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1
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Kulkarni DH, Newberry RD. Antigen Uptake in the Gut: An Underappreciated Piece to the Puzzle? Annu Rev Immunol 2025; 43:571-588. [PMID: 40279313 PMCID: PMC12068241 DOI: 10.1146/annurev-immunol-082523-090154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/27/2025]
Abstract
The mammalian gut is a vast, diverse, and dynamic single-layer epithelial surface exposed to trillions of microbes, microbial products, and the diet. Underlying this epithelium lies the largest collection of immune cells in the body; these cells encounter luminal substances to generate antigen-specific immune responses characterized by tolerance at homeostasis and inflammation during enteric infections. How the outcomes of antigen-specific tolerance and inflammation are appropriately balanced is a central question in mucosal immunology. Furthermore, how substances large enough to generate antigen-specific responses cross the epithelium and encounter the immune system in homeostasis and during inflammation remains largely unexplored. Here we discuss the challenges presented to the gut immune system, the identified pathways by which luminal substances cross the epithelium, and insights suggesting that the pathways used by substances to cross the epithelium affect the ensuing immune response.
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Affiliation(s)
- Devesha H Kulkarni
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA
| | - Rodney D Newberry
- John T. Milliken Department of Medicine, School of Medicine, Washington University, Saint Louis, Missouri, USA;
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2
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Bravo Iniguez A, Du M, Zhu MJ. α-Ketoglutarate for Preventing and Managing Intestinal Epithelial Dysfunction. Adv Nutr 2024; 15:100200. [PMID: 38438107 PMCID: PMC11016550 DOI: 10.1016/j.advnut.2024.100200] [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: 11/22/2023] [Revised: 02/16/2024] [Accepted: 02/29/2024] [Indexed: 03/06/2024] Open
Abstract
The epithelium lining the intestinal tract serves a multifaceted role. It plays a crucial role in nutrient absorption and immune regulation and also acts as a protective barrier, separating underlying tissues from the gut lumen content. Disruptions in the delicate balance of the gut epithelium trigger inflammatory responses, aggravate conditions such as inflammatory bowel disease, and potentially lead to more severe complications such as colorectal cancer. Maintaining intestinal epithelial homeostasis is vital for overall health, and there is growing interest in identifying nutraceuticals that can strengthen the intestinal epithelium. α-Ketoglutarate, a metabolite of the tricarboxylic acid cycle, displays a variety of bioactive effects, including functioning as an antioxidant, a necessary cofactor for epigenetic modification, and exerting anti-inflammatory effects. This article presents a comprehensive overview of studies investigating the potential of α-ketoglutarate supplementation in preventing dysfunction of the intestinal epithelium.
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Affiliation(s)
| | - Min Du
- Department of Animal Sciences, Washington State University, Pullman, WA, United States
| | - Mei-Jun Zhu
- School of Food Science, Washington State University, Pullman, WA, United States.
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3
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Molotla-Torres DE, Guzmán-Mejía F, Godínez-Victoria M, Drago-Serrano ME. Role of Stress on Driving the Intestinal Paracellular Permeability. Curr Issues Mol Biol 2023; 45:9284-9305. [PMID: 37998758 PMCID: PMC10670774 DOI: 10.3390/cimb45110581] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 11/05/2023] [Accepted: 11/13/2023] [Indexed: 11/25/2023] Open
Abstract
The gut epithelium is a polarized monolayer that exhibits apical and basolateral membrane surfaces. Monolayer cell components are joined side by side via protein complexes known as tight junction proteins (TJPs), expressed at the most apical extreme of the basolateral membrane. The gut epithelium is a physical barrier that determinates intestinal permeability, referred to as the measurement of the transit of molecules from the intestinal lumen to the bloodstream or, conversely, from the blood to the gut lumen. TJPs play a role in the control of intestinal permeability that can be disrupted by stress through signal pathways triggered by the ligation of receptors with stress hormones like glucocorticoids. Preclinical studies conducted under in vitro and/or in vivo conditions have addressed underlying mechanisms that account for the impact of stress on gut permeability. These mechanisms may provide insights for novel therapeutic interventions in diseases in which stress is a risk factor, like irritable bowel syndrome. The focus of this study was to review, in an integrative context, the neuroendocrine effects of stress, with special emphasis on TJPs along with intestinal permeability.
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Affiliation(s)
- Daniel Efrain Molotla-Torres
- Doctorado en Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana, Calzada del Hueso No. 1100, Ciudad de México CP 04960, Mexico;
| | - Fabiola Guzmán-Mejía
- Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana Unidad Xochimilco, Calzada del Hueso No. 1100, Ciudad de México CP 04960, Mexico
| | - Marycarmen Godínez-Victoria
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, Ciudad de México CP 11340, Mexico;
| | - Maria Elisa Drago-Serrano
- Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana Unidad Xochimilco, Calzada del Hueso No. 1100, Ciudad de México CP 04960, Mexico
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4
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Leigh SJ, Uhlig F, Wilmes L, Sanchez-Diaz P, Gheorghe CE, Goodson MS, Kelley-Loughnane N, Hyland NP, Cryan JF, Clarke G. The impact of acute and chronic stress on gastrointestinal physiology and function: a microbiota-gut-brain axis perspective. J Physiol 2023; 601:4491-4538. [PMID: 37756251 DOI: 10.1113/jp281951] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 09/06/2023] [Indexed: 09/29/2023] Open
Abstract
The physiological consequences of stress often manifest in the gastrointestinal tract. Traumatic or chronic stress is associated with widespread maladaptive changes throughout the gut, although comparatively little is known about the effects of acute stress. Furthermore, these stress-induced changes in the gut may increase susceptibility to gastrointestinal disorders and infection, and impact critical features of the neural and behavioural consequences of the stress response by impairing gut-brain axis communication. Understanding the mechanisms behind changes in enteric nervous system circuitry, visceral sensitivity, gut barrier function, permeability, and the gut microbiota following stress is an important research objective with pathophysiological implications in both neurogastroenterology and psychiatry. Moreover, the gut microbiota has emerged as a key aspect of physiology sensitive to the effects of stress. In this review, we focus on different aspects of the gastrointestinal tract including gut barrier function as well as the immune, humoral and neuronal elements involved in gut-brain communication. Furthermore, we discuss the evidence for a role of stress in gastrointestinal disorders. Existing gaps in the current literature are highlighted, and possible avenues for future research with an integrated physiological perspective have been suggested. A more complete understanding of the spatial and temporal dynamics of the integrated host and microbial response to different kinds of stressors in the gastrointestinal tract will enable full exploitation of the diagnostic and therapeutic potential in the fast-evolving field of host-microbiome interactions.
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Affiliation(s)
- Sarah-Jane Leigh
- APC Microbiome Ireland, Cork, Ireland
- Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
| | - Friederike Uhlig
- APC Microbiome Ireland, Cork, Ireland
- Department of Physiology, University College Cork, Cork, Ireland
| | - Lars Wilmes
- APC Microbiome Ireland, Cork, Ireland
- Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | - Paula Sanchez-Diaz
- APC Microbiome Ireland, Cork, Ireland
- Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
| | - Cassandra E Gheorghe
- APC Microbiome Ireland, Cork, Ireland
- Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
| | - Michael S Goodson
- 711th Human Performance Wing, Air Force Research Laboratory, Wright-Patterson Air Force Base, Dayton, Ohio, USA
| | - Nancy Kelley-Loughnane
- Materials and Manufacturing Directorate, Air Force Research Laboratory, Wright-Patterson Air Force Base, Dayton, Ohio, USA
| | - Niall P Hyland
- APC Microbiome Ireland, Cork, Ireland
- Department of Physiology, University College Cork, Cork, Ireland
| | - John F Cryan
- APC Microbiome Ireland, Cork, Ireland
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | - Gerard Clarke
- APC Microbiome Ireland, Cork, Ireland
- Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
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5
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Sulit AK, Daigneault M, Allen-Vercoe E, Silander OK, Hock B, McKenzie J, Pearson J, Frizelle FA, Schmeier S, Purcell R. Bacterial lipopolysaccharide modulates immune response in the colorectal tumor microenvironment. NPJ Biofilms Microbiomes 2023; 9:59. [PMID: 37612266 PMCID: PMC10447454 DOI: 10.1038/s41522-023-00429-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 08/15/2023] [Indexed: 08/25/2023] Open
Abstract
Immune responses can have opposing effects in colorectal cancer (CRC), the balance of which may determine whether a cancer regresses, progresses, or potentially metastasizes. These effects are evident in CRC consensus molecular subtypes (CMS) where both CMS1 and CMS4 contain immune infiltrates yet have opposing prognoses. The microbiome has previously been associated with CRC and immune response in CRC but has largely been ignored in the CRC subtype discussion. We used CMS subtyping on surgical resections from patients and aimed to determine the contributions of the microbiome to the pleiotropic effects evident in immune-infiltrated subtypes. We integrated host gene-expression and meta-transcriptomic data to determine the link between immune characteristics and microbiome contributions in these subtypes and identified lipopolysaccharide (LPS) binding as a potential functional mechanism. We identified candidate bacteria with LPS properties that could affect immune response, and tested the effects of their LPS on cytokine production of peripheral blood mononuclear cells (PBMCs). We focused on Fusobacterium periodonticum and Bacteroides fragilis in CMS1, and Porphyromonas asaccharolytica in CMS4. Treatment of PBMCs with LPS isolated from these bacteria showed that F. periodonticum stimulates cytokine production in PBMCs while both B. fragilis and P. asaccharolytica had an inhibitory effect. Furthermore, LPS from the latter two species can inhibit the immunogenic properties of F. periodonticum LPS when co-incubated with PBMCs. We propose that different microbes in the CRC tumor microenvironment can alter the local immune activity, with important implications for prognosis and treatment response.
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Affiliation(s)
- A K Sulit
- School of Natural Sciences, Massey University, Auckland, New Zealand.
- Department of Surgery and Critical Care, University of Otago, Christchurch, New Zealand.
| | - M Daigneault
- Department of Molecular and Cellular Biology, University of Guelph, Ontario, Canada
| | - E Allen-Vercoe
- Department of Molecular and Cellular Biology, University of Guelph, Ontario, Canada
| | - O K Silander
- School of Natural Sciences, Massey University, Auckland, New Zealand
| | - B Hock
- Haematology Research Group, University of Otago, Christchurch, New Zealand
| | - J McKenzie
- Haematology Research Group, University of Otago, Christchurch, New Zealand
| | - J Pearson
- Biostatistics and Computational Biology Unit, University of Otago, Christchurch, New Zealand
| | - F A Frizelle
- Department of Surgery and Critical Care, University of Otago, Christchurch, New Zealand
| | - S Schmeier
- School of Natural Sciences, Massey University, Auckland, New Zealand
- Evotec SE, Hamburg, Germany
| | - R Purcell
- Department of Surgery and Critical Care, University of Otago, Christchurch, New Zealand
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6
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Chen H, Kan Q, Zhao L, Ye G, He X, Tang H, Shi F, Zou Y, Liang X, Song X, Liu R, Luo J, Li Y. Prophylactic effect of Tongxieyaofang polysaccharide on depressive behavior in adolescent male mice with chronic unpredictable stress through the microbiome-gut-brain axis. Biomed Pharmacother 2023; 161:114525. [PMID: 36921537 DOI: 10.1016/j.biopha.2023.114525] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 03/09/2023] [Accepted: 03/10/2023] [Indexed: 03/17/2023] Open
Abstract
Major depression disorder is more common among adolescents and is a primary reason for suicide in adolescents. Some antidepressants are ineffective and may possess side effects. Therefore, developing an adolescent antidepressant is the need of the hour. We designed the stress model of adolescent male mice induced by chronic unpredictable stress (CUS). The mice were treated using Tongxieyaofang neutral polysaccharide (TXYF-NP), Tongxieyaofang acidic polysaccharide (TXYF-AP), TXYF-AP + TXYF-NP and fructooligosaccharide + galactooligosaccharides to determine their body weight, behavior, and serum hormone levels. RT-qPCR was used to detect the gene expression of Crhr1, Nr3c1, and Nr3c2 in the hypothalamus and hippocampus and the gene expression of glutamic acid and γ-aminobutyric acid-related receptors in the hippocampus. RT-qPCR, Western blot, and ELISA detected tryptophan metabolism in the colon, serum, and hippocampus. 16s rDNA helped sequence colon microflora, and non-targeted metabolomics enabled the collection of metabolic profiles of colon microflora. In adolescent male mice, CUS induced depression-like behavior, hypothalamic-pituitary-adrenal axis hyperactivity, hippocampal tissue damage, abnormal expression of its related receptors, and dysregulation of tryptophan metabolism. The 16s rDNA and non-targeted metabolomics revealed that CUS led to colon microflora disorder and bile acid metabolism abnormality. Tongxieyaofang polysaccharide could improve the bacterial community and bile acid metabolism disorder by upregulating the relative abundance of Lactobacillus gasseri, Lachnospiraceae bacterium 28-4, Bacteroides and Ruminococcaceae UCG-014 while preventing CUS-induced changes. TXYF-P can inhibit depression-like behavior due to CUS by regulating colonic microflora and restoring bile acid metabolism disorder. Thus, based on the different comparisons, TXYF-NP possessed the best effect.
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Affiliation(s)
- Helin Chen
- College of Veterinary Medicine, Sichuan Agricultural University, 211 Huimin Road, Chengdu 611130, Sichuan, China
| | - Qibin Kan
- College of Veterinary Medicine, Sichuan Agricultural University, 211 Huimin Road, Chengdu 611130, Sichuan, China
| | - Ling Zhao
- College of Veterinary Medicine, Sichuan Agricultural University, 211 Huimin Road, Chengdu 611130, Sichuan, China
| | - Gang Ye
- College of Veterinary Medicine, Sichuan Agricultural University, 211 Huimin Road, Chengdu 611130, Sichuan, China
| | - Xiaoli He
- College of Science, Sichuan Agricultural University, 211 Huimin Road, Chengdu 611130, Sichuan, China
| | - Huaqiao Tang
- College of Veterinary Medicine, Sichuan Agricultural University, 211 Huimin Road, Chengdu 611130, Sichuan, China
| | - Fei Shi
- College of Veterinary Medicine, Sichuan Agricultural University, 211 Huimin Road, Chengdu 611130, Sichuan, China
| | - Yuanfeng Zou
- College of Veterinary Medicine, Sichuan Agricultural University, 211 Huimin Road, Chengdu 611130, Sichuan, China
| | - Xiaoxia Liang
- College of Veterinary Medicine, Sichuan Agricultural University, 211 Huimin Road, Chengdu 611130, Sichuan, China
| | - Xu Song
- College of Veterinary Medicine, Sichuan Agricultural University, 211 Huimin Road, Chengdu 611130, Sichuan, China
| | - Rui Liu
- National Ethnic Affairs Commission Key Open Laboratory of Traditional Chinese Veterinary Medicine, Tongren Polytechnic College, Tongren 554300, China
| | - Jie Luo
- National Ethnic Affairs Commission Key Open Laboratory of Traditional Chinese Veterinary Medicine, Tongren Polytechnic College, Tongren 554300, China.
| | - Yinglun Li
- College of Veterinary Medicine, Sichuan Agricultural University, 211 Huimin Road, Chengdu 611130, Sichuan, China.
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7
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Jiang ZF, Wu W, Hu HB, Li ZY, Zhong M, Zhang L. P2X7 receptor as the regulator of T-cell function in intestinal barrier disruption. World J Gastroenterol 2022; 28:5265-5279. [PMID: 36185635 PMCID: PMC9521516 DOI: 10.3748/wjg.v28.i36.5265] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 06/20/2022] [Accepted: 09/01/2022] [Indexed: 02/06/2023] Open
Abstract
The intestinal mucosa is a highly compartmentalized structure that forms a direct barrier between the host intestine and the environment, and its dysfunction could result in a serious disease. As T cells, which are important components of the mucosal immune system, interact with gut microbiota and maintain intestinal homeostasis, they may be involved in the process of intestinal barrier dysfunction. P2X7 receptor (P2X7R), a member of the P2X receptors family, mediates the effects of extracellular adenosine triphosphate and is expressed by most innate or adaptive immune cells, including T cells. Current evidence has demonstrated that P2X7R is involved in inflammation and mediates the survival and differentiation of T lymphocytes, indicating its potential role in the regulation of T cell function. In this review, we summarize the available research about the regulatory role and mechanism of P2X7R on the intestinal mucosa-derived T cells in the setting of intestinal barrier dysfunction.
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Affiliation(s)
- Zhi-Feng Jiang
- Center of Emergency & Intensive Care Unit, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Wei Wu
- Department of Critical Care Medicine, Zhongshan Hospital of Fudan University, Shanghai 200032, China
| | - Han-Bing Hu
- Center of Emergency & Intensive Care Unit, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Zheng-Yang Li
- Department of Gastroenterology, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Ming Zhong
- Department of Critical Care Medicine, Zhongshan Hospital of Fudan University, Shanghai 200032, China
| | - Lin Zhang
- Center of Emergency & Intensive Care Unit, Jinshan Hospital of Fudan University, Shanghai 201508, China
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8
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Liu B, Yang L, Wu Y, Zhao X. Protective effect of Limosilactobacillus fermentum HFY06 on dextran sulfate sodium-induced colitis in mice. Front Microbiol 2022; 13:935792. [PMID: 36171753 PMCID: PMC9512270 DOI: 10.3389/fmicb.2022.935792] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 08/11/2022] [Indexed: 11/13/2022] Open
Abstract
Ulcerative colitis is one of the main gastrointestinal diseases that threaten human health. This study investigated the effect of Limosilactobacillus fermentum HFY06 (LF-HFY06) on dextran sulfate sodium (DSS)-induced murine colitis. The protective effect of LF-HFY06 was evaluated by examining the length and histopathological sections of colon, related biochemical indicators, and genes related to inflammation. Direct and microscopic observations showed that LF-HFY06 increased the length of the colon and ameliorated the pathological damage induced by DSS. The biochemical indicators showed that LF-HFY06 enhanced the activities of antioxidant enzymes total superoxide dismutase (T-SOD) and catalase (CAT) in serum, while reducing the level of malondialdehyde (MDA). It was also observed that the serum inflammatory cytokines levels of tumor necrosis factor-α (TNF-α), interferon (IFN)-γ, interleukin (IL)-1β, IL-6, and IL-12 were decreased, and the anti-inflammatory cytokine IL-10 level was increased. The qPCR experiment revealed that LF-HFY06 downregulated the mRNA expression levels of nuclear factor-κB-p65 (Rela), Tnf, Il 1b, Il 6, and prostaglandin-endoperoxide synthase 2 (Ptgs2) in colon tissues, and upregulated the mRNA expression of NF-κB inhibitor-α (Nfkbia) and Il 10. These data indicated that LF-HFY06 inhibited inflammation through the NF-κB signaling pathway to prevent the occurrence and development of colitis. This research demonstrates that probiotics LF-HFY06 have the potential to prevent and treat colitis.
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Affiliation(s)
- Bihui Liu
- Collaborative Innovation Center for Child Nutrition and Health Development, Chongqing University of Education, Chongqing, China
- Chongqing Engineering Research Center of Functional Food, Chongqing University of Education, Chongqing, China
- Chongqing Engineering Laboratory for Research and Development of Functional Food, Chongqing University of Education, Chongqing, China
- College of Biological and Chemical Engineering, Chongqing University of Education, Chongqing, China
| | - Lei Yang
- Department of Urology, First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Ya Wu
- Collaborative Innovation Center for Child Nutrition and Health Development, Chongqing University of Education, Chongqing, China
- Chongqing Engineering Research Center of Functional Food, Chongqing University of Education, Chongqing, China
- Chongqing Engineering Laboratory for Research and Development of Functional Food, Chongqing University of Education, Chongqing, China
- College of Biological and Chemical Engineering, Chongqing University of Education, Chongqing, China
| | - Xin Zhao
- Collaborative Innovation Center for Child Nutrition and Health Development, Chongqing University of Education, Chongqing, China
- Chongqing Engineering Research Center of Functional Food, Chongqing University of Education, Chongqing, China
- Chongqing Engineering Laboratory for Research and Development of Functional Food, Chongqing University of Education, Chongqing, China
- *Correspondence: Xin Zhao,
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9
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Jiang WD, Zhang L, Feng L, Wu P, Liu Y, Kuang SY, Li SW, Tang L, Mi HF, Zhang L, Zhou XQ. New Insight on the Immune Modulation and Physical Barrier Protection Caused by Vitamin A in Fish Gills Infected With Flavobacterium columnare. Front Immunol 2022; 13:833455. [PMID: 35401542 PMCID: PMC8992971 DOI: 10.3389/fimmu.2022.833455] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Accepted: 02/23/2022] [Indexed: 11/13/2022] Open
Abstract
In this study, we have investigated the influence of vitamin A on gill barrier function of grass carp (Ctenopharyngodon idella) infected with Flavobacterium columnare. The fish were fed different concentrations of vitamin A diets for 10 weeks and then infected with F. columnare by immersion. We observed that optimal vitamin A significantly prevented gill rot morbidity in fish infected with F. columnare. Further investigations revealed that vitamin A boosted the gill immunity by increasing the contents of complements (C3 and C4), activities of acid phosphatase (ACP) and lysozyme, mRNAs of β-defensin-1, liver-expressed antimicrobial peptide 2A and 2B (LEAP-2A and LEAP-2B), hepcidin, and anti-inflammatory cytokines like transforming growth factor β1 (TGF-β1), TGF-β2, interleukin-10 (IL-10), and IL-11. It also enhanced the levels of various related signaling molecules including inhibitor protein κBα (IκBα), target of rapamycin (TOR), and ribosome protein S6 kinase 1 (S6K1) but downregulated the expression of pro-inflammatory cytokines including IL-1β, IL-8, tumor necrosis factor α (TNF-α), and interferon γ2 (IFN-γ2) and related signaling molecules including nuclear factor κB p65 (NF-κB p65) (rather than NF-κB p52), IκB kinase β (IKKβ), IKKγ (rather than IKKα), eIF4E-binding protein 1 (4E-BP1), and 4E-BP2 mRNA levels in fish gills. In addition, dietary vitamin A markedly lowered the concentrations of reactive oxygen species (ROS), malondialdehyde (MDA), and protein carbonyl (PC), increased both the activities and mRNAs of copper/zinc superoxide dismutase (Cu/ZnSOD), MnSOD, glutathione transferases (GSTs), glutathione peroxidase (GPx), and glutathione reductase (GR) associated with upregulation of NF-E2-related factor 2 (Nrf2) mRNAs and downregulation of Kelch-like-ECH-associated protein (Keap1a) and Keap1b mRNAs. Moreover, vitamin A decreased the mRNAs of different apoptotic mediators [caspases 8, 9, 3 (rather than 7)] associated with downregulation of signaling molecule p38 mitogen-activated protein kinase (p38MAPK) mRNAs in fish gills. Besides, vitamin A promoted tight junction (TJ) complex mRNAs [including claudin-b, -c, -3, -7, -12, occludin, and zonula occludens-1 (ZO-1)] that have been linked to the downregulation of myosin light chain kinase (MLCK) signaling. Taken together, the current study demonstrated for the first time that vitamin A markedly enhanced gill health associated with immune modulation and physical barrier protection. Based on protecting fish against gill rot morbidity, ACP activity, and against lipid peroxidation, optimum vitamin A concentrations in on-growing grass carp (262-997 g) were found to be 1,991, 2,188, and 2,934 IU/kg diet, respectively.
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Affiliation(s)
- Wei-Dan Jiang
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-Resistance Nutrition, Ministry of Education, Ministry of Agriculture and Rural Affairs, Key Laboratory of Sichuan Province, Sichuan, China
| | - Li Zhang
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Lin Feng
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-Resistance Nutrition, Ministry of Education, Ministry of Agriculture and Rural Affairs, Key Laboratory of Sichuan Province, Sichuan, China
| | - Pei Wu
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-Resistance Nutrition, Ministry of Education, Ministry of Agriculture and Rural Affairs, Key Laboratory of Sichuan Province, Sichuan, China
| | - Yang Liu
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-Resistance Nutrition, Ministry of Education, Ministry of Agriculture and Rural Affairs, Key Laboratory of Sichuan Province, Sichuan, China
| | - Sheng-Yao Kuang
- Animal Nutrition Institute, Sichuan Academy of Animal Science, Sichuan Animtech Feed Co. Ltd., Chengdu, China
| | - Shu-Wei Li
- Animal Nutrition Institute, Sichuan Academy of Animal Science, Sichuan Animtech Feed Co. Ltd., Chengdu, China
| | - Ling Tang
- Animal Nutrition Institute, Sichuan Academy of Animal Science, Sichuan Animtech Feed Co. Ltd., Chengdu, China
| | - Hai-Feng Mi
- Tongwei Co., Ltd., Healthy Aquaculture Key Laboratory of Sichuan Province, Chengdu, China
| | - Lu Zhang
- Tongwei Co., Ltd., Healthy Aquaculture Key Laboratory of Sichuan Province, Chengdu, China
| | - Xiao-Qiu Zhou
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China.,Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease-Resistance Nutrition, Ministry of Education, Ministry of Agriculture and Rural Affairs, Key Laboratory of Sichuan Province, Sichuan, China
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10
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Fortea M, Albert-Bayo M, Abril-Gil M, Ganda Mall JP, Serra-Ruiz X, Henao-Paez A, Expósito E, González-Castro AM, Guagnozzi D, Lobo B, Alonso-Cotoner C, Santos J. Present and Future Therapeutic Approaches to Barrier Dysfunction. Front Nutr 2021; 8:718093. [PMID: 34778332 PMCID: PMC8582318 DOI: 10.3389/fnut.2021.718093] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 09/29/2021] [Indexed: 12/12/2022] Open
Abstract
There is converging and increasing evidence, but also uncertainty, for the role of abnormal intestinal epithelial barrier function in the origin and development of a growing number of human gastrointestinal and extraintestinal inflammatory disorders, and their related complaints. Despite a vast literature addressing factors and mechanisms underlying changes in intestinal permeability in humans, and its connection to the appearance and severity of clinical symptoms, the ultimate link remains to be established in many cases. Accordingly, there are no directives or clinical guidelines related to the therapeutic management of intestinal permeability disorders that allow health professionals involved in the management of these patients to carry out a consensus treatment based on clinical evidence. Instead, there are multiple pseudoscientific approaches and commercial propaganda scattered on the internet that confuse those affected and health professionals and that often lack scientific rigor. Therefore, in this review we aim to shed light on the different therapeutic options, which include, among others, dietary management, nutraceuticals and medical devices, microbiota and drugs, and epigenetic and exosomes-manipulation, through an objective evaluation of the scientific publications in this field. Advances in the knowledge and management of intestinal permeability will sure enable better options of dealing with this group of common disorders to enhance quality of life of those affected.
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Affiliation(s)
- Marina Fortea
- Laboratory for Enteric NeuroScience, Translational Research Center for GastroIntestinal Disorders, University of Leuven, Leuven, Belgium
| | - Mercé Albert-Bayo
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Mar Abril-Gil
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - John-Peter Ganda Mall
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Xavier Serra-Ruiz
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Alejandro Henao-Paez
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Elba Expósito
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Ana María González-Castro
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Danila Guagnozzi
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Facultad de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERHED), Instituto de Salud Carlos III, Madrid, Spain
| | - Beatriz Lobo
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Facultad de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Carmen Alonso-Cotoner
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Facultad de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERHED), Instituto de Salud Carlos III, Madrid, Spain
| | - Javier Santos
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Gastroenterology, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Facultad de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERHED), Instituto de Salud Carlos III, Madrid, Spain
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Pham HHS, Matsubayashi M, Tsuji N, Hatabu T. Relationship between Eimeria tenella associated-early clinical signs and molecular changes in the intestinal barrier function. Vet Immunol Immunopathol 2021; 240:110321. [PMID: 34520968 DOI: 10.1016/j.vetimm.2021.110321] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 07/21/2021] [Accepted: 08/26/2021] [Indexed: 01/01/2023]
Abstract
The major clinical signs of coccidiosis in chickens due to Eimeria parasite are diarrhea and bloody feces. Previous studies showed that the impairment of the intestinal epithelial barrier and the elevation of the intestinal permeability are causes of clinical signs associated with coccidia challenges. Nevertheless, the information about molecular changes of the epithelial barrier at the early stage of the infection with a specific Eimeria species has not been mentioned. Hence, this study aims to elucidate the temporal relationships between epithelial barrier conditions and clinical signs in chickens infected with Eimeria tenella over the time from the earliest stages of infection. White Leghorn chickens were inoculated with 1 × 104 oocysts of E. tenella. Thereafter the chickens were monitored for their daily clinical signs through observation, and between 5 dpi to 10 dpi, feces were collected for oocysts counting. Chickens were then administrated with fluorescein isothiocyanate-dextran (FITC-d) for gastrointestinal permeability test and tissues were collected each day for histopathological observation and total RNA extraction. Finally, the mRNA expression levels of the tight and adherens junction genes and cytokine genes were evaluated using the quantitative real-time polymerase chain reaction (qRT-PCR). In this study, clinical signs such as diarrhea and bloody feces were observed concurrently from 3 to 8 dpi. Histopathology changes such as severe inflammation, hemorrhage, and epithelial desquamation were identified in the cecum specimens. The FITC-d level in the E. tenella-infected group was significantly higher than in the control group. In the infected group, the expression of claudin-2 gene was also upregulated, whereas the expressions of claudin-3 and E-cadherin genes were decreased as compared to the control group. These results implied that clinical signs of avian coccidiosis were associated with the intestinal barrier disruption via changes in expression levels of claudins and E-cadherin at the intestine.
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Affiliation(s)
- Hung Hoang Son Pham
- Laboratory of Animal Physiology, Graduate School of Environmental and Life Science, Okayama University, 1-1-1 Tsushima-Naka, Kita-Ku, Okayama, 700-8530, Japan
| | - Makoto Matsubayashi
- Department of Veterinary Science, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Izumisano, Osaka, 598-8531, Japan
| | - Naotoshi Tsuji
- Department of Molecular and Cellular Parasitology, Kitasato University Graduate School of Medical Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Japan
| | - Toshimitsu Hatabu
- Laboratory of Animal Physiology, Graduate School of Environmental and Life Science, Okayama University, 1-1-1 Tsushima-Naka, Kita-Ku, Okayama, 700-8530, Japan.
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12
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Hung YK, Ho ST, Kuo CY, Chen MJ. In vitro effects of velvet antler water extracts from Formosan Sambar deer and red deer on barrier integrity in Caco-2 cell. Int J Med Sci 2021; 18:1778-1785. [PMID: 33746595 PMCID: PMC7976581 DOI: 10.7150/ijms.53599] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 01/13/2021] [Indexed: 12/16/2022] Open
Abstract
Background: The mucus integrity and abnormal inflammatory response are the crucial biomarker of inflammatory bowel disease (IBD). Velvet antler (VA) has been used as traditional Chinese medicines for many years. Anti-inflammatory property was demonstrated via suppression of cyclooxygenase-2 and cytokines protein expression. And it has further proved to promote wound healing in streptozotocin-induced diabetic rats model. The aforementioned functionalities of VA extracts may be associated with the treatment of IBD. Thus, the aim of present study was to evaluate the effect of velvet antler water extracts form Formosan Sambar deer (Rusa unicolor swinhoei, SVAE) and red deer (Cervus elaphus, RVAE) on the barrier function and to investigate the possible mechanism using in vitro model. Methods: Human colonic epithelial cell models (Caco-2) were co-cultured with various concentrations of both SVAE and RVAE (250-500 µg mL-1) in dextran sulfate sodium (DSS)-induced colitis model. Trans-epithelial electrical resistance (TEER) value and the macromolecule permeability of Fluorescein isothiocyanate (FITC)-labeled dextran were measured to evaluate the integrity of monolayer of Caco-2. Western blotting was performed for analysis of protein expressions of occludin, Zonula occludens-1 (ZO-1), claudin-1, claudin-2 and myosin light chain kinase (MLCK). The cytotoxicity was conducted by MTT assay. Results: Results indicated that both SVAE and RVAE could enhance integrity of monolayer in dextran sulfate sodium (DSS)-induced colonic epithelial cell model (Caco-2) through reducing the decline of trans-epithelial electrical resistance (TEER) and macromolecule permeability at the concentration of 250 μg mL-1. RVAE significantly increased the expression of tight junction proteins (occludin and ZO-1) while SVAE significantly reduced the activity of MLCK (P < 0.05.). Elevated C-C chemokine ligand 20 (CCL20) production suggested that both SVAE and RVAE could enhance the repair of epithelial cell. Besides, MTT assay revealed that both extracts showed no cytotoxicity. Conclusion: Thus, SVAE and RVAE supplementation may attenuate barrier damage by enhancing the occludin and ZO-1 protein expression, decreasing MLCK expression, promoting the CCL20 production. In the future, animal study is needed for further confirmation.
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Affiliation(s)
- Ying-Kai Hung
- Department of Animal Science and Technology, National Taiwan University, Taipei 106, Taiwan
| | - Shang-Tse Ho
- Department of Wood Based Materials and Design, National Chiayi University, Chiayi 600, Taiwan
| | - Ching-Yun Kuo
- Taiwan Livestock Research Institute, Council of Agriculture, Tainan 712, Taiwan
| | - Ming-Ju Chen
- Department of Animal Science and Technology, National Taiwan University, Taipei 106, Taiwan
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Awad WA, Ruhnau D, Hess C, Hess M. Campylobacter jejuni increases the paracellular permeability of broiler chickens in a dose-dependent manner. Poult Sci 2020; 99:5407-5414. [PMID: 33142457 PMCID: PMC7647851 DOI: 10.1016/j.psj.2020.08.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 07/28/2020] [Accepted: 08/06/2020] [Indexed: 12/15/2022] Open
Abstract
In recent years, several studies emphasize the deleterious effects of Campylobacter jejuni on the chicken intestine. In this context, it was shown that C. jejuni, contrary to the general belief, has a negative influence on the gut barrier in chickens. More precisely, we demonstrated that C. jejuni affects gut physiology characterized by changes in ion transport and transepithelial ion conductance, but the underlying mechanism is yet to be investigated. In the actual study, to determine epithelial paracellular permeability, the mucosal to serosal flux of 14C-mannitol in the small and large intestine was measured applying Ussing chamber. A total of seventy-five 1-day-old Ross 308 broiler chickens were housed in floor pens on wood shavings with feed and water provided ad libitum. Birds were randomly allocated to 3 different groups (n = 25 with 5 replicates/group) and infected at 14 d of age with a high (108 colony forming units [CFU]) or a low (104 CFU) dose of C. jejuni and a third group kept as noninfected control. Infection with the low dose of C. jejuni resulted in delayed cecal colonization but equalized at 21 d postinfection, independent of the dose. Invasion of liver and spleen with C. jejuni was only noticed in birds infected with 108 (CFU). Body weight (BW) and body weight gain of all birds infected with C. jejuni were lower than in the control group and varied with the dose of infection, confirming a negative correlation between the infection dose and birds BW. Mannitol flux in jejunum and cecum was significantly (P < 0.05) higher in all C. jejuni infected birds compared with control birds. Likewise, significant differences in mannitol flux of both jejunum and cecum were detected depending on the infection dose of C. jejuni. The correlation analyses revealed a positive relationship between Campylobacter dose and mannitol flux of both jejunum and cecum. Altogether, the actual results emphasize that the adverse effect of C. jejuni on gut permeability arises in a dose-dependent manner.
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Affiliation(s)
- Wageha A Awad
- Department for Farm Animals and Veterinary Public Health, Clinic for Poultry and Fish Medicine, University of Veterinary Medicine, Vienna, Austria.
| | - Daniel Ruhnau
- Department for Farm Animals and Veterinary Public Health, Clinic for Poultry and Fish Medicine, University of Veterinary Medicine, Vienna, Austria
| | - Claudia Hess
- Department for Farm Animals and Veterinary Public Health, Clinic for Poultry and Fish Medicine, University of Veterinary Medicine, Vienna, Austria
| | - Michael Hess
- Department for Farm Animals and Veterinary Public Health, Clinic for Poultry and Fish Medicine, University of Veterinary Medicine, Vienna, Austria
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14
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The role of the microbiota in acute stress-induced myeloid immune cell trafficking. Brain Behav Immun 2020; 84:209-217. [PMID: 31812778 DOI: 10.1016/j.bbi.2019.12.003] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 11/21/2019] [Accepted: 12/02/2019] [Indexed: 12/17/2022] Open
Abstract
There has been a growing recognition of the involvement of the gastrointestinal microbiota in the development of stress-related disorders. Acute stress leads to activation of neuroendocrine systems, which in turn orchestrate a large-scale redistribution of innate immune cells. Both these response systems are independently known to be primed by the microbiota, even though much is still unclear about the role of the gastrointestinal microbiota in acute stress-induced immune activation. In this study, we investigated whether the microbiota influences acute stress-induced changes in innate immunity using conventionally colonised mice, mice devoid of any microbiota (i.e. germ-free, GF), and colonised GF mice (CGF). We also explored the kinetics of stress-induced immune cell mobilisation in the blood, the spleen and mesenteric lymph nodes (MLNs). Mice were either euthanised prior to stress or underwent restraint stress and were then euthanised at various time points (i.e. 0, 45- and 240-minutes) post-stress. Plasma adrenaline and noradrenaline levels were analysed using ELISA and immune cell levels were quantified using flow cytometry. GF mice had increased baseline levels of adrenaline and noradrenaline, of which adrenaline was normalised in CGF mice. In tandem, GF mice had decreased circulating levels of LY6Chi and LY6Cmid, CCR2+ monocytes, and granulocytes, but not LY6C-, CX3CR1+ monocytes. These deficits were normalised in CGF mice. Acute stress decreased blood LY6Chi and LY6Cmid, CCR2+ monocytes while increasing granulocyte levels in all groups 45 min post-stress. However, only GF mice showed stress-induced changes in LY6Chi monocytes and granulocytes 240 min post-stress, indicating impairments in the recovery from acute stress-induced changes in levels of specific innate immune cell types. LY6C-, CX3CR1+ monocytes remained unaffected by stress, indicating that acute stress impacts systemic innate immunity in a cell-type-specific manner. Overall, these data reveal novel cell-type-specific changes in the innate immune system in response to acute stress, which in turn are impacted by the microbiota. In conclusion, the microbiota influences the priming and recovery of the innate immune system to an acute stressor and may inform future microbiota-targeted therapeutics aimed at modulating stress-induced immune activation in stress-related disorders.
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15
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Intestinal Permeability and IgA Provoke Immune Vasculitis Linked to Cardiovascular Inflammation. Immunity 2019; 51:508-521.e6. [PMID: 31471109 DOI: 10.1016/j.immuni.2019.05.021] [Citation(s) in RCA: 98] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 04/18/2019] [Accepted: 05/29/2019] [Indexed: 02/07/2023]
Abstract
Recent experimental data and clinical, genetic, and transcriptome evidence from patients converge to suggest a key role of interleukin-1β (IL-1β) in the pathogenesis of Kawasaki disease (KD). However, the molecular mechanisms involved in the development of cardiovascular lesions during KD vasculitis are still unknown. Here, we investigated intestinal barrier function in KD vasculitis and observed evidence of intestinal permeability and elevated circulating secretory immunoglobulin A (sIgA) in KD patients, as well as elevated sIgA and IgA deposition in vascular tissues in a mouse model of KD vasculitis. Targeting intestinal permeability corrected gut permeability, prevented IgA deposition and ameliorated cardiovascular pathology in the mouse model. Using genetic and pharmacologic inhibition of IL-1β signaling, we demonstrate that IL-1β lies upstream of disrupted intestinal barrier function, subsequent IgA vasculitis development, and cardiac inflammation. Targeting mucosal barrier dysfunction and the IL-1β pathway may also be applicable to other IgA-related diseases, including IgA vasculitis and IgA nephropathy.
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16
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He W, Wang Y, Wang P, Wang F. Intestinal barrier dysfunction in severe burn injury. BURNS & TRAUMA 2019; 7:24. [PMID: 31372365 PMCID: PMC6659221 DOI: 10.1186/s41038-019-0162-3] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Accepted: 05/30/2019] [Indexed: 12/24/2022]
Abstract
Severe burn injury is often accompanied by intestinal barrier dysfunction, which is closely associated with post-burn shock, bacterial translocation, systemic inflammatory response syndrome, hypercatabolism, sepsis, multiple organ dysfunction syndrome, and other complications. The intestinal epithelium forms a physical barrier that separates the intestinal lumen from the internal milieu, in which the tight junction plays a principal role. It has been well documented that after severe burn injury, many factors such as stress, ischemia/hypoxia, proinflammatory cytokines, and endotoxins can induce intestinal barrier dysfunction via multiple signaling pathways. Recent advances have provided new insights into the mechanisms and the therapeutic strategies of intestinal epithelial barrier dysfunction associated with severe burn injury. In this review, we will describe the current knowledge of the mechanisms involved in intestinal barrier dysfunction in response to severe burn injury and the emerging therapies for treating intestinal barrier dysfunction following severe burn injury.
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Affiliation(s)
- Wen He
- State Key Laboratory of Trauma, Burns, and Combined Injury, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038 China
| | - Yu Wang
- Department of Gastroenterology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038 China
| | - Pei Wang
- State Key Laboratory of Trauma, Burns, and Combined Injury, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038 China
| | - Fengjun Wang
- State Key Laboratory of Trauma, Burns, and Combined Injury, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038 China
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17
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Rincel M, Olier M, Minni A, Monchaux de Oliveira C, Matime Y, Gaultier E, Grit I, Helbling JC, Costa AM, Lépinay A, Moisan MP, Layé S, Ferrier L, Parnet P, Theodorou V, Darnaudéry M. Pharmacological restoration of gut barrier function in stressed neonates partially reverses long-term alterations associated with maternal separation. Psychopharmacology (Berl) 2019; 236:1583-1596. [PMID: 31147734 DOI: 10.1007/s00213-019-05252-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Accepted: 04/22/2019] [Indexed: 02/06/2023]
Abstract
RATIONALE Intestinal permeability plays an important role in gut-brain axis communication. Recent studies indicate that intestinal permeability increases in neonate pups during maternal separation (MS). OBJECTIVES The present study aims to determine whether pharmacological inhibition of myosin light chain kinase (MLCK), which regulates tight junction contraction and controls intestinal permeability, in stressed neonates, protects against the long-term effects of MS. METHODS Male Wistar rats were exposed to MS (3 h per day from post-natal day (PND)2 to PND14) or left undisturbed and received daily intraperitoneal injection of a MLCK inhibitor (ML-7, 5 mg/kg) or vehicle during the same period. At adulthood, emotional behaviors, corticosterone response to stress, and gut microbiota composition were analyzed. RESULTS ML-7 restored gut barrier function in MS rats specifically during the neonatal period. Remarkably, ML-7 prevented MS-induced sexual reward-seeking impairment and reversed the alteration of corticosterone response to stress at adulthood. The effects of ML-7 were accompanied by the normalization of the abundance of members of Lachnospiraceae, Clostridiales, Desulfovibrio, Bacteroidales, Enterorhabdus, and Bifidobacterium in the feces of MS rats at adulthood. CONCLUSIONS Altogether, our work suggests that improvement of intestinal barrier defects during development may alleviate some of the long-term effects of early-life stress and provides new insight on brain-gut axis communication in a context of stress.
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Affiliation(s)
- Marion Rincel
- Univ. Bordeaux, INRA, Bordeaux INP, NutriNeuro, UMR 1286, 33076, Bordeaux, France
| | - Maïwenn Olier
- Laboratoire Toxalim, UMR 1331, University of Toulouse III (UPS), INP-EI-Purpan, INRA, Toulouse, France
| | - Amandine Minni
- Univ. Bordeaux, INRA, Bordeaux INP, NutriNeuro, UMR 1286, 33076, Bordeaux, France
| | | | - Yann Matime
- Univ. Bordeaux, INRA, Bordeaux INP, NutriNeuro, UMR 1286, 33076, Bordeaux, France
| | - Eric Gaultier
- Laboratoire Toxalim, UMR 1331, University of Toulouse III (UPS), INP-EI-Purpan, INRA, Toulouse, France
| | - Isabelle Grit
- UMR 1280, Institut des maladies de l'appareil digestif, PhAN, INRA, University of Nantes, Nantes, France
| | | | - Anna Maria Costa
- Univ. Bordeaux, INRA, Bordeaux INP, NutriNeuro, UMR 1286, 33076, Bordeaux, France
| | - Amandine Lépinay
- Univ. Bordeaux, INRA, Bordeaux INP, NutriNeuro, UMR 1286, 33076, Bordeaux, France
| | - Marie-Pierre Moisan
- Univ. Bordeaux, INRA, Bordeaux INP, NutriNeuro, UMR 1286, 33076, Bordeaux, France
| | - Sophie Layé
- Univ. Bordeaux, INRA, Bordeaux INP, NutriNeuro, UMR 1286, 33076, Bordeaux, France
| | - Laurent Ferrier
- Laboratoire Toxalim, UMR 1331, University of Toulouse III (UPS), INP-EI-Purpan, INRA, Toulouse, France
| | - Patricia Parnet
- UMR 1280, Institut des maladies de l'appareil digestif, PhAN, INRA, University of Nantes, Nantes, France
| | - Vassilia Theodorou
- Laboratoire Toxalim, UMR 1331, University of Toulouse III (UPS), INP-EI-Purpan, INRA, Toulouse, France
| | - Muriel Darnaudéry
- Univ. Bordeaux, INRA, Bordeaux INP, NutriNeuro, UMR 1286, 33076, Bordeaux, France.
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Dou D, Chen L, Di H, Song Z, Li S, Bu X, Dai Q, Wang S, Li JX, Zhu X, Jing H. Vasopressin augments TNBS-induced colitis through enteric neuronal V 1a receptor-mediated COX-2-dependent prostaglandin release from mast cells in mice. Neurogastroenterol Motil 2019; 31:e13493. [PMID: 30334342 DOI: 10.1111/nmo.13493] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 09/04/2018] [Accepted: 09/20/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a functional disorder with chronic and relapsing clinical features. Vasopressin (VP) is a hormone responsible for water and stress homeostasis and also regulates gastrointestinal inflammation and motility. We explored whether VP was related to IBD pathogenesis and its possible pathway. METHODS Colitis was induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) in mice. The disease activity and colonic damage were evaluated through a scoring system. Locations of the V1a receptor were revealed by immunochemistry method in colon. Ussing chamber technique was performed for the electrophysiological characterization by using rat ileum. The (Arg8 )-Vasopressin (AVP)-evoked short-circuit current (Isc) was recorded in the presence of conivaptan (V1a and V2 receptor antagonist), tolvaptan (V1b receptor antagonist), tetrodotoxin (TTX), atropine, cyclooxygenase (COX) inhibitors (indomethacin, nonspecific COX antagonist; SC560, COX-1 antagonist; NS560, COX-2 antagonist), and a stabilizer of mast cell (cromolyn sodium), respectively. KEY RESULTS TNBS resulted in the obvious loss of body weight and tissue damages in mice. AVP significantly aggravated the TNBS-induced colitis, which was attenuated by conivaptan but not tolvaptan. V1a receptors were found immunopositive in neurons among the enteric nervous system. AVP evoked a pulsatile response in Isc. Its amplitude, frequency, and cycle duration were around 8-15 µA/cm2 , 10-11 mHz, and 1.5 minutes, respectively. Notably, the AVP-evoked change in Isc was abolished by TTX, atropine, conivaptan, indomethacin, NS560, and cromolyn sodium, respectively. CONCLUSIONS AND INFERENCES VP-V1a receptor played the proinflammatory role in TNBS-induced colitis by promoting COX-2-dependent prostaglandin release from mucosal mast cells, which was mediated by the cholinergic pathway.
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Affiliation(s)
- Dandan Dou
- Department of Physiology, School of Basic Medical Science, Shandong University, Jinan, China
| | - Lixin Chen
- School of Medicine, Shandong University, Jinan, China
| | - Hong Di
- School of Medicine, Shandong University, Jinan, China
| | - Zhuoran Song
- School of Medicine, Shandong University, Jinan, China
| | - Shirui Li
- School of Medicine, Shandong University, Jinan, China
| | - Xinjie Bu
- School of Medicine, Shandong University, Jinan, China
| | - Qing Dai
- School of Medicine, Shandong University, Jinan, China
| | - Shuai Wang
- School of Medicine, Shandong University, Jinan, China
| | - Jing Xin Li
- Department of Physiology, School of Basic Medical Science, Shandong University, Jinan, China
| | - Xiaolong Zhu
- Department of Cardiac Surgery Cardiac, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Haiyan Jing
- Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
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Abstract
Intestinal damage driven by unrestricted immune responses against the intestinal microbiota can lead to the development of inflammatory diseases including inflammatory bowel disease. How such breakdown in tolerance occurs alongside the mechanisms to reinforce homeostasis with the microbiota are a focus of many studies. Our recent work demonstrates coordinated interactions between intact microbiota and CX3CR1 expressing intestinal antigen presenting cells (APCs) that limits T helper 1 cell responses and promotes differentiation of regulatory T cells (Treg) against intestinal antigens including pathogens, soluble proteins and the microbiota itself. We find a microbial attachment to intestinal epithelial cells is necessary to support these anti-inflammatory immune functions. In this addendum, we discuss how our findings enhance understanding of microbiota-directed homeostatic functions of the intestinal immune system and implications of modulating this interaction in ameliorating inflammatory disease.
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Affiliation(s)
- Myunghoo Kim
- Alkek Center for Metagenomics and Microbiome Research and the Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA,Department of Animal Science, Pusan National University, Busan, Republic of Korea
| | - Andrea A. Hill
- Alkek Center for Metagenomics and Microbiome Research and the Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Wan-Jung Wu
- Alkek Center for Metagenomics and Microbiome Research and the Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Gretchen E. Diehl
- Alkek Center for Metagenomics and Microbiome Research and the Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA,Biology of Inflammation Center, Baylor College of Medicine, Houston, TX, USA,CONTACT Gretchen E. Diehl
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20
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Time-Dependent Alterations of Gut Wall Integrity in Small Bowel Obstruction in Mice. J Surg Res 2019; 233:249-255. [DOI: 10.1016/j.jss.2018.07.038] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Revised: 06/18/2018] [Accepted: 07/13/2018] [Indexed: 01/01/2023]
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21
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Plantamura E, Dzutsev A, Chamaillard M, Djebali S, Moudombi L, Boucinha L, Grau M, Macari C, Bauché D, Dumitrescu O, Rasigade JP, Lippens S, Plateroti M, Kress E, Cesaro A, Bondu C, Rothermel U, Heikenwälder M, Lina G, Bentaher-Belaaouaj A, Marie JC, Caux C, Trinchieri G, Marvel J, Michallet MC. MAVS deficiency induces gut dysbiotic microbiota conferring a proallergic phenotype. Proc Natl Acad Sci U S A 2018; 115:10404-10409. [PMID: 30249647 PMCID: PMC6187193 DOI: 10.1073/pnas.1722372115] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Prominent changes in the gut microbiota (referred to as "dysbiosis") play a key role in the development of allergic disorders, but the underlying mechanisms remain unknown. Study of the delayed-type hypersensitivity (DTH) response in mice contributed to our knowledge of the pathophysiology of human allergic contact dermatitis. Here we report a negative regulatory role of the RIG-I-like receptor adaptor mitochondrial antiviral signaling (MAVS) on DTH by modulating gut bacterial ecology. Cohousing and fecal transplantation experiments revealed that the dysbiotic microbiota of Mavs-/- mice conferred a proallergic phenotype that is communicable to wild-type mice. DTH sensitization coincided with increased intestinal permeability and bacterial translocation within lymphoid organs that enhanced DTH severity. Collectively, we unveiled an unexpected impact of RIG-I-like signaling on the gut microbiota with consequences on allergic skin disease outcome. Primarily, these data indicate that manipulating the gut microbiota may help in the development of therapeutic strategies for the treatment of human allergic skin pathologies.
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Affiliation(s)
- Emilie Plantamura
- Centre International de Recherche en Infectiologie, INSERM U1111-CNRS UMR5308, 69365 Lyon Cedex 07, France
| | - Amiran Dzutsev
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702
- Leidos Biomedical Research, Inc., Frederick, MD 21702
| | - Mathias Chamaillard
- Center for Infection and Immunity of Lille, Institut Pasteur de Lille, INSERM U1019, F-59000 Lille, France
- Center for Infection and Immunity of Lille, University of Lille, F-59000 Lille, France
- UMR 8204, Centre National de la Recherche Scientifique, F-59000 Lille, France
- U1019, Team 7, Equipe Fondation pour la Recherche Médicale, Institut National de la Santé et de la Recherche Médicale, F-59000 Lille, France
| | - Sophia Djebali
- Centre International de Recherche en Infectiologie, INSERM U1111-CNRS UMR5308, 69365 Lyon Cedex 07, France
| | - Lyvia Moudombi
- Centre International de Recherche en Infectiologie, INSERM U1111-CNRS UMR5308, 69365 Lyon Cedex 07, France
| | - Lilia Boucinha
- Centre International de Recherche en Infectiologie, INSERM U1111-CNRS UMR5308, 69365 Lyon Cedex 07, France
| | - Morgan Grau
- Centre International de Recherche en Infectiologie, INSERM U1111-CNRS UMR5308, 69365 Lyon Cedex 07, France
| | - Claire Macari
- Centre International de Recherche en Infectiologie, INSERM U1111-CNRS UMR5308, 69365 Lyon Cedex 07, France
| | - David Bauché
- Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, INSERM 1052, CNRS 5286, 69008 Lyon, France
- University of Lyon, Université Claude Bernard Lyon 1, 69008 Lyon, France
- Transforming Growth Factor-b and Immune-Evasion Group, German Cancer Research Center, 69120 Heidelberg, Germany
| | - Oana Dumitrescu
- Centre International de Recherche en Infectiologie, INSERM U1111-CNRS UMR5308, 69365 Lyon Cedex 07, France
- Department of Clinical Microbiology, Hospices Civils de Lyon, 69002 Lyon, France
| | - Jean-Philippe Rasigade
- Centre International de Recherche en Infectiologie, INSERM U1111-CNRS UMR5308, 69365 Lyon Cedex 07, France
- Department of Clinical Microbiology, Hospices Civils de Lyon, 69002 Lyon, France
| | - Saskia Lippens
- Inflammation Research Center, Department of Biomedical Molecular Biology, Ghent University, Flanders Institute for Biotechnology, 9000 Ghent, Belgium
| | - Michelina Plateroti
- Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, INSERM 1052, CNRS 5286, 69008 Lyon, France
- University of Lyon, Université Claude Bernard Lyon 1, 69008 Lyon, France
| | - Elsa Kress
- Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, INSERM 1052, CNRS 5286, 69008 Lyon, France
- University of Lyon, Université Claude Bernard Lyon 1, 69008 Lyon, France
| | - Annabelle Cesaro
- Center for Infection and Immunity of Lille, Institut Pasteur de Lille, INSERM U1019, F-59000 Lille, France
| | - Clovis Bondu
- Center for Infection and Immunity of Lille, Institut Pasteur de Lille, INSERM U1019, F-59000 Lille, France
| | - Ulrike Rothermel
- Chronic Inflammation and Cancer, German Cancer Research Center, 69120 Heidelberg, Germany
| | - Mathias Heikenwälder
- Chronic Inflammation and Cancer, German Cancer Research Center, 69120 Heidelberg, Germany
| | - Gerard Lina
- Centre International de Recherche en Infectiologie, INSERM U1111-CNRS UMR5308, 69365 Lyon Cedex 07, France
- Department of Clinical Microbiology, Hospices Civils de Lyon, 69002 Lyon, France
| | - Azzak Bentaher-Belaaouaj
- Centre International de Recherche en Infectiologie, INSERM U1111-CNRS UMR5308, 69365 Lyon Cedex 07, France
| | - Julien C Marie
- Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, INSERM 1052, CNRS 5286, 69008 Lyon, France
- University of Lyon, Université Claude Bernard Lyon 1, 69008 Lyon, France
- Transforming Growth Factor-b and Immune-Evasion Group, German Cancer Research Center, 69120 Heidelberg, Germany
| | - Christophe Caux
- Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, INSERM 1052, CNRS 5286, 69008 Lyon, France
- University of Lyon, Université Claude Bernard Lyon 1, 69008 Lyon, France
| | - Giorgio Trinchieri
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702
| | - Jacqueline Marvel
- Centre International de Recherche en Infectiologie, INSERM U1111-CNRS UMR5308, 69365 Lyon Cedex 07, France
| | - Marie-Cecile Michallet
- Centre International de Recherche en Infectiologie, INSERM U1111-CNRS UMR5308, 69365 Lyon Cedex 07, France;
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22
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Luo H, Sun Y, Li Y, Lv H, Sheng L, Wang L, Qian J. Perceived stress and inappropriate coping behaviors associated with poorer quality of life and prognosis in patients with ulcerative colitis. J Psychosom Res 2018; 113:66-71. [PMID: 30190050 DOI: 10.1016/j.jpsychores.2018.07.013] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2017] [Revised: 07/21/2018] [Accepted: 07/25/2018] [Indexed: 01/20/2023]
Abstract
OBJECTIVE To explore the effect of perceived stress and coping behaviors on quality of life and clinical outcomes in patients with ulcerative colitis. METHODS This is a prospective cohort study in a tertiary inflammatory bowel disease center in China. A total of 263 ulcerative colitis patients were enrolled consecutively between June 2013 and February 2015. The Perceived Stress Scale, the Medical Coping Modes Questionnaire, and the Inflammatory Bowel Disease Questionnaire were used to assess perceived stress, medical coping and quality of life at baseline. Patients were followed up for hospitalization due to relapse over a one-year period. Multivariate analyses were performed to identify whether perceived stress and medical coping behavior were related to quality of life and hospitalization. RESULTS Patients with invalid questionnaires (n = 6) and those lost to follow-up (n = 28) were excluded. A total of 229 ulcerative colitis patients (mean age 40.4 ± 12.6, 50.7% male) were included in the final analysis, and 23 patients had been hospitalized during the one-year follow-up period. After adjusting other associated variables, perceived stress (OR: 1.13; 95% CI: 1.07 to 1.19) and acceptance-resignation behavior (OR: 1.41; 95% CI: 1.21 to 1.65) were independently associated with poor quality of life. Patients scoring highly for acceptance-resignation behavior (OR: 1.23; 95% CI: 1.04 to 1.46) were more likely to be hospitalized during the one-year follow-up period. CONCLUSION In patients with ulcerative colitis, identifying those who adopted more acceptance-resignation behavior and improving their medical coping behavior by psychotherapy could be helpful to achieve better quality of life and disease control.
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Affiliation(s)
- Hanqing Luo
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Peking Union Medical College, Beijing, China; Department of Health Care, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Peking Union Medical College, Beijing, China
| | - Yuanyuan Sun
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Yue Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Peking Union Medical College, Beijing, China
| | - Hong Lv
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Peking Union Medical College, Beijing, China
| | - Li Sheng
- Beijing United Family Hospital, Beijing, China
| | - Li Wang
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Jiaming Qian
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Peking Union Medical College, Beijing, China.
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23
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Long Y, Du L, Kim JJ, Chen B, Zhu Y, Zhang Y, Yao S, He H, Zheng X, Huang Z, Dai N. MLCK-mediated intestinal permeability promotes immune activation and visceral hypersensitivity in PI-IBS mice. Neurogastroenterol Motil 2018; 30:e13348. [PMID: 29644768 DOI: 10.1111/nmo.13348] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 03/08/2018] [Indexed: 02/05/2023]
Abstract
BACKGROUND Alterations in intestinal permeability regulated by tight junctions (TJs) are associated with immune activation and visceral hypersensitivity in irritable bowel syndrome (IBS). Myosin light chain kinase (MLCK) is an important mediator of epithelial TJ. The aim of this study is to investigate the role of MLCK in the pathogenesis of IBS using a post infectious IBS (PI-IBS) mouse model. METHODS Trichinella spiralis-infected PI-IBS mouse model was used. Urine lactulose/mannitol ratio was measured to assess intestinal epithelial permeability. Western blotting was used to evaluate intestinal TJ protein (zonula occludens-1) and MLCK-associated protein expressions. Immune profile was assessed by measuring Th (T helper) 1/Th2 cytokine expression. Visceral sensitivity was determined by abdominal withdrawal reflex in response to colorectal distension. RESULTS Eight weeks after inoculation with T. spiralis, PI-IBS mice developed decreased pain and volume thresholds during colorectal distention, increased urine lactulose/mannitol ratio, elevated colonic Th1/Th2 cytokine ratio, and decreased zonula occludens-1 expression compared to the control mice. MLCK expression was dramatically elevated in the colonic mucosa of PI-IBS mice compared to the control mice, alongside increased pMLC/MLC and decreased MLCP expression. Administration of MLCK inhibitor and TJ blocker both reversed the increased intestinal permeability, visceral hypersensitivity, and Th1-dominant immune profile in PI-IBS mice. CONCLUSION MLCK is a pivotal step in inducing increased intestinal permeability promoting low-grade intestinal immune activation and visceral hypersensitivity in PI-IBS mice. MLCK inhibitor may provide a potential therapeutic option in the treatment of IBS.
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Affiliation(s)
- Y Long
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - L Du
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - J J Kim
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
- Division of Gastroenterology, Loma Linda University Medical Center, Loma Linda, CA, USA
| | - B Chen
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Y Zhu
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Y Zhang
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - S Yao
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - H He
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - X Zheng
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Z Huang
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - N Dai
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
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24
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Nizzoli G, Burrello C, Cribiù FM, Lovati G, Ercoli G, Botti F, Trombetta E, Porretti L, Todoerti K, Neri A, Giuffrè MR, Geginat J, Vecchi M, Rescigno M, Paroni M, Caprioli F, Facciotti F. Pathogenicity of In Vivo Generated Intestinal Th17 Lymphocytes is IFNγ Dependent. J Crohns Colitis 2018; 12:981-992. [PMID: 29697763 DOI: 10.1093/ecco-jcc/jjy051] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 04/19/2018] [Indexed: 12/24/2022]
Abstract
BACKGROUND AND AIMS T helper 17 [Th17] cells are crucially involved in the immunopathogenesis of inflammatory bowel diseases in humans. Nevertheless, pharmacological blockade of interleukin 17A [IL17A], the Th17 signature cytokine, yielded negative results in patients with Crohn's disease [CD], and attempts to elucidate the determinants of Th17 cells' pathogenicity in the gut have so far proved unsuccessful. Here, we aimed to identify and functionally validate the pathogenic determinants of intestinal IL-17-producing T cells. METHODS In vivo-generated murine intestinal IL-17-producing T cells were adoptively transferred into immunodeficient Rag1-/- recipients to test their pathogenicity. Human IL-17, IFNγ/IL-17, and IFNγ actively secreting T cell clones were generated from lamina propria lymphocytes of CD patients. The pathogenic activity of intestinal IL-17-producing T cells against the intestinal epithelium was evaluated. RESULTS IL-17-producing cells with variable colitogenic activity can be generated in vivo using different experimental colitis models. The pathogenicity of IL-17-secreting cells was directly dependent on their IFNγ secretion capacity, as demonstrated by the reduced colitogenic activity of IL-17-secreting cells isolated from IFNγ-/- mice. Moreover, IFNγ production is a distinguished attribute of CD-derived lamina propria Th17 cells. IFNγ secretion by CD-derived IL-17-producing intestinal clones is directly implicated in the epithelial barrier disruption through the modulation of tight junction proteins. CONCLUSIONS Intestinal Th17 cell pathogenicity is associated with IFNγ production, which directly affects intestinal permeability through the disruption of epithelial tight junctions.
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Affiliation(s)
- Giulia Nizzoli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.,Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Claudia Burrello
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.,Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
| | - Fulvia Milena Cribiù
- Pathology Unit, Fondazione IRCCS Ca' Granda Ospedale Policlinico di Milano, Milan, Italy
| | - Giulia Lovati
- Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
| | - Giulia Ercoli
- Pathology Unit, Fondazione IRCCS Ca' Granda Ospedale Policlinico di Milano, Milan, Italy
| | - Fiorenzo Botti
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.,General and Emergency Surgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Elena Trombetta
- Flow Cytometry Service, Clinical Chemistry and Microbiology Laboratory Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Laura Porretti
- Flow Cytometry Service, Clinical Chemistry and Microbiology Laboratory Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Katia Todoerti
- Laboratory of Pre-clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture, Italy
| | - Antonino Neri
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.,Hematology Unit, Fondazione IRCCS Ca ' Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Maria Rita Giuffrè
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Jens Geginat
- INGM ? National Institute of Molecular Genetics "Romeo ed Enrico Invernizzi" Milan, Italy
| | - Maurizio Vecchi
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.,Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milan, Italy
| | - Maria Rescigno
- Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
| | - Moira Paroni
- Department of Biosciences, Università degli Studi di Milano, Milan, Italy
| | - Flavio Caprioli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.,Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Federica Facciotti
- Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
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25
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Wiley JW, Chang L. Functional Bowel Disorders. Gastroenterology 2018; 155:1-4. [PMID: 29454798 DOI: 10.1053/j.gastro.2018.02.014] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Revised: 01/31/2018] [Accepted: 02/02/2018] [Indexed: 12/15/2022]
Affiliation(s)
- John W Wiley
- Department Internal Medicine, University of Michigan, Ann Arbor, Michigan.
| | - Lin Chang
- G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA, Vatche and Tamar Manoukian Division of Gastroenterology, University of California, Los Angeles, Los Angeles, California
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26
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Jin M, Zhang H, Zhao K, Xu C, Shao D, Huang Q, Shi J, Yang H. Responses of Intestinal Mucosal Barrier Functions of Rats to Simulated Weightlessness. Front Physiol 2018; 9:729. [PMID: 29962963 PMCID: PMC6011188 DOI: 10.3389/fphys.2018.00729] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Accepted: 05/25/2018] [Indexed: 12/29/2022] Open
Abstract
Exposure to microgravity or weightlessness leads to various adaptive and pathophysiological alterations in digestive structures and physiology. The current study was carried out to investigate responses of intestinal mucosal barrier functions to simulated weightlessness, by using the hindlimb unloading rats model. Compared with normal controls, simulated weightlessness damaged the intestinal villi and structural integrity of tight junctions, up-regulated the expression of pro-apoptotic protein Bax while down-regulated the expression of anti-apoptotic protein Bcl-2, thus improved the intestinal permeability. It could also influence intestinal microbiota composition with the expansion of Bacteroidetes and decrease of Firmicutes. The predicted metagenomic analysis emphasized significant dysbiosis associated differences in genes involved in membrane transport, cofactors and vitamins metabolism, energy metabolism, and genetic information processing. Moreover, simulated weightlessness could modify the intestinal immune status characterized by the increase of proinflammatory cytokines, decrease of secretory immunoglobulin A, and activation of TLR4/MyD88/NF-κB signaling pathway in ileum. These results indicate the simulated weightlessness disrupts intestinal mucosal barrier functions in animal model. The data also emphasize the necessity of monitoring and regulating astronauts’ intestinal health during real space flights to prevent breakdowns in intestinal homeostasis of crewmembers.
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Affiliation(s)
- Mingliang Jin
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Hao Zhang
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Ke Zhao
- College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an, China
| | - Chunlan Xu
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Dongyan Shao
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Qingsheng Huang
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Junling Shi
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Hui Yang
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
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27
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Yang G, Bibi S, Du M, Suzuki T, Zhu MJ. Regulation of the intestinal tight junction by natural polyphenols: A mechanistic perspective. Crit Rev Food Sci Nutr 2017; 57:3830-3839. [PMID: 27008212 DOI: 10.1080/10408398.2016.1152230] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Impairment of the epithelial barrier function is closely linked to the pathogenesis of various gastrointestinal diseases, food allergies, type I diabetes, and other systematic diseases. Plant-derived polyphenols are natural secondary metabolites and exert various physiological benefits, including anti-inflammatory, anti-oxidative, anti-carcinogenic, and anti-aging effects. Recent studies also show the role of plant polyphenols in regulation of the intestinal barrier and prevention of intestinal inflammatory diseases. Here we summarize the regulatory pathways and mediators linking polyphenols to their beneficial effects on tight junction and gut epithelial barrier functions, and provide useful information about using polyphenols as nutraceuticals for intestinal diseases.
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Affiliation(s)
- Guan Yang
- a School of Food Science , Washington State University , Pullman , Washington , USA
| | - Shima Bibi
- a School of Food Science , Washington State University , Pullman , Washington , USA
| | - Min Du
- b Department of Animal Science , Washington State University , Pullman , Washington , USA
| | - Takuya Suzuki
- c Department of Biofunctional Science and Technology , Hiroshima University , Higashi-Hiroshima , Japan
| | - Mei-Jun Zhu
- a School of Food Science , Washington State University , Pullman , Washington , USA
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28
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Malaisé Y, Ménard S, Cartier C, Lencina C, Sommer C, Gaultier E, Houdeau E, Guzylack-Piriou L. Consequences of bisphenol a perinatal exposure on immune responses and gut barrier function in mice. Arch Toxicol 2017; 92:347-358. [DOI: 10.1007/s00204-017-2038-2] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Accepted: 07/13/2017] [Indexed: 02/02/2023]
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29
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Complementary Roles of Nod2 in Hematopoietic and Nonhematopoietic Cells in Preventing Gut Barrier Dysfunction Dependent on MLCK Activity. Inflamm Bowel Dis 2017; 23:1109-1119. [PMID: 28520587 DOI: 10.1097/mib.0000000000001135] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Crohn's disease (CD) pathogenesis is multifactorial involving genetic and environmental factors. Loss of function mutations in the nucleotide oligomerization domain 2 (NOD2) gene are the main genetic risk factor for CD. Like patients with CD, Nod2 mice are characterized by an enhanced Th1 immune response and a defective mucosal barrier function evidenced by increased intestinal permeability. We previously showed that the latter is related to hematopoietic Nod2 deficiency. Our aim was to explore the mechanisms by which Nod2 expressed in the hematopoietic and in the nonhematopoietic compartments interplay to control epithelial paracellular permeability. METHODS Depletion of CD4 T cells in Nod2 mice and treatments with inhibitors were conducted in chimeric mice transplanted with bone marrow cells from Nod2-deficient donors into Nod2-sufficient recipients or vice versa. Caco-2 cells overexpressing a NOD2 gene which did or did not include a CD-associated polymorphism were treated with inhibitors or siRNAs and cocultured with hematopoietic cells from Peyer's patches. RESULTS In vivo and in vitro Nod2 in hematopoietic cells regulates epithelial paracellular permeability through cytokine production influencing myosin light chain kinase (MLCK) activity. Indeed, tumor necrosis factor-α and interferon-γ secretion by CD4 T cells upregulated expression and activity of epithelial MLCK leading to increased epithelial tight junction opening. When stimulated by muramyl dipeptide, Nod2 in the nonhematopoietic compartment normalized the permeability and T-cell cytokine secretion and regulated MLCK activity. This MLCK regulation is mediated by TAK1 and RICK-dependent mechanisms. CONCLUSIONS Our study demonstrates how hematopoietic and nonhematopoietic Nod2 regulate intestinal barrier function, improving our knowledge on the mechanisms involved in CD pathogenesis.
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30
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van Bilsen JHM, Sienkiewicz-Szłapka E, Lozano-Ojalvo D, Willemsen LEM, Antunes CM, Molina E, Smit JJ, Wróblewska B, Wichers HJ, Knol EF, Ladics GS, Pieters RHH, Denery-Papini S, Vissers YM, Bavaro SL, Larré C, Verhoeckx KCM, Roggen EL. Application of the adverse outcome pathway (AOP) concept to structure the available in vivo and in vitro mechanistic data for allergic sensitization to food proteins. Clin Transl Allergy 2017; 7:13. [PMID: 28507730 PMCID: PMC5429547 DOI: 10.1186/s13601-017-0152-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Accepted: 05/03/2017] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The introduction of whole new foods in a population may lead to sensitization and food allergy. This constitutes a potential public health problem and a challenge to risk assessors and managers as the existing understanding of the pathophysiological processes and the currently available biological tools for prediction of the risk for food allergy development and the severity of the reaction are not sufficient. There is a substantial body of in vivo and in vitro data describing molecular and cellular events potentially involved in food sensitization. However, these events have not been organized in a sequence of related events that is plausible to result in sensitization, and useful to challenge current hypotheses. The aim of this manuscript was to collect and structure the current mechanistic understanding of sensitization induction to food proteins by applying the concept of adverse outcome pathway (AOP). MAIN BODY The proposed AOP for food sensitization is based on information on molecular and cellular mechanisms and pathways evidenced to be involved in sensitization by food and food proteins and uses the AOPs for chemical skin sensitization and respiratory sensitization induction as templates. Available mechanistic data on protein respiratory sensitization were included to fill out gaps in the understanding of how proteins may affect cells, cell-cell interactions and tissue homeostasis. Analysis revealed several key events (KE) and biomarkers that may have potential use in testing and assessment of proteins for their sensitizing potential. CONCLUSION The application of the AOP concept to structure mechanistic in vivo and in vitro knowledge has made it possible to identify a number of methods, each addressing a specific KE, that provide information about the food allergenic potential of new proteins. When applied in the context of an integrated strategy these methods may reduce, if not replace, current animal testing approaches. The proposed AOP will be shared at the www.aopwiki.org platform to expand the mechanistic data, improve the confidence in each of the proposed KE and key event relations (KERs), and allow for the identification of new, or refinement of established KE and KERs.
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Affiliation(s)
| | | | | | | | | | - Elena Molina
- Instituto de Investigación en Ciencias de la Alimentación, Madrid, Spain
| | | | - Barbara Wróblewska
- Institute of Animal Reproduction and Food Research of Polish Academy of Sciences, Olsztyn, Poland
| | - Harry J Wichers
- Wageningen University and Research, Wageningen, The Netherlands
| | - Edward F Knol
- University Medical Center Utrecht, Utrecht, The Netherlands
| | | | | | | | | | - Simona L Bavaro
- Institute of Sciences of Food Production, National Research Council, Bari, Italy
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Shao Y, Wolf PG, Guo S, Guo Y, Gaskins HR, Zhang B. Zinc enhances intestinal epithelial barrier function through the PI3K/AKT/mTOR signaling pathway in Caco-2 cells. J Nutr Biochem 2017; 43:18-26. [PMID: 28193579 DOI: 10.1016/j.jnutbio.2017.01.013] [Citation(s) in RCA: 114] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 01/17/2017] [Accepted: 01/19/2017] [Indexed: 12/24/2022]
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Calcium-mediated oxidative stress: a common mechanism in tight junction disruption by different types of cellular stress. Biochem J 2017; 474:731-749. [PMID: 28057718 DOI: 10.1042/bcj20160679] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Revised: 08/10/2016] [Accepted: 01/05/2017] [Indexed: 02/07/2023]
Abstract
The role of reactive oxygen species (ROS) in osmotic stress, dextran sulfate sodium (DSS) and cyclic stretch-induced tight junction (TJ) disruption was investigated in Caco-2 cell monolayers in vitro and restraint stress-induced barrier dysfunction in mouse colon in vivo Live cell imaging showed that osmotic stress, cyclic stretch and DSS triggered rapid production of ROS in Caco-2 cell monolayers, which was blocked by depletion of intracellular Ca2+ by 1,2-bis-(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid. Knockdown of CaV1.3 or TRPV6 channels blocked osmotic stress and DSS-induced ROS production and attenuated TJ disruption and barrier dysfunction. N-Acetyl l-cysteine (NAC) and l-NG-Nitroarginine methyl ester (l-NAME) blocked stress-induced TJ disruption and barrier dysfunction. NAC and l-NAME also blocked stress-induced activation of c-Jun N-terminal kinase (JNK) and c-Src. ROS was colocalized with the mitochondrial marker in stressed cells. Cyclosporin A blocked osmotic stress and DSS-induced ROS production, barrier dysfunction, TJ disruption and JNK activation. Mitochondria-targeted Mito-TEMPO blocked osmotic stress and DSS-induced barrier dysfunction and TJ disruption. Chronic restraint stress in mice resulted in the elevation of intracellular Ca2+, activation of JNK and c-Src, and disruption of TJ in the colonic epithelium. Furthermore, corticosterone administration induced JNK and c-Src activation, TJ disruption and protein thiol oxidation in colonic mucosa. The present study demonstrates that oxidative stress is a common signal in the mechanism of TJ disruption in the intestinal epithelium by different types of cellular stress in vitro and bio behavioral stress in vivo.
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The role of neuroimmune signaling in alcoholism. Neuropharmacology 2017; 122:56-73. [PMID: 28159648 DOI: 10.1016/j.neuropharm.2017.01.031] [Citation(s) in RCA: 232] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Revised: 01/24/2017] [Accepted: 01/29/2017] [Indexed: 02/07/2023]
Abstract
Alcohol consumption and stress increase brain levels of known innate immune signaling molecules. Microglia, the innate immune cells of the brain, and neurons respond to alcohol, signaling through Toll-like receptors (TLRs), high-mobility group box 1 (HMGB1), miRNAs, pro-inflammatory cytokines and their associated receptors involved in signaling between microglia, other glia and neurons. Repeated cycles of alcohol and stress cause a progressive, persistent induction of HMGB1, miRNA and TLR receptors in brain that appear to underlie the progressive and persistent loss of behavioral control, increased impulsivity and anxiety, as well as craving, coupled with increasing ventral striatal responses that promote reward seeking behavior and increase risk of developing alcohol use disorders. Studies employing anti-oxidant, anti-inflammatory, anti-depressant, and innate immune antagonists further link innate immune gene expression to addiction-like behaviors. Innate immune molecules are novel targets for addiction and affective disorders therapies. This article is part of the Special Issue entitled "Alcoholism".
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Liu B, Yang T, Zeng L, Shi L, Li Y, Xia Z, Xia X, Lin Q, Luo F. Crude extract of Fuzhuan brick tea ameliorates DSS-induced colitis in mice. Int J Food Sci Technol 2016. [DOI: 10.1111/ijfs.13241] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Bo Liu
- Molecular Nutrition Department; Food Science and Engineering College; Central South University of Forestry and Technology; Changsha Hunan 410004 China
| | - Tao Yang
- Molecular Nutrition Department; Food Science and Engineering College; Central South University of Forestry and Technology; Changsha Hunan 410004 China
| | - Linna Zeng
- Molecular Nutrition Department; Food Science and Engineering College; Central South University of Forestry and Technology; Changsha Hunan 410004 China
| | - Limin Shi
- Molecular Nutrition Department; Food Science and Engineering College; Central South University of Forestry and Technology; Changsha Hunan 410004 China
| | - Yan Li
- Molecular Nutrition Department; Food Science and Engineering College; Central South University of Forestry and Technology; Changsha Hunan 410004 China
| | - Zanguo Xia
- Hunan Axiang Tea and Fruit Foods Co., Ltd; Anhua Hunan 413500 China
| | - Xuping Xia
- Hunan Axiang Tea and Fruit Foods Co., Ltd; Anhua Hunan 413500 China
| | - Qinlu Lin
- Molecular Nutrition Department; Food Science and Engineering College; Central South University of Forestry and Technology; Changsha Hunan 410004 China
| | - Feijun Luo
- Molecular Nutrition Department; Food Science and Engineering College; Central South University of Forestry and Technology; Changsha Hunan 410004 China
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Awad W, Dublecz F, Hess C, Dublecz K, Khayal B, Aschenbach J, Hess M. Campylobacter jejuni colonization promotes the translocation of Escherichia coli to extra-intestinal organs and disturbs the short-chain fatty acids profiles in the chicken gut. Poult Sci 2016; 95:2259-65. [DOI: 10.3382/ps/pew151] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 02/29/2016] [Indexed: 11/20/2022] Open
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Kell DB, Pretorius E. On the translocation of bacteria and their lipopolysaccharides between blood and peripheral locations in chronic, inflammatory diseases: the central roles of LPS and LPS-induced cell death. Integr Biol (Camb) 2016; 7:1339-77. [PMID: 26345428 DOI: 10.1039/c5ib00158g] [Citation(s) in RCA: 125] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
We have recently highlighted (and added to) the considerable evidence that blood can contain dormant bacteria. By definition, such bacteria may be resuscitated (and thus proliferate). This may occur under conditions that lead to or exacerbate chronic, inflammatory diseases that are normally considered to lack a microbial component. Bacterial cell wall components, such as the endotoxin lipopolysaccharide (LPS) of Gram-negative strains, are well known as potent inflammatory agents, but should normally be cleared. Thus, their continuing production and replenishment from dormant bacterial reservoirs provides an easy explanation for the continuing, low-grade inflammation (and inflammatory cytokine production) that is characteristic of many such diseases. Although experimental conditions and determinants have varied considerably between investigators, we summarise the evidence that in a great many circumstances LPS can play a central role in all of these processes, including in particular cell death processes that permit translocation between the gut, blood and other tissues. Such localised cell death processes might also contribute strongly to the specific diseases of interest. The bacterial requirement for free iron explains the strong co-existence in these diseases of iron dysregulation, LPS production, and inflammation. Overall this analysis provides an integrative picture, with significant predictive power, that is able to link these processes via the centrality of a dormant blood microbiome that can resuscitate and shed cell wall components.
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Affiliation(s)
- Douglas B Kell
- School of Chemistry and The Manchester Institute of Biotechnology, The University of Manchester, 131, Princess St, Manchester M1 7DN, Lancs, UK.
| | - Etheresia Pretorius
- Department of Physiology, Faculty of Health Sciences, University of Pretoria, Arcadia 0007, South Africa.
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Arase S, Watanabe Y, Setoyama H, Nagaoka N, Kawai M, Matsumoto S. Disturbance in the Mucosa-Associated Commensal Bacteria Is Associated with the Exacerbation of Chronic Colitis by Repeated Psychological Stress; Is That the New Target of Probiotics? PLoS One 2016; 11:e0160736. [PMID: 27500935 PMCID: PMC4976886 DOI: 10.1371/journal.pone.0160736] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Accepted: 07/25/2016] [Indexed: 12/31/2022] Open
Abstract
Psychological stress can exacerbate inflammatory bowel disease. However, the mechanisms underlying how psychological stress affects gut inflammation remain unclear. Here, we focused on the relationship between changes in the microbial community of mucosa-associated commensal bacteria (MACB) and mucosal immune responses induced by chronic psychological stress in a murine model of ulcerative colitis. Furthermore, we examined the effect of probiotic treatment on exacerbated colitis and MACB composition changes induced by chronic psychological stress. Repeated water avoidance stress (rWAS) in B6-Tcra-/- mice severely exacerbated colitis, which was evaluated by both colorectal tissue weight and histological score of colitis. rWAS treatment increased mRNA expression of UCN2 and IFN-γ in large intestinal lamina propria mononuclear cells (LI-LPMC). Interestingly, exacerbated colitis was associated with changes in the microbial community of MACB, specifically loss of bacterial species diversity and an increase in the component ratio of Clostridium, revealed by 16S rRNA gene amplicon analysis. Finally, the oral administration of a probiotic Lactobacillus strain was protective against the exacerbation of colitis and was associated with a change in the bacterial community of MACB in rWAS-exposed Tcra-/- mice. Taken together, these results suggested that loss of species diversity in MACB might play a key role in exacerbated colitis induced by chronic psychological stress. In addition, probiotic treatment may be used as a tool to preserve the diversity of bacterial species in MACB and alleviate gut inflammation induced by psychological stress.
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Affiliation(s)
- Sohei Arase
- Yakult Central Institute, Kunitachi-shi, Tokyo, Japan
- * E-mail:
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Li L, Xiong L, Yao J, Zhuang X, Zhang S, Yu Q, Xiao Y, Cui Y, Chen M. Increased small intestinal permeability and RNA expression profiles of mucosa from terminal ileum in patients with diarrhoea-predominant irritable bowel syndrome. Dig Liver Dis 2016; 48:880-7. [PMID: 27246797 DOI: 10.1016/j.dld.2016.05.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2015] [Revised: 04/15/2016] [Accepted: 05/02/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Altered intestinal permeability in diarrhoea-predominant irritable bowel syndrome (IBS-D) has been reported in some studies. AIMS The study aimed to investigate the altered intestinal permeability and its associated clinical characteristics and RNA expression profiles in IBS-D. METHODS We stratified IBS-D patients into two groups according to the P95 value of the permeability in controls. The clinical characteristics of the two groups were evaluated, and two biopsy cases from each of the two groups were selected for the RNA-seq analysis. RESULTS IBS-D patients had a significant increase in the small intestinal permeability compared with controls [0.0245 (0.0229) median (interquartile range)] versus 0.0156 (0.0098), P=0.010), but no significant difference was found in the colonic permeability [23.286 (10.470) versus 21.650 (6.650), P=0.574]. The IBS-D patients with increased small intestinal permeability had worse psychological effects (P=0.027) and quality of life (P=0.044). Analysis of RNA-seq data revealed 185 genes differentially expressed, many of which were related to mucosal inflammation and immunity. CONCLUSIONS Small intestinal permeability, but not colonic permeability, is increased in IBS-D patients. IBS-D patients with increased small intestinal permeability tend to be more severely impaired in terms of psychological effects and quality of life, and analysis of RNA-seq data reveals that increased small intestinal permeability is related to mucosal inflammation and immunity.
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Affiliation(s)
- Li Li
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Lishou Xiong
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
| | - Junhua Yao
- Instrumental Analysis and Research Centre, Sun Yat-Sen University, Guangzhou, China
| | - Xiaojun Zhuang
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Shenghong Zhang
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Qiao Yu
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Yinglian Xiao
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Yi Cui
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Minhu Chen
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
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Mager LF, Wasmer MH, Rau TT, Krebs P. Cytokine-Induced Modulation of Colorectal Cancer. Front Oncol 2016; 6:96. [PMID: 27148488 DOI: 10.3389/fonc.2016.00096] [Citation(s) in RCA: 166] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Accepted: 04/02/2016] [Indexed: 12/12/2022] Open
Abstract
The emergence of novel immunomodulatory cancer therapies over the last decade, above all immune checkpoint blockade, has significantly advanced tumor treatment. For colorectal cancer (CRC), a novel scoring system based on the immune cell infiltration in tumors has greatly improved disease prognostic evaluation and guidance to more specific therapy. These findings underline the relevance of tumor immunology in the future handling and therapeutic approach of malignant disease. Inflammation can either promote or suppress CRC pathogenesis and inflammatory mediators, mainly cytokines, critically determine the pro- or anti-tumorigenic signals within the tumor environment. Here, we review the current knowledge on the cytokines known to be critically involved in CRC development and illustrate their mechanisms of action. We also highlight similarities and differences between CRC patients and murine models of CRC and point out cytokines with an ambivalent role for intestinal cancer. We also identify some of the future challenges in the field that should be addressed for the development of more effective immunomodulatory therapies.
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Affiliation(s)
- Lukas F Mager
- Institute of Pathology, University of Bern , Bern , Switzerland
| | - Marie-Hélène Wasmer
- Institute of Pathology, University of Bern, Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Tilman T Rau
- Institute of Pathology, University of Bern , Bern , Switzerland
| | - Philippe Krebs
- Institute of Pathology, University of Bern , Bern , Switzerland
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Yarandi SS, Peterson DA, Treisman GJ, Moran TH, Pasricha PJ. Modulatory Effects of Gut Microbiota on the Central Nervous System: How Gut Could Play a Role in Neuropsychiatric Health and Diseases. J Neurogastroenterol Motil 2016; 22:201-12. [PMID: 27032544 PMCID: PMC4819858 DOI: 10.5056/jnm15146] [Citation(s) in RCA: 175] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Revised: 01/12/2016] [Accepted: 01/27/2016] [Indexed: 12/11/2022] Open
Abstract
Gut microbiome is an integral part of the Gut-Brain axis. It is becoming increasingly recognized that the presence of a healthy and diverse gut microbiota is important to normal cognitive and emotional processing. It was known that altered emotional state and chronic stress can change the composition of gut microbiome, but it is becoming more evident that interaction between gut microbiome and central nervous system is bidirectional. Alteration in the composition of the gut microbiome can potentially lead to increased intestinal permeability and impair the function of the intestinal barrier. Subsequently, neuro-active compounds and metabolites can gain access to the areas within the central nervous system that regulate cognition and emotional responses. Deregulated inflammatory response, promoted by harmful microbiota, can activate the vagal system and impact neuropsychological functions. Some bacteria can produce peptides or short chain fatty acids that can affect gene expression and inflammation within the central nervous system. In this review, we summarize the evidence supporting the role of gut microbiota in modulating neuropsychological functions of the central nervous system and exploring the potential underlying mechanisms.
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Affiliation(s)
- Shadi S Yarandi
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
| | - Daniel A Peterson
- Division of Immunology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Glen J Treisman
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Timothy H Moran
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Pankaj J Pasricha
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
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Goyer M, Loiselet A, Bon F, L’Ollivier C, Laue M, Holland G, Bonnin A, Dalle F. Intestinal Cell Tight Junctions Limit Invasion of Candida albicans through Active Penetration and Endocytosis in the Early Stages of the Interaction of the Fungus with the Intestinal Barrier. PLoS One 2016; 11:e0149159. [PMID: 26933885 PMCID: PMC4775037 DOI: 10.1371/journal.pone.0149159] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Accepted: 01/28/2016] [Indexed: 01/20/2023] Open
Abstract
C. albicans is a commensal yeast of the mucous membranes in healthy humans that can also cause disseminated candidiasis, mainly originating from the digestive tract, in vulnerable patients. It is necessary to understand the cellular and molecular mechanisms of the interaction of C. albicans with enterocytes to better understand the basis of commensalism and pathogenicity of the yeast and to improve the management of disseminated candidiasis. In this study, we investigated the kinetics of tight junction (TJ) formation in parallel with the invasion of C. albicans into the Caco-2 intestinal cell line. Using invasiveness assays on Caco-2 cells displaying pharmacologically altered TJ (i.e. differentiated epithelial cells treated with EGTA or patulin), we were able to demonstrate that TJ protect enterocytes against invasion of C. albicans. Moreover, treatment with a pharmacological inhibitor of endocytosis decreased invasion of the fungus into Caco-2 cells displaying altered TJ, suggesting that facilitating access of the yeast to the basolateral side of intestinal cells promotes endocytosis of C. albicans in its hyphal form. These data were supported by SEM observations of differentiated Caco-2 cells displaying altered TJ, which highlighted membrane protrusions engulfing C. albicans hyphae. We furthermore demonstrated that Als3, a hypha-specific C. albicans invasin, facilitates internalization of the fungus by active penetration and induced endocytosis by differentiated Caco-2 cells displaying altered TJ. However, our observations failed to demonstrate binding of Als3 to E-cadherin as the trigger mechanism of endocytosis of C. albicans into differentiated Caco-2 cells displaying altered TJ.
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Affiliation(s)
- Marianne Goyer
- UMR 1347, Univ Bourgogne-Franche Comté, 17 Rue Sully, BP 86 510, F-21065 Dijon Cedex, France
- Centre Hospitalier Universitaire, Service de Parasitologie Mycologie, 2 Rue Angélique Ducoudray, F-21079 Dijon Cedex, France
| | - Alicia Loiselet
- UMR 1347, Univ Bourgogne-Franche Comté, 17 Rue Sully, BP 86 510, F-21065 Dijon Cedex, France
- Centre Hospitalier Universitaire, Service de Parasitologie Mycologie, 2 Rue Angélique Ducoudray, F-21079 Dijon Cedex, France
| | - Fabienne Bon
- UMR 1347, Univ Bourgogne-Franche Comté, 17 Rue Sully, BP 86 510, F-21065 Dijon Cedex, France
| | - Coralie L’Ollivier
- Laboratoire de Parasitologie-Mycologie, Aix-Marseille Univ. Marseille; AP-HM, CHU Timone, F-13385 Marseille cedex 05, France
| | - Michael Laue
- Robert Koch-Institute, Centre for Biological Threats and Special Pathogens, Advanced Light and Electron Microscopy, Nordufer 20, 13353 Berlin, Germany
| | - Gudrun Holland
- Robert Koch-Institute, Centre for Biological Threats and Special Pathogens, Advanced Light and Electron Microscopy, Nordufer 20, 13353 Berlin, Germany
| | - Alain Bonnin
- UMR 1347, Univ Bourgogne-Franche Comté, 17 Rue Sully, BP 86 510, F-21065 Dijon Cedex, France
- Centre Hospitalier Universitaire, Service de Parasitologie Mycologie, 2 Rue Angélique Ducoudray, F-21079 Dijon Cedex, France
| | - Frederic Dalle
- UMR 1347, Univ Bourgogne-Franche Comté, 17 Rue Sully, BP 86 510, F-21065 Dijon Cedex, France
- Centre Hospitalier Universitaire, Service de Parasitologie Mycologie, 2 Rue Angélique Ducoudray, F-21079 Dijon Cedex, France
- * E-mail:
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He JP, Tang GD, Qin MB, Shi HR, Fu HZ, Lin SD, Luo Q. Role of myosin light chain kinase in hypertriglyceridemia-associated acute pancreatitis in rats. Shijie Huaren Xiaohua Zazhi 2016; 24:19-27. [DOI: 10.11569/wcjd.v24.i1.19] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of myosin light chain kinase (MLCK) in hypertriglyceridemia-associated acute pancreatitis (HTGP).
METHODS: Forty-eight male SD rats were randomly divided into two groups to be fed either a high-fat diet (group A) or a normal diet (group B). After being raised for 4 weeks, blood was harvested from the retroorbital venous plexus to measure serum triglyceride (TG) levels. After that, group A was randomly divided into three subgroups: HTG, HTG + AP, and HTG + AP + ML-7; group B were also randomly divided into three subgroups: C, AP, and AP + ML-7. All rats were sacrificed 24 h after the last injection of cerulein. The pancreases were carefully removed for HE staining and transmission electron microscopy to observe the morphological changes, ultrastructure and tight junction (TJ). Blood was obtained from the heart to measure serum amylase levels. The expression and localization of MLCK and p-JNK in the pancreas were assayed by immunohistochemistry.
RESULTS: Compared with group B, serum TG level was significantly increased in group A after being fed a high fat diet (P < 0.01). The pathologic score of the pancreas and serum amylase (AMY) activity were significantly elevated in the HTG + AP group, compared with the AP group (P < 0.05). The ultrastructure of the pancreas in the HTG + AP and AP groups was damaged and the TJ was broadened (most significant in the HTG + AP group). Besides, MLCK and p-JNK were significantly up-regulated in the HTG + AP group compared with those in the AP group (P < 0.05), and there was a positive correlation between the expression of MLCK and p-JNK in the pancreas and the pathologic score of the pancreas (r1 = 0.795, r2 = 0.789, P < 0.01). ML-7, an inhibitor of MLCK, significantly ameliorated the pathologic signs of the pancreas, down-regulated AMY level (P < 0.01), improved the TJ and decreased the expression of p-JNK (P < 0.05).
CONCLUSION: MLCK may be associated with the severity of HTGP, and involved in the formation of HTGP by broadening cell-cell TJ and activation of the JNK pathway.
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Xu XJ, Liu L, Yao SK. Nerve growth factor and diarrhea-predominant irritable bowel syndrome (IBS-D): a potential therapeutic target? J Zhejiang Univ Sci B 2016; 17:1-9. [PMID: 26739521 PMCID: PMC4710835 DOI: 10.1631/jzus.b1500181] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2015] [Accepted: 11/07/2015] [Indexed: 02/05/2023]
Abstract
Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder characterized by recurrent abdominal pain or discomfort associated with abnormal bowel habits. Diarrhea-predominant IBS (IBS-D) is a major subtype of IBS, the predominant manifestations of which are abdominal pain and diarrhea. The pathogenesis of IBS-D remained unknown until recently. The effects of psychosocial stress, central hypervigilance, neuroendocrine abnormality, disturbed gastrointestinal motility, mucosal immune activation, intestinal barrier dysfunction, visceral hypersensitivity (VH), altered gut flora, and genetic susceptibility may be involved in its development. Recently, increased attention has been placed on the neural-immune-endocrine network mechanism in IBS-D, especially the role of various neuroendocrine mediators. As a member of the neurotrophin family, nerve growth factor (NGF) has diverse biological effects, and participates in the pathogenesis of many diseases. Basic studies have demonstrated that NGF is associated with inflammatory- and stress-related VH, as well as stress-related intestinal barrier dysfunction. The aim of this study is to summarize recent literature and discuss the role of NGF in the pathophysiology of IBS-D, especially in VH and intestinal barrier dysfunction, as well as its potential as a therapeutic target in IBS-D.
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Affiliation(s)
- Xiao-juan Xu
- Gastroenterology Department, China-Japan Friendship Hospital, Beijing 100029, China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100073, China
| | - Liang Liu
- Jinan Central Hospital Affiliated to Shandong University, Jinan 250014, China
| | - Shu-kun Yao
- Gastroenterology Department, China-Japan Friendship Hospital, Beijing 100029, China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100073, China
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Kell DB, Kenny LC. A Dormant Microbial Component in the Development of Preeclampsia. Front Med (Lausanne) 2016; 3:60. [PMID: 27965958 PMCID: PMC5126693 DOI: 10.3389/fmed.2016.00060] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Accepted: 11/04/2016] [Indexed: 12/12/2022] Open
Abstract
Preeclampsia (PE) is a complex, multisystem disorder that remains a leading cause of morbidity and mortality in pregnancy. Four main classes of dysregulation accompany PE and are widely considered to contribute to its severity. These are abnormal trophoblast invasion of the placenta, anti-angiogenic responses, oxidative stress, and inflammation. What is lacking, however, is an explanation of how these themselves are caused. We here develop the unifying idea, and the considerable evidence for it, that the originating cause of PE (and of the four classes of dysregulation) is, in fact, microbial infection, that most such microbes are dormant and hence resist detection by conventional (replication-dependent) microbiology, and that by occasional resuscitation and growth it is they that are responsible for all the observable sequelae, including the continuing, chronic inflammation. In particular, bacterial products such as lipopolysaccharide (LPS), also known as endotoxin, are well known as highly inflammagenic and stimulate an innate (and possibly trained) immune response that exacerbates the inflammation further. The known need of microbes for free iron can explain the iron dysregulation that accompanies PE. We describe the main routes of infection (gut, oral, and urinary tract infection) and the regularly observed presence of microbes in placental and other tissues in PE. Every known proteomic biomarker of "preeclampsia" that we assessed has, in fact, also been shown to be raised in response to infection. An infectious component to PE fulfills the Bradford Hill criteria for ascribing a disease to an environmental cause and suggests a number of treatments, some of which have, in fact, been shown to be successful. PE was classically referred to as endotoxemia or toxemia of pregnancy, and it is ironic that it seems that LPS and other microbial endotoxins really are involved. Overall, the recognition of an infectious component in the etiology of PE mirrors that for ulcers and other diseases that were previously considered to lack one.
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Affiliation(s)
- Douglas B. Kell
- School of Chemistry, The University of Manchester, Manchester, UK
- The Manchester Institute of Biotechnology, The University of Manchester, Manchester, UK
- Centre for Synthetic Biology of Fine and Speciality Chemicals, The University of Manchester, Manchester, UK
- *Correspondence: Douglas B. Kell,
| | - Louise C. Kenny
- The Irish Centre for Fetal and Neonatal Translational Research (INFANT), University College Cork, Cork, Ireland
- Department of Obstetrics and Gynecology, University College Cork, Cork, Ireland
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Kelly JR, Kennedy PJ, Cryan JF, Dinan TG, Clarke G, Hyland NP. Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders. Front Cell Neurosci 2015; 9:392. [PMID: 26528128 PMCID: PMC4604320 DOI: 10.3389/fncel.2015.00392] [Citation(s) in RCA: 701] [Impact Index Per Article: 70.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Accepted: 09/21/2015] [Indexed: 12/12/2022] Open
Abstract
The emerging links between our gut microbiome and the central nervous system (CNS) are regarded as a paradigm shift in neuroscience with possible implications for not only understanding the pathophysiology of stress-related psychiatric disorders, but also their treatment. Thus the gut microbiome and its influence on host barrier function is positioned to be a critical node within the brain-gut axis. Mounting preclinical evidence broadly suggests that the gut microbiota can modulate brain development, function and behavior by immune, endocrine and neural pathways of the brain-gut-microbiota axis. Detailed mechanistic insights explaining these specific interactions are currently underdeveloped. However, the concept that a "leaky gut" may facilitate communication between the microbiota and these key signaling pathways has gained traction. Deficits in intestinal permeability may underpin the chronic low-grade inflammation observed in disorders such as depression and the gut microbiome plays a critical role in regulating intestinal permeability. In this review we will discuss the possible role played by the gut microbiota in maintaining intestinal barrier function and the CNS consequences when it becomes disrupted. We will draw on both clinical and preclinical evidence to support this concept as well as the key features of the gut microbiota which are necessary for normal intestinal barrier function.
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Affiliation(s)
- John R Kelly
- Laboratory of Neurogastroenterology, APC Microbiome Institute, University College Cork Cork, Ireland ; Department of Psychiatry and Neurobehavioural Science, University College Cork Cork, Ireland
| | - Paul J Kennedy
- Laboratory of Neurogastroenterology, APC Microbiome Institute, University College Cork Cork, Ireland
| | - John F Cryan
- Laboratory of Neurogastroenterology, APC Microbiome Institute, University College Cork Cork, Ireland ; Department of Anatomy and Neuroscience, University College Cork Cork, Ireland
| | - Timothy G Dinan
- Laboratory of Neurogastroenterology, APC Microbiome Institute, University College Cork Cork, Ireland ; Department of Psychiatry and Neurobehavioural Science, University College Cork Cork, Ireland
| | - Gerard Clarke
- Laboratory of Neurogastroenterology, APC Microbiome Institute, University College Cork Cork, Ireland ; Department of Psychiatry and Neurobehavioural Science, University College Cork Cork, Ireland
| | - Niall P Hyland
- Laboratory of Neurogastroenterology, APC Microbiome Institute, University College Cork Cork, Ireland ; Department of Pharmacology and Therapeutics, University College Cork Cork, Ireland
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Kelly JR, Kennedy PJ, Cryan JF, Dinan TG, Clarke G, Hyland NP. Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders. Front Cell Neurosci 2015. [DOI: 10.3389/fncel.2015.00392 order by 1-- -] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023] Open
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Kelly JR, Kennedy PJ, Cryan JF, Dinan TG, Clarke G, Hyland NP. Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders. Front Cell Neurosci 2015. [DOI: 10.3389/fncel.2015.00392 order by 8029-- -] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023] Open
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Kelly JR, Kennedy PJ, Cryan JF, Dinan TG, Clarke G, Hyland NP. Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders. Front Cell Neurosci 2015. [DOI: 10.3389/fncel.2015.00392 order by 8029-- #] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023] Open
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49
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Kelly JR, Kennedy PJ, Cryan JF, Dinan TG, Clarke G, Hyland NP. Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders. Front Cell Neurosci 2015. [DOI: 10.3389/fncel.2015.00392 order by 1-- gadu] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023] Open
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50
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Kelly JR, Kennedy PJ, Cryan JF, Dinan TG, Clarke G, Hyland NP. Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders. Front Cell Neurosci 2015. [DOI: 10.3389/fncel.2015.00392 order by 8029-- awyx] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023] Open
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