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Song W, Chen J, Ai G, Xiong P, Song Q, Wei Q, Zou Z, Chen X. Mechanisms of the effects of turpiniae folium extract on growth performance, immunity, antioxidant activity and intestinal barrier function in LPS-challenged broilers. Poult Sci 2025; 104:104903. [PMID: 39985896 PMCID: PMC11904579 DOI: 10.1016/j.psj.2025.104903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Revised: 01/24/2025] [Accepted: 02/16/2025] [Indexed: 02/24/2025] Open
Abstract
Turpiniae folium extract (TFE) has shown anti-inflammatory and immunomodulatory effects in broilers. However, its mechanisms remain unclear. The aim of this study is to investigate the underlying mechanisms by which TFE influences growth performance, jejunal morphology, immune function, antioxidant capacity and barrier integrity in broilers challenged with Lipopolysaccharide (LPS). A total of 240 one-day-old female broilers were randomly divided into four groups with six replicates of ten birds each. A 2 × 2 factorial design with TFE (basal diets supplemented with 0 or 500 mg/kg TFE) and LPS challenge (intraperitoneal injection of 1 mg/kg body weight of sterile saline or LPS at 21, 23 and 25 days of age). The trial lasted for 26 days. The results showed that: Prior to the LPS challenge, dietary supplementation with TFE for 21 days increased both average daily gain (ADG) (P = 0.037) and average daily feed intake (ADFI) (P = 0.045) in broilers. During the LPS challenge period, LPS challenge led to a decline in growth performance and a negative impact on intestinal morphology, while TFE supplementation significantly reversed these adverse effects, as evidenced by increases in ADG (P = 0.004), ADFI (P = 0.046), jejunal villus height (VH) (P = 0.035), the villus height to crypt depth ratio (VH/CD) (P = 0.007) and decreases in the feed-to-gain ratio (F/G) (P = 0.025), jejunal crypt depth (CD) (P = 0.049). LPS induced inflammatory responses and oxidative stress in the jejunum, leading to a significant upregulation of pro-inflammatory factor gene and protein expression, and a marked downregulation of anti-inflammatory and antioxidant gene and protein expression. TFE supplementation mitigated these effects by yielding completely opposite results except for the expression of toll-like receptor 4 (TLR4) protein (P = 0.916). LPS negatively regulates the expression of genes and proteins involved in intestinal mucosal barrier function. In contrast, TFE supplementation significantly upregulated the expression of zonula occludens-1 (ZO-1) (P < 0.001) gene and ZO-1 (P < 0.001), occludin (OCLN) (P < 0.001), claudin (CLDN) (P < 0.001) proteins. In conclusion, dietary supplementation with TFE effectively counteracts the intestinal immune and oxidative stress induced by LPS challenge in broilers, improves intestinal mucosal barrier integrity and tissue morphology, and ultimately mitigates the negative impact of LPS on broiler growth performance. This effect may involve the modulation of the Nrf2 and nuclear factor kappa B (NF-κB) signaling pathways.
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Affiliation(s)
- Wenjing Song
- Institute of Animal Husbandry and Veterinary Science, Jiangxi Academy of Agricultural Sciences, Nanchang 330200, PR China; Jiangxi Province Key Laboratory of Animal Green and Healthy Breeding, Nanchang 330200, PR China
| | - Jiang Chen
- Institute of Animal Husbandry and Veterinary Science, Jiangxi Academy of Agricultural Sciences, Nanchang 330200, PR China; Jiangxi Province Key Laboratory of Animal Green and Healthy Breeding, Nanchang 330200, PR China
| | - Gaoxiang Ai
- Institute of Animal Husbandry and Veterinary Science, Jiangxi Academy of Agricultural Sciences, Nanchang 330200, PR China; Jiangxi Province Key Laboratory of Animal Green and Healthy Breeding, Nanchang 330200, PR China
| | - Pingwen Xiong
- Institute of Animal Husbandry and Veterinary Science, Jiangxi Academy of Agricultural Sciences, Nanchang 330200, PR China; Jiangxi Province Key Laboratory of Animal Green and Healthy Breeding, Nanchang 330200, PR China
| | - Qiongli Song
- Institute of Animal Husbandry and Veterinary Science, Jiangxi Academy of Agricultural Sciences, Nanchang 330200, PR China; Jiangxi Province Key Laboratory of Animal Green and Healthy Breeding, Nanchang 330200, PR China
| | - Qipeng Wei
- Institute of Animal Husbandry and Veterinary Science, Jiangxi Academy of Agricultural Sciences, Nanchang 330200, PR China; Jiangxi Province Key Laboratory of Animal Green and Healthy Breeding, Nanchang 330200, PR China
| | - Zhiheng Zou
- Institute of Animal Husbandry and Veterinary Science, Jiangxi Academy of Agricultural Sciences, Nanchang 330200, PR China; Jiangxi Province Key Laboratory of Animal Green and Healthy Breeding, Nanchang 330200, PR China
| | - Xiaolian Chen
- Institute of Animal Husbandry and Veterinary Science, Jiangxi Academy of Agricultural Sciences, Nanchang 330200, PR China; Jiangxi Province Key Laboratory of Animal Green and Healthy Breeding, Nanchang 330200, PR China.
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Dodero VI, Herrera MG. Oligomerization of 33-mer Gliadin Peptides: Supramolecular Assemblies in Celiac Disease. ChemMedChem 2025; 20:e202400789. [PMID: 39635969 DOI: 10.1002/cmdc.202400789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 12/04/2024] [Accepted: 12/05/2024] [Indexed: 12/07/2024]
Abstract
The 33-mer gliadin peptide and its deamidated derivative, known as 33-mer DGP, are proteolytically resistant peptides central to the pathomechanism of celiac disease (CeD), the autoimmune presentation of gluten-related disorders (GRD). Both peptides can form spontaneous oligomers in the nanomolar concentration, leading to the formation of nanostructures. In other protein-related diseases, oligomers and aggregates are central in their pathomechanism; therefore, it was hypothesized that the oligomerization of proteolytical-resistant 33-mer gliadin peptides could be an underrecognized disease trigger. This review focuses on the current understanding of 33-mer peptides and their oligomers in vitro and cellular experiments. We intend to give the necessary details that incentivize the chemistry community to get involved in the effort to understand the self-assembly of gliadin peptides and the role of their supramolecular structures in CeD and the other GRD. More research is needed to design effective and safe chemical and/or nutritional interventions beyond the gluten-free diet.
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Affiliation(s)
- Verónica I Dodero
- Department of Chemistry, Bielefeld University, Universitätsstr. 25, 33615, Bielefeld, Germany
| | - María G Herrera
- Molecular Cell Biology, Faculty of Medicine, Ruhr University Bochum, Universitätsstr. 150, 44801, Bochum, Germany
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Wan C, Ji T, Wang L, Wu Q, Chen Q, Wang Y, Li Y, He F, Liu W, Zhong W, Wang B. Exploring the molecular mechanisms and shared gene signatures between celiac disease and ulcerative colitis based on bulk RNA and single-cell sequencing: Experimental verification. Int Immunopharmacol 2024; 133:112059. [PMID: 38615385 DOI: 10.1016/j.intimp.2024.112059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 12/31/2023] [Accepted: 04/08/2024] [Indexed: 04/16/2024]
Abstract
Many immune-mediated diseases have the common genetic basis, as an autoimmune disorder, celiac disease (CeD) primarily affects the small intestine, and is caused by the ingestion of gluten in genetically susceptible individuals. As for ulcerative colitis (UC), which most likely involves a complex interplay between some components of the commensal microbiota and other environmental factors in its origin. These two autoimmune diseases share a specific target organ, the bowel. The etiology and immunopathogenesis of both conditions characterized by chronic intestinal inflammation, ulcerative colitis and celiac disease, are not completely understood. Both are complex diseases with genetics and the environmental factors contributing to dysregulation of innate and adaptive immune responses, leading to chronic inflammation and disease. This study is designed to further clarify the relationship between UC and CeD. The GEO database was used to download gene expression profiles for CeD (GSE112102) and UC (GSE75214). The GSEA KEGG pathway analysis revealed that immune-related pathways were significantly associated with both diseases. Further, we screened 187 shared differentially expressed genes (DEGs) of the two diseases. Gene Ontology (GO) and WikiPathways were carried out to perform the biological process and pathway enrichment analysis. Subsequently, based on the DEGs, the least absolute shrinkage and selection operator (LASSO) analysis was performed to screen for the diagnostic biomarkers of the diseases. Moreover, single-cell RNA-sequencing (RNA-seq) data from five colonic propria with UC showed that REG4 expression was present in Goblet cell, Enteroendocrine cell, and Epithelial. Finally, our work identified REG4 is the shared gene of UC and CeD via external data validation, cellular experiments, and immunohistochemistry. In conclusion, our study elucidated that abnormal immune response could be the common pathogenesis of UC and CeD, and REG4 might be a key potential biomarker and therapeutic target for the comorbidity of these two diseases.
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Affiliation(s)
- Changshan Wan
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Tao Ji
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China; Department of Gastroenterology, Linyi People's Hospital, Shandong 276000, China
| | - Liwei Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Qiuyan Wu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Qiuyu Chen
- Department of Gastroenterology, Tianjin First Central Hospital of Tianjin Medical University, Tianjin 300192, China
| | - Yali Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Yaqian Li
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Fengming He
- Department of Clinical Laboratory Medicine, Shanxi Medical University, Taiyuan 030600, Shanxi, China
| | - Wentian Liu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China.
| | - Weilong Zhong
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China.
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China.
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Herrera MG, Amundarain MJ, Dörfler PW, Dodero VI. The Celiac-Disease Superantigen Oligomerizes and Increases Permeability in an Enterocyte Cell Model. Angew Chem Int Ed Engl 2024; 63:e202317552. [PMID: 38497459 DOI: 10.1002/anie.202317552] [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: 11/17/2023] [Revised: 03/03/2024] [Accepted: 03/05/2024] [Indexed: 03/19/2024]
Abstract
Celiac disease (CeD) is an autoimmune disorder triggered by gluten proteins, affecting approximately 1 % of the global population. The 33-mer deamidated gliadin peptide (DGP) is a metabolically modified wheat-gluten superantigen for CeD. Here, we demonstrate that the 33-mer DGP spontaneously assembles into oligomers with a diameter of approximately 24 nm. The 33-mer DGP oligomers present two main secondary structural motifs-a major polyproline II helix and a minor β-sheet structure. Importantly, in the presence of 33-mer DGP oligomers, there is a statistically significant increase in the permeability in the gut epithelial cell model Caco-2, accompanied by the redistribution of zonula occludens-1, a master tight junction protein. These findings provide novel molecular and supramolecular insights into the impact of 33-mer DGP in CeD and highlight the relevance of gliadin peptide oligomerization.
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Affiliation(s)
- Maria G Herrera
- Department of Chemistry, Bielefeld University, Universitätsstr. 25, 33615, Bielefeld, Germany
- Department of Physiology and Molecular and Cellular Biology, Institute of Biosciences, Biotechnology and Translational Biology (iB3), Faculty of Exact and Natural Sciences, University of Buenos Aires, Buenos Aires, C1428EG, Argentina
| | - Maria J Amundarain
- Department of Chemistry, Bielefeld University, Universitätsstr. 25, 33615, Bielefeld, Germany
| | - Philipp W Dörfler
- Department of Chemistry, Bielefeld University, Universitätsstr. 25, 33615, Bielefeld, Germany
| | - Veronica I Dodero
- Department of Chemistry, Bielefeld University, Universitätsstr. 25, 33615, Bielefeld, Germany
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Suntornsaratoon P, Antonio JM, Flores J, Upadhyay R, Veltri J, Bandyopadhyay S, Dadala R, Kim M, Liu Y, Balasubramanian I, Turner JR, Su X, Li WV, Gao N, Ferraris RP. Lactobacillus rhamnosus GG Stimulates Dietary Tryptophan-Dependent Production of Barrier-Protecting Methylnicotinamide. Cell Mol Gastroenterol Hepatol 2024; 18:101346. [PMID: 38641207 PMCID: PMC11193042 DOI: 10.1016/j.jcmgh.2024.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 04/10/2024] [Accepted: 04/11/2024] [Indexed: 04/21/2024]
Abstract
BACKGROUND & AIMS Lacticaseibacillus rhamnosus GG (LGG) is the world's most consumed probiotic but its mechanism of action on intestinal permeability and differentiation along with its interactions with an essential source of signaling metabolites, dietary tryptophan (trp), are unclear. METHODS Untargeted metabolomic and transcriptomic analyses were performed in LGG monocolonized germ-free mice fed trp-free or -sufficient diets. LGG-derived metabolites were profiled in vitro under anaerobic and aerobic conditions. Multiomic correlations using a newly developed algorithm discovered novel metabolites tightly linked to tight junction and cell differentiation genes whose abundances were regulated by LGG and dietary trp. Barrier-modulation by these metabolites were functionally tested in Caco2 cells, mouse enteroids, and dextran sulfate sodium experimental colitis. The contribution of these metabolites to barrier protection is delineated at specific tight junction proteins and enterocyte-promoting factors with gain and loss of function approaches. RESULTS LGG, strictly with dietary trp, promotes the enterocyte program and expression of tight junction genes, particularly Ocln. Functional evaluations of fecal and serum metabolites synergistically stimulated by LGG and trp revealed a novel vitamin B3 metabolism pathway, with methylnicotinamide (MNA) unexpectedly being the most robust barrier-protective metabolite in vitro and in vivo. Reduced serum MNA is significantly associated with increased disease activity in patients with inflammatory bowel disease. Exogenous MNA enhances gut barrier in homeostasis and robustly promotes colonic healing in dextran sulfate sodium colitis. MNA is sufficient to promote intestinal epithelial Ocln and RNF43, a master inhibitor of Wnt. Blocking trp or vitamin B3 absorption abolishes barrier recovery in vivo. CONCLUSIONS Our study uncovers a novel LGG-regulated dietary trp-dependent production of MNA that protects the gut barrier against colitis.
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Affiliation(s)
- Panan Suntornsaratoon
- Department of Pharmacology, Physiology and Neurosciences, New Jersey Medical School, Rutgers University, Newark, New Jersey; Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Jayson M Antonio
- Department of Pharmacology, Physiology and Neurosciences, New Jersey Medical School, Rutgers University, Newark, New Jersey
| | - Juan Flores
- Department of Biological Sciences, Rutgers University, Newark, New Jersey
| | - Ravij Upadhyay
- Department of Pharmacology, Physiology and Neurosciences, New Jersey Medical School, Rutgers University, Newark, New Jersey
| | - John Veltri
- Department of Pharmacology, Physiology and Neurosciences, New Jersey Medical School, Rutgers University, Newark, New Jersey
| | | | - Rhema Dadala
- Department of Pharmacology, Physiology and Neurosciences, New Jersey Medical School, Rutgers University, Newark, New Jersey
| | - Michael Kim
- Department of Pharmacology, Physiology and Neurosciences, New Jersey Medical School, Rutgers University, Newark, New Jersey
| | - Yue Liu
- Department of Biological Sciences, Rutgers University, Newark, New Jersey
| | | | - Jerrold R Turner
- Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Xiaoyang Su
- Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey
| | - Wei Vivian Li
- Department of Statistics, University of California, Riverside, Riverside, California
| | - Nan Gao
- Department of Pharmacology, Physiology and Neurosciences, New Jersey Medical School, Rutgers University, Newark, New Jersey; Department of Biological Sciences, Rutgers University, Newark, New Jersey.
| | - Ronaldo P Ferraris
- Department of Pharmacology, Physiology and Neurosciences, New Jersey Medical School, Rutgers University, Newark, New Jersey.
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6
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Abbasi A, Bazzaz S, A. Ibrahim S, Hekmatdoost A, Hosseini H, Sabahi S, Sheykhsaran E, Rahbar Saadat Y, Asghari Ozma M, Lahouty M. A Critical Review on the Gluten-Induced Enteropathy/Celiac Disease: Gluten-Targeted Dietary and Non-Dietary Therapeutic Approaches. FOOD REVIEWS INTERNATIONAL 2024; 40:883-923. [DOI: 10.1080/87559129.2023.2202405] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Affiliation(s)
- Amin Abbasi
- Student Research Committee, Department of Food Science and Technology, National Nutrition and Food Technology Research Institute, Faculty of Nutrition Science and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sara Bazzaz
- Department of Food Science and Technology, National Nutrition and Food Technology Research Institute, Faculty of Nutrition Science and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Salam A. Ibrahim
- Food Microbiology and Biotechnology Laboratory, Food and Nutritional Sciences Program, College of Agriculture and Environmental Sciences, North Carolina A & T State University, Greensboro, North Carolina, USA
| | - Azita Hekmatdoost
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hedayat Hosseini
- Department of Food Science and Technology, National Nutrition and Food Technology Research Institute, Faculty of Nutrition Science and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sahar Sabahi
- Department of Nutrition, School of Allied Medical Sciences, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Elham Sheykhsaran
- Department of Medical Bacteriology and Virology, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Mahdi Asghari Ozma
- Department of Medical Bacteriology and Virology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Masoud Lahouty
- Department of Microbiology, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
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Di Sabatino A, Santacroce G, Rossi CM, Broglio G, Lenti MV. Role of mucosal immunity and epithelial-vascular barrier in modulating gut homeostasis. Intern Emerg Med 2023; 18:1635-1646. [PMID: 37402104 PMCID: PMC10504119 DOI: 10.1007/s11739-023-03329-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Accepted: 05/25/2023] [Indexed: 07/05/2023]
Abstract
The intestinal mucosa represents the most extensive human barrier having a defense function against microbial and food antigens. This barrier is represented externally by a mucus layer, consisting mainly of mucins, antimicrobial peptides, and secretory immunoglobulin A (sIgA), which serves as the first interaction with the intestinal microbiota. Below is placed the epithelial monolayer, comprising enterocytes and specialized cells, such as goblet cells, Paneth cells, enterochromaffin cells, and others, each with a specific protective, endocrine, or immune function. This layer interacts with both the luminal environment and the underlying lamina propria, where mucosal immunity processes primarily take place. Specifically, the interaction between the microbiota and an intact mucosal barrier results in the activation of tolerogenic processes, mainly mediated by FOXP3+ regulatory T cells, underlying intestinal homeostasis. Conversely, the impairment of the mucosal barrier function, the alteration of the normal luminal microbiota composition (dysbiosis), or the imbalance between pro- and anti-inflammatory mucosal factors may result in inflammation and disease. Another crucial component of the intestinal barrier is the gut-vascular barrier, formed by endothelial cells, pericytes, and glial cells, which regulates the passage of molecules into the bloodstream. The aim of this review is to examine the various components of the intestinal barrier, assessing their interaction with the mucosal immune system, and focus on the immunological processes underlying homeostasis or inflammation.
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Affiliation(s)
- Antonio Di Sabatino
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy.
- First Department of Internal Medicine, San Matteo Hospital Foundation, Pavia, Italy.
- Clinica Medica I, Fondazione IRCCS Policlinico San Matteo, Università di Pavia, Viale Golgi 19, 27100, Pavia, Italy.
| | - Giovanni Santacroce
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy
- First Department of Internal Medicine, San Matteo Hospital Foundation, Pavia, Italy
| | - Carlo Maria Rossi
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy
- First Department of Internal Medicine, San Matteo Hospital Foundation, Pavia, Italy
| | - Giacomo Broglio
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy
- First Department of Internal Medicine, San Matteo Hospital Foundation, Pavia, Italy
| | - Marco Vincenzo Lenti
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy
- First Department of Internal Medicine, San Matteo Hospital Foundation, Pavia, Italy
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8
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Barone MV, Auricchio R, Nanayakkara M, Greco L, Troncone R, Auricchio S. Pivotal Role of Inflammation in Celiac Disease. Int J Mol Sci 2022; 23:ijms23137177. [PMID: 35806180 PMCID: PMC9266393 DOI: 10.3390/ijms23137177] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 06/20/2022] [Accepted: 06/22/2022] [Indexed: 01/27/2023] Open
Abstract
Celiac disease (CD) is an immune-mediated enteropathy triggered in genetically susceptible individuals by gluten-containing cereals. A central role in the pathogenesis of CD is played by the HLA-restricted gliadin-specific intestinal T cell response generated in a pro-inflammatory environment. The mechanisms that generate this pro-inflammatory environment in CD is now starting to be addressed. In vitro study on CD cells and organoids, shows that constant low-grade inflammation is present also in the absence of gluten. In vivo studies on a population at risk, show before the onset of the disease and before the introduction of gluten in the diet, cellular and metabolic alterations in the absence of a T cell-mediated response. Gluten exacerbates these constitutive alterations in vitro and in vivo. Inflammation, may have a main role in CD, adding this disease tout court to the big family of chronic inflammatory diseases. Nutrients can have pro-inflammatory or anti-inflammatory effects, also mediated by intestinal microbiota. The intestine function as a crossroad for the control of inflammation both locally and at distance. The aim of this review is to discuss the recent literature on the main role of inflammation in the natural history of CD, supported by cellular fragility with increased sensitivity to gluten and other pro-inflammatory agents.
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Affiliation(s)
- Maria Vittoria Barone
- Department of Translational Medical Science, University Federico II, Via S. Pansini 5, 80131 Naples, Italy; (R.A.); (M.N.); (L.G.); (R.T.)
- European Laboratory for the Investigation of Food Induced Disease (ELFID), University Federico II, Via S. Pansini 5, 80131 Naples, Italy;
- Correspondence:
| | - Renata Auricchio
- Department of Translational Medical Science, University Federico II, Via S. Pansini 5, 80131 Naples, Italy; (R.A.); (M.N.); (L.G.); (R.T.)
- European Laboratory for the Investigation of Food Induced Disease (ELFID), University Federico II, Via S. Pansini 5, 80131 Naples, Italy;
| | - Merlin Nanayakkara
- Department of Translational Medical Science, University Federico II, Via S. Pansini 5, 80131 Naples, Italy; (R.A.); (M.N.); (L.G.); (R.T.)
- European Laboratory for the Investigation of Food Induced Disease (ELFID), University Federico II, Via S. Pansini 5, 80131 Naples, Italy;
| | - Luigi Greco
- Department of Translational Medical Science, University Federico II, Via S. Pansini 5, 80131 Naples, Italy; (R.A.); (M.N.); (L.G.); (R.T.)
- European Laboratory for the Investigation of Food Induced Disease (ELFID), University Federico II, Via S. Pansini 5, 80131 Naples, Italy;
| | - Riccardo Troncone
- Department of Translational Medical Science, University Federico II, Via S. Pansini 5, 80131 Naples, Italy; (R.A.); (M.N.); (L.G.); (R.T.)
- European Laboratory for the Investigation of Food Induced Disease (ELFID), University Federico II, Via S. Pansini 5, 80131 Naples, Italy;
| | - Salvatore Auricchio
- European Laboratory for the Investigation of Food Induced Disease (ELFID), University Federico II, Via S. Pansini 5, 80131 Naples, Italy;
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Micronutrient Improvement of Epithelial Barrier Function in Various Disease States: A Case for Adjuvant Therapy. Int J Mol Sci 2022; 23:ijms23062995. [PMID: 35328419 PMCID: PMC8951934 DOI: 10.3390/ijms23062995] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 03/01/2022] [Indexed: 02/04/2023] Open
Abstract
The published literature makes a very strong case that a wide range of disease morbidity associates with and may in part be due to epithelial barrier leak. An equally large body of published literature substantiates that a diverse group of micronutrients can reduce barrier leak across a wide array of epithelial tissue types, stemming from both cell culture as well as animal and human tissue models. Conversely, micronutrient deficiencies can exacerbate both barrier leak and morbidity. Focusing on zinc, Vitamin A and Vitamin D, this review shows that at concentrations above RDA levels but well below toxicity limits, these micronutrients can induce cell- and tissue-specific molecular-level changes in tight junctional complexes (and by other mechanisms) that reduce barrier leak. An opportunity now exists in critical care—but also medical prophylactic and therapeutic care in general—to consider implementation of select micronutrients at elevated dosages as adjuvant therapeutics in a variety of disease management. This consideration is particularly pointed amidst the COVID-19 pandemic.
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10
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Implication of Intestinal Barrier Dysfunction in Gut Dysbiosis and Diseases. Biomedicines 2022; 10:biomedicines10020289. [PMID: 35203499 PMCID: PMC8869546 DOI: 10.3390/biomedicines10020289] [Citation(s) in RCA: 147] [Impact Index Per Article: 49.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/21/2022] [Accepted: 01/24/2022] [Indexed: 02/04/2023] Open
Abstract
The intestinal mucosal barrier, also referred to as intestinal barrier, is widely recognized as a critical player in gut homeostasis maintenance as it ensures the complex crosstalk between gut microbes (both commensals and pathogens) and the host immune system. Highly specialized epithelial cells constantly cope with several protective and harmful agents to maintain the multiple physiological functions of the barrier as well as its integrity. However, both genetic defects and environmental factors can break such equilibrium, thus promoting gut dysbiosis, dysregulated immune-inflammatory responses, and even the development of chronic pathological conditions. Here, we review and discuss the molecular and cellular pathways underlying intestinal barrier structural and functional homeostasis, focusing on potential alterations that may undermine this fine balance.
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11
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Vanuytsel T, Tack J, Farre R. The Role of Intestinal Permeability in Gastrointestinal Disorders and Current Methods of Evaluation. Front Nutr 2021; 8:717925. [PMID: 34513903 PMCID: PMC8427160 DOI: 10.3389/fnut.2021.717925] [Citation(s) in RCA: 128] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 08/04/2021] [Indexed: 12/12/2022] Open
Abstract
An increased intestinal permeability has been described in various gastrointestinal and non-gastrointestinal disorders. Nevertheless, the concept and definition of intestinal permeability is relatively broad and includes not only an altered paracellular route, regulated by tight junction proteins, but also the transcellular route involving membrane transporters and channels, and endocytic mechanisms. Paracellular intestinal permeability can be assessed in vivo by using different molecules (e.g., sugars, polyethylene glycols, 51Cr-EDTA) and ex vivo in Ussing chambers combining electrophysiology and probes of different molecular sizes. The latter is still the gold standard technique for assessing the epithelial barrier function, whereas in vivo techniques, including putative blood biomarkers such as intestinal fatty acid-binding protein and zonulin, are broadly used despite limitations. In the second part of the review, the current evidence of the role of impaired barrier function in the pathophysiology of selected gastrointestinal and liver diseases is discussed. Celiac disease is one of the conditions with the best evidence for impaired barrier function playing a crucial role with zonulin as its proposed regulator. Increased permeability is clearly present in inflammatory bowel disease, but the question of whether this is a primary event or a consequence of inflammation remains unsolved. The gut-liver axis with a crucial role in impaired intestinal barrier function is increasingly recognized in chronic alcoholic and metabolic liver disease. Finally, the current evidence does not support an important role for increased permeability in bile acid diarrhea.
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Affiliation(s)
- Tim Vanuytsel
- Department of Chronic Diseases, Translational Research Center for Gastrointestinal Disorders, Metabolism and Ageing, Catholic University Leuven, Leuven, Belgium.,Division of Gastroenterology and Hepatology, Leuven University Hospital, Leuven, Belgium
| | - Jan Tack
- Department of Chronic Diseases, Translational Research Center for Gastrointestinal Disorders, Metabolism and Ageing, Catholic University Leuven, Leuven, Belgium.,Division of Gastroenterology and Hepatology, Leuven University Hospital, Leuven, Belgium
| | - Ricard Farre
- Department of Chronic Diseases, Translational Research Center for Gastrointestinal Disorders, Metabolism and Ageing, Catholic University Leuven, Leuven, Belgium
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12
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Perez F, Ruera CN, Miculan E, Carasi P, Chirdo FG. Programmed Cell Death in the Small Intestine: Implications for the Pathogenesis of Celiac Disease. Int J Mol Sci 2021; 22:7426. [PMID: 34299046 PMCID: PMC8306608 DOI: 10.3390/ijms22147426] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 06/17/2021] [Accepted: 06/18/2021] [Indexed: 12/15/2022] Open
Abstract
The small intestine has a high rate of cell turnover under homeostatic conditions, and this increases further in response to infection or damage. Epithelial cells mostly die by apoptosis, but recent studies indicate that this may also involve pro-inflammatory pathways of programmed cell death, such as pyroptosis and necroptosis. Celiac disease (CD), the most prevalent immune-based enteropathy, is caused by loss of oral tolerance to peptides derived from wheat, rye, and barley in genetically predisposed individuals. Although cytotoxic cells and gluten-specific CD4+ Th1 cells are the central players in the pathology, inflammatory pathways induced by cell death may participate in driving and sustaining the disease through the release of alarmins. In this review, we summarize the recent literature addressing the role of programmed cell death pathways in the small intestine, describing how these mechanisms may contribute to CD and discussing their potential implications.
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Affiliation(s)
- Federico Perez
- Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP), UNLP, CONICET, CIC PBA, Departamento de Ciencias Biológicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, La Plata B1900, Argentina; (C.N.R.); (E.M.); (P.C.)
| | | | | | | | - Fernando Gabriel Chirdo
- Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP), UNLP, CONICET, CIC PBA, Departamento de Ciencias Biológicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, La Plata B1900, Argentina; (C.N.R.); (E.M.); (P.C.)
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13
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Discepolo V, Lania G, Ten Eikelder MLG, Nanayakkara M, Sepe L, Tufano R, Troncone R, Auricchio S, Auricchio R, Paolella G, Barone MV. Pediatric Celiac Disease Patients Show Alterations of Dendritic Cell Shape and Actin Rearrangement. Int J Mol Sci 2021; 22:ijms22052708. [PMID: 33800150 PMCID: PMC7962447 DOI: 10.3390/ijms22052708] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 02/24/2021] [Accepted: 02/24/2021] [Indexed: 12/26/2022] Open
Abstract
Celiac disease (CD) is a frequent intestinal inflammatory disease occurring in genetically susceptible individuals upon gluten ingestion. Recent studies point to a role in CD for genes involved in cell shape, adhesion and actin rearrangements, including a Rho family regulator, Rho GTPase-activating protein 31 (ARHGAP31). In this study, we investigated the morphology and actin cytoskeletons of peripheral monocyte-derived dendritic cells (DCs) from children with CD and controls when in contact with a physiological substrate, fibronectin. DCs were generated from peripheral blood monocytes of pediatric CD patients and controls. After adhesion on fibronectin, DCs showed a higher number of protrusions and a more elongated shape in CD patients compared with controls, as assessed by immunofluorescence actin staining, transmitted light staining and video time-lapse microscopy. These alterations did not depend on active intestinal inflammation associated with gluten consumption and were specific to CD, since they were not found in subjects affected by other intestinal inflammatory conditions. The elongated morphology was not a result of differences in DC activation or maturation status, and did not depend on the human leukocyte antigen (HLA)-DQ2 haplotype. Notably, we found that ARH-GAP31 mRNA levels were decreased while RhoA-GTP activity was increased in CD DCs, pointing to an impairment of the Rho pathway in CD cells. Accordingly, Rho inhibition was able to prevent the cytoskeleton rearrangements leading to the elongated morphology of celiac DCs upon adhesion on fibronectin, confirming the role of this pathway in the observed phenotype. In conclusion, adhesion on fibronectin discriminated CD from the controls' DCs, revealing a gluten-independent CD-specific cellular phenotype related to DC shape and regulated by RhoA activity.
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Affiliation(s)
- Valentina Discepolo
- European Laboratory for the Investigation of Food Induced Diseases, Department of Translational Medical Science, Section of Pediatrics, and ELFID, University Federico II, Via S. Pansini 5, 80131 Naples, Italy; (V.D.); (G.L.); (M.N.); (R.T.); (S.A.); (R.A.); (G.P.)
| | - Giuliana Lania
- European Laboratory for the Investigation of Food Induced Diseases, Department of Translational Medical Science, Section of Pediatrics, and ELFID, University Federico II, Via S. Pansini 5, 80131 Naples, Italy; (V.D.); (G.L.); (M.N.); (R.T.); (S.A.); (R.A.); (G.P.)
| | | | - Merlin Nanayakkara
- European Laboratory for the Investigation of Food Induced Diseases, Department of Translational Medical Science, Section of Pediatrics, and ELFID, University Federico II, Via S. Pansini 5, 80131 Naples, Italy; (V.D.); (G.L.); (M.N.); (R.T.); (S.A.); (R.A.); (G.P.)
| | - Leandra Sepe
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy; (L.S.); (R.T.)
| | - Rossella Tufano
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy; (L.S.); (R.T.)
| | - Riccardo Troncone
- European Laboratory for the Investigation of Food Induced Diseases, Department of Translational Medical Science, Section of Pediatrics, and ELFID, University Federico II, Via S. Pansini 5, 80131 Naples, Italy; (V.D.); (G.L.); (M.N.); (R.T.); (S.A.); (R.A.); (G.P.)
| | - Salvatore Auricchio
- European Laboratory for the Investigation of Food Induced Diseases, Department of Translational Medical Science, Section of Pediatrics, and ELFID, University Federico II, Via S. Pansini 5, 80131 Naples, Italy; (V.D.); (G.L.); (M.N.); (R.T.); (S.A.); (R.A.); (G.P.)
| | - Renata Auricchio
- European Laboratory for the Investigation of Food Induced Diseases, Department of Translational Medical Science, Section of Pediatrics, and ELFID, University Federico II, Via S. Pansini 5, 80131 Naples, Italy; (V.D.); (G.L.); (M.N.); (R.T.); (S.A.); (R.A.); (G.P.)
| | - Giovanni Paolella
- European Laboratory for the Investigation of Food Induced Diseases, Department of Translational Medical Science, Section of Pediatrics, and ELFID, University Federico II, Via S. Pansini 5, 80131 Naples, Italy; (V.D.); (G.L.); (M.N.); (R.T.); (S.A.); (R.A.); (G.P.)
| | - Maria Vittoria Barone
- European Laboratory for the Investigation of Food Induced Diseases, Department of Translational Medical Science, Section of Pediatrics, and ELFID, University Federico II, Via S. Pansini 5, 80131 Naples, Italy; (V.D.); (G.L.); (M.N.); (R.T.); (S.A.); (R.A.); (G.P.)
- Correspondence:
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Choo J, Heo G, Pothoulakis C, Im E. Posttranslational modifications as therapeutic targets for intestinal disorders. Pharmacol Res 2021; 165:105412. [PMID: 33412276 DOI: 10.1016/j.phrs.2020.105412] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/14/2020] [Accepted: 12/22/2020] [Indexed: 02/08/2023]
Abstract
A variety of biological processes are regulated by posttranslational modifications. Posttranslational modifications including phosphorylation, ubiquitination, glycosylation, and proteolytic cleavage, control diverse physiological functions in the gastrointestinal tract. Therefore, a better understanding of their implications in intestinal diseases, including inflammatory bowel disease, irritable bowel syndrome, celiac disease, and colorectal cancer would provide a basis for the identification of novel biomarkers as well as attractive therapeutic targets. Posttranslational modifications can be common denominators, as well as distinct biomarkers, characterizing pathological differences of various intestinal diseases. This review provides experimental evidence that identifies changes in posttranslational modifications from patient samples, primary cells, or cell lines in intestinal disorders, and a summary of carefully selected information on the use of pharmacological modulators of protein modifications as therapeutic options.
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Affiliation(s)
- Jieun Choo
- College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea
| | - Gwangbeom Heo
- College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea
| | - Charalabos Pothoulakis
- Section of Inflammatory Bowel Disease & Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA
| | - Eunok Im
- College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea.
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15
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Jauregi-Miguel A. The tight junction and the epithelial barrier in coeliac disease. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2020; 358:105-132. [PMID: 33707052 DOI: 10.1016/bs.ircmb.2020.09.010] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Epithelial barriers are essential to maintain multicellular organisms well compartmentalized and protected from external environment. In the intestine, the epithelial layer orchestrates a dynamic balance between nutrient absorption and prevention of microorganisms, and antigen intrusion. Intestinal barrier function has been shown to be altered in coeliac disease but whether it contributes to the pathogenesis development or if it is merely a phenomenon secondary to the aberrant immune response is still unknown. The tight junction complexes are multiprotein cell-cell adhesions that seal the epithelial intercellular space and regulate the paracellular permeability of ions and solutes. These structures have a fundamental role in epithelial barrier integrity as well as in signaling mechanisms that control epithelial-cell polarization, the formation of apical domains and cellular processes such as cell proliferation, migration, differentiation, and survival. In coeliac disease, the molecular structures and function of tight junctions appear disrupted and are not completely recovered after treatment with gluten-free diet. Moreover, zonulin, the only known physiological regulator of the tight junction permeability, appears augmented in autoimmune conditions associated with TJ dysfunction, including coeliac disease. This chapter will examine recent discoveries about the molecular architecture of tight junctions and their functions. We will discuss how different factors contribute to tight junction disruption and intestinal barrier impairment in coeliac disease. To conclude, new insights into zonulin-driven disruption of tight junction structures and barrier integrity in coeliac disease are presented together with the advancements in novel therapy to treat the barrier defect seen in pathogenesis.
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Affiliation(s)
- Amaia Jauregi-Miguel
- Wallenberg Centre for Molecular Medicine, Linköping University, Linköping, Sweden; Department of Biomedical and Clinical Sciences, Faculty of Health Science, Linköping University, Linköping, Sweden.
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16
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Jin Y, Blikslager AT. The Regulation of Intestinal Mucosal Barrier by Myosin Light Chain Kinase/Rho Kinases. Int J Mol Sci 2020; 21:ijms21103550. [PMID: 32443411 PMCID: PMC7278945 DOI: 10.3390/ijms21103550] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 05/15/2020] [Accepted: 05/16/2020] [Indexed: 12/19/2022] Open
Abstract
The intestinal epithelial apical junctional complex, which includes tight and adherens junctions, contributes to the intestinal barrier function via their role in regulating paracellular permeability. Myosin light chain II (MLC-2), has been shown to be a critical regulatory protein in altering paracellular permeability during gastrointestinal disorders. Previous studies have demonstrated that phosphorylation of MLC-2 is a biochemical marker for perijunctional actomyosin ring contraction, which increases paracellular permeability by regulating the apical junctional complex. The phosphorylation of MLC-2 is dominantly regulated by myosin light chain kinase- (MLCK-) and Rho-associated coiled-coil containing protein kinase- (ROCK-) mediated pathways. In this review, we aim to summarize the current state of knowledge regarding the role of MLCK- and ROCK-mediated pathways in the regulation of the intestinal barrier during normal homeostasis and digestive diseases. Additionally, we will also suggest potential therapeutic targeting of MLCK- and ROCK-associated pathways in gastrointestinal disorders that compromise the intestinal barrier.
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Affiliation(s)
- Younggeon Jin
- Department of Animal and Avian Sciences, College of Agriculture and Natural Resources, University of Maryland, College Park, MD 20742, USA;
| | - Anthony T. Blikslager
- Department of Clinical Sciences, Comparative Medicine Institute, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607, USA
- Correspondence:
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17
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18
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Sowińska A, Morsy Y, Czarnowska E, Oralewska B, Konopka E, Woynarowski M, Szymańska S, Ejmont M, Scharl M, Bierła JB, Wawrzyniak M, Cukrowska B. Transcriptional and Ultrastructural Analyses Suggest Novel Insights into Epithelial Barrier Impairment in Celiac Disease. Cells 2020; 9:cells9020516. [PMID: 32102433 PMCID: PMC7072847 DOI: 10.3390/cells9020516] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 02/11/2020] [Accepted: 02/20/2020] [Indexed: 12/13/2022] Open
Abstract
Disruption of epithelial junctional complex (EJC), especially tight junctions (TJ), resulting in increased intestinal permeability, is supposed to activate the enhanced immune response to gluten and to induce the development of celiac disease (CD). This study is aimed to present the role of EJC in CD pathogenesis. To analyze differentially expressed genes the next-generation mRNA sequencing data from CD326+ epithelial cells isolated from non-celiac and celiac patients were involved. Ultrastructural studies with morphometry of EJC were done in potential CD, newly recognized active CD, and non-celiac controls. The transcriptional analysis suggested disturbances of epithelium and the most significant gene ontology enriched terms in epithelial cells from CD patients related to the plasma membrane, extracellular exome, extracellular region, and extracellular space. Ultrastructural analyses showed significantly tighter TJ, anomalies in desmosomes, dilatations of intercellular space, and shorter microvilli in potential and active CD compared to controls. Enterocytes of fetal-like type and significantly wider adherence junctions were observed only in active CD. In conclusion, the results do not support the hypothesis that an increased passage of gluten peptides by unsealing TJ precedes CD development. However, increased intestinal permeability due to abnormality of epithelium might play a role in CD onset.
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Affiliation(s)
- Agnieszka Sowińska
- Department of Pathology, The Children Memorial Health Institute, Al. Dzieci Polskich 20, 04-730 Warsaw, Poland; (A.S.); (E.C.); (E.K.); (S.S.); (M.E.); (B.C.)
| | - Yasser Morsy
- Department of Gastroenterology and Hepatology, University Hospital Zürich, CH-8001 Zürich, Switzerland; (M.S.); (M.W.); (Y.M.)
| | - Elżbieta Czarnowska
- Department of Pathology, The Children Memorial Health Institute, Al. Dzieci Polskich 20, 04-730 Warsaw, Poland; (A.S.); (E.C.); (E.K.); (S.S.); (M.E.); (B.C.)
| | - Beata Oralewska
- Clinic of Gastroenterology, The Children Memorial Health Institute, Al. Dzieci Polskich 20, 04-730 Warsaw, Poland; (B.O.); (M.W.)
| | - Ewa Konopka
- Department of Pathology, The Children Memorial Health Institute, Al. Dzieci Polskich 20, 04-730 Warsaw, Poland; (A.S.); (E.C.); (E.K.); (S.S.); (M.E.); (B.C.)
| | - Marek Woynarowski
- Clinic of Gastroenterology, The Children Memorial Health Institute, Al. Dzieci Polskich 20, 04-730 Warsaw, Poland; (B.O.); (M.W.)
| | - Sylwia Szymańska
- Department of Pathology, The Children Memorial Health Institute, Al. Dzieci Polskich 20, 04-730 Warsaw, Poland; (A.S.); (E.C.); (E.K.); (S.S.); (M.E.); (B.C.)
| | - Maria Ejmont
- Department of Pathology, The Children Memorial Health Institute, Al. Dzieci Polskich 20, 04-730 Warsaw, Poland; (A.S.); (E.C.); (E.K.); (S.S.); (M.E.); (B.C.)
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital Zürich, CH-8001 Zürich, Switzerland; (M.S.); (M.W.); (Y.M.)
| | - Joanna B. Bierła
- Department of Pathology, The Children Memorial Health Institute, Al. Dzieci Polskich 20, 04-730 Warsaw, Poland; (A.S.); (E.C.); (E.K.); (S.S.); (M.E.); (B.C.)
- Correspondence: ; Tel.: +48-22-815-19-69
| | - Marcin Wawrzyniak
- Department of Gastroenterology and Hepatology, University Hospital Zürich, CH-8001 Zürich, Switzerland; (M.S.); (M.W.); (Y.M.)
| | - Bożena Cukrowska
- Department of Pathology, The Children Memorial Health Institute, Al. Dzieci Polskich 20, 04-730 Warsaw, Poland; (A.S.); (E.C.); (E.K.); (S.S.); (M.E.); (B.C.)
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Jauregi-Miguel A, Santin I, Garcia-Etxebarria K, Olazagoitia-Garmendia A, Romero-Garmendia I, Sebastian-delaCruz M, Irastorza I, Castellanos-Rubio A, Bilbao JR. MAGI2 Gene Region and Celiac Disease. Front Nutr 2019; 6:187. [PMID: 31921880 PMCID: PMC6930898 DOI: 10.3389/fnut.2019.00187] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 12/03/2019] [Indexed: 12/13/2022] Open
Abstract
Celiac disease (CD) patients present a loss of intestinal barrier function due to structural alterations in the tight junction (TJ) network, the most apical unions between epithelial cells. The association of TJ-related gene variants points to an implication of this network in disease susceptibility. This work aims to characterize the functional implication of TJ-related, disease-associated loci in CD pathogenesis. We performed an association study of 8 TJ-related gene variants in a cohort of 270 CD and 91 non-CD controls. The expression level of transcripts located in the associated SNP region was analyzed by RT-PCR in several human tissues and in duodenal biopsies of celiac patients and non-CD controls. (si)RNA-driven silencing combined with gliadin in the Caco2 intestinal cell line was used to analyze the implication of transcripts from the associated region in the regulation of TJ genes. We replicated the association of rs6962966*A variant [p = 0.0029; OR = 1.88 (95%1.24–2.87)], located in an intron of TJ-related MAGI2 coding gene and upstream of RP4-587D13.2 transcript, bioinformatically classified as a long non-coding RNA (lncRNA). The expression of both genes is correlated and constitutively downregulated in CD intestine. Silencing of lncRNA decreases the levels of MAGI2 protein. At the same time, silencing of MAGI2 affects the expression of several TJ-related genes. The associated region is functionally altered in disease, probably affecting CD-related TJ genes.
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Affiliation(s)
- Amaia Jauregi-Miguel
- Department of Genetics, Physical Anthropology and Animal Physiology, Biocruces-Bizkaia Health Research Institute, University of the Basque Country (Universidad del País Vasco/Euskal Herriko Unibertsitatea), Leioa, Spain
| | - Izortze Santin
- Department of Biochemistry and Molecular Biology, Biocruces-Bizkaia Health Research Institute, University of the Basque Country (Universidad del País Vasco/Euskal Herriko Unibertsitatea), Leioa, Spain.,CIBER in Diabetes and Associated Metabolic Diseases, Madrid, Spain
| | - Koldo Garcia-Etxebarria
- Department of Genetics, Physical Anthropology and Animal Physiology, Biocruces-Bizkaia Health Research Institute, University of the Basque Country (Universidad del País Vasco/Euskal Herriko Unibertsitatea), Leioa, Spain
| | - Ane Olazagoitia-Garmendia
- Department of Genetics, Physical Anthropology and Animal Physiology, Biocruces-Bizkaia Health Research Institute, University of the Basque Country (Universidad del País Vasco/Euskal Herriko Unibertsitatea), Leioa, Spain
| | - Irati Romero-Garmendia
- Department of Genetics, Physical Anthropology and Animal Physiology, Biocruces-Bizkaia Health Research Institute, University of the Basque Country (Universidad del País Vasco/Euskal Herriko Unibertsitatea), Leioa, Spain
| | - Maialen Sebastian-delaCruz
- Department of Genetics, Physical Anthropology and Animal Physiology, Biocruces-Bizkaia Health Research Institute, University of the Basque Country (Universidad del País Vasco/Euskal Herriko Unibertsitatea), Leioa, Spain
| | - Iñaki Irastorza
- Department of Pediatrics, Biocruces-Bizkaia Health Research Institute, Cruces University Hospital, University of the Basque Country (Universidad del País Vasco/Euskal Herriko Unibertsitatea), Barakaldo, Spain
| | | | - Ainara Castellanos-Rubio
- Department of Genetics, Physical Anthropology and Animal Physiology, Biocruces-Bizkaia Health Research Institute, University of the Basque Country (Universidad del País Vasco/Euskal Herriko Unibertsitatea), Leioa, Spain.,Ikerbasque, Basque Foundation for Science, Bilbao, Spain
| | - Jose Ramón Bilbao
- Department of Genetics, Physical Anthropology and Animal Physiology, Biocruces-Bizkaia Health Research Institute, University of the Basque Country (Universidad del País Vasco/Euskal Herriko Unibertsitatea), Leioa, Spain.,CIBER in Diabetes and Associated Metabolic Diseases, Madrid, Spain
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Celiac Disease Monocytes Induce a Barrier Defect in Intestinal Epithelial Cells. Int J Mol Sci 2019; 20:ijms20225597. [PMID: 31717494 PMCID: PMC6888450 DOI: 10.3390/ijms20225597] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 11/05/2019] [Accepted: 11/05/2019] [Indexed: 02/07/2023] Open
Abstract
Intestinal epithelial barrier function in celiac disease (CeD) patients is altered. However, the mechanism underlying this effect is not fully understood. The aim of the current study was to evaluate the role of monocytes in eliciting the epithelial barrier defect in CeD. For this purpose, human monocytes were isolated from peripheral blood mononuclear cells (PBMCs) from active and inactive CeD patients and healthy controls. PBMCs were sorted for expression of CD14 and co-cultured with intestinal epithelial cells (IECs, Caco2BBe). Barrier function, as well as tight junctional alterations, were determined. Monocytes were characterized by profiling of cytokines and surface marker expression. Transepithelial resistance was found to be decreased only in IECs that had been exposed to celiac monocytes. In line with this, tight junctional alterations were found by confocal laser scanning microscopy and Western blotting of ZO-1, occludin, and claudin-5. Analysis of cytokine concentrations in monocyte supernatants revealed higher expression of interleukin-6 and MCP-1 in celiac monocytes. However, surface marker expression, as analyzed by FACS analysis after immunostaining, did not reveal significant alterations in celiac monocytes. In conclusion, CeD peripheral monocytes reveal an intrinsically elevated pro-inflammatory cytokine pattern that is associated with the potential of peripheral monocytes to affect barrier function by altering TJ composition.
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21
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Intestinal Barrier Function in Gluten-Related Disorders. Nutrients 2019; 11:nu11102325. [PMID: 31581491 PMCID: PMC6835310 DOI: 10.3390/nu11102325] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Revised: 09/25/2019] [Accepted: 09/27/2019] [Indexed: 12/15/2022] Open
Abstract
Gluten-related disorders include distinct disease entities, namely celiac disease, wheat-associated allergy and non-celiac gluten/wheat sensitivity. Despite having in common the contact of the gastrointestinal mucosa with components of wheat and other cereals as a causative factor, these clinical entities have distinct pathophysiological pathways. In celiac disease, a T-cell mediate immune reaction triggered by gluten ingestion is central in the pathogenesis of the enteropathy, while wheat allergy develops as a rapid immunoglobulin E- or non-immunoglobulin E-mediated immune response. In non-celiac wheat sensitivity, classical adaptive immune responses are not involved. Instead, recent research has revealed that an innate immune response to a yet-to-be-defined antigen, as well as the gut microbiota, are pivotal in the development in this disorder. Although impairment of the epithelial barrier has been described in all three clinical conditions, its role as a potential pathogenetic co-factor, specifically in celiac disease and non-celiac wheat sensitivity, is still a matter of investigation. This article gives a short overview of the mucosal barrier of the small intestine, summarizes the aspects of barrier dysfunction observed in all three gluten-related disorders and reviews literature data in favor of a primary involvement of the epithelial barrier in the development of celiac disease and non-celiac wheat sensitivity.
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Dietary Factors and Mucosal Immune Response in Celiac Disease Patients Having Persistent Symptoms Despite a Gluten-free Diet. J Clin Gastroenterol 2019; 53:507-513. [PMID: 29505551 DOI: 10.1097/mcg.0000000000001013] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
GOALS The aim of this study was to investigate the role of dietary factors, distinct small-bowel mucosal immune cell types, and epithelial integrity in the perpetuation of gastrointestinal symptoms in treated celiac disease patients. BACKGROUND For unexplained reasons, many celiac disease patients suffer from persistent symptoms, despite a strict gluten-free diet (GFD) and recovered intestinal mucosa. STUDY We compared clinical and serological data and mucosal recovery in 22 asymptomatic and 25 symptomatic celiac patients on a long-term GFD. The density of CD3 and γδ intraepithelial lymphocytes (IELs), CD25 and FOXP3 regulatory T cells, and CD117 mast cells, and the expression of tight junction proteins claudin-3 and occludin, heat shock protein 60, interleukin 15, and Toll-like receptor 2 and 4 were evaluated in duodenal biopsies. RESULTS All subjects kept a strict GFD and had negative celiac autoantibodies and recovered mucosal morphology. The asymptomatic patients had higher mean fiber intake (20.2 vs. 15.2 g/d, P=0.028) and density of CD3 IELs (59.3 vs. 45.0 cell/mm, P=0.045) than those with persistent symptoms. There was a similar but nonsignificant trend in γδ IELs (17.9 vs. 13.5, P=0.149). There were no differences between the groups in other parameters measured. CONCLUSIONS Low fiber intake may predispose patients to persistent symptoms in celiac disease. There were no differences between the groups in the markers of innate immunity, epithelial stress or epithelial integrity. A higher number of IELs in asymptomatic subjects may indicate that the association between symptoms and mucosal inflammation is more complicated than previously thought.
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Orlando A, Linsalata M, Bianco G, Notarnicola M, D'Attoma B, Scavo MP, Tafaro A, Russo F. Lactobacillus rhamnosus GG Protects the Epithelial Barrier of Wistar Rats from the Pepsin-Trypsin-Digested Gliadin (PTG)-Induced Enteropathy. Nutrients 2018; 10:nu10111698. [PMID: 30405050 PMCID: PMC6265991 DOI: 10.3390/nu10111698] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 09/25/2018] [Accepted: 10/24/2018] [Indexed: 02/07/2023] Open
Abstract
Celiac disease (CD) is a chronic immune-mediated disorder, characterized by enhanced paracellular permeability across the intestinal epithelium. The complex system of intercellular junctions, including tight junctions (TJs) and adherens junctions (AJs), seals together the epithelial cells to form a continuous layer. The improvements in barrier integrity have been related to modifications in intercellular junction protein expression. Polyamines (spermidine, spermine, and putrescine) actively participate in the modulation of the AJ expression. Both in vitro and in vivo studies have demonstrated that also probiotics can promote the integrity and the function of the intestinal barrier. On these bases, the present work investigated the protective effects exerted by Lactobacillus rhamnosus GG (L.GG) against the pepsin-trypsin-digested gliadin (PTG)-induced enteropathy in jejunal tissue samples of Wistar rats. In particular, the probiotic effects have been evaluated on the intestinal mucosal architecture, polyamine metabolism and intercellular junction protein expression (ZO-1, Occludin, Claudin-1, β-catenin and E-cadherin). The results from this study indicate that L.GG protects the intestinal mucosa of rats from PTG-induced damage, by preventing the reduction of the expression of the intercellular junction proteins. Consequently, a role for L.GG in the therapeutic management of the gluten-related disorders in humans could be hypothesized.
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Affiliation(s)
- Antonella Orlando
- Laboratory of Nutritional Pathophysiology, National Institute of Gastroenterology "S. de Bellis" Research Hospital, 70013 Castellana Grotte (Ba), Italy.
| | - Michele Linsalata
- Laboratory of Nutritional Pathophysiology, National Institute of Gastroenterology "S. de Bellis" Research Hospital, 70013 Castellana Grotte (Ba), Italy.
| | - Giusy Bianco
- Animal Facility, National Institute of Gastroenterology "S. de Bellis" Research Hospital, 70013 Castellana Grotte (Ba), Italy.
| | - Maria Notarnicola
- Laboratory of Nutritional Biochemistry, National Institute of Gastroenterology "S. de Bellis" Research Hospital, 70013 Castellana Grotte (Ba), Italy.
| | - Benedetta D'Attoma
- Laboratory of Nutritional Pathophysiology, National Institute of Gastroenterology "S. de Bellis" Research Hospital, 70013 Castellana Grotte (Ba), Italy.
| | - Maria Principia Scavo
- National Institute of Gastroenterology "S. de Bellis" Research Hospital, 70013 Castellana Grotte (Ba), Italy.
| | - Angela Tafaro
- Animal Facility, National Institute of Gastroenterology "S. de Bellis" Research Hospital, 70013 Castellana Grotte (Ba), Italy.
| | - Francesco Russo
- Laboratory of Nutritional Pathophysiology, National Institute of Gastroenterology "S. de Bellis" Research Hospital, 70013 Castellana Grotte (Ba), Italy.
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Finamore A, Ambra R, Nobili F, Garaguso I, Raguzzini A, Serafini M. Redox Role of Lactobacillus casei Shirota Against the Cellular Damage Induced by 2,2'-Azobis (2-Amidinopropane) Dihydrochloride-Induced Oxidative and Inflammatory Stress in Enterocytes-Like Epithelial Cells. Front Immunol 2018; 9:1131. [PMID: 29881384 PMCID: PMC5976738 DOI: 10.3389/fimmu.2018.01131] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 05/04/2018] [Indexed: 12/27/2022] Open
Abstract
In western societies where most of the day is spent in the postprandial state, the existence of oxidative and inflammatory stress conditions makes postprandial stress an important factor involved in the development of cardiovascular risk factors. A large body of evidence have been accumulated on the anti-inflammatory effects of probiotics, but no information is available on the mechanisms through which intestinal microbiota modulates redox unbalance associated with inflammatory stress. Here, we aimed to investigate the ability of Lactobacillus casei Shirota (LS) to induce an antioxidant response to counteract oxidative and inflammatory stress in an in vitro model of enterocytes. Our results show that pretreatment of enterocytes with LS prevents membrane barrier disruption and cellular reactive oxygen species (ROS) accumulation inside the cells, modulates the expression of the gastro-intestinal glutathione peroxidase (GPX2) antioxidant enzyme, and reduces p65 phosphorylation, supporting the involvement of the Nfr2 and nuclear factor kappa B pathways in the activation of antioxidant cellular defenses by probiotics. These results suggest, for the first time, a redox mechanism by LS in protecting intestinal cells from AAPH-induced oxidative and inflammatory stress.
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Affiliation(s)
- Alberto Finamore
- Centre for Food and Nutrition, Council for Agricultural Research and Economics, Rome, Italy
| | - Roberto Ambra
- Centre for Food and Nutrition, Council for Agricultural Research and Economics, Rome, Italy
| | - Fabio Nobili
- Centre for Food and Nutrition, Council for Agricultural Research and Economics, Rome, Italy
| | - Ivana Garaguso
- Centre for Food and Nutrition, Council for Agricultural Research and Economics, Rome, Italy
| | - Anna Raguzzini
- Centre for Food and Nutrition, Council for Agricultural Research and Economics, Rome, Italy
| | - Mauro Serafini
- Functional Foods and Metabolic Stress Prevention Laboratory, Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy
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Cukrowska B, Sowińska A, Bierła JB, Czarnowska E, Rybak A, Grzybowska-Chlebowczyk U. Intestinal epithelium, intraepithelial lymphocytes and the gut microbiota - Key players in the pathogenesis of celiac disease. World J Gastroenterol 2017; 23:7505-7518. [PMID: 29204051 PMCID: PMC5698244 DOI: 10.3748/wjg.v23.i42.7505] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Revised: 07/31/2017] [Accepted: 08/15/2017] [Indexed: 02/06/2023] Open
Abstract
Celiac disease (CD) is a chronic immune-mediated disorder triggered by the ingestion of gluten in genetically predisposed individuals. Before activating the immune system, gluten peptides are transferred by the epithelial barrier to the mucosal lamina propria, where they are deamidated by intestinal tissue transglutaminase 2. As a result, they strongly bind to human leucocyte antigens (HLAs), especially HLA-DQ2 and HLA-DQ8, expressed on antigen-presenting cells. This induces an inflammatory response, which results in small bowel enteropathy. Although gluten is the main external trigger activating both innate and adaptive (specific) immunity, its presence in the intestinal lumen does not fully explain CD pathogenesis. It has been hypothesized that an early disruption of the gut barrier in genetically susceptible individuals, which would result in an increased intestinal permeability, could precede the onset of gluten-induced immune events. The intestinal barrier is a complex functional structure, whose functioning is dependent on intestinal microbiota homeostasis, epithelial layer integrity, and the gut-associated lymphoid tissue with its intraepithelial lymphocytes (IELs). The aim of this paper was to review the current literature and summarize the role of the gut microbiota, epithelial cells and their intercellular junctions, and IELs in CD development.
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Affiliation(s)
- Bożena Cukrowska
- Department of Pathology, The Children’s Memorial Health Institute, Warsaw 04-730, Poland
| | - Agnieszka Sowińska
- Department of Pathology, The Children’s Memorial Health Institute, Warsaw 04-730, Poland
| | - Joanna Beata Bierła
- Department of Pathology, The Children’s Memorial Health Institute, Warsaw 04-730, Poland
| | - Elżbieta Czarnowska
- Department of Pathology, The Children’s Memorial Health Institute, Warsaw 04-730, Poland
| | - Anna Rybak
- Department of Gastroenterology, Division of Neurogastroenterology and Motility, Great Ormond Street Hospital, London WC1N 3JH, United Kingdom
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Xing T, Camacho Salazar R, Chen YH. Animal models for studying epithelial barriers in neonatal necrotizing enterocolitis, inflammatory bowel disease and colorectal cancer. Tissue Barriers 2017; 5:e1356901. [PMID: 28795875 DOI: 10.1080/21688370.2017.1356901] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The intestinal epithelial cells line the luminal surface of the entire gastrointestinal tract which is crucial for the absorption of nutrients and prevention of pathogens entering from the external environment. The epithelial barrier plays an important role in organ development, disease pathogenesis, and aging. The major component of an epithelial barrier is the single columnar epithelium and tight junctions. Tight junctions are located at the most apical region of the junctional complex and contain many integral membrane proteins, such as occludin, the claudin family, and junctional adhesion molecules (JAMs). The disruption of intestinal epithelial barriers may lead to several pathophysiological conditions causing malabsorption of nutrition and chronic inflammation. In this review, we provide an update on the alterations of epithelial barriers associated with gut diseases using experimental animal models; we appraise the role of tight junctions in neonatal necrotizing enterocolitis (NEC), inflammatory bowel disease (IBD), and colorectal cancer; we also compare some common features as well as differences and similarities in the pathophysiology of intestinal inflammation in neonatal (NEC) and adult (IBD) gut.
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Affiliation(s)
- Tiaosi Xing
- a Department of Anatomy and Cell Biology , Brody School of Medicine, East Carolina University , Greenville , NC , USA
| | - Rolando Camacho Salazar
- b Department of Pediatrics , Brody School of Medicine, East Carolina University , Greenville , NC , USA
| | - Yan-Hua Chen
- a Department of Anatomy and Cell Biology , Brody School of Medicine, East Carolina University , Greenville , NC , USA.,b Department of Pediatrics , Brody School of Medicine, East Carolina University , Greenville , NC , USA
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Lechuga S, Ivanov AI. Disruption of the epithelial barrier during intestinal inflammation: Quest for new molecules and mechanisms. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2017; 1864:1183-1194. [PMID: 28322932 DOI: 10.1016/j.bbamcr.2017.03.007] [Citation(s) in RCA: 184] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/22/2017] [Revised: 03/13/2017] [Accepted: 03/15/2017] [Indexed: 02/06/2023]
Abstract
The intestinal epithelium forms a key protective barrier that separates internal organs from the harmful environment of the gut lumen. Increased permeability of the gut barrier is a common manifestation of different inflammatory disorders contributing to the severity of disease. Barrier permeability is controlled by epithelial adherens junctions and tight junctions. Junctional assembly and integrity depend on fundamental homeostatic processes such as cell differentiation, rearrangements of the cytoskeleton, and vesicle trafficking. Alterations of intestinal epithelial homeostasis during mucosal inflammation may impair structure and remodeling of apical junctions, resulting in increased permeability of the gut barrier. In this review, we summarize recent advances in our understanding of how altered epithelial homeostasis affects the structure and function of adherens junctions and tight junctions in the inflamed gut. Specifically, we focus on the transcription reprogramming of the cell, alterations in the actin cytoskeleton, and junctional endocytosis and exocytosis. We pay special attention to knockout mouse model studies and discuss the relevance of these mechanisms to human gastrointestinal disorders.
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Affiliation(s)
- Susana Lechuga
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Andrei I Ivanov
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA; Virginia Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
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Pérez S, Taléns-Visconti R, Rius-Pérez S, Finamor I, Sastre J. Redox signaling in the gastrointestinal tract. Free Radic Biol Med 2017; 104:75-103. [PMID: 28062361 DOI: 10.1016/j.freeradbiomed.2016.12.048] [Citation(s) in RCA: 195] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2016] [Revised: 12/20/2016] [Accepted: 12/31/2016] [Indexed: 12/16/2022]
Abstract
Redox signaling regulates physiological self-renewal, proliferation, migration and differentiation in gastrointestinal epithelium by modulating Wnt/β-catenin and Notch signaling pathways mainly through NADPH oxidases (NOXs). In the intestine, intracellular and extracellular thiol redox status modulates the proliferative potential of epithelial cells. Furthermore, commensal bacteria contribute to intestine epithelial homeostasis through NOX1- and dual oxidase 2-derived reactive oxygen species (ROS). The loss of redox homeostasis is involved in the pathogenesis and development of a wide diversity of gastrointestinal disorders, such as Barrett's esophagus, esophageal adenocarcinoma, peptic ulcer, gastric cancer, ischemic intestinal injury, celiac disease, inflammatory bowel disease and colorectal cancer. The overproduction of superoxide anion together with inactivation of superoxide dismutase are involved in the pathogenesis of Barrett's esophagus and its transformation to adenocarcinoma. In Helicobacter pylori-induced peptic ulcer, oxidative stress derived from the leukocyte infiltrate and NOX1 aggravates mucosal damage, especially in HspB+ strains that downregulate Nrf2. In celiac disease, oxidative stress mediates most of the cytotoxic effects induced by gluten peptides and increases transglutaminase levels, whereas nitrosative stress contributes to the impairment of tight junctions. Progression of inflammatory bowel disease relies on the balance between pro-inflammatory redox-sensitive pathways, such as NLRP3 inflammasome and NF-κB, and the adaptive up-regulation of Mn superoxide dismutase and glutathione peroxidase 2. In colorectal cancer, redox signaling exhibits two Janus faces: On the one hand, NOX1 up-regulation and derived hydrogen peroxide enhance Wnt/β-catenin and Notch proliferating pathways; on the other hand, ROS may disrupt tumor progression through different pro-apoptotic mechanisms. In conclusion, redox signaling plays a critical role in the physiology and pathophysiology of gastrointestinal tract.
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Affiliation(s)
- Salvador Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain
| | - Raquel Taléns-Visconti
- Department of Pharmacy and Pharmaceutical Technology and Parasitology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain
| | - Sergio Rius-Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain
| | - Isabela Finamor
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain
| | - Juan Sastre
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain.
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Schumann M, Siegmund B, Schulzke JD, Fromm M. Celiac Disease: Role of the Epithelial Barrier. Cell Mol Gastroenterol Hepatol 2017; 3:150-162. [PMID: 28275682 PMCID: PMC5331784 DOI: 10.1016/j.jcmgh.2016.12.006] [Citation(s) in RCA: 103] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Accepted: 12/20/2016] [Indexed: 12/12/2022]
Abstract
In celiac disease (CD) a T-cell-mediated response to gluten is mounted in genetically predisposed individuals, resulting in a malabsorptive enteropathy histologically highlighted by villous atrophy and crypt hyperplasia. Recent data point to the epithelial layer as an under-rated hot spot in celiac pathophysiology to date. This overview summarizes current functional and genetic evidence on the role of the epithelial barrier in CD, consisting of the cell membranes and the apical junctional complex comprising sealing as well as ion and water channel-forming tight junction proteins and the adherens junction. Moreover, the underlying mechanisms are discussed, including apoptosis of intestinal epithelial cells, biology of intestinal stem cells, alterations in the apical junctional complex, transcytotic uptake of gluten peptides, and possible implications of a defective epithelial polarity. Current research is directed toward new treatment options for CD that are alternatives or complementary therapeutics to a gluten-free diet. Thus, strategies to target an altered epithelial barrier therapeutically also are discussed.
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Key Words
- Bmp, bone morphogenetic protein
- CBC, crypt base columnar cell
- CD, celiac disease
- Celiac Sprue
- EGF, epidermal growth factor
- Epithelial Polarity
- GFD, gluten-free diet
- GI, gastrointestinal
- GWAS, genome-wide association studies
- Gluten-Sensitive Enteropathy
- IEC, intestinal epithelial cell
- IL, interleukin
- MIC-A, major histocompatibility complex class I chain–related gene-A
- Partitioning-Defective Proteins
- SNP, single-nucleotide polymorphism
- TJ, tight junction
- Tight Junction
- ZO, zonula occludens
- aPKC, atypical protein kinase C
- α-Gliadin 33mer
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Affiliation(s)
- Michael Schumann
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité–Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health, Berlin, Germany
- Berlin-Brandenburg School for Regenerative Therapies, Berlin, Germany
| | - Britta Siegmund
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Jörg D. Schulzke
- Institute of Clinical Physiology, Campus Benjamin Franklin, Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Michael Fromm
- Institute of Clinical Physiology, Campus Benjamin Franklin, Charité–Universitätsmedizin Berlin, Berlin, Germany
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Bidmon-Fliegenschnee B, Lederhuber HC, Csaicsich D, Pichler J, Herzog R, Memaran-Dadgar N, Huber WD, Aufricht C, Kratochwill K. Overexpression of Hsp70 confers cytoprotection during gliadin exposure in Caco-2 cells. Pediatr Res 2015; 78:358-64. [PMID: 26086640 DOI: 10.1038/pr.2015.112] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2014] [Accepted: 03/10/2015] [Indexed: 12/22/2022]
Abstract
BACKGROUND In Celiac disease (CD), cytoskeletal integrity of intestinal cells is disrupted by gliadin exposure. This study investigates the role of heat shock protein (Hsp)70 during cytoskeletal recovery in CD by assessing its induction and effects on junctional proteins. METHODS Using an in-vitro model of CD, cytoskeletal injury and recovery was assessed in gliadin-exposed Caco-2 cells by measuring cellular distribution of ezrin, E-cadherin, and Hsp70 by differential centrifugation. Effects of Hsp70 were tested by an in-vitro repair assay, based on the incubation of injured or recovered cytoskeletal cellular fractions in noncytoskeletal supernatants containing low or high levels of Hsp70, or by transient transfection of Caco-2 cells with Hsp70. RESULTS Cytoskeletal disruption of ezrin and E-cadherin was demonstrated in gliadin-exposed Caco-2 cells by their significant shift from the cytoskeletal pellet into the noncytoskeletal supernatant fraction. Recovery from gliadin exposure was associated with induction and cytoskeletal redistribution of Hsp70. The in-vitro repair assay delineated direct evidence for HSP-mediated repair by stabilization of junctional proteins by Hsp70. Overexpression of Hsp70 resulted in significantly increased cytoskeletal integrity. CONCLUSION Our results establish an essential role of HSP-mediated cytoskeletal repair in Caco-2 cells during recovery from in-vitro gliadin exposure.
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Affiliation(s)
| | - Hans Ch Lederhuber
- Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
| | - Dagmar Csaicsich
- Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
| | - Judith Pichler
- Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
| | - Rebecca Herzog
- Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
| | - Nima Memaran-Dadgar
- Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
| | - Wolf-Dietrich Huber
- Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
| | - Christoph Aufricht
- Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
| | - Klaus Kratochwill
- Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
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Claudin-related intestinal diseases. Semin Cell Dev Biol 2015; 42:30-8. [PMID: 25999319 DOI: 10.1016/j.semcdb.2015.05.006] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Revised: 05/09/2015] [Accepted: 05/12/2015] [Indexed: 02/07/2023]
Abstract
With up to 200 m(2) the human intestine is the organ with the largest absorptive surface of the body. It is lined by a single layer of epithelial cells that separates the host from the environment. The intestinal epithelium provides both, selective absorption of nutrients, ions, and water but also a highly effective barrier function which includes the first line of defense against environmental antigens. The paracellular part of this barrier function is provided by tight junction (TJ) proteins, especially the large family of claudins. Changes in abundance or molecular structure of claudins can generally result in three typical effects, (i) decreased absorptive passage, (ii) increased secretory passage of small solutes and water causing leak flux diarrhea and (iii) increased absorptive passage of macromolecules which may induce inflammatory processes. Several intestinal diseases are associated with such changes that can result in intestinal inflammation and symptoms like weight loss, abdominal pain or diarrhea. This review summarizes our current knowledge on barrier dysfunction and claudin dysregulation in several intestinal diseases gastroenterologists are often faced with, like inflammatory bowel disease, microscopic colitis, celiac disease, irritable bowel syndrome, gallstones and infectious diseases like HIV enteropathy, Campylobacter jejuni and Clostridium perfringens infection.
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Luettig J, Rosenthal R, Barmeyer C, Schulzke JD. Claudin-2 as a mediator of leaky gut barrier during intestinal inflammation. Tissue Barriers 2015; 3:e977176. [PMID: 25838982 DOI: 10.4161/21688370.2014.977176] [Citation(s) in RCA: 197] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Accepted: 10/10/2014] [Indexed: 02/07/2023] Open
Abstract
The epithelial tight junction determines the paracellular water and ion movement in the intestine and also prevents uptake of larger molecules, including antigens, in an uncontrolled manner. Claudin-2, one of the 27 mammalian claudins regulating that barrier function, forms a paracellular channel for small cations and water. It is typically expressed in leaky epithelia like proximal nephron and small intestine and provides a major pathway for the paracellular transport of sodium, potassium, and fluid. In intestinal inflammation (Crohn's disease, ulcerative colitis), immune-mediated diseases (celiac disease), and infections (HIV enteropathy), claudin-2 is upregulated in small and large intestine and contributes to diarrhea via a leak flux mechanism. In parallel to that upregulation, other epithelial and tight junctional features are altered and the luminal uptake of antigenic macromolecules is enhanced, for which claudin-2 may be partially responsible through induction of tight junction strand discontinuities.
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Key Words
- AP, activator protein
- CARD15, caspase recruitment domain-containing protein 15
- Crohn's disease
- DSS, dextran sodium sulfate
- ECL, extracellular loop
- ERK, extracellular-regulated kinase
- HIV
- HIV, human immunodeficiency virus
- HNF, hepatocyte nuclear factor
- IBD, inflammatory bowel disease
- IFN, interferon
- IFNγ
- IL, interleukin
- JAM, junctional adhesion molecule
- JNK, c-jun N-terminal kinase
- LPS, lipopolysaccharides
- MAPK, mitogen-activated protein kinase
- MDCK, Madine Darby canine kidney
- MLC, myosin light chain
- NFκB, nuclear factor kappa B
- NOD2, nucleotide-binding oligomerization domain-containing protein 2
- PI3K, phosphatidyl-inositol-3-kinase
- ROCK, Rho kinase
- Rho, ras homolog
- STAT, signal transducers and activators of transcription
- TEER, transepithelial electrical resistance
- TJ, tight junction
- TNBS, 2,4,6-trinitrobenzene sulfonic acid
- TNF, tumor necrosis factor
- TNFα
- Tat, trans-activator of transcription
- Vpr, viral protein r; ZO, zonula occludens
- celiac disease
- claudin-2
- gp, glycoprotein
- inflammatory bowel disease
- tight junction
- ulcerative colitis
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Affiliation(s)
- J Luettig
- Institute of Clinical Physiology; Department of Gastroenterology; Charité ; Berlin, Germany
| | - R Rosenthal
- Institute of Clinical Physiology; Department of Gastroenterology; Charité ; Berlin, Germany
| | - C Barmeyer
- Institute of Clinical Physiology; Department of Gastroenterology; Charité ; Berlin, Germany
| | - J D Schulzke
- Institute of Clinical Physiology; Department of Gastroenterology; Charité ; Berlin, Germany
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Ciccocioppo R, Cangemi GC, Roselli EA, Kruzliak P. Are stem cells a potential therapeutic tool in coeliac disease? Cell Mol Life Sci 2015; 72:1317-29. [PMID: 25511197 PMCID: PMC11113911 DOI: 10.1007/s00018-014-1797-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Revised: 11/02/2014] [Accepted: 12/01/2014] [Indexed: 02/08/2023]
Abstract
Despite the growing understanding of its pathogenesis, the treatment of coeliac disease is still based on a lifelong gluten-free diet that, although efficacious, is troublesome for affected patients, and a definitive cure is still an unmet need. In this regard, the development of new chemical- and biological-derived agents has often resulted in unsatisfactory effects when tested in vivo, probably because of their ability to target only a single pathway, whilst the immunological cascade responsible for tissue injury is complex and redundant. The advent of cellular therapies, mainly based on the use of stem cells, is an emerging area of interest since it has the advantage of a multi-target strategy. Both haematopoietic and mesenchymal stem cells have been employed in the treatment of refractory patients suffering from autoimmune diseases, with promising results. However, the lack of immunogenicity makes mesenchymal stem cells more suitable than their haematopoietic counterpart, since their transplantation may be performed in the absence of a myeloablative conditioning regimen. In addition, mesenchymal stem cells have been shown to harbour strong modulatory effects on almost all cells involved in immune response, together with a potent regenerative action. It is therefore conceivable that over the next few years their therapeutic use will increase as their biological interactions with injured tissues become clearer.
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Affiliation(s)
- Rachele Ciccocioppo
- Center for the Study and Cure of Coeliac Disease, Clinica Medica I, IRCCS San Matteo Hospital Foundation, University of Pavia, Piazzale Golgi, 19, 27100 Pavia, Italy
| | - Giuseppina Cristina Cangemi
- Center for the Study and Cure of Coeliac Disease, Clinica Medica I, IRCCS San Matteo Hospital Foundation, University of Pavia, Piazzale Golgi, 19, 27100 Pavia, Italy
| | - Emanuela Anna Roselli
- Center for the Study and Cure of Coeliac Disease, Clinica Medica I, IRCCS San Matteo Hospital Foundation, University of Pavia, Piazzale Golgi, 19, 27100 Pavia, Italy
| | - Peter Kruzliak
- International Clinical Research Center, St. Anne’s University Hospital and Masaryk University, Pekarska 53, 656 91 Brno, Czech Republic
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Zhao H, Zhao C, Dong Y, Zhang M, Wang Y, Li F, Li X, McClain C, Yang S, Feng W. Inhibition of miR122a by Lactobacillus rhamnosus GG culture supernatant increases intestinal occludin expression and protects mice from alcoholic liver disease. Toxicol Lett 2015; 234:194-200. [PMID: 25746479 DOI: 10.1016/j.toxlet.2015.03.002] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Revised: 02/25/2015] [Accepted: 03/04/2015] [Indexed: 02/07/2023]
Abstract
Alcoholic liver disease (ALD) has a high morbidity and mortality. Chronic alcohol consumption causes disruption of intestinal microflora homeostasis, intestinal tight junction barrier dysfunction, increased endotoxemia, and eventually liver steatosis/steatohepatitis. Probiotic Lactobacillus rhamnosus GG (LGG) and the bacteria-free LGG culture supernatant (LGGs) have been shown to promote intestinal epithelial integrity and protect intestinal barrier function in ALD. However, little is known about how LGGs mechanistically works to increase intestinal tight junction proteins. Here we show that chronic ethanol exposure increased intestinal miR122a expression, which decreased occludin expression leading to increased intestinal permeability. Moreover, LGGs supplementation decreased ethanol-elevated miR122a level and attenuated ethanol-induced liver injury in mice. Similar to the effect of ethanol exposure, overexpression of miR122a in Caco-2 monolayers markedly decreased occludin protein levels. In contrast, inhibition of miR122a increased occludin expression. We conclude that LGGs supplementation functions in intestinal integrity by inhibition of miR122a, leading to occludin restoration in mice exposed to chronic ethanol.
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Affiliation(s)
- Haiyang Zhao
- School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu 210094, China; Department of Medicine, Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, United States; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Cuiqing Zhao
- Department of Medicine, Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, United States; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China
| | - Yuanyuan Dong
- School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu 210094, China; Department of Medicine, Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, United States; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Min Zhang
- Department of Medicine, Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, United States; Schools of Life Sciences and Technology, and Food Sciences and Technology, Jilin Agricultural University, Changchun, Jilin 130118, China
| | - Yuhua Wang
- Department of Medicine, Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, United States; Schools of Life Sciences and Technology, and Food Sciences and Technology, Jilin Agricultural University, Changchun, Jilin 130118, China
| | - Fengyuan Li
- Department of Medicine, Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, United States
| | - Xiaokun Li
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Craig McClain
- Department of Medicine, Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, United States; Robley Rex VA Medical Center, Louisville, KY 40202, United States
| | - Shulin Yang
- School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu 210094, China.
| | - Wenke Feng
- Department of Medicine, Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, United States; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
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Claudin-3 and occludin tissue content in the glands of colonic mucosa with and without a fecal stream. J Mol Histol 2015; 46:183-94. [PMID: 25649016 DOI: 10.1007/s10735-015-9610-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Accepted: 01/28/2015] [Indexed: 02/07/2023]
Abstract
The synthesis of the proteins of the apical tight junctions (TJs) depends on a continuous supply of short-chain fatty acids (SCFAs) in colonic epithelium. No studies have evaluated the tissue contents of the TJs proteins in colon segments devoid of a fecal stream. To evaluate the contents of claudin-3 and occludin in the glands of colonic mucosa devoid of a fecal stream. Forty-five rats underwent a diversion of the fecal stream via a left side colostomy and distal mucous fistula. Three groups of 15 animals each were sacrificed at 6, 12 or 18 weeks after surgery. The presence and severity of colitis were defined by histology and inflammation grading scales, respectively. The expression of claudin-3 and occludin were evaluated by immunohistochemistry, and their contents were evaluated by computer-assisted image analysis. Mann-Whitney and Kruskal-Wallis tests were used to evaluate the results at a significance level of 5% (p < 0.05). The colonic epithelium without a fecal stream had a higher degree of inflammation. Colonic glands without a fecal stream showed a reduction in claudin-3 content independent of the time and reduction in occludin content after 12 weeks of intestinal exclusion. The content of claudin-3 and occludin were mainly reduced at the apical surfaces of the colon glands, whereas segments retaining the fecal stream were maintained. The content of claudin-3 was not reduced with time, although the levels of occludin were reduced after 6 weeks and did not vary thereafter. Deficiencies in SCFAs decreased the content of claudin-3 and occludin in colonic glands with the areas of worst inflammation, confirming the importance of an adequate supply of SCFAs in maintaining the integrity of TJ proteins.
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Skrovanek S, DiGuilio K, Bailey R, Huntington W, Urbas R, Mayilvaganan B, Mercogliano G, Mullin JM. Zinc and gastrointestinal disease. World J Gastrointest Pathophysiol 2014; 5:496-513. [PMID: 25400994 PMCID: PMC4231515 DOI: 10.4291/wjgp.v5.i4.496] [Citation(s) in RCA: 90] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Revised: 09/18/2014] [Accepted: 10/01/2014] [Indexed: 02/06/2023] Open
Abstract
This review is a current summary of the role that both zinc deficiency and zinc supplementation can play in the etiology and therapy of a wide range of gastrointestinal diseases. The recent literature describing zinc action on gastrointestinal epithelial tight junctions and epithelial barrier function is described. Zinc enhancement of gastrointestinal epithelial barrier function may figure prominently in its potential therapeutic action in several gastrointestinal diseases.
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Barone MV, Troncone R, Auricchio S. Gliadin peptides as triggers of the proliferative and stress/innate immune response of the celiac small intestinal mucosa. Int J Mol Sci 2014; 15:20518-37. [PMID: 25387079 PMCID: PMC4264181 DOI: 10.3390/ijms151120518] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Revised: 10/27/2014] [Accepted: 10/27/2014] [Indexed: 02/06/2023] Open
Abstract
Celiac disease (CD) is a frequent inflammatory intestinal disease, with a genetic background, caused by gliadin-containing food. Undigested gliadin peptides induce innate and adaptive T cell-mediated immune responses. The major mediator of the stress and innate immune response to gliadin peptides (i.e., peptide 31–43, P31–43) is the cytokine interleukin-15 (IL-15). The role of epithelial growth factor (EGF) as a mediator of enterocyte proliferation and the innate immune response has been described. In this paper, we review the most recent literature on the mechanisms responsible for triggering the up-regulation of these mediators in CD by gliadin peptides. We will discuss the role of P31–43 in enterocyte proliferation, structural changes and the innate immune response in CD mucosa in cooperation with EGF and IL-15, and the mechanism of up-regulation of these mediators related to vesicular trafficking. We will also review the literature that focuses on constitutive alterations of the structure, signalling/proliferation and stress/innate immunity pathways of CD cells. Finally, we will discuss how these pathways can be triggered by gliadin peptide P31–43 in controls, mimicking the celiac cellular phenotype.
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Affiliation(s)
- Maria Vittoria Barone
- Department of Translational Medical Science (Section of Pediatrics), University of Naples Federico II, Via S. Pansini 5, Naples 80131, Italy.
| | - Riccardo Troncone
- Department of Translational Medical Science (Section of Pediatrics), University of Naples Federico II, Via S. Pansini 5, Naples 80131, Italy.
| | - Salvatore Auricchio
- European Laboratory for the Investigation of Food Induced Diseases (ELFID), University of Naples Federico II, Via S. Pansini 5, Naples 80131, Italy.
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Yadav VR, Hussain A, Sahoo K, Awasthi V. Remediation of hemorrhagic shock-induced intestinal barrier dysfunction by treatment with diphenyldihaloketones EF24 and CLEFMA. J Pharmacol Exp Ther 2014; 351:413-22. [PMID: 25204337 PMCID: PMC4201268 DOI: 10.1124/jpet.114.217331] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2014] [Accepted: 09/08/2014] [Indexed: 12/14/2022] Open
Abstract
Gut is very sensitive to hypoperfusion and hypoxia, and deranged gastrointestinal barrier is implicated in systemic failure of various organs. We recently demonstrated that diphenyldihaloketone EF24 [3,5-bis(2-fluorobenzylidene)piperidin-4-one] improves survival in a rat model of hemorrhagic shock. In this study, we tested EF24 and its other analog CLEFMA (4-[3,5-bis(2-chlorobenzylidene)-4-oxo-piperidine-1-yl]-4-oxo-2-butenoic acid) for their effect on intestinal barrier dysfunction in hypovolemic shock. Hypovolemia was induced in rats by withdrawing 50% of blood. EF24 or CLEFMA (0.4 mg/kg i.p.) treatment was provided, without volume resuscitation, after 1 hour of hemorrhage. Ileum was collected 5 hours after the treatment to investigate the expression of tight junction proteins (zonula occludens, claudin, and occludin) and epithelial injury markers [myeloperoxidase, ileal lipid-binding protein (ILBP), CD163, and plasma citrulline]. The ileal permeability for dextran-fluoroisothiocyanate and Evan's blue dye was determined. EF24 and CLEFMA reduced the hypovolemia-induced plasma citrulline levels and the ileal expression of myeloperoxidase, ILBP, and CD163. The drugs also restored the basal expression levels of zonula occludens, claudin, and occludin, which were substantially deranged by hypovolemia. In ischemic ileum, the expression of phospho(tyrosine)-zonula occludens-1 was reduced, which was reinstated by EF24 and CLEFMA. In contrast, the drug treatments maintained the hypovolemia-induced expression of phospho(threonine)-occludin, but reduced that of phospho(tyrosine)-occludin. Both EF24 and CLEFMA treatments reduced the intestinal permeability enhanced by hypovolemia. EF24 and CLEFMA attenuate hypovolemic gut pathology and protect barrier function by restoring the status of tight junction proteins. These effects were observed in unresuscitated shock, implying the benefit of EF24 and CLEFMA in prehospital care of shock.
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Affiliation(s)
- Vivek R Yadav
- Department of Pharmaceutical Sciences, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma
| | - Alamdar Hussain
- Department of Pharmaceutical Sciences, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma
| | - Kaustuv Sahoo
- Department of Pharmaceutical Sciences, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma
| | - Vibhudutta Awasthi
- Department of Pharmaceutical Sciences, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma
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Mansueto P, Seidita A, D'Alcamo A, Carroccio A. Non-celiac gluten sensitivity: literature review. J Am Coll Nutr 2014; 33:39-54. [PMID: 24533607 DOI: 10.1080/07315724.2014.869996] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND A significant percentage of the general population report problems caused by wheat and/or gluten ingestion, even though they do not have celiac disease (CD) or wheat allergy (WA), because they test negative both for CD-specific serology and histopathology and for immunoglobulin E (IgE)-mediated assays. Most patients report both gastrointestinal and nongastrointestinal symptoms, and all report improvement of symptoms on a gluten-free diet. This clinical condition has been named non-celiac gluten sensitivity (NCGS). AIM We attempt to define the current pathogenic, clinical, and diagnostic criteria of this "new" disease, to provide a practical view that might be useful to evaluate, diagnose, and manage NCGS patients. METHODS We reviewed the international literature through PubMed and Medline, using the search terms "wheat (hyper)sensitivity," "wheat allergy," "wheat intolerance," "gluten (hyper)sensitivity," and "gluten intolerance," and we discuss current knowledge about NCGS. RESULTS It has been demonstrated that patients suffering from NCGS are a heterogeneous group, composed of several subgroups, each characterized by different pathogenesis, clinical history, and, probably, clinical course. NCGS diagnosis can be reached only by excluding CD and WA. Recent evidence shows that a personal history of food allergy in infancy, coexistent atopy, positive for immunoglobulin G (IgG) antigliadin antibodies and flow cytometric basophil activation test, with wheat and duodenal and/or ileum-colon intraepithelial and lamina propria eosinophil counts, could be useful to identify NCGS patients. CONCLUSIONS Future research should aim to identify reliable biomarkers for NCGS diagnosis and to better define the different NCGS subgroups. Key teaching points: • Most patients report both gastrointestinal and nongastrointestinal symptoms, and all agree that there is an improvement of symptoms on a gluten-free diet. • NCGS diagnosis can be reached only by excluding celiac disease and wheat allergy. • Patients suffering from NCGS are a heterogeneous group, composed of several subgroups, each characterized by different pathogenesis, clinical history, and, probably, clinical course. • A personal history of food allergy in infancy, coexistent atopy, positive IgG antigliadin antibodies (AGA) and flow cytometric basophil activation test, with wheat and duodenal and/or ileum-colon intraepithelial and lamina propria eosinophil counts, could be useful to identify NCGS patients. • Future research should aim to identify reliable biomarkers for NCGS diagnosis and to better define the different NCGS subgroup.
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Affiliation(s)
- Pasquale Mansueto
- a Internal Medicine, University Hospital of Palermo , Palermo , ITALY
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Rauhavirta T, Lindfors K, Koskinen O, Laurila K, Kurppa K, Saavalainen P, Mäki M, Collin P, Kaukinen K. Impaired epithelial integrity in the duodenal mucosa in early stages of celiac disease. Transl Res 2014; 164:223-31. [PMID: 25005738 DOI: 10.1016/j.trsl.2014.02.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2013] [Revised: 02/25/2014] [Accepted: 02/25/2014] [Indexed: 02/08/2023]
Abstract
The small-bowel mucosal damage characteristic of celiac disease (CD) develops from normal villus morphology to inflammation and finally to villus atrophy with crypt hyperplasia. Patients with early stage CD may already suffer from abdominal symptoms before the development of villus atrophy. Although epithelial junctional integrity is compromised in overt disease, the appearance of such changes in early phases of the disorder is not known. We investigated whether alterations in epithelial junction protein expression occur already in early stage CD with normal mucosal morphology, and whether this correlates with inflammation indicators and clinical symptoms. The study involved 10 patients with early stage and 10 patients with overt villus atrophy that were followed yearly according to the study protocol. As controls, 20 nonceliac subjects were included. The expression of junction proteins (occludin, claudin 3, zonula occludens 1, and E-cadherin) was studied in small-intestinal biopsies using immunohistochemistry and Western blot. The correlation between junctional proteins and mucosal morphology, autoantibodies, the number of intraepithelial lymphocytes (IELs), and gastrointestinal symptoms was assessed. The expression of all junction proteins was already decreased in early stage CD when compared with nonceliac controls (P < 0.05). Junction protein expression correlated positively with mucosal villus morphology and negatively with the number of IELs, the intensity of small-intestinal autoantibody deposits, and serum autoantibodies. The expression of claudin 3 showed a negative correlation with diarrheal score (R = -0.314, P = 0.04). These findings show that the mucosal epithelial integrity is disrupted already in early stage CD before the disorder progresses to full-blown enteropathy.
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Affiliation(s)
- Tiina Rauhavirta
- Tampere Center for Child Health Research, University of Tampere and Tampere University Hospital, Tampere, Finland
| | - Katri Lindfors
- Tampere Center for Child Health Research, University of Tampere and Tampere University Hospital, Tampere, Finland.
| | - Outi Koskinen
- School of Medicine, University of Tampere, Tampere, Finland
| | - Kaija Laurila
- Tampere Center for Child Health Research, University of Tampere and Tampere University Hospital, Tampere, Finland
| | - Kalle Kurppa
- Tampere Center for Child Health Research, University of Tampere and Tampere University Hospital, Tampere, Finland
| | - Päivi Saavalainen
- Research Program Unit, Immunology, and Haartman Institute, Department of Medical Genetics, University of Helsinki, Helsinki, Finland
| | - Markku Mäki
- Tampere Center for Child Health Research, University of Tampere and Tampere University Hospital, Tampere, Finland
| | - Pekka Collin
- School of Medicine, University of Tampere, Tampere, Finland; Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland
| | - Katri Kaukinen
- School of Medicine, University of Tampere, Tampere, Finland; Department of Internal Medicine, Tampere University Hospital, Tampere, Finland; Department of Internal Medicine, Seinäjoki Central Hospital, Seinäjoki, Finland
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Cichon C, Sabharwal H, Rüter C, Schmidt MA. MicroRNAs regulate tight junction proteins and modulate epithelial/endothelial barrier functions. Tissue Barriers 2014; 2:e944446. [PMID: 25610754 PMCID: PMC4292042 DOI: 10.4161/21688362.2014.944446] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Accepted: 06/22/2014] [Indexed: 02/06/2023] Open
Abstract
Tightly controlled epithelial and endothelial barriers are a prerequisite for life as these barriers separate multicellular organisms from their environment and serve as first lines of defense. Barriers between neighboring epithelial cells are formed by multiple intercellular junctions including the ‘apical junctional complex—AJC’ with tight junctions (TJ), adherens junctions (AJ), and desmosomes. TJ consist of tetraspan transmembrane proteins like occludin, various claudins that directly control paracellular permeability, and the ‘Junctional Adhesion Molecules’ (JAMs). For establishing tight barriers TJ are essential but at the same time have to allow also selective permeability. For this, TJ need to be tightly regulated and controlled. This is organized by a variety of adaptor molecules, i.e., protein kinases, phosphatases and GTPases, which in turn are regulated and fine-tuned involving microRNAs (miRNAs). In this review we summarize available data on the role and targeting of miRNAs in the maintenance of epithelial and/or endothelial barriers.
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Affiliation(s)
- Christoph Cichon
- Institute of Infectiology-Center for Molecular Biology of Inflammation (ZMBE); University of Münster ; Münster, Germany
| | - Harshana Sabharwal
- Institute of Infectiology-Center for Molecular Biology of Inflammation (ZMBE); University of Münster ; Münster, Germany
| | - Christian Rüter
- Institute of Infectiology-Center for Molecular Biology of Inflammation (ZMBE); University of Münster ; Münster, Germany
| | - M Alexander Schmidt
- Institute of Infectiology-Center for Molecular Biology of Inflammation (ZMBE); University of Münster ; Münster, Germany
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Abstract
OBJECTIVE The aim of the present study was to characterize the deregulation of epithelial tight junction genes and investigate its reversibility on removal of dietary gluten in small intestinal mucosa in celiac disease (CD). METHODS The expression levels of 23 genes related to tight junctions were studied in biopsies from 16 patients with active CD and compared with biopsies from the same patients taken after 2 years on gluten-free diet (GFD) and with 16 non-CD controls. RESULTS Nine genes showed altered expression levels in patients with active disease (CLDN2, PARD6A, ZAK, SYMPK, MYH14, and ACTB were upregulated, whereas MAGI1, TJP1, and PPP2R3A were downregulated). Alterations were reversible after 2 years on treatment, except for PPP2R3A, implicated in the negative control of cell growth and division. At the biological network level, important dysfunctions in several processes within the pathway were observed, including intestinal permeability, apicobasal polarity, and cell proliferation. CONCLUSIONS Our work confirms the involvement of tight junction genes related to permeability, polarity, and cell proliferation in the epithelial destruction observed in CD. Coexpression patterns of several genes support the idea of a common regulatory mechanism that seems to be altered in active CD. In general, GFD normalization confirms the reversibility of the process, except for the constitutive downregulation of PPP2R3A suggestive of a genetic implication. Further studies in proteins and cells or tissues are necessary to confirm these findings.
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Vanheel H, Vicario M, Vanuytsel T, Van Oudenhove L, Martinez C, Keita ÅV, Pardon N, Santos J, Söderholm JD, Tack J, Farré R. Impaired duodenal mucosal integrity and low-grade inflammation in functional dyspepsia. Gut 2014; 63:262-71. [PMID: 23474421 DOI: 10.1136/gutjnl-2012-303857] [Citation(s) in RCA: 310] [Impact Index Per Article: 28.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Functional dyspepsia (FD) is an extremely common functional gastrointestinal disorder, the pathophysiology of which is poorly understood. We hypothesised that impaired intestinal barrier function is involved in the onset and persistence of this disorder by inducing low-grade inflammation. Therefore, our aim was to evaluate duodenal mucosal integrity and low-grade inflammation in patients with FD. DESIGN Duodenal biopsy specimens were obtained from 15 patients with FD fulfilling the Rome III criteria and 15 age- and gender-matched healthy volunteers. Transepithelial electrical resistance (TEER) and paracellular permeability were measured in Ussing chambers. Expression of cell-to-cell adhesion proteins was evaluated by real-time PCR, western blot and/or immunofluorescence. Numbers of mast cells, eosinophils and intraepithelial lymphocytes were assessed by immunohistochemistry. RESULTS Patients with FD displayed lower TEER and increased paracellular passage compared with healthy controls, which is indicative of impaired mucosal integrity. In addition, abnormal expression of cell-to-cell adhesion proteins at the level of tight junctions, adherens junctions and desmosomes was shown. Furthermore, patients were characterised by the presence of low-grade inflammation, as demonstrated by increased infiltration of mucosal mast cells and eosinophils. A significant association between the expression level of several cell-to-cell adhesion proteins, the extent of increased permeability and the severity of low-grade inflammation was found. CONCLUSIONS These findings challenge the classical paradigm that patients with FD show no structural changes in the gastrointestinal tract. We suggest that impaired intestinal barrier function is a pathophysiological mechanism in FD. Thus, restoration of intestinal barrier integrity may be a potential therapeutic target for treating patients with FD.
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Affiliation(s)
- Hanne Vanheel
- Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders, KU Leuven, , Leuven, Belgium
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Abstract
Coeliac disease is a common and fairly well-characterized systemic disorder that mainly affects the small intestine, but also has extraintestinal manifestations. The environmental trigger (gluten derived from wheat, rye and barley), the genetic predisposition conferred by the HLA-DQ2 and HLA-DQ8 haplotypes and many steps in the disease pathogenesis are known. This knowledge has enabled researchers to suggest novel alternative treatments or adjunctive therapies to the gluten-free diet, which is currently the only available and effective treatment for the condition. This Review focuses on emerging and potential treatment strategies that are based on the current concept of the disease pathophysiology. The search for novel future treatment modes, including nonpharmacological and pharmacological approaches, is also outlined. The potential pitfalls associated with the various research avenues are also discussed.
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Nanayakkara M, Kosova R, Lania G, Sarno M, Gaito A, Galatola M, Greco L, Cuomo M, Troncone R, Auricchio S, Auricchio R, Barone MV. A celiac cellular phenotype, with altered LPP sub-cellular distribution, is inducible in controls by the toxic gliadin peptide P31-43. PLoS One 2013; 8:e79763. [PMID: 24278174 PMCID: PMC3838353 DOI: 10.1371/journal.pone.0079763] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2013] [Accepted: 09/27/2013] [Indexed: 12/22/2022] Open
Abstract
Celiac disease (CD) is a frequent inflammatory intestinal disease, with a genetic background, caused by gliadin-containing food. Undigested gliadin peptides P31-43 and P57-68 induce innate and adaptive T cell-mediated immune responses, respectively. Alterations in the cell shape and actin cytoskeleton are present in celiac enterocytes, and gliadin peptides induce actin rearrangements in both the CD mucosa and cell lines. Cell shape is maintained by the actin cytoskeleton and focal adhesions, sites of membrane attachment to the extracellular matrix. The locus of the human Lipoma Preferred Partner (LPP) gene was identified as strongly associated with CD using genome-wide association studies (GWAS). The LPP protein plays an important role in focal adhesion architecture and acts as a transcription factor in the nucleus. In this study, we examined the hypothesis that a constitutive alteration of the cell shape and the cytoskeleton, involving LPP, occurs in a cell compartment far from the main inflammation site in CD fibroblasts from skin explants. We analyzed the cell shape, actin organization, focal adhesion number, focal adhesion proteins, LPP sub-cellular distribution and adhesion to fibronectin of fibroblasts obtained from CD patients on a Gluten-Free Diet (GFD) and controls, without and with treatment with A-gliadin peptide P31-43. We observed a “CD cellular phenotype” in these fibroblasts, characterized by an altered cell shape and actin organization, increased number of focal adhesions, and altered intracellular LPP protein distribution. The treatment of controls fibroblasts with gliadin peptide P31-43 mimics the CD cellular phenotype regarding the cell shape, adhesion capacity, focal adhesion number and LPP sub-cellular distribution, suggesting a close association between these alterations and CD pathogenesis.
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Affiliation(s)
- Merlin Nanayakkara
- Department of Translational Medical Science, University of Naples Federico II, Naples, Italy
- European Laboratory for the Investigation of Food Induced Disease, (ELFID) University of Naples Federico II, Naples, Italy
| | - Roberta Kosova
- Department of Translational Medical Science, University of Naples Federico II, Naples, Italy
- European Laboratory for the Investigation of Food Induced Disease, (ELFID) University of Naples Federico II, Naples, Italy
| | - Giuliana Lania
- Department of Translational Medical Science, University of Naples Federico II, Naples, Italy
- European Laboratory for the Investigation of Food Induced Disease, (ELFID) University of Naples Federico II, Naples, Italy
| | - Marco Sarno
- Department of Translational Medical Science, University of Naples Federico II, Naples, Italy
- European Laboratory for the Investigation of Food Induced Disease, (ELFID) University of Naples Federico II, Naples, Italy
| | - Alessandra Gaito
- Department of Translational Medical Science, University of Naples Federico II, Naples, Italy
- European Laboratory for the Investigation of Food Induced Disease, (ELFID) University of Naples Federico II, Naples, Italy
| | - Martina Galatola
- Department of Translational Medical Science, University of Naples Federico II, Naples, Italy
- European Laboratory for the Investigation of Food Induced Disease, (ELFID) University of Naples Federico II, Naples, Italy
| | - Luigi Greco
- Department of Translational Medical Science, University of Naples Federico II, Naples, Italy
- European Laboratory for the Investigation of Food Induced Disease, (ELFID) University of Naples Federico II, Naples, Italy
| | - Marialaura Cuomo
- Department of Translational Medical Science, University of Naples Federico II, Naples, Italy
- European Laboratory for the Investigation of Food Induced Disease, (ELFID) University of Naples Federico II, Naples, Italy
| | - Riccardo Troncone
- Department of Translational Medical Science, University of Naples Federico II, Naples, Italy
- European Laboratory for the Investigation of Food Induced Disease, (ELFID) University of Naples Federico II, Naples, Italy
| | - Salvatore Auricchio
- Department of Translational Medical Science, University of Naples Federico II, Naples, Italy
- European Laboratory for the Investigation of Food Induced Disease, (ELFID) University of Naples Federico II, Naples, Italy
| | - Renata Auricchio
- Department of Translational Medical Science, University of Naples Federico II, Naples, Italy
- European Laboratory for the Investigation of Food Induced Disease, (ELFID) University of Naples Federico II, Naples, Italy
| | - Maria Vittoria Barone
- Department of Translational Medical Science, University of Naples Federico II, Naples, Italy
- European Laboratory for the Investigation of Food Induced Disease, (ELFID) University of Naples Federico II, Naples, Italy
- * E-mail:
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Mooney PD, Aziz I, Sanders DS. Non-celiac gluten sensitivity: clinical relevance and recommendations for future research. Neurogastroenterol Motil 2013; 25:864-71. [PMID: 23937528 DOI: 10.1111/nmo.12216] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2013] [Accepted: 07/25/2013] [Indexed: 01/30/2023]
Abstract
BACKGROUND There has been increasing interest in the entity of Non-Celiac Gluten Sensitivity (NCGS) in recent years; however, it still remains a controversial topic and its pathogenesis is not well understood. Celiac Disease, in contrast, is a well-studied condition that has become increasingly recognized as a prevalent condition arising from a heightened immunological response to gluten. Wheat allergy is an IgE-mediated condition capable of causing a variety of gastrointestinal symptoms. However, the number of patients who have neither celiac disease nor wheat allergy, but appear to derive benefit from a gluten-free diet, is also increasing substantially. The use of the term NCGS as a way of describing this condition has become increasingly prevalent in recent years. PURPOSE In this review, we will focus on gastrointestinal manifestations of NCGS and discuss the evidence for the condition and its putative pathogenesis. We will discuss areas of controversy and areas for potential future research.
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Affiliation(s)
- P D Mooney
- Regional GI and Liver Unit, Royal Hallamshire Hospital, Sheffield, UK
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Ivanov AI, Naydenov NG. Dynamics and regulation of epithelial adherens junctions: recent discoveries and controversies. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2013; 303:27-99. [PMID: 23445808 DOI: 10.1016/b978-0-12-407697-6.00002-7] [Citation(s) in RCA: 92] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Adherens junctions (AJs) are evolutionarily conserved plasma-membrane structures that mediate cell-cell adhesions in multicellular organisms. They are organized by several types of adhesive integral membrane proteins, most notably cadherins and nectins that are clustered and stabilized by a number of cytoplasmic scaffolds. AJs are key regulators of tissue architecture and dynamics via control of cell proliferation, polarity, shape, motility, and survival. They are absolutely critical for normal tissue morphogenesis and their disruption results in pathological abnormalities in different tissues. Although the field of adherens-junction research dramatically progressed in recent years, a number of important questions remain controversial and poorly understood. This review outlines basic principles that regulate organization of AJs in mammalian epithelia and discusses recent advances and standing controversies in the field. A special attention is paid to the regulation of AJs by vesicle trafficking and the intracellular cytoskeleton as well as roles and mechanisms of adherens-junction disruption during tumor progression and tissue inflammation.
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Affiliation(s)
- Andrei I Ivanov
- Department of Human and Molecular Genetics, Virginia Institute of Molecular Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
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