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1
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Pan Q, Zhang XL. Roles of core fucosylation modification in immune system and diseases. CELL INSIGHT 2025; 4:100211. [PMID: 39624801 PMCID: PMC11609374 DOI: 10.1016/j.cellin.2024.100211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 10/01/2024] [Accepted: 10/02/2024] [Indexed: 01/04/2025]
Abstract
Core fucosylation, catalyzed by α1,6-fucosyltransferase (FUT8), is an important N-glycosylation modification process that attaches a fucose residue via an α1,6-linkage to the core N-acetylglucosamine of N-glycans in mammals. Research over the past three decades has revealed the critical role of FUT8-mediated core fucosylation modification in various physiological and pathological processes, including cell growth, adhesion, receptor activation, antibody-dependent cellular cytotoxicity (ADCC), tumor metastasis and infections. This review discusses the immune system function involving FUT8 and the mechanisms by which core fucosylation regulates immunity and contributes to disease. A deeper understanding of these mechanisms can provide insights into cellular biology and suggest new therapeutic approaches and targets for related diseases.
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Affiliation(s)
- Qiu Pan
- Hubei Province Key Laboratory of Allergy and Immunology, Department of Allergy Zhongnan Hospital of Wuhan University, Department of Immunology Wuhan University Taikang Medical School (School of Basic Medical Sciences), Wuhan, 430071, China
- State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, Wuhan University School of Medicine, Wuhan, 430071, China
| | - Xiao-Lian Zhang
- Hubei Province Key Laboratory of Allergy and Immunology, Department of Allergy Zhongnan Hospital of Wuhan University, Department of Immunology Wuhan University Taikang Medical School (School of Basic Medical Sciences), Wuhan, 430071, China
- State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, Wuhan University School of Medicine, Wuhan, 430071, China
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2
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Demirturk M, Cinar MS, Avci FY. The immune interactions of gut glycans and microbiota in health and disease. Mol Microbiol 2024; 122:313-330. [PMID: 38703041 DOI: 10.1111/mmi.15267] [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: 10/13/2023] [Revised: 04/11/2024] [Accepted: 04/12/2024] [Indexed: 05/06/2024]
Abstract
The human digestive system harbors a vast diversity of commensal bacteria and maintains a symbiotic relationship with them. However, imbalances in the gut microbiota accompany various diseases, such as inflammatory bowel diseases (IBDs) and colorectal cancers (CRCs), which significantly impact the well-being of populations globally. Glycosylation of the mucus layer is a crucial factor that plays a critical role in maintaining the homeostatic environment in the gut. This review delves into how the gut microbiota, immune cells, and gut mucus layer work together to establish a balanced gut environment. Specifically, the role of glycosylation in regulating immune cell responses and mucus metabolism in this process is examined.
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Affiliation(s)
- Mahmut Demirturk
- Department of Biochemistry, Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Mukaddes Sena Cinar
- Department of Biochemistry, Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Fikri Y Avci
- Department of Biochemistry, Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA
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3
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Woelfel S, Silva MS, Stecher B. Intestinal colonization resistance in the context of environmental, host, and microbial determinants. Cell Host Microbe 2024; 32:820-836. [PMID: 38870899 DOI: 10.1016/j.chom.2024.05.002] [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: 02/15/2024] [Revised: 05/07/2024] [Accepted: 05/07/2024] [Indexed: 06/15/2024]
Abstract
Microbial communities that colonize the human gastrointestinal (GI) tract defend against pathogens through a mechanism known as colonization resistance (CR). Advances in technologies such as next-generation sequencing, gnotobiotic mouse models, and bacterial cultivation have enhanced our understanding of the underlying mechanisms and the intricate microbial interactions involved in CR. Rather than being attributed to specific microbial clades, CR is now understood to arise from a dynamic interplay between microbes and the host and is shaped by metabolic, immune, and environmental factors. This evolving perspective underscores the significance of contextual factors, encompassing microbiome composition and host conditions, in determining CR. This review highlights recent research that has shifted its focus toward elucidating how these factors interact to either promote or impede enteric infections. It further discusses future research directions to unravel the complex relationship between host, microbiota, and environmental determinants in safeguarding against GI infections to promote human health.
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Affiliation(s)
- Simon Woelfel
- Max von Pettenkofer-Institute for Hygiene and Clinical Microbiology, Ludwig Maximilian University of Munich, 80336 Munich, Germany
| | - Marta Salvado Silva
- Max von Pettenkofer-Institute for Hygiene and Clinical Microbiology, Ludwig Maximilian University of Munich, 80336 Munich, Germany
| | - Bärbel Stecher
- Max von Pettenkofer-Institute for Hygiene and Clinical Microbiology, Ludwig Maximilian University of Munich, 80336 Munich, Germany; German Center for Infection Research (DZIF), partner site LMU Munich, Munich, Germany.
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4
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Mizoguchi E, Sadanaga T, Nanni L, Wang S, Mizoguchi A. Recently Updated Role of Chitinase 3-like 1 on Various Cell Types as a Major Influencer of Chronic Inflammation. Cells 2024; 13:678. [PMID: 38667293 PMCID: PMC11049018 DOI: 10.3390/cells13080678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 04/08/2024] [Accepted: 04/11/2024] [Indexed: 04/28/2024] Open
Abstract
Chitinase 3-like 1 (also known as CHI3L1 or YKL-40) is a mammalian chitinase that has no enzymatic activity, but has the ability to bind to chitin, the polymer of N-acetylglucosamine (GlcNAc). Chitin is a component of fungi, crustaceans, arthropods including insects and mites, and parasites, but it is completely absent from mammals, including humans and mice. In general, chitin-containing organisms produce mammalian chitinases, such as CHI3L1, to protect the body from exogenous pathogens as well as hostile environments, and it was thought that it had a similar effect in mammals. However, recent studies have revealed that CHI3L1 plays a pathophysiological role by inducing anti-apoptotic activity in epithelial cells and macrophages. Under chronic inflammatory conditions such as inflammatory bowel disease and chronic obstructive pulmonary disease, many groups already confirmed that the expression of CHI3L1 is significantly induced on the apical side of epithelial cells, and activates many downstream pathways involved in inflammation and carcinogenesis. In this review article, we summarize the expression of CHI3L1 under chronic inflammatory conditions in various disorders and discuss the potential roles of CHI3L1 in those disorders on various cell types.
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Affiliation(s)
- Emiko Mizoguchi
- Department of Immunology, Kurume University School of Medicine, Kurume 830-0011, Japan; (T.S.); (S.W.); (A.M.)
- Department of Molecular Microbiology and Immunology, Brown University Alpert Medical School, Providence, RI 02912, USA
| | - Takayuki Sadanaga
- Department of Immunology, Kurume University School of Medicine, Kurume 830-0011, Japan; (T.S.); (S.W.); (A.M.)
- Department of Molecular Microbiology and Immunology, Brown University Alpert Medical School, Providence, RI 02912, USA
| | - Linda Nanni
- Catholic University of the Sacred Heart, 00168 Rome, Italy;
| | - Siyuan Wang
- Department of Immunology, Kurume University School of Medicine, Kurume 830-0011, Japan; (T.S.); (S.W.); (A.M.)
| | - Atsushi Mizoguchi
- Department of Immunology, Kurume University School of Medicine, Kurume 830-0011, Japan; (T.S.); (S.W.); (A.M.)
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5
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Chen L, Li J, Xiao B. The role of sialidases in the pathogenesis of bacterial vaginosis and their use as a promising pharmacological target in bacterial vaginosis. Front Cell Infect Microbiol 2024; 14:1367233. [PMID: 38495652 PMCID: PMC10940449 DOI: 10.3389/fcimb.2024.1367233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 02/19/2024] [Indexed: 03/19/2024] Open
Abstract
Bacterial vaginosis (BV) is an infection of the genital tract characterized by disturbance of the normally Lactobacilli-dominated vaginal flora due to the overgrowth of Gardnerella and other anaerobic bacteria. Gardnerella vaginalis, an anaerobic pathogen and the major pathogen of BV, produces sialidases that cleave terminal sialic acid residues off of human glycans. By desialylation, sialidases not only alter the function of sialic acid-containing glycoconjugates but also play a vital role in the attachment, colonization and spread of many other vaginal pathogens. With known pathogenic effects, excellent performance of sialidase-based diagnostic tests, and promising therapeutic potentials of sialidase inhibitors, sialidases could be used as a biomarker of BV. This review explores the sources of sialidases and their role in vaginal dysbiosis, in aims to better understand their participation in the pathogenesis of BV and their value in the diagnosis and treatment of BV.
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Affiliation(s)
- Liuyan Chen
- Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing, China
| | - Jiayue Li
- School of Medicine, University College Dublin, Dublin, Ireland
| | - Bingbing Xiao
- Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing, China
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6
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McCoy R, Oldroyd S, Yang W, Wang K, Hoven D, Bulmer D, Zilbauer M, Owens RM. In Vitro Models for Investigating Intestinal Host-Pathogen Interactions. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2306727. [PMID: 38155358 PMCID: PMC10885678 DOI: 10.1002/advs.202306727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 12/01/2023] [Indexed: 12/30/2023]
Abstract
Infectious diseases are increasingly recognized as a major threat worldwide due to the rise of antimicrobial resistance and the emergence of novel pathogens. In vitro models that can adequately mimic in vivo gastrointestinal physiology are in high demand to elucidate mechanisms behind pathogen infectivity, and to aid the design of effective preventive and therapeutic interventions. There exists a trade-off between simple and high throughput models and those that are more complex and physiologically relevant. The complexity of the model used shall be guided by the biological question to be addressed. This review provides an overview of the structure and function of the intestine and the models that are developed to emulate this. Conventional models are discussed in addition to emerging models which employ engineering principles to equip them with necessary advanced monitoring capabilities for intestinal host-pathogen interrogation. Limitations of current models and future perspectives on the field are presented.
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Affiliation(s)
- Reece McCoy
- Department of Chemical Engineering and BiotechnologyUniversity of CambridgeCambridgeCB3 0ASUK
| | - Sophie Oldroyd
- Department of Chemical Engineering and BiotechnologyUniversity of CambridgeCambridgeCB3 0ASUK
| | - Woojin Yang
- Department of Chemical Engineering and BiotechnologyUniversity of CambridgeCambridgeCB3 0ASUK
- Wellcome‐MRC Cambridge Stem Cell InstituteUniversity of CambridgeCambridgeCB2 0AWUK
| | - Kaixin Wang
- Department of Chemical Engineering and BiotechnologyUniversity of CambridgeCambridgeCB3 0ASUK
| | - Darius Hoven
- Department of Chemical Engineering and BiotechnologyUniversity of CambridgeCambridgeCB3 0ASUK
| | - David Bulmer
- Department of PharmacologyUniversity of CambridgeCambridgeCB2 1PDUK
| | - Matthias Zilbauer
- Wellcome‐MRC Cambridge Stem Cell InstituteUniversity of CambridgeCambridgeCB2 0AWUK
| | - Róisín M. Owens
- Department of Chemical Engineering and BiotechnologyUniversity of CambridgeCambridgeCB3 0ASUK
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7
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Matoba H, Iwaya M, Fujii C, Nakayama J. Identification of Terminal βGlcNAc on Brachyspira Species in Human Intestinal Spirochetosis. J Histochem Cytochem 2024; 72:71-78. [PMID: 38189179 PMCID: PMC10851879 DOI: 10.1369/00221554231222963] [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: 08/01/2023] [Accepted: 12/06/2023] [Indexed: 01/09/2024] Open
Abstract
Human intestinal spirochetosis (HIS) is a colorectal bacterial infection caused by the Brachyspira species. Griffonia simplicifolia-II (GS-II) is a lectin specific to terminal α/βGlcNAc residues. Here, we investigated terminal βGlcNAc residues in the context of HIS infection using GS-II-horseradish peroxidase staining and HIK1083 immunostaining specific to terminal αGlcNAc residues. Fourteen of 15 HIS cases were GS-II-positive on the bacterial body. No cases showed HIK1083 positivity. The percentage of bacterial bodies staining positively for GS-II based on comparison with anti-Treponema immunostaining was ≤30% in seven cases, 30-70% in two, and >70% in six. Of 15 HIS cases analyzed, none were comorbid with tubular adenomas, and three were comorbid with sessile serrated lesions (SSLs). To determine the species of spirochete infected, the B. aalborgi-specific or B. pilosicoli-specific NADPH oxidase genes were amplified by PCR. After direct sequencing of the PCR products, all nine cases in which PCR products were observed were found to be infected with B. aalborgi alone. These results indicate that the HIS bacterial body, especially of B. aalborgi, is characterized by terminal βGlcNAc and also indicate that terminal βGlcNAc on the HIS bacterial body is associated with HIS preference for SSLs.
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Affiliation(s)
- Hisanori Matoba
- Department of Infection and Host Defense (HM); Department of Molecular Pathology (HM, CF, JN); Center for Medical Education and Clinical Training (CF), Shinshu University School of Medicine, Matsumoto, Japan; Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan (MI); Department of Biotechnology, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto, Japan (CF); and Department of Pathology, North Alps Medical Center Azumi Hospital, Kitaazumi-gun, Japan (JN)
| | - Mai Iwaya
- Department of Infection and Host Defense (HM); Department of Molecular Pathology (HM, CF, JN); Center for Medical Education and Clinical Training (CF), Shinshu University School of Medicine, Matsumoto, Japan; Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan (MI); Department of Biotechnology, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto, Japan (CF); and Department of Pathology, North Alps Medical Center Azumi Hospital, Kitaazumi-gun, Japan (JN)
| | - Chifumi Fujii
- Department of Infection and Host Defense (HM); Department of Molecular Pathology (HM, CF, JN); Center for Medical Education and Clinical Training (CF), Shinshu University School of Medicine, Matsumoto, Japan; Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan (MI); Department of Biotechnology, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto, Japan (CF); and Department of Pathology, North Alps Medical Center Azumi Hospital, Kitaazumi-gun, Japan (JN)
| | - Jun Nakayama
- Department of Infection and Host Defense (HM); Department of Molecular Pathology (HM, CF, JN); Center for Medical Education and Clinical Training (CF), Shinshu University School of Medicine, Matsumoto, Japan; Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan (MI); Department of Biotechnology, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto, Japan (CF); and Department of Pathology, North Alps Medical Center Azumi Hospital, Kitaazumi-gun, Japan (JN)
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8
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Pan Q, Xie Y, Zhang Y, Guo X, Wang J, Liu M, Zhang XL. EGFR core fucosylation, induced by hepatitis C virus, promotes TRIM40-mediated-RIG-I ubiquitination and suppresses interferon-I antiviral defenses. Nat Commun 2024; 15:652. [PMID: 38253527 PMCID: PMC10803816 DOI: 10.1038/s41467-024-44960-6] [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: 06/14/2023] [Accepted: 01/08/2024] [Indexed: 01/24/2024] Open
Abstract
Aberrant N-glycosylation has been implicated in viral diseases. Alpha-(1,6)-fucosyltransferase (FUT8) is the sole enzyme responsible for core fucosylation of N-glycans during glycoprotein biosynthesis. Here we find that multiple viral envelope proteins, including Hepatitis C Virus (HCV)-E2, Vesicular stomatitis virus (VSV)-G, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-Spike and human immunodeficiency virus (HIV)-gp120, enhance FUT8 expression and core fucosylation. HCV-E2 manipulates host transcription factor SNAIL to induce FUT8 expression through EGFR-AKT-SNAIL activation. The aberrant increased-FUT8 expression promotes TRIM40-mediated RIG-I K48-ubiquitination and suppresses the antiviral interferon (IFN)-I response through core fucosylated-EGFR-JAK1-STAT3-RIG-I signaling. FUT8 inhibitor 2FF, N-glycosylation site-specific mutation (Q352AT) of EGFR, and tissue-targeted Fut8 silencing significantly increase antiviral IFN-I responses and suppress RNA viral replication, suggesting that core fucosylation mediated by FUT8 is critical for antiviral innate immunity. These findings reveal an immune evasion mechanism in which virus-induced FUT8 suppresses endogenous RIG-I-mediated antiviral defenses by enhancing core fucosylated EGFR-mediated activation.
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Grants
- This work was supported by grants from the National Natural Science Foundation of China (82230078, 22077097, 91740120, 82272978, 21572173 and 21721005), National Outstanding Youth Foundation of China (81025008), National Key R&D Program of China (2022YFA1303500, 2018YFA0507603), Medical Science Advancement Program (Basical Medical Sciences) of Wuhan University (TFJC 2018002.), Key R&D Program of Hubei Province (2020BCB020), the Hubei Province’s Outstanding Medical Academic Leader Program (523-276003), the Innovative Group Project of Hubei Health Committee (WJ2021C002), the Foundational Research Funds for the Central University of China (2042022dx0003, 2042023kf1011) and Natural Science Foundation Project of Hubei Province (2021CFB484), Natural Science Foundation Project of Hubei Province (2021CFB484 to M.L).
- This work was supported by grants from the Natural Science Foundation of Hubei Province (2021CFB484), National Natural Science Foundation of China 82272978
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Affiliation(s)
- Qiu Pan
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, and Department of Immunology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, 430071, China
| | - Yan Xie
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, and Department of Immunology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, 430071, China
| | - Ying Zhang
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, and Department of Immunology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, 430071, China
| | - Xinqi Guo
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, and Department of Immunology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, 430071, China
| | - Jing Wang
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, and Department of Immunology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, 430071, China
| | - Min Liu
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, and Department of Immunology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, 430071, China.
| | - Xiao-Lian Zhang
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, and Department of Immunology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, 430071, China.
- Department of Allergy, Zhongnan Hospital of Wuhan University, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, 430071, China.
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9
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Budzinski L, von Goetze V, Chang HD. Single-cell phenotyping of bacteria combined with deep sequencing for improved contextualization of microbiome analyses. Eur J Immunol 2024; 54:e2250337. [PMID: 37863831 DOI: 10.1002/eji.202250337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 10/17/2023] [Accepted: 10/19/2023] [Indexed: 10/22/2023]
Abstract
Great effort was made to characterize the bacterial communities inhabiting the human body as a factor in disease, resulting in the realization that a wide spectrum of diseases is associated with an altered composition of the microbiome. However, the identification of disease-relevant bacteria has been hindered by the high cross-sectional diversity of individual microbiomes, and in most cases, it remains unclear whether the observed alterations are cause or consequence of disease. Hence, innovative analysis approaches are required that enable inquiries of the microbiome beyond mere taxonomic cataloging. This review highlights the utility of microbiota flow cytometry, a single-cell analysis platform to directly interrogate cellular interactions, cell conditions, and crosstalk with the host's immune system within the microbiome to take into consideration the role of microbes as critical interaction partners of the host and the spectrum of microbiome alterations, beyond compositional changes. In conjunction with advanced sequencing approaches it could reveal the genetic potential of target bacteria and advance our understanding of taxonomic diversity and gene usage in the context of the microenvironment. Single-cell bacterial phenotyping has the potential to change our perspective on the human microbiome and empower microbiome research for the development of microbiome-based therapy approaches and personalized medicine.
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Affiliation(s)
- Lisa Budzinski
- Schwiete Laboratory for Microbiota and Inflammation, German Rheumatism Research Centre Berlin - A Leibniz Institute, Berlin, Germany
| | - Victoria von Goetze
- Schwiete Laboratory for Microbiota and Inflammation, German Rheumatism Research Centre Berlin - A Leibniz Institute, Berlin, Germany
| | - Hyun-Dong Chang
- Schwiete Laboratory for Microbiota and Inflammation, German Rheumatism Research Centre Berlin - A Leibniz Institute, Berlin, Germany
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10
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Tóth Š, Fagová Z, Holodová M, Zeidan D, Hartel P, Čurgali K, Mechírová E, Maretta M, Nemcová R, Gancarčíková S, Danková M. Influence of Escherichia coli infection on intestinal mucosal barrier integrity of germ-free piglets. Life Sci 2023; 331:122036. [PMID: 37633417 DOI: 10.1016/j.lfs.2023.122036] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 08/11/2023] [Accepted: 08/21/2023] [Indexed: 08/28/2023]
Abstract
AIMS We focused on investigating the influence of Escherichia coli (E. coli) on the intestinal barrier. MATERIAL AND METHODS We studied changes in the distribution and secretory activities of goblet cells and enteroendocrine cells (EECs), as well as changes in the population of mast cells (MCs) in the jejunal and colonic mucosa of germ-free (GF) piglets as a healthy control group and GF piglets whose intestines were colonised with E. coli bacteria on day 5. KEY FINDINGS The results suggest that the colon of GF piglets is more resistant and less prone to coliform bacterial infection compared to the jejunum. This can be confirmed by a lower degree of histopathological injury index as well as an improvement of the morphometric parameters of the colonic mucosa, together with a significantly increased (p < 0.05) expression of MUC1/EMA, and ZO-3. We also observed a significant decrease in the population of activated MCs (p < 0.001) and EECs (p < 0.001). These findings may indicate a rapid response and better preparation of the intestinal barrier for possible pathological attacks and the subsequent development of mucosal lesions during the development and progression of the intestinal diseases. SIGNIFICANCE To date, gut-targeted therapeutic approaches that can modulate bacterial translocation and chronic inflammation are still in their infancy but represent one of the most promising areas of research for the development of new effective treatments or clinical strategies in the future. Therefore, a better understanding of these processes can significantly contribute to the development of these targeted strategies for disease prevention and treatment.
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Affiliation(s)
- Štefan Tóth
- Pavol Jozef Šafárik University, Faculty of Medicine, Department of Histology and Embryology, Šrobárova 2, 040 01 Košice, Slovak Republic
| | - Zuzana Fagová
- Pavol Jozef Šafárik University, Faculty of Medicine, Department of Histology and Embryology, Šrobárova 2, 040 01 Košice, Slovak Republic
| | - Monika Holodová
- Pavol Jozef Šafárik University, Faculty of Medicine, Department of Histology and Embryology, Šrobárova 2, 040 01 Košice, Slovak Republic
| | - Dema Zeidan
- Pavol Jozef Šafárik University, Faculty of Medicine, Department of Histology and Embryology, Šrobárova 2, 040 01 Košice, Slovak Republic
| | - Patrick Hartel
- Pavol Jozef Šafárik University, Faculty of Medicine, Department of Histology and Embryology, Šrobárova 2, 040 01 Košice, Slovak Republic
| | - Kristína Čurgali
- Pavol Jozef Šafárik University, Faculty of Medicine, Department of Histology and Embryology, Šrobárova 2, 040 01 Košice, Slovak Republic
| | - Eva Mechírová
- Pavol Jozef Šafárik University, Faculty of Medicine, Department of Histology and Embryology, Šrobárova 2, 040 01 Košice, Slovak Republic
| | - Milan Maretta
- Pavol Jozef Šafárik University, Faculty of Medicine, Department of Neurology and L. Pasteur University Hospital, Trieda SNP 1, 040 01 Košice, Slovak Republic
| | - Radomíra Nemcová
- University of Veterinary Medicine and Pharmacy in Košice, Department of Microbiology and Immunology, Komenského 73, 041 70 Košice, Slovak Republic
| | - Soňa Gancarčíková
- University of Veterinary Medicine and Pharmacy in Košice, Department of Microbiology and Immunology, Komenského 73, 041 70 Košice, Slovak Republic
| | - Marianna Danková
- Comenius University in Bratislava, Faculty of Medicine, Institute of Histology and Embryology, Sasinkova 4, 811 04 Bratislava, Slovak Republic.
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11
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Gonciarz W, Chyb M, Chmiela M. Diminishing of Helicobacter pylori adhesion to Cavia porcellus gastric epithelial cells by BCG vaccine mycobacteria. Sci Rep 2023; 13:16305. [PMID: 37770504 PMCID: PMC10539345 DOI: 10.1038/s41598-023-43571-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 09/26/2023] [Indexed: 09/30/2023] Open
Abstract
Mycobacterium bovis onco-BCG bacilli used in immunotherapy of bladder cancer are candidates for training of immune cells towards microbial pathogens. Increasing antibiotic resistance of gastric pathogen Helicobacter pylori (Hp) prompts the search for new anti-Hp and immunomodulatory formulations. Colonization of gastric mucosa by Hp through mucin 5 AC (MUC5AC) ligands could potentially be a therapeutic target. The aim of this study was to examine the ability of onco-BCG mycobacteria to reduce Hp adhesion to gastric epithelial cells using Cavia porcellus model. Animals were inoculated per os with 0.85% NaCl, Hp alone, onco-BCG alone or with onco-BCG and Hp. After 7/28 days Mucin5AC and Hp binding to gastric epithelium were assessed in gastric tissue specimens by staining with anti-Mucin5AC and anti-Hp antibodies, respectively, both fluorescently labeled. Primary gastric epithelial cells were treated ex vivo with live Hp or Hp surface antigens (glycine extract or lipopolysaccharide) alone or with onco-BCG. In such cells MUC5AC and Hp binding were determined as above. Mycobacteria reduced the amount of MUC5AC animals infected with Hp and in gastric epithelial cells pulsed in vitro with Hp components. Decrease of MUC5AC driven in cell cultures in vitro and in gastric tissue exposed ex vivo to mycobacteria was related to diminished adhesion of H. pylori bacilli. Vaccine mycobacteria by diminishing the amount of MUC5AC in gastric epithelial cells may reduce Hp adhesion.
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Affiliation(s)
- Weronika Gonciarz
- Department of Immunology and Infectious Biology, Institute of Microbiology, Biotechnology and Immunology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12-16, 90-237, Lodz, Poland.
| | - Maciej Chyb
- Department of Molecular Microbiology, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland
- Bio-Med-Chem Doctoral School of the University of Lodz and Lodz Institutes of the Polish Academy of Sciences, Lodz, Poland
| | - Magdalena Chmiela
- Department of Immunology and Infectious Biology, Institute of Microbiology, Biotechnology and Immunology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12-16, 90-237, Lodz, Poland.
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12
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Hansen AW, Venkatachalam KV. Sulfur-Element containing metabolic pathways in human health and crosstalk with the microbiome. Biochem Biophys Rep 2023; 35:101529. [PMID: 37601447 PMCID: PMC10439400 DOI: 10.1016/j.bbrep.2023.101529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 08/09/2023] [Accepted: 08/10/2023] [Indexed: 08/22/2023] Open
Abstract
In humans, methionine derived from dietary proteins is necessary for cellular homeostasis and regeneration of sulfur containing pathways, which produce inorganic sulfur species (ISS) along with essential organic sulfur compounds (OSC). In recent years, inorganic sulfur species have gained attention as key players in the crosstalk of human health and the gut microbiome. Endogenously, ISS includes hydrogen sulfide (H2S), sulfite (SO32-), thiosulfate (S2O32-), and sulfate (SO42-), which are produced by enzymes in the transsulfuration and sulfur oxidation pathways. Additionally, sulfate-reducing bacteria (SRB) in the gut lumen are notable H2S producers which can contribute to the ISS pools of the human host. In this review, we will focus on the systemic effects of sulfur in biological pathways, describe the contrasting mechanisms of sulfurylation versus phosphorylation on the hydroxyl of serine/threonine and tyrosine residues of proteins in post-translational modifications, and the role of the gut microbiome in human sulfur metabolism.
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Affiliation(s)
- Austin W. Hansen
- College of Allopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL, 33328, USA
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13
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Miao YB, Xu T, Gong Y, Chen A, Zou L, Jiang T, Shi Y. Cracking the intestinal lymphatic system window utilizing oral delivery vehicles for precise therapy. J Nanobiotechnology 2023; 21:263. [PMID: 37559085 PMCID: PMC10413705 DOI: 10.1186/s12951-023-01991-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 07/09/2023] [Indexed: 08/11/2023] Open
Abstract
Oral administration is preferred over other drug delivery methods due to its safety, high patient compliance, ease of ingestion without discomfort, and tolerance of a wide range of medications. However, oral drug delivery is limited by the poor oral bioavailability of many drugs, caused by extreme conditions and absorption challenges in the gastrointestinal tract. This review thoroughly discusses the targeted drug vehicles to the intestinal lymphatic system (ILS). It explores the structure and physiological barriers of the ILS, highlighting its significance in dietary lipid and medication absorption and transport. The review presents various approaches to targeting the ILS using spatially precise vehicles, aiming to enhance bioavailability, achieve targeted delivery, and reduce first-pass metabolism with serve in clinic. Furthermore, the review outlines several methods for leveraging these vehicles to open the ILS window, paving the way for potential clinical applications in cancer treatment and oral vaccine delivery. By focusing on targeted drug vehicles to the ILS, this article emphasizes the critical role of these strategies in improving therapeutic efficacy and patient outcomes. Overall, this article emphasizes the critical role of targeted drug vehicles to the ILS and the potential impact of these strategies on improving therapeutic efficacy and patient outcomes.
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Affiliation(s)
- Yang-Bao Miao
- Department of Haematology, School of Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, No. 32, West Section 2, First Ring Road, Qingyang District, Chengdu, 610000, China.
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China.
| | - Tianxing Xu
- Department of Haematology, School of Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, No. 32, West Section 2, First Ring Road, Qingyang District, Chengdu, 610000, China
| | - Ying Gong
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, People's Republic of China
| | - Anmei Chen
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, People's Republic of China
| | - Liang Zou
- School of Food and Biological Engineering, Chengdu University, Chengdu, Sichuan, 610106, China
| | - Tao Jiang
- Department of Haematology, School of Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, No. 32, West Section 2, First Ring Road, Qingyang District, Chengdu, 610000, China.
| | - Yi Shi
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China.
- Natural Products Research Center, Institute of Chengdu Biology, Sichuan Translational Medicine Hospital, Chinese Academy of Sciences, Chengdu, Sichuan, 610072, China.
- Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan, 610072, China.
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14
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Yamaguchi M, Yamamoto K. Mucin glycans and their degradation by gut microbiota. Glycoconj J 2023; 40:493-512. [PMID: 37318672 DOI: 10.1007/s10719-023-10124-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 03/13/2023] [Accepted: 05/22/2023] [Indexed: 06/16/2023]
Abstract
The human intestinal tract is inhabited by a tremendous number of microorganisms, which are collectively termed "the gut microbiota". The intestinal epithelium is covered with a dense layer of mucus that prevents penetration of the gut microbiota into underlying tissues of the host. Recent studies have shown that the maturation and function of the mucus layer are strongly influenced by the gut microbiota, and alteration in the structure and function of the gut microbiota is implicated in several diseases. Because the intestinal mucus layer is at a crucial interface between microbes and their host, its breakdown leads to gut bacterial invasion that can eventually cause inflammation and infection. The mucus is composed of mucin, which is rich in glycans, and the various structures of the complex carbohydrates of mucins can select for distinct mucosa-associated bacteria that are able to bind mucin glycans, and sometimes degrade them as a nutrient source. Mucin glycans are diverse molecules, and thus mucin glycan degradation is a complex process that requires a broad range of glycan-degrading enzymes. Because of the increased recognition of the role of mucus-associated microbes in human health, how commensal bacteria degrade and use host mucin glycans has become of increased interest. This review provides an overview of the relationships between the mucin glycan of the host and gut commensal bacteria, with a focus on mucin degradation.
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Affiliation(s)
- Masanori Yamaguchi
- Department of Organic Bio Chemistry, Faculty of Education, Wakayama University, 930, Sakaedani, Wakayama, 640-8510, Japan.
| | - Kenji Yamamoto
- Center for Innovative and Joint Research, Wakayama University, 930, Sakaedani, Wakayama, 640-8510, Japan
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15
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Marín-Quílez A, Díaz-Ajenjo L, Di Buduo CA, Zamora-Cánovas A, Lozano ML, Benito R, González-Porras JR, Balduini A, Rivera J, Bastida JM. Inherited Thrombocytopenia Caused by Variants in Crucial Genes for Glycosylation. Int J Mol Sci 2023; 24:5109. [PMID: 36982178 PMCID: PMC10049517 DOI: 10.3390/ijms24065109] [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: 12/30/2022] [Revised: 02/13/2023] [Accepted: 03/03/2023] [Indexed: 03/30/2023] Open
Abstract
Protein glycosylation, including sialylation, involves complex and frequent post-translational modifications, which play a critical role in different biological processes. The conjugation of carbohydrate residues to specific molecules and receptors is critical for normal hematopoiesis, as it favors the proliferation and clearance of hematopoietic precursors. Through this mechanism, the circulating platelet count is controlled by the appropriate platelet production by megakaryocytes, and the kinetics of platelet clearance. Platelets have a half-life in blood ranging from 8 to 11 days, after which they lose the final sialic acid and are recognized by receptors in the liver and eliminated from the bloodstream. This favors the transduction of thrombopoietin, which induces megakaryopoiesis to produce new platelets. More than two hundred enzymes are responsible for proper glycosylation and sialylation. In recent years, novel disorders of glycosylation caused by molecular variants in multiple genes have been described. The phenotype of the patients with genetic alterations in GNE, SLC35A1, GALE and B4GALT is consistent with syndromic manifestations, severe inherited thrombocytopenia, and hemorrhagic complications.
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Affiliation(s)
- Ana Marín-Quílez
- Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-U765, 30003 Murcia, Spain
| | - Lorena Díaz-Ajenjo
- IBSAL, CIC, IBMCC, Universidad de Salamanca-CSIC, 37007 Salamanca, Spain
| | | | - Ana Zamora-Cánovas
- Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-U765, 30003 Murcia, Spain
| | - María Luisa Lozano
- Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-U765, 30003 Murcia, Spain
| | - Rocío Benito
- IBSAL, CIC, IBMCC, Universidad de Salamanca-CSIC, 37007 Salamanca, Spain
| | - José Ramón González-Porras
- Department of Hematology, Complejo Asistencial Universitario de Salamanca (CAUSA), Instituto de Investigación Biomédica de Salamanca (IBSAL), Universidad de Salamanca (USAL), 37007 Salamanca, Spain
| | - Alessandra Balduini
- Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
- Department of Biomedical Engineering, Tufts University, Medford, MA 02155, USA
| | - José Rivera
- Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-U765, 30003 Murcia, Spain
| | - José María Bastida
- Department of Hematology, Complejo Asistencial Universitario de Salamanca (CAUSA), Instituto de Investigación Biomédica de Salamanca (IBSAL), Universidad de Salamanca (USAL), 37007 Salamanca, Spain
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16
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Lin SJH, Helm ET, Gabler NK, Burrough ER. Acute infection with Brachyspira hyodysenteriae affects mucin expression, glycosylation, and fecal MUC5AC. Front Cell Infect Microbiol 2023; 12:1042815. [PMID: 36683692 PMCID: PMC9852840 DOI: 10.3389/fcimb.2022.1042815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 11/28/2022] [Indexed: 01/08/2023] Open
Abstract
Introduction Infection with strongly β-hemolytic strains of Brachyspira hyodysenteriae leads to swine dysentery (SD), a production-limiting disease that causes mucohemorrhagic diarrhea and typhlocolitis in pigs. This pathogen has strong chemotactic activity toward mucin, and infected pigs often have a disorganized mucus layer and marked de novo expression of MUC5AC, which is not constitutively expressed in the colon. It has been shown that fucose is chemoattractant for B. hyodysenteriae, and a highly fermentable fiber diet can mitigate and delay the onset of SD. Methods We used lectins targeting sialic acids in α-2,6 or α-2,3 linkages, N-acetylglucosamine (GlcNAc), α-linked L-fucose, and an immunohistochemical stain targeting N-glycolylneuraminic acid (NeuGc) to investigate the local expression of these mucin glycans in colonic tissues of pigs with acute SD. We used a commercial enzyme-linked immunosorbent assay (ELISA) to quantify fecal MUC5AC in infected pigs and assess its potential as a diagnostic monitoring tool and RNA in situ hybridization to detect IL-17A in the colonic mucosa. Results Colonic mucin glycosylation during SD has an overall increase in fucose, a spatially different distribution of GlcNAc with more expression within the crypt lumens of the upper colonic mucosa, and decreased expression or a decreased trend of sialic acids in α-2,6 or α-2,3 linkages, and NeuGc compared to the controls. The degree of increased fucosylation was less in the colonic mucosa of pigs with SD and fed the highly fermentable fiber diet. There was a significant increase in MUC5AC in fecal and colonic samples of pigs with SD at the endpoint compared to the controls, but the predictive value for disease progression was limited. Discussion Fucosylation and the impact of dietary fiber may play important roles in the pathogenesis of SD. The lack of predictive value for fecal MUC5AC quantification by ELISA is possibly due to the presence of other non-colonic sources of MUC5AC in the feces. The moderate correlation between IL-17A, neutrophils and MUC5AC confirms its immunoregulatory and mucin stimulatory role. Our study characterizes local alteration of mucin glycosylation in the colonic mucosa of pigs with SD after B. hyodysenteriae infection and may provide insight into host-pathogen interaction.
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Affiliation(s)
- Susanne Je-Han Lin
- Department of Veterinary Pathology, Iowa State University, Ames, IA, United States
| | - Emma T Helm
- Department of Animal Science, Iowa State University, Ames, IA, United States
| | - Nicholas K Gabler
- Department of Animal Science, Iowa State University, Ames, IA, United States
| | - Eric R Burrough
- Department of Veterinary Diagnostic and Production Animal Medicine, Iowa State University, Ames, IA, United States
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17
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Overbeeke A, Hausmann B, Nikolov G, Pereira FC, Herbold CW, Berry D. Nutrient niche specificity for glycosaminoglycans is reflected in polysaccharide utilization locus architecture of gut Bacteroides species. Front Microbiol 2022; 13:1033355. [PMID: 36523841 PMCID: PMC9745678 DOI: 10.3389/fmicb.2022.1033355] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 11/11/2022] [Indexed: 09/24/2023] Open
Abstract
Introduction Glycosaminoglycans (GAGs) present in the mucosal layer can be used as nutrients by certain intestinal bacteria, particularly members of the Bacteroides. GAG abundances are altered in some diseases such as inflammatory bowel diseases, which may affect microbial composition and activity, and it is therefore important to understand GAG utilization by members of the gut microbiota. Methods We used growth assays, transcriptomics, and comparative genomics to evaluate chondroitin sulfate (CS) and hyaluronan (HA) degradation ability by multiple gut Bacteroides species. Results and discussion We found that not all Bacteroides species able to degrade CS could also degrade HA, despite having lyases which act on both compounds. We propose that in the model organism Bacteroides thetaiotaomicron, the lyase BT_3328 in combination with surface binding proteins BT_3329 and BT_3330 and potentially BT_4411 are involved in HA breakdown. Furthermore, degradation of both compounds provides public goods for other Bacteroides, including non-degraders, suggesting that cooperative degradation as well as cross-feeding may be widespread in the mucosal glycan utilization clade.
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Affiliation(s)
- Annelieke Overbeeke
- Centre for Microbiology and Environmental Systems Science, University of Vienna, Vienna, Austria
- Doctoral School in Microbiology and Environmental Science, University of Vienna, Vienna, Austria
| | - Bela Hausmann
- Joint Microbiome Facility, Medical University of Vienna, Vienna, Austria
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Georgi Nikolov
- Centre for Microbiology and Environmental Systems Science, University of Vienna, Vienna, Austria
| | - Fatima C. Pereira
- Centre for Microbiology and Environmental Systems Science, University of Vienna, Vienna, Austria
| | - Craig W. Herbold
- Centre for Microbiology and Environmental Systems Science, University of Vienna, Vienna, Austria
| | - David Berry
- Centre for Microbiology and Environmental Systems Science, University of Vienna, Vienna, Austria
- Joint Microbiome Facility, Medical University of Vienna, Vienna, Austria
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18
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Lei C, Sun R, Xu G, Tan Y, Feng W, McClain CJ, Deng Z. Enteric VIP-producing neurons maintain gut microbiota homeostasis through regulating epithelium fucosylation. Cell Host Microbe 2022; 30:1417-1434.e8. [PMID: 36150396 PMCID: PMC9588764 DOI: 10.1016/j.chom.2022.09.001] [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: 01/28/2022] [Revised: 05/18/2022] [Accepted: 08/31/2022] [Indexed: 12/12/2022]
Abstract
Interactions between the enteric nervous system (ENS) and intestinal epithelium are thought to play a vital role in intestinal homeostasis. How the ENS monitors the frontier with commensal and pathogenic microbes while maintaining epithelial function remains unclear. Here, by combining subdiaphragmatic vagotomy with transcriptomics, chemogenetic strategy, and coculture of enteric neuron-intestinal organoid, we show that enteric neurons expressing VIP shape the α1,2-fucosylation of intestinal epithelial cells (IECs). Mechanistically, neuropeptide VIP activates fut2 expression via the Erk1/2-c-Fos pathway through the VIPR1 receptor on IECs. We further demonstrate that perturbation of enteric neurons leads to gut dysbiosis through α1,2-fucosylation in the steady state and results in increased susceptibility to alcohol-associated liver disease (ALD). This was attributed to an imbalance between beneficial Bifidobacterium and opportunistic pathogenic Enterococcus faecalis in ALD. In addition, Bifidobacterium α1,2-fucosidase may promote Bifidobacterium adhesion to the mucosal surface, which restricts Enterococcus faecalis overgrowth and prevents ALD progression.
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Affiliation(s)
- Chao Lei
- Department of Surgery, Division of Immunotherapy, University of Louisville, Louisville, KY, USA; Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Rui Sun
- Department of Surgery, Division of Immunotherapy, University of Louisville, Louisville, KY, USA; Brown Cancer Center, University of Louisville, Louisville, KY, USA; Central Laboratory and Department of Oncology, Wuhan Fourth Hospital, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430033, China
| | - Guangzhong Xu
- Department of Medicine, University of Louisville, Louisville, KY, USA
| | - Yi Tan
- Department of Pediatrics, University of Louisville, Louisville, KY, USA
| | - Wenke Feng
- Department of Medicine, University of Louisville, Louisville, KY, USA; Alcohol Research Center, University of Louisville, Louisville, KY, USA; Hepatobiology & Toxicology Center, University of Louisville, Louisville, KY, USA
| | - Craig J McClain
- Department of Medicine, University of Louisville, Louisville, KY, USA; Alcohol Research Center, University of Louisville, Louisville, KY, USA; Hepatobiology & Toxicology Center, University of Louisville, Louisville, KY, USA; Robley Rex VA Medical Center, Louisville, KY, USA
| | - Zhongbin Deng
- Department of Surgery, Division of Immunotherapy, University of Louisville, Louisville, KY, USA; Brown Cancer Center, University of Louisville, Louisville, KY, USA; Alcohol Research Center, University of Louisville, Louisville, KY, USA; Hepatobiology & Toxicology Center, University of Louisville, Louisville, KY, USA.
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19
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Recent findings in Akkermansia muciniphila-regulated metabolism and its role in intestinal diseases. Clin Nutr 2022; 41:2333-2344. [DOI: 10.1016/j.clnu.2022.08.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 07/22/2022] [Accepted: 08/27/2022] [Indexed: 11/22/2022]
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20
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Suwandi A, Alvarez KG, Galeev A, Steck N, Riedel CU, Puente JL, Baines JF, Grassl GA. B4galnt2-mediated host glycosylation influences the susceptibility to Citrobacter rodentium infection. Front Microbiol 2022; 13:980495. [PMID: 36033875 PMCID: PMC9403859 DOI: 10.3389/fmicb.2022.980495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 07/25/2022] [Indexed: 11/13/2022] Open
Abstract
Histo-blood group antigens in the intestinal mucosa play important roles in host–microbe interactions and modulate the susceptibility to enteric pathogens. The B4galnt2 gene, expressed in the GI tract of most mammals, including humans, encodes a beta-1,4-N-acetylgalactosaminyltransferase enzyme which catalyzes the last step in the biosynthesis of the Sd(a) and Cad blood group antigens by adding an N-acetylgalactosamine (GalNAc) residue to the precursor molecules. In our study, we found that loss of B4galnt2 expression is associated with increased susceptibility to Citrobacter rodentium infection, a murine model pathogen for human enteropathogenic Escherichia coli. We observed increased histopathological changes upon C. rodentium infection in mice lacking B4galnt2 compared to B4galnt2-expressing wild-type mice. In addition, wild-type mice cleared the C. rodentium infection faster than B4galnt2−/− knockout mice. It is known that C. rodentium uses its type 1 fimbriae adhesive subunit to bind specifically to D-mannose residues on mucosal cells. Flow cytometry analysis of intestinal epithelial cells showed the absence of GalNAc-modified glycans but an increase in mannosylated glycans in B4galnt2-deficient mice compared to B4galnt2-sufficient mice. Adhesion assays using intestinal epithelial organoid-derived monolayers revealed higher C. rodentium adherence to cells lacking B4galnt2 expression compared to wild-type cells which in turn was reduced in the absence of type I fimbriae. In summary, we show that B4galnt2 expression modulates the susceptibility to C. rodentium infection, which is partly mediated by fimbriae-mannose interaction.
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Affiliation(s)
- Abdulhadi Suwandi
- Institute of Cell Biochemistry, Center of Biochemistry, Hannover Medical School, Hannover, Germany
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School and German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany
| | - Kris Gerard Alvarez
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School and German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany
| | - Alibek Galeev
- Section of Evolutionary Medicine, Institute for Experimental Medicine, Kiel University, Kiel, Germany
- Max Planck Institute for Evolutionary Biology, Plön, Germany
| | - Natalie Steck
- Section of Evolutionary Medicine, Institute for Experimental Medicine, Kiel University, Kiel, Germany
| | - Christian U. Riedel
- Institute of Microbiology and Biotechnology, University of Ulm, Ulm, Germany
| | - José Luis Puente
- Departamento de Microbiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Morelos, Mexico
| | - John F. Baines
- Section of Evolutionary Medicine, Institute for Experimental Medicine, Kiel University, Kiel, Germany
- Max Planck Institute for Evolutionary Biology, Plön, Germany
| | - Guntram A. Grassl
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School and German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany
- *Correspondence: Guntram A. Grassl,
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Subramanian DA, Langer R, Traverso G. Mucus interaction to improve gastrointestinal retention and pharmacokinetics of orally administered nano-drug delivery systems. J Nanobiotechnology 2022; 20:362. [PMID: 35933341 PMCID: PMC9356434 DOI: 10.1186/s12951-022-01539-x] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 06/27/2022] [Indexed: 11/29/2022] Open
Abstract
Oral delivery of therapeutics is the preferred route of administration due to ease of administration which is associated with greater patient medication adherence. One major barrier to oral delivery and intestinal absorption is rapid clearance of the drug and the drug delivery system from the gastrointestinal (GI) tract. To address this issue, researchers have investigated using GI mucus to help maximize the pharmacokinetics of the therapeutic; while mucus can act as a barrier to effective oral delivery, it can also be used as an anchoring mechanism to improve intestinal residence. Nano-drug delivery systems that use materials which can interact with the mucus layers in the GI tract can enable longer residence time, improving the efficacy of oral drug delivery. This review examines the properties and function of mucus in the GI tract, as well as diseases that alter mucus. Three broad classes of mucus-interacting systems are discussed: mucoadhesive, mucus-penetrating, and mucolytic drug delivery systems. For each class of system, the basis for mucus interaction is presented, and examples of materials that inform the development of these systems are discussed and reviewed. Finally, a list of FDA-approved mucoadhesive, mucus-penetrating, and mucolytic drug delivery systems is reviewed. In summary, this review highlights the progress made in developing mucus-interacting systems, both at a research-scale and commercial-scale level, and describes the theoretical basis for each type of system.
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Affiliation(s)
- Deepak A Subramanian
- Department of Chemical Engineering and David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Robert Langer
- Department of Chemical Engineering and David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.,Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Giovanni Traverso
- Department of Chemical Engineering and David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. .,Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. .,Division of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
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22
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Yu S, Sun Y, Shao X, Zhou Y, Yu Y, Kuai X, Zhou C. Leaky Gut in IBD: Intestinal Barrier-Gut Microbiota Interaction. J Microbiol Biotechnol 2022; 32:825-834. [PMID: 35791076 PMCID: PMC9628915 DOI: 10.4014/jmb.2203.03022] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 06/26/2022] [Accepted: 06/28/2022] [Indexed: 12/15/2022]
Abstract
Inflammatory bowel disease (IBD) is a global disease that is in increasing incidence. The gut, which contains the largest amount of lymphoid tissue in the human body, as well as a wide range of nervous system components, is integral in ensuring intestinal homeostasis and function. By interacting with gut microbiota, immune cells, and the enteric nervous system, the intestinal barrier, which is a solid barrier, protects the intestinal tract from the external environment, thereby maintaining homeostasis throughout the body. Destruction of the intestinal barrier is referred to as developing a "leaky gut," which causes a series of changes relating to the occurrence of IBD. Changes in the interactions between the intestinal barrier and gut microbiota are particularly crucial in the development of IBD. Exploring the leaky gut and its interaction with the gut microbiota, immune cells, and the neuroimmune system may help further explain the pathogenesis of IBD and provide potential therapeutic methods for future use.
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Affiliation(s)
- Shunying Yu
- Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou 215001, Jiangsu, P.R. China
| | - Yibin Sun
- Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou 215001, Jiangsu, P.R. China
| | - Xinyu Shao
- Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou 215001, Jiangsu, P.R. China
| | - Yuqing Zhou
- Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou 215001, Jiangsu, P.R. China
| | - Yang Yu
- Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou 215001, Jiangsu, P.R. China
| | - Xiaoyi Kuai
- Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou 215001, Jiangsu, P.R. China,
X. Kuai Phone: +86-13776084279 E-mail:
| | - Chunli Zhou
- Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou 215001, Jiangsu, P.R. China,Corresponding authors C. Zhou Phone: +86-13962124345 E-mail:
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Zhang JY, Liu XX, Lin JY, Bao XY, Peng JQ, Gong ZP, Luan X, Chen Y. Biomimetic engineered nanocarriers inspired by viruses for oral-drug delivery. Int J Pharm 2022; 624:121979. [DOI: 10.1016/j.ijpharm.2022.121979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 06/20/2022] [Accepted: 06/30/2022] [Indexed: 10/17/2022]
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Genome-wide siRNA screening reveals several host receptors for the binding of human gut commensal Bifidobacterium bifidum. NPJ Biofilms Microbiomes 2022; 8:50. [PMID: 35768415 PMCID: PMC9243078 DOI: 10.1038/s41522-022-00312-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 05/31/2022] [Indexed: 11/08/2022] Open
Abstract
Bifidobacterium spp. are abundant gut commensals, especially in breast-fed infants. Bifidobacteria are associated with many health-promoting effects including maintenance of epithelial barrier and integrity as well as immunomodulation. However, the protective mechanisms of bifidobacteria on intestinal epithelium at molecular level are poorly understood. In this study, we developed a high-throughput in vitro screening assay to explore binding receptors of intestinal epithelial cells for Bifidobacterium bifidum. Short interfering RNAs (siRNA) were used to silence expression of each gene in the Caco-2 cell line one by one. The screen yielded four cell surface proteins, SERPINB3, LGICZ1, PKD1 and PAQR6, which were identified as potential receptors as the siRNA knock-down of their expression decreased adhesion of B. bifidum to the cell line repeatedly during the three rounds of siRNA screening. Furthermore, blocking of these host cell proteins by specific antibodies decreased the binding of B. bifidum significantly to Caco-2 and HT29 cell lines. All these molecules are located on the surface of epithelial cells and three out of four, SERPINB3, PKD1 and PAQR6, are involved in the regulation of cellular processes related to proliferation, differentiation and apoptosis as well as inflammation and immunity. Our results provide leads to the first steps in the mechanistic cascade of B. bifidum-host interactions leading to regulatory effects in the epithelium and may partly explain how this commensal bacterium is able to promote intestinal homeostasis.
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25
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Yang T, Shen J. Small nucleolar RNAs and SNHGs in the intestinal mucosal barrier: Emerging insights and current roles. J Adv Res 2022; 46:75-85. [PMID: 35700920 PMCID: PMC10105082 DOI: 10.1016/j.jare.2022.06.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 05/23/2022] [Accepted: 06/08/2022] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Previous studies have focused on the involvement of small nucleolar RNAs (snoRNAs) and SNHGs in tumor cell proliferation, apoptosis, invasion, and metastasis via multiple pathways, including phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT), Wnt/β catenin, and mitogen-activated protein kinase (MAPK). These molecular mechanisms affect the integrity of the intestinal mucosal barrier. AIM OF REVIEW Current evidence regarding snoRNAs and SNHGs in the context of the mucosal barrier and modulation of homeostasis is fragmented. In this review, we collate the established information on snoRNAs and SNHGs as well as discuss the major pathways affecting the mucosal barrier. KEY SCIENTIFIC CONCEPTS OF REVIEW Intestinal mucosal immunity, microflora, and the physical barrier are altered in non-neoplastic diseases such as inflammatory bowel diseases. Dysregulated snoRNAs and SNHGs may impact the intestinal mucosal barrier to promote the pathogenesis and progression of multiple diseases. SnoRNAs or SNHGs has been shown to be associated with poor disease behaviors, indicating that they may be exploited as prognostic biomarkers. Additionally, clarifying the complicated interactions between snoRNAs or SNHGs and the mucosal barrier may provide novel insights for the therapeutic treatment targeting strengthen the intestinal mucosal barrier.
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Affiliation(s)
- Tian Yang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center. Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160# Pu Jian Ave, Shanghai 200127, China; Shanghai Institute of Digestive Disease, China
| | - Jun Shen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center. Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160# Pu Jian Ave, Shanghai 200127, China; Shanghai Institute of Digestive Disease, China.
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26
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Rawat PS, Seyed Hameed AS, Meng X, Liu W. Utilization of glycosaminoglycans by the human gut microbiota: participating bacteria and their enzymatic machineries. Gut Microbes 2022; 14:2068367. [PMID: 35482895 PMCID: PMC9067506 DOI: 10.1080/19490976.2022.2068367] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Glycosaminoglycans (GAGs) are consistently present in the human colon in free forms and as part of proteoglycans. Their utilization is critical for the colonization and proliferation of gut bacteria and also the health of hosts. Hence, it is essential to determine the GAG-degrading members of the gut bacteria and their enzymatic machinery for GAG depolymerization. In this review, we have summarized the reported GAG utilizers from Bacteroides and presented their polysaccharide utilization loci (PUL) and related enzymatic machineries for the degradation of chondroitin and heparin/heparan sulfate. Although similar comprehensive knowledge of GAG degradation is not available for other gut phyla, we have specified recently isolated GAG degraders from gut Firmicutes and Proteobacteria, and analyzed their genomes for the presence of putative GAG PULs. Deciphering the precise GAG utilization mechanism for various phyla will augment our understanding of their effects on human health.
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Affiliation(s)
- Parkash Singh Rawat
- State Key Laboratory of Microbial Technology, Microbial Technology Institute, Shandong University, No.72 Binhai Road, Qingdao266237, P. R. China
| | - Ahkam Saddam Seyed Hameed
- State Key Laboratory of Microbial Technology, Microbial Technology Institute, Shandong University, No.72 Binhai Road, Qingdao266237, P. R. China
| | - Xiangfeng Meng
- State Key Laboratory of Microbial Technology, Microbial Technology Institute, Shandong University, No.72 Binhai Road, Qingdao266237, P. R. China,CONTACT Xiangfeng Meng State Key Laboratory of Microbial Technology, Microbial Technology Institute, Shandong University, No.72 Binhai Road, Qingdao266237, P. R. China
| | - Weifeng Liu
- State Key Laboratory of Microbial Technology, Microbial Technology Institute, Shandong University, No.72 Binhai Road, Qingdao266237, P. R. China
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27
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Wu Q, Liang Y, Kong Y, Zhang F, Feng Y, Ouyang Y, Wang C, Guo Z, Xiao J, Feng N. Role of glycated proteins in vivo: Enzymatic glycated proteins and non-enzymatic glycated proteins. Food Res Int 2022; 155:111099. [DOI: 10.1016/j.foodres.2022.111099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 02/24/2022] [Accepted: 03/03/2022] [Indexed: 11/04/2022]
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28
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Aziz F, Khan I, Shukla S, Dey DK, Yan Q, Chakraborty A, Yoshitomi H, Hwang SK, Sonwal S, Lee H, Haldorai Y, Xiao J, Huh YS, Bajpai VK, Han YK. Partners in crime: The Lewis Y antigen and fucosyltransferase IV in Helicobacter pylori-induced gastric cancer. Pharmacol Ther 2022; 232:107994. [PMID: 34571111 DOI: 10.1016/j.pharmthera.2021.107994] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 09/09/2021] [Accepted: 09/13/2021] [Indexed: 02/05/2023]
Abstract
Helicobacter pylori (H. pylori) is a major causative agent of chronic gastritis, gastric ulcer and gastric carcinoma. H. pylori cytotoxin associated antigen A (CagA) plays a crucial role in the development of gastric cancer. Gastric cancer is associated with glycosylation alterations in glycoproteins and glycolipids on the cell surface. H. pylori cytotoxin associated antigen A (CagA) plays a significant role in the progression of gastric cancer through post-translation modification of fucosylation to develop gastric cancer. The involvement of a variety of sugar antigens in the progression and development of gastric cancer has been investigated, including type II blood group antigens. Lewis Y (LeY) is overexpressed on the tumor cell surface either as a glycoprotein or glycolipid. LeY is a difucosylated oligosaccharide, which is catalyzed by fucosyltransferases such as FUT4 (α1,3). FUT4/LeY overexpression may serve as potential correlative biomarkers for the prognosis of gastric cancer. We discuss the various aspects of H. pylori in relation to fucosyltransferases (FUT1-FUT9) and its fucosylated Lewis antigens (LeY, LeX, LeA, and LeB) and gastric cancer. In this review, we summarize the carcinogenic effect of H. pylori CagA in association with LeY and its synthesis enzyme FUT4 in the development of gastric cancer as well as discuss its importance in the prognosis and its inhibition by combination therapy of anti-LeY antibody and celecoxib through MAPK signaling pathway preventing gastric carcinogenesis.
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Affiliation(s)
- Faisal Aziz
- The Hormel Institute-University of Minnesota, Austin, MN 55912, USA; Department of Biochemistry and Molecular Biology, Dalian Medical University, Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, Dalian 116044, PR China.
| | - Imran Khan
- The Hormel Institute-University of Minnesota, Austin, MN 55912, USA
| | - Shruti Shukla
- TERI-Deakin Nanobiotechnology Centre, The Energy and Resources Institute, Gwal Pahari, Gurugram, Haryana 122003, India
| | - Debasish Kumar Dey
- Department of Biotechnology, College of Engineering, Daegu University, Gyeongsan 38453, Republic of Korea
| | - Qiu Yan
- Department of Biochemistry and Molecular Biology, Dalian Medical University, Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, Dalian 116044, PR China
| | | | - Hisae Yoshitomi
- The Hormel Institute-University of Minnesota, Austin, MN 55912, USA
| | - Seung-Kyu Hwang
- Department of Biological Engineering, NanoBio High-Tech Materials Research Center, Inha University, 100 Inha-ro, Nam-gu, Incheon 22212, Republic of Korea
| | - Sonam Sonwal
- Department of Biological Engineering, NanoBio High-Tech Materials Research Center, Inha University, 100 Inha-ro, Nam-gu, Incheon 22212, Republic of Korea
| | - Hoomin Lee
- Department of Biological Engineering, NanoBio High-Tech Materials Research Center, Inha University, 100 Inha-ro, Nam-gu, Incheon 22212, Republic of Korea
| | - Yuvaraj Haldorai
- Department of Nanoscience and Technology, Bharathiar University, Coimbatore, Tamilnadu 641046, India
| | - Jianbo Xiao
- Institute of Food Safety and Nutrition, Jinan University, Guangzhou 510632, China; University of Vigo, Nutrition and Bromatology Group, Department of Analytical Chemistry and Food Science, Faculty of Science, E32004 Ourense, Spain.
| | - Yun Suk Huh
- Department of Biological Engineering, NanoBio High-Tech Materials Research Center, Inha University, 100 Inha-ro, Nam-gu, Incheon 22212, Republic of Korea.
| | - Vivek K Bajpai
- Department of Energy and Materials Engineering, Dongguk University-Seoul, 30 Pildong-ro 1-gil, Seoul 04620, Republic of Korea.
| | - Young-Kyu Han
- Department of Energy and Materials Engineering, Dongguk University-Seoul, 30 Pildong-ro 1-gil, Seoul 04620, Republic of Korea.
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Chandel S, Joon A, Ghosh S. Enteroaggregative Escherichia coli induces altered glycosylation in membrane proteins of cultured human intestinal epithelial cells. Biochimie 2022; 199:68-80. [DOI: 10.1016/j.biochi.2022.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 03/11/2022] [Accepted: 04/05/2022] [Indexed: 11/02/2022]
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Ornelas A, Dowdell AS, Lee JS, Colgan SP. Microbial Metabolite Regulation of Epithelial Cell-Cell Interactions and Barrier Function. Cells 2022; 11:cells11060944. [PMID: 35326394 PMCID: PMC8946845 DOI: 10.3390/cells11060944] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 03/04/2022] [Accepted: 03/07/2022] [Indexed: 02/04/2023] Open
Abstract
Epithelial cells that line tissues such as the intestine serve as the primary barrier to the outside world. Epithelia provide selective permeability in the presence of a large constellation of microbes, termed the microbiota. Recent studies have revealed that the symbiotic relationship between the healthy host and the microbiota includes the regulation of cell–cell interactions at the level of epithelial tight junctions. The most recent findings have identified multiple microbial-derived metabolites that influence intracellular signaling pathways which elicit activities at the epithelial apical junction complex. Here, we review recent findings that place microbiota-derived metabolites as primary regulators of epithelial cell–cell interactions and ultimately mucosal permeability in health and disease.
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Affiliation(s)
- Alfredo Ornelas
- Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, 12700 E. 19th Ave, Mailstop B146, Aurora, CO 80045, USA; (A.O.); (A.S.D.); (J.S.L.)
| | - Alexander S. Dowdell
- Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, 12700 E. 19th Ave, Mailstop B146, Aurora, CO 80045, USA; (A.O.); (A.S.D.); (J.S.L.)
| | - J. Scott Lee
- Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, 12700 E. 19th Ave, Mailstop B146, Aurora, CO 80045, USA; (A.O.); (A.S.D.); (J.S.L.)
| | - Sean P. Colgan
- Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, 12700 E. 19th Ave, Mailstop B146, Aurora, CO 80045, USA; (A.O.); (A.S.D.); (J.S.L.)
- Rocky Mountain Regional Veterans Affairs Medical Center, 1700 N. Wheeling St., Aurora, CO 80045, USA
- Correspondence:
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Delon L, Gibson R, Prestidge C, Thierry B. Mechanisms of uptake and transport of particulate formulations in the small intestine. J Control Release 2022; 343:584-599. [PMID: 35149142 DOI: 10.1016/j.jconrel.2022.02.006] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 02/03/2022] [Accepted: 02/04/2022] [Indexed: 10/19/2022]
Abstract
Micro- and nano-scale particulate formulations are widely investigated towards improving the oral bioavailability of both biologics and drugs with low solubility and/or low intestinal permeability. Particulate formulations harnessing physiological intestinal transport pathways have recently yielded remarkably high oral bioavailabilities, illustrating the need for better understanding the specific pathways underpinning particle small intestinal absorption and the relative role of intestinal cells. Mechanistic knowledge has been hampered by the well acknowledged limitations of current in vitro, in vivo and ex vivo models relevant to the human intestinal physiology and the lack of standardization in studies reporting absorption data. Here we review the relevant literature and critically discusses absorption pathways with a focus on the role of specific intestinal epithelial and immune cells. We conclude that while Microfold (M) cells are a valid target for oral vaccines, enterocytes play a greater role in the systemic bioavailability of orally administrated particulate formulations, particularly within the sub-micron size range. We also comment on less-reported mechanisms such as paracellular permeability of particles, persorption due to cell damage and uptake by migratory immune cells.
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Affiliation(s)
- Ludivine Delon
- Future Industries Institute, University of South Australia, Mawson Lakes Campus, Mawson Lakes, Adelaide, South Australia 5095, Australia; Clinical and Health Sciences, University of South Australia, Adelaide, South Australia 5000, Australia
| | - Rachel Gibson
- Australia School of Allied Health Science and Practice, University of Adelaide, South Australia 5005, Australia
| | - Clive Prestidge
- Clinical and Health Sciences, University of South Australia, Adelaide, South Australia 5000, Australia
| | - Benjamin Thierry
- Future Industries Institute, University of South Australia, Mawson Lakes Campus, Mawson Lakes, Adelaide, South Australia 5095, Australia.
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32
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Antwi SO, Rabe KG, Bamlet WR, Meyer M, Chandra S, Fagan SE, Hu C, Couch FJ, McWilliams RR, Oberg AL, Petersen GM. Influence of Cancer Susceptibility Gene Mutations and ABO Blood Group of Pancreatic Cancer Probands on Concomitant Risk to First-Degree Relatives. Cancer Epidemiol Biomarkers Prev 2022; 31:372-381. [PMID: 34782396 PMCID: PMC8825751 DOI: 10.1158/1055-9965.epi-21-0745] [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: 06/16/2021] [Revised: 09/16/2021] [Accepted: 11/03/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND ABO blood group is associated with pancreatic cancer risk. Whether ABO blood group alone or when combined with inherited mutation status of index pancreatic cancer cases (probands) can enhance pancreatic cancer risk estimation in first-degree relatives (FDR) is unclear. We examined FDRs' risk for pancreatic cancer based on probands' ABO blood group and probands' cancer susceptibility gene mutation status. METHODS Data on 23,739 FDRs, identified through 3,268 pancreatic cancer probands, were analyzed. Probands' ABO blood groups were determined serologically or genetically, and 20 cancer susceptibility genes were used to classify probands as "mutation-positive" or "mutation-negative." SIRs and 95% confidence intervals (CI) were calculated, comparing observed pancreatic cancer cases in the FDRs with the number expected in SEER-21 (reference population). RESULTS Overall, FDRs had 2-fold risk of pancreatic cancer (SIR = 2.00; 95% CI = 1.79-2.22). Pancreatic cancer risk was higher in FDRs of mutation-positive (SIR = 3.80; 95% CI = 2.81-5.02) than mutation-negative (SIR = 1.79; 95% CI = 1.57-2.04) probands (P < 0.001). The magnitude of risk did not differ by ABO blood group alone (SIRblood-group-O = 1.57; 95% CI = 1.20-2.03, SIRnon-O = 1.83; 95% CI = 1.53-2.17; P = 0.33). Among FDRs of probands with non-O blood group, pancreatic cancer risk was higher in FDRs of mutation-positive (SIR = 3.98; 95% CI = 2.62-5.80) than mutation-negative (SIR = 1.66; 95% CI = 1.35-2.03) probands (P < 0.001), but risk magnitudes were statistically similar when probands had blood group O (SIRmutation-positive = 2.65; 95% CI = 1.09-5.47, SIRmutation-negative = 1.48; 95% CI = 1.06-5.47; P = 0.16). CONCLUSIONS There is a range of pancreatic cancer risk to FDRs according to probands' germline mutation status and ABO blood group, ranging from 1.48 for FDRs of probands with blood group O and mutation-negative to 3.98 for FDRs of probands with non-O blood group and mutation-positive. IMPACT Combined ABO blood group and germline mutation status of probands can inform pancreatic cancer risk estimation in FDRs.
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Affiliation(s)
- Samuel O Antwi
- Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, Florida.
| | - Kari G Rabe
- Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota
| | - William R Bamlet
- Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota
| | - Margaret Meyer
- Department of Medical and Molecular Genetics, Indiana University, Bloomington, Indiana
| | - Shruti Chandra
- Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota
| | - Sarah E Fagan
- Epidemiology and Genomics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, Maryland
| | - Chunling Hu
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Fergus J Couch
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | | | - Ann L Oberg
- Division of Computational Biology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota
| | - Gloria M Petersen
- Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota
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Zhang Y, Wang L, Ocansey DKW, Wang B, Wang L, Xu Z. Mucin-Type O-Glycans: Barrier, Microbiota, and Immune Anchors in Inflammatory Bowel Disease. J Inflamm Res 2021; 14:5939-5953. [PMID: 34803391 PMCID: PMC8598207 DOI: 10.2147/jir.s327609] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 09/19/2021] [Indexed: 12/21/2022] Open
Abstract
Inflammatory bowel disease (IBD), which affects about 7 million people globally, is a chronic inflammatory condition of the gastrointestinal tract caused by gut microbiota alterations, immune dysregulation, and genetic and environmental factors. The association of microbial and immune molecules with mucin-type O-glycans has been increasingly noticed by researchers. Mucin is the main component of mucus, which forms a protective barrier between the microbiota and immune cells in the colon. Mucin-type O-glycans alter the diversity of gastrointestinal microorganisms, which in turn increases the level of O-glycosylation of host intestinal proteins via the utilization of glycans. Additionally, alterations in mucin-type O-glycans not only increase the activity and stability of immune cells but are also involved in the maintenance of intestinal mucosal immune tolerance. Although there is accumulating evidence indicating that mucin-type O-glycans play an important role in IBD, there is limited literature that integrates available data to present a complete picture of exactly how O-glycans affect IBD. This review emphasizes the roles of the mucin-type O-glycans in IBD. This seeks to provide a better understanding and encourages future studies on IBD glycosylation and the design of novel glycan-inspired therapies for IBD.
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Affiliation(s)
- Yaqin Zhang
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, People's Republic of China
| | - Lan Wang
- Danyang Blood Station, Zhenjiang, Jiangsu, 212300, People's Republic of China
| | - Dickson Kofi Wiredu Ocansey
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, People's Republic of China.,Directorate of University Health Services, University of Cape Coast, PMB, Cape Coast, Ghana
| | - Bo Wang
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, People's Republic of China
| | - Li Wang
- Huai'an Maternity and Children Hospital, Huaian, Jiangsu, 223002, People's Republic of China
| | - Zhiwei Xu
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, People's Republic of China
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34
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Helena Macedo M, Baião A, Pinto S, Barros AS, Almeida H, Almeida A, das Neves J, Sarmento B. Mucus-producing 3D cell culture models. Adv Drug Deliv Rev 2021; 178:113993. [PMID: 34619286 DOI: 10.1016/j.addr.2021.113993] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 08/23/2021] [Accepted: 09/29/2021] [Indexed: 10/20/2022]
Abstract
In vitro cell-based models have been used for a long time since they are normally easily obtained and have an advantageous cost-benefit. Besides, they can serve a variety of ends, from studying drug absorption and metabolism to disease modeling. However, some in vitro models are too simplistic, not accurately representing the living tissues. It has been shown, mainly in the last years, that fully mimicking a tissue composition and architecture can be paramount for cellular behavior and, consequently, for the outcomes of the studies using such models. Because of this, 3D in vitro cell models have been gaining much attention, since they are able to better replicate the in vivo environment. In this review we focus on 3D models that contain mucus-producing cells, as mucus can play a pivotal role in drug absorption. Being frequently overlooked, this viscous fluid can have an impact on drug delivery. Thus, the aim of this review is to understand to which extent can mucus affect mucosal drug delivery and to provide a state-of-the-art report on the existing 3D cell-based mucus models.
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35
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Maresca M, Alatou R, Pujol A, Nicoletti C, Perrier J, Giardina T, Simon G, Méjean V, Fons M. RadA, a MSCRAMM Adhesin of the Dominant Symbiote Ruminococcus gnavus E1, Binds Human Immunoglobulins and Intestinal Mucins. Biomolecules 2021; 11:1613. [PMID: 34827611 PMCID: PMC8615915 DOI: 10.3390/biom11111613] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 10/27/2021] [Accepted: 10/29/2021] [Indexed: 01/10/2023] Open
Abstract
Adhesion to the digestive mucosa is considered a key factor for bacterial persistence within the gut. In this study, we show that Ruminococcus gnavus E1 can express the radA gene, which encodes an adhesin of the MSCRAMMs family, only when it colonizes the gut. The RadA N-terminal region contains an all-β bacterial Ig-like domain known to interact with collagens. We observed that it preferentially binds human immunoglobulins (IgA and IgG) and intestinal mucins. Using deglycosylated substrates, we also showed that the RadA N-terminal region recognizes two different types of motifs, the protein backbone of human IgG and the glycan structure of mucins. Finally, competition assays with lectins and free monosaccharides identified Galactose and N-Acetyl-Galactosamine motifs as specific targets for the binding of RadA to mucins and the surface of human epithelial cells.
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Affiliation(s)
- Marc Maresca
- Aix Marseille University, CNRS, Centrale Marseille, ISM2, IM2B, 13007 Marseille, France; (A.P.); (C.N.); (J.P.); (T.G.)
| | - Radia Alatou
- Laboratoire de Biologie Moléculaire et Cellulaire, Université des Frères Mentouri Constantine 1, RN79 Constantine, Algeria;
| | - Ange Pujol
- Aix Marseille University, CNRS, Centrale Marseille, ISM2, IM2B, 13007 Marseille, France; (A.P.); (C.N.); (J.P.); (T.G.)
| | - Cendrine Nicoletti
- Aix Marseille University, CNRS, Centrale Marseille, ISM2, IM2B, 13007 Marseille, France; (A.P.); (C.N.); (J.P.); (T.G.)
| | - Josette Perrier
- Aix Marseille University, CNRS, Centrale Marseille, ISM2, IM2B, 13007 Marseille, France; (A.P.); (C.N.); (J.P.); (T.G.)
| | - Thierry Giardina
- Aix Marseille University, CNRS, Centrale Marseille, ISM2, IM2B, 13007 Marseille, France; (A.P.); (C.N.); (J.P.); (T.G.)
| | - Gwenola Simon
- Aix Marseille University, Université de Toulon, CNRS, IRD, MIO UM 110, 13007 Marseille, France;
| | - Vincent Méjean
- Aix Marseille University, CNRS, BIP UMR7281, IMM, IM2B, 13007 Marseille, France;
| | - Michel Fons
- Aix Marseille University, CNRS, BIP UMR7281, IMM, IM2B, 13007 Marseille, France;
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Geerlings SY, Ouwerkerk JP, Koehorst JJ, Ritari J, Aalvink S, Stecher B, Schaap PJ, Paulin L, de Vos WM, Belzer C. Genomic convergence between Akkermansia muciniphila in different mammalian hosts. BMC Microbiol 2021; 21:298. [PMID: 34715771 PMCID: PMC8555344 DOI: 10.1186/s12866-021-02360-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 10/12/2021] [Indexed: 02/07/2023] Open
Abstract
Background Akkermansia muciniphila is a member of the human gut microbiota where it resides in the mucus layer and uses mucin as the sole carbon, nitrogen and energy source. A. muciniphila is the only representative of the Verrucomicrobia phylum in the human gut. However, A. muciniphila 16S rRNA gene sequences have also been found in the intestines of many vertebrates. Results We detected A. muciniphila-like bacteria in the intestines of animals belonging to 15 out of 16 mammalian orders. In addition, other species belonging to the Verrucomicrobia phylum were detected in fecal samples. We isolated 10 new A. muciniphila strains from the feces of chimpanzee, siamang, mouse, pig, reindeer, horse and elephant. The physiology and genome of these strains were highly similar in comparison to the type strain A. muciniphila MucT. Overall, the genomes of the new strains showed high average nucleotide identity (93.9 to 99.7%). In these genomes, we detected considerable conservation of at least 75 of the 78 mucin degradation genes that were previously detected in the genome of the type strain MucT. Conclusions The low genomic divergence observed in the new strains may indicate that A. muciniphila favors mucosal colonization independent of the differences in hosts. In addition, the conserved mucus degradation capability points towards a similar beneficial role of the new strains in regulating host metabolic health. Supplementary Information The online version contains supplementary material available at 10.1186/s12866-021-02360-6.
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Affiliation(s)
- Sharon Y Geerlings
- Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands
| | - Janneke P Ouwerkerk
- Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands
| | - Jasper J Koehorst
- Laboratory of Systems and Synthetic Biology, Wageningen University, Wageningen, The Netherlands
| | - Jarmo Ritari
- Finnish Red Cross Blood Service, Helsinki, Finland
| | - Steven Aalvink
- Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands
| | - Bärbel Stecher
- Max von Pettenkofer Institute of Hygiene and Medical Microbiology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Peter J Schaap
- Laboratory of Systems and Synthetic Biology, Wageningen University, Wageningen, The Netherlands
| | - Lars Paulin
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland
| | - Willem M de Vos
- Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Clara Belzer
- Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands.
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37
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Mucolytic bacteria: prevalence in various pathological diseases. World J Microbiol Biotechnol 2021; 37:176. [PMID: 34519941 DOI: 10.1007/s11274-021-03145-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 09/07/2021] [Indexed: 02/07/2023]
Abstract
All mucins are highly glycosylated and a key constituent of the mucus layer that is vigilant against pathogens in many organ systems of animals and humans. The viscous layer is organized in bilayers, i.e., an outer layer that is loosely arranged, variable in thickness, home to the commensal microbiota that grows in the complex environment, and an innermost layer that is stratified, non-aspirated, firmly adherent to the epithelial cells and devoid of any microorganisms. The O-glycosylation moiety represents the site of adhesion for pathogens and due to the increase of motility, mucolytic activity, and upregulation of virulence factors, some microorganisms can circumvent the component of the mucus layer and cause disruption in organ homeostasis. A dysbiotic microbiome, defective mucus barrier, and altered immune response often result in various diseases. In this review, paramount emphasis is given to the role played by the bacterial species directly or indirectly involved in mucin degradation, alteration in mucus secretion or its composition or mucin gene expression, which instigates many diseases in the digestive, respiratory, and other organ systems. A systematic view can help better understand the etiology of some complex disorders such as cystic fibrosis, ulcerative colitis and expand our knowledge about mucin degraders to develop new therapeutic approaches to correct ill effects caused by these mucin-dwelling pathogens.
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38
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Sauvaitre T, Etienne-Mesmin L, Sivignon A, Mosoni P, Courtin CM, Van de Wiele T, Blanquet-Diot S. Tripartite relationship between gut microbiota, intestinal mucus and dietary fibers: towards preventive strategies against enteric infections. FEMS Microbiol Rev 2021; 45:5918835. [PMID: 33026073 DOI: 10.1093/femsre/fuaa052] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 10/05/2020] [Indexed: 02/06/2023] Open
Abstract
The human gut is inhabited by a large variety of microorganims involved in many physiological processes and collectively referred as to gut microbiota. Disrupted microbiome has been associated with negative health outcomes and especially could promote the onset of enteric infections. To sustain their growth and persistence within the human digestive tract, gut microbes and enteric pathogens rely on two main polysaccharide compartments, namely dietary fibers and mucus carbohydrates. Several evidences suggest that the three-way relationship between gut microbiota, dietary fibers and mucus layer could unravel the capacity of enteric pathogens to colonise the human digestive tract and ultimately lead to infection. The review starts by shedding light on similarities and differences between dietary fibers and mucus carbohydrates structures and functions. Next, we provide an overview of the interactions of these two components with the third partner, namely, the gut microbiota, under health and disease situations. The review will then provide insights into the relevance of using dietary fibers interventions to prevent enteric infections with a focus on gut microbial imbalance and impaired-mucus integrity. Facing the numerous challenges in studying microbiota-pathogen-dietary fiber-mucus interactions, we lastly describe the characteristics and potentialities of currently available in vitro models of the human gut.
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Affiliation(s)
- Thomas Sauvaitre
- Université Clermont Auvergne, UMR 454 INRAe, Microbiology, Digestive Environment and Health (MEDIS), Clermont-Ferrand, France.,Ghent University, Faculty of Bioscience Engineering, Center for Microbial Ecology and Technology (CMET), Ghent, Belgium
| | - Lucie Etienne-Mesmin
- Université Clermont Auvergne, UMR 454 INRAe, Microbiology, Digestive Environment and Health (MEDIS), Clermont-Ferrand, France
| | - Adeline Sivignon
- Université Clermont Auvergne, UMR 1071 Inserm, USC-INRAe 2018, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Clermont-Ferrand, France
| | - Pascale Mosoni
- Université Clermont Auvergne, UMR 454 INRAe, Microbiology, Digestive Environment and Health (MEDIS), Clermont-Ferrand, France
| | - Christophe M Courtin
- KU Leuven, Faculty of Bioscience Engineering, Laboratory of Food Chemistry and Biochemistry & Leuven Food Science and Nutrition Research Centre (LFoRCe), Leuven, Belgium
| | - Tom Van de Wiele
- Ghent University, Faculty of Bioscience Engineering, Center for Microbial Ecology and Technology (CMET), Ghent, Belgium
| | - Stéphanie Blanquet-Diot
- Université Clermont Auvergne, UMR 454 INRAe, Microbiology, Digestive Environment and Health (MEDIS), Clermont-Ferrand, France
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39
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Morosi LG, Cutine AM, Cagnoni AJ, Manselle-Cocco MN, Croci DO, Merlo JP, Morales RM, May M, Pérez-Sáez JM, Girotti MR, Méndez-Huergo SP, Pucci B, Gil AH, Huernos SP, Docena GH, Sambuelli AM, Toscano MA, Rabinovich GA, Mariño KV. Control of intestinal inflammation by glycosylation-dependent lectin-driven immunoregulatory circuits. SCIENCE ADVANCES 2021; 7:7/25/eabf8630. [PMID: 34144987 PMCID: PMC8213219 DOI: 10.1126/sciadv.abf8630] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 05/04/2021] [Indexed: 05/14/2023]
Abstract
Diverse immunoregulatory circuits operate to preserve intestinal homeostasis and prevent inflammation. Galectin-1 (Gal1), a β-galactoside-binding protein, promotes homeostasis by reprogramming innate and adaptive immunity. Here, we identify a glycosylation-dependent "on-off" circuit driven by Gal1 and its glycosylated ligands that controls intestinal immunopathology by targeting activated CD8+ T cells and shaping the cytokine profile. In patients with inflammatory bowel disease (IBD), augmented Gal1 was associated with dysregulated expression of core 2 β6-N-acetylglucosaminyltransferase 1 (C2GNT1) and α(2,6)-sialyltransferase 1 (ST6GAL1), glycosyltransferases responsible for creating or masking Gal1 ligands. Mice lacking Gal1 exhibited exacerbated colitis and augmented mucosal CD8+ T cell activation in response to 2,4,6-trinitrobenzenesulfonic acid; this phenotype was partially ameliorated by treatment with recombinant Gal1. While C2gnt1-/- mice exhibited aggravated colitis, St6gal1-/- mice showed attenuated inflammation. These effects were associated with intrinsic T cell glycosylation. Thus, Gal1 and its glycosylated ligands act to preserve intestinal homeostasis by recalibrating T cell immunity.
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Affiliation(s)
- Luciano G Morosi
- Laboratorio de Glicómica Funcional y Molecular, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1428 Ciudad de Buenos Aires, Argentina
- Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1428 Ciudad de Buenos Aires, Argentina
| | - Anabela M Cutine
- Laboratorio de Glicómica Funcional y Molecular, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1428 Ciudad de Buenos Aires, Argentina
- Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1428 Ciudad de Buenos Aires, Argentina
| | - Alejandro J Cagnoni
- Laboratorio de Glicómica Funcional y Molecular, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1428 Ciudad de Buenos Aires, Argentina
- Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1428 Ciudad de Buenos Aires, Argentina
| | - Montana N Manselle-Cocco
- Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1428 Ciudad de Buenos Aires, Argentina
| | - Diego O Croci
- Instituto de Histología y Embriología de Mendoza (IHEM-CONICET), Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Cuyo, 5500 Mendoza, Argentina
| | - Joaquín P Merlo
- Laboratorio de Glicómica Funcional y Molecular, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1428 Ciudad de Buenos Aires, Argentina
- Laboratorio de Inmuno-oncología Translacional, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1428 Ciudad de Buenos Aires, Argentina
| | - Rosa M Morales
- Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1428 Ciudad de Buenos Aires, Argentina
| | - María May
- Instituto de Investigaciones Farmacológicas (ININFA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1113 Ciudad de Buenos Aires, Argentina
| | - Juan M Pérez-Sáez
- Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1428 Ciudad de Buenos Aires, Argentina
| | - María R Girotti
- Laboratorio de Inmuno-oncología Translacional, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1428 Ciudad de Buenos Aires, Argentina
| | - Santiago P Méndez-Huergo
- Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1428 Ciudad de Buenos Aires, Argentina
| | - Betiana Pucci
- Sección de Enfermedades Inflamatorias, Hospital de Gastroenterología Carlos Bonorino Udaondo, 1264 Ciudad de Buenos Aires, Argentina
| | - Aníbal H Gil
- Sección de Enfermedades Inflamatorias, Hospital de Gastroenterología Carlos Bonorino Udaondo, 1264 Ciudad de Buenos Aires, Argentina
| | - Sergio P Huernos
- Sección de Enfermedades Inflamatorias, Hospital de Gastroenterología Carlos Bonorino Udaondo, 1264 Ciudad de Buenos Aires, Argentina
| | - Guillermo H Docena
- Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP-CONICET), Facultad de Ciencias Exactas, Universidad Nacional de La Plata (UNLP), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) y Comisión de Investigaciones Científicas de la Provincia de Buenos Aires (CIC), 1900 La Plata, Argentina
| | - Alicia M Sambuelli
- Sección de Enfermedades Inflamatorias, Hospital de Gastroenterología Carlos Bonorino Udaondo, 1264 Ciudad de Buenos Aires, Argentina
| | - Marta A Toscano
- Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1428 Ciudad de Buenos Aires, Argentina
| | - Gabriel A Rabinovich
- Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1428 Ciudad de Buenos Aires, Argentina.
- Laboratorio de Inmuno-oncología Translacional, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1428 Ciudad de Buenos Aires, Argentina
- Facultad de Ciencias Exactas y Naturales (FCEyN), Universidad de Buenos Aires, 1428 Ciudad de Buenos Aires, Argentina
| | - Karina V Mariño
- Laboratorio de Glicómica Funcional y Molecular, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1428 Ciudad de Buenos Aires, Argentina.
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40
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Buzzanca D, Botta C, Ferrocino I, Alessandria V, Houf K, Rantsiou K. Functional pangenome analysis reveals high virulence plasticity of Aliarcobacter butzleri and affinity to human mucus. Genomics 2021; 113:2065-2076. [PMID: 33961980 DOI: 10.1016/j.ygeno.2021.05.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 04/27/2021] [Accepted: 05/01/2021] [Indexed: 12/12/2022]
Abstract
Aliarcobacter butzleri is an emerging pathogen that may cause enteritis in humans, however, the incidence of disease caused by this member of the Campylobacteriaceae family is still underestimated. Furthermore, little is known about the precise virulence mechanism and behavior during infection. Therefore, in the present study, through complementary use of comparative genomics and physiological tests on human gut models, we sought to elucidate the genetic background of a set of 32 A. butzleri strains of diverse origin and to explore the correlation with the ability to colonize and invade human intestinal cells in vitro. The simulated infection of human intestinal models showed a higher colonization rate in presence of mucus-producing cells. For some strains, human mucus significantly improved the resistance to physical removal from the in vitro mucosa, while short time-frame growth was even observed. Pangenome analysis highlighted a hypervariable accessory genome, not strictly correlated to the isolation source. Likewise, the strain phylogeny was unrelated to their shared origin, despite a certain degree of segregation was observed among strains isolated from different segments of the intestinal tract of pigs. The putative virulence genes detected in all strains were mostly encompassed in the accessory fraction of the pangenome. The LPS biosynthesis and in particular the chain glycosylation of the O-antigen is harbored in a region of high plasticity of the pangenome, which would indicate frequent horizontal gene transfer phenomena, as well as the involvement of this hypervariable structure in the adaptive behavior and sympatric evolution of A. butzleri. Results of the present study deepen the current knowledge on A. butzleri pangenome by extending the pool of genes regarded as virulence markers and provide bases to develop new diagnostic approaches for the detection of those strains with a higher virulence potential.
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Affiliation(s)
- Davide Buzzanca
- Department of Agricultural, Forest and Food Sciences (DISAFA), University of Turin, Italy; Department of Veterinary Public Health, Faculty of Veterinary Medicine, Ghent University, Belgium
| | - Cristian Botta
- Department of Agricultural, Forest and Food Sciences (DISAFA), University of Turin, Italy
| | - Ilario Ferrocino
- Department of Agricultural, Forest and Food Sciences (DISAFA), University of Turin, Italy
| | - Valentina Alessandria
- Department of Agricultural, Forest and Food Sciences (DISAFA), University of Turin, Italy
| | - Kurt Houf
- Department of Veterinary Public Health, Faculty of Veterinary Medicine, Ghent University, Belgium
| | - Kalliopi Rantsiou
- Department of Agricultural, Forest and Food Sciences (DISAFA), University of Turin, Italy.
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Galeev A, Suwandi A, Cepic A, Basu M, Baines JF, Grassl GA. The role of the blood group-related glycosyltransferases FUT2 and B4GALNT2 in susceptibility to infectious disease. Int J Med Microbiol 2021; 311:151487. [PMID: 33662872 DOI: 10.1016/j.ijmm.2021.151487] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 02/01/2021] [Accepted: 02/23/2021] [Indexed: 12/12/2022] Open
Abstract
The glycosylation profile of the gastrointestinal tract is an important factor mediating host-microbe interactions. Variation in these glycan structures is often mediated by blood group-related glycosyltransferases, and can lead to wide-ranging differences in susceptibility to both infectious- as well as chronic disease. In this review, we focus on the interplay between host glycosylation, the intestinal microbiota and susceptibility to gastrointestinal pathogens based on studies of two exemplary blood group-related glycosyltransferases that are conserved between mice and humans, namely FUT2 and B4GALNT2. We highlight that differences in susceptibility can arise due to both changes in direct interactions, such as bacterial adhesion, as well as indirect effects mediated by the intestinal microbiota. Although a large body of experimental work exists for direct interactions between host and pathogen, determining the more complex and variable mechanisms underlying three-way interactions involving the intestinal microbiota will be the subject of much-needed future research.
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Affiliation(s)
- Alibek Galeev
- Max Planck Institute for Evolutionary Biology, Plön, Germany and Institute for Experimental Medicine, Kiel University, Kiel, Germany
| | - Abdulhadi Suwandi
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School and German Center for Infection Research (DZIF), Hannover, Germany
| | - Aleksa Cepic
- Max Planck Institute for Evolutionary Biology, Plön, Germany and Institute for Experimental Medicine, Kiel University, Kiel, Germany
| | - Meghna Basu
- Max Planck Institute for Evolutionary Biology, Plön, Germany and Institute for Experimental Medicine, Kiel University, Kiel, Germany
| | - John F Baines
- Max Planck Institute for Evolutionary Biology, Plön, Germany and Institute for Experimental Medicine, Kiel University, Kiel, Germany.
| | - Guntram A Grassl
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School and German Center for Infection Research (DZIF), Hannover, Germany.
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Schulz-Kuhnt A, Neurath MF, Wirtz S, Atreya I. Innate Lymphoid Cells as Regulators of Epithelial Integrity: Therapeutic Implications for Inflammatory Bowel Diseases. Front Med (Lausanne) 2021; 8:656745. [PMID: 33869257 PMCID: PMC8044918 DOI: 10.3389/fmed.2021.656745] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 03/05/2021] [Indexed: 02/06/2023] Open
Abstract
The occurrence of epithelial defects in the gut relevantly contributes to the pathogenesis of inflammatory bowel diseases (IBD), whereby the impairment of intestinal epithelial barrier integrity seems to represent a primary trigger as well as a disease amplifying consequence of the chronic inflammatory process. Besides epithelial cell intrinsic factors, accumulated and overwhelmingly activated immune cells and their secretome have been identified as critical modulators of the pathologically altered intestinal epithelial cell (IEC) function in IBD. In this context, over the last 10 years increasing levels of attention have been paid to the group of innate lymphoid cells (ILCs). This is in particular due to a preferential location of these rather newly described innate immune cells in close proximity to mucosal barriers, their profound capacity to secrete effector cytokines and their numerical and functional alteration under chronic inflammatory conditions. Aiming on a comprehensive and updated summary of our current understanding of the bidirectional mucosal crosstalk between ILCs and IECs, this review article will in particular focus on the potential capacity of gut infiltrating type-1, type-2, and type-3 helper ILCs (ILC1s, ILC2s, and ILC3s, respectively) to impact on the survival, differentiation, and barrier function of IECs. Based on data acquired in IBD patients or in experimental models of colitis, we will discuss whether the different ILC subgroups could serve as potential therapeutic targets for maintenance of epithelial integrity and/or mucosal healing in IBD.
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Affiliation(s)
- Anja Schulz-Kuhnt
- Department of Medicine 1, University Hospital of Erlangen, Erlangen, Germany
| | - Markus F. Neurath
- Department of Medicine 1, University Hospital of Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Stefan Wirtz
- Department of Medicine 1, University Hospital of Erlangen, Erlangen, Germany
| | - Imke Atreya
- Department of Medicine 1, University Hospital of Erlangen, Erlangen, Germany
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43
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Takayama Y. Reduced Intestinal Fucosylation in Mice Exposed to Psychological Stress. TRENDS GLYCOSCI GLYC 2021. [DOI: 10.4052/tigg.2001.1j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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44
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Takayama Y. Reduced Intestinal Fucosylation in Mice Exposed to Psychological Stress. TRENDS GLYCOSCI GLYC 2021. [DOI: 10.4052/tigg.2001.1e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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45
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das Neves J, Sverdlov Arzi R, Sosnik A. Molecular and cellular cues governing nanomaterial-mucosae interactions: from nanomedicine to nanotoxicology. Chem Soc Rev 2021; 49:5058-5100. [PMID: 32538405 DOI: 10.1039/c8cs00948a] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Mucosal tissues constitute the largest interface between the body and the surrounding environment and they regulate the access of molecules, supramolecular structures, particulate matter, and pathogens into it. All mucosae are characterized by an outer mucus layer that protects the underlying cells from physicochemical, biological and mechanical insults, a mono-layered or stratified epithelium that forms tight junctions and controls the selective transport of solutes across it and associated lymphoid tissues that play a sentinel role. Mucus is a gel-like material comprised mainly of the glycoprotein mucin and water and it displays both hydrophilic and hydrophobic domains, a net negative charge, and high porosity and pore interconnectivity, providing an efficient barrier for the absorption of therapeutic agents. To prolong the residence time, absorption and bioavailability of a broad spectrum of active compounds upon mucosal administration, mucus-penetrating and mucoadhesive particles have been designed by tuning the chemical composition, the size, the density, and the surface properties. The benefits of utilizing nanomaterials that interact intimately with mucosae by different mechanisms in the nanomedicine field have been extensively reported. To ensure the safety of these nanosystems, their compatibility is evaluated in vitro and in vivo in preclinical and clinical trials. Conversely, there is a growing concern about the toxicity of nanomaterials dispersed in air and water effluents that unintentionally come into contact with the airways and the gastrointestinal tract. Thus, deep understanding of the key nanomaterial properties that govern the interplay with mucus and tissues is crucial for the rational design of more efficient drug delivery nanosystems (nanomedicine) and to anticipate the fate and side-effects of nanoparticulate matter upon acute or chronic exposure (nanotoxicology). This review initially overviews the complex structural features of mucosal tissues, including the structure of mucus, the epithelial barrier, the mucosal-associated lymphatic tissues and microbiota. Then, the most relevant investigations attempting to identify and validate the key particle features that govern nanomaterial-mucosa interactions and that are relevant in both nanomedicine and nanotoxicology are discussed in a holistic manner. Finally, the most popular experimental techniques and the incipient use of mathematical and computational models to characterize these interactions are described.
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Affiliation(s)
- José das Neves
- i3S - Instituto de Investigação e Inovação em Saúde & INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal
| | - Roni Sverdlov Arzi
- Laboratory of Pharmaceutical Nanomaterials Science, Department of Materials Science and Engineering, Technion-Israel Institute of Technology, De-Jur Building, Office 607, Haifa, 3200003, Israel.
| | - Alejandro Sosnik
- Laboratory of Pharmaceutical Nanomaterials Science, Department of Materials Science and Engineering, Technion-Israel Institute of Technology, De-Jur Building, Office 607, Haifa, 3200003, Israel.
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Din AU, Mazhar M, Waseem M, Ahmad W, Bibi A, Hassan A, Ali N, Gang W, Qian G, Ullah R, Shah T, Ullah M, Khan I, Nisar MF, Wu J. SARS-CoV-2 microbiome dysbiosis linked disorders and possible probiotics role. Biomed Pharmacother 2021; 133:110947. [PMID: 33197765 PMCID: PMC7657099 DOI: 10.1016/j.biopha.2020.110947] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Revised: 10/21/2020] [Accepted: 10/25/2020] [Indexed: 01/07/2023] Open
Abstract
In December 2019, a pneumonia outbreak of unknown etiology was reported which caused panic in Wuhan city of central China, which was later identified as Coronavirus disease (COVID-19) caused by a novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) by the Chinese Centre for Disease Control and Prevention (CDC) and WHO. To date, the SARS-CoV-2 spread has already become a global pandemic with a considerable death toll. The associated symptoms of the COVID-19 infection varied with increased inflammation as an everyday pathological basis. Among various other symptoms such as fever, cough, lethargy, gastrointestinal (GI) symptoms included diarrhea and IBD with colitis, have been reported. Currently, there is no sole cure for COVID-19, and researchers are actively engaged to search out appropriate treatment and develop a vaccine for its prevention. Antiviral for controlling viral load and corticosteroid therapy for reducing inflammation seems to be inadequate to control the fatality rate. Based on the available related literature, which documented GI symptoms with diarrhea, inflammatory bowel diseases (IBD) with colitis, and increased deaths in the intensive care unit (ICU), conclude that dysbiosis occurs during SARS-COV-2 infection as the gut-lung axis cannot be ignored. As probiotics play a therapeutic role for GI, IBD, colitis, and even in viral infection. So, we assume that the inclusion of studies to investigate gut microbiome and subsequent therapies such as probiotics might help decrease the inflammatory response of viral pathogenesis and respiratory symptoms by strengthening the host immune system, amelioration of gut microbiome, and improvement of gut barrier function.
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Affiliation(s)
- Ahmad Ud Din
- Drug Discovery Research Center, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Maryam Mazhar
- Research Center of Integrated Traditional Chinese and Western Medicine, Affiliated Traditional Medicine Hospital, Southwest Medical University, Luzhou, China
| | - Muhammed Waseem
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, College of Horticulture, South China Agricultural University, Guangzhou, 510642, China
| | - Waqar Ahmad
- Drug Discovery Research Center, Southwest Medical University, Luzhou, 646000, Sichuan, China; College of Marine Life Sciences and Institute of Evolution and Marine Biodiversity, Ocean University of China, Qingdao, 266003, China
| | - Asma Bibi
- Institute of Zoonosis Anhui Medical University, Hefei Anhui, 230032, China
| | - Adil Hassan
- Key Laboratory for Bio-rheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants Bioengineering College of Chongqing University, Chongqing, 400030, China
| | - Niaz Ali
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-bio-resources, College of Life Science and Technology, Guangxi University, 100 Daxue Road, Nanning, 530004, Guangxi, China
| | - Wang Gang
- Drug Discovery Research Center, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Gao Qian
- Drug Discovery Research Center, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Razi Ullah
- Key Laboratory for Bio-rheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants Bioengineering College of Chongqing University, Chongqing, 400030, China
| | - Tariq Shah
- State Key Laboratory of Grassland Agro-Ecosystem, School of Life Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Mehraj Ullah
- Department of Biotechnology School of Fermentation Engineering Tianjin University of Science and Technology China, China
| | - Israr Khan
- School of Life Sciences, Lanzhou University, China
| | - Muhammad Farrukh Nisar
- Department of Physiology and Biochemistry, Cholistan University of Veterinary and Animal Sciences (CUVAS), Bahawalpur, 63100, Pakistan
| | - Jianbo Wu
- Drug Discovery Research Center, Southwest Medical University, Luzhou, 646000, Sichuan, China.
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Kim J, Lee B, Lee J, Ji M, Park CS, Lee J, Kang M, Kim J, Jin M, Kim HH. N-Glycan Modifications with Negative Charge in a Natural Polymer Mucin from Bovine Submaxillary Glands, and Their Structural Role. Polymers (Basel) 2020; 13:polym13010103. [PMID: 33383793 PMCID: PMC7796149 DOI: 10.3390/polym13010103] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 12/23/2020] [Accepted: 12/23/2020] [Indexed: 12/18/2022] Open
Abstract
Bovine submaxillary mucin (BSM) is a natural polymer used in biomaterial applications for its viscoelasticity, lubricity, biocompatibility, and biodegradability. N-glycans are important for mucin stability and function, but their structures have not been fully characterized, unlike that of O-glycans. In this study, BSM N-glycans were investigated using liquid chromatography-tandem mass spectrometry. The microheterogeneous structures of 32 N-glycans were identified, and the quantities (%) of each N-glycan relative to total N-glycans (100%) were obtained. The terminal N-acetylgalactosamines in 12 N-glycans (sum of relative quantities; 27.9%) were modified with mono- (10 glycans) and disulfations (2 glycans). Total concentration of all sulfated N-glycans was 6.1 pmol in BSM (20 µg), corresponding to 25.3% of all negatively charged glycans (sum of present N-glycans and reported O-glycans). No N-glycans with sialylated or phosphorylated forms were identified, and sulfate modification ions were the only negative charges in BSM N-glycans. Mucin structures, including sulfated N-glycans located in the hydrophobic terminal regions, were indicated. This is the first study to identify the structures and quantities of 12 sulfated N-glycans in natural mucins. These sulfations play important structural roles in hydration, viscoelasticity control, protection from bacterial sialidases, and polymer stabilization to support the functionality of BSM via electrostatic interactions.
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Affiliation(s)
- Jihye Kim
- Biotherapeutics and Glycomics Laboratory, College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 06974, Korea; (J.K.); (B.L.); (J.L.); (M.J.); (C.S.P.); (J.L.); (M.K.); (J.K.); (M.J.)
- Department of Global Innovative Drugs, Graduate School of Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 06974, Korea
| | - Byoungju Lee
- Biotherapeutics and Glycomics Laboratory, College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 06974, Korea; (J.K.); (B.L.); (J.L.); (M.J.); (C.S.P.); (J.L.); (M.K.); (J.K.); (M.J.)
| | - Junmyoung Lee
- Biotherapeutics and Glycomics Laboratory, College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 06974, Korea; (J.K.); (B.L.); (J.L.); (M.J.); (C.S.P.); (J.L.); (M.K.); (J.K.); (M.J.)
| | - Minkyoo Ji
- Biotherapeutics and Glycomics Laboratory, College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 06974, Korea; (J.K.); (B.L.); (J.L.); (M.J.); (C.S.P.); (J.L.); (M.K.); (J.K.); (M.J.)
- Department of Global Innovative Drugs, Graduate School of Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 06974, Korea
| | - Chi Soo Park
- Biotherapeutics and Glycomics Laboratory, College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 06974, Korea; (J.K.); (B.L.); (J.L.); (M.J.); (C.S.P.); (J.L.); (M.K.); (J.K.); (M.J.)
- Department of Global Innovative Drugs, Graduate School of Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 06974, Korea
| | - Jaeryong Lee
- Biotherapeutics and Glycomics Laboratory, College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 06974, Korea; (J.K.); (B.L.); (J.L.); (M.J.); (C.S.P.); (J.L.); (M.K.); (J.K.); (M.J.)
- Department of Global Innovative Drugs, Graduate School of Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 06974, Korea
| | - Minju Kang
- Biotherapeutics and Glycomics Laboratory, College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 06974, Korea; (J.K.); (B.L.); (J.L.); (M.J.); (C.S.P.); (J.L.); (M.K.); (J.K.); (M.J.)
- Department of Global Innovative Drugs, Graduate School of Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 06974, Korea
| | - Jeongeun Kim
- Biotherapeutics and Glycomics Laboratory, College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 06974, Korea; (J.K.); (B.L.); (J.L.); (M.J.); (C.S.P.); (J.L.); (M.K.); (J.K.); (M.J.)
- Department of Global Innovative Drugs, Graduate School of Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 06974, Korea
| | - Mijung Jin
- Biotherapeutics and Glycomics Laboratory, College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 06974, Korea; (J.K.); (B.L.); (J.L.); (M.J.); (C.S.P.); (J.L.); (M.K.); (J.K.); (M.J.)
- Department of Global Innovative Drugs, Graduate School of Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 06974, Korea
| | - Ha Hyung Kim
- Biotherapeutics and Glycomics Laboratory, College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 06974, Korea; (J.K.); (B.L.); (J.L.); (M.J.); (C.S.P.); (J.L.); (M.K.); (J.K.); (M.J.)
- Department of Global Innovative Drugs, Graduate School of Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 06974, Korea
- Correspondence: ; Tel.: +82-2-820-5612
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Sanchez H, Hopkins D, Demirdjian S, Gutierrez C, O'Toole GA, Neelamegham S, Berwin B. Identification of cell-surface glycans that mediate motility-dependent binding and internalization of Pseudomonas aeruginosa by phagocytes. Mol Immunol 2020; 131:68-77. [PMID: 33358569 DOI: 10.1016/j.molimm.2020.12.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Revised: 11/30/2020] [Accepted: 12/06/2020] [Indexed: 11/15/2022]
Abstract
Phagocytic cells are critical to host defense against Pseudomonas aeruginosa, a Gram-negative bacterium that is an opportunistic pathogen. Accordingly, susceptible individuals frequently have impaired innate immune responses, including those with cystic fibrosis or neutropenia. Previous studies identified that the downregulation, or loss, of bacterial flagellar motility enables bacteria to evade interactions with phagocytic cells that result in phagocytic uptake of the bacteria. However, the mechanistic bases for motility-dependent interactions between P. aeruginosa and host cell surfaces that lead to phagocytic uptake of the bacteria are poorly understood. A recent insight is that exogenous addition of a negatively charged phospholipid, phosphatidylinositol-(3,4,5)-triphosphate (PIP3), promotes the engagement of non-motile strains of P. aeruginosa with phagocytes leading to uptake of the bacteria. Thus, we hypothesized that the engagement of P. aeruginosa by phagocytic cells is mediated by motility-dependent interactions with cell-surface polyanions. Here we report that endogenous polyanionic N-linked glycans and heparan sulfate mediate bacterial binding of P. aeruginosa by human monocytic cells. These specific interactions resulted in P. aeruginosa phagocytosis, bacterial type 3 secretion system (T3SS)-mediated cellular intoxication and the IL-1β response of host innate immune cells. Importantly, the bacterial interactions with the glycans were motility-dependent and could be recapitulated with purified, immobilized glycans. Therefore, this work describes novel interactions of P. aeruginosa with specific phagocyte cell-surface glycans that modulate relevant host innate immune responses to the bacteria, including phagocytosis, inflammation and cytotoxicity.
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Affiliation(s)
- Hector Sanchez
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH, 03756, USA
| | - Daniel Hopkins
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH, 03756, USA
| | - Sally Demirdjian
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH, 03756, USA
| | - Cecilia Gutierrez
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH, 03756, USA
| | - George A O'Toole
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH, 03756, USA
| | - Sriram Neelamegham
- Department of Chemical & Biological Engineering and Clinical &Translational Research Center, State University of New York, Buffalo, NY, 14260 USA
| | - Brent Berwin
- The Jackson Laboratory, Bar Harbor, ME, 04609, USA.
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49
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Sunds AV, Bunyatratchata A, Robinson R, Glantz M, Paulsson M, Leskauskaite D, Pihlanto A, Inglingstad R, Devold TG, Vegarud GE, Birgisdottir BE, Gudjonsdottir M, Barile D, Larsen LB, Poulsen NA. Comparison of bovine milk oligosaccharides in native North European cattle breeds. Int Dairy J 2020; 114. [PMID: 33304057 DOI: 10.1016/j.idairyj.2020.104917] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Milk oligosaccharides are of high interest due to their bioactive properties. This study is the first to characterise milk oligosaccharides from native North European cattle breeds, as represented by 80 milk samples collected from eight native breeds originated from Norway (Norwegian Doela cattle and Norwegian Telemark cattle), Sweden (Swedish Mountain cattle), Denmark (Danish Red anno 1970), Iceland (Icelandic cattle), Lithuania (native Lithuanian Black and White) and Finland (Western Finncattle and Eastern Finncattle). Using high-performance liquid-chromatography chip/quadrupole time-of-flight mass-spectrometry, 18 unique monosaccharide compositions and a multitude of isomers were identified. No N-glycolylneuraminic acid was identified among these breeds. Western Finncattle milk was most abundant in neutral, acidic and fucosylated oligosaccharides. Further, Eastern Finncattle milk was significantly higher in acidic oligosaccharides and Icelandic cattle milk significantly higher in fucosylated oligosaccharides, compared to the mean. This study highlights specific native breeds of particular interest for future exploitation of milk oligosaccharides and breeding strategies.
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Affiliation(s)
- Anne Vuholm Sunds
- Department of Food Science, Aarhus University, Agro Food Park 48, 8200 Aarhus N, Denmark
| | | | - Randall Robinson
- Department of Food Science and Technology, University of California, Davis, USA
| | - Maria Glantz
- Department of Food Technology, Engineering and Nutrition, Lund University, Sweden
| | - Marie Paulsson
- Department of Food Technology, Engineering and Nutrition, Lund University, Sweden
| | - Daiva Leskauskaite
- Department of Food Science and Technology, Kaunas University of Technology, Lithuania
| | | | - Ragnhild Inglingstad
- Norwegian University of Life Sciences, Faculty of Chemistry, Biotechnology and Food Science, Norway
| | - Tove G Devold
- Norwegian University of Life Sciences, Faculty of Chemistry, Biotechnology and Food Science, Norway
| | - Gerd E Vegarud
- Norwegian University of Life Sciences, Faculty of Chemistry, Biotechnology and Food Science, Norway
| | - Bryndis Eva Birgisdottir
- Faculty of Food Science and Nutrition, School of Health Sciences, University of Iceland, Iceland
| | - Maria Gudjonsdottir
- Faculty of Food Science and Nutrition, School of Health Sciences, University of Iceland, Iceland
| | - Daniela Barile
- Department of Food Science and Technology, University of California, Davis, USA
| | - Lotte Bach Larsen
- Department of Food Science, Aarhus University, Agro Food Park 48, 8200 Aarhus N, Denmark
| | - Nina Aagaard Poulsen
- Department of Food Science, Aarhus University, Agro Food Park 48, 8200 Aarhus N, Denmark
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50
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Akkermansia muciniphila uses human milk oligosaccharides to thrive in the early life conditions in vitro. Sci Rep 2020; 10:14330. [PMID: 32868839 PMCID: PMC7459334 DOI: 10.1038/s41598-020-71113-8] [Citation(s) in RCA: 91] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 07/10/2020] [Indexed: 02/07/2023] Open
Abstract
Akkermansia muciniphila is a well-studied anaerobic bacterium specialized in mucus degradation and associated with human health. Because of the structural resemblance of mucus glycans and free human milk oligosaccharides (HMOs), we studied the ability of A. muciniphila to utilize human milk oligosaccharides. We found that A. muciniphila was able to grow on human milk and degrade HMOs. Analyses of the proteome of A. muciniphila indicated that key-glycan degrading enzymes were expressed when the bacterium was grown on human milk. Our results display the functionality of the key-glycan degrading enzymes (α-l-fucosidases, β-galactosidases, exo-α-sialidases and β-acetylhexosaminidases) to degrade the HMO-structures 2′-FL, LNT, lactose, and LNT2. The hydrolysation of the host-derived glycan structures allows A. muciniphila to promote syntrophy with other beneficial bacteria, contributing in that way to a microbial ecological network in the gut. Thus, the capacity of A. muciniphila to utilize human milk will enable its survival in the early life intestine and colonization of the mucosal layer in early life, warranting later life mucosal and metabolic health.
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