2025; 28:1-10. [PMID: 37889383 DOI: 10.1007/s10123-023-00440-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 10/12/2023] [Accepted: 10/19/2023] [Indexed: 10/28/2023]
Abstract
The utilization of Aga1P anchor protein in the display system for expressing heterologous proteins on the surface of Saccharomyces cerevisiae has been shown to be an ideal approach. This system has the ability to improve the expression of target proteins beyond the cell surface, resulting in increased activity and stability of the expression system. Recent studies have demonstrated that a new L-type lectin from Litopenaeus vannamei (LvLTLC1) has been found to possess the capability of agglutinating Vibrio parahaemolyticus, a pathogen responsible for causing acute hepatopancreatic necrosis disease (AHPND) in shrimp. In this study, LvLTLC1 protein was designed to be expressed on the surface of S. cerevisiae via Aga1P anchor. The expression of LvLTLC1 protein on the surface of S. cerevisiae::pYIP-LvLTLC1-Aga1P was confirmed through the use of analytical techniques including SDS-PAGE, dot blot, and fluorescent immunoassay with LvLTC1-specific antibody. Subsequently, the newly generated yeast strain was evaluated for its ability to agglutinate V. parahaemolyticus and A. hydrophila. The obtained results indicated that S. cerevisiae expressing LvLTLC1 protein on its surface had the ability to agglutinate both AHPND-causing V. parahaemolyticus and A. hydrophila. This newly generated yeast strain could be served as a feed supplement for controlling bacteria in general and AHPND in particular.
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Affiliation(s)
- Phuong-Thao Thi Nguyen
- Department of Molecular and Environmental Biotechnology; Laboratory of Biosensors, Faculty of Biology and Biotechnology, University of Science, Ho Chi Minh City, Vietnam
- Laboratory of Molecular Biotechnology, University of Science, Ho Chi Minh City, Vietnam
- Vietnam National University, Ho Chi Minh City, Vietnam
- Faculty of Agriculture and Food Technology, Tien Giang University, My Tho, Vietnam
| | - Thuan-Thien Dinh
- Department of Molecular and Environmental Biotechnology; Laboratory of Biosensors, Faculty of Biology and Biotechnology, University of Science, Ho Chi Minh City, Vietnam
- Laboratory of Molecular Biotechnology, University of Science, Ho Chi Minh City, Vietnam
- Vietnam National University, Ho Chi Minh City, Vietnam
| | - Hieu Tran-Van
- Department of Molecular and Environmental Biotechnology; Laboratory of Biosensors, Faculty of Biology and Biotechnology, University of Science, Ho Chi Minh City, Vietnam.
- Laboratory of Molecular Biotechnology, University of Science, Ho Chi Minh City, Vietnam.
- Vietnam National University, Ho Chi Minh City, Vietnam.
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Dickson KB, Stadnyk AW, Zhou J, Lehmann C. Mucosal Immunity: Lessons from the Lower Respiratory and Small Intestinal Epithelia. Biomedicines 2025; 13:1052. [PMID: 40426880 DOI: 10.3390/biomedicines13051052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2025] [Revised: 04/23/2025] [Accepted: 04/24/2025] [Indexed: 05/29/2025] Open
Abstract
Mucosal epithelia represent a diverse group of tissues that function as a barrier against the external environment and exert a wide variety of tissue-specific secondary functions. This review focuses on the lower respiratory tract and small intestinal epithelia, which serve as two distinct sites within the body with respect to their physiological functions. This review provides an overview of their physiology, including both physiological and mechanical defense systems, and their immune responses, which allow both tissues to tolerate commensal organisms while mounting a response against potential pathogens. By highlighting the commonalities and differences across the two tissue types, opportunities to learn from these tissues emerge, which can inform the development of novel therapeutic strategies that harness the unique properties of mucosal epithelia.
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Affiliation(s)
- Kayle B Dickson
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada
| | - Andrew W Stadnyk
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada
- Department of Pediatrics, Dalhousie University, Halifax, NS B3H 4R2, Canada
| | - Juan Zhou
- Department of Anesthesiology, Pain Management and Perioperative Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada
| | - Christian Lehmann
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada
- Department of Anesthesiology, Pain Management and Perioperative Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada
- Department of Pharmacology, Dalhousie University, Halifax, NS B3H 4R2, Canada
- Department of Physiology and Biophysics, Dalhousie University, Halifax, NS B3H 4R2, Canada
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Okumura R, Takeda K. The role of the mucosal barrier system in maintaining gut symbiosis to prevent intestinal inflammation. Semin Immunopathol 2024; 47:2. [PMID: 39589551 PMCID: PMC11599372 DOI: 10.1007/s00281-024-01026-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 09/29/2024] [Indexed: 11/27/2024]
Abstract
In the intestinal tract, where numerous intestinal bacteria reside, intestinal epithelial cells produce and release various antimicrobial molecules that form a complex barrier on the mucosal surface. These barrier molecules can be classified into two groups based on their functions: those that exhibit bactericidal activity through chemical reactions, such as antimicrobial peptides, and those that physically hinder bacterial invasion, like mucins, which lack bactericidal properties. In the small intestine, where Paneth cells specialize in producing antimicrobial peptides, the chemical barrier molecules primarily inhibit bacterial growth. In contrast, in the large intestine, where Paneth cells are absent, allowing bacterial growth, the primary defense mechanism is the physical barrier, mainly composed of mucus, which controls bacterial movement and prevents their invasion of intestinal tissues. The expression of these barrier molecules is regulated by metabolites produced by bacteria in the intestinal lumen and cytokines produced by immune cells in the lamina propria. This regulation establishes a defense mechanism that adapts to changes in the intestinal environment, such as alterations in gut microbial composition and the presence of pathogenic bacterial infections. Consequently, when the integrity of the gut mucosal barrier is compromised, commensal bacteria and pathogenic microorganisms from outside the body can invade intestinal tissues, leading to conditions such as intestinal inflammation, as observed in cases of inflammatory bowel disease.
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Affiliation(s)
- Ryu Okumura
- Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan
- WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, 565-0871, Japan
- Institute for Open and Transdisciplinary Research Initiative, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Kiyoshi Takeda
- Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan.
- WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, 565-0871, Japan.
- Institute for Open and Transdisciplinary Research Initiative, Osaka University, Suita, Osaka, 565-0871, Japan.
- Center for Infectious Disease Education and Research, Osaka University, Suita, Osaka, 565-0871, Japan.
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Xiao X, Wang J, Ma J, Peng X, Wu S, Chen X, Lu H, Tan C, Fang L, Xiao S. Interferon lambda 4 is a gut antimicrobial protein. Proc Natl Acad Sci U S A 2024; 121:e2409684121. [PMID: 39436662 PMCID: PMC11536128 DOI: 10.1073/pnas.2409684121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Accepted: 09/11/2024] [Indexed: 10/23/2024] Open
Abstract
To withstand complex microbial challenges, the mammalian gut largely depends on the secretion of diverse antimicrobial proteins. Type III interferons (IFNλs) are ordinarily considered inducible antiviral cytokines involved in intestinal immunity. Unlike other IFNλs, we found that newly identified IFNλ4 is an intestinal antibacterial protein. Large amounts of natural IFNλ4 are present in the secretory layer of the intestinal tracts of healthy piglets, which suggests that IFNλ4 is in direct physiological contact with microbial pathogens. We also identified two biochemical functions of mammalian IFNλ4, the induction of bacterial agglutination and direct microbial killing, which are not functions of the other IFNλs. Further mechanistic investigations revealed that after binding to the carbohydrate fraction of lipopolysaccharide, mammalian IFNλ4 self-assembles into bacteria-surrounding nanoparticles that agglutinate bacteria, and that its unique cationic amphiphilic molecular structure facilitates the destruction of bacterial membranes. Our data reveal features of IFNλ4 distinct from those of previously reported IFNλs and suggest that noncanonical IFNλ4 is deeply involved in intestinal immunity, beyond simply cytokine signaling.
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Affiliation(s)
- Xun Xiao
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan430070, China
- The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan430070, China
| | - Jinting Wang
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan430070, China
- The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan430070, China
| | - Jun Ma
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan430070, China
- The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan430070, China
| | - Xuan Peng
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan430070, China
- The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan430070, China
| | - Shengqiang Wu
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan430070, China
- The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan430070, China
| | - Xiaolei Chen
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan430070, China
- The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan430070, China
| | - Hao Lu
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan430070, China
- The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan430070, China
| | - Chen Tan
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan430070, China
- The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan430070, China
| | - Liurong Fang
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan430070, China
- The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan430070, China
| | - Shaobo Xiao
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan430070, China
- The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan430070, China
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6
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You X, Wang L, Wang H, Xu Y, Chen Y, Xu H, Ji X, Ma X, Xu X. Liver abscess induced by intestinal hypervirulent Klebsiella pneumoniae through down-regulation of tryptophan-IPA-IL22 axis. iScience 2024; 27:110849. [PMID: 39429788 PMCID: PMC11490733 DOI: 10.1016/j.isci.2024.110849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 06/08/2024] [Accepted: 08/27/2024] [Indexed: 10/22/2024] Open
Abstract
Hypervirulent Klebsiella pneumoniae (hvKp) is a significant causative agent of invasive hepatic abscess syndrome in Asia, presenting substantial clinical challenges due to its intricate pathogenesis. This study revealed the crucial role of the gut microbiota in fortifying the host's defense against hvKp infection by enhancing interleukin-22 (IL-22), probably through regulating downstream antimicrobial peptides such as Reg3β. In antibiotic-treated mice, we observed that gut microbiota disruption impaired the transformation of tryptophan to indole, a key ligand for the aryl hydrocarbon receptor (AhR), consequently affecting the regulatory functions of IL-22. Our experimental findings revealed that administering rIL-22 or indole propionic acid notably diminished the translocation of hvKp from the intestine to the liver. This research not only underscores the pivotal role of the gut microbiome in modulating tryptophan metabolism and the IL-22 pathway but also highlights its critical function in preventing hvKp migration from the colon to the liver.
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Affiliation(s)
- Xiu You
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Key Laboratory of Laboratory Medical Designated by the Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
- School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Liping Wang
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Key Laboratory of Laboratory Medical Designated by the Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Hong Wang
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Key Laboratory of Laboratory Medical Designated by the Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
- School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Yizheng Xu
- Key Laboratory of Laboratory Medical Designated by the Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
- Department of Clinical Laboratory, Sichuan Orthopedic Hospital, Chengdu, Sichuan 610000, China
| | - Yongzheng Chen
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Key Laboratory of Laboratory Medical Designated by the Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Huizhen Xu
- Key Laboratory of Laboratory Medical Designated by the Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
- School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Xuelian Ji
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Xiangsong Ma
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Xiuyu Xu
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
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7
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Peiffer AL, Dugan AE, Kiessling LL. Soluble Human Lectins at the Host-Microbe Interface. Annu Rev Biochem 2024; 93:565-601. [PMID: 38640018 PMCID: PMC11296910 DOI: 10.1146/annurev-biochem-062917-012322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/21/2024]
Abstract
Human lectins are integral to maintaining microbial homeostasis on the skin, in the blood, and at mucosal barriers. These proteins can recognize microbial glycans and inform the host about its microbial status. In accordance with their roles, their production can vary with tissue type. They also can have unique structural and biochemical properties, and they can influence microbial colonization at sites proximal and distal to their tissue of origin. In line with their classification as innate immune proteins, soluble lectins have long been studied in the context of acute infectious disease, but only recently have we begun to appreciate their roles in maintaining commensal microbial communities (i.e., the human microbiota). This review provides an overview of soluble lectins that operate at host-microbe interfaces, their glycan recognition properties, and their roles in physiological and pathological mechanisms.
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Affiliation(s)
- Amanda L Peiffer
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA;
| | - A E Dugan
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA;
| | - L L Kiessling
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA;
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8
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Kuo CH, Wu LL, Chen HP, Yu J, Wu CY. Direct effects of alcohol on gut-epithelial barrier: Unraveling the disruption of physical and chemical barrier of the gut-epithelial barrier that compromises the host-microbiota interface upon alcohol exposure. J Gastroenterol Hepatol 2024; 39:1247-1255. [PMID: 38509796 DOI: 10.1111/jgh.16539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 02/27/2024] [Accepted: 02/28/2024] [Indexed: 03/22/2024]
Abstract
The development of alcohol-associated diseases is multifactorial, mechanism of which involves metabolic alteration, dysregulated immune response, and a perturbed intestinal host-environment interface. Emerging evidence has pinpointed the critical role of the intestinal host-microbiota interaction in alcohol-induced injuries, suggesting its contribution to disease initiation and development. To maintain homeostasis in the gut, the intestinal mucosa serves as the first-line defense against exogenous factors in the gastrointestinal tract, including dietary contents and the commensal microbiota. The gut-epithelial barrier comprises a physical barrier lined with a single layer of intestinal epithelial cells and a chemical barrier with mucus trapping host regulatory factors and gut commensal bacteria. In this article, we review recent studies pertaining to the disrupted gut-epithelial barrier upon alcohol exposure and examine how alcohol and its metabolism can affect the regulatory ability of intestinal epithelium.
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Affiliation(s)
- Cheng-Hao Kuo
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Clinical Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Li-Ling Wu
- Institute of Physiology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Health Innovation Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Microbiota Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Hsiao-Ping Chen
- Institute of Biomedical Informatics, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Translational Research, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Jun Yu
- Department of Medicine and Therapeutics, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China
| | - Chun-Ying Wu
- Institute of Clinical Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Health Innovation Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Microbiota Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Biomedical Informatics, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Translational Research, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
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9
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Melchior K, Gerner RR, Hossain S, Nuccio SP, Moreira CG, Raffatellu M. IL-22-dependent responses and their role during Citrobacter rodentium infection. Infect Immun 2024; 92:e0009924. [PMID: 38557196 PMCID: PMC11075456 DOI: 10.1128/iai.00099-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 03/06/2024] [Indexed: 04/04/2024] Open
Abstract
The mouse pathogen Citrobacter rodentium is utilized as a model organism for studying infections caused by the human pathogens enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC) and to elucidate mechanisms of mucosal immunity. In response to C. rodentium infection, innate lymphoid cells and T cells secrete interleukin (IL)-22, a cytokine that promotes mucosal barrier function. IL-22 plays a pivotal role in enabling mice to survive and recover from C. rodentium infection, although the exact mechanisms involved remain incompletely understood. Here, we investigated whether particular components of the host response downstream of IL-22 contribute to the cytokine's protective effects during C. rodentium infection. In line with previous research, mice lacking the IL-22 gene (Il22-/- mice) were highly susceptible to C. rodentium infection. To elucidate the role of specific antimicrobial proteins modulated by IL-22, we infected the following knockout mice: S100A9-/- (calprotectin), Lcn2-/- (lipocalin-2), Reg3b-/- (Reg3β), Reg3g-/- (Reg3γ), and C3-/- (C3). All knockout mice tested displayed a considerable level of resistance to C. rodentium infection, and none phenocopied the lethality observed in Il22-/- mice. By investigating another arm of the IL-22 response, we observed that C. rodentium-infected Il22-/- mice exhibited an overall decrease in gene expression related to intestinal barrier integrity as well as significantly elevated colonic inflammation, gut permeability, and pathogen levels in the spleen. Taken together, these results indicate that host resistance to lethal C. rodentium infection may depend on multiple antimicrobial responses acting in concert, or that other IL-22-regulated processes, such as tissue repair and maintenance of epithelial integrity, play crucial roles in host defense to attaching and effacing pathogens.
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Affiliation(s)
- Karine Melchior
- Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, California, USA
- School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara, São Paulo, Brazil
| | - Romana R. Gerner
- Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, California, USA
- School of Life Sciences, ZIEL – Institute for Food and Health, Freising-Weihenstephan, Technical University of Munich, Munich, Germany
- Department of Internal Medicine III, University Hospital rechts der Isar, Technical University of Munich, Munich, Germany
| | - Suzana Hossain
- Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, California, USA
| | - Sean-Paul Nuccio
- Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, California, USA
| | - Cristiano Gallina Moreira
- School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara, São Paulo, Brazil
- Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana, USA
| | - Manuela Raffatellu
- Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, California, USA
- Center for Microbiome Innovation, University of California San Diego, La Jolla, California, USA
- Chiba University-UC San Diego Center for Mucosal Immunology, Allergy, and Vaccines (CU-UCSD cMAV), La Jolla, California, USA
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10
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Muchhala KH, Kallurkar PS, Kang M, Koseli E, Poklis JL, Xu Q, Dewey WL, Fettweis JM, Jimenez NR, Akbarali HI. The role of morphine- and fentanyl-induced impairment of intestinal epithelial antibacterial activity in dysbiosis and its impact on the microbiota-gut-brain axis. FASEB J 2024; 38:e23603. [PMID: 38648368 PMCID: PMC11047137 DOI: 10.1096/fj.202301590rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 03/22/2024] [Accepted: 03/26/2024] [Indexed: 04/25/2024]
Abstract
Recent evidence suggests that chronic exposure to opioid analgesics such as morphine disrupts the intestinal epithelial layer and causes intestinal dysbiosis. Depleting gut bacteria can preclude the development of tolerance to opioid-induced antinociception, suggesting an important role of the gut-brain axis in mediating opioid effects. The mechanism underlying opioid-induced dysbiosis, however, remains unclear. Host-produced antimicrobial peptides (AMPs) are critical for the integrity of the intestinal epithelial barrier as they prevent the pathogenesis of the enteric microbiota. Here, we report that chronic morphine or fentanyl exposure reduces the antimicrobial activity in the ileum, resulting in changes in the composition of bacteria. Fecal samples from morphine-treated mice had increased levels of Akkermansia muciniphila with a shift in the abundance ratio of Firmicutes and Bacteroidetes. Fecal microbial transplant (FMT) from morphine-naïve mice or oral supplementation with butyrate restored (a) the antimicrobial activity, (b) the expression of the antimicrobial peptide, Reg3γ, (c) prevented the increase in intestinal permeability and (d) prevented the development of antinociceptive tolerance in morphine-dependent mice. Improved epithelial barrier function with FMT or butyrate prevented the enrichment of the mucin-degrading A. muciniphila in morphine-dependent mice. These data implicate impairment of the antimicrobial activity of the intestinal epithelium as a mechanism by which opioids disrupt the microbiota-gut-brain axis.
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Affiliation(s)
- Karan H. Muchhala
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States
| | - Prajkta S. Kallurkar
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States
| | - Minho Kang
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States
| | - Eda Koseli
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States
| | - Justin L. Poklis
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States
| | - Qingguo Xu
- Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, United States
| | - William L. Dewey
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States
| | - Jennifer M. Fettweis
- Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States
| | - Nicole R. Jimenez
- Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States
| | - Hamid I. Akbarali
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States
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Forsyth CB, Shaikh M, Engen PA, Preuss F, Naqib A, Palmen BA, Green SJ, Zhang L, Bogin ZR, Lawrence K, Sharma D, Swanson GR, Bishehsari F, Voigt RM, Keshavarzian A. Evidence that the loss of colonic anti-microbial peptides may promote dysbiotic Gram-negative inflammaging-associated bacteria in aging mice. FRONTIERS IN AGING 2024; 5:1352299. [PMID: 38501032 PMCID: PMC10945560 DOI: 10.3389/fragi.2024.1352299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 02/02/2024] [Indexed: 03/20/2024]
Abstract
Introduction: Aging studies in humans and mice have played a key role in understanding the intestinal microbiome and an increased abundance of "inflammaging" Gram-negative (Gn) bacteria. The mechanisms underlying this inflammatory profile in the aging microbiome are unknown. We tested the hypothesis that an aging-related decrease in colonic crypt epithelial cell anti-microbial peptide (AMP) gene expression could promote colonic microbiome inflammatory Gn dysbiosis and inflammaging. Methods: As a model of aging, C57BL/6J mice fecal (colonic) microbiota (16S) and isolated colonic crypt epithelial cell gene expression (RNA-seq) were assessed at 2 months (mth) (human: 18 years old; yo), 15 mth (human: 50 yo), and 25 mth (human: 84 yo). Informatics examined aging-related microbial compositions, differential colonic crypt epithelial cell gene expressions, and correlations between colonic bacteria and colonic crypt epithelial cell gene expressions. Results: Fecal microbiota exhibited significantly increased relative abundances of pro-inflammatory Gn bacteria with aging. Colonic crypt epithelial cell gene expression analysis showed significant age-related downregulation of key AMP genes that repress the growth of Gn bacteria. The aging-related decrease in AMP gene expressions is significantly correlated with an increased abundance in Gn bacteria (dysbiosis), loss of colonic barrier gene expression, and senescence- and inflammation-related gene expression. Conclusion: This study supports the proposed model that aging-related loss of colonic crypt epithelial cell AMP gene expression promotes increased relative abundances of Gn inflammaging-associated bacteria and gene expression markers of colonic inflammaging. These data may support new targets for aging-related therapies based on intestinal genes and microbiomes.
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Affiliation(s)
- Christopher B. Forsyth
- Department of Internal Medicine, Rush University Medical Center, Chicago, IL, United States
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, IL, United States
- Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, IL, United States
| | - Maliha Shaikh
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, IL, United States
| | - Phillip A. Engen
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, IL, United States
| | - Fabian Preuss
- Department of Biological Sciences, University of Wisconsin Parkside, Kenosha, WI, United States
| | - Ankur Naqib
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, IL, United States
- Genomics and Microbiome Core Facility, Rush University Medical Center, Chicago, IL, United States
| | - Breanna A. Palmen
- Department of Biological Sciences, University of Wisconsin Parkside, Kenosha, WI, United States
| | - Stefan J. Green
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, IL, United States
- Genomics and Microbiome Core Facility, Rush University Medical Center, Chicago, IL, United States
| | - Lijuan Zhang
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, IL, United States
| | - Zlata R. Bogin
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, IL, United States
| | - Kristi Lawrence
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, IL, United States
| | - Deepak Sharma
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, IL, United States
| | - Garth R. Swanson
- Department of Internal Medicine, Rush University Medical Center, Chicago, IL, United States
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, IL, United States
- Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, IL, United States
| | - Faraz Bishehsari
- Department of Internal Medicine, Rush University Medical Center, Chicago, IL, United States
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, IL, United States
- Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, IL, United States
| | - Robin M. Voigt
- Department of Internal Medicine, Rush University Medical Center, Chicago, IL, United States
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, IL, United States
- Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, IL, United States
| | - Ali Keshavarzian
- Department of Internal Medicine, Rush University Medical Center, Chicago, IL, United States
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, IL, United States
- Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, IL, United States
- Department of Physiology, Rush University Medical Center, Chicago, IL, United States
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12
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Ra YE, Bang YJ. Balancing Act of the Intestinal Antimicrobial Proteins on Gut Microbiota and Health. J Microbiol 2024; 62:167-179. [PMID: 38630349 DOI: 10.1007/s12275-024-00122-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 02/15/2024] [Accepted: 02/16/2024] [Indexed: 05/15/2024]
Abstract
The human gut houses a diverse and dynamic microbiome critical for digestion, metabolism, and immune development, exerting profound effects on human health. However, these microorganisms pose a potential threat by breaching the gut barrier, entering host tissues, and triggering infections, uncontrolled inflammation, and even sepsis. The intestinal epithelial cells form the primary defense, acting as a frontline barrier against microbial invasion. Antimicrobial proteins (AMPs), produced by these cells, serve as innate immune effectors that regulate the gut microbiome by directly killing or inhibiting microbes. Abnormal AMP production, whether insufficient or excessive, can disturb the microbiome equilibrium, contributing to various intestinal diseases. This review delves into the complex interactions between AMPs and the gut microbiota and sheds light on the role of AMPs in governing host-microbiota interactions. We discuss the function and mechanisms of action of AMPs, their regulation by the gut microbiota, microbial evasion strategies, and the consequences of AMP dysregulation in disease. Understanding these complex interactions between AMPs and the gut microbiota is crucial for developing strategies to enhance immune responses and combat infections within the gut microbiota. Ongoing research continues to uncover novel aspects of this intricate relationship, deepening our understanding of the factors shaping gut health. This knowledge has the potential to revolutionize therapeutic interventions, offering enhanced treatments for a wide range of gut-related diseases.
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Affiliation(s)
- Ye Eun Ra
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
| | - Ye-Ji Bang
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
- Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
- Institute of Infectious Diseases, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
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13
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Yamazaki F, Kobayashi K, Mochizuki J, Sashihara T. Interleukin-22 enhanced the mucosal barrier and inhibited the invasion of Salmonella enterica in human-induced pluripotent stem cell-derived small intestinal epithelial cells. FEMS Microbiol Lett 2024; 371:fnae006. [PMID: 38268488 DOI: 10.1093/femsle/fnae006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 01/10/2024] [Accepted: 01/23/2024] [Indexed: 01/26/2024] Open
Abstract
Human-induced pluripotent stem cell-derived small intestinal epithelial cell (hiPSC-SIEC) monolayers are useful in vitro models for evaluating the gut mucosal barrier; however, their reactivity to cytokines, which are closely related to the regulation of mucosal barrier function, remains unclear. Interleukin (IL)-22 is a cytokine that contributes to regulate the mucosal barrier in the intestinal epithelia. Using microarray and gene set enrichment analysis, we found that hiPSC-SIEC monolayers activate the immune response and enhance the mucosal barrier in response to IL-22. Moreover, hiPSC-SIEC monolayers induced the gene expression of antimicrobials, including the regenerating islet-derived protein 3 family. Furthermore, IL-22 stimulation upregulated Mucin 2 secretion and gene expression of an enzyme that modifies sugar chains, suggesting alteration of the state of the mucus layer of hiPSC-SIEC monolayers. To evaluate its physiological significance, we measured the protective activity against Salmonella enterica subsp. enterica infection in hiPSC-SIEC monolayers and found that prestimulation with IL-22 reduced the number of viable intracellular bacteria. Collectively, these results suggest that hiPSC-SIEC monolayers enhance the mucosal barrier and inhibit infection by pathogenic bacteria in response to IL-22, as previously reported. These results can contribute to the further application of hiPSC-SIECs in evaluating mucosal barriers.
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Affiliation(s)
- Fuka Yamazaki
- Food Microbiology and Function Research Laboratories, R&D Division, Meiji Co., Ltd, 1-29-1 Nanakuni, Hachioji, Tokyo 192-0919, Japan
| | - Kyosuke Kobayashi
- Food Microbiology and Function Research Laboratories, R&D Division, Meiji Co., Ltd, 1-29-1 Nanakuni, Hachioji, Tokyo 192-0919, Japan
| | - Junko Mochizuki
- Food Microbiology and Function Research Laboratories, R&D Division, Meiji Co., Ltd, 1-29-1 Nanakuni, Hachioji, Tokyo 192-0919, Japan
| | - Toshihiro Sashihara
- Food Microbiology and Function Research Laboratories, R&D Division, Meiji Co., Ltd, 1-29-1 Nanakuni, Hachioji, Tokyo 192-0919, Japan
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14
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Li WS, Chen TJ, Lee SW, Yang CC, Tian YF, Kuo YH, Tsai HH, Wu LC, Yeh CF, Shiue YL, Chou CL, Lai HY. REG3A overexpression functions as a negative predictive and prognostic biomarker in rectal cancer patients receiving CCRT. Histol Histopathol 2024; 39:91-104. [PMID: 37042618 DOI: 10.14670/hh-18-615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/13/2023]
Abstract
BACKGROUND Concurrent chemoradiotherapy (CCRT) is suggested before resection surgery in the control of rectal cancer. Unfortunately, treatment outcomes are widely variable and highly patient-specific. Notably, rectal cancer patients with distant metastasis generally have a much lower survival rate. Accordingly, a better understanding of the genetic background of patient cohorts can aid in predicting CCRT efficacy and clinical outcomes for rectal cancer before distant metastasis. METHODS A published transcriptome dataset (GSE35452) (n=46) was utilized to distinguish prospective genes concerning the response to CCRT. We recruited 172 rectal cancer patients, and the samples were collected during surgical resection after CCRT. Immunohistochemical (IHC) staining was performed to evaluate the expression level of regenerating family member 3 alpha (REG3A). Pearson's chi-squared test appraised the relevance of REG3A protein expression to clinicopathological parameters. The Kaplan-Meier method was utilized to generate survival curves, and the log-rank test was performed to compare the survival distributions between two given groups. RESULTS Employing a transcriptome dataset (GSE35452) and focusing on the inflammatory response (GO: 0006954), we recognized that REG3A is the most significantly upregulated gene among CCRT nonresponders (log2 ratio=1.2472, p=0.0079). Following IHC validation, high immunoexpression of REG3A was considerably linked to advanced post-CCRT tumor status (p<0.001), post-CCRT lymph node metastasis (p=0.042), vascular invasion (p=0.028), and low-grade tumor regression (p=0.009). In the multivariate analysis, high immunoexpression of REG3A was independently correlated with poor disease-specific survival (DSS) (p=0.004) and metastasis-free survival (MeFS) (p=0.045). The results of the bioinformatic analysis also supported the idea that REG3A overexpression is implicated in rectal carcinogenesis. CONCLUSION In the current study, we demonstrated that REG3A overexpression is correlated with poor CCRT effectiveness and inferior patient survival in rectal cancer. The predictive and prognostic utility of REG3A expression may direct patient stratification and decision-making more accurately for those patients.
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Affiliation(s)
- Wan-Shan Li
- Department of Pathology, Chi Mei Medical Center, Tainan, Taiwan
- Department of Medical Technology, Chung Hwa University of Medical Technology, Tainan, Taiwan
- Institute of Biomedical Science, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Tzu-Ju Chen
- Department of Medical Technology, Chung Hwa University of Medical Technology, Tainan, Taiwan
- Department of Clinical Pathology, Chi Mei Medical Center, Tainan, Taiwan
| | - Sung-Wei Lee
- Department of Radiation Oncology, Chi Mei Medical Center, Liouying, Taiwan
| | - Ching-Chieh Yang
- Department of Radiation Oncology, Chi Mei Medical Center, Tainan, Taiwan
- Department of Pharmacy, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan
| | - Yu-Feng Tian
- Division of Colon and Rectal Surgery, Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan
| | - Yu-Hsuan Kuo
- Division of Hematology and Oncology, Department of Internal Medicine, Chi-Mei Medical Center, Tainan, Taiwan
- College of Pharmacy and Science, Chia Nan University, Tainan, Taiwan
| | - Hsin-Hwa Tsai
- Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan
- Trans-Omic Laboratory for Precision Medicine, Precision Medicine Center, Chi Mei Medical Center, Tainan, Taiwan
- Department of Laboratory Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Li-Ching Wu
- Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan
- Trans-Omic Laboratory for Precision Medicine, Precision Medicine Center, Chi Mei Medical Center, Tainan, Taiwan
| | - Cheng-Fa Yeh
- Division of General Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan
- Department of Environment Engineering and Science, Chia Nan University of Pharmacy and Science, Tainan, Taiwan
| | - Yow-Ling Shiue
- Institute of Precision Medicine, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Chia-Lin Chou
- Department of Medical Technology, Chung Hwa University of Medical Technology, Tainan, Taiwan
- Division of Colon and Rectal Surgery, Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan.
| | - Hong-Yue Lai
- Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan
- Trans-Omic Laboratory for Precision Medicine, Precision Medicine Center, Chi Mei Medical Center, Tainan, Taiwan
- Department of Pharmacology, School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan.
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15
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Solov'eva TF, Bakholdina SI, Naberezhnykh GA. Host Defense Proteins and Peptides with Lipopolysaccharide-Binding Activity from Marine Invertebrates and Their Therapeutic Potential in Gram-Negative Sepsis. Mar Drugs 2023; 21:581. [PMID: 37999405 PMCID: PMC10672452 DOI: 10.3390/md21110581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 10/16/2023] [Accepted: 10/30/2023] [Indexed: 11/25/2023] Open
Abstract
Sepsis is a life-threatening complication of an infectious process that results from the excessive and uncontrolled activation of the host's pro-inflammatory immune response to a pathogen. Lipopolysaccharide (LPS), also known as endotoxin, which is a major component of Gram-negative bacteria's outer membrane, plays a key role in the development of Gram-negative sepsis and septic shock in humans. To date, no specific and effective drug against sepsis has been developed. This review summarizes data on LPS-binding proteins from marine invertebrates (ILBPs) that inhibit LPS toxic effects and are of interest as potential drugs for sepsis treatment. The structure, physicochemical properties, antimicrobial, and LPS-binding/neutralizing activity of these proteins and their synthetic analogs are considered in detail. Problems that arise during clinical trials of potential anti-endotoxic drugs are discussed.
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Affiliation(s)
- Tamara Fedorovna Solov'eva
- G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-Eastern Branch of the Russian Academy of Science, Vladivostok 690022, Russia
| | - Svetlana Ivanovna Bakholdina
- G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-Eastern Branch of the Russian Academy of Science, Vladivostok 690022, Russia
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16
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Nakatani A, Okumura R, Ishibashi A, Okamoto S, Sakaki K, Ito Y, Okuzaki D, Inohara H, Takeda K. Differential dependence on microbiota of IL-23/IL-22-dependent gene expression between the small- and large-intestinal epithelia. Genes Cells 2023; 28:776-788. [PMID: 37680073 DOI: 10.1111/gtc.13065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 08/25/2023] [Accepted: 08/27/2023] [Indexed: 09/09/2023]
Abstract
In the intestine, interleukin (IL)-23 and IL-22 from immune cells in the lamina propria contribute to maintenance of the gut epithelial barrier through the induction of antimicrobial production and the promotion of epithelial cell proliferation. Several previous studies suggested that some of the functions of the IL-23/IL-22 axis on intestinal epithelial cells are shared between the small and large intestines. However, the similarities and differences of the IL-23/IL-22 axis on epithelial cells between these two anatomical sites remain unclear. Here, we comprehensively analyzed the gene expression of intestinal epithelial cells in the ileum and colon of germ-free, Il23-/- , and Il22-/- mice by RNA-sequencing. We found that while the IL-23/IL-22 axis is largely dependent on gut microbiota in the small intestine, it is much less dependent on it in the large intestine. In addition, the negative regulation of lipid metabolism in the epithelial cells by IL-23 and IL-22 in the small intestine was revealed, whereas the positive regulation of epithelial cell proliferation by IL-23 and IL-22 in the large intestine was highlighted. These findings shed light on the intestinal site-specific role of the IL-23/IL-22 axis in maintaining the physiological functions of intestinal epithelial cells.
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Affiliation(s)
- Ayaka Nakatani
- Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
- Department of Otorhinolaryngology-Head and Neck Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Ryu Okumura
- Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
- WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan
- Institute for Open and Transdisciplinary Research Initiative, Osaka University, Suita, Osaka, Japan
| | - Airi Ishibashi
- Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Shota Okamoto
- Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Kei Sakaki
- Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Yuki Ito
- Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Daisuke Okuzaki
- WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan
- Institute for Open and Transdisciplinary Research Initiative, Osaka University, Suita, Osaka, Japan
- Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
- Center for Infectious Disease Education and Research, Osaka University, Suita, Osaka, Japan
| | - Hidenori Inohara
- Department of Otorhinolaryngology-Head and Neck Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Kiyoshi Takeda
- Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
- WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan
- Institute for Open and Transdisciplinary Research Initiative, Osaka University, Suita, Osaka, Japan
- Center for Infectious Disease Education and Research, Osaka University, Suita, Osaka, Japan
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17
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Zha H, Zhang H, Zhong J, Zhao L, Liu Y, Zhu Q. Pathogenic bacteria defense and complement activation function analysis of Collectin-10 from Hexagrammos otakii. FISH & SHELLFISH IMMUNOLOGY 2023; 140:108972. [PMID: 37488038 DOI: 10.1016/j.fsi.2023.108972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 07/14/2023] [Accepted: 07/20/2023] [Indexed: 07/26/2023]
Abstract
With the tremendous success of the artificial breeding of Hexagrammos otakii, the yield has been substantially improved. However, intensive farming often results in bacterial diseases; hence it is imperative to find new antimicrobial molecules. In the present study, we identified a homologous cDNA fragment of collectin-10 from H. otakii, designated as HoCL-10. The cDNA length is 899 bp, which contains an open reading frame (ORF) of 816 bp encoding a secreted protein with 272 amino acid residues. The peptide of HoCL-10 contains an N-terminal collagen domain, a neck region, and a C-terminal carbohydrate recognition domain. The qRT-PCR results revealed that HoCL-10 mRNA was highest expressed in the liver and skin and was significantly induced post-LPS stimulation. The sugar and bacteria binding assay suggested that the recombinant HoCL-10 (rHoCL-10) could recognize various pathogen-associated molecular patterns (PAMPs) and bacteria. For effect on cells, rHoCL-10 enhanced the phagocytosis and migration ability of the macrophage indicated using pro-phagocytosis assay and trans-well assay. To determine the role of HoCL-10 in the complement system, the interaction between HoCL-10 and mannose-binding lectin associated serine protease 1, 2 (MASP-1, 2) were analyzed and demonstrated using ELISA and Far-western. And in vivo, the concentration of membrane-attack complex (MAC) in fish plasma was significantly down-regulated post-injection with HoCL-10 antibody. Finally, the bacteria challenge experiment was performed, implying that HoCL-10 may assist the host in defending against microbial invasion. The findings suggest that HoCL-10 may play crucial roles in host defense against microorganisms, possibly through opsonizing pathogens and activating the complement system.
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Affiliation(s)
- Haidong Zha
- Marine College, Shandong University (Weihai), Weihai, 264209, China
| | - Haoyue Zhang
- Marine College, Shandong University (Weihai), Weihai, 264209, China
| | - Jinmiao Zhong
- Marine College, Shandong University (Weihai), Weihai, 264209, China
| | - Lihua Zhao
- Marine College, Shandong University (Weihai), Weihai, 264209, China
| | - Yingying Liu
- Marine College, Shandong University (Weihai), Weihai, 264209, China.
| | - Qian Zhu
- Marine College, Shandong University (Weihai), Weihai, 264209, China.
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18
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Zhang L, Yan J, Zhang C, Feng S, Zhan Z, Bao Y, Zhang S, Chao G. Improving intestinal inflammaging to delay aging? A new perspective. Mech Ageing Dev 2023; 214:111841. [PMID: 37393959 DOI: 10.1016/j.mad.2023.111841] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 06/14/2023] [Accepted: 06/29/2023] [Indexed: 07/04/2023]
Abstract
Greying population is becoming an increasingly critical issue for social development. In advanced aging context, organismal multiple tissues and organs experience a progressive deterioration, initially presenting with functional decline, followed by structural disruption and eventually organ failure. The aging of the gut is one of the key links. Decreased gut function leads to reduced nutrient absorption and can perturb systemic metabolic rates. The degeneration of the intestinal structure causes the migration of harmful components such as pathogens and toxins, inducing pathophysiological changes in other organs through the "brain-gut axis" and "liver-gut axis". There is no accepted singular underlying mechanism of aged gut. While the inflamm-aging theory was first proposed in 2000, the mutual promotion of chronic inflammation and aging has attracted much attention. Numerous studies have established that gut microbiome composition, gut immune function, and gut barrier integrity are involved in the formation of inflammaging in the aging gut. Remarkably, inflammaging additionally drives the development of aging-like phenotypes, such as microbiota dysbiosis and impaired intestinal barrier, via a broad array of inflammatory mediators. Here we demonstrate the mechanisms of inflammaging in the gut and explore whether aging-like phenotypes in the gut can be negated by improving gut inflammaging.
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Affiliation(s)
- Lan Zhang
- Department of General Practice, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou 310000, China
| | - Junbin Yan
- The Second Affiliated Hospital of Zhejiang Chinese Medical University, The Xin Hua Hospital of Zhejiang Province, Hangzhou 310000, China
| | - Chi Zhang
- Endoscopic Center, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou 310000, China
| | - Shuyan Feng
- Zhejiang Chinese Medical University, Hangzhou 310000, China
| | - Zheli Zhan
- Department of General Practice, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou 310000, China
| | - Yang Bao
- Department of General Practice, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou 310000, China
| | - Shuo Zhang
- The Second Affiliated Hospital of Zhejiang Chinese Medical University, The Xin Hua Hospital of Zhejiang Province, Hangzhou 310000, China.
| | - Guanqun Chao
- Department of General Practice, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou 310000, China.
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19
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Muchhala K, Kang M, Koseli E, Poklis J, Xu Q, Dewey W, Fettweis J, Jimenez N, Akbarali H. The Role of Morphine-Induced Impairment of Intestinal Epithelial Antibacterial Activity in Dysbiosis and its Impact on the Microbiota-Gut-Brain Axis.. [PMID: 37503065 PMCID: PMC10371156 DOI: 10.21203/rs.3.rs-3084467/v2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/04/2024]
Abstract
Abstract
Recent evidence suggests that chronic exposure to opioid analgesics such as morphine disrupt the intestinal epithelial layer and cause intestinal dysbiosis. Inhibiting opioid-induced dysbiosis can preclude the development of tolerance to opioid-induced antinociception, suggesting an important role of the gut-brain axis in mediating opioid effects. However, the mechanism underlying opioid-induced dysbiosis remains unclear. Host-produced antimicrobial peptides (AMPs) are critical for the integrity of the intestinal epithelial barrier as they prevent the pathogenesis of the enteric microbiota. Here, we report that chronic morphine exposure reduces expression of the antimicrobial peptide, Regenerating islet-derived 3 gamma (Reg3γ), in the ileum resulting in reduced intestinal antimicrobial activity against Gram-positive bacteria, L. reuteri. Fecal samples from morphine-treated mice had reduced levels of the phylum, Firmicutes, concomitant with reduced levels of short-chain fatty acid, butyrate. Fecal microbial transplant (FMT) from morphine-naïve mice restored the antimicrobial activity, the expression of Reg3γ, and prevented the increase in intestinal permeability and the development of antinociceptive tolerance in morphine-dependent mice. Similarly, oral gavage with sodium butyrate dose-dependently reduced the development of antinociceptive tolerance, and prevented the downregulation of Reg3γ and the reduction in antimicrobial activity. The alpha diversity of the microbiome was also restored by oral butyrate in morphine-dependent mice. These data implicate impairment of the antimicrobial activity of the intestinal epithelium as a mechanism by which morphine disrupts the microbiota-gut-brain axis.
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20
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Muchhala K, Kang M, Koseli E, Poklis J, Xu Q, Dewey W, Fettweis J, Jimenez N, Akbarali H. The Role of Morphine-Induced Impairment of Intestinal Epithelial Antibacterial Activity in Dysbiosis and its Impact on the Microbiota-Gut-Brain Axis. RESEARCH SQUARE 2023:rs.3.rs-3084467. [PMID: 37503065 PMCID: PMC10371156 DOI: 10.21203/rs.3.rs-3084467/v1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/29/2023]
Abstract
Recent evidence suggests that chronic exposure to opioid analgesics such as morphine disrupt the intestinal epithelial layer and cause intestinal dysbiosis. Inhibiting opioid-induced dysbiosis can preclude the development of tolerance to opioid-induced antinociception, suggesting an important role of the gut-brain axis in mediating opioid effects. However, the mechanism underlying opioid-induced dysbiosis remains unclear. Host-produced antimicrobial peptides (AMPs) are critical for the integrity of the intestinal epithelial barrier as they prevent the pathogenesis of the enteric microbiota. Here, we report that chronic morphine exposure reduces expression of the antimicrobial peptide, Regenerating islet-derived 3 gamma (Reg3γ), in the ileum resulting in reduced intestinal antimicrobial activity against Gram-positive bacteria, L. reuteri. Fecal samples from morphine-treated mice had reduced levels of the phylum, Firmicutes, concomitant with reduced levels of short-chain fatty acid, butyrate. Fecal microbial transplant (FMT) from morphine-naïve mice restored the antimicrobial activity, the expression of Reg3γ, and prevented the increase in intestinal permeability and the development of antinociceptive tolerance in morphine-dependent mice. Similarly, oral gavage with sodium butyrate dose-dependently reduced the development of antinociceptive tolerance, and prevented the downregulation of Reg3γ and the reduction in antimicrobial activity. The alpha diversity of the microbiome was also restored by oral butyrate in morphine-dependent mice. These data implicate impairment of the antimicrobial activity of the intestinal epithelium as a mechanism by which morphine disrupts the microbiota-gut-brain axis.
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21
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Wang S, Liu J, Cheng D, Ren L, Zheng L, Chen F, Zeng T. Bacillus subtilis pretreatment alleviates ethanol-induced acute liver injury by regulating the Gut-liver axis in mice. Toxicology 2023; 488:153487. [PMID: 36907542 DOI: 10.1016/j.tox.2023.153487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Revised: 02/25/2023] [Accepted: 03/08/2023] [Indexed: 03/12/2023]
Abstract
This study was designed to investigate the hepatoprotective effects of Bacillus subtilis, a commensal bacterial species in the human gut, on ethanol-induced acute liver damage and the underlying mechanisms in mice. Male ICR mice challenged with three doses of ethanol (5.5 g/kg BW) exhibited a significant increase in serum aminotransferase activities and TNF-α level, liver fat accumulation, and activation of NF-κB signaling and NLRP3 inflammasome, which was suppressed by pretreatment with Bacillus subtilis. Besides, Bacillus subtilis inhibited acute ethanol-induced intestinal villi shortening and epithelial loss, the decline of protein levels of intestinal tight junction protein ZO-1 and occludin, and elevation of serum LPS level. Furthermore, the upregulation of mucin-2 (MUC2) and the downregulation of anti-microbial Reg3B and Reg3G levels induced by ethanol were repressed by Bacillus subtilis. Lastly, Bacillus subtilis pretreatment significantly increased the abundance of the intestinal Bacillus, but had no effects on the binge drinking-induced increase of Prevotellaceae abundance. These results demonstrate that Bacillus subtilis supplementation could ameliorate binge drinking-induced liver injury, and thus may serve as a functional dietary supplement for binge drinkers.
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Affiliation(s)
- Shuo Wang
- School of Pharmaceutical Sciences, Liaocheng University, Liaocheng, Shandong 252059, China
| | - Jinqian Liu
- School of Pharmaceutical Sciences, Liaocheng University, Liaocheng, Shandong 252059, China
| | - Dong Cheng
- Department of Health Test and Detection, Shandong Center for Disease Control and Prevention, Jinan, Shandong 250014, China
| | - Lehao Ren
- School of Pharmaceutical Sciences, Liaocheng University, Liaocheng, Shandong 252059, China
| | - Lixue Zheng
- School of Pharmaceutical Sciences, Liaocheng University, Liaocheng, Shandong 252059, China
| | - Fang Chen
- School of Pharmaceutical Sciences, Liaocheng University, Liaocheng, Shandong 252059, China.
| | - Tao Zeng
- Institute of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
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22
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Wang J, Guo XL, Chen HY, Xiao LX, Yang GW, Yang HT. A novel l-rhamnose-binding lectin participates in defending against bacterial infection in zebrafish. FISH & SHELLFISH IMMUNOLOGY 2023; 134:108553. [PMID: 36693487 DOI: 10.1016/j.fsi.2023.108553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 12/26/2022] [Accepted: 01/15/2023] [Indexed: 06/17/2023]
Abstract
l-rhamnose-binding lectin (RBL), which is a class of animal lectins independent of Ca2+, can specifically bind l-rhamnose or d-galactose. Although several lectins in zebrafish have been reported, their functional mechanisms have not been fully uncovered. In this study, we discovered a novel l-rhamnose binding lectin (DrRBL) and studied its innate immune function. The DrRBL protein contains only one carbohydrate-recognition domain (CRD), which includes two strictly conserved motifs, "YGR" and "DPC". DrRBL was detected in all tested tissues and was present at high levels in the spleen, hepatopancreas and skin. After Aeromonas hydrophila challenge, the DrRBL mRNA level was significantly upregulated. Additionally, DrRBL was secreted into the extracellular matrix. Recombinant DrRBL (rDrRBL) could significantly inhibit the growth of gram-positive/negative bacteria, bind to several bacteria and cause obvious agglutination. The rDrRBL protein could combine with polysaccharides, such as PGN and LPS, rather than LTA. A more detailed study showed that rDrRBL could combine with monosaccharides, such as mannose, rhamnose and glucose, which are important components of PGN and LPS. However, rDrRBL could not bind to ribitol, which is an important component of LTA. The DrRBL deletion mutants, DrRBLΔ144-150 and DrRBLΔ198-200, were also constructed. DrRBLΔ144-150 ("ANYGRTD" deficient) showed weak bacterial inhibiting ability. However, DrRBLΔ198-200 ("DPC" deficient) showed weak agglutination ability. These results suggest that the "DPC" domain is important for agglutination. The conserved domain "ANYGRTD" is essential for inhibiting bacterial growth.
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Affiliation(s)
- Jing Wang
- Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan, 250014, China
| | - Xin-Lu Guo
- Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan, 250014, China
| | - Hong-Ye Chen
- Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan, 250014, China
| | - Lin-Xi Xiao
- Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan, 250014, China
| | - Gui-Wen Yang
- Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan, 250014, China
| | - Hui-Ting Yang
- Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan, 250014, China.
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23
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Wang W, Liu MY, Fei CJ, Li CH, Chen J. Molecular and functional characterization of a ladderlectin-like molecule from ayu (Plecoglossus altivelis). FISH & SHELLFISH IMMUNOLOGY 2022; 131:419-430. [PMID: 36257553 DOI: 10.1016/j.fsi.2022.10.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 10/09/2022] [Accepted: 10/12/2022] [Indexed: 06/16/2023]
Abstract
Ladderlectin is a member of C-type lectins (CTLs) in teleost fish and involved in innate immune defense. In this study, ayu (Plecoglossus altivelis) ladderlecin-like (PaLL-like) sequence was cloned, which encodes a polypeptide of 172 amino acids that includes a signal peptide and characteristic C-type lectin-like domains (CTLDs). Phylogenetically, PaLL-like was most closely related to its teleost counterpart from shishamo smelt (Spirinchus lanceolatus). Expression analysis revealed a ubiquitous expression profile, with highest expression detected in liver and its expression was up-regulated following Vibiro anguillarum infection. Similar to canonical CTLs, PaLL-like exhibited carbohydrate-binidng capacities to a wide range of well-defined mono-/di-saccharides and likely confer PaLL-like the ability to agglutinate all tested bacterial, including three Gram-positive species (i.e., Listeria monocytogenes, Staphylococcus aureus and Streptococcus iniae) and eight Gram-negative species (i.e., Edwardsiella tarda, Aeromonas (A.) hydrophila, Escherichia coli, Vibrio (V.) harveyi, V. anguillarum, V. parahemolyticus, A. versoni and V. vulnificus), in a calcium-dependent manner. Further functional studies revealed that PaLL-like displayed immunomodulatory activities leading to enhanced bactericidal activity of serum, pathogen opsonization and macrophage activation with increased expression of pro-inflammatory cytokines (i.e., PaIL-1β and PaTNF-α). Collectively, these immunomodulatory activities of PaLL-like suppressed proliferations of V. anguillarum in targeted tissued in vivo and likely contributed to the increased survival rate of infected-fish. Overall, our results demonstrated PaLL-like is a critical component of innate immunity and provides protective effects against bacterial infection.
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Affiliation(s)
- Wei Wang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, 315211, China; Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Meishan Campus, Ningbo University, Ningbo, 315832, China; Key Laboratory of Applied Marine Biotechnology of Ministry of Education, Meishan Campus, Ningbo University, Ningbo, 315832, China
| | - Mei-Yi Liu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, 315211, China; Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Meishan Campus, Ningbo University, Ningbo, 315832, China; Key Laboratory of Applied Marine Biotechnology of Ministry of Education, Meishan Campus, Ningbo University, Ningbo, 315832, China
| | - Chen-Jie Fei
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, 315211, China; Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Meishan Campus, Ningbo University, Ningbo, 315832, China; Key Laboratory of Applied Marine Biotechnology of Ministry of Education, Meishan Campus, Ningbo University, Ningbo, 315832, China.
| | - Chang-Hong Li
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, 315211, China; Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Meishan Campus, Ningbo University, Ningbo, 315832, China; Key Laboratory of Applied Marine Biotechnology of Ministry of Education, Meishan Campus, Ningbo University, Ningbo, 315832, China.
| | - Jiong Chen
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, 315211, China; Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Meishan Campus, Ningbo University, Ningbo, 315832, China; Key Laboratory of Applied Marine Biotechnology of Ministry of Education, Meishan Campus, Ningbo University, Ningbo, 315832, China
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24
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Wang W, Wang Y, Lu Y, Zhu J, Tian X, Wu B, Du J, Cai W, Xiao Y. Reg4 protects against Salmonella infection-associated intestinal inflammation via adopting a calcium-dependent lectin-like domain. Int Immunopharmacol 2022; 113:109310. [DOI: 10.1016/j.intimp.2022.109310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Revised: 09/19/2022] [Accepted: 09/30/2022] [Indexed: 11/05/2022]
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25
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Ning H, Zhang J, Wang Y, Lin H, Wang J. Development of highly efficient artilysins against Vibrio parahaemolyticus via virtual screening assisted by molecular docking. Food Control 2022. [DOI: 10.1016/j.foodcont.2022.109521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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26
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Gabius H, Cudic M, Diercks T, Kaltner H, Kopitz J, Mayo KH, Murphy PV, Oscarson S, Roy R, Schedlbauer A, Toegel S, Romero A. What is the Sugar Code? Chembiochem 2022; 23:e202100327. [PMID: 34496130 PMCID: PMC8901795 DOI: 10.1002/cbic.202100327] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 09/07/2021] [Indexed: 12/18/2022]
Abstract
A code is defined by the nature of the symbols, which are used to generate information-storing combinations (e. g. oligo- and polymers). Like nucleic acids and proteins, oligo- and polysaccharides are ubiquitous, and they are a biochemical platform for establishing molecular messages. Of note, the letters of the sugar code system (third alphabet of life) excel in coding capacity by making an unsurpassed versatility for isomer (code word) formation possible by variability in anomery and linkage position of the glycosidic bond, ring size and branching. The enzymatic machinery for glycan biosynthesis (writers) realizes this enormous potential for building a large vocabulary. It includes possibilities for dynamic editing/erasing as known from nucleic acids and proteins. Matching the glycome diversity, a large panel of sugar receptors (lectins) has developed based on more than a dozen folds. Lectins 'read' the glycan-encoded information. Hydrogen/coordination bonding and ionic pairing together with stacking and C-H/π-interactions as well as modes of spatial glycan presentation underlie the selectivity and specificity of glycan-lectin recognition. Modular design of lectins together with glycan display and the nature of the cognate glycoconjugate account for the large number of post-binding events. They give an entry to the glycan vocabulary its functional, often context-dependent meaning(s), hereby building the dictionary of the sugar code.
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Affiliation(s)
- Hans‐Joachim Gabius
- Institute of Physiological ChemistryFaculty of Veterinary MedicineLudwig-Maximilians-University MunichVeterinärstr. 1380539MunichGermany
| | - Maré Cudic
- Department of Chemistry and BiochemistryCharles E. Schmidt College of ScienceFlorida Atlantic University777 Glades RoadBoca RatonFlorida33431USA
| | - Tammo Diercks
- Center for Cooperative Research in Biosciences (CIC bioGUNE)Basque Research and Technology Alliance (BRTA)Bizkaia Technology Park, Building 801 A48160DerioBizkaiaSpain
| | - Herbert Kaltner
- Institute of Physiological ChemistryFaculty of Veterinary MedicineLudwig-Maximilians-University MunichVeterinärstr. 1380539MunichGermany
| | - Jürgen Kopitz
- Institute of PathologyDepartment of Applied Tumor BiologyFaculty of MedicineRuprecht-Karls-University HeidelbergIm Neuenheimer Feld 22469120HeidelbergGermany
| | - Kevin H. Mayo
- Department of BiochemistryMolecular Biology & BiophysicsUniversity of MinnesotaMinneapolisMN 55455USA
| | - Paul V. Murphy
- CÚRAM – SFI Research Centre for Medical Devices and theSchool of ChemistryNational University of Ireland GalwayUniversity RoadGalwayH91 TK33Ireland
| | - Stefan Oscarson
- Centre for Synthesis and Chemical BiologyUniversity College DublinBelfieldDublin 4Ireland
| | - René Roy
- Département de Chimie et BiochimieUniversité du Québec à MontréalCase Postale 888Succ. Centre-Ville MontréalQuébecH3C 3P8Canada
| | - Andreas Schedlbauer
- Center for Cooperative Research in Biosciences (CIC bioGUNE)Basque Research and Technology Alliance (BRTA)Bizkaia Technology Park, Building 801 A48160DerioBizkaiaSpain
| | - Stefan Toegel
- Karl Chiari Lab for Orthopaedic BiologyDepartment of Orthopedics and Trauma SurgeryMedical University of ViennaViennaAustria
| | - Antonio Romero
- Department of Structural and Chemical BiologyCIB Margarita Salas, CSICRamiro de Maeztu 928040MadridSpain
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27
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Relationship between gut microbiota and colorectal cancer: Probiotics as a potential strategy for prevention. Food Res Int 2022; 156:111327. [DOI: 10.1016/j.foodres.2022.111327] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 04/27/2022] [Accepted: 04/28/2022] [Indexed: 12/15/2022]
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28
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Feng C, Liu X, Tang Y, Feng M, Zhou Z, Liu S. A novel ladderlectin from hybrid crucian carp possesses antimicrobial activity and protects intestinal mucosal barrier against Aeromonas hydrophila infection. FISH & SHELLFISH IMMUNOLOGY 2022; 124:1-11. [PMID: 35378306 DOI: 10.1016/j.fsi.2022.03.036] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Revised: 03/20/2022] [Accepted: 03/23/2022] [Indexed: 06/14/2023]
Abstract
Ladderlectin is a pattern recognition receptor (PRR) in fish that is critical for rapid detection of bacteria in vitro, but the immunological function of ladderlectin in vivo is essentially unknown. In this study, we examined the expression and function of a ladderlectin homologue (WR-ladderlectin) from hybrid crucian carp. WR-ladderlectin contains 157 amino acids and possesses the conserved C-type lectin domain. WR-ladderlectin is mainly expressed in the intestine and is upregulated by bacterial infection. Recombinant WR-ladderlectin (rWR-ladderlectin) agglutinated Aeromonas hydrophila and Escherichia coli. rWR-ladderlectin also bound the A. hydrophila and E. coli in a protein dose-dependent manner. As well as its ability to bind bacterial cells, rWR-ladderlectin displayed apparent bactericidal activity against A. hydrophila and E. coli in vitro. When introduced in vivo, rWR-ladderlectin induced significant expression of the antimicrobial molecules and tight junctions in the intestine. In addition, rWR-ladderlectin prevented significant decrease in the length of intestine villus and enhanced the host's resistance to bacterial infection. These results indicate that WR-ladderlectin is a classic pattern recognition molecule that protects intestinal mucosal barrier against bacterial infection.
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Affiliation(s)
- Chen Feng
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, 410081, China
| | - Xiaofeng Liu
- Department of Nutrition, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yiyang Tang
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, 410081, China
| | - Mengzhe Feng
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, 410081, China
| | - Zejun Zhou
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, 410081, China.
| | - Shaojun Liu
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, 410081, China.
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29
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Zhang Z, Tanaka I, Pan Z, Ernst PB, Kiyono H, Kurashima Y. Intestinal homeostasis and inflammation: gut microbiota at the crossroads of pancreas-intestinal barrier axis. Eur J Immunol 2022; 52:1035-1046. [PMID: 35476255 PMCID: PMC9540119 DOI: 10.1002/eji.202149532] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 04/21/2022] [Accepted: 04/25/2022] [Indexed: 11/24/2022]
Abstract
The pancreas contains exocrine glands, which release enzymes (e.g., amylase, trypsin, and lipase) that are important for digestion and islets, which produce hormones. Digestive enzymes and hormones are secreted from the pancreas into the duodenum and bloodstream, respectively. Growing evidence suggests that the roles of the pancreas extend to not only the secretion of digestive enzymes and hormones but also to the regulation of intestinal homeostasis and inflammation (e.g., mucosal defense to pathogens and pathobionts). Organ crosstalk between the pancreas and intestine is linked to a range of physiological, immunological, and pathological activities, such as the regulation of the gut microbiota by the pancreatic proteins and lipids, the retroaction of the gut microbiota on the pancreas, the relationship between inflammatory bowel disease, and pancreatic diseases. We herein discuss the current understanding of the pancreas–intestinal barrier axis and the control of commensal bacteria in intestinal inflammation.
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Affiliation(s)
- Zhongwei Zhang
- Department of Innovative Medicine, Graduate School of Medicine, Chiba University, Chiba, 260-8670, Japan
| | - Izumi Tanaka
- Department of Innovative Medicine, Graduate School of Medicine, Chiba University, Chiba, 260-8670, Japan
| | - Zhen Pan
- Department of Innovative Medicine, Graduate School of Medicine, Chiba University, Chiba, 260-8670, Japan
| | - Peter B Ernst
- Division of Comparative Pathology and Medicine, Department of Pathology, University of California San Diego, San Diego, CA, 92093-0956, USA.,Center for Veterinary Sciences and Comparative Medicine, University of California, San Diego, CA, 92093-0956, USA.,Departments of Medicine and Pathology, CU-UCSD Center for Mucosal Immunology, Allergy and Vaccines (CU-UCSD cMAV), University of California, San Diego, CA, 92093-0956, USA.,International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan
| | - Hiroshi Kiyono
- Division of Comparative Pathology and Medicine, Department of Pathology, University of California San Diego, San Diego, CA, 92093-0956, USA.,Departments of Medicine and Pathology, CU-UCSD Center for Mucosal Immunology, Allergy and Vaccines (CU-UCSD cMAV), University of California, San Diego, CA, 92093-0956, USA.,Department of Mucosal Immunology, The University of Tokyo Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.,International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.,Department of Human Mucosal Vaccinology, Chiba University, Chiba, 260-8670, Japan
| | - Yosuke Kurashima
- Department of Innovative Medicine, Graduate School of Medicine, Chiba University, Chiba, 260-8670, Japan.,Division of Comparative Pathology and Medicine, Department of Pathology, University of California San Diego, San Diego, CA, 92093-0956, USA.,Departments of Medicine and Pathology, CU-UCSD Center for Mucosal Immunology, Allergy and Vaccines (CU-UCSD cMAV), University of California, San Diego, CA, 92093-0956, USA.,Department of Mucosal Immunology, The University of Tokyo Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.,International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.,Department of Human Mucosal Vaccinology, Chiba University, Chiba, 260-8670, Japan.,Institute for Advanced Academic Research, Chiba University, Chiba, 260-8670, Japan
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30
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Zindl CL, Witte SJ, Laufer VA, Gao M, Yue Z, Janowski KM, Cai B, Frey BF, Silberger DJ, Harbour SN, Singer JR, Turner H, Lund FE, Vallance BA, Rosenberg AF, Schoeb TR, Chen JY, Hatton RD, Weaver CT. A nonredundant role for T cell-derived interleukin 22 in antibacterial defense of colonic crypts. Immunity 2022; 55:494-511.e11. [PMID: 35263568 PMCID: PMC9126440 DOI: 10.1016/j.immuni.2022.02.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 11/11/2021] [Accepted: 02/04/2022] [Indexed: 02/05/2023]
Abstract
Interleukin (IL)-22 is central to immune defense at barrier sites. We examined the contributions of innate lymphoid cell (ILC) and T cell-derived IL-22 during Citrobacter rodentium (C.r) infection using mice that both report Il22 expression and allow lineage-specific deletion. ILC-derived IL-22 activated STAT3 in C.r-colonized surface intestinal epithelial cells (IECs) but only temporally restrained bacterial growth. T cell-derived IL-22 induced a more robust and extensive activation of STAT3 in IECs, including IECs lining colonic crypts, and T cell-specific deficiency of IL-22 led to pathogen invasion of the crypts and increased mortality. This reflected a requirement for T cell-derived IL-22 for the expression of a host-protective transcriptomic program that included AMPs, neutrophil-recruiting chemokines, and mucin-related molecules, and it restricted IFNγ-induced proinflammatory genes. Our findings demonstrate spatiotemporal differences in the production and action of IL-22 by ILCs and T cells during infection and reveal an indispensable role for IL-22-producing T cells in the protection of the intestinal crypts.
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Affiliation(s)
- Carlene L Zindl
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
| | - Steven J Witte
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Vincent A Laufer
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Min Gao
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Informatics Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Zongliang Yue
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Informatics Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Karen M Janowski
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Baiyi Cai
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Blake F Frey
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Daniel J Silberger
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Stacey N Harbour
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Jeffrey R Singer
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Henrietta Turner
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Frances E Lund
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Bruce A Vallance
- Department of Pediatrics, University of British Columbia, Vancouver, BC V6H 3V4, Canada
| | - Alexander F Rosenberg
- Informatics Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Trenton R Schoeb
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Jake Y Chen
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Informatics Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Robin D Hatton
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Casey T Weaver
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
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31
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Kini A, Zhao B, Basic M, Roy U, Iljazovic A, Odak I, Ye Z, Riederer B, Di Stefano G, Römermann D, Koenecke C, Bleich A, Strowig T, Seidler U. Upregulation of antimicrobial peptide expression in slc26a3-/- mice with colonic dysbiosis and barrier defect. Gut Microbes 2022; 14:2041943. [PMID: 35230892 PMCID: PMC8890434 DOI: 10.1080/19490976.2022.2041943] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 02/09/2022] [Indexed: 02/04/2023] Open
Abstract
Genetic defects in SLC26A3 (DRA), an intestinal Cl-/HCO3- exchanger, result in congenital chloride diarrhea (CLD), marked by lifelong acidic diarrhea and a high risk of inflammatory bowel disease. Slc26a3-/- mice serve as a model to understand the pathophysiology of CLD and search for treatment options. This study investigates the microbiota changes in slc26a3-/- colon, the genotype-related causes for the observed microbiota alterations, its inflammatory potential, as well as the corresponding host responses. The luminal and the mucosa-adherent cecal and colonic microbiota of cohoused slc26a3-/- and wt littermates were analyzed by 16S rRNA gene sequencing. Fecal microbiota transfer from cohoused slc26a3-/- and wt littermates to germ-free wt mice was performed to analyze the stability and the inflammatory potential of the communities.The cecal and colonic luminal and mucosa-adherent microbiota of slc26a3-/- mice was abnormal from an early age, with a loss of diversity, of short-chain fatty acid producers, and an increase of pathobionts. The transfer of slc26a3-/- microbiota did not result in intestinal inflammation and the microbial diversity in the recipient mice normalized over time. A strong increase in the expression of Il22, Reg3β/γ, Relmβ, and other proteins with antimicrobial functions was observed in slc26a3-/- colon from juvenile age, while the mucosal and systemic inflammatory signature was surprisingly mild. The dysbiotic microbiota, low mucosal pH, and mucus barrier defect in slc26a3-/- colon are accompanied by a stark upregulation of the expression of a panel of antimicrobial proteins. This may explain the low inflammatory burden in the gut of these mice.
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Affiliation(s)
| | - Bei Zhao
- Microbial Immune Regulation Research Group, Helmholtz Center for Infection Research, Braunschweig, Germany
| | | | - Urmi Roy
- Microbial Immune Regulation Research Group, Helmholtz Center for Infection Research, Braunschweig, Germany
| | - Aida Iljazovic
- Microbial Immune Regulation Research Group, Helmholtz Center for Infection Research, Braunschweig, Germany
| | - Ivan Odak
- Institute of Immunology Hannover Medical School Hannover, Germany
| | | | | | | | | | | | | | - Till Strowig
- Microbial Immune Regulation Research Group, Helmholtz Center for Infection Research, Braunschweig, Germany
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32
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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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33
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Santos VF, Costa MS, Campina FF, Rodrigues RR, Santos ALE, Pereira FM, Batista KLR, Silva RC, Pereira RO, Rocha BAM, Coutinho HDM, Teixeira CS. The Galactose-Binding Lectin Isolated from Vatairea macrocarpa Seeds Enhances the Effect of Antibiotics Against Staphylococcus aureus-Resistant Strain. Probiotics Antimicrob Proteins 2021; 12:82-90. [PMID: 30737650 DOI: 10.1007/s12602-019-9526-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The use of natural products together with standard antimicrobial drugs has recently received more attention as a strategy to combat infectious diseases caused by multidrug-resistant (MDR) microorganisms. This study aimed to evaluate the capacity of a galactose-binding lectin from Vatairea macrocarpa seeds (VML) to modulate antibiotic activity against standard and MDR Staphylococcus aureus and Escherichia coli bacterial strains. The minimum inhibitory concentration (MIC) obtained for VML against all strains was not clinically relevant (MIC ≥ 1024 μg/mL). However, when VML was combined with the antibacterial drugs gentamicin, norfloxacin and penicillin, a significant increase in antibiotic activity was observed against S. aureus, whereas the combination of VML and norfloxacin presented decreased and, hence, antagonistic antibiotic activity against E. coli. By its inhibition of hemagglutinating activity, gentamicin (MIC = 50 mM) revealed its interaction with the carbohydrate-binding site (CBS) of VML. Using molecular docking, it was found that gentamicin interacts with residues that constitute the CBS of VML with a score of - 120.79 MDS. It is this interaction between the antibiotic and the lectin's CBS that may be responsible for the enhanced activity of gentamicin in S. aureus. Thus, our results suggest that the VML can be an effective modulating agent against S. aureus. This is the first study to report the effect of lectins as modulators of bacterial sensitivity, and as such, the outcome of this study could lay the groundwork for future research involving the use of lectins and conventional antibiotics against such infectious diseases such as community-acquired methicillin-resistant S. aureus (MRSA).
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Affiliation(s)
- Valdenice F Santos
- Centro de Ciências Agrárias e Ambientais, Universidade Federal do Maranhão, Campus Chapadinha S/N, Chapadinha, Maranhão, 65500-000, Brazil
| | - Maria S Costa
- Departamento de Química Biológica, Universidade Regional do Cariri, Crato, Ceará, Brazil
| | - Fábia F Campina
- Departamento de Química Biológica, Universidade Regional do Cariri, Crato, Ceará, Brazil
| | - Renato R Rodrigues
- Centro de Ciências Agrárias e Ambientais, Universidade Federal do Maranhão, Campus Chapadinha S/N, Chapadinha, Maranhão, 65500-000, Brazil
| | - Ana L E Santos
- Centro de Ciências Agrárias e Ambientais, Universidade Federal do Maranhão, Campus Chapadinha S/N, Chapadinha, Maranhão, 65500-000, Brazil
| | - Felipe M Pereira
- Centro de Ciências Agrárias e Ambientais, Universidade Federal do Maranhão, Campus Chapadinha S/N, Chapadinha, Maranhão, 65500-000, Brazil
| | - Karla L R Batista
- Centro de Ciências Agrárias e Ambientais, Universidade Federal do Maranhão, Campus Chapadinha S/N, Chapadinha, Maranhão, 65500-000, Brazil
| | - Rafael C Silva
- Centro de Ciências Agrárias e Ambientais, Universidade Federal do Maranhão, Campus Chapadinha S/N, Chapadinha, Maranhão, 65500-000, Brazil
| | - Raquel O Pereira
- Centro de Ciências Agrárias e Ambientais, Universidade Federal do Maranhão, Campus Chapadinha S/N, Chapadinha, Maranhão, 65500-000, Brazil
| | - Bruno A M Rocha
- Departamento de Bioquímica e Biologia Molecular, Universidade Federal do Ceará, Fortaleza, Ceará, Brazil
| | - Henrique D M Coutinho
- Departamento de Química Biológica, Universidade Regional do Cariri, Crato, Ceará, Brazil
| | - Claudener S Teixeira
- Centro de Ciências Agrárias e Ambientais, Universidade Federal do Maranhão, Campus Chapadinha S/N, Chapadinha, Maranhão, 65500-000, Brazil.
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34
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Labarta-Bajo L, Nilsen SP, Humphrey G, Schwartz T, Sanders K, Swafford A, Knight R, Turner JR, Zúñiga EI. Type I IFNs and CD8 T cells increase intestinal barrier permeability after chronic viral infection. J Exp Med 2021; 217:152069. [PMID: 32880630 PMCID: PMC7953738 DOI: 10.1084/jem.20192276] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 06/29/2020] [Accepted: 08/06/2020] [Indexed: 12/16/2022] Open
Abstract
Intestinal barrier leakage constitutes a potential therapeutic target for many inflammatory diseases and represents a disease progression marker during chronic viral infections. However, the causes of altered gut barrier remain mostly unknown. Using murine infection with lymphocytic choriomeningitis virus, we demonstrate that, in contrast to an acute viral strain, a persistent viral isolate leads to long-term viral replication in hematopoietic and mesenchymal cells, but not epithelial cells (IECs), in the intestine. Viral persistence drove sustained intestinal epithelial barrier leakage, which was characterized by increased paracellular flux of small molecules and was associated with enhanced colitis susceptibility. Type I IFN signaling caused tight junction dysregulation in IECs, promoted gut microbiome shifts and enhanced intestinal CD8 T cell responses. Notably, both type I IFN receptor blockade and CD8 T cell depletion prevented infection-induced barrier leakage. Our study demonstrates that infection with a virus that persistently replicates in the intestinal mucosa increases epithelial barrier permeability and reveals type I IFNs and CD8 T cells as causative factors of intestinal leakage during chronic infections.
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Affiliation(s)
- Lara Labarta-Bajo
- Division of Biological Sciences, University of California, San Diego, La Jolla, CA
| | - Steven P Nilsen
- Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Gregory Humphrey
- Department of Pediatrics, University of California, San Diego, La Jolla, CA
| | - Tara Schwartz
- Department of Pediatrics, University of California, San Diego, La Jolla, CA
| | - Karenina Sanders
- Department of Pediatrics, University of California, San Diego, La Jolla, CA
| | - Austin Swafford
- Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA
| | - Rob Knight
- Department of Pediatrics, University of California, San Diego, La Jolla, CA.,Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA.,Department of Bioengineering, University of California, San Diego, La Jolla, CA.,Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA
| | - Jerrold R Turner
- Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Elina I Zúñiga
- Division of Biological Sciences, University of California, San Diego, La Jolla, CA
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35
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Cao Y, Tian Y, Liu Y, Su Z. Reg3β: A Potential Therapeutic Target for Tissue Injury and Inflammation-Associated Disorders. Int Rev Immunol 2021; 41:160-170. [PMID: 33426979 DOI: 10.1080/08830185.2020.1869731] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Since regenerating islet-derived 3β (Reg3β) was first reported, various studies have been conducted to explore the involvement of Reg3β in a gamut of maladies, such as diabetes, pancreatitis, pancreatic ductal adenocarcinoma, and extrapancreatic maladies such as inflammatory bowel disease, acute liver failure, and myocardial infarction. Surprisingly, there is currently no systematic review of Reg3β. Therefore, we summarize the structural characteristics, transcriptional regulation, putative receptors, and signaling pathways of Reg3β. The exact functional roles in various diseases, especially gastrointestinal and liver diseases, are also discussed. Reg3β plays multiple roles in promoting proliferation, inducing differentiation, preventing apoptosis, and resisting bacteria. The present review may provide new directions for the diagnosis and treatment of gastrointestinal, liver, and pancreatic diseases.
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Affiliation(s)
- Yuwen Cao
- International Genome Center, Jiangsu University, Zhenjiang, China.,Department of Immunology, Jiangsu University, Zhenjiang, China
| | - Yu Tian
- International Genome Center, Jiangsu University, Zhenjiang, China.,Department of Immunology, Jiangsu University, Zhenjiang, China
| | - Yueqin Liu
- Laboratory Center, the Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Zhaoliang Su
- International Genome Center, Jiangsu University, Zhenjiang, China.,Department of Immunology, Jiangsu University, Zhenjiang, China.,Laboratory Center, the Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China
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36
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Jiang XW, Li YT, Ye JZ, Lv LX, Yang LY, Bian XY, Wu WR, Wu JJ, Shi D, Wang Q, Fang DQ, Wang KC, Wang QQ, Lu YM, Xie JJ, Li LJ. New strain of Pediococcus pentosaceus alleviates ethanol-induced liver injury by modulating the gut microbiota and short-chain fatty acid metabolism. World J Gastroenterol 2020; 26:6224-6240. [PMID: 33177795 PMCID: PMC7596634 DOI: 10.3748/wjg.v26.i40.6224] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 08/08/2020] [Accepted: 09/10/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Intestinal dysbiosis has been shown to be associated with the pathogenesis of alcoholic liver disease (ALD), which includes changes in the microbiota composition and bacterial overgrowth, but an effective microbe-based therapy is lacking. Pediococcus pentosaceus (P. pentosaceus) CGMCC 7049 is a newly isolated strain of probiotic that has been shown to be resistant to ethanol and bile salts. However, further studies are needed to determine whether P. pentosaceus exerts a protective effect on ALD and to elucidate the potential mechanism.
AIM To evaluate the protective effect of the probiotic P. pentosaceus on ethanol-induced liver injury in mice.
METHODS A new ethanol-resistant strain of P. pentosaceus CGMCC 7049 was isolated from healthy adults in our laboratory. The chronic plus binge model of experimental ALD was established to evaluate the protective effects. Twenty-eight C57BL/6 mice were randomly divided into three groups: The control group received a pair-fed control diet and oral gavage with sterile phosphate buffered saline, the EtOH group received a ten-day Lieber-DeCarli diet containing 5% ethanol and oral gavage with phosphate buffered saline, and the P. pentosaceus group received a 5% ethanol Lieber-DeCarli diet but was treated with P. pentosaceus. One dose of isocaloric maltose dextrin or ethanol was administered by oral gavage on day 11, and the mice were sacrificed nine hours later. Blood and tissue samples (liver and gut) were harvested to evaluate gut barrier function and liver injury-related parameters. Fresh cecal contents were collected, gas chromatography–mass spectrometry was used to measure short-chain fatty acid (SCFA) concentrations, and the microbiota composition was analyzed using 16S rRNA gene sequencing.
RESULTS The P. pentosaceus treatment improved ethanol-induced liver injury, with lower alanine aminotransferase, aspartate transaminase and triglyceride levels and decreased neutrophil infiltration. These changes were accompanied by decreased levels of endotoxin and inflammatory cytokines, including interleukin-5, tumor necrosis factor-α, granulocyte colony-stimulating factor, keratinocyte-derived protein chemokine, macrophage inflammatory protein-1α and monocyte chemoattractant protein-1. Ethanol feeding resulted in intestinal dysbiosis and gut barrier disruption, increased relative abundance of potentially pathogenic Escherichia and Staphylococcus, and the depletion of SCFA-producing bacteria, such as Prevotella, Faecalibacterium, and Clostridium. In contrast, P. pentosaceus administration increased the microbial diversity, restored the relative abundance of Lactobacillus, Pediococcus, Prevotella, Clostridium and Akkermansia and increased propionic acid and butyric acid production by modifying SCFA-producing bacteria. Furthermore, the levels of the tight junction protein ZO-1, mucin proteins (mucin [MUC]-1, MUC-2 and MUC-4) and the antimicrobial peptide Reg3β were increased after probiotic supplementation.
CONCLUSION Based on these results, the new strain of P. pentosaceus alleviated ethanol-induced liver injury by reversing gut microbiota dysbiosis, regulating intestinal SCFA metabolism, improving intestinal barrier function, and reducing circulating levels of endotoxin and proinflammatory cytokines and chemokines. Thus, this strain is a potential probiotic treatment for ALD.
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Affiliation(s)
- Xian-Wan Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Ya-Ting Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Jian-Zhong Ye
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Long-Xian Lv
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Li-Ya Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Xiao-Yuan Bian
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Wen-Rui Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Jing-Jing Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Ding Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Qing Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Dai-Qiong Fang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Kai-Cen Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Qiang-Qiang Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Yan-Meng Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Jiao-Jiao Xie
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Lan-Juan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
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37
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Todoric J, Di Caro G, Reibe S, Henstridge DC, Green CR, Vrbanac A, Ceteci F, Conche C, McNulty R, Shalapour S, Taniguchi K, Meikle PJ, Watrous JD, Moranchel R, Najhawan M, Jain M, Liu X, Kisseleva T, Diaz-Meco MT, Moscat J, Knight R, Greten FR, Lau LF, Metallo CM, Febbraio MA, Karin M. Fructose stimulated de novo lipogenesis is promoted by inflammation. Nat Metab 2020; 2:1034-1045. [PMID: 32839596 PMCID: PMC8018782 DOI: 10.1038/s42255-020-0261-2] [Citation(s) in RCA: 205] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 07/13/2020] [Indexed: 12/11/2022]
Abstract
Benign hepatosteatosis, affected by lipid uptake, de novo lipogenesis and fatty acid (FA) oxidation, progresses to non-alcoholic steatohepatitis (NASH) on stress and inflammation. A key macronutrient proposed to increase hepatosteatosis and NASH risk is fructose. Excessive intake of fructose causes intestinal-barrier deterioration and endotoxaemia. However, how fructose triggers these alterations and their roles in hepatosteatosis and NASH pathogenesis remain unknown. Here we show, using mice, that microbiota-derived Toll-like receptor (TLR) agonists promote hepatosteatosis without affecting fructose-1-phosphate (F1P) and cytosolic acetyl-CoA. Activation of mucosal-regenerative gp130 signalling, administration of the YAP-induced matricellular protein CCN1 or expression of the antimicrobial peptide Reg3b (beta) peptide counteract fructose-induced barrier deterioration, which depends on endoplasmic-reticulum stress and subsequent endotoxaemia. Endotoxin engages TLR4 to trigger TNF production by liver macrophages, thereby inducing lipogenic enzymes that convert F1P and acetyl-CoA to FA in both mouse and human hepatocytes.
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Affiliation(s)
- Jelena Todoric
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA, USA
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Giuseppe Di Caro
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Saskia Reibe
- Garvan Institute of Medical Research, Sydney, Australia
| | | | - Courtney R Green
- Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA
| | - Alison Vrbanac
- Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA, USA
| | - Fatih Ceteci
- Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt/Main, Germany
- Frankfurt Cancer Institute, Goethe University Frankfurt, Frankfurt/Main, Germany
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Claire Conche
- Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt/Main, Germany
- Frankfurt Cancer Institute, Goethe University Frankfurt, Frankfurt/Main, Germany
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Reginald McNulty
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA, USA
- Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA
| | - Shabnam Shalapour
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Koji Taniguchi
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA, USA
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan
| | - Peter J Meikle
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Jeramie D Watrous
- Departments of Medicine and Pharmacology, University of California San Diego, La Jolla, CA, USA
| | - Rafael Moranchel
- Departments of Medicine and Pharmacology, University of California San Diego, La Jolla, CA, USA
| | - Mahan Najhawan
- Departments of Medicine and Pharmacology, University of California San Diego, La Jolla, CA, USA
| | - Mohit Jain
- Departments of Medicine and Pharmacology, University of California San Diego, La Jolla, CA, USA
| | - Xiao Liu
- Departments of Medicine and Pharmacology, University of California San Diego, La Jolla, CA, USA
| | - Tatiana Kisseleva
- Departments of Medicine and Pharmacology, University of California San Diego, La Jolla, CA, USA
| | - Maria T Diaz-Meco
- Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Jorge Moscat
- Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Rob Knight
- Department of Pediatrics, Department of Computer Science and Engineering, Department of Bioengineering, and The Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA, USA
| | - Florian R Greten
- Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt/Main, Germany
- Frankfurt Cancer Institute, Goethe University Frankfurt, Frankfurt/Main, Germany
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Lester F Lau
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago College of Medicine, Chicago, IL, USA
| | - Christian M Metallo
- Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA
| | - Mark A Febbraio
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA, USA.
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Sabihi M, Böttcher M, Pelczar P, Huber S. Microbiota-Dependent Effects of IL-22. Cells 2020; 9:E2205. [PMID: 33003458 PMCID: PMC7599675 DOI: 10.3390/cells9102205] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 09/24/2020] [Accepted: 09/25/2020] [Indexed: 02/07/2023] Open
Abstract
Cytokines are important contributors to immune responses against microbial and environmental threats and are of particular importance at epithelial barriers. These interfaces are continuously exposed to external factors and thus require immune components to both protect the host from pathogen invasion and to regulate overt inflammation. Recently, substantial efforts have been devoted to understanding how cytokines act on certain cells at barrier sites, and why the dysregulation of immune responses may lead to pathogenesis. In particular, the cytokine IL-22 is involved in preserving an intact epithelium, maintaining a balanced microbiota and a functioning defense system against external threats. However, a tight regulation of IL-22 is generally needed, since uncontrolled IL-22 production can lead to the progression of autoimmunity and cancer. Our aim in this review is to summarize novel findings on IL-22 and its interactions with specific microbial stimuli, and subsequently, to understand their contributions to the function of IL-22 and the clinical outcome. We particularly focus on understanding the detrimental effects of dysregulated control of IL-22 in certain disease contexts.
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Affiliation(s)
| | | | | | - Samuel Huber
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany; (M.S.); (M.B.); (P.P.)
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Mendes BG, Schnabl B. From intestinal dysbiosis to alcohol-associated liver disease. Clin Mol Hepatol 2020; 26:595-605. [PMID: 32911590 PMCID: PMC7641547 DOI: 10.3350/cmh.2020.0086] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 07/27/2020] [Indexed: 12/11/2022] Open
Abstract
Alcohol-associated intestinal dysbiosis and bacterial overgrowth can lead to a dysregulation of tryptophan metabolism and lower production of indoles. Several of these indole derivatives are aryl hydrocarbon receptor ligands that, in turn, are involved in antimicrobial defense via induction of interleukin-22 (IL-22). IL-22 increases the expression of intestinal regenerating islet-derived 3 (Reg3) lectins, which maintain low bacterial colonization of the inner mucus layer and reduce bacterial translocation to the liver. Chronic alcohol consumption is associated with reduced intestinal expression of Reg3β and Reg3γ, increased numbers of mucosa-associated bacteria and bacterial translocation. Translocated microbial products and viable bacteria reach the liver and activate the innate immune system. Release of inflammatory molecules promotes inflammation, contributes to hepatocyte death and results in a fibrotic response. This review summarizes the mechanisms by which chronic alcohol intake changes the gut microbiota and contributes to alcohol-associated liver disease by changing microbial-derived metabolites.
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Affiliation(s)
- Beatriz Garcia Mendes
- Department of Clinical Analysis, Federal University of Santa Catarina, Florianopolis, SC, Brazil.,Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
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40
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Pardhi DM, Şen Karaman D, Timonen J, Wu W, Zhang Q, Satija S, Mehta M, Charbe N, McCarron PA, Tambuwala MM, Bakshi HA, Negi P, Aljabali AA, Dua K, Chellappan DK, Behera A, Pathak K, Watharkar RB, Rautio J, Rosenholm JM. Anti-bacterial activity of inorganic nanomaterials and their antimicrobial peptide conjugates against resistant and non-resistant pathogens. Int J Pharm 2020; 586:119531. [PMID: 32540348 DOI: 10.1016/j.ijpharm.2020.119531] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Revised: 06/04/2020] [Accepted: 06/06/2020] [Indexed: 12/20/2022]
Abstract
This review details the antimicrobial applications of inorganic nanomaterials of mostly metallic form, and the augmentation of activity by surface conjugation of peptide ligands. The review is subdivided into three main sections, of which the first describes the antimicrobial activity of inorganic nanomaterials against gram-positive, gram-negative and multidrug-resistant bacterial strains. The second section highlights the range of antimicrobial peptides and the drug resistance strategies employed by bacterial species to counter lethality. The final part discusses the role of antimicrobial peptide-decorated inorganic nanomaterials in the fight against bacterial strains that show resistance. General strategies for the preparation of antimicrobial peptides and their conjugation to nanomaterials are discussed, emphasizing the use of elemental and metallic oxide nanomaterials. Importantly, the permeation of antimicrobial peptides through the bacterial membrane is shown to aid the delivery of nanomaterials into bacterial cells. By judicious use of targeting ligands, the nanomaterial becomes able to differentiate between bacterial and mammalian cells and, thus, reduce side effects. Moreover, peptide conjugation to the surface of a nanomaterial will alter surface chemistry in ways that lead to reduction in toxicity and improvements in biocompatibility.
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Affiliation(s)
- Dinesh M Pardhi
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
| | - Didem Şen Karaman
- Pharmaceutical Sciences Laboratory, Faculty of Science & Engineering, Åbo Akademi University, 20500 Turku, Finland; Biomedical Engineering Department, Faculty of Engineering and Architecture, İzmir Katip Çelebi University, İzmir, Turkey
| | - Juri Timonen
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland
| | - Wei Wu
- Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, China
| | - Qi Zhang
- Department of Chemistry, Fudan University, Shanghai, China
| | - Saurabh Satija
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411, Punjab, India; Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Meenu Mehta
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411, Punjab, India; Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Nitin Charbe
- Departamento de Química Orgánica, Facultad de Química, Pontificia Universidad Católica de Chile, Av. Vicuña McKenna 4860, Macul, Santiago 7820436, Chile
| | - Paul A McCarron
- School of Pharmacy and Pharmaceutical Sciences, Ulster University, Coleraine, County Londonderry, Northern Ireland BT52 1SA, UK
| | - Murtaza M Tambuwala
- School of Pharmacy and Pharmaceutical Sciences, Ulster University, Coleraine, County Londonderry, Northern Ireland BT52 1SA, UK
| | - Hamid A Bakshi
- School of Pharmacy and Pharmaceutical Sciences, Ulster University, Coleraine, County Londonderry, Northern Ireland BT52 1SA, UK
| | - Poonam Negi
- School of Pharmaceutical Sciences, Shoolini University of Biotechnology and Management Sciences, Solan, India
| | - Alaa A Aljabali
- Department of Pharmaceutics and Pharmaceutical Technology, Yarmouk University, Faculty of Pharmacy, Irbid 566, Jordan
| | - Kamal Dua
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo, NSW 2007, Australia; School of Pharmaceutical Sciences, Shoolini University of Biotechnology and Management Sciences, Solan, India; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute (HMRI) and School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales (NSW) 230, Australia
| | - Dinesh K Chellappan
- Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil, Malaysia
| | - Ajit Behera
- Department of Metallurgical & Materials Engineering National Institute of Technology, Rourkela, Odisha 769008, India
| | - Kamla Pathak
- Uttar Pradesh University of Medical Sciences SAIFAI, Etawah 206130, India
| | - Ritesh B Watharkar
- Shramshakti College of Food Technology, Maldad, Sangamner, Ahmednagar, Maharashtra 422608, India
| | - Jarkko Rautio
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland
| | - Jessica M Rosenholm
- Pharmaceutical Sciences Laboratory, Faculty of Science & Engineering, Åbo Akademi University, 20500 Turku, Finland.
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Edwards JA, Tan N, Toussaint N, Ou P, Mueller C, Stanek A, Zinsou V, Roudnitsky S, Sagal M, Dresner L, Schwartzman A, Huan C. Role of regenerating islet-derived proteins in inflammatory bowel disease. World J Gastroenterol 2020; 26:2702-2714. [PMID: 32550748 PMCID: PMC7284176 DOI: 10.3748/wjg.v26.i21.2702] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 03/26/2020] [Accepted: 05/13/2020] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is an inflammatory disorder of the gastrointestinal tract that affects millions of patients worldwide. It has a complex and multifactorial etiology leading to excessive exposure of intestinal epithelium to microbial antigens, inappropriate activation of the immune system and ultimately to the damage of intestinal tissues. Although numerous efforts have been made to improve the disease management, IBD remains persistently recurring and beyond cure. This is due largely to the gaps in our understanding of the pathogenesis of IBD that hamper the development of timely diagnoses and effective treatment. However, some recent discoveries, including the beneficial effects of interleukin-22 (IL-22) on the inflamed intestine, have shed light on a self-protective mechanism in IBD. Regenerating islet-derived (REG/Reg) proteins are small secretory proteins which function as IL-22's downstream effectors. Mounting studies have demonstrated that IBD patients have significantly increased REG expressions in the injured intestine, but with undefined mechanisms and roles. The reported functions of REG/Reg proteins in intestinal homeostasis, such as those of antibacterial, anti-inflammatory and tissue repair, lead us to discuss their potential mechanisms and clinical relevance in IBD in order to advance IBD research and management.
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Affiliation(s)
- Jodi-Ann Edwards
- Department of Surgery, State University of New York, Downstate Health Sciences University, Brooklyn, NY 11203, United States
| | - Nicholas Tan
- College of Medicine, State University of New York, Downstate Health Sciences University, Brooklyn, NY 11203, United States
| | - Nadlie Toussaint
- College of Medicine, State University of New York, Downstate Health Sciences University, Brooklyn, NY 11203, United States
| | - Peiqi Ou
- MCB program, School of Graduate Studies, State University of New York, Downstate Health Sciences University, Brooklyn, NY 11203, United States
| | - Cathy Mueller
- Department of Surgery, State University of New York, Downstate Health Sciences University, Brooklyn, NY 11203, United States
| | - Albert Stanek
- Department of Surgery, State University of New York, Downstate Health Sciences University, Brooklyn, NY 11203, United States
| | - Vladimir Zinsou
- College of Medicine, State University of New York, Downstate Health Sciences University, Brooklyn, NY 11203, United States
| | - Sean Roudnitsky
- Department of Surgery, State University of New York, Downstate Health Sciences University, Brooklyn, NY 11203, United States
| | - Michelle Sagal
- Department of Surgery, State University of New York, Downstate Health Sciences University, Brooklyn, NY 11203, United States
| | - Lisa Dresner
- Department of Surgery, State University of New York, Downstate Health Sciences University, Brooklyn, NY 11203, United States
| | - Alexander Schwartzman
- Department of Surgery, State University of New York, Downstate Health Sciences University, Brooklyn, NY 11203, United States
| | - Chongmin Huan
- Department of Surgery and Cell Biology, State University of New York, Downstate Health Sciences University, Brooklyn, NY 11203, United States
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Perazza LR, Mitchell PL, Jensen BAH, Daniel N, Boyer M, Varin TV, Bouchareb R, Nachbar RT, Bouchard M, Blais M, Gagné A, Joubert P, Sweeney G, Roy D, Arsenault BJ, Mathieu P, Marette A. Dietary sucrose induces metabolic inflammation and atherosclerotic cardiovascular diseases more than dietary fat in LDLr -/-ApoB 100/100 mice. Atherosclerosis 2020; 304:9-21. [PMID: 32563005 DOI: 10.1016/j.atherosclerosis.2020.05.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 04/12/2020] [Accepted: 05/07/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Poor dietary habits contribute to the obesity pandemic and related cardiovascular diseases but the respective impact of high saturated fat versus added sugar consumption remains debated. Herein, we aimed to disentangle the individual role of dietary fat versus sugar in cardiometabolic disease progression. METHODS We fed pro-atherogenic LDLr-/-ApoB100/100 mice either a low-fat/high-sucrose (LFHS) or a high-fat/low-sucrose (HFLS) diet for 24 weeks. Weekly body weight gain was registered. 16S rRNA gene-based gut microbial analysis was performed to investigate gut microbial modulations. Intraperitoneal insulin (ipITT) and oral glucose tolerance test (oGTT) were conducted to assess glucose homeostasis and insulin sensitivity. Cytokines were assessed in fasted plasma, epididymal white adipose tissue and liver lysates. Heart function was evaluated by echocardiography. Aortic atheroma lesions were quantified according to the en face technique. RESULTS HFLS feeding increased obesity, insulin resistance and dyslipidemia compared to LFHS feeding. Conversely, high sucrose consumption decreased gut microbial diversity while augmenting inflammation and the adaptative immune defense against metabolic endotoxemia and reduced macrophage cholesterol efflux capacity. This led to more severe cardiovascular complications as revealed by remarkably high level of atherosclerotic lesions and the early development of cardiac dysfunction in LFHS vs HFLS fed mice. CONCLUSIONS We uncoupled obesity-associated insulin resistance from cardiovascular diseases and provided novel evidence that dietary sucrose, not fat, is the main driver of metabolic inflammation accelerating severe atherosclerosis in hyperlipidemic mice.
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Affiliation(s)
- Laís R Perazza
- Quebec Heart and Lung Institute, Department of Medicine, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada; Institute of Nutraceuticals and Functional Foods, Laval University, Quebec City, Quebec, Canada
| | - Patricia L Mitchell
- Quebec Heart and Lung Institute, Department of Medicine, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada; Institute of Nutraceuticals and Functional Foods, Laval University, Quebec City, Quebec, Canada
| | - Benjamin A H Jensen
- Quebec Heart and Lung Institute, Department of Medicine, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada; Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Human Genomics and Metagenomics in Metabolism, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Noëmie Daniel
- Quebec Heart and Lung Institute, Department of Medicine, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada; Institute of Nutraceuticals and Functional Foods, Laval University, Quebec City, Quebec, Canada
| | - Marjorie Boyer
- Quebec Heart and Lung Institute, Department of Medicine, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada
| | - Thibault V Varin
- Quebec Heart and Lung Institute, Department of Medicine, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada; Institute of Nutraceuticals and Functional Foods, Laval University, Quebec City, Quebec, Canada
| | - Rihab Bouchareb
- Quebec Heart and Lung Institute, Department of Medicine, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada
| | - Renato T Nachbar
- Quebec Heart and Lung Institute, Department of Medicine, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada
| | - Michaël Bouchard
- Sherbrooke Research and Development Centre, Agriculture and Agri-Food, Canada, Sherbrooke, Québec, Canada
| | - Mylène Blais
- Sherbrooke Research and Development Centre, Agriculture and Agri-Food, Canada, Sherbrooke, Québec, Canada
| | - Andréanne Gagné
- Quebec Heart and Lung Institute, Department of Medicine, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada
| | - Philippe Joubert
- Quebec Heart and Lung Institute, Department of Medicine, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada
| | - Gary Sweeney
- Department of Biology, York University, Toronto, Ontario, Canada
| | - Denis Roy
- Institute of Nutraceuticals and Functional Foods, Laval University, Quebec City, Quebec, Canada
| | - Benoit J Arsenault
- Quebec Heart and Lung Institute, Department of Medicine, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada
| | - Patrick Mathieu
- Quebec Heart and Lung Institute, Department of Medicine, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada
| | - André Marette
- Quebec Heart and Lung Institute, Department of Medicine, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada; Institute of Nutraceuticals and Functional Foods, Laval University, Quebec City, Quebec, Canada.
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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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Liu WC, Chen PH, Chen LW. Supplementation of endogenous Ahr ligands reverses insulin resistance and associated inflammation in an insulin-dependent diabetic mouse model. J Nutr Biochem 2020; 83:108384. [PMID: 32512500 DOI: 10.1016/j.jnutbio.2020.108384] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 01/11/2020] [Accepted: 03/26/2020] [Indexed: 01/10/2023]
Abstract
Aryl-hydrocarbon receptor (Ahr) plays an important role in the regulation of intestinal homeostasis. Diabetes is characterized by vascular complications and intestinal dysfunction. We aimed at understanding the relationship between intestinal defense impairment and inflammation in diabetes and effects of Ahr ligands on diabetes-induced insulin resistance, endovascular inflammation, and intercellular adhesion molecule (ICAM) and flavin mono-oxygenase (FMO3) expression. Effects of Ahr ligands, such as tryptophan (Trp) and indole-3-carbinol (I3C) on intestinal barrier and inflammation of Ins2Akita mice were examined. Myeloid differentiation primary response 88 (MYD88) is the adaptor for inflammatory signaling pathways. Ins2Akita-MyD88-/- mice were used to study the role of MyD88. Ins2Akita mice demonstrated decreased Ahr and regenerating islet-derived 3-β (Reg3β) expression, and increased Klebsiella pneumoniae translocation. Ins2Akita mice demonstrated increased inducible nitric oxide synthase (iNOS) expression of intestine; ICAM, iNOS, interleukin 1 beta (IL-1β), and FMO3 expression of liver; and ICAM, iNOS, and FMO3 expression in aorta. Trp and I3C decreased diabetes-induced translocation and increased Ahr and Reg3β expression of intestine. Ahr ligands reduced diabetes-induced ICAM and FMO3 expression in liver and aorta; IL-6, tumor necrosis factor alpha (TNF-α), and iNOS expression in Kupffer cells; plasma IL-6 and TNF-α levels; dipeptidyl peptidase (DPP4) activity; and insulin insensitivity. Ins2Akita-MyD88-/- mice demonstrated decreased expression of p-NF-κB of liver and ICAM of aorta compared with Ins2Akita mice. Altogether, our data suggest that diabetes induces ICAM and FMO3 expression through the decrease in intestinal defense and MyD88. Ahr ligands reverse diabetes-induced intestinal defense impairment, insulin insensitivity, FMO3/ICAM expression, and systemic inflammation.
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Affiliation(s)
- Wen-Chung Liu
- Department of Surgery, Kaohsiung Veterans General Hospital, No.386, Ta-chung 1(st) Road, Kaohsiung, 813, Taiwan; School of Medicine, National Yang-Ming University, No.155, Sec.2, Linong Street, Taipei, 112, Taiwan
| | - Pei-Hsuan Chen
- Department of Surgery, Kaohsiung Veterans General Hospital, No.386, Ta-chung 1(st) Road, Kaohsiung, 813, Taiwan
| | - Lee-Wei Chen
- Department of Surgery, Kaohsiung Veterans General Hospital, No.386, Ta-chung 1(st) Road, Kaohsiung, 813, Taiwan; Institute of Emergency and Critical Care Medicine, National Yang-Ming University, No.155, Sec.2, Linong Street, Taipei, 112, Taiwan; Department of Biological Sciences, National Sun Yat-Sen University, No.70, Lien-Hai Road, Kaohsiung, 804, Taiwan.
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Sato M, Inaba A, Iwatsuki K, Saito Y, Tadaishi M, Shimizu M, Kobayashi-Hattori K. Identification of Reg3β-producing cells using IL-22-stimulated enteroids. Biosci Biotechnol Biochem 2020; 84:594-597. [PMID: 31760857 DOI: 10.1080/09168451.2019.1695575] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Accepted: 11/13/2019] [Indexed: 12/14/2022]
Abstract
Reg3β, a lectin, displays antibacterial activity. This study investigated Reg3β-expressing cells using IL-22-stimulated enteroids. IL-22 stimulation elevated the mRNA and protein levels of Reg3β. IL-22 also increased the mRNA levels of CD133 (a transit-amplifying cell marker) and lysozyme (a Paneth cell marker). Immunohistochemistry showed partial colocalization of Reg3β- and lysozyme-positive cells, suggesting that Paneth cells are one of Reg3β-producing cells.
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Affiliation(s)
- Mika Sato
- Department of Nutritional Science, Faculty of Applied Bioscience, Tokyo University of Agriculture, Tokyo, Japan
| | - Akihiko Inaba
- Department of Nutritional Science and Food Safety, Faculty of Applied Bioscience, Tokyo University of Agriculture, Tokyo, Japan
| | - Ken Iwatsuki
- Department of Nutritional Science and Food Safety, Faculty of Applied Bioscience, Tokyo University of Agriculture, Tokyo, Japan
| | - Yuki Saito
- Department of Nutritional Science, Faculty of Applied Bioscience, Tokyo University of Agriculture, Tokyo, Japan
| | - Miki Tadaishi
- Department of Nutritional Science, Faculty of Applied Bioscience, Tokyo University of Agriculture, Tokyo, Japan
| | - Makoto Shimizu
- Department of Nutritional Science, Faculty of Applied Bioscience, Tokyo University of Agriculture, Tokyo, Japan
| | - Kazuo Kobayashi-Hattori
- Department of Nutritional Science, Faculty of Applied Bioscience, Tokyo University of Agriculture, Tokyo, Japan
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Twin-Arginine Translocation System Is Involved in Citrobacter rodentium Fitness in the Intestinal Tract. Infect Immun 2020; 88:IAI.00892-19. [PMID: 31818958 DOI: 10.1128/iai.00892-19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Accepted: 11/27/2019] [Indexed: 01/16/2023] Open
Abstract
The twin-arginine translocation (Tat) system is involved in not only a wide array of cellular processes but also pathogenesis in many bacterial pathogens; thus, this system is expected to become a novel therapeutic target to treat infections. To the best of our knowledge, involvement of the Tat system has not been reported in the gut infection caused by Citrobacter rodentium Here, we studied the role of Tat in C. rodentium gut infection, which resembles human infection with enterohemorrhagic Escherichia coli (EHEC) and enteropathogenic E. coli (EPEC). A C. rodentium Tat loss-of-function mutant displayed prolonged gut colonization, which was explained by reduced inflammatory responses and, particularly, neutrophil infiltration. Further, the Tat mutant had colonization defects upon coinfection with the wild-type strain of C. rodentium The Tat mutant also became hypersensitive to bile acids, and an increase in fecal bile acids fostered C. rodentium clearance from the gut lumen. Finally, we show that the chain form of C. rodentium cells, induced by a Tat-dependent cell division defect, exhibits impaired resistance to bile acids. Our findings indicate that the Tat system is involved in gut colonization by C. rodentium, which is associated with neutrophil infiltration and resistance to bile acids. Interventions that target the Tat system, as well as luminal bile acids, might thus be promising therapeutic strategies to treat human EHEC and EPEC infections.
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Kim SW, Kim S, Son M, Cheon JH, Park YS. Melatonin controls microbiota in colitis by goblet cell differentiation and antimicrobial peptide production through Toll-like receptor 4 signalling. Sci Rep 2020; 10:2232. [PMID: 32042047 PMCID: PMC7010660 DOI: 10.1038/s41598-020-59314-7] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 01/14/2020] [Indexed: 12/12/2022] Open
Abstract
Microbial dysbiosis has long been postulated to be associated with the pathogenesis of inflammatory bowel disease (IBD). Although evidence supporting the anti-colitic effects of melatonin have been accumulating, it is not clear how melatonin affects the microbiota. Herein, we investigated the effects of melatonin on the microbiome in colitis and identified involvement of Toll-like receptor (TLR) 4 signalling in the effects. Melatonin improved dextran sulfate sodium (DSS)-induced colitis and reverted microbial dysbiosis in wild-type (WT) mice but not in TLR4 knockout (KO) mice. Induction of goblet cells was observed with melatonin administration, which was accompanied by suppression of Il1b and Il17a and induction of melatonin receptor and Reg3β, an antimicrobial peptide (AMP) against Gram-negative bacteria. In vitro, melatonin treatment of HT-29 intestinal epithelial cells promotes mucin and wound healing and inhibits growth of Escherichia coli. Herein, we showed that melatonin significantly increases goblet cells, Reg3β, and the ratio of Firmicutes to Bacteriodetes by suppressing Gram-negative bacteria through TLR4 signalling. Our study suggests that sensing of bacteria through TLR4 and regulation of bacteria through altered goblet cells and AMPs is involved in the anti-colitic effects of melatonin. Melatonin may have use in therapeutics for IBD.
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Affiliation(s)
- Seung Won Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.,Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.,Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Soochan Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.,Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Mijeong Son
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.,Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.,Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Jae Hee Cheon
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.,Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.,Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Young Sook Park
- Department of Internal Medicine, Eulji Hospital, Eulji University School of Medicine, Seoul, Korea.
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Xu X, Fukui H, Ran Y, Wang X, Inoue Y, Ebisudani N, Nishimura H, Tomita T, Oshima T, Watari J, Kiyama H, Miwa H. The Link between Type III Reg and STAT3-Associated Cytokines in Inflamed Colonic Tissues. Mediators Inflamm 2019; 2019:7859460. [PMID: 31780871 PMCID: PMC6875322 DOI: 10.1155/2019/7859460] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 09/10/2019] [Accepted: 09/25/2019] [Indexed: 02/08/2023] Open
Abstract
Reg (regenerating gene) family proteins are known to be overexpressed in gastrointestinal (GI) tissues under conditions of inflammation. However, the pathophysiological significance of Reg family protein overexpression and its regulation is still unclear. In the present study, we investigated the profile of Reg family gene expression in a colitis model and focused on the regulation of Reg IIIβ and IIIγ, which are overexpressed in inflamed colonic mucosa. C57BL/6 mice were administered 2% dextran sulfate sodium (DSS) in drinking water for five days, and their colonic tissues were investigated histopathologically at interval for up to 12 weeks. Gene expression of the Reg family and cytokines (IL-6, IL-17, and IL-22) was evaluated by real-time RT-PCR, and Reg IIIβ/γ expression was examined by immunohistochemistry. The effects of cytokines on STAT3 phosphorylation and HIP/PAP (type III REG) expression in Caco2 and HCT116 cells were examined by Western blot analysis. Among Reg family genes, Reg IIIβ and IIIγ were alternatively overexpressed in the colonic tissues of mice with DSS-induced colitis. The expression of STAT3-associated cytokines (IL-6, IL-17, and IL-22) was also significantly increased in those tissues, being significantly correlated with that of Reg IIIβ/γ. STAT3 phosphorylation and HIP/PAP expression were significantly enhanced in Caco2 cells upon stimulation with IL-6, IL-17, and IL-22. In HCT116 cells, those enhancements were also observed by IL-6 and IL-22 stimulations but not IL-17. The link between type III Reg and STAT3-associated cytokines appears to play a pivotal role in the pathophysiology of DSS-induced colitis.
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Affiliation(s)
- Xin Xu
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Hirokazu Fukui
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Ying Ran
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Xuan Wang
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Yoshihito Inoue
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Nobuhiko Ebisudani
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Heihachiro Nishimura
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Toshihiko Tomita
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Tadayuki Oshima
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Jiro Watari
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Hiroshi Kiyama
- Department of Functional Anatomy and Neuroscience, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroto Miwa
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
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Wotzka SY, Kreuzer M, Maier L, Arnoldini M, Nguyen BD, Brachmann AO, Berthold DL, Zünd M, Hausmann A, Bakkeren E, Hoces D, Gül E, Beutler M, Dolowschiak T, Zimmermann M, Fuhrer T, Moor K, Sauer U, Typas A, Piel J, Diard M, Macpherson AJ, Stecher B, Sunagawa S, Slack E, Hardt WD. Escherichia coli limits Salmonella Typhimurium infections after diet shifts and fat-mediated microbiota perturbation in mice. Nat Microbiol 2019; 4:2164-2174. [PMID: 31591555 PMCID: PMC6881180 DOI: 10.1038/s41564-019-0568-5] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Accepted: 08/23/2019] [Indexed: 12/16/2022]
Abstract
The microbiota confers colonization resistance, which blocks Salmonella gut colonization1. As diet affects microbiota composition, we studied whether food composition shifts enhance susceptibility to infection. Shifting mice to diets with reduced fibre or elevated fat content for 24 h boosted Salmonella Typhimurium or Escherichia coli gut colonization and plasmid transfer. Here, we studied the effect of dietary fat. Colonization resistance was restored within 48 h of return to maintenance diet. Salmonella gut colonization was also boosted by two oral doses of oleic acid or bile salts. These pathogen blooms required Salmonella's AcrAB/TolC-dependent bile resistance. Our data indicate that fat-elicited bile promoted Salmonella gut colonization. Both E. coli and Salmonella show much higher bile resistance than the microbiota. Correspondingly, competitive E. coli can be protective in the fat-challenged gut. Diet shifts and fat-elicited bile promote S. Typhimurium gut infections in mice lacking E. coli in their microbiota. This mouse model may be useful for studying pathogen-microbiota-host interactions, the protective effect of E. coli, to analyse the spread of resistance plasmids and assess the impact of food components on the infection process.
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Affiliation(s)
- Sandra Y Wotzka
- Institute of Microbiology, D-BIOL, ETH Zürich, Zürich, Switzerland
| | - Markus Kreuzer
- Institute of Microbiology, D-BIOL, ETH Zürich, Zürich, Switzerland
| | - Lisa Maier
- European Molecular Biology Laboratory, Heidelberg, Heidelberg, Germany
| | - Markus Arnoldini
- Institute of Microbiology, D-BIOL, ETH Zürich, Zürich, Switzerland
| | - Bidong D Nguyen
- Institute of Microbiology, D-BIOL, ETH Zürich, Zürich, Switzerland
| | | | | | - Mirjam Zünd
- Institute of Microbiology, D-BIOL, ETH Zürich, Zürich, Switzerland
| | - Annika Hausmann
- Institute of Microbiology, D-BIOL, ETH Zürich, Zürich, Switzerland
| | - Erik Bakkeren
- Institute of Microbiology, D-BIOL, ETH Zürich, Zürich, Switzerland
| | - Daniel Hoces
- Institute of Microbiology, D-BIOL, ETH Zürich, Zürich, Switzerland
| | - Ersin Gül
- Institute of Microbiology, D-BIOL, ETH Zürich, Zürich, Switzerland
| | - Markus Beutler
- Max von Pettenkofer Institute, Faculty of Medicine, LMU Munich, Munich, Germany
| | | | - Michael Zimmermann
- Institute of Molecular Systems Biology, D-BIOL, ETH Zürich, Zürich, Switzerland
| | - Tobias Fuhrer
- Institute of Molecular Systems Biology, D-BIOL, ETH Zürich, Zürich, Switzerland
| | - Kathrin Moor
- Institute of Microbiology, D-BIOL, ETH Zürich, Zürich, Switzerland
| | - Uwe Sauer
- Institute of Molecular Systems Biology, D-BIOL, ETH Zürich, Zürich, Switzerland
| | - Athanasios Typas
- European Molecular Biology Laboratory, Heidelberg, Heidelberg, Germany
| | - Jörn Piel
- Institute of Microbiology, D-BIOL, ETH Zürich, Zürich, Switzerland
| | - Médéric Diard
- Institute of Microbiology, D-BIOL, ETH Zürich, Zürich, Switzerland
| | - Andrew J Macpherson
- Maurice Müller Laboratories, University Clinic for Visceral Surgery and Medicine, University of Bern, Bern, Switzerland
| | - Bärbel Stecher
- Max von Pettenkofer Institute, Faculty of Medicine, LMU Munich, Munich, Germany.,German Center for Infection Research (DZIF), Munich, Germany
| | | | - Emma Slack
- Institute of Microbiology, D-BIOL, ETH Zürich, Zürich, Switzerland
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50
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Abstract
C-type lectins of the Reg3 family belong to antimicrobial peptides (AMPs), which function as a barrier to protect body surfaces against microorganisms. Reg3 mainly expressed throughout the small intestine modulate host defense process via bactericidal activity. A wide range of studies indicate that Reg3 family plays an important role in the physical segregation of microbiota from host as well as the immune response induced by enteric pathogens. In this review, we review a growing literature on the potential metabolic functions of Reg3 proteins and their potential to act as important gut hormones.
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Affiliation(s)
- Jae Hoon Shin
- Department of Surgery, University of Michigan, Ann Arbor, Michigan
| | - Randy J Seeley
- Department of Surgery, University of Michigan, Ann Arbor, Michigan
- Department of Surgery, Internal Medicine and Nutritional Sciences, University of Michigan, Ann Arbor, Michigan
- Correspondence: Randy J. Seeley, PhD, Department of Surgery, Internal Medicine and Nutritional Science, University of Michigan, Ann Arbor, Michigan 48109. E-mail:
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