|
1
|
Kapalczynska M, Lin M, Maertzdorf J, Heuberger J, Muellerke S, Zuo X, Vidal R, Shureiqi I, Fischer AS, Sauer S, Berger H, Kidess E, Mollenkopf HJ, Tacke F, Meyer TF, Sigal M. BMP feed-forward loop promotes terminal differentiation in gastric glands and is interrupted by H. pylori-driven inflammation. Nat Commun 2022; 13:1577. [PMID: 35332152 PMCID: PMC8948225 DOI: 10.1038/s41467-022-29176-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 02/19/2022] [Indexed: 12/13/2022] Open
Abstract
Helicobacter pylori causes gastric inflammation, gland hyperplasia and is linked to gastric cancer. Here, we studied the interplay between gastric epithelial stem cells and their stromal niche under homeostasis and upon H. pylori infection. We find that gastric epithelial stem cell differentiation is orchestrated by subsets of stromal cells that either produce BMP inhibitors in the gland base, or BMP ligands at the surface. Exposure to BMP ligands promotes a feed-forward loop by inducing Bmp2 expression in the epithelial cells themselves, enforcing rapid lineage commitment to terminally differentiated mucous pit cells. H. pylori leads to a loss of stromal and epithelial Bmp2 expression and increases expression of BMP inhibitors, promoting self-renewal of stem cells and accumulation of gland base cells, which we mechanistically link to IFN-γ signaling. Mice that lack IFN-γ signaling show no alterations of BMP gradient upon infection, while exposure to IFN-γ resembles H. pylori-driven mucosal responses. Helicobacter pylori causes gastric inflammation, gland hyperplasia and is linked to gastric cancer. Here the authors identify a BMP feedback loop between the stomach epithelium and surrounding stroma that controls gland homeostasis and demonstrate its interruption upon infection with H. pylori.
Collapse
Affiliation(s)
- Marta Kapalczynska
- Department of Hepatology and Gastroenterology, Charité University Medicine, 13353, Berlin, Germany.,Department of Molecular Biology, Max Planck Institute for Infection Biology, 10117, Berlin, Germany
| | - Manqiang Lin
- Department of Hepatology and Gastroenterology, Charité University Medicine, 13353, Berlin, Germany.,Department of Molecular Biology, Max Planck Institute for Infection Biology, 10117, Berlin, Germany
| | - Jeroen Maertzdorf
- Department of Immunology, Max Planck Institute for Infection Biology, 10117, Berlin, Germany
| | - Julian Heuberger
- Department of Hepatology and Gastroenterology, Charité University Medicine, 13353, Berlin, Germany.,Department of Molecular Biology, Max Planck Institute for Infection Biology, 10117, Berlin, Germany
| | - Stefanie Muellerke
- Department of Hepatology and Gastroenterology, Charité University Medicine, 13353, Berlin, Germany
| | - Xiangsheng Zuo
- Departments of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ramon Vidal
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine, 10115, Berlin, Germany
| | - Imad Shureiqi
- Departments of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anne-Sophie Fischer
- Department of Hepatology and Gastroenterology, Charité University Medicine, 13353, Berlin, Germany
| | - Sascha Sauer
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine, 10115, Berlin, Germany
| | - Hilmar Berger
- Department of Hepatology and Gastroenterology, Charité University Medicine, 13353, Berlin, Germany.,Department of Molecular Biology, Max Planck Institute for Infection Biology, 10117, Berlin, Germany
| | - Evelyn Kidess
- Department of Hepatology and Gastroenterology, Charité University Medicine, 13353, Berlin, Germany
| | - Hans-Joachim Mollenkopf
- Department of Molecular Biology, Max Planck Institute for Infection Biology, 10117, Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité University Medicine, 13353, Berlin, Germany
| | - Thomas F Meyer
- Department of Molecular Biology, Max Planck Institute for Infection Biology, 10117, Berlin, Germany.,Laboratory of Infection Oncology, Institute of Clinical Molecular Biology (IKMB), Christian Albrechts University of Kiel, Kiel, Germany
| | - Michael Sigal
- Department of Hepatology and Gastroenterology, Charité University Medicine, 13353, Berlin, Germany. .,Department of Molecular Biology, Max Planck Institute for Infection Biology, 10117, Berlin, Germany. .,Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine, 10115, Berlin, Germany. .,Berlin Institute of Health, 10117, Berlin, Germany.
| |
Collapse
|
|
2
|
Nestares T, Martín-Masot R, Flor-Alemany M, Bonavita A, Maldonado J, Aparicio VA. Influence of Ultra-Processed Foods Consumption on Redox Status and Inflammatory Signaling in Young Celiac Patients. Nutrients 2021; 13:nu13010156. [PMID: 33418957 PMCID: PMC7825019 DOI: 10.3390/nu13010156] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 12/29/2020] [Accepted: 12/29/2020] [Indexed: 12/21/2022] Open
Abstract
The current study was designed to assess the influence of consumption of ultra-processed (UPF) on oxidative/antioxidant balance and evoked inflammatory signaling in young patients with celiac disease (CD). The study included 85 children. The celiac group (n = 53) included children with CD with a long (>18 months, n = 17) or recent (<18 months, n = 36) adherence to a gluten-free diet (GFD). The control group (n = 32) included healthy children with a significantly lower consumption of UPF compared to the CD group, both expressed as kcal/day (p = 0.043) and as percentage of daily energy intake (p = 0.023). Among children with CD, the group with the lowest consumption of UPF (below the 50% of daily energy intake) had a greater Mediterranean diet (MD) adherence and higher moderate physical activity levels. In addition, CD children with the lowest consumption of UPF had healthier redox (lower soluble superoxide dismutase-1 and 15-F2t-isoprostanes) and inflammatory profiles (lower macrophage inflammatory protein-1α) compared to the group with the highest consumption of UPF (all, p < 0.05) regardless of the time on a GFD. These findings highlight the importance of a correct monitoring of the GFD. An unbalanced GFD with high consumption of UPF and an unhealthy pattern with less physical activity and worse adherence to MD results in a worse inflammatory profile, which could act as a parallel pathway that could have important consequences on the pathophysiology of the disease.
Collapse
Affiliation(s)
- Teresa Nestares
- Department of Physiology, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain; (T.N.); (M.F.-A.); (A.B.)
- Institute of Nutrition and Food Technology “José Mataix Verdú” (INYTA), Biomedical Research Centre (CIBM), University of Granada, 18100 Armilla, Spain
| | - Rafael Martín-Masot
- Pediatric Gastroenterology and Nutrition Unit, Hospital Regional Universitario de Malaga, 19010 Málaga, Spain;
| | - Marta Flor-Alemany
- Department of Physiology, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain; (T.N.); (M.F.-A.); (A.B.)
- Institute of Nutrition and Food Technology “José Mataix Verdú” (INYTA), Biomedical Research Centre (CIBM), University of Granada, 18100 Armilla, Spain
- Sport and Health University Research Centre (iMUDS), University of Granada, 18100 Armilla, Spain
| | - Antonela Bonavita
- Department of Physiology, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain; (T.N.); (M.F.-A.); (A.B.)
| | - José Maldonado
- Department of Pediatrics, University of Granada, 18071 Granada, Spain;
- Biohealth Research Institute, 18071 Granada, Spain
- Maternal and Child Health Network, Carlos III Health Institute, 28029 Madrid, Spain
- Pediatric Clinical Management Unit, “Virgen de las Nieves” University Hospital, 18071 Granada, Spain
| | - Virginia A. Aparicio
- Department of Physiology, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain; (T.N.); (M.F.-A.); (A.B.)
- Institute of Nutrition and Food Technology “José Mataix Verdú” (INYTA), Biomedical Research Centre (CIBM), University of Granada, 18100 Armilla, Spain
- Sport and Health University Research Centre (iMUDS), University of Granada, 18100 Armilla, Spain
- Correspondence:
| |
Collapse
|
|
3
|
Veres-Székely A, Bernáth M, Pap D, Rokonay R, Szebeni B, Takács IM, Lippai R, Cseh Á, Szabó AJ, Vannay Á. PARK7 Diminishes Oxidative Stress-Induced Mucosal Damage in Celiac Disease. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:4787202. [PMID: 32963695 PMCID: PMC7492931 DOI: 10.1155/2020/4787202] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 08/11/2020] [Accepted: 08/17/2020] [Indexed: 02/06/2023]
Abstract
Coeliac disease (CD) is a chronic, immune-mediated small intestinal enteropathy, accompanied with gluten-triggered oxidative damage of duodenal mucosa. Previously, our research group reported an increased mucosal level of the antioxidant protein Parkinson's disease 7 (PARK7) in children with CD. In the present study, we investigated the role of increased PARK7 level on the epithelial cell and mucosal integrity of the small intestine. The presence of PARK7 was investigated using immunofluorescent staining on duodenal mucosa of children with CD and on FHs74Int duodenal epithelial cells. To investigate the role of oxidative stress, FHs74Int cells were treated with H2O2 in the absence or presence of Comp23, a PARK7-binding compound. Intracellular accumulation of reactive oxygen species (ROS) was determined by DCFDA-based assay. Cell viability was measured by MTT, LDH, and Annexin V apoptosis assays. Disruption of cytoskeleton and cell adhesion was investigated by immunofluorescence staining and by real-time RT PCR. Effect of PARK7 on mucosal permeability was investigated ex vivo using intestinal sacs derived from control and Comp-23-pretreated mice. Comp23 treatment reduced the H2O2-induced intracellular accumulation of ROS, thus preserving the integrity of the cytoskeleton and also the viability of the FHs74Int cells. Accordingly, Comp23 treatment increased the expression of antioxidants (NRF2, TRX1, GCLC, HMOX1, NQO1), cell-cycle regulators (TP53, CDKN1A, PCNA, BCL2, BAX), and cell adhesion molecules (ZO1, CDH1, VCL, ITGB5) of H2O2-treated cells. Pretreatment with Comp23 considerably decreased the small intestinal permeability. In this study, we demonstrate that PARK7-binding Comp23 reduces the oxidative damage of duodenal epithelial cells, via increased expression of NRF2- and P53-regulated genes. Our results suggest that PARK7 plays a significant role in the maintenance of mucosal integrity in CD.
Collapse
Affiliation(s)
- Apor Veres-Székely
- 1st Department of Paediatrics, Semmelweis University, 1085 Budapest, Hungary
| | - Mária Bernáth
- 1st Department of Paediatrics, Semmelweis University, 1085 Budapest, Hungary
| | - Domonkos Pap
- MTA-SE Pediatrics and Nephrology Research Group, 1085 Budapest, Hungary
| | - Réka Rokonay
- 1st Department of Paediatrics, Semmelweis University, 1085 Budapest, Hungary
| | - Beáta Szebeni
- MTA-SE Pediatrics and Nephrology Research Group, 1085 Budapest, Hungary
| | - István M. Takács
- 1st Department of Paediatrics, Semmelweis University, 1085 Budapest, Hungary
| | - Rita Lippai
- 1st Department of Paediatrics, Semmelweis University, 1085 Budapest, Hungary
| | - Áron Cseh
- 1st Department of Paediatrics, Semmelweis University, 1085 Budapest, Hungary
| | - Attila J. Szabó
- 1st Department of Paediatrics, Semmelweis University, 1085 Budapest, Hungary
- MTA-SE Pediatrics and Nephrology Research Group, 1085 Budapest, Hungary
| | - Ádám Vannay
- 1st Department of Paediatrics, Semmelweis University, 1085 Budapest, Hungary
- MTA-SE Pediatrics and Nephrology Research Group, 1085 Budapest, Hungary
| |
Collapse
|
|
4
|
Oxidative stress, DNA stability and evoked inflammatory signaling in young celiac patients consuming a gluten-free diet. Eur J Nutr 2019; 59:1577-1584. [PMID: 31144026 DOI: 10.1007/s00394-019-02013-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 05/24/2019] [Indexed: 01/01/2023]
Abstract
PURPOSE Celiac disease (CD) is a multifactorial, autoimmune, gluten-sensitive inflammatory disorder of the small intestine. Taking into account the pathogenesis of CD, a strict gluten-free diet (GFD) is the only treatment able to restore epithelium integrity and eliminate complications. The current study was designed to assess whether the use of a GFD is sufficient for maintaining a correct oxidative/antioxidant balance and ameliorating the evoked inflammatory signaling in young patients with CD. METHODS The study covered 80 children, aged between 7 and 18 years, attending the Gastroenterology Service of the Gastroenterology, Hepatology and Child Nutrition Service from the Virgen de las Nieves Hospital in Granada. Children with CD diagnosed were included in the celiac group who followed a strict GFD for 2 years (n = 40) and the control group (n = 40) included healthy children, with negative serological screening. Soluble superoxide dismutase 1 and 2, total antioxidant status, 8-hydroxy-2'-deoxyguanosine, cortisol, melatonin and inflammatory parameters in plasma, 15-F2t-isoprostanes in urine, and DNA breaks in peripheral blood lymphocytes were analysed. RESULTS No differences were found in oxidative stress between CD patients and controls; however, IFN-γ, IL-1α, IP-10 and TNF-β were higher in the CD patients. VEGF was also higher than in the control group. CONCLUSION The GFD in the CD patients is enough to reduce the oxidative stress; however, in the case of the inflammatory signaling, the initial exposure to gluten prior to stablish the GFD is strong enough to induce an inflammatory state which is maintained (even when consuming the GFD); meanwhile the increase in VEGF recorded in the CD group could be a compensatory mechanism to restore the damaged mucosa and duodenal villous atrophy, due to its role in endothelial activation and generation of new functional and stable vascular networks.
Collapse
|
|
5
|
Monguzzi E, Marabini L, Elli L, Vaira V, Ferrero S, Ferretti F, Branchi F, Gaudioso G, Scricciolo A, Lombardo V, Doneda L, Roncoroni L. Gliadin effect on the oxidative balance and DNA damage: An in-vitro, ex-vivo study. Dig Liver Dis 2019; 51:47-54. [PMID: 30055963 DOI: 10.1016/j.dld.2018.06.020] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Revised: 05/29/2018] [Accepted: 06/20/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Gliadins are involved in gluten-related disorders and are responsible for the alteration of the cellular redox balance. It is not clear if the gliadin-related oxidative stress can induce DNA damage in enterocytes. AIM To investigate any possible genotoxicity caused by gliadin and to assess its relationship with oxidative stress in vitro and ex vivo. METHODS Caco-2 cells were exposed for 6-12-24 h to increasing concentrations (250 μg/mL-1000 μg/mL) of digested gliadin. We investigated: cytotoxicity, oxidative balance (reactive oxygen species, ROS), DNA damage (comet assay and γ-H2AX detection), transglutaminase type 2 (TG2) activity and annexin V expression. H2AX and 8-OHG immunohistochemistry has been evaluated on duodenal biopsies of celiac subjects and controls. RESULTS Gliadin induced a significant increase (+50%) of ROS after 12 h of exposition starting with a 500 μg/mL dose of gliadin. Comet assay and γ-H2AX demonstrated DNA damage, evident at the gliadin concentration of 500 μg/mL after 24 h. TG2 activity increased in chromatin and cytoskeleton cellular compartments at different gliadin doses (250/500/1000 μg/mL). The γ-H2AX and 8-OHG immunohistochemistry was altered in the duodenal biopsies of celiac patients. CONCLUSIONS Gliadin induces cellular oxidative stress, DNA damage and pro-apoptotic stimulation in Caco-2 cells and in the duodenal mucosa of celiac patients.
Collapse
Affiliation(s)
- Erika Monguzzi
- Gastroenterology and Endoscopy Unit - Center for Prevention and Diagnosis of Celiac Disease, IRCCS Ca's Granda Foundation "Ospedale Maggiore Policlinico", Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Laura Marabini
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Italy
| | - Luca Elli
- Gastroenterology and Endoscopy Unit - Center for Prevention and Diagnosis of Celiac Disease, IRCCS Ca's Granda Foundation "Ospedale Maggiore Policlinico", Milan, Italy.
| | - Valentina Vaira
- Division of Pathology, IRCCS Ca' Granda Foundation "Ospedale Maggiore Policlinico", Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Stefano Ferrero
- Division of Pathology, IRCCS Ca' Granda Foundation "Ospedale Maggiore Policlinico", Milan, Italy; Department of Biomedical, Surgical and Dental Sciences, Università degli Studi di Milano, Milan, Italy
| | - Francesca Ferretti
- Gastroenterology and Endoscopy Unit - Center for Prevention and Diagnosis of Celiac Disease, IRCCS Ca's Granda Foundation "Ospedale Maggiore Policlinico", Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Federica Branchi
- Gastroenterology and Endoscopy Unit - Center for Prevention and Diagnosis of Celiac Disease, IRCCS Ca's Granda Foundation "Ospedale Maggiore Policlinico", Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Gabriella Gaudioso
- Division of Pathology, IRCCS Ca' Granda Foundation "Ospedale Maggiore Policlinico", Milan, Italy
| | - Alice Scricciolo
- Gastroenterology and Endoscopy Unit - Center for Prevention and Diagnosis of Celiac Disease, IRCCS Ca's Granda Foundation "Ospedale Maggiore Policlinico", Milan, Italy
| | - Vincenza Lombardo
- Gastroenterology and Endoscopy Unit - Center for Prevention and Diagnosis of Celiac Disease, IRCCS Ca's Granda Foundation "Ospedale Maggiore Policlinico", Milan, Italy
| | - Luisa Doneda
- Department of Biomedical, Surgical and Dental Sciences, Università degli Studi di Milano, Milan, Italy
| | - Leda Roncoroni
- Gastroenterology and Endoscopy Unit - Center for Prevention and Diagnosis of Celiac Disease, IRCCS Ca's Granda Foundation "Ospedale Maggiore Policlinico", Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy; Department of Biomedical, Surgical and Dental Sciences, Università degli Studi di Milano, Milan, Italy
| |
Collapse
|
|
6
|
Immune Response to Rotavirus and Gluten Sensitivity. J Immunol Res 2018; 2018:9419204. [PMID: 29736406 PMCID: PMC5875030 DOI: 10.1155/2018/9419204] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 12/18/2017] [Accepted: 12/25/2017] [Indexed: 12/21/2022] Open
Abstract
Rotavirus is a double-stranded RNA virus belonging to the family of Reoviridae. The virus is transmitted by the faecal-oral route and infects intestinal cells causing gastroenteritis. Rotaviruses are the main cause of severe acute diarrhoea in children less than 5 years of age worldwide. In our previous work we have shown a link between rotavirus infection and celiac disease. Nonceliac gluten sensitivity (NCGS) is emerging as new clinical entity lacking specific diagnostic biomarkers which has been reported to occur in 6–10% of the population. Clinical manifestations include gastrointestinal and/or extraintestinal symptoms which recede with gluten withdrawal. The pathogenesis of the disease is still unknown. Aim of this work is to clarify some aspects of its pathogenesis using a gene array approach. Our results suggest that NCGS may have an autoimmune origin. This is based both on gene expression data (i.e., TH17-interferon signatures) and on the presence of TH17 cells and of serological markers of autoimmunity in NCGS. Our results also indicate a possible involvement of rotavirus infection in the pathogenesis of nonceliac gluten sensitivity similarly to what we have previously shown in celiac disease.
Collapse
|
|
7
|
Kumar S, Lal S, Bhatnagar A. Regulatory T cell subsets in peripheral blood of celiac disease patients and TLR2 expression: correlation with oxidative stress. APMIS 2017; 125:888-901. [DOI: 10.1111/apm.12735] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Accepted: 05/22/2017] [Indexed: 01/21/2023]
Affiliation(s)
- Sanjay Kumar
- Department of Biochemistry; Panjab University; Chandigarh India
| | - Sadhna Lal
- Department of Gastroenterology; Postgraduate Institute of Medical Education & Research; Chandigarh India
| | | |
Collapse
|
|
8
|
Kaplan M, Ates I, Yuksel M, Ozderin Ozin Y, Alisik M, Erel O, Kayacetin E. Thiol/disulphide homeostasis in celiac disease. World J Gastrointest Pharmacol Ther 2017; 8:120-126. [PMID: 28533921 PMCID: PMC5421110 DOI: 10.4292/wjgpt.v8.i2.120] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 01/25/2017] [Accepted: 03/12/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To determine dynamic thiol/disulphide homeostasis in celiac disease and to examine the associate with celiac autoantibodies and gluten-free diet. METHODS Seventy three patients with celiac disease and 73 healthy volunteers were enrolled in the study. In both groups, thiol/disulphide homeostasis was examined with a new colorimetric method recently developed by Erel and Neselioglu. RESULTS In patients with celiac disease, native thiol (P = 0.027) and total thiol (P = 0.031) levels were lower, while disulphide (P < 0.001) level, disulphide/native thiol (P < 0.001) and disulphide/total thiol (P < 0.001) ratios were higher compared to the control group. In patients who do not comply with a gluten-free diet, disulphide/native thiol ratio was found higher compared to the patients who comply with the diet (P < 0.001). In patients with any autoantibody-positive, disulphide/native thiol ratio was observed higher compared to the patients with autoantibody-negative (P < 0.05). It is found that there is a negative correlation between celiac autoantibodies, and native thiol, total thiol levels and native thiol/total thiol ratio, while a positive correlation is observed between disulphide, disulphide/native thiol and disulphide/total thiol levels. CONCLUSION This study is first in the literature which found that the patients with celiac disease the dynamic thiol/disulphide balance shifts through disulphide form compared to the control group.
Collapse
|
|
9
|
Pérez S, Taléns-Visconti R, Rius-Pérez S, Finamor I, Sastre J. Redox signaling in the gastrointestinal tract. Free Radic Biol Med 2017; 104:75-103. [PMID: 28062361 DOI: 10.1016/j.freeradbiomed.2016.12.048] [Citation(s) in RCA: 181] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2016] [Revised: 12/20/2016] [Accepted: 12/31/2016] [Indexed: 12/16/2022]
Abstract
Redox signaling regulates physiological self-renewal, proliferation, migration and differentiation in gastrointestinal epithelium by modulating Wnt/β-catenin and Notch signaling pathways mainly through NADPH oxidases (NOXs). In the intestine, intracellular and extracellular thiol redox status modulates the proliferative potential of epithelial cells. Furthermore, commensal bacteria contribute to intestine epithelial homeostasis through NOX1- and dual oxidase 2-derived reactive oxygen species (ROS). The loss of redox homeostasis is involved in the pathogenesis and development of a wide diversity of gastrointestinal disorders, such as Barrett's esophagus, esophageal adenocarcinoma, peptic ulcer, gastric cancer, ischemic intestinal injury, celiac disease, inflammatory bowel disease and colorectal cancer. The overproduction of superoxide anion together with inactivation of superoxide dismutase are involved in the pathogenesis of Barrett's esophagus and its transformation to adenocarcinoma. In Helicobacter pylori-induced peptic ulcer, oxidative stress derived from the leukocyte infiltrate and NOX1 aggravates mucosal damage, especially in HspB+ strains that downregulate Nrf2. In celiac disease, oxidative stress mediates most of the cytotoxic effects induced by gluten peptides and increases transglutaminase levels, whereas nitrosative stress contributes to the impairment of tight junctions. Progression of inflammatory bowel disease relies on the balance between pro-inflammatory redox-sensitive pathways, such as NLRP3 inflammasome and NF-κB, and the adaptive up-regulation of Mn superoxide dismutase and glutathione peroxidase 2. In colorectal cancer, redox signaling exhibits two Janus faces: On the one hand, NOX1 up-regulation and derived hydrogen peroxide enhance Wnt/β-catenin and Notch proliferating pathways; on the other hand, ROS may disrupt tumor progression through different pro-apoptotic mechanisms. In conclusion, redox signaling plays a critical role in the physiology and pathophysiology of gastrointestinal tract.
Collapse
Affiliation(s)
- Salvador Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain
| | - Raquel Taléns-Visconti
- Department of Pharmacy and Pharmaceutical Technology and Parasitology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain
| | - Sergio Rius-Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain
| | - Isabela Finamor
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain
| | - Juan Sastre
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain.
| |
Collapse
|
|
10
|
Oittinen M, Popp A, Kurppa K, Lindfors K, Mäki M, Kaikkonen MU, Viiri K. Polycomb Repressive Complex 2 Enacts Wnt Signaling in Intestinal Homeostasis and Contributes to the Instigation of Stemness in Diseases Entailing Epithelial Hyperplasia or Neoplasia. Stem Cells 2016; 35:445-457. [PMID: 27570105 DOI: 10.1002/stem.2479] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Revised: 07/11/2016] [Accepted: 07/29/2016] [Indexed: 12/15/2022]
Abstract
Canonical Wnt/β-catenin signaling regulates the homeostasis of intestinal epithelium by controlling the balance between intestinal stem cell self-renewal and differentiation but epigenetic mechanisms enacting the process are not known. We hypothesized that epigenetic regulator, Polycomb Repressive Complex-2 (PRC2), is involved in Wnt-mediated epithelial homeostasis on the crypt-villus axis and aberrancies therein are implicated both in celiac disease and in intestinal malignancies. We found that PRC2 establishes repressive crypt and villus specific trimethylation of histone H3 lysine 27 (H3K27me3) signature on genes responsible for, for example, nutrient transport and cell killing in crypts and, for example, proliferation and differentiation in mature villi, suggesting that PRC2 facilitates the Wnt-governed intestinal homeostasis. When celiac patients are on gluten-containing diet PRC2 is out-of-bounds active and consequently its target genes were found affected in intestinal epithelium. Significant set of effective intestinal PRC2 targets are also differentially expressed in colorectal adenoma and carcinomas. Our results suggest that PRC2 gives rise and maintains polar crypt and villus specific H3K27me3 signatures. As H3K27me3 is a mark enriched in developmentally important genes, identified intestinal PRC2 targets are possibly imperative drivers for enterocyte differentiation and intestinal stem cell maintenance downstream to Wnt-signaling. Our work also elucidates the mechanism sustaining the crypt hyperplasia in celiac disease and suggest that PRC2-dependent fostering of epithelial stemness is a common attribute in intestinal diseases in which epithelial hyperplasia or neoplasia prevails. Finally, this work demonstrates that in intestine PRC2 represses genes having both pro-stemness and pro-differentiation functions, fact need to be considered when designing epigenetic therapies including PRC2 as a drug target. Stem Cells 2017;35:445-457.
Collapse
Affiliation(s)
- Mikko Oittinen
- Tampere Centre for Child Health Research, University of Tampere, Department of Pediatrics and Tampere University Hospital, Tampere, Finland
| | - Alina Popp
- Tampere Centre for Child Health Research, University of Tampere, Department of Pediatrics and Tampere University Hospital, Tampere, Finland.,University of Medicine and Pharmacy "Carol Davila", Department of Pediatrics and Institute for Mother and Child Care, Bucharest, Romania
| | - Kalle Kurppa
- Tampere Centre for Child Health Research, University of Tampere, Department of Pediatrics and Tampere University Hospital, Tampere, Finland
| | - Katri Lindfors
- Tampere Centre for Child Health Research, University of Tampere, Department of Pediatrics and Tampere University Hospital, Tampere, Finland
| | - Markku Mäki
- Tampere Centre for Child Health Research, University of Tampere, Department of Pediatrics and Tampere University Hospital, Tampere, Finland
| | - Minna U Kaikkonen
- Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Keijo Viiri
- Tampere Centre for Child Health Research, University of Tampere, Department of Pediatrics and Tampere University Hospital, Tampere, Finland
| |
Collapse
|
|
11
|
Bressan P, Kramer P. Bread and Other Edible Agents of Mental Disease. Front Hum Neurosci 2016; 10:130. [PMID: 27065833 PMCID: PMC4809873 DOI: 10.3389/fnhum.2016.00130] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Accepted: 03/10/2016] [Indexed: 12/16/2022] Open
Abstract
Perhaps because gastroenterology, immunology, toxicology, and the nutrition and agricultural sciences are outside of their competence and responsibility, psychologists and psychiatrists typically fail to appreciate the impact that food can have on their patients' condition. Here we attempt to help correct this situation by reviewing, in non-technical, plain English, how cereal grains-the world's most abundant food source-can affect human behavior and mental health. We present the implications for the psychological sciences of the findings that, in all of us, bread (1) makes the gut more permeable and can thus encourage the migration of food particles to sites where they are not expected, prompting the immune system to attack both these particles and brain-relevant substances that resemble them, and (2) releases opioid-like compounds, capable of causing mental derangement if they make it to the brain. A grain-free diet, although difficult to maintain (especially for those that need it the most), could improve the mental health of many and be a complete cure for others.
Collapse
Affiliation(s)
- Paola Bressan
- Department of General Psychology, University of PaduaPadova, Italy
| | - Peter Kramer
- Department of General Psychology, University of PaduaPadova, Italy
| |
Collapse
|
|
12
|
Efe TH, Ertem AG, Coskun Y, Bilgin M, Algul E, Beton O, Asarcikli LD, Erat M, Ayturk M, Yuksel I, Yeter E. Atrial Electromechanical Properties in Coeliac Disease. Heart Lung Circ 2016; 25:160-5. [PMID: 26412487 DOI: 10.1016/j.hlc.2015.08.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Revised: 07/31/2015] [Accepted: 08/17/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND Coeliac disease (CD) is an autoimmune and inflammatory disorder of the small intestine. There is reasonable evidence linking inflammation to the initiation and continuation of atrial fibrillation (AF) in inflammatory conditions. Atrial electro-mechanic delay (EMD) was suggested as an early marker of AF in previous studies. The objectives of this study were to evaluate atrial electromechanical properties measured by tissue Doppler imaging and simultaneous electrocardiography (ECG) tracing in patients with CD. METHODS Thirty-nine patients with coeliac disease (CD), and 26 healthy volunteers, matched for age and sex, were enrolled in the study. Atrial electromechanical properties were measured by using transthoracic echocardiography and surface ECG. Interatrial electro-mechanic delay (EMD), left intraatrial EMD, right intratrial EMD were calculated. RESULTS There was no difference between CD patients and healthy volunteers in terms of basal characteristics. Patients with CD had significantly prolonged left and right intraatrial EMDs, and interatrial EMD compared to healthy controls (p= 0.03, p= 0.02, p<0.0001, respectively). Interatrial EMD was positively correlated with age, disease duration, anti-gliadin IgG, anti-endomysium and disease status. In multiple linear regression, interatrial EMD was independently associated with disease duration, anti-endomysium and disease status after adjusting for age and sex. CONCLUSIONS In the present study, atrial EMDs were found significantly higher in patients with CD compared with healthy individuals. Measurement of atrial EMD parameters might be used to predict the risk of development of AF in patients with CD.
Collapse
Affiliation(s)
- Tolga Han Efe
- Department of Cardiology, Diskapi Education and Training Hospital, Ankara, Turkey.
| | - Ahmet Goktug Ertem
- Department of Cardiology, Ankara Ataturk Education and Training Hospital, Ankara, Turkey
| | - Yusuf Coskun
- Department of Gastroenterology, Diskapi Education and Training Hospital, Ankara, Turkey
| | - Murat Bilgin
- Department of Cardiology, Diskapi Education and Training Hospital, Ankara, Turkey
| | - Engin Algul
- Department of Cardiology, Diskapi Education and Training Hospital, Ankara, Turkey
| | - Osman Beton
- Department of Cardiology, Diskapi Education and Training Hospital, Ankara, Turkey
| | - Lale Dinc Asarcikli
- Department of Cardiology, Diskapi Education and Training Hospital, Ankara, Turkey
| | - Mehmet Erat
- Department of Cardiology, Diskapi Education and Training Hospital, Ankara, Turkey
| | - Mehmet Ayturk
- Department of Cardiology, Diskapi Education and Training Hospital, Ankara, Turkey
| | - Ilhami Yuksel
- Department of Gastroenterology, Diskapi Education and Training Hospital, Ankara, Turkey
| | - Ekrem Yeter
- Department of Cardiology, Diskapi Education and Training Hospital, Ankara, Turkey
| |
Collapse
|
|
13
|
Adaptive response activated by dietary cis9, trans11 conjugated linoleic acid prevents distinct signs of gliadin-induced enteropathy in mice. Eur J Nutr 2015; 55:729-740. [PMID: 25840667 DOI: 10.1007/s00394-015-0893-2] [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] [Received: 09/02/2014] [Accepted: 03/25/2015] [Indexed: 12/19/2022]
Abstract
PURPOSE The beneficial effects of conjugated linoleic acid (CLA) mixture (cis9, trans11, c9; trans10, cis12, t10) against gliadin-induced toxicity in HLA-DQ8-transgenic mice (DQ8) have been associated with improved duodenal cytoprotective mechanisms [nuclear factor-E2-related factor-2, Nrf2; acylpeptide hydrolase (APEH)/proteasome]. The present study was aimed at investigating the ability of individual CLA isomers to improve the efficacy of these defensive mechanisms and to protect against duodenal injury caused by the combined administration of gliadin and indomethacin (GI). METHODS Gluten-mediated enteropathy was induced in DQ8 mice by three intra-gastric administration of gliadin (20 mg kg(-1)/bw) and indomethacin (15 mg L(-1)) in drinking water for 10 days (GI). C9 or t10 CLA (520 mg kg(-1)/bw/day) were orally administered for 2 weeks. Pro-oxidant and toxic effects associated with GI treatment, anti-oxidant/detoxifying ability of c9 or t10-CLA and the protective effect induced by c9 pre-treatment (c9 + GI) were evaluated in DQ8 mice duodenum by combining enzymatic, immunoblotting, histological evaluation and quantitative real-time PCR assays. RESULTS GI treatment produces the time-dependent decline of the considered detoxifying mechanisms thus leading to pro-apoptotic and pro-oxidant effects. APEH/proteasome pathway was not markedly affected by individual CLA isomers, but duodenal redox status and activity/mRNA levels of Nrf2-activated enzymes were significantly improved by c9 administration. c9 pre-treatment protects against GI-mediated accumulation of oxidative stress markers, and histological examination reveals the increase of goblet cells number in mouse duodenum but induces only a partial recovery of APEH/proteasome activity. CONCLUSIONS The activation of and adaptive response by low doses of c9 supplementation prevents distinct signs of gliadin-induced enteropathy in DQ8 mice.
Collapse
|
|
14
|
Giovanna Z, Marzia D, Claudio L, Puccetti A. Celiac Disease and Rotavirus Infection. INFECTION AND AUTOIMMUNITY 2015:453-464. [DOI: 10.1016/b978-0-444-63269-2.00028-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
|
|
15
|
Sziksz E, Pap D, Veres G, Fekete A, Tulassay T, Vannay &A. Involvement of heat shock proteins in gluten-sensitive enteropathy. World J Gastroenterol 2014; 20:6495-6503. [PMID: 24914370 PMCID: PMC4047334 DOI: 10.3748/wjg.v20.i21.6495] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Revised: 02/12/2014] [Accepted: 03/10/2014] [Indexed: 02/06/2023] Open
Abstract
Gluten-sensitive enteropathy, also known as coeliac disease (CD), is an autoimmune disorder occurring in genetically susceptible individuals that damages the small intestine and interferes with the absorption of other nutrients. As it is triggered by dietary gluten and related prolamins present in wheat, rye and barley, the accepted treatment for CD is a strict gluten-free diet. However, a complete exclusion of gluten-containing cereals from the diet is often difficult, and new therapeutic strategies are urgently needed. A class of proteins that have already emerged as drug targets for other autoimmune diseases are the heat shock proteins (HSPs), which are highly conserved stress-induced chaperones that protect cells against harmful extracellular factors. HSPs are expressed in several tissues, including the gastrointestinal tract, and their levels are significantly increased under stress circumstances. HSPs exert immunomodulatory effects, and also play a crucial role in the maintenance of epithelial cell structure and function, as they are responsible for adequate protein folding, influence the degradation of proteins and cell repair processes after damage, and modulate cell signalling, cell proliferation and apoptosis. The present review discusses the involvement of HSPs in the pathophysiology of CD. Furthermore, HSPs may represent a useful therapeutic target for the treatment of CD due to the cytoprotective, immunomodulatory, and anti-apoptotic effects in the intestinal mucosal barrier.
Collapse
|
|
16
|
Gliadin activates arginase pathway in RAW264.7 cells and in human monocytes. Biochim Biophys Acta Mol Basis Dis 2014; 1842:1364-71. [PMID: 24793417 DOI: 10.1016/j.bbadis.2014.04.021] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2014] [Revised: 04/10/2014] [Accepted: 04/25/2014] [Indexed: 11/21/2022]
Abstract
Celiac disease (CD) is an autoimmune enteropathy triggered in susceptible individuals by the ingestion of gliadin-containing grains. Recent studies have demonstrated that macrophages play a key role in the pathogenesis of CD through the release of inflammatory mediators such as cytokines and nitric oxide (NO). Since arginine is the obliged substrate of iNOS (inducible nitric oxide synthase), the enzyme that produces large amount of NO, the aim of this work is to investigate arginine metabolic pathways in RAW264.7 murine macrophages after treatment with PT-gliadin (PTG) in the absence and in the presence of IFNγ. Our results demonstrate that, besides strengthening the IFNγ-dependent activation of iNOS, gliadin is also an inducer of arginase, the enzyme that transforms arginine into ornithine and urea. Gliadin treatment increases, indeed, the expression and the activity of arginase, leading to the production of polyamines through the subsequent induction of ornithine decarboxylase. This effect is strengthened by IFNγ. The activation of these pathways takes advantage of the increased availability of arginine due to a decreased system y(+)l-mediated efflux, likely ascribable to a reduced expression of Slc7a6 transporter. A significant induction of arginase expression is also observed in human monocytes from healthy subject upon treatment with gliadin, thus demonstrating that gluten components trigger changes in arginine metabolism in monocyte/macrophage cells.
Collapse
|
|
17
|
Lahdenperä AI, Fälth-Magnusson K, Högberg L, Ludvigsson J, Vaarala O. Expression pattern of T-helper 17 cell signaling pathway and mucosal inflammation in celiac disease. Scand J Gastroenterol 2014; 49:145-56. [PMID: 24325470 DOI: 10.3109/00365521.2013.863966] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE The aim was to investigate the mucosal activation of a broad range of genes associated with the T-helper 17 cell (Th17) signaling pathway in children at different stages of celiac disease (CD), including children with increased risk for CD and children with untreated and gluten-free diet (GFD)-treated CD. MATERIAL AND METHODS Small intestinal biopsies were taken from children with untreated and GFD-treated CD, transglutaminase antibody (TGA)-positive children with potential CD, and reference children. Real-time polymerase chain reaction (PCR) arrays were used to study the gene expression pattern of Th17-related genes, and quantitative PCR was used to study the interleukin (IL)-17A expression. RESULTS The mucosal expression of CD8A was elevated at all stages of CD. Children with untreated CD had diminished levels of IL-17RE, IL-23R, RORc, STAT6, CCL22, NFATC2, IL-18, CD4, CD247, and matrix metalloproteinase (MMP)9 but had elevated levels of MMP3, IL-17, interferon-γ (IFN-γ) and CD8A, compared to references. The majority of the aforementioned genes, being differentially expressed in untreated CD, displayed similar expression in GFD-treated children and references. Children with untreated and GFD-treated CD had elevated expression of IFN-γ but had reduced expression of CD247. Interestingly, children with potential CD displayed reduced FOXP3, IL-21, and IL-17A levels. CONCLUSION Mucosal upregulation of Th17 immunity occurs at the late stage of disease and is downregulated with dietary treatment, thus indicating that IL-17 immunity is not a fundamental feature of CD as Th1 immunity, which is not fully downregulated by GFD.
Collapse
Affiliation(s)
- Anne I Lahdenperä
- Department of Clinical and Experimental Medicine, Division of Paediatrics, Faculty of Health Sciences, Linköping University , Linköping , Sweden
| | | | | | | | | |
Collapse
|
|
18
|
Dolcino M, Zanoni G, Bason C, Tinazzi E, Boccola E, Valletta E, Contreas G, Lunardi C, Puccetti A. A subset of anti-rotavirus antibodies directed against the viral protein VP7 predicts the onset of celiac disease and induces typical features of the disease in the intestinal epithelial cell line T84. Immunol Res 2014; 56:465-76. [PMID: 23572432 DOI: 10.1007/s12026-013-8420-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Celiac disease (CD) is an autoimmune disorder of the small intestine triggered by environmental factors in genetically predisposed individuals. A strong association between type 1 diabetes (T1DM) and CD has been reported. We have previously shown that rotavirus infection may be involved in the pathogenesis of CD through a mechanism of molecular mimicry. Indeed, we identified a subset of anti-transglutaminase IgA antibodies that recognize the rotavirus viral protein VP7. In this study, we aimed at evaluating whether such antibodies may predict the onset of CD in children affected by T1DM. Moreover, to further analyze the link between rotavirus infection and pathogenesis of CD, we analyzed the effect of anti-rotavirus VP7 antibodies on T84 intestinal epithelial cells using the gene-array technique, complemented by the analysis of molecules secreted in the supernatant of stimulated cells. We found that anti-rotavirus VP7 antibodies are present in the vast majority (81%) of T1DM-CD tested sera, but are detectable also in a fraction (27%) of T1DM children without CD. Moreover, we found that anti-rotavirus VP7 antibodies are present before the CD onset, preceding the detection of anti-tTG and anti-endomysium antibodies. The gene-array analysis showed that purified anti-rotavirus VP7 antibodies modulate genes that are involved in apoptosis, inflammation, and alteration of the epithelial barrier integrity in intestinal epithelial cells, all typical features of CD. Taken together, these new data further support the involvement of rotavirus infection in the pathogenesis of CD and suggest a predictive role of anti-rotavirus VP7 antibodies.
Collapse
|
|
19
|
Adriaanse MPM, Tack GJ, Passos VL, Damoiseaux JGMC, Schreurs MWJ, van Wijck K, Riedl RG, Masclee AAM, Buurman WA, Mulder CJJ, Vreugdenhil ACE. Serum I-FABP as marker for enterocyte damage in coeliac disease and its relation to villous atrophy and circulating autoantibodies. Aliment Pharmacol Ther 2013; 37:482-90. [PMID: 23289539 DOI: 10.1111/apt.12194] [Citation(s) in RCA: 144] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2012] [Revised: 07/19/2012] [Accepted: 12/07/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND Enterocyte damage is the hallmark of coeliac disease (CD) resulting in malabsorption. Little is known about the recovery of enterocyte damage and its clinical consequences. Serum intestinal fatty acid binding protein (I-FABP) is a sensitive marker to study enterocyte damage. AIMS To evaluate the severity of enterocyte damage in adult-onset CD and its course upon a gluten-free diet (GFD). Furthermore, the correlation among enterocyte damage, CD autoantibodies and histological abnormalities during the course of disease is studied. METHODS Serum I-FABP levels were determined in 96 biopsy-proven adult CD patients and in 69 patients repeatedly upon a GFD. A total of 141 individuals with normal antitissue transglutaminase antibody (IgA-tTG) levels served as controls. I-FABP levels were related to the degree of villous atrophy (Marsh grade) and IgA-tTG. RESULTS I-FABP levels were elevated in untreated CD (median 691 pg/mL) compared with controls (median 178 pg/mL, P < 0.001) and correlated with Marsh grade (r = 0.265, P < 0.05) and IgA-tTG (r = 0.403, P < 0.01). Upon a GFD serum levels decreased significantly, however, not within the range observed in controls, despite the common observed normalisation of IgA-tTG levels and Marsh grade. CD patients with elevated I-FABP levels nonresponding to GFD showed persistent histological abnormalities. CONCLUSIONS Enterocyte damage assessed by serum I-FABP correlates with the severity of villous atrophy in coeliac disease at the time of diagnosis. Although enterocyte damage improves upon treatment, substantial enterocyte damage persists despite absence of villous atrophy and low IgA-tTG levels in the majority of cases. Elevated I-FABP levels nonresponding to gluten-free diet are indicative of histological abnormalities and warrant further evaluation.
Collapse
Affiliation(s)
- M P M Adriaanse
- Department of Paediatrics & Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University Medical Centre, Maastricht, the Netherlands.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
20
|
Brown K, DeCoffe D, Molcan E, Gibson DL. Diet-induced dysbiosis of the intestinal microbiota and the effects on immunity and disease. Nutrients 2012; 4:1095-119. [PMID: 23016134 PMCID: PMC3448089 DOI: 10.3390/nu4081095] [Citation(s) in RCA: 458] [Impact Index Per Article: 35.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2012] [Revised: 08/09/2012] [Accepted: 08/15/2012] [Indexed: 02/07/2023] Open
Abstract
The gastrointestinal (GI) microbiota is the collection of microbes which reside in the GI tract and represents the largest source of non-self antigens in the human body. The GI tract functions as a major immunological organ as it must maintain tolerance to commensal and dietary antigens while remaining responsive to pathogenic stimuli. If this balance is disrupted, inappropriate inflammatory processes can result, leading to host cell damage and/or autoimmunity. Evidence suggests that the composition of the intestinal microbiota can influence susceptibility to chronic disease of the intestinal tract including ulcerative colitis, Crohn’s disease, celiac disease and irritable bowel syndrome, as well as more systemic diseases such as obesity, type 1 diabetes and type 2 diabetes. Interestingly, a considerable shift in diet has coincided with increased incidence of many of these inflammatory diseases. It was originally believed that the composition of the intestinal microbiota was relatively stable from early childhood; however, recent evidence suggests that diet can cause dysbiosis, an alteration in the composition of the microbiota, which could lead to aberrant immune responses. The role of the microbiota and the potential for diet-induced dysbiosis in inflammatory conditions of the GI tract and systemic diseases will be discussed.
Collapse
Affiliation(s)
- Kirsty Brown
- Department of Biology, University of British Columbia Okanagan, Kelowna, BC, Canada.
| | | | | | | |
Collapse
|
|
21
|
Ferretti G, Bacchetti T, Masciangelo S, Saturni L. Celiac disease, inflammation and oxidative damage: a nutrigenetic approach. Nutrients 2012; 4:243-57. [PMID: 22606367 PMCID: PMC3347005 DOI: 10.3390/nu4040243] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2011] [Revised: 03/02/2012] [Accepted: 03/16/2012] [Indexed: 01/04/2023] Open
Abstract
Celiac disease (CD), a common heritable chronic inflammatory condition of the small intestine caused by permanent intolerance to gluten/gliadin (prolamin), is characterized by a complex interplay between genetic and environmental factors. Developments in proteomics have provided an important contribution to the understanding of the biochemical and immunological aspects of the disease and the mechanisms involved in toxicity of prolamins. It has been demonstrated that some gliadin peptides resistant to complete proteolytic digestion may directly affect intestinal cell structure and functions by modulating gene expression and oxidative stress. In recent years, the creation of the two research fields Nutrigenomics and Nutrigenetics, has enabled the elucidation of some interactions between diet, nutrients and genes. Various dietary components including long chain ω-3 fatty acids, plant flavonoids, and carotenoids have been demonstrated to modulate oxidative stress, gene expression and production of inflammatory mediators. Therefore their adoption could preserve intestinal barrier integrity, play a protective role against toxicity of gliadin peptides and have a role in nutritional therapy of celiac disease.
Collapse
Affiliation(s)
- Gianna Ferretti
- Department of Odontostomatologic and Specialistic Clinics Sciences, Polytechnic University of Marche, via Ranieri 65, 60100 Ancona, Italy;
| | - Tiziana Bacchetti
- Department of Life and Environmental Sciences, Polytechnic University of Marche, via Ranieri 65, 60100 Ancona, Italy; (T.B.); (S.M.)
| | - Simona Masciangelo
- Department of Life and Environmental Sciences, Polytechnic University of Marche, via Ranieri 65, 60100 Ancona, Italy; (T.B.); (S.M.)
| | - Letizia Saturni
- Ibero-American University Foundation—FUNIBER, via Ranieri 65, 60100 Ancona, Italy
| |
Collapse
|
|
22
|
Lipid peroxidation and paraoxonase-1 activity in celiac disease. J Lipids 2012; 2012:587479. [PMID: 22536510 PMCID: PMC3321446 DOI: 10.1155/2012/587479] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2011] [Revised: 01/16/2012] [Accepted: 01/19/2012] [Indexed: 12/15/2022] Open
Abstract
Paraoxonase-1 (PON1) plays an antioxidant and anti-inflammatory role. Aim of the study was to investigate the alteration of paraoxonase-1 activity in celiac disease (CD), an intestinal disorder characterized by toxic injury exerted by gluten peptides. Activities of PON1, levels of biochemical markers of lipid peroxidation and total antioxidant capacity were evaluated in serum obtained from 27 celiac patients (11 at diagnosis, 16 treated with gluten free diet) and 25 healthy subjects. Moreover, the serum susceptibility of Cu2+-induced lipid peroxidation was investigated in controls and patients. The results showed a lower PON1 activity in serum of both groups of celiac patients with respect to control subjects. PON1 activity in CD was related with markers of disease severity and was negatively correlated with the levels of lipid hydroperoxide and with the susceptibility of serum to lipid peroxidation induced in vitro by metal ions. The alteration of PON1 activity and markers of lipid peroxidation realized at lower extent in patients who were on a gluten-free diet.
Collapse
|
|
23
|
Bergamo P, Gogliettino M, Palmieri G, Cocca E, Maurano F, Stefanile R, Balestrieri M, Mazzarella G, David C, Rossi M. Conjugated linoleic acid protects against gliadin-induced depletion of intestinal defenses. Mol Nutr Food Res 2011; 55 Suppl 2:S248-56. [PMID: 21954188 DOI: 10.1002/mnfr.201100295] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2011] [Revised: 07/01/2011] [Accepted: 07/13/2011] [Indexed: 12/22/2022]
Abstract
SCOPE The involvement of oxidative stress in gluten-induced toxicity has been evidenced in vitro and in clinical studies but has never been examined in vivo. We recently demonstrated the protective activity of conjugated linoleic acid (CLA), which functions by the activation of nuclear factor erythroid 2-related factor2 (Nrf2), a key transcription factor for the synthesis of antioxidant and detoxifying enzymes (phase 2). Here, we evaluate the involvement of nuclear factor erythroid 2-related factor2 in gliadin-mediated toxicity in human Caco-2 intestinal cells and in gliadin-sensitive human leukocyte antigen-DQ8 transgenic mice (DQ8) and the protective activity of CLA. METHODS AND RESULTS Gliadin effects in differentiated Caco-2 cells and in DQ8 mice, fed with a gliadin-containing diet with or without CLA supplementation, were evaluated by combining enzymatic, immunochemical, immunohistochemical, and quantitative real-time PCR (qRT-PCR) assays. Gliadin toxicity was accompanied by downregulation of phase 2 and elevates proteasome-acylpeptide hydrolase activities in vitro and in vivo. Notably, gliadin was unable to generate severe oxidative stress extent or pathological consequences in DQ8 mice intestine comparable to those found in celiac patients and the alterations produced were hampered by CLA. CONCLUSION The beneficial effects of CLA against the depletion of crucial intestinal cytoprotective defenses indicates a novel nutritional approach for the treatment of intestinal disease associated with altered redox homeostasis.
Collapse
Affiliation(s)
- Paolo Bergamo
- Istituto di Scienze dell'Alimentazione, Consiglio Nazionale delle Ricerche (CNR-ISA), Avellino, Italy.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
24
|
Mollazadegan K, Kugelberg M, Lindblad BE, Ludvigsson JF. Increased risk of cataract among 28,000 patients with celiac disease. Am J Epidemiol 2011; 174:195-202. [PMID: 21624959 DOI: 10.1093/aje/kwr069] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Vitamin deficiencies are prevalent in celiac disease (CD) and are associated with cataract formation, but it is unknown whether persons with CD are at increased risk of cataract. The authors' objective in this population-based cohort study was to determine the risk of cataract among persons with biopsy-verified CD. Data on CD were collected from reports on small intestinal biopsies performed between July 1969 and February 2008 in the 28 regional pathology departments in Sweden. The authors identified 28,756 persons with CD (villous atrophy, Marsh pathology stage 3). For each person with CD, Statistics Sweden selected up to 5 controls matched for age and sex from the Total Population Register. Data on cataract were obtained from the Swedish National Hospital Discharge Register and the National Day-Surgery Register. Cox regression analysis was used to estimate the risk of cataract. During a median follow-up period of 9 years, the authors identified 1,159 cataracts among persons with CD (909 were expected) (hazard ratio = 1.28, 95% confidence interval: 1.19, 1.36). The absolute risk of cataract was 397/100,000 person-years in CD, with an excess risk of 86/100,000 person-years. In conclusion, this study found an increased risk of developing cataract in patients with CD.
Collapse
Affiliation(s)
- Kaziwe Mollazadegan
- Clinical Epidemiology Unit, Department of Medicine, Karolinska University Hospital, Solna, Sweden.
| | | | | | | |
Collapse
|
|
25
|
Mamone G, Picariello G, Addeo F, Ferranti P. Proteomic analysis in allergy and intolerance to wheat products. Expert Rev Proteomics 2011; 8:95-115. [PMID: 21329430 DOI: 10.1586/epr.10.98] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Owing to its extensive use in the human diet, wheat is among the most common causes of food-related allergies and intolerances. Allergies to wheat are provoked by ingestion, inhalation or contact with either the soluble or the insoluble gluten proteins in wheat. Gluten proteins, and particularly the gliadin fraction, are also the main factor triggering celiac disease, a common enteropathy induced by ingestion of wheat gluten proteins and related prolamins from oat, rye and barley in genetically susceptible individuals. The role of gliadin and of its derived peptides in eliciting the adverse reactions in celiac disease are still far from being completely explained. Owing to its unique pathogenesis, celiac disease is widely investigated as a model immunogenetic disorder. The structural characterization of the injuring agents, the gluten proteins, assumes a particular significance in order to deepen the understanding of the events that trigger this and similar diseases at the molecular level. Recent developments in proteomics have provided an important contribution to the understanding of several basic aspects of wheat protein-related diseases. These include: the identification of gluten fractions and derived peptides involved in wheat allergy and intolerance, including celiac disease, and the elucidation of their mechanism of toxicity; the development and validation of sensitive and specific methods for detecting trace amounts of gluten proteins in gluten-free foods for intolerant patients; and the formulation of completely new substitute foods and ingredients to replace the gluten-based ones. In this article, the main aspects of current and prospective applications of mass spectrometry and proteomic technologies to the structural characterization of gluten proteins and derived peptides are critically presented, with a focus on issues related to their detection, identification and quantification, which are relevant to the biochemical, immunological and toxicological aspects of wheat intolerance.
Collapse
|
|
26
|
Szaflarska-Poplawska A, Siomek A, Czerwionka-Szaflarska M, Gackowski D, Rózalski R, Guz J, Szpila A, Zarakowska E, Olinski R. Oxidatively damaged DNA/oxidative stress in children with celiac disease. Cancer Epidemiol Biomarkers Prev 2010; 19:1960-5. [PMID: 20696659 DOI: 10.1158/1055-9965.epi-10-0295] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Because patients with celiac disease face increased risk of cancer and there is considerable circumstantial evidence that oxidatively damaged DNA may be used as a marker predictive of cancer development, we decided, for the first time, to characterize oxidative stress/oxidative DNA damage in celiac disease patients. METHODS Two kinds of oxidatively damaged DNA biomarkers, namely, urinary excretion of 8-oxodG and 8-oxoGua, and the level of oxidatively damaged DNA in the leukocytes, as well as the level of antioxidant vitamins were analyzed using high-performance liquid chromatography (HPLC) and HPLC/gas chromatography with isotope dilution mass detection methods. These parameters were determined in three groups: (a) children with untreated celiac disease, (b) patients with celiac disease on a strict gluten-free diet, and (c) healthy children. RESULTS The mean level of 8-oxodG in DNA isolated from the leukocytes and in the urine samples of the two groups of celiacs was significantly higher than in controls, irrespective of diet. There was no statistically significant difference in these parameters between treated and untreated celiacs. The mean plasma retinol and alpha-tocopherol concentration in the samples of untreated celiacs was significantly lower than in treated celiacs. CONCLUSION Our results suggest that although diet can be partially responsible for oxidative stress/oxidatively damaged DNA in celiac patients, there is a factor independent of diet. IMPACT It is possible that celiac disease patients may be helped by dietary supplementation rich in vitamin A (and E) to minimize the risk of cancer development.
Collapse
Affiliation(s)
- Anna Szaflarska-Poplawska
- Department of Clinical Biochemistry, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, ul. Karlowicza 24, Bydgoszcz, Poland
| | | | | | | | | | | | | | | | | |
Collapse
|
|
27
|
Diosdado B, Buffart TE, Watkins R, Carvalho B, Ylstra B, Tijssen M, Bolijn AS, Lewis F, Maude K, Verbeke C, Nagtegaal ID, Grabsch H, Mulder CJJ, Quirke P, Howdle P, Meijer GA. High-resolution array comparative genomic hybridization in sporadic and celiac disease-related small bowel adenocarcinomas. Clin Cancer Res 2010; 16:1391-401. [PMID: 20179237 DOI: 10.1158/1078-0432.ccr-09-1773] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE The molecular pathogenesis of small intestinal adenocarcinomas is not well understood. Understanding the molecular characteristics of small bowel adenocarcinoma may lead to more effective patient treatment. EXPERIMENTAL DESIGN Forty-eight small bowel adenocarcinomas (33 non-celiac disease related and 15 celiac disease related) were characterized for chromosomal aberrations by high-resolution array comparative hybridization, microsatellite instability, and APC promoter methylation and mutation status. Findings were compared with clinicopathologic and survival data. Furthermore, molecular alterations were compared between celiac disease-related and non-celiac disease-related small bowel adenocarcinomas. RESULTS DNA copy number changes were observed in 77% small bowel adenocarcinomas. The most frequent DNA copy number changes found were gains on 5p15.33-5p12, 7p22.3-7q11.21, 7q21.2-7q21.3, 7q22.1-7q34, 7q36.1, 7q36.3, 8q11.21-8q24.3, 9q34.11-9q34.3, 13q11-13q34, 16p13.3, 16p11.2, 19q13.2, and 20p13-20q13.33, and losses on 4p13-4q35.2, 5q15-5q21.1, and 21p11.2-21q22.11. Seven highly amplified regions were identified on 6p21.1, 7q21.1, 8p23.1, 11p13, 16p11.2, 17q12-q21.1, and 19q13.2. Celiac disease-related and non-celiac disease-related small bowel adenocarcinomas displayed similar chromosomal aberrations. Promoter hypermethylation of the APC gene was found in 48% non-celiac disease-related and 73% celiac disease-related small bowel adenocarcinomas. No nonsense mutations were found. Thirty-three percent of non-celiac disease-related small bowel adenocarcinomas showed microsatellite instability, whereas 67% of celiac disease-related small bowel adenocarcinomas were microsatellite unstable. CONCLUSIONS Our study characterized chromosomal aberrations and amplifications involved in small bowel adenocarcinoma. At the chromosomal level, celiac disease-related and non-celiac disease-related small bowel adenocarcinomas did not differ. A defect in the mismatch repair pathways seems to be more common in celiac disease-related than in non-celiac disease-related small bowel adenocarcinomas. In contrast to colon and gastric cancers, no APC nonsense mutations were found in small bowel adenocarcinoma. However, APC promoter methylation seems to be a common event in celiac disease-related small bowel adenocarcinoma. Clin Cancer Res; 16(5); 1391-401.
Collapse
Affiliation(s)
- Begoña Diosdado
- Departments of Pathology and Gastroenterology, VU University Medical Center, Amsterdam, The Netherlands.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
28
|
Sánchez D, Palová-Jelínková L, Felsberg J, Simsová M, Pekáriková A, Pecharová B, Swoboda I, Mothes T, Mulder CJJ, Benes Z, Tlaskalová-Hogenová H, Tucková L. Anti-calreticulin immunoglobulin A (IgA) antibodies in refractory coeliac disease. Clin Exp Immunol 2008; 153:351-9. [PMID: 18637103 DOI: 10.1111/j.1365-2249.2008.03701.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Refractory coeliac disease (RCD) is a very rare and dangerous form of CD, in which gluten-free diet loses its therapeutic effect and the damage of intestinal mucosa persists. Because of the adherence to the diet, serological markers of CD [immunoglobulin A (IgA) antibodies against gliadin, tissue transglutaminase (tTG) and endomysium] are often missing in RCD patients. We found substantially elevated levels of IgA anti-calreticulin (CRT) antibodies in the sera of almost all RCD patients tested. These sera were negative for IgA antibodies to gliadin and tTG and only some of them showed IgA antibodies to enterocytes. Analysis of patients' IgA reactivity to CRT fragments (quarters and halves) by Western blotting revealed differences in the specificity of IgA antibodies between RCD and CD patients. We therefore used the Pepscan technique with synthetic overlapping decapeptides of CRT to characterize antigenic epitopes recognized by serum IgA antibodies of RCD patients. Employing this method we demonstrated several dominant antigenic epitopes recognized by IgA antibodies of RCD patients on the CRT molecule. Epitope GVTKAAEKQMKD was recognized predominantly by serum IgA of RCD patients. Our results suggest that testing for serum IgA antibodies against CRT and its selected peptide could be a very useful tool in RCD differential diagnosis.
Collapse
Affiliation(s)
- D Sánchez
- Department of Immunology, Institute of Microbiology, Czech Academy of Sciences, Prague, Czech Republic.
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
29
|
MacFarlane AJ, Stover PJ. Convergence of genetic, nutritional and inflammatory factors in gastrointestinal cancers. Nutr Rev 2008; 65:S157-66. [PMID: 18240541 DOI: 10.1111/j.1753-4887.2007.tb00355.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Gastrointestinal cancers account for 20% of all cancer incidences worldwide. Colorectal cancer is the second most common cause of all cancer-related mortality and is increasing in Western societies. Infection and inflammation contribute to 15-20% of all malignancies, and are predisposing risk factors for gastrointestinal cancers. Helicobacter pylori infection is commonly associated with gastric cancers, and chronic inflammation increases the risk of colorectal cancer by 1% per year. Micronutrient status and common genetic variations in human populations modify risk for gastrointestinal cancer. Chronic inflammation promotes carcinogenesis by inducing gene mutations, inhibiting apoptosis, and stimulating angiogenesis and cell proliferation. Inflammation also induces epigenetic alterations that are associated with cancer development. Two key genes in the inflammatory process, cyclooxygenase-2 (COX-2) and nuclear factor-kappa B (NF-kappaB), provide a mechanistic link between inflammation and cancer and are targets for chemoprevention. Dietary components, and human genetic variation that affects nutrient utilization, can directly modify inflammatory processes and/or suppress genomic alterations that are the molecular antecedents of cancers. The present report focuses on the convergence of genetic, nutritional, and inflammatory factors in the initiation and progression of gastrointestinal cancers, and the emerging dietary strategies for cancer prevention.
Collapse
|
|
30
|
Juuti-Uusitalo K, Mäki M, Kainulainen H, Isola J, Kaukinen K. Gluten affects epithelial differentiation-associated genes in small intestinal mucosa of coeliac patients. Clin Exp Immunol 2007; 150:294-305. [PMID: 17888028 PMCID: PMC2219351 DOI: 10.1111/j.1365-2249.2007.03500.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/13/2007] [Indexed: 01/25/2023] Open
Abstract
In coeliac disease gluten induces an immunological reaction in genetically susceptible patients, and influences on epithelial cell proliferation and differentiation in the small-bowel mucosa. Our aim was to find novel genes which operate similarly in epithelial proliferation and differentiation in an epithelial cell differentiation model and in coeliac disease patient small-bowel mucosal biopsy samples. The combination of cDNA microarray data originating from a three-dimensional T84 epithelial cell differentiation model and small-bowel mucosal biopsy samples from untreated and treated coeliac disease patients and healthy controls resulted in 30 genes whose mRNA expression was similarly affected. Nine of 30 were located directly or indirectly in the receptor tyrosine kinase pathway starting from the epithelial growth factor receptor. Removal of gluten from the diet resulted in a reversion in the expression of 29 of the 30 genes in the small-bowel mucosal biopsy samples. Further characterization by blotting and labelling revealed increased epidermal growth factor receptor and beta-catenin protein expression in the small-bowel mucosal epithelium in untreated coeliac disease patients compared to healthy controls and treated coeliac patients. We found 30 genes whose mRNA expression was affected similarly in the epithelial cell differentiation model and in the coeliac disease patient small-bowel mucosal biopsy samples. In particular, those genes involved in the epithelial growth factor-mediated signalling pathways may be involved in epithelial cell differentiation and coeliac disease pathogenesis. The epithelial cell differentiation model is a useful tool for studying gene expression changes in the crypt-villus axis.
Collapse
Affiliation(s)
- K Juuti-Uusitalo
- Paediatric Research Centre, Medical School and Department of Paediatrics, Tampere University Hospital and Medical School, University of Tampere, Tampere, Finland
| | | | | | | | | |
Collapse
|
|
31
|
Rizzello CG, De Angelis M, Di Cagno R, Camarca A, Silano M, Losito I, De Vincenzi M, De Bari MD, Palmisano F, Maurano F, Gianfrani C, Gobbetti M. Highly efficient gluten degradation by lactobacilli and fungal proteases during food processing: new perspectives for celiac disease. Appl Environ Microbiol 2007; 73:4499-507. [PMID: 17513580 PMCID: PMC1932817 DOI: 10.1128/aem.00260-07] [Citation(s) in RCA: 188] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Presently, the only effective treatment for celiac disease is a life-long gluten-free diet. In this work, we used a new mixture of selected sourdough lactobacilli and fungal proteases to eliminate the toxicity of wheat flour during long-time fermentation. Immunological (R5 antibody-based sandwich and competitive enzyme-linked immunosorbent assay [ELISA] and R5 antibody-based Western blot), two-dimensional electrophoresis, and mass spectrometry (matrix-assisted laser desorption ionization-time of flight, strong-cation-exchange-liquid chromatography/capillary liquid chromatography-electrospray ionization-quadrupole-time of flight [SCX-LC/CapLC-ESI-Q-TOF], and high-pressure liquid chromatography-electrospray ionization-ion trap mass spectrometry) analyses were used to determine the gluten concentration. Assays based on the proliferation of peripheral blood mononuclear cells (PBMCs) and gamma interferon production by PBMCs and intestinal T-cell lines (iTCLs) from 12 celiac disease patients were used to determine the protein toxicity of the pepsin-trypsin digests from fermented wheat dough (sourdough). As determined by R5-based sandwich and competitive ELISAs, the residual concentration of gluten in sourdough was 12 ppm. Albumins, globulins, and gliadins were completely hydrolyzed, while ca. 20% of glutenins persisted. Low-molecular-weight epitopes were not detectable by SCX-LC/CapLC-ESI-Q-TOF mass spectrometry and R5-based Western blot analyses. The kinetics of the hydrolysis of the 33-mer by lactobacilli were highly efficient. All proteins extracted from sourdough activated PBMCs and induced gamma interferon production at levels comparable to the negative control. None of the iTCLs demonstrated immunoreactivity towards pepsin-trypsin digests. Bread making was standardized to show the suitability of the detoxified wheat flour. Food processing by selected sourdough lactobacilli and fungal proteases may be considered an efficient approach to eliminate gluten toxicity.
Collapse
Affiliation(s)
- Carlo G Rizzello
- Department of Plant Protection and Applied Microbiology, University of Bari, Bari, Italy
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
32
|
Brandt I, Scharpé S, Lambeir AM. Suggested functions for prolyl oligopeptidase: a puzzling paradox. Clin Chim Acta 2006; 377:50-61. [PMID: 17034776 DOI: 10.1016/j.cca.2006.09.001] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2006] [Revised: 08/29/2006] [Accepted: 09/01/2006] [Indexed: 10/24/2022]
Abstract
Prolyl oligopeptidase (PO, E.C. 3.4.21.26) is a post-proline cleaving enzyme with endopeptidase activity towards peptides not longer than 30 amino acids. It has been purified and characterized from various mammalian and bacterial sources, but despite its thorough enzymological and structural characterization, the exact function of PO remains obscure. Many investigations have addressed the physiological role of this enzyme, mainly by the use of specific PO inhibitors, activity measurements in clinical samples and (neuro)peptide degradation studies. From the combined results emerges a puzzling paradox: how can an intracellular, cytoplasmatic oligopeptidase affect not only the amount of extracellular neuropeptides but also signal transduction and secretion? This report provides a review of the literature on the suggested functions for PO, highlighting possible pitfalls and contradictions.
Collapse
Affiliation(s)
- Inger Brandt
- Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences University of Antwerp, Universiteitsplein 1, Blg S6 B-2610 Antwerp (Wilrijk), Belgium
| | | | | |
Collapse
|