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Bose D. Introduction to Nutrition and Autoimmune Diseases. ADVANCES IN MEDICAL DIAGNOSIS, TREATMENT, AND CARE 2024:415-431. [DOI: 10.4018/979-8-3693-5528-2.ch015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Celiac disease is an autoimmune hereditary disorder that occurs in genetically predisposed people where the ingestion of gluten leads to damage in their small intestine. When people with celiac disease consume gluten, their body mounts an immune response that attacks the villi of small intestine, which are small finger like projections that promote nutrient absorption. A damaged villi is incapable of absorbing food properly. If left untreated, celiac disease can lead to additional serious health problems. Gluten free diet is the only option to keep the symptoms low. Recently, probiotics have acquired significant attention because of their potential benefits in a wide range of biomedical applications. Thus, administering probiotics as a plausible therapeutic measure for improving the gut health and overall quality of life of patients suffering with this disease is of notable concern. The chapter aims to examine such probiotic applications for patients suffering from celiac disease through comprehensive literature analysis with emphasis on dietary supplements and requirements.
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Abdelfatah SH, Yassin AM, Khattab MS, Abdel-Razek AS, Saad AH. Spirulina platensis as a growth booster for broiler; Insights into their nutritional, molecular, immunohistopathological, and microbiota modulating effects. BMC Vet Res 2024; 20:11. [PMID: 38183085 PMCID: PMC10768351 DOI: 10.1186/s12917-023-03858-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 12/18/2023] [Indexed: 01/07/2024] Open
Abstract
BACKGROUND The present study is designed to assess the effect of adding various doses of Spirulina platensis (SP) on broiler chicken growth performance, gut health, antioxidant biomarkers, cecal microbiota, histopathology, and immunohistochemistry of inducible nitric oxide synthase (iNOS). 240 male Cobb 500 broiler chicks (1 day old) were placed into four groups (sixty birds/group), then each group was further divided into three replicates of 20 chickens each for 35 days. Birds were allocated as follows; the 1st group (G1), the control group, fed on basal diet, the 2nd group (G2): basal diet plus SP (0.1%), the 3rd group (G3): basal diet plus SP (0.3%), and the 4th group (G4): basal diet plus SP (0.5%). RESULTS Throughout the trial (d 1 to 35), SP fortification significantly increased body weight growth (BWG) and feed conversion rate (FCR) (P < 0.05). Bursa considerably increased among the immunological organs in the Spirulina-supplemented groups. Within SP-supplemented groups, there was a substantial increase in catalase activity, blood total antioxidant capacity, jejunal superoxide dismutase (SOD), and glutathione peroxidase (GPX) activity (P < 0.05). Fatty acid binding protein 2 (FABP2), one of the gut barrier health biomarkers, significantly increased in the SP-supplemented groups but the IL-1β gene did not significantly differ across the groups (P < 0.05). Different organs in the control group showed histopathological changes, while the SP-supplemented chicken showed fewer or no signs of these lesions. The control group had higher levels of iNOS expression in the gut than the SP-supplemented groups (p < 0.05). Cecal Lactobacillus count significantly elevated with increasing the rate of SP inclusion rate (p < 0.05). CONCLUSION Supplementing broiler diets with SP, particularly at 0.5%, can improve productivity and profitability by promoting weight increase, feed utilization, antioxidant status, immunity, and gastrointestinal health.
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Affiliation(s)
- Samar H Abdelfatah
- Department of Nutrition and Clinical Nutrition, Faculty of Veterinary Medicine, Cairo, University, Giza, 12211, Egypt
| | - Aya M Yassin
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Cairo University, Giza, 12211, Egypt.
| | - Marwa S Khattab
- Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Giza, 12211, Egypt
| | - Ahmed S Abdel-Razek
- Microbial Chemistry Department, Genetic Engineering and Biotechnology Research Division, National Research Center, Dokki-Giza, Egypt
| | - Adel H Saad
- Nutrition and Clinical Nutrition Department, Faculty of Veterinary Medicine, Matrouh University, Matrouh, Egypt
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Grizzi F, Hegazi MA. Functional foods and celiac disease prevalent in North America and globally. FUNCTIONAL FOODS AND CHRONIC DISEASE 2024:105-114. [DOI: 10.1016/b978-0-323-91747-6.00006-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Di Cristo L, Sabella S. Cell Cultures at the Air-Liquid Interface and Their Application in Cancer Research. Methods Mol Biol 2023; 2645:41-64. [PMID: 37202611 DOI: 10.1007/978-1-0716-3056-3_2] [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] [Indexed: 05/20/2023]
Abstract
Air-liquid interface (ALI) cell cultures are considered a valid tool for the replacement of animals in biomedical research. By mimicking crucial features of the human in vivo epithelial barriers (e.g., lung, intestine, and skin), ALI cell cultures enable proper structural architectures and differentiated functions of normal and diseased tissue barriers. Thereby, ALI models realistically resemble tissue conditions and provide in vivo-like responses. Since their implementation, they are routinely used in several applications, from toxicity testing to cancer research, receiving an appreciable level of acceptance (in some cases a regulatory acceptance) as attractive testing alternatives to animals. In this chapter, an overview of the ALI cell cultures will be presented together with their application in cancer cell culture, highlighting the potential advantages and disadvantages of the model.
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Affiliation(s)
- Luisana Di Cristo
- D3 PharmaChemistry, Nanoregulatory Group, Italian Institute of Technology, Genoa, Italy.
| | - Stefania Sabella
- D3 PharmaChemistry, Nanoregulatory Group, Italian Institute of Technology, Genoa, Italy
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Seroprevalence of Anti-tTg-IgA among Symptomized Celiac Disease Patients and Their Correlation with Rotavirus Infection. BIOMED RESEARCH INTERNATIONAL 2022; 2022:6972624. [PMID: 36193310 PMCID: PMC9526599 DOI: 10.1155/2022/6972624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Revised: 08/12/2022] [Accepted: 08/24/2022] [Indexed: 11/18/2022]
Abstract
Celiac disease (CD) is a chronic inflammatory disorder in the intestinal tract as a response to the use of gluten in genetically predisposed individuals. It is a worldwide problem, with a high prevalence rate in North America. This is a descriptive cross-sectional study involving 1090 samples collected from different hospitals of Rawalpindi and Islamabad, Pakistan, from January 2019 to December 2019. In this study, 1090 blood samples screened for seroprevalence of anti-tTG antibodies in CD symptomatic patients via ELISA (enzyme-linked immunosorbent assay). 1090 fecal samples from the same CD patients were collected and tested for the presence of rotavirus (RV) via ELISA and RT-PCR. Of the 1090 patients tested for seroprevalence of anti-tTG antibodies, 112/1090 (10.3%) were found to be positive. Of the 112 anti-tTG-positive patients, 78/112 (70%) were positive for RV via ELISA and 74/112 (66.1%) were RV positive via RT-PCR. A statistically significant association was reported between rotavirus infection and celiac disease (p˂0.05). Anti-tTG antibodies were higher in age group 6 (12-18 years) patients (18.4%) and at minimum in age group 3 (1-3 years) patients (4.8%). However, there was a statistically insignificant relationship between group age and CD prevalence (p > 0.05). The highest CD prevalence was noted during winter season (19.6%) and the lowest (3.0%) during fall/autumn. Our study findings demonstrate that Pakistan has a high prevalence of CD compared to other studies. Further studies in the fields of environmental risk factors and treatment with more advanced serological and histopathological studies are needed in the future.
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Khoramjoo SM, Kazemifard N, Baradaran Ghavami S, Farmani M, Shahrokh S, Asadzadeh Aghdaei H, Sherkat G, Zali MR. Overview of Three Proliferation Pathways (Wnt, Notch, and Hippo) in Intestine and Immune System and Their Role in Inflammatory Bowel Diseases (IBDs). Front Med (Lausanne) 2022; 9:865131. [PMID: 35677821 PMCID: PMC9170180 DOI: 10.3389/fmed.2022.865131] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 04/14/2022] [Indexed: 12/15/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a disorder, which involves the gastrointestinal (GI) tract consisting Crohn's disease (CD) and ulcerative colitis (UC). The etiology of this disease is not yet clear and, hence, there are numerous medications and treatments for patients with IBD, although a definite and permanent treatment is still missing. Therefore, finding novel therapeutic approaches are vital for curing patients with IBD. In the GI tract, there are various lineages of cells with different roles that their existence is necessary for the barrier function of intestinal epithelial cells (IECs). Therefore, signaling pathways, which manage the hemostasis of cell lineages in intestine, such as Wnt, Notch, and Hippo, could have crucial roles in regulation of barrier function in the intestine. Additionally, these signaling pathways function as a governor of cell growth, tissue homeostasis, and organ size. In patients with IBD, recent studies have revealed that these signaling pathways are dysregulated that it could result in depletion or excess of a cell lineage in the intestine. Moreover, dysregulation of these signaling pathways in different cell lineages of the immune system could lead to dysregulation of the immune system's responses in IBD. In this article, we summarized the components and signaling of Wnt, Notch, and Hippo pathways and their role in the intestine and immune system. Furthermore, we reviewed latest scientific literature on the crosstalk among these three signaling pathways in IBD. An overview of these three signaling pathways and their interactions in IBD could provide a novel insight for prospective study directions into finding efficient medications or treatments.
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Affiliation(s)
- Seyed Mobin Khoramjoo
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nesa Kazemifard
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shaghayegh Baradaran Ghavami
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- *Correspondence: Shaghayegh Baradaran Ghavami
| | - Maryam Farmani
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shabnam Shahrokh
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ghazal Sherkat
- Faculty of Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Asrani P, Ali A, Tiwari K. Millets as an alternative diet for gluten-sensitive individuals: A critical review on nutritional components, sensitivities and popularity of wheat and millets among consumers. FOOD REVIEWS INTERNATIONAL 2022. [DOI: 10.1080/87559129.2021.2012790] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Purva Asrani
- Indian Council of Agricultural Research, National Institute for Plant Biotechnology, New Delhi, India
| | - Ansheef Ali
- Division of Biochemistry, Indian Agricultural Research Institute, New Delhi, India
| | - Keshav Tiwari
- Indian Council of Agricultural Research, National Institute for Plant Biotechnology, New Delhi, India
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Maes M, Kubera M, Kotańska M. Aberrations in the Cross-Talks Among Redox, Nuclear Factor-κB, and Wnt/β-Catenin Pathway Signaling Underpin Myalgic Encephalomyelitis and Chronic Fatigue Syndrome. Front Psychiatry 2022; 13:822382. [PMID: 35599774 PMCID: PMC9120845 DOI: 10.3389/fpsyt.2022.822382] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 03/23/2022] [Indexed: 01/07/2023] Open
Abstract
There is evidence that chronic fatigue spectrum disorders (CFAS-Ds), including myalgic encephalomyelitis (ME), chronic fatigue syndrome (CFS), and chronic fatigue with physiosomatic symptoms including when due to comorbid medical disease, are characterized by neuroimmune and neuro-oxidative biomarkers. This study was performed to delineate the protein-protein interaction (PPI) network of CFAS-D and to discover the pathways, molecular patterns, and domains enriched in their PPI network. We performed network, enrichment, and annotation analyses using differentially expressed proteins and metabolics, which were established in patients with CFAS-D. The PPI network analysis revealed that the backbone of the highly connective CFAS-D network comprises NFKB1, CTNNB1, ALB, peroxides, NOS2, tumor necrosis factor (TNF), and interleukin-6 (IL-6) and that the network comprises interconnected immune-oxidative-nitrosative and Wnt/β-catenin subnetworks. Multiomics enrichment analysis shows that the CFAS-D network is highly significantly associated with cellular (antioxidant) detoxification, hydrogen peroxide metabolic process, peroxidase and oxidoreductase activity, interleukin-10 (IL-10) anti-inflammatory signaling and neurodegenerative canonical Wnt, the β-catenin complex, cadherin domains, cell-cell junctions and TLR2/4 pathways, and the transcription factors nuclear factor kappa B (NF-κB) and RELA. The top 10 DOID annotations of the CFAS-D network include four intestinal, three immune system disorders, cancer, and infectious disease. The custom Gene Ontology (GO) term annotation analysis revealed that the CFAS-D network is associated with a response to a toxic substance, lipopolysaccharides, bacterium, or virus. In conclusion, CFAS-D may be triggered by a variety of stimuli and their effects are mediated by aberrations in the cross-talks between redox, NF-κB, and Wnt/β-catenin signaling pathways leading to dysfunctions in multicellular organismal homeostatic processes.
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Affiliation(s)
- Michael Maes
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.,Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria.,IMPACT Strategic Research Center, Deakin University, Geelong, VIC, Australia
| | - Marta Kubera
- Laboratory of Immunoendocrinology, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
| | - Magdalena Kotańska
- Department of Pharmacological Screening, Medical College, Jagiellonian University, Kraków, Poland
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Azpiroz MA, Orguilia L, Palacio MI, Malpartida A, Mayol S, Mor G, Gutiérrez G. Potential biomarkers of infertility associated with microbiome imbalances. Am J Reprod Immunol 2021; 86:e13438. [PMID: 33960055 PMCID: PMC8464490 DOI: 10.1111/aji.13438] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 04/28/2021] [Accepted: 05/03/2021] [Indexed: 12/13/2022] Open
Abstract
PROBLEM The aim of this study was to investigate the possible relationship between vaginal/rectal microbiome disbalances and miRNA expression with infertility. METHOD OF STUDY Observational, exploratory, preliminary study. A total of 287 multiple IVF failure infertile patients were recruited. Twenty fertile women, not IVF failure, were recruited as the control group. Swab samples were collected from the vagina and rectum. Microbial composition by NGS and miRNA expression by real-time PCR of vaginal and rectal samples was measured. Immunometabolic markers from blood (insulin, vitamin D, LDL-cholesterol, ANA, TPO, Tg, and ASCA antibodies) and saliva (sIgA) were analyzed. RESULT(S) Infertile patients showed a lower bacterial richness and increased Firmicutes/Bacteroidetes ratio at rectal level and an increased Lactobacillus brevis/Lactobacillus iners ratio in vaginal samples regarding the fertile group. In the same rectal swab samples, we found that miR-21-5p, which is associated with tight junction disruption and yeast overgrowth, is upregulated and that miR-155-5p, which is associated with inflammation, is overexpressed in the unexplained infertile group (*p < .05). These deregulated miRNAs were also upregulated in the vaginal samples from the same patients (*p < .05). CONCLUSION miRNAs could be potential biomarkers of the inflammatory impact of microbiome disbalances in unexplained infertile women.
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Affiliation(s)
| | - Lucila Orguilia
- Inmunogenesis, Buenos Aires, Argentina
- CONICET, Buenos Aires, Argentina
| | | | | | | | - Gil Mor
- Wayne State University, Detroit, MI, USA
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Voigt RM, Raeisi S, Yang J, Leurgans S, Forsyth CB, Buchman AS, Bennett DA, Keshavarzian A. Systemic brain derived neurotrophic factor but not intestinal barrier integrity is associated with cognitive decline and incident Alzheimer's disease. PLoS One 2021; 16:e0240342. [PMID: 33661922 PMCID: PMC7932071 DOI: 10.1371/journal.pone.0240342] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 02/15/2021] [Indexed: 11/19/2022] Open
Abstract
The inflammatory hypothesis posits that sustained neuroinflammation is sufficient to induce neurodegeneration and the development of Alzheimer's disease (AD) and Alzheimer's dementia. One potential source of inflammation is the intestine which harbors pro-inflammatory microorganisms capable of promoting neuroinflammation. Systemic inflammation is robustly associated with neuroinflammation as well as low levels of brain derived neurotrophic factor (BDNF) in the systemic circulation and brain. Thus, in this pilot study, we tested the hypothesis that intestinal barrier dysfunction precedes risk of death, incident AD dementia and MCI, cognitive impairment and neuropathology. Serum BDNF was associated with changes in global cognition, working memory, and perceptual speed but not risk of death, incident AD dementia, incident MCI, or neuropathology. Neither of the markers of intestinal barrier integrity examined, including lipopolysaccharide binding protein (LBP) nor intestinal fatty acid binding protein (IFABP), were associated with risk of death, incident AD dementia, incident mild cognitive impairment (MCI), change in cognition (global or domains), or neuropathology. Taken together, the data in this pilot study suggest that intestinal barrier dysfunction does not precede diagnosis of AD or MCI, changes in cognition, or brain pathology. However, since MCI and AD are related to global cognition, the findings with BDNF and the contiguous cognitive measures suggest low power with the trichotomous cognitive status measures. Future studies with larger sample sizes are necessary to further investigate the results from this pilot study.
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Affiliation(s)
- Robin M. Voigt
- Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, United States of America
- * E-mail:
| | - Shohreh Raeisi
- Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, United States of America
| | - Jingyun Yang
- Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois, United States of America
- Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, United States of America
| | - Sue Leurgans
- Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois, United States of America
- Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, United States of America
| | - Christopher B. Forsyth
- Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, United States of America
| | - Aron S. Buchman
- Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois, United States of America
- Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, United States of America
| | - David A. Bennett
- Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois, United States of America
- Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, United States of America
| | - Ali Keshavarzian
- Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, United States of America
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Xie Z, Wang Y, Yang G, Han J, Zhu L, Li L, Zhang S. The role of the Hippo pathway in the pathogenesis of inflammatory bowel disease. Cell Death Dis 2021; 12:79. [PMID: 33436549 PMCID: PMC7804279 DOI: 10.1038/s41419-021-03395-3] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 12/24/2020] [Accepted: 12/28/2020] [Indexed: 01/29/2023]
Abstract
Inflammatory bowel disease (IBD) is a chronic and recurrent inflammatory disorder that primarily comprises Crohn's disease (CD) and ulcerative colitis (UC). Owing to its increasing prevalence in Eastern countries and the intractable challenges faced during IBD treatment, extensive research on IBD has been carried out over the last few years. Although the precise aetiology of IBD is undefined, the currently accepted hypothesis for IBD pathogenesis considers it to be a combination of environment, genetic predisposition, gut microbiota, and abnormal immunity. A recently emerged signalling pathway, the Hippo pathway, acts as a key regulator of cell growth, tissue homoeostasis, organ size, and has been implicated in several human cancers. In the past few years, studies have revealed the importance of the Hippo pathway in gastrointestinal tract physiology and gastrointestinal diseases, such as colorectal cancer and IBD. However, the role of the Hippo pathway and its exact impact in IBD remains to be elucidated. This review summarises the latest scientific literature on the involvement of this pathway in IBD from the following perspectives that account for the IBD pathogenesis: intestinal epithelial cell regeneration, immune regulation, gut microbiota, and angiogenesis. A comprehensive understanding of the specific role of the Hippo pathway in IBD will provide novel insights into future research directions and clinical implications of the Hippo pathway.
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Affiliation(s)
- Zhuo Xie
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Ying Wang
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Guang Yang
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Jing Han
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Liguo Zhu
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Li Li
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Shenghong Zhang
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.
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Duodenal acidification induces gastric relaxation and alters epithelial barrier function by a mast cell independent mechanism. Sci Rep 2020; 10:17448. [PMID: 33060783 PMCID: PMC7562901 DOI: 10.1038/s41598-020-74491-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 09/30/2020] [Indexed: 01/19/2023] Open
Abstract
Duodenal hyperpermeability and low-grade inflammation in functional dyspepsia is potentially related to duodenal acid exposure. We aimed to evaluate in healthy volunteers the involvement of mast cell activation on the duodenogastric reflex and epithelial integrity during duodenal acidification. This study consisted of 2 parts: (1) Duodenal infusion of acid or saline during thirty minutes in a randomized, double-blind cross-over manner with measurement of intragastric pressure (IGP) using high resolution manometry and collection of duodenal biopsies to measure epithelial barrier function and the expression of cell-to-cell adhesion proteins. Mast cells and eosinophils were counted and activation and degranulation status were assessed. (2) Oral treatment with placebo or mast cell stabilizer disodiumcromoglycate (DSCG) prior to duodenal perfusion with acid, followed by the procedures described above. Compared with saline, acidification resulted in lower IGP (P < 0.01), increased duodenal permeability (P < 0.01) and lower protein expression of claudin-3 (P < 0.001). Protein expression of tryptase (P < 0.001) was increased after acid perfusion. Nevertheless, an ultrastructural examination did not reveal degranulation of mast cells. DSCG did not modify the drop in IGP and barrier dysfunction induced by acid. Duodenal acidification activates an inhibitory duodenogastric motor reflex and, impairs epithelial integrity in healthy volunteers. However, these acid mediated effects occur independently from mast cell activation.
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13
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Intestinal stem cells and intestinal organoids. J Genet Genomics 2020; 47:289-299. [PMID: 32883604 DOI: 10.1016/j.jgg.2020.06.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 06/15/2020] [Accepted: 06/25/2020] [Indexed: 01/15/2023]
Abstract
The intestinal epithelium is one of the most rapidly renewing tissues, which is fueled by stem cells at the base of the crypts. Strategies of genetic lineage tracing and organoids, which capture major features of original tissues, are powerful avenues for exploring the biology of intestinal stem cells in vivo and in vitro, respectively. The combination of intestinal organoid-culturing system and genetic modification approaches provides an attractive platform to uncover the mechanism of colorectal cancer and genetic disorders in the human minigut. Here, we will provide a comprehensive overview of studies on intestinal epithelium and intestinal stem cells. We will also review the applications of organoids and genetic markers in intestinal research studies. Furthermore, we will discuss the advantages and drawbacks of organoids as disease models compared with mice models and cell lines.
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Arreguin-Nava MA, Hernández-Patlán D, Solis-Cruz B, Latorre JD, Hernandez-Velasco X, Tellez G, El-Ashram S, Hargis BM, Tellez-Isaias G. Isolation and Identification of Lactic Acid Bacteria Probiotic Culture Candidates for the Treatment of Salmonella enterica Serovar Enteritidis in Neonatal Turkey Poults. Animals (Basel) 2019; 9:ani9090696. [PMID: 31533370 PMCID: PMC6770488 DOI: 10.3390/ani9090696] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 08/28/2019] [Accepted: 09/16/2019] [Indexed: 12/16/2022] Open
Abstract
The effect of Lactobacillus spp.-based probiotic candidates on Salmonella enterica serovar Enteritidis (SE) colonization was evaluated in two separate experiments. In each experiment, sixty-one day-of-hatch female turkey poults were obtained from a local hatchery. In both experiments, poults were challenged via oral gavage with 104 cfu/poult of SE and randomly allocated to one of two groups (n = 30 poults): (1) the positive control group and (2) the probiotic treated group. Heated brooder batteries were used for housing each group separately and poults were allowed ad libitum access to water and unmedicated turkey starter feed. 1 h following the SE challenge, poults were treated with 106 cfu/poult of probiotic culture via oral gavage or phosphate-buffered saline （PBS）to control groups. A total of 24 h post-treatment, poults were euthanized and the ceca and cecal tonsils from twenty poults were collected aseptically for SE recovery. In both trials, a significant reduction in the incidence and log10 cfu/g of SE were observed in poults treated with the probiotic when compared with control poults (p ≤ 0.05). The results of the present study suggest that the administration of this lactic acid-producing bacteria (LAB)-based probiotic 1 h after an SE challenge can be useful in reducing the cecal colonization of this pathogen in neonatal poults.
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Affiliation(s)
| | - Daniel Hernández-Patlán
- Laboratorio 5: LEDEFAR, Unidad de Investigación Multidisciplinaria, Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de México (UNAM), Cuautitlán Izcalli Estado de México 54714, Mexico; (D.H.-P.); (B.S.-C.)
| | - Bruno Solis-Cruz
- Laboratorio 5: LEDEFAR, Unidad de Investigación Multidisciplinaria, Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de México (UNAM), Cuautitlán Izcalli Estado de México 54714, Mexico; (D.H.-P.); (B.S.-C.)
| | - Juan D. Latorre
- Department of Poultry Science, University of Arkansas, Fayetteville, AR 72701, USA; (J.D.L.); (B.M.H.)
| | - Xochitl Hernandez-Velasco
- Departamento de Medicina y Zootecnia de Aves, Facultad de Medicina Veterinaria y Zootecnia, UNAM, Cd. de Mexico 04510, Mexico;
| | - Guillermo Tellez
- Department of Poultry Science, University of Arkansas, Fayetteville, AR 72701, USA; (J.D.L.); (B.M.H.)
| | - Saeed El-Ashram
- School of Life Science and Engineering, Foshan University, Foshan 528231, Guangdong, China;
- Faculty of Science, Kafrelsheikh University, Kafr el-Sheikh 33516, Egypt
| | - Billy M. Hargis
- Department of Poultry Science, University of Arkansas, Fayetteville, AR 72701, USA; (J.D.L.); (B.M.H.)
| | - Guillermo Tellez-Isaias
- Department of Poultry Science, University of Arkansas, Fayetteville, AR 72701, USA; (J.D.L.); (B.M.H.)
- Correspondence:
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15
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Zhao DY, Qi QQ, Long X, Li X, Chen FX, Yu YB, Zuo XL. Ultrastructure of intestinal mucosa in diarrhea-predominant irritable bowel syndrome. Physiol Int 2019; 106:225-235. [PMID: 31560236 DOI: 10.1556/2060.106.2019.20] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
OBJECTIVES Impaired intestinal barrier function has been demonstrated in the pathophysiology of diarrhea-predominant irritable bowel syndrome (IBS-D). This study aimed to describe the intestinal ultrastructural findings in the intestinal mucosal layer of IBS-D patients. METHODS In total, 10 healthy controls and 10 IBS-D patients were analyzed in this study. The mucosa of each patient's rectosigmoid colon was first assessed by confocal laser endomicroscopy (CLE); next, biopsied specimens of these sites were obtained. Intestinal tissues of IBS-D patients and healthy volunteers were examined to observe cellular changes by transmission electron microscopy (TEM). RESULTS CLE showed no visible epithelial damage or inflammatory changes in the colonic mucosa of IBS-D compared with healthy volunteers. On transmission electron microscopic examination, patients with IBS-D displayed a larger apical intercellular distance with a higher proportion of dilated (>20 nm) intercellular junctional complexes, which was indicative of impaired mucosal integrity. In addition, microvillus exfoliation, extracellular vesicle as well as increased presence of multivesicular bodies were visible in IBS-D patients. Single epithelial cells appeared necrotic, as characterized by cytoplasmic vacuolization, cytoplasmic swelling, and presence of autolysosome. A significant association between bowel habit, frequency of abdominal pain, and enlarged intercellular distance was found. CONCLUSION This study showed ultrastructural alterations in the architecture of intestinal epithelial cells and intercellular junctional complexes in IBS-D patients, potentially representing a pathophysiological mechanism in IBS-D.
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Affiliation(s)
- D-Y Zhao
- Department of Gastroenterology, Puyang Oilfield General Hospital, Puyang, P. R. China
| | - Q-Q Qi
- Department of Gastroenterology, Qilu Hospital, Shandong University, Shandong Province, P. R. China
| | - X Long
- Department of Gastroenterology, Qilu Hospital, Shandong University, Shandong Province, P. R. China
| | - X Li
- Department of Gastroenterology, Qilu Hospital, Shandong University, Shandong Province, P. R. China
| | - F-X Chen
- Department of Gastroenterology, Qilu Hospital, Shandong University, Shandong Province, P. R. China
| | - Y-B Yu
- Department of Gastroenterology, Qilu Hospital, Shandong University, Shandong Province, P. R. China
| | - X-L Zuo
- Department of Gastroenterology, Qilu Hospital, Shandong University, Shandong Province, P. R. China
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16
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López-Santiago R, Sánchez-Argáez AB, De Alba-Núñez LG, Baltierra-Uribe SL, Moreno-Lafont MC. Immune Response to Mucosal Brucella Infection. Front Immunol 2019; 10:1759. [PMID: 31481953 PMCID: PMC6710357 DOI: 10.3389/fimmu.2019.01759] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Accepted: 07/11/2019] [Indexed: 01/18/2023] Open
Abstract
Brucellosis is one of the most prevalent bacterial zoonosis of worldwide distribution. The disease is caused by Brucella spp., facultative intracellular pathogens. Brucellosis in animals results in abortion of fetuses, while in humans, it frequently manifests flu-like symptoms and a typical undulant fever, being osteoarthritis a common complication of the chronic infection. The two most common ways to acquire the infection in humans are through the ingestion of contaminated dairy products or by inhalation of contaminated aerosols. Brucella spp. enter the body mainly through the gastrointestinal and respiratory mucosa; however, most studies of immune response to Brucella spp. are performed analyzing models of systemic immunity. It is necessary to better understand the mucosal immune response induced by Brucella infection since this is the main entry site for the bacterium. In this review, some virulence factors and the mechanisms needed for pathogen invasion and persistence are discussed. Furthermore, some aspects of local immune responses induced during Brucella infection will be reviewed. With this knowledge, better vaccines can be designed focused on inducing protective mucosal immune response.
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Affiliation(s)
- Rubén López-Santiago
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Ana Beatriz Sánchez-Argáez
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Liliana Gabriela De Alba-Núñez
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico
| | | | - Martha Cecilia Moreno-Lafont
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico
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Combined Exposure of Activated Intestinal Epithelial Cells to Nondigestible Oligosaccharides and CpG-ODN Suppresses Th2-Associated CCL22 Release While Enhancing Galectin-9, TGF β, and Th1 Polarization. Mediators Inflamm 2019; 2019:8456829. [PMID: 31427886 PMCID: PMC6683774 DOI: 10.1155/2019/8456829] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 04/22/2019] [Accepted: 06/08/2019] [Indexed: 12/18/2022] Open
Abstract
Background Short-chain galacto- and long-chain fructo-oligosaccharides (scGOS/lcFOS) and CpG-ODN affect intestinal epithelial cells (IEC). Epithelial IL1α may contribute to allergic sensitization via autocrine mediator release affecting dendritic cells (DC). We studied whether IL1α contributes to Th2-associated mediator release by activated IEC and IEC/DC cocultures and possible modulation by scGOS/lcFOS±CpG-ODN. Methods Solid phase or transwell cultured IEC were preincubated with IL1α and/or IFNγ/TNFα for 6 h. The transwell IEC were also apically exposed to scGOS/lcFOS±CpG-ODN for 6 h, washed, and re-exposed, while cocultured with immature moDC (ccDC) for 48 h. These ccDC were subsequently added to allogeneic naïve T cells (MLR). IEC- and/or DC-derived mediators and T cell cytokines were measured. Results IL1α tended to enhance IL25 and enhanced IL33 and CCL20 release by IEC, while IL1α or TNFα or IFNγ enhanced CCL22. These were all further increased upon combined exposure of IFNγ/TNFα±IL1α coinciding with increased IL33 secretion in the solid phase culture. In the transwell, IL25 and IL33 remained under detection, while CCL20 and CCL22 were induced by IL1α or IFNγ/TNFα, respectively, and a synergistic increase was observed upon combined exposure of IFNγ/TNFα and IL1α. Furthermore, IFNγ was found to enhance galectin-9 secretion, which was more pronounced in IFNγ/TNFα±IL1α-exposed IEC and coincided with TGFβ increase. Epithelial CpG-ODN exposure further increased CCL20, while reducing CCL22 release by IFNγ/TNFα/IL1α-activated IEC; however, scGOS/lcFOS suppressed both. Combined scGOS/lcFOS and CpG-ODN reduced CCL22, while CCL20 and regulatory galectin-9 and TGFβ remained high in the supernatant of IFNγ/TNFα/IL1α-activated IEC and the following IEC/DC coculture. ccDC of scGOS/lcFOS- and CpG-ODN-exposed IFNγ/TNFα/IL1α-activated IEC increased IFNγ, IL10, TGFβ, and galectin-9 secretion in the MLR compared to ccDC exposed to control-activated IEC. Conclusion IL1α enhanced CCL20 and Th2-associated CCL22 release by IFNγ/TNFα-activated IEC. Combined scGOS/lcFOS and CpG-ODN exposure suppressed CCL22, while maintaining high CCL20, TGFβ, and galectin-9 concentrations. In addition, ccDC derived from this IEC/DC coculture enhanced Th1 and regulatory mediator secretion mimicking known in vivo effects.
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18
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Slaymi C, Vignal E, Crès G, Roux P, Blangy A, Raynaud P, Fort P. The atypical RhoU/Wrch1 Rho GTPase controls cell proliferation and apoptosis in the gut epithelium. Biol Cell 2019; 111:121-141. [PMID: 30834544 DOI: 10.1111/boc.201800062] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 01/07/2019] [Accepted: 02/07/2019] [Indexed: 01/07/2023]
Abstract
BACKGROUND The mammalian gut epithelium displays among the highest rates of self-renewal, with a turnover time of less than 5 days. Renewal involves concerted proliferation at the bottom of the crypt, migration and differentiation along the crypt-villus axis and anoïkis/shedding in the luminal epithelium. Renewal is controlled by interplay between signalling pathways, among which canonical and non-canonical Wnt signals play prominent roles. Overall 92% of colon tumours show increased canonical Wnt signalling resulting from mutations, established as major driver steps towards carcinogenesis. RESULTS Here, we examined the physiological role of RhoU/Wrch1 in gut homeostasis. RhoU is an atypical Rho GTPase related to Cdc42/Rac1 and identified as a transcriptional target of non-canonical Wnt signalling. We found that RHOU expression is reduced in human colorectal tumour samples. We show that RhoU is mainly expressed in the differentiated compartment of the gut epithelium. Rhou specific invalidation in the mouse gut elicits cell hyperplasia and is associated in the colon with a highly disorganized luminal epithelium. Hyperplasia affects all cell types in the small intestine and colon and has a higher impact on goblet cells. Hyperplasia is associated with a reduction of apoptosis and an increased proliferation. RhoU knockdown in human DLD-1 colon cancer cells also elicits a higher growth index and reduces cell apoptosis. Last, loss of RhoU function in the mouse gut epithelium or in DLD-1 cells increases RhoA activity and the level of phosphorylated Myosin Light Chain-2, which may functionally link RhoU activity to apoptosis. CONCLUSION RhoU is mostly expressed in the differentiated compartment of the gut. It plays a role in homeostasis as its specific invalidation elicits hyperplasia of all cell types. This mainly results from a reduction of apoptosis, through actomyosin-dependent mechanisms. SIGNIFICANCE RhoU negatively controls cell growth in the intestinal epithelium. Since its expression is sensitive to non-canonical Wnt signals and is reduced in colorectal tumours, downregulating RhoU may thus have an instrumental role in tumour progression.
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Affiliation(s)
- Chaker Slaymi
- CRBM, CNRS, University of Montpellier, 34293, Montpellier CEDEX 5, France
| | - Emmanuel Vignal
- CRBM, CNRS, University of Montpellier, 34293, Montpellier CEDEX 5, France
| | - Gaëlle Crès
- CRBM, CNRS, University of Montpellier, 34293, Montpellier CEDEX 5, France
| | - Pierre Roux
- CRBM, CNRS, University of Montpellier, 34293, Montpellier CEDEX 5, France
| | - Anne Blangy
- CRBM, CNRS, University of Montpellier, 34293, Montpellier CEDEX 5, France
| | - Peggy Raynaud
- CRBM, CNRS, University of Montpellier, 34293, Montpellier CEDEX 5, France
| | - Philippe Fort
- CRBM, CNRS, University of Montpellier, 34293, Montpellier CEDEX 5, France
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19
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Becer E, Hanoğlu DY, Kabadayı H, Hanoğlu A, Vatansever S, Yavuz DÖ, Meriçli F, Meriçli AH. The effect of Colchicum pusillum in human colon cancer cells via Wnt/β-catenin pathway. Gene 2018; 686:213-219. [PMID: 30458290 DOI: 10.1016/j.gene.2018.11.047] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Revised: 10/29/2018] [Accepted: 11/15/2018] [Indexed: 10/27/2022]
Abstract
OBJECTIVE Colchicum pusillum belongs to the family Colchicaceae that particularly rich in tropolonic alkaloids. The aim of this study was to investigate the cytotoxicity and in vitro anticancer activity of Colchicum pusillum ethanolic extract on Colo-320 primer and Colo-741 metastatic colon adenocarcinoma cell lines. MATERIALS AND METHODS Colchicum pusillum was collected and extracted with ethanol. Different concentrations of Colchicum pusillum extract were incubated for 24 h and 48 h with Colo-320 and Colo-741 cells. Cell growth and cytotoxicity were measured by 3‑(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphenyltetrazolium bromide (MTT) assays. Anticancer and antiproliferative activities of Colchicum pusillum were investigated by immunocytochemistry using antibodies directed against to β-catenin, Ki-67, LGR-5 Ki-67, DKK1, Frizzled-4, Wnt4, Wnt7a and caspase3 in Colo-741 cells. RESULTS All concentrations of Colchicum pusillum extract had toxic effect in Colo-320 cells. Because of this, we used Colchicum pusillum extract at 20 μg/ml for evaluate anticancer activities only in Colo-741 cells. As a result of immunohistochemical staining, β-catenin, LGR-5 and caspase-3 immunoreactivities were significantly increased while Wnt7a immunostaining intensity was decreased in Colo-741 cells. Conclusion We conclude that Colchicum pusillum extract increased β-catenin and LGR-5 via Wnt/β-catenin pathway in colon cancer cells. Interestingly, it decreased other signaling molecule, Wnt7a which is assumed to play protective role during carcinogenesis. Also, it increased significantly caspase-3 immunoreactivity showing that apoptotic pathways were triggered.
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Affiliation(s)
- Eda Becer
- Department of Biochemistry, Faculty of Pharmacy, Near East University, Nicosia, Cyprus; Experimental Health Research Center of Health Sciences, Near East University, Nicosia, Cyprus.
| | - Duygu Yiğit Hanoğlu
- Department of Pharmaceutical Botany, Faculty of Pharmacy, Near East University, Nicosia, Cyprus
| | - Hilal Kabadayı
- Department of Histology and Embryology, Faculty of Medicine, Celal Bayar University, Manisa, Turkey
| | - Azmi Hanoğlu
- Department of Pharmaceutical Botany, Faculty of Pharmacy, Near East University, Nicosia, Cyprus
| | - Seda Vatansever
- Experimental Health Research Center of Health Sciences, Near East University, Nicosia, Cyprus; Department of Histology and Embryology, Faculty of Medicine, Celal Bayar University, Manisa, Turkey
| | - Dudu Özkum Yavuz
- Department of Pharmaceutical Botany, Faculty of Pharmacy, Near East University, Nicosia, Cyprus
| | - Filiz Meriçli
- Department of Pharmacognosy-Phytotherapy, Faculty of Pharmacy, Near East University, Nicosia, Cyprus
| | - Ali Hikmet Meriçli
- Department of Pharmacognosy-Phytotherapy, Faculty of Pharmacy, Near East University, Nicosia, Cyprus
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Acharya P, Kutum R, Pandey R, Mishra A, Saha R, Munjal A, Ahuja V, Mukerji M, Makharia GK. First Degree Relatives of Patients with Celiac Disease Harbour an Intestinal Transcriptomic Signature that Might Protect them from Enterocyte Damage. Clin Transl Gastroenterol 2018; 9:195. [PMID: 30293993 PMCID: PMC6174158 DOI: 10.1038/s41424-018-0059-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Revised: 08/02/2018] [Accepted: 09/08/2018] [Indexed: 12/15/2022] Open
Abstract
INTRODUCTION Celiac disease (CeD) is an autoimmune enteropathy which affects approximately 0.7% of the global population. While first-degree relatives (FDR) of patients with CeD have a 7.5% risk of developing enteropathy, many remain protected. Therefore, intestinal mucosa of FDR might have protective compensatory mechanisms against immunological injury. We have explored the protective mechanisms that may be active in intestinal mucosa of FDR. METHODS Intestinal mucosal biopsies (4-5 pieces) from treatment naïve patients with CeD (n = 12), FDR (n = 12) (anti-tTG negative) and controls (n = 12) (anti-tTG negative) were obtained from each individual and subjected to microarray analysis using HT-12-v4 Human Expression BeadChips (Illumina). Differential gene expression analysis was carried out among CeD, FDR and controls; and resulting gene lists were analyzed using gene ontology and pathway enrichment tools. RESULTS Patients with CeD, FDR and control groups displayed significant differential gene expression. Thirty seven genes were upregulated and 372 were downregulated in the intestinal mucosa of FDR in comparison to CeD and controls. Pseudogenes constituted about 18% (315/1751) of FDR differentially expressed genes, and formed "clusters" that associated uniquely with individual study groups. The three study groups segregated into distinct clusters in unsupervised (PCA) and supervised (random forests) modelling approaches. Pathways analysis revealed an emphasis on crypt-villous maintenance and immune regulation in the intestinal mucosa of FDR. CONCLUSIONS Our analysis suggests that the intestinal mucosa of celiac FDR consist of a unique molecular phenotype that is distinct from CeD and controls. The transcriptomic landscape of FDR promotes maintenance of crypt-villous axis and modulation of immune mechanisms. These differences clearly demonstrate the existence of compensatory protective mechanisms in the FDR intestinal mucosa.
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Affiliation(s)
- Pragyan Acharya
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Rintu Kutum
- Genomics and Molecular Medicine and CSIR-TRISUTRA Ayurgenomics Unit, Council for Scientific and Industrial Research-Institute of Genomics and Integrative Biology, New Delhi, India
- Academy of Scientific and Innovative Research, CSIR-IGIB, Delhi, India
| | - Rajesh Pandey
- Genomics and Molecular Medicine and CSIR-TRISUTRA Ayurgenomics Unit, Council for Scientific and Industrial Research-Institute of Genomics and Integrative Biology, New Delhi, India
- Mammalian Genetics Unit, MRC Harwell Institute, Harwell Science and Innovation Campus, Oxfordshire, OX11 0RD, United Kingdom
| | - Asha Mishra
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Rohini Saha
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Akshay Munjal
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Vineet Ahuja
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Mitali Mukerji
- Genomics and Molecular Medicine and CSIR-TRISUTRA Ayurgenomics Unit, Council for Scientific and Industrial Research-Institute of Genomics and Integrative Biology, New Delhi, India
- Academy of Scientific and Innovative Research, CSIR-IGIB, Delhi, India
| | - Govind K Makharia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, 110029, India.
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Arvidsson Y, Rehammar A, Bergström A, Andersson E, Altiparmak G, Swärd C, Wängberg B, Kristiansson E, Nilsson O. miRNA profiling of small intestinal neuroendocrine tumors defines novel molecular subtypes and identifies miR-375 as a biomarker of patient survival. Mod Pathol 2018; 31:1302-1317. [PMID: 29487354 DOI: 10.1038/s41379-018-0010-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Revised: 12/08/2017] [Accepted: 12/08/2017] [Indexed: 12/30/2022]
Abstract
The aim of this study was to define the miRNA profile of small intestinal neuroendocrine tumors and to search for novel molecular subgroups and prognostic biomarkers. miRNA profiling was conducted on 42 tumors from 37 patients who underwent surgery for small intestinal neuroendocrine tumors. Unsupervised hierarchical clustering analysis of miRNA profiles identified two groups of tumor metastases, denoted cluster M1 and M2. The smaller cluster M1 was associated with shorter overall survival and contained tumors with higher grade (WHO grade G2/3) and multiple chromosomal gains including gain of chromosome 14. Tumors of cluster M1 had elevated expression of miR-1246 and miR-663a, and reduced levels of miR-488-3p. Pathway analysis predicted Wnt signaling to be the most significantly altered signaling pathway between clusters M1 and M2. Analysis of miRNA expression in relation to tumor proliferation rate showed significant alterations including downregulation of miR-137 and miR-204-5p in tumors with Ki67 index above 3%. Similarly, tumor progression was associated with significant alterations in miRNA expression, e.g. higher expression of miR-95 and miR-210, and lower expression of miR-378a-3p in metastases. Pathway analysis predicted Wnt signaling to be altered during tumor progression, which was supported by decreased nuclear translocation of β-catenin in metastases. Survival analysis revealed that downregulation of miR-375 was associated with shorter overall survival. We performed in situ hybridization on biopsies from an independent cohort of small intestinal neuroendocrine tumors using tissue microarrays. Expression of miR-375 was found in 578/635 (91%) biopsies and survival analysis confirmed that there was a correlation between downregulation of miR-375 in tumor metastases and shorter patient survival. We conclude that miRNA profiling defines novel molecular subgroups of metastatic small intestinal neuroendocrine tumors and identifies miRNAs associated with tumor proliferation rate and progression. miR-375 is highly expressed in small intestinal neuroendocrine tumors and may be used as a prognostic biomarker.
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Affiliation(s)
- Yvonne Arvidsson
- Sahlgrenska Cancer Center, Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
| | - Anna Rehammar
- Department of Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden
| | - Anders Bergström
- Sahlgrenska Cancer Center, Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Ellinor Andersson
- Sahlgrenska Cancer Center, Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Gülay Altiparmak
- Sahlgrenska Cancer Center, Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Christina Swärd
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Bo Wängberg
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Erik Kristiansson
- Department of Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden
| | - Ola Nilsson
- Sahlgrenska Cancer Center, Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
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22
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Zhao DY, Zhang WX, Qi QQ, Long X, Li X, Yu YB, Zuo XL. Brain-derived neurotrophic factor modulates intestinal barrier by inhibiting intestinal epithelial cells apoptosis in mice. Physiol Res 2018; 67:475-485. [PMID: 29527912 DOI: 10.33549/physiolres.933641] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
We aimed to investigate the effects of brain-derived neurotrophic factor (BDNF) on apoptosis of intestinal epithelial cells (IECs) and alterations of intestinal barrier integrity using BDNF knock-out mice model. Colonic tissues from BDNF(+/+) mice and BDNF(+/-) mice were prepared for this study. The integrity of colonic mucosa was evaluated by measuring trans-mucosa electrical resistance and tissue conductance in Ussing chamber. The colonic epithelial structure was analyzed by transmission electron microscopy. Apoptosis involvement was determined with TUNEL staining, active caspase-3 immunostaining and Western blotting for the protein expression of active caspase-3, Bax and Bcl-2. The expression levels and distribution of tight junction proteins were evaluated by immunohistochemistry or Western blots. Compared with BDNF(+/+) mice, BDNF(+/-) mice displayed impaired integrity and ultrastructure alterations in their colonic mucosa, which was characterized by diminished microvilli, mitochondrial swelling and epithelial cells apoptosis. Altered intestinal barrier function was linked to excessive apoptosis of IECs demonstrated by the higher proportion of TUNEL-positive apoptotic cells and enhanced caspase activities in BDNF(+/-) mice. Increased expression of Bax and claudin-2 proteins and reduced Bcl-2 and tight junction proteins (occludin, ZO-1 and claudin-1) expression were also detected in the colonic mucosa of BDNF(+/-) mice. BDNF may play a role in the maintenance of intestinal barrier integrity via its anti-apoptotic properties.
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Affiliation(s)
- D Y Zhao
- Department of Gastroenterology, Puyang Oilfield General Hospital, Puyang, China; Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, P.R. China.
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23
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Wu J, Zhong Y, Shen X, Yang K, Cai W. Maternal and early-life vitamin D deficiency enhances allergic reaction in an ovalbumin-sensitized BALB/c mouse model. Food Nutr Res 2018; 62:1401. [PMID: 29881333 PMCID: PMC5985744 DOI: 10.29219/fnr.v62.1401] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Revised: 04/16/2018] [Accepted: 04/17/2018] [Indexed: 12/11/2022] Open
Abstract
Background Recent studies have shown that vitamin D deficiency may contribute to the high prevalence of food allergy but the underlying mechanisms are far from clear. Objective The present study was designed to investigate the effect of maternal and early-life vitamin D deficiency in the development of food allergy. Design BALB/c mice were treated with ovalbumin (OVA) to trigger allergic reactions, under vitamin D-deficient (by maternal and early-life feeding of vitamin D deprived chow diet) or vitamin D-sufficient conditions. Results Increased occurrence and severity of allergic diarrhea as well as decreased rectal temperature were observed after OVA sensitization. For vitamin D deficiency groups, OVA-specific IgE and IL-4 levels were significantly increased, while IFN-γ levels were unchanged. Vitamin D deficiency also attenuated the structure of small intestinal villi and decreased the expression of the tight junction protein between adjacent epithelial cells and the percentages of CD4+CD25+Foxp3+Treg cell in spleen and mesenteric lymph nodes. Conclusions Maternal and early-life vitamin D deficiency have notable influence on the susceptibility to food allergy, which may relate with the reduced population of Treg cell and the dysfunction of intestinal epithelial barrier.
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Affiliation(s)
- Jiang Wu
- Department of Clinical Nutrition, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China, 200092
| | - Yan Zhong
- Department of Clinical Nutrition, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of Nutrition, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiuhua Shen
- Department of Clinical Nutrition, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of Nutrition, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kefeng Yang
- Department of Clinical Nutrition, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of Nutrition, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China, 200092
| | - Wei Cai
- Department of Clinical Nutrition, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of Nutrition, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China, 200092
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Du L, Shen J, Kim JJ, He H, Chen B, Dai N. Impact of gluten consumption in patients with functional dyspepsia: A case-control study. J Gastroenterol Hepatol 2018; 33:128-133. [PMID: 28452428 DOI: 10.1111/jgh.13813] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Revised: 04/13/2017] [Accepted: 04/25/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Dietary factors and immune dysfunction may induce symptoms in patients with functional dyspepsia (FD). The aim of the study was to evaluate whether gluten consumption impacts symptom onset in patients with FD and to evaluate for possible histologic alterations in the duodenum of patients with FD. METHODS We prospectively enrolled 101 patients newly diagnosed with FD and 31 asymptomatic controls. Specific FD symptoms and gluten consumption patterns were evaluated by self-reported questionnaires. Tight junction protein (claudin-1) expression and presence of intraepithelial lymphocyte (IEL) infiltration in the bulb (D1) and second portion (D2) of the duodenum were assessed by immunohistochemistry. RESULTS Wheat bun consumption had higher frequency (P = 0.047) and increased average consumption (P = 0.01) scores in patients with FD compared with the control group. Of the 101 patients with FD, early satiety (P = 0.03) was associated with increased wheat bun consumption frequency score. On histologic evaluation, claudin-1 expression was decreased in D1 (0.003 ± 0.001 vs 0.012 ± 0.002, P = 0.003) and D2 (0.002 ± 0.0004 vs 0.012 ± 0.001, P < 0.001), while duodenal IEL counts were increased in D1 (15.5 ± 7.8 vs 3.1 ± 2.5, P < 0.001) and D2 (20.6 ± 7.7 vs 5.8 ± 3.4, P < 0.001) among patients with FD compared with the control group. Finally, Helicobacter pylori infection was associated with increased IELs in D1 (20.6 ± 7.0 vs 14.2 ± 7.4, P = 0.001) among patients with FD. CONCLUSIONS Among patients with FD, gluten-rich food may lead to symptom onset, specifically early satiety. Intestinal epithelial barrier dysfunction characterized by decreased claudin-1 expression and mucosal immune activation demonstrated by IEL infiltration may contribute to the pathogenesis of FD.
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Affiliation(s)
- Lijun Du
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jinhua Shen
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Department of Gastroenterology, Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang, China
| | - John J Kim
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Division of Gastroenterology, Loma Linda University Medical Center, Loma Linda, California, USA
| | - Huiqin He
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Binrui Chen
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Ning Dai
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
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25
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Gokulan K, Cerniglia CE, Thomas C, Pineiro SA, Khare S. Effects of residual levels of tetracycline on the barrier functions of human intestinal epithelial cells. Food Chem Toxicol 2017; 109:253-263. [DOI: 10.1016/j.fct.2017.09.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Revised: 08/30/2017] [Accepted: 09/02/2017] [Indexed: 12/12/2022]
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26
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Tabung FK, Birmann BM, Epstein MM, Martínez-Maza O, Breen EC, Wu K, Giovannucci EL. Influence of Dietary Patterns on Plasma Soluble CD14, a Surrogate Marker of Gut Barrier Dysfunction. Curr Dev Nutr 2017; 1:e001396. [PMID: 29595830 PMCID: PMC5867900 DOI: 10.3945/cdn.117.001396] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Revised: 07/31/2017] [Accepted: 10/17/2017] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Specific foods and nutrients, including alcohol, may contribute to gut barrier dysfunction. However, to our knowledge, the influence of whole diets is currently unknown. OBJECTIVE We aimed to cross-sectionally investigate associations of dietary patterns with plasma soluble CD14 (sCD14), which is released by macrophages on stimulation with endotoxin and has been used as a marker of gut hyperpermeability. METHODS We used food-frequency questionnaire data collected from 689 women in the Nurses' Health Study and 509 men in the Health Professionals Follow-Up Study. Our principal component analysis identified 2 dietary patterns: "Western" (higher intakes of red meat, processed meat, desserts, and refined grains) and "prudent" (higher intakes of fruits, vegetables, fish, and whole grains). In multivariable-adjusted logistic regression analyses, we estimated ORs and 95% CIs for high (equal to or greater than the median compared with less than the median) sCD14 concentrations in quintiles of each dietary pattern. Using logistic regression, we also investigated the joint association of the Western dietary pattern and alcohol intake or C-reactive protein (CRP) with sCD14 concentrations. RESULTS Western dietary pattern scores were positively associated with sCD14 concentrations (OR: 1.86; 95% CI: 1.24, 2.79; P-trend = 0.0005; comparing extreme quintiles). Analyses of joint associations suggested that the strongest associations with higher sCD14 concentrations were for persons with both high Western pattern scores and high alcohol intake compared with participants with low scores for both (OR: 2.96; 95% CI: 1.61, 5.45) or for participants with both high Western pattern scores and high CRP values compared with those with low scores for both (OR: 4.11; 95% CI: 2.57, 6.58). The prudent pattern was not associated with sCD14 concentrations. CONCLUSIONS Higher consumption of the Western dietary pattern is associated with a marker of macrophage activation and gut hyperpermeability, especially when coupled with high alcohol intake and heightened systemic inflammation. Our findings need confirmation in studies with additional markers of gut barrier dysfunction.
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Affiliation(s)
- Fred K Tabung
- Departments of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA
- Departments of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
| | - Brenda M Birmann
- Departments of Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Mara M Epstein
- Department of Medicine and the Meyers Primary Care Institute, University of Massachusetts Medical School, Worcester, MA
| | - Otoniel Martínez-Maza
- Departments of Obstetrics and Gynecology, Immunology, and Molecular Genetics
- Departments of Microbiology, Immunology, and Molecular Genetics
- Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, CA
| | - Elizabeth C Breen
- Department of Psychiatry and Biobehavioral Sciences, Cousins Center for Psychoneuroimmunology, David Geffen School of Medicine
| | - Kana Wu
- Departments of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA
| | - Edward L Giovannucci
- Departments of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA
- Departments of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
- Departments of Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
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27
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Venkatasubramanian PB, Toydemir G, de Wit N, Saccenti E, Martins Dos Santos VAP, van Baarlen P, Wells JM, Suarez-Diez M, Mes JJ. Use of Microarray Datasets to generate Caco-2-dedicated Networks and to identify Reporter Genes of Specific Pathway Activity. Sci Rep 2017; 7:6778. [PMID: 28755007 PMCID: PMC5533711 DOI: 10.1038/s41598-017-06355-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Accepted: 06/09/2017] [Indexed: 12/30/2022] Open
Abstract
Intestinal epithelial cells, like Caco-2, are commonly used to study the interaction between food, other luminal factors and the host, often supported by microarray analysis to study the changes in gene expression as a result of the exposure. However, no compiled dataset for Caco-2 has ever been initiated and Caco-2-dedicated gene expression networks are barely available. Here, 341 Caco-2-specific microarray samples were collected from public databases and from in-house experiments pertaining to Caco-2 cells exposed to pathogens, probiotics and several food compounds. Using these datasets, a gene functional association network specific for Caco-2 was generated containing 8937 nodes 129711 edges. Two in silico methods, a modified version of biclustering and the new Differential Expression Correlation Analysis, were developed to identify Caco-2-specific gene targets within a pathway of interest. These methods were subsequently applied to the AhR and Nrf2 signalling pathways and altered expression of the predicted target genes was validated by qPCR in Caco-2 cells exposed to coffee extracts, known to activate both AhR and Nrf2 pathways. The datasets and in silico method(s) to identify and predict responsive target genes can be used to more efficiently design experiments to study Caco-2/intestinal epithelial-relevant biological processes.
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Affiliation(s)
| | - Gamze Toydemir
- Alanya Alaaddin Keykubat University, Faculty of Engineering, Food Engineering Department, Kestel-Alanya, 07450, Antalya, Turkey
| | - Nicole de Wit
- Wageningen University & Research, Food & Biobased Research, Bornse Weilanden 9, 6708 WG, Wageningen, The Netherlands
| | - Edoardo Saccenti
- Wageningen University & Research, Systems and Synthetic Biology, Stippeneng 4, 6708 WE, Wageningen, The Netherlands
| | - Vitor A P Martins Dos Santos
- Wageningen University & Research, Systems and Synthetic Biology, Stippeneng 4, 6708 WE, Wageningen, The Netherlands
- LifeGlimmerGmbH, Markelstrasse 38, 12163, Berlin, Germany
| | - Peter van Baarlen
- Wageningen University & Research, Host-Microbe Interactomics, De Elst 1, 6708 WD, Wageningen, The Netherlands
| | - Jerry M Wells
- Wageningen University & Research, Host-Microbe Interactomics, De Elst 1, 6708 WD, Wageningen, The Netherlands
| | - Maria Suarez-Diez
- Wageningen University & Research, Systems and Synthetic Biology, Stippeneng 4, 6708 WE, Wageningen, The Netherlands
| | - Jurriaan J Mes
- Wageningen University & Research, Food & Biobased Research, Bornse Weilanden 9, 6708 WG, Wageningen, The Netherlands.
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Parzanese I, Qehajaj D, Patrinicola F, Aralica M, Chiriva-Internati M, Stifter S, Elli L, Grizzi F. Celiac disease: From pathophysiology to treatment. World J Gastrointest Pathophysiol 2017; 8:27-38. [PMID: 28573065 PMCID: PMC5437500 DOI: 10.4291/wjgp.v8.i2.27] [Citation(s) in RCA: 157] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2016] [Revised: 03/08/2017] [Accepted: 03/23/2017] [Indexed: 02/06/2023] Open
Abstract
Celiac disease, also known as "celiac sprue", is a chronic inflammatory disorder of the small intestine, produced by the ingestion of dietary gluten products in susceptible people. It is a multifactorial disease, including genetic and environmental factors. Environmental trigger is represented by gluten while the genetic predisposition has been identified in the major histocompatibility complex region. Celiac disease is not a rare disorder like previously thought, with a global prevalence around 1%. The reason of its under-recognition is mainly referable to the fact that about half of affected people do not have the classic gastrointestinal symptoms, but they present nonspecific manifestations of nutritional deficiency or have no symptoms at all. Here we review the most recent data concerning epidemiology, pathogenesis, clinical presentation, available diagnostic tests and therapeutic management of celiac disease.
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29
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Shimizu M. Multifunctions of dietary polyphenols in the regulation of intestinal inflammation. J Food Drug Anal 2017; 25:93-99. [PMID: 28911547 PMCID: PMC9333418 DOI: 10.1016/j.jfda.2016.12.003] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Accepted: 07/24/2016] [Indexed: 01/12/2023] Open
Abstract
Food for specified health use is a type of functional food approved by the Japanese government, with more than 1250 products in 10 health-claim categories being approved as of April 2016. Polyphenols are currently used as functional ingredients in seven of the 10 categories. Although they have not yet been used for the food-for-specified-health-use category of “gut health promotion,” polyphenols are expected to contribute to the future development of gut-modulating food. Intestinal functions include digestion/absorption, acting as a barrier, recognition of external factors, and signal transduction. Owing to incessant exposure to external stress factors including food substances, bacteria, and environmental chemicals, intestines are always inflammatory to some extent, which may cause damage to and dysfunction of intestinal tissues depending on the situation. We identified food factors that could suppress immoderate inflammation in the intestines. In addition to certain amino acids and peptides, polyphenols such as chlorogenic acid and isoflavones were found to suppress inflammation in intestinal cells. Intestinal inflammation is caused by various factors in diverse mechanisms. Recent studies revealed that activation of pattern recognition receptors, such as Toll-like receptors and nucleotide-binding oligomerization domain proteins, in epithelial cells triggers intestinal inflammation. Intracellular receptors or signaling molecules controlling the intestinal detoxification system are also involved in the regulation of inflammation. Differentiation of regulatory T cells by activating a transcription factor Foxp-3 is known to suppress intestinal inflammation. A variety of phytochemicals including polyphenols modulate these receptors and signaling molecules, and are thus anti-inflammatory. Polyphenols affect epigenetic changes occurring in intestinal tissues by interacting with the enzymes responsible for DNA methylation and histone acetylation. New types of anti-inflammatory food factors may be discovered by examining dietary substances that interact with the abovementioned target molecules.
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Affiliation(s)
- Makoto Shimizu
- Corresponding author: Department of Applied Bioscience, Tokyo University of Agriculture, Setagaya-ku, Tokyo 156-8502, Japan. E-mail address:
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30
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Moheb-Alian A, Forouzesh F, Rostami-Nejad M, Rostami K. Mesenchymal stem cells as potential therapeutic approaches in celiac disease. GASTROENTEROLOGY AND HEPATOLOGY FROM BED TO BENCH 2016; 9:S1-S7. [PMID: 28224021 PMCID: PMC5310793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
As a chronic immune complication, celiac disease has a broad spectrum of clinical manifestations and gluten ingestion as an external trigger will induce the onset of this disease in genetically predisposed individuals. Because of the complex nature of celiac disease and various cascades of immunological pathways, therapies which are tend to target a single pathway or factor, often have unsatisfactory results. Thus, it should be considered that the new emerging area of cellular therapy by targeting multiple pathways may hold the key for treating celiac affected patients with complicated forms of this disease. The aim of this review is to discuss different pathways which are affected by celiac disease and to compare how various strategies, mainly cellular therapies, can regulate these pathways.
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Affiliation(s)
- Ali Moheb-Alian
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterologyand Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Flora Forouzesh
- Department of Genetics, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran
| | - Mohammad Rostami-Nejad
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kamran Rostami
- Department of Gastroenterology Milton Keynes University Hospital, United Kingdom
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31
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Spadoni I, Pietrelli A, Pesole G, Rescigno M. Gene expression profile of endothelial cells during perturbation of the gut vascular barrier. Gut Microbes 2016; 7:540-548. [PMID: 27723418 PMCID: PMC5153614 DOI: 10.1080/19490976.2016.1239681] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
It has been widely demonstrated that tolerance against gut microbiota is compartmentalized to mucosal sites where microbes mostly reside. How the commensal bacteria are excluded from the entrance into the blood stream via intestinal capillaries that are located beneath the gut epithelium was not clear. We recently described the existence of a new anatomical structure, the 'gut vascular barrier' (GVB), both in murine and human intestines that plays a fundamental role in avoiding indiscriminate trafficking of bacteria from the gut into the blood circulation. The vascular barrier integrity could be altered by Salmonella typhimurium, a pathogen capable of systemic dissemination, through the modulation of the Wnt/β-catenin signaling pathway. Here we have analyzed the differences in gut endothelial gene expression profiles during Salmonella infection and have identified some interesting characteristics of endothelial to mesenchymal transition. These findings add new insights in the gut-liver axis.
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Affiliation(s)
- Ilaria Spadoni
- Department of Experimental Oncology, European
Institute of Oncology, Milan, Italy
| | - Alessandro Pietrelli
- Istituto Nazionale di Genetica Molecolare,
Romeo ed Enrica Invernizzi, Bioinformatic Group, Milan,
Italy,Department of Pathophysiology and
Transplantation, University of Milan, Fondazione IRCCS Ca' Granda Ospedale
Policlinico, Milan, Italy
| | - Graziano Pesole
- Institute of Biomembranes and Bioenergetics,
Consiglio Nazionale delle Ricerche and Department of Biosciences, Biotechnology and
Biopharmaceutics, University of Bari, Bari, Italy
| | - Maria Rescigno
- Department of Experimental Oncology, European
Institute of Oncology, Milan, Italy,Department of Oncology and Hemato-oncology,
University of Milan, Milan, Italy,CONTACT Maria Rescigno, PhD Director of Dendritic cell biology and immunotherapy Unit, Department of
Experimental Oncology, European Institute of Oncology, Via
Adamello, 16, 20139 Milan, Italy
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Anbazhagan AN, Priyamvada S, Gujral T, Bhattacharyya S, Alrefai WA, Dudeja PK, Borthakur A. A novel anti-inflammatory role of GPR120 in intestinal epithelial cells. Am J Physiol Cell Physiol 2016; 310:C612-21. [PMID: 26791484 DOI: 10.1152/ajpcell.00123.2015] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2015] [Accepted: 01/04/2016] [Indexed: 12/14/2022]
Abstract
GPR120 (free fatty acid receptor-4) is a G protein-coupled receptor for medium- and long-chain unsaturated fatty acids, including ω-3 fatty acids. Recent studies have shown GPR120 to play cardinal roles in metabolic disorders via modulation of gut hormone secretion and insulin sensitivity and to exert anti-inflammatory effects in macrophages and adipose tissues. However, information on anti-inflammatory role of GPR120 at the level of intestinal epithelium is very limited. Current studies demonstrated differential levels of GPR120 mRNA and protein along the length of the human, mouse, and rat intestine and delineated distinct anti-inflammatory responses following GPR120 activation in model human intestinal epithelial Caco-2 cells, but not in model mouse intestinal epithelial endocrine cell line STC-1. In Caco-2 cells, GPR120 was internalized, bound to β-arrestin-2, and attenuated NF-κB activation in response to 30-min exposure to the agonists GW9508, TUG-891, or docosahexaenoic acid. These effects were abrogated in response to small interfering RNA silencing of β-arrestin-2. Treatment of STC-1 cells with these agonists did not induce receptor internalization and had no effects on NF-κB activation, although treatment with the agonists GW9508 or TUG-891 for 6 h augmented the synthesis and secretion of the gut hormone glucagon-like peptide-1 in this cell line. Our studies for the first time demonstrated a GPR120-mediated novel anti-inflammatory pathway in specific intestinal epithelial cell types that could be of therapeutic relevance to intestinal inflammatory disorders.
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Affiliation(s)
- Arivarasu N Anbazhagan
- Department of Medicine, Division of Gastroenterology & Hepatology, University of Illinois at Chicago, Chicago, Illinois; and
| | - Shubha Priyamvada
- Department of Medicine, Division of Gastroenterology & Hepatology, University of Illinois at Chicago, Chicago, Illinois; and
| | - Tarunmeet Gujral
- Department of Medicine, Division of Gastroenterology & Hepatology, University of Illinois at Chicago, Chicago, Illinois; and
| | - Sumit Bhattacharyya
- Department of Medicine, Division of Gastroenterology & Hepatology, University of Illinois at Chicago, Chicago, Illinois; and
| | - Waddah A Alrefai
- Department of Medicine, Division of Gastroenterology & Hepatology, University of Illinois at Chicago, Chicago, Illinois; and Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois
| | - Pradeep K Dudeja
- Department of Medicine, Division of Gastroenterology & Hepatology, University of Illinois at Chicago, Chicago, Illinois; and Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois
| | - Alip Borthakur
- Department of Medicine, Division of Gastroenterology & Hepatology, University of Illinois at Chicago, Chicago, Illinois; and
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Tsuji M, Koriyama C, Yamamoto M, Anan A, Shibata E, Kawamoto T. The association between maternal psychological stress and inflammatory cytokines in allergic young children. PeerJ 2016; 4:e1585. [PMID: 26819847 PMCID: PMC4727978 DOI: 10.7717/peerj.1585] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Accepted: 12/18/2015] [Indexed: 11/30/2022] Open
Abstract
Background. Previous studies have shown that psychological stress is linked to asthma prevalence. Parental psychological stress may potentially influence inflammatory responses in their allergic children. The purpose of this study is to clarify the association between maternal psychological status and inflammatory response of allergic young children. Methods. The study subjects were 152 young allergic children (median age: 13 months) who had not shown any allergic symptoms in the past one month. mRNA expression levels of the inflammatory response genes IL-6, IL-8, IL-10 and IL-22 were quantified by qRT-PCR. Maternal psychological status was assessed by standardized questionnaires: the Centre for Epidemiological Studies Depression Scale (CES-D) for depression and the Japanese Perceived Stress Scale (JPSS) for perceived stress. Results. A significant positive association was observed between maternal CES-D scores and IL-6 mRNA expression in the children with asthma. The JPSS scores were also positively associated with IL-8 mRNA expression in asthmatic children and IL-6 mRNA expression in children with allergic rhinitis. Similar trends were observed among children positive for house dust mite-specific IgE, but these associations were not significant. Conclusion. This study supports the hypothesis that maternal psychological stress affects the inflammatory response in their allergic children.
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Affiliation(s)
- Mayumi Tsuji
- Department of Environmental Health, University of Occupational and Environmental Health, Kitakyusyu, Japan; Department of Environmental Toxicology, University of California, Davis, United States
| | - Chihaya Koriyama
- Department of Epidemiology and Preventive Medicine, Kagoshima University , Kagoshima , Japan
| | - Megumi Yamamoto
- Integrated Physiology Section, Department of Basic Medical Science, National Institute for Minamata Disease , Minamata , Japan
| | - Ayumi Anan
- Department of Clinical Nursing, School of Health Sciences, University of Occupational and Environmental Health , Kitakyusyu , Japan
| | - Eiji Shibata
- Department of Obstetrics and Gynecology, University of Occupational and Environmental Health , Kitakyusyu , Japan
| | - Toshihiro Kawamoto
- Department of Environmental Health, University of Occupational and Environmental Health , Kitakyusyu , Japan
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Rasmussen DN, Karstensen JG, Riis LB, Brynskov J, Vilmann P. Confocal Laser Endomicroscopy in Inflammatory Bowel Disease--A Systematic Review. J Crohns Colitis 2015. [PMID: 26209861 DOI: 10.1093/ecco-jcc/jjv131] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Confocal laser endomicroscopy is an endoscopic method that provides in vivo real-time imaging of the mucosa at a cellular level, elucidating mucosal changes that are undetectable by white light endoscopy. This paper systematically reviews current indications and perspectives of confocal laser endomicroscopy for inflammatory bowel disease. METHODS Available literature was searched systematically for studies applying confocal laser endomicroscopy in Crohn's disease or ulcerative colitis. Relevant literature was reviewed and only studies reporting original clinical data were included. Next, eligible studies were analysed with respect to several parameters, such as technique and clinical aim and definitions of outcomes. RESULTS Confocal laser endomicroscopy has been used for a wide range of purposes in inflammatory bowel disease, covering assessment of inflammatory severity, prediction of therapeutic response and relapse and adenoma surveillance in patients with ulcerative colitis. Methods for measurement of the histological changes ranged from subjective grading to objective quantification analysed by computer-aided models. The studies derived their conclusions from assessment of histological features such as colonic crypts, epithelial gaps and epithelial leakiness to fluorescein. CONCLUSIONS Confocal laser endomicroscopy remains an experimental but emerging tool for assessment of inflammatory bowel disease. It is the only method that enables in vivo functional assessment of intestinal barrier function. There is great heterogeneity in the literature and no single approach has been validated and reproduced to the level of general acceptance.
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Affiliation(s)
- Ditlev Nytoft Rasmussen
- Department of Gastroenterology and Gastrointestinal Surgery, Copenhagen University Hospital Hvidovre, Copenhagen, Denmark
| | - John Gásdal Karstensen
- Gastro Unit, Division of Endoscopy, Copenhagen University Hospital Herlev, Copenhagen, Denmark
| | - Lene Buhl Riis
- Department of Pathology, Copenhagen University Hospital Herlev, Copenhagen, Denmark
| | - Jørn Brynskov
- Gastro Unit, Division of Endoscopy, Copenhagen University Hospital Herlev, Copenhagen, Denmark
| | - Peter Vilmann
- Gastro Unit, Division of Endoscopy, Copenhagen University Hospital Herlev, Copenhagen, Denmark
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Besseling-van der Vaart I, Heath MD, Guagnini F, Kramer MF. In vitro evidence for efficacy in food intolerance for the multispecies probiotic formulation Ecologic® Tolerance (Syngut™). Benef Microbes 2015; 7:111-118. [PMID: 26565083 DOI: 10.3920/bm2015.0051] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The beneficial effects of probiotics are currently the subject of extensive studies in health and medical research. The aim of this research was to specifically design a new probiotic formulation for supplementation in people suffering from food intolerance. The selection of strains was focussed on the capacity to influence mechanisms of action that are important in development of food intolerance with the following parameters measure: in vitro capacity to produce β-galactosidase, in vitro strengthening of the epithelial barrier, in vitro stimulation of cytokines produced by regulatory T cells, in addition to assessing fundamental quality criteria (stability, gastrointestinal (GI)-survival, multispecies concept, allergen-free). Ecologic®Tolerance/Syngut™ was subsequently developed consisting of a multispecies concept using 4 different probiotic strains (Bifidobacterium lactis W51, Lactobacillus acidophilus W22, Lactobacillus plantarum W21 and Lactococcus lactis W19). Each of these strains demonstrated ability to survive the GI-tract and strain specific effects in producing β-galactosidase, strengthening the gut barrier function after immunological-induced stress and inhibiting Th2 cytokines (IL-4, IL-5 and IL-13 (≥50%), in addition to stimulating interleukin-10 levels; thus, providing in vitro evidence for the efficacy of the selected strains to provide beneficial effects in patients suffering from food intolerance.
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Affiliation(s)
| | - M D Heath
- 2 Allergy Therapeutics plc., Dominion Way, Worthing, West Sussex BN14 8SA, United Kingdom
| | - F Guagnini
- 3 Allergy Therapeutics Italia, Via IV Novembre 76, 20019 Settimo Milanese, Italy
| | - M F Kramer
- 4 Bencard Allergy GmbH, Messerschmitstrasse 4, 80992 München, Germany
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Faghfoori Z, Pourghassem Gargari B, Saber Gharamaleki A, Bagherpour H, Yari Khosroushahi A. Cellular and molecular mechanisms of probiotics effects on colorectal cancer. J Funct Foods 2015; 18:463-472. [DOI: 10.1016/j.jff.2015.08.013] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Sasada T, Hinoi T, Saito Y, Adachi T, Takakura Y, Kawaguchi Y, Sotomaru Y, Sentani K, Oue N, Yasui W, Ohdan H. Chlorinated Water Modulates the Development of Colorectal Tumors with Chromosomal Instability and Gut Microbiota in Apc-Deficient Mice. PLoS One 2015; 10:e0132435. [PMID: 26186212 PMCID: PMC4505894 DOI: 10.1371/journal.pone.0132435] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Accepted: 06/16/2015] [Indexed: 01/28/2023] Open
Abstract
The gastrointestinal tract is continuously exposed to a variety of chemicals and commensal bacteria. Recent studies have shown that changes in gut microbial populations caused by chlorine or other chemicals in the drinking water influence the development of human colorectal cancer, although the mechanism of tumorigenesis in the gut epithelium is obfuscated by the diversity of microflora and complexity of the tumor microenvironment. In this regard, mouse models that recapitulate human colorectal cancer are an invaluable tool. In this study, we used two conditional adenomatous polyposis coli (Apc) knockout mouse models to investigate the effect of chlorinated water on tumorigenesis in the digestive tract. Mice with colon-specific carcinoma--caused by either chromosomal (CDX2P 9.5-NLS Cre;Apc(+/flox), abbreviated to CPC;Apc) or microsatellite (CDX2P9.5-G19Cre;Apc(flox/flox) and CDX2P9.5-G22Cre;Apc(flox/flox)) instability, respectively--were administered chlorinated (10.0 mg/L chlorine) or tap (0.7 mg/L chlorine) water and evaluated for colon polyp formation. In CPC;Apc mice given chlorinated drinking water, tumors tended to develop in the colon, whereas in those that drank tap water, tumors were mostly observed in the small intestine. There was no difference in the rate of tumor formation of CDX2P9.5-G19Cre;Apc(flox/flox) and CDX2P9.5-G22Cre;Apc(flox/flox) mice consuming chlorinated as compared to tap water, suggesting that microsatellite instability in the Apc gene does not significantly affect tumorigenesis. Chlorinated water altered the enteric environment by reducing the fecal populations of the obligatory anaerobes Clostridium perfringens and C. difficile, as well as species belonging to the Atopobium cluster, including Enterobacteriaceae and Staphylococcus sp., which was associated with colon tumorigenesis in CPC;Apc mice. These results suggest that differences in tumorigenesis among CPC;Apc mice consuming chlorinated versus tap water may be due to differences in gastrointestinal commensal populations.
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Affiliation(s)
- Tatsunari Sasada
- Department of Gastroenterological and Transplant Surgery, Applied Life Science, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takao Hinoi
- Department of Gastroenterological and Transplant Surgery, Applied Life Science, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yasufumi Saito
- Department of Gastroenterological and Transplant Surgery, Applied Life Science, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Tomohiro Adachi
- Department of Gastroenterological and Transplant Surgery, Applied Life Science, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuji Takakura
- Department of Gastroenterological and Transplant Surgery, Applied Life Science, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yasuo Kawaguchi
- Department of Gastroenterological and Transplant Surgery, Applied Life Science, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yusuke Sotomaru
- Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan
| | - Kazuhiro Sentani
- Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan
| | - Naohide Oue
- Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan
| | - Wataru Yasui
- Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Applied Life Science, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
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Jerman UD, Kreft ME, Veranič P. Epithelial-Mesenchymal Interactions in Urinary Bladder and Small Intestine and How to Apply Them in Tissue Engineering. TISSUE ENGINEERING PART B-REVIEWS 2015; 21:521-30. [PMID: 26066408 DOI: 10.1089/ten.teb.2014.0678] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Reciprocal interactions between the epithelium and mesenchyme are essential for the establishment of proper tissue morphology during organogenesis and tissue regeneration as well as for the maintenance of cell differentiation. With this review, we highlight the importance of epithelial-mesenchymal cross talk in healthy tissue and further discuss its significance in engineering functional tissues in vitro. We focus on the urinary bladder and small intestine, organs that are often compromised by disease and are as such in need of research that would advance effective treatment or tissue replacement. To date, the understanding of epithelial-mesenchymal reciprocal interactions has enabled the development of in vitro biomimetic tissue equivalents that have provided many possibilities in treating defective, damaged, or even cancerous tissues. Although research of the past several years has advanced the field of bladder and small intestine tissue engineering, one must be aware of its current limitations in successfully and above all safely introducing tissue-engineered constructs into clinical practice. Special attention is in particular needed when treating cancerous tissues, as initially successful tumor excision and tissue reconstruction may later on result in cancer recurrence due to oncogenic signals originating from an altered stroma. Recent rather poor outcomes in pioneering clinical trials of bladder reconstructions should serve as a reminder that recreating a functional organ to replace a dysfunctional one is an objective far more difficult to reach than initially foreseen. When considering effective tissue engineering approaches for diseased tissues in humans, it is imperative to introduce animal models with dysfunctional or, even more importantly, cancerous organs, which would greatly contribute to predicting possible complications and, hence, reducing risks when translating to the clinic.
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Affiliation(s)
- Urška Dragin Jerman
- Faculty of Medicine, Institute of Cell Biology, University of Ljubljana , Ljubljana, Slovenia
| | - Mateja Erdani Kreft
- Faculty of Medicine, Institute of Cell Biology, University of Ljubljana , Ljubljana, Slovenia
| | - Peter Veranič
- Faculty of Medicine, Institute of Cell Biology, University of Ljubljana , Ljubljana, Slovenia
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Lerner A, Matthias T. Changes in intestinal tight junction permeability associated with industrial food additives explain the rising incidence of autoimmune disease. Autoimmun Rev 2015; 14:479-489. [PMID: 25676324 DOI: 10.1016/j.autrev.2015.01.009] [Citation(s) in RCA: 311] [Impact Index Per Article: 31.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2015] [Accepted: 01/18/2015] [Indexed: 12/11/2022]
Abstract
The incidence of autoimmune diseases is increasing along with the expansion of industrial food processing and food additive consumption. The intestinal epithelial barrier, with its intercellular tight junction, controls the equilibrium between tolerance and immunity to non-self-antigens. As a result, particular attention is being placed on the role of tight junction dysfunction in the pathogenesis of AD. Tight junction leakage is enhanced by many luminal components, commonly used industrial food additives being some of them. Glucose, salt, emulsifiers, organic solvents, gluten, microbial transglutaminase, and nanoparticles are extensively and increasingly used by the food industry, claim the manufacturers, to improve the qualities of food. However, all of the aforementioned additives increase intestinal permeability by breaching the integrity of tight junction paracellular transfer. In fact, tight junction dysfunction is common in multiple autoimmune diseases and the central part played by the tight junction in autoimmune diseases pathogenesis is extensively described. It is hypothesized that commonly used industrial food additives abrogate human epithelial barrier function, thus, increasing intestinal permeability through the opened tight junction, resulting in entry of foreign immunogenic antigens and activation of the autoimmune cascade. Future research on food additives exposure-intestinal permeability-autoimmunity interplay will enhance our knowledge of the common mechanisms associated with autoimmune progression.
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Affiliation(s)
- Aaron Lerner
- Pediatric Gastroenterology and Nutrition Unit, Carmel Medical Center, B, Rappaport School of Medicine, Technion-Israel institute of Technology, Michal St, No. 7, Haifa 34362, Israel.
| | - Torsten Matthias
- Aesku.Kipp Institute, Mikroforum Ring 2, Wendelsheim 55234, Germany.
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Chen J, Tellez G, Richards JD, Escobar J. Identification of Potential Biomarkers for Gut Barrier Failure in Broiler Chickens. Front Vet Sci 2015; 2:14. [PMID: 26664943 PMCID: PMC4672187 DOI: 10.3389/fvets.2015.00014] [Citation(s) in RCA: 147] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Accepted: 05/08/2015] [Indexed: 01/10/2023] Open
Abstract
The objective of the present study was to identify potential biomarkers for gut barrier failure in chickens. A total of 144 day-of-hatch Ross 308 male broiler chickens were housed in 24 battery cages with six chicks per cage. Cages were randomly assigned to either a control group (CON) or gut barrier failure (GBF) group. During the first 13 days, birds in CON or GBF groups were fed a common corn–soy starter diet. On day 14, CON chickens were switched to a corn grower diet, and GBF chickens were switched to rye–wheat–barley grower diet. In addition, on day 21, GBF chickens were orally challenged with a coccidiosis vaccine. At days 21 and 28, birds were weighed by cage and feed intake was recorded to calculate feed conversion ratio. At day 28, one chicken from each cage was euthanized to collect intestinal samples for morphometric analysis, blood for serum, and intestinal mucosa scrapings for gene expression. Overall performance and feed efficiency was severely affected (P < 0.05) by a GBF model when compared with CON group at days 21 and 28. Duodenum of GBF birds had wider villi, longer crypt depth, and higher crypt depth/villi height ratio than CON birds. Similarly, GBF birds had longer crypt depth in jejunum and ileum when compared with CON birds. Protein levels of endotoxin and α1-acid glycoprotein (AGP) in serum, as well as mRNA levels of interleukin (IL)-8, IL-1β, transforming growth factor (TGF)-β4, and fatty acid-binding protein (FABP) 6 were increased (P < 0.05) in GBF birds compared to CON birds; however, mRNA levels of FABP2, occludin, and mucin 2 (MUC2) were reduced by 34% (P < 0.05), 24% (P = 0.107), and 29% (P = 0.088), respectively, in GBF birds compared to CON birds. The results from the present study suggest that serum endotoxin and AGP, as well as, gene expression of FABP2, FABP6, IL-8, IL-1β, TGF-β4, occludin, and MUC2 in mucosa may work as potential biomarkers for gut barrier health in chickens.
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Affiliation(s)
- Juxing Chen
- Novus International, Inc. , St. Charles, MO , USA
| | - Guillermo Tellez
- Department of Poultry Science, University of Arkansas , Fayetteville, AR , USA
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Tsuji M, Kawamoto T, Koriyama C, Yamamoto M, Tsuchiya T, Matsumura F. Association of PCBs and allergies in children. PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY 2015; 120:21-26. [PMID: 25987216 DOI: 10.1016/j.pestbp.2014.10.014] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Revised: 10/21/2014] [Accepted: 10/21/2014] [Indexed: 06/04/2023]
Abstract
Recently, the incidence rates of childhood allergies have been rising around the world. The presence of persistent chemical pollutants in the environment and exposure to air pollutants are often cited as potential causes of childhood allergies. Accordingly, epidemiological studies of the associations between exposure to low levels of pollutants and adverse health effects are essential. However, at present no useful biomarkers for evaluating such associations have been developed. Thus, using a molecular epidemiological approach we planned to identify candidate biomarkers of pollutant-induced adverse health effects that can be used in children. In asthmatic children, we found that the serum levels of several polychlorinated biphenyl (PCB) congener sub-types were significantly positively correlated with interleukin (IL)-8 mRNA expression, whereas in a sub-group of children who displayed positive immunoglobulin E (IgE) responses to milk or egg proteins IL-22 mRNA expression was demonstrated to be useful for detecting the adverse health effects of environmental pollutants, particularly PCB congeners. In conclusion, the mRNA expression levels of IL-8 and IL-22 can be used to detect children who are at particular risk of adverse health events caused by environmental pollutants, especially PCBs.
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Affiliation(s)
- Mayumi Tsuji
- Department of Environmental Toxicology, University of California, Davis, CA 95616, USA; Department of Environmental Health, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyusyu 807-8555, Japan.
| | - Toshihiro Kawamoto
- Department of Environmental Health, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyusyu 807-8555, Japan
| | - Chihaya Koriyama
- Department of Epidemiology and Preventive Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan
| | - Megumi Yamamoto
- Integrated Physiology Section, Department of Basic Medical Science, National Institute for Minamata Disease, 4058-18 Hama, Minamata, Kumamoto 867-0008, Japan
| | - Takuto Tsuchiya
- Department of Environmental Health, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyusyu 807-8555, Japan
| | - Fumio Matsumura
- Department of Environmental Toxicology, University of California, Davis, CA 95616, USA
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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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Kozakova H, Schwarzer M, Tuckova L, Srutkova D, Czarnowska E, Rosiak I, Hudcovic T, Schabussova I, Hermanova P, Zakostelska Z, Aleksandrzak-Piekarczyk T, Koryszewska-Baginska A, Tlaskalova-Hogenova H, Cukrowska B. Colonization of germ-free mice with a mixture of three lactobacillus strains enhances the integrity of gut mucosa and ameliorates allergic sensitization. Cell Mol Immunol 2015; 13:251-62. [PMID: 25942514 DOI: 10.1038/cmi.2015.09] [Citation(s) in RCA: 114] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Revised: 12/16/2014] [Accepted: 01/13/2015] [Indexed: 12/16/2022] Open
Abstract
Increasing numbers of clinical trials and animal experiments have shown that probiotic bacteria are promising tools for allergy prevention. Here, we analyzed the immunomodulatory properties of three selected lactobacillus strains and the impact of their mixture on allergic sensitization to Bet v 1 using a gnotobiotic mouse model. We showed that Lactobacillus (L.) rhamnosus LOCK0900, L. rhamnosus LOCK0908 and L. casei LOCK0919 are recognized via Toll-like receptor 2 (TLR2) and nucleotide-binding oligomerization domain-containing protein 2 (NOD2) receptors and stimulate bone marrow-derived dendritic cells to produce cytokines in species- and strain-dependent manners. Colonization of germ-free (GF) mice with a mixture of all three strains (Lmix) improved the intestinal barrier by strengthening the apical junctional complexes of enterocytes and restoring the structures of microfilaments extending into the terminal web. Mice colonized with Lmix and sensitized to the Bet v 1 allergen showed significantly lower levels of allergen-specific IgE, IgG1 and IgG2a and an elevated total IgA level in the sera and intestinal lavages as well as an increased transforming growth factor (TGF)-β level compared with the sensitized GF mice. Splenocytes and mesenteric lymph node cells from the Lmix-colonized mice showed the significant upregulation of TGF-β after in vitro stimulation with Bet v 1. Our results show that Lmix colonization improved the gut epithelial barrier and reduced allergic sensitization to Bet v 1. Furthermore, these findings were accompanied by the increased production of circulating and secretory IgA and the regulatory cytokine TGF-β. Thus, this mixture of three lactobacillus strains shows potential for use in the prevention of increased gut permeability and the onset of allergies in humans.
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Affiliation(s)
- Hana Kozakova
- Laboratory of Gnotobiology, Institute of Microbiology, Academy of Sciences of the Czech Republic, Novy Hradek, Czech Republic
| | - Martin Schwarzer
- Laboratory of Gnotobiology, Institute of Microbiology, Academy of Sciences of the Czech Republic, Novy Hradek, Czech Republic
| | - Ludmila Tuckova
- Laboratory of Gnotobiology, Institute of Microbiology, Academy of Sciences of the Czech Republic, Novy Hradek, Czech Republic
| | - Dagmar Srutkova
- Laboratory of Gnotobiology, Institute of Microbiology, Academy of Sciences of the Czech Republic, Novy Hradek, Czech Republic
| | - Elzbieta Czarnowska
- Department of Pathology, the Children's Memorial Health Institute, Warsaw, Poland
| | - Ilona Rosiak
- Department of Pathology, the Children's Memorial Health Institute, Warsaw, Poland
| | - Tomas Hudcovic
- Laboratory of Gnotobiology, Institute of Microbiology, Academy of Sciences of the Czech Republic, Novy Hradek, Czech Republic
| | - Irma Schabussova
- Institute of Specific Prophylaxis and Tropical Medicine, Medical University of Vienna, Vienna, Austria
| | - Petra Hermanova
- Laboratory of Gnotobiology, Institute of Microbiology, Academy of Sciences of the Czech Republic, Novy Hradek, Czech Republic
| | - Zuzana Zakostelska
- Laboratory of Gnotobiology, Institute of Microbiology, Academy of Sciences of the Czech Republic, Novy Hradek, Czech Republic
| | | | | | - Helena Tlaskalova-Hogenova
- Laboratory of Gnotobiology, Institute of Microbiology, Academy of Sciences of the Czech Republic, Novy Hradek, Czech Republic
| | - Bozena Cukrowska
- Department of Pathology, the Children's Memorial Health Institute, Warsaw, Poland
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Kuksin CA, Minter LM. The Link between Autoimmunity and Lymphoma: Does NOTCH Signaling Play a Contributing Role? Front Oncol 2015; 5:51. [PMID: 25759795 PMCID: PMC4338678 DOI: 10.3389/fonc.2015.00051] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Accepted: 02/11/2015] [Indexed: 12/17/2022] Open
Abstract
An association between certain autoimmune conditions and increased risk of developing lymphoma is well documented. Recent evidence points to NOTCH signaling as a strong driver of autoimmunity. Furthermore, a role for NOTCH in various lymphomas, including classical Hodgkin lymphoma, non-Hodgkin lymphoma, and T cell lymphoma has also been described. In this mini-review, we will outline what is known about involvement of NOTCH signaling in those autoimmune conditions, such as rheumatoid arthritis and primary Sjörgren’s syndrome, which show an increased risk for subsequent diagnosis of lymphoma. Furthermore, we will detail what is known about the lymphomas associated with these autoimmune conditions and how aberrant or sustained NOTCH signaling in the immune cells that mediate these diseases may contribute to lymphoma.
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Affiliation(s)
- Christina Arieta Kuksin
- Department of Veterinary and Animal Sciences, University of Massachusetts Amherst , Amherst, MA , USA
| | - Lisa M Minter
- Department of Veterinary and Animal Sciences, University of Massachusetts Amherst , Amherst, MA , USA ; Program in Molecular and Cellular Biology, University of Massachusetts Amherst , Amherst, MA , USA
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Tsuji M. Useful biomarkers for assessing the adverse health effects of PCBs in allergic children: pediatric molecular epidemiology. Environ Health Prev Med 2015; 20:3-11. [PMID: 25344634 PMCID: PMC4284252 DOI: 10.1007/s12199-014-0419-1] [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: 09/18/2014] [Accepted: 09/30/2014] [Indexed: 01/09/2023] Open
Abstract
The incidences of childhood allergies have been increasing in recent years in many parts of the world. The development of allergic disorders is attributed to a complex series of interactions between individuals' genetic backgrounds and their immune and psychoneurotic responses to environmental factors. Among the various possible environmental causes of childhood allergies, the early exposure of developing infants to air pollutants and the presence of persistent chemical pollutants such as pesticides have been suggested most frequently. Therefore, it is very important to obtain epidemiological evidence of direct associations between clearly defined adverse health effects and exposure to low levels of pollutants. However, there are no useful biomarkers for assessing such associations. Thus, we planned to establish reliable health-related biomarkers that could be used to investigate these relationships in children. The serum concentrations of several sub-types of polychlorinated biphenyl (PCB) congeners were found to be significantly correlated with interleukin (IL)-8 mRNA expression among asthmatic children. In addition, IL-22 mRNA expression was found to be particularly useful for detecting the effects of environmental pollutants, especially PCB congeners, in a sub-population of vulnerable children who exhibited positive immunoglobulin E (IgE) responses to milk or egg. Furthermore, we detected significant differences in IL-22 mRNA expression between the IgE-negative non-asthmatic subjects and the asthmatic children who exhibited positive IgE reactions toward egg or milk. In conclusion, IL-8 and IL-22 mRNA expressions could be useful biomarkers for detecting sub-populations of children who are particularly vulnerable to the adverse health effects of environmental pollutants, especially PCBs.
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Affiliation(s)
- Mayumi Tsuji
- Department of Environmental Health, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyusyu, 807-8555, Japan,
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Intestinal barrier function and the brain-gut axis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2014; 817:73-113. [PMID: 24997030 DOI: 10.1007/978-1-4939-0897-4_4] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The luminal-mucosal interface of the intestinal tract is the first relevant location where microorganism-derived antigens and all other potentially immunogenic particles face the scrutiny of the powerful mammalian immune system. Upon regular functioning conditions, the intestinal barrier is able to effectively prevent most environmental and external antigens to interact openly with the numerous and versatile elements that compose the mucosal-associated immune system. This evolutionary super system is capable of processing an astonishing amount of antigens and non-immunogenic particles, approximately 100 tons in one individual lifetime, only considering food-derived components. Most important, to develop oral tolerance and proper active immune responses needed to prevent disease and inflammation, this giant immunogenic load has to be managed in a way that physiological inflammatory balance is constantly preserved. Adequate functioning of the intestinal barrier involves local and distant regulatory networks integrating the so-called brain-gut axis. Along this complex axis both brain and gut structures participate in the processing and execution of response signals to external and internal changes coming from the digestive tract, using multidirectional pathways to communicate. Dysfunction of brain-gut axis facilitates malfunctioning of the intestinal barrier, and vice versa, increasing the risk of uncontrolled immunological reactions that may trigger mucosal and brain low-grade inflammation, a putative first step to the initiation of more permanent gut disorders. In this chapter, we describe the structure, function and interactions of intestinal barrier, microbiota and brain-gut axis in both healthy and pathological conditions.
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Heylen M, Ruyssers NE, Gielis EM, Vanhomwegen E, Pelckmans PA, Moreels TG, De Man JG, De Winter BY. Of worms, mice and man: an overview of experimental and clinical helminth-based therapy for inflammatory bowel disease. Pharmacol Ther 2014; 143:153-167. [PMID: 24603369 DOI: 10.1016/j.pharmthera.2014.02.011] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Accepted: 02/25/2014] [Indexed: 12/17/2022]
Abstract
The incidence of inflammatory and autoimmune disorders is highest in well-developed countries which is directly related to their higher hygienic standards: it is suggested that the lack of exposure to helminths contributes to the susceptibility for immune-related diseases. Epidemiological, experimental and clinical data support the idea that helminths provide protection against immune-mediated diseases such as inflammatory bowel disease (IBD). The most likely mechanism for the suppression of immune responses by helminths is the release of helminth-derived immunomodulatory molecules. This article reviews the experimental and clinical studies investigating the therapeutic potential of helminth-based therapy in IBD and also focuses on the current knowledge of its immunomodulatory mechanisms of action highlighting innate as well as adaptive immune mechanisms. Identifying the mechanisms by which these helminths and helminth-derived molecules modulate the immune system will help in creating novel drugs for the treatment of IBD and other disorders that result from an overactive immune response.
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Affiliation(s)
- Marthe Heylen
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium
| | - Nathalie E Ruyssers
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium
| | - Els M Gielis
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium
| | - Els Vanhomwegen
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium
| | - Paul A Pelckmans
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium; Antwerp University Hospital, Division of Gastroenterology & Hepatology, Antwerp, Belgium
| | - Tom G Moreels
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium; Antwerp University Hospital, Division of Gastroenterology & Hepatology, Antwerp, Belgium
| | - Joris G De Man
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium
| | - Benedicte Y De Winter
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium.
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The small GTPase RAB-11 directs polarized exocytosis of the intracellular pathogen N. parisii for fecal-oral transmission from C. elegans. Proc Natl Acad Sci U S A 2014; 111:8215-20. [PMID: 24843160 DOI: 10.1073/pnas.1400696111] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Pathogen exit is a key stage in the spread and propagation of infectious disease, with the fecal-oral route being a common mode of disease transmission. However, it is poorly understood which molecular pathways provide the major modes for intracellular pathogen exit and fecal-oral transmission in vivo. Here, we use the transparent nematode Caenorhabditis elegans to investigate intestinal cell exit and fecal-oral transmission by the natural intracellular pathogen Nematocida parisii, which is a recently identified species of microsporidia. We show that N. parisii exits from polarized host intestinal cells by co-opting the host vesicle trafficking system and escaping into the lumen. Using a genetic screen, we identified components of the host endocytic recycling pathway that are required for N. parisii spore exit via exocytosis. In particular, we show that the small GTPase RAB-11 localizes to apical spores, is required for spore-containing compartments to fuse with the apical plasma membrane, and is required for spore exit. In addition, we find that RAB-11-deficient animals exhibit impaired contagiousness, supporting an in vivo role for this host trafficking factor in microsporidia disease transmission. Altogether, these findings provide an in vivo example of the major mode of exit used by a natural pathogen for disease spread via fecal-oral transmission.
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