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Slager J, Simpson HL, Gacesa R, Chen L, Tan IL, Gelderloos J, Maatman A, Wijmenga C, Zhernakova A, Fu J, Weersma RK, Gonera G, Jonkers IH, Withoff S. High-resolution analysis of the treated coeliac disease microbiome reveals strain-level variation. Gut Microbes 2025; 17:2489071. [PMID: 40289251 PMCID: PMC12036492 DOI: 10.1080/19490976.2025.2489071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 03/05/2025] [Accepted: 03/31/2025] [Indexed: 04/30/2025] Open
Abstract
BACKGROUND Coeliac disease (CeD) is an immune-mediated disorder primarily affecting the small intestine, characterized by an inflammatory immune reaction to dietary gluten. CeD onset results from a multifaceted interplay of genetic and environmental factors. While recent data show that alterations in gut microbiome composition could play an important role, many current studies are constrained by small sample sizes and limited resolution. METHODS To address these limitations, we analyzed fecal gut microbiota from two Dutch cohorts, CeDNN (128 treated CeD patients (tCeD), 106 controls) and the Lifelines Dutch Microbiome Project (24 self-reported tCeD, 654 controls), using shotgun metagenomic sequencing. Self-reported IBS (570 cases, 1710 controls) and IBD (93 cases, 465 controls) were used as comparative conditions of the gastrointestinal tract. Interindividual variation within the case and control groups was calculated at whole microbiome and strain level. Finally, species-specific gene repertoires were analyzed in tCeD patients and controls. RESULTS Within-individual microbiome diversity was decreased in patients with self-reported IBS and IBD but not in tCeD patients. Each condition displayed a unique microbial pattern and, in addition to confirming previously reported microbiome associations, we identify an increase in the levels of Clostridium sp. CAG:253, Roseburia hominis, and Eggerthella lenta, amongst others. We further show that the observed changes can partially be explained by gluten-free diet adherence. We also observe increased interindividual variation of gut microbiome composition among tCeD patients and a higher bacterial mutation frequency in tCeD that contributes to higher interindividual variation at strain level. In addition, the immotile European subspecies of Eubacterium rectale, which has a distinct carbohydrate metabolism potential, was nearly absent in tCeD patients. CONCLUSION Our study sheds light on the complex interplay between the gut microbiome and CeD, revealing increased interindividual variation and strain-level variation in tCeD patients. These findings expand our understanding of the microbiome's role in intestinal health and disease.
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Affiliation(s)
- Jelle Slager
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Hanna L. Simpson
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Ranko Gacesa
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Lianmin Chen
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Cardiology, Nanjing Medical University, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Cardiovascular Research Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Ineke L. Tan
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Jody Gelderloos
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Astrid Maatman
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Cisca Wijmenga
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Alexandra Zhernakova
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Jingyuan Fu
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Rinse K. Weersma
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Gieneke Gonera
- Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Pediatrics, Wilhelmina Hospital Assen, Assen, The Netherlands
| | - Iris H. Jonkers
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Sebo Withoff
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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Leo S, Leonard MM, Valitutti F, Fasano A. Gut dysbiosis: cause or consequence of intestinal inflammation in celiac disease? Expert Rev Gastroenterol Hepatol 2025; 19:505-513. [PMID: 40133841 DOI: 10.1080/17474124.2025.2483406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 03/19/2025] [Indexed: 03/27/2025]
Abstract
INTRODUCTION Celiac disease (CeD) is an immune-mediated condition that occurs in genetically predisposed individuals ingesting gluten. It is characterized by enteropathy leading to both gastrointestinal and extra-intestinal symptoms. The prevalence of CeD has increased world-wide. Evidence suggests that genetic predisposition and exposure to gluten are necessary but not sufficient for CeD onset, implying that other unknown factors are at play in its pathogenesis. AREAS COVERED This review summarizes the current knowledge on the contribution of the gut microbiota to CeD pathogenesis, aiming to address the question of whether it is the cause or consequence of the celiac enteropathy. We reviewed the current literature (studies published in PubMed database between 2007 and 2023), linking gut microbiota dysbiosis and CeD, focusing specifically on prospective birth cohorts' studies and discussing how multi-omics and artificial intelligence (AI) could transform the diagnosis of CeD in a personalized medicine approach. EXPERT OPINION A multi-omic approach will allow for better clarification of the pivotal role of the microbiome in epigenetically triggering CeD pathogenesis. Further, the combination of multi-omics results with AI would pave the way to an improved CeD diagnosis and to the identification of new personalized therapeutic interventions.
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Affiliation(s)
- Stefano Leo
- European Biomedical Research Institute of Salerno, Salerno, Italy
| | - Maureen M Leonard
- Division of Pediatric Gastroenterology and Nutrition, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA, USA
- Mucosal Immunology and Biology Research Center, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA, USA
- Celiac Research Program, Harvard Medical School, Boston, MA, USA
| | - Francesco Valitutti
- Pediatrics Section, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Alessio Fasano
- European Biomedical Research Institute of Salerno, Salerno, Italy
- Division of Pediatric Gastroenterology and Nutrition, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA, USA
- Mucosal Immunology and Biology Research Center, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA, USA
- Celiac Research Program, Harvard Medical School, Boston, MA, USA
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Kelley K, Dogru D, Huang Q, Yang Y, Palm NW, Altindis E, Ludvigsson J. Children who develop celiac disease are predicted to exhibit distinct metabolic pathways among their gut microbiota years before diagnosis. Microbiol Spectr 2025; 13:e0146824. [PMID: 39902908 PMCID: PMC11878042 DOI: 10.1128/spectrum.01468-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 01/07/2025] [Indexed: 02/06/2025] Open
Abstract
Celiac disease (CD) is an autoimmune disease caused by a loss of gluten tolerance in genetically predisposed individuals. While 30%-40% of people possess the predisposing alleles, only 1%-2% are diagnosed with CD, suggesting that environmental factors are involved in disease pathogenesis. To determine an association between pediatric CD and the gut microbiome, we analyzed fecal samples from a prospective cohort study (ABIS). These samples were collected from children who later developed CD (CD progressors) and age-matched healthy children (at ages 1, 2.5, and 5) with similar HLA genotypes, breastfeeding durations, and gluten exposure times. We previously reported gut microbiome differences at ages 2.5 and 5 in this cohort; here, we present findings from samples collected at age 1 (n = 5). We identified 14 ASVs differing significantly between CD progressors and controls, including taxa linked to CD pathogenesis. CD progressors had increased Firmicutes and higher alpha diversity in IgA- bacteria. Using PICRUSt, we analyzed metabolic pathways enriched in CD progressors compared to controls at ages 1, 2.5, and 5 (n = 5-16), revealing enriched inflammatory and pathogenic pathways potentially contributing to CD-related immune dysregulation. While results are based on the primary EdgeR analysis, we also applied a non-parametric method of statistical analysis, reporting those results with supplementary figures. In conclusion, our findings suggest distinct metabolic pathways enriched in the gut microbiome of CD progressors years before diagnosis, which could inform targeted therapeutics for CD. As discussed in the limitations section, this small pilot study should be replicated with larger sample sizes for broader generalization. IMPORTANCE We analyzed gut microbiome data from children who later developed celiac disease (CD progressors) compared to healthy children in the first 5 years of life. Using fecal samples corresponding to the three phases of gut microbiome development, we uncovered enriched functional microbial pathways in CD progressors at age 1. Some of these pathways, implicated in bacterial pathogenesis, microbiota modulation, and inflammation, have been correlated with CD. We also identified taxa in CD progressors at age 1 including Lachnospiraceae, Alistipes, and Bifidobacterium dentium that were previously associated with CD. These findings suggest a potential role for these taxa and enriched pathways in pediatric CD onset years before diagnosis, highlighting potential for early interventions. While the findings of this exploratory study should be validated with larger sample sizes, our study suggests microbial metabolic pathways related to CD onset, enhancing our understanding of CD pathogenesis and the role of gut microbiome-mediated early alterations.
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Affiliation(s)
- Kristina Kelley
- Boston College Biology Department, Chestnut Hill, Massachusetts, USA
| | - Dogus Dogru
- Boston College Biology Department, Chestnut Hill, Massachusetts, USA
| | - Qian Huang
- Boston College Biology Department, Chestnut Hill, Massachusetts, USA
| | - Yi Yang
- Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Noah W. Palm
- Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Emrah Altindis
- Boston College Biology Department, Chestnut Hill, Massachusetts, USA
| | - Johnny Ludvigsson
- Crown Princess Victoria’s Children’s Hospital, Region Östergötland, Linköping, Sweden
- Division of Pediatrics, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
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Stødle IH, Koldsland OC, Lukina P, Andersen IL, Mjønes P, Rønne E, Høvik H, Ness-Jensen E, Verket A. Undiagnosed Celiac Disease and Periodontal Bone Loss: A Cross-Sectional Radiological Assessment from the HUNT Study. Int J Dent 2024; 2024:1952244. [PMID: 39257416 PMCID: PMC11383648 DOI: 10.1155/2024/1952244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 03/27/2024] [Accepted: 08/12/2024] [Indexed: 09/12/2024] Open
Abstract
Objective The objective was to assess radiographic periodontal bone loss in a population with previously undiagnosed celiac disease, and to compare it to a reference group without celiac disease. Background Periodontitis and celiac disease are chronic inflammatory diseases with possible similar features related to immune reactions and microbial dysbiosis. The relationship between these two diseases is not clear. Methods Clinical variables, blood samples, and answers to questionnaires were collected from participants in the fourth Trøndelag Health Study (HUNT4). Celiac disease was determined based on transglutaminase 2 (TG2), immunoglobulin A (IgA), and G (IgG) in serum samples. Seropositive individuals were invited to endoscopic examination and tissue sampling. Radiographically assessed bone loss caused by periodontitis in two different levels of severity was applied as outcome, that is, ≥15% and >33% of root length. Bone loss was determined in panoramic images in participants that had attended radiographic examination in the HUNT4 Oral Health Study or in the HUNT4 Coeliac Disease Study. The association between previously undiagnosed celiac disease and radiographic bone loss was estimated by adjusted Poisson regression models. Results Radiographic assessment was completed in 485 individuals with celiac disease determined by positive serology and in 4,727 individuals with negative serology (without celiac disease). Compared to nonceliacs, seropositive participants were less likely to present with ≥15% radiographic bone loss (prevalence ratio (PR) 0.89 (95% CI 0.84-0.96). A similar association was also observed after histopathological confirmation of celiac disease (PR 0.89 (95% CI 0.82-0.98). No association between undiagnosed celiac disease and periodontal bone loss was observed when analyses were limited to individuals with severe bone loss (>33%). Conclusion In this study of previously undiagnosed celiac disease and periodontal bone loss, newly diagnosed celiac disease was associated with less likelihood of presenting with ≥15% radiographic bone loss compared to a nonceliac reference group.
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Affiliation(s)
- Ida Haukåen Stødle
- Department of Periodontology Institute of Clinical Dentistry Faculty of Dentistry University of Oslo, Oslo, Norway
| | - Odd Carsten Koldsland
- Department of Periodontology Institute of Clinical Dentistry Faculty of Dentistry University of Oslo, Oslo, Norway
| | - Polina Lukina
- HUNT Research Centre Department of Public Health and Nursing Norwegian University of Science and Technology (NTNU), Levanger, Norway
| | - Ina L Andersen
- HUNT Research Centre Department of Public Health and Nursing Norwegian University of Science and Technology (NTNU), Levanger, Norway
- Department of Medicine Levanger Hospital Nord-Trøndelag Hospital Trust, Levanger, Norway
| | - Patricia Mjønes
- Department of Clinical and Molecular Medicine Norwegian University of Science and Technology (NTNU), Trondheim, Norway
- Department of Pathology St. Olav's Hospital Trondheim University Hospital, Trondheim, Norway
| | - Elin Rønne
- Department of Pathology St. Olav's Hospital Trondheim University Hospital, Trondheim, Norway
| | - Hedda Høvik
- Center for Oral Health Services and Research, Mid-Norway (TkMidt), Trondheim, Norway
| | - Eivind Ness-Jensen
- HUNT Research Centre Department of Public Health and Nursing Norwegian University of Science and Technology (NTNU), Levanger, Norway
- Department of Medicine Levanger Hospital Nord-Trøndelag Hospital Trust, Levanger, Norway
- Department of Molecular Medicine and Surgery Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - Anders Verket
- Department of Periodontology Institute of Clinical Dentistry Faculty of Dentistry University of Oslo, Oslo, Norway
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Iorfida D, Valitutti F, Vestri A, D'Adamo G, Passaro T, Crocco M, Malerba F, Monzani A, Rabbone I, Pensabene L, Giancotti L, Graziano F, Citrano M, Ferretti F, Trovato CM, Pacenza C, Iasevoli M, Banzato C, Lubrano R, Montuori M. Prevalence of delivery mode in an Italian nationwide cohort with celiac disease: a SIGENP multicenter retrospective study (the CD-deliver-IT). Ital J Pediatr 2024; 50:129. [PMID: 39061072 PMCID: PMC11282831 DOI: 10.1186/s13052-024-01710-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 07/20/2024] [Indexed: 07/28/2024] Open
Abstract
BACKGROUND Studies have indicated an association between cesarean section (CS), especially elective CS, and an increased risk of celiac disease (CD), but the conclusions of other studies are contradictory. The primary aim of this study (CD-deliver-IT) was to evaluate the rate of CS in a large population of CD patients throughout Italy. METHODS: This national multicenter retrospective study was conducted between December 2020 and November 2021. The coordinating center was the Pediatric Gastroenterology and Liver Unit of Policlinico Umberto I, Sapienza, University of Rome, Lazio, Italy. Eleven other referral centers for CD have participated to the study. Each center has collected data on mode of delivery and perinatal period of all CD patients referring to the center in the last 40 years. RESULTS Out of 3,259 CD patients recruited in different Italian regions, data on the mode of delivery were obtained from 3,234. One thousand nine hundred forty-one (1,941) patients (60%) were born vaginally and 1,293 (40%) by CS (8.3% emergency CS, 30.1% planned CS, 1.5% undefined CS). A statistically significant difference was found comparing median age at time of CD diagnosis of patients who were born by emergency CS (4 years, CI 95% 3.40-4.59), planned CS (7 years, CI 95% 6.02-7.97) and vaginal delivery (6 years, CI 95% 5.62-6.37) (log rank p < 0.0001). CONCLUSIONS This is the first Italian multicenter study aiming at evaluating the rate of CS in a large population of CD patients through Italy. The CS rate found in our CD patients is higher than rates reported in the general population over the last 40 years and emergency CS seems to be associated with an earlier onset of CD compared to vaginal delivery or elective CS in our large nationwide retrospective cohort. This suggests a potential role of the mode of delivery on the risk of developing CD and on its age of onset, but it is more likely that it works in concert with other perinatal factors. Further prospective studies on other perinatal factors potentially influencing gut microbiota are awaited in order to address heavy conflicting evidence reaming in this research field.
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Affiliation(s)
- Donatella Iorfida
- Department of Maternal and Child Health, Pediatrics and Neonatology Unit, Santa Maria Goretti Hospital, Sapienza - University of Rome, Latina, Italy
| | - Francesco Valitutti
- Department of Surgical and Biomedical Sciences, Pediatric Clinic, University of Perugia, Perugia, Italy
| | - Annarita Vestri
- Department of Public Health and Infectious Disease, Sapienza - University of Rome, Rome, Italy
| | - Grazia D'Adamo
- Pediatric Unit, AOU Salerno, P.O. Cava de' Tirreni, Salerno, Italy
| | - Tiziana Passaro
- Pediatric Unit, AOU Salerno, P.O. Cava de' Tirreni, Salerno, Italy
| | - Marco Crocco
- Pediatric Gastroenterology and Endoscopy Unit, IRCCS Istituto Giannina Gaslini, Genoa, 16147, Italy
| | - Federica Malerba
- Pediatric Gastroenterology and Endoscopy Unit, IRCCS Istituto Giannina Gaslini, Genoa, 16147, Italy
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
| | - Alice Monzani
- Department of Health Sciences, Division of Paediatrics, University of Piemonte Orientale, Novara, Italy
| | - Ivana Rabbone
- Department of Health Sciences, Division of Paediatrics, University of Piemonte Orientale, Novara, Italy
| | - Licia Pensabene
- Department of Surgical and Medical Sciences, Pediatric Unit, Magna Graecia University, Catanzaro, Italy
| | - Laura Giancotti
- Department of Surgical and Medical Sciences, Pediatric Unit, Magna Graecia University, Catanzaro, Italy
| | | | - Michele Citrano
- Pediatric Unit, Villa Sofia - Cervello Hospital, Palermo, Italy
| | - Francesca Ferretti
- Hepatology Gastroenterology and Nutrition Unit, Bambino Gesù Children Hospital, Rome, Italy
| | - Chiara Maria Trovato
- Hepatology Gastroenterology and Nutrition Unit, Bambino Gesù Children Hospital, Rome, Italy
| | | | - Mario Iasevoli
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", Pediatrics Section, University of Salerno, Baronissi, Italy
| | | | - Riccardo Lubrano
- Department of Maternal and Child Health, Pediatrics and Neonatology Unit, Santa Maria Goretti Hospital, Sapienza - University of Rome, Latina, Italy
| | - Monica Montuori
- Maternal and Child Health Department, Pediatric Gastroenterology and Liver Unit, Sapienza - University of Rome, Rome, Italy.
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Matera M, Guandalini S. How the Microbiota May Affect Celiac Disease and What We Can Do. Nutrients 2024; 16:1882. [PMID: 38931237 PMCID: PMC11206804 DOI: 10.3390/nu16121882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 06/02/2024] [Accepted: 06/05/2024] [Indexed: 06/28/2024] Open
Abstract
Celiac disease (CeD) is an autoimmune disease with a strong association with human leukocyte antigen (HLA), characterized by the production of specific autoantibodies and immune-mediated enterocyte killing. CeD is a unique autoimmune condition, as it is the only one in which the environmental trigger is known: gluten, a storage protein present in wheat, barley, and rye. How and when the loss of tolerance of the intestinal mucosa to gluten occurs is still unknown. This event, through the activation of adaptive immune responses, enhances epithelial cell death, increases the permeability of the epithelial barrier, and induces secretion of pro-inflammatory cytokines, resulting in the transition from genetic predisposition to the actual onset of the disease. While the role of gastrointestinal infections as a possible trigger has been considered on the basis of a possible mechanism of antigen mimicry, a more likely alternative mechanism appears to involve a complex disruption of the gastrointestinal microbiota ecosystem triggered by infections, rather than the specific effect of a single pathogen on intestinal mucosal homeostasis. Several lines of evidence show the existence of intestinal dysbiosis that precedes the onset of CeD in genetically at-risk subjects, characterized by the loss of protective bacterial elements that both epigenetically and functionally can influence the response of the intestinal epithelium leading to the loss of gluten tolerance. We have conducted a literature review in order to summarize the current knowledge about the complex and in part still unraveled dysbiosis that precedes and accompanies CeD and present some exciting new data on how this dysbiosis might be prevented and/or counteracted. The literature search was conducted on PubMed.gov in the time frame 2010 to March 2024 utilizing the terms "celiac disease and microbiota", "celiac disease and microbiome", and "celiac disease and probiotics" and restricting the search to the following article types: Clinical Trials, Meta-Analysis, Review, and Systematic Review. A total of 364 papers were identified and reviewed. The main conclusions of this review can be outlined as follows: (1) quantitative and qualitative changes in gut microbiota have been clearly documented in CeD patients; (2) intestinal microbiota's extensive and variable interactions with enterocytes, viral and bacterial pathogens and even gluten combine to impact the inflammatory immune response to gluten and the loss of gluten tolerance, ultimately affecting the pathogenesis, progression, and clinical expression of CeD; (3) gluten-free diet fails to restore the eubiosis of the digestive tract in CeD patients, and also negatively affects microbial homeostasis; (4) new tools allowing targeted microbiota therapy, such as the use of probiotics (a good example being precision probiotics like the novel strain of B. vulgatus (20220303-A2) begin to show exciting potential applications.
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Affiliation(s)
- Mariarosaria Matera
- Pediatric Clinical Microbiomics Service, Misericordia Hospital, Via Senese 161, 58100 Grosseto, Italy;
| | - Stefano Guandalini
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Celiac Disease Center, University of Chicago Medicine, 5841 S. Maryland Ave. MC 4065, Chicago, IL 60637, USA
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Gorini F, Tonacci A. Vitamin D: An Essential Nutrient in the Dual Relationship between Autoimmune Thyroid Diseases and Celiac Disease-A Comprehensive Review. Nutrients 2024; 16:1762. [PMID: 38892695 PMCID: PMC11174782 DOI: 10.3390/nu16111762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 05/29/2024] [Accepted: 06/03/2024] [Indexed: 06/21/2024] Open
Abstract
Autoimmune thyroid diseases (AITD) are among the most frequent autoimmune disorders, with a multifactorial etiology in which both genetic and environmental determinants are probably involved. Celiac disease (CeD) also represents a public concern, given its increasing prevalence due to the recent improvement of screening programs, leading to the detection of silent subtypes. The two conditions may be closely associated due to common risk factors, including genetic setting, changes in the composition and diversity of the gut microbiota, and deficiency of nutrients like vitamin D. This comprehensive review discussed the current evidence on the pivotal role of vitamin D in modulating both gut microbiota dysbiosis and immune system dysfunction, shedding light on the possible relevance of an adequate intake of this nutrient in the primary prevention of AITD and CeD. While future technology-based strategies for proper vitamin D supplementation could be attractive in the context of personalized medicine, several issues remain to be defined, including standardized assays for vitamin D determination, timely recommendations on vitamin D intake for immune system functioning, and longitudinal studies and randomized controlled trials to definitely establish a causal relationship between serum vitamin D levels and the onset of AITD and CeD.
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Affiliation(s)
- Francesca Gorini
- Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy;
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Annunziato A, Vacca M, Cristofori F, Dargenio VN, Celano G, Francavilla R, De Angelis M. Celiac Disease: The Importance of Studying the Duodenal Mucosa-Associated Microbiota. Nutrients 2024; 16:1649. [PMID: 38892582 PMCID: PMC11174386 DOI: 10.3390/nu16111649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 05/24/2024] [Accepted: 05/24/2024] [Indexed: 06/21/2024] Open
Abstract
There is increasing evidence indicating that changes in both the composition and functionality of the intestinal microbiome are closely associated with the development of several chronic inflammatory diseases, with celiac disease (CeD) being particularly noteworthy. Thanks to the advent of culture-independent methodologies, the ability to identify and quantify the diverse microbial communities residing within the human body has been significantly improved. However, in the context of CeD, a notable challenge lies in characterizing the specific microbiota present on the mucosal surfaces of the intestine, rather than relying solely on fecal samples, which may not fully represent the relevant microbial populations. Currently, our comprehension of the composition and functional importance of mucosa-associated microbiota (MAM) in CeD remains an ongoing field of research because the limited number of available studies have reported few and sometimes contradictory results. MAM plays a crucial role in the development and progression of CeD, potentially acting as both a trigger and modulator of the immune response within the intestinal mucosa, given its proximity to the epithelial cells and direct interaction. According to this background, this review aims to consolidate the existing literature specifically focused on MAM in CeD. By elucidating the complex interplay between the host immune system and the gut microbiota, we aim to pave the way for new interventions based on novel therapeutic targets and diagnostic biomarkers for MAM in CeD.
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Affiliation(s)
- Alessandro Annunziato
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, Via Amendola 165/a, 70126 Bari, Italy; (A.A.); (G.C.); (M.D.A.)
| | - Mirco Vacca
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, Via Amendola 165/a, 70126 Bari, Italy; (A.A.); (G.C.); (M.D.A.)
| | - Fernanda Cristofori
- Interdisciplinary Department of Medicine, Pediatric Section, Children’s Hospital ‘Giovanni XXIII’, University of Bari Aldo Moro, 70126 Bari, Italy; (F.C.); (V.N.D.); (R.F.)
| | - Vanessa Nadia Dargenio
- Interdisciplinary Department of Medicine, Pediatric Section, Children’s Hospital ‘Giovanni XXIII’, University of Bari Aldo Moro, 70126 Bari, Italy; (F.C.); (V.N.D.); (R.F.)
| | - Giuseppe Celano
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, Via Amendola 165/a, 70126 Bari, Italy; (A.A.); (G.C.); (M.D.A.)
| | - Ruggiero Francavilla
- Interdisciplinary Department of Medicine, Pediatric Section, Children’s Hospital ‘Giovanni XXIII’, University of Bari Aldo Moro, 70126 Bari, Italy; (F.C.); (V.N.D.); (R.F.)
| | - Maria De Angelis
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, Via Amendola 165/a, 70126 Bari, Italy; (A.A.); (G.C.); (M.D.A.)
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Skoracka K, Hryhorowicz S, Tovoli F, Raiteri A, Rychter AM, Słomski R, Dobrowolska A, Granito A, Krela-Kaźmierczak I. From an understanding of etiopathogenesis to novel therapies-what is new in the treatment of celiac disease? Front Pharmacol 2024; 15:1378172. [PMID: 38698821 PMCID: PMC11063403 DOI: 10.3389/fphar.2024.1378172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 04/02/2024] [Indexed: 05/05/2024] Open
Abstract
Celiac disease, a chronic autoimmune disorder caused by genetic factors and exposure to gluten, is increasingly being recognized and diagnosed in both children and adults. Scientists have been searching for a cure for this disease for many years, but despite the impressive development of knowledge in this field, a gluten-free diet remains the only recommended therapy for all patients. At the same time, the increasing diagnosis of celiac disease in adults, which was considered a childhood disease in the 20th century, has opened a discussion on the etiopathology of the disease, which is proven to be very complex and involves genetic, immunological, nutritional, environmental and gut microbiota-related factors. In this review, we extensively discuss these factors and summarize the knowledge of the proposed state-of-the-art treatments for celiac disease to address the question of whether a better understanding of the etiopathogenesis of celiac disease has opened new directions for therapy.
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Affiliation(s)
- Kinga Skoracka
- Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
- Doctoral School, Poznan University of Medical Sciences, Poznan, Poland
| | | | - Francesco Tovoli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Alberto Raiteri
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Anna Maria Rychter
- Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
- Laboratory of Nutrigenetics, Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - Ryszard Słomski
- Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
| | - Agnieszka Dobrowolska
- Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - Alessandro Granito
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Iwona Krela-Kaźmierczak
- Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
- Laboratory of Nutrigenetics, Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
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Agrawal A, Anjankar A. Alterations of Gastrointestinal Microbe Composition in Various Human Diseases and Its Significance in the Early Diagnosis of Diseases. Cureus 2024; 16:e52435. [PMID: 38371166 PMCID: PMC10870805 DOI: 10.7759/cureus.52435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Accepted: 01/16/2024] [Indexed: 02/20/2024] Open
Abstract
A 100 trillion bacteria, viruses, fungi, and archaea make up the human gut microbe. It has co-evolved with its human host and carries out essential tasks that improve general health. The relationship between gastrointestinal microbes and human health has been a growing field of interest and research in recent times. The gastrointestinal microbes are connected by complex networks and connections, and the host has given birth to the gut-microbe-brain axis, which shows the crucial effect that this circumstance could have on the health and diseases of the brain and spinal cord (or the central nervous system [CNS]). The microbe and the CNS interact bi-directionally via autonomic, neuroendocrine, gastrointestinal, and immune system pathways. The gut microbe has been connected to a range of gastrointestinal and extra-gastrointestinal diseases. The recent investigation supports the suspicion that the gut-microbe-brain axis could play a role in neuropsychiatric disorders including depression, dementia, post-traumatic stress disorder, anxiousness, bipolar disorder, schizophrenia, and obsessive-compulsive disorder, alongside chronic host illnesses such as obesity, diabetes, and inflammation. Studies point to gut microorganisms as possible biomarkers for a wide range of mental health issues. Changes in the gut microbe may be a crucial factor in the onset and advancement of non-alcoholic fatty liver damage. Gut microbes have been seen to influence microglia's response to the CNS's regional signals and thus to pain and inflammation. Data suggest that altering the gut microbe in those with chronic pain may be a successful method for reducing pain. Numerous investigations have documented alterations in the gut microbes made in Alzheimer patients and schizophrenic patients. The risk of breast cancer can be reduced by restoring gut microbe homeostasis and reducing systemic estrogen levels.
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Affiliation(s)
- Aman Agrawal
- Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Ashish Anjankar
- Biochemistry, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
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11
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Fasano A, Matera M. Probiotics to Prevent Celiac Disease and Inflammatory Bowel Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1449:95-111. [PMID: 39060733 DOI: 10.1007/978-3-031-58572-2_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/28/2024]
Abstract
The incidence of chronic inflammatory diseases (CIDs) is dramatically increasing in the developed world, resulting in an increased burden of disease in childhood. Currently, there are limited effective strategies for treating or preventing these conditions. To date, myriads of cross-sectional studies have described alterations in the composition of the gut microbiota in a variety of disease states, after the disease has already occurred. We suggest that to mechanically link these microbiome changes with disease pathogenesis, a prospective cohort design is needed to capture changes that precede or coincide with disease onset and symptoms. In addition, these prospective studies must integrate microbiological, metagenomic, meta transcriptomic and metabolomic data with minimal and standardized clinical and environmental metadata that allow to correctly compare and interpret the results of the analysis of the human microbiota in order to build a system-level model of the interactions between the host and the development of the disease. The creation of new biological computational models thus constructed will allow us to finally move from the detection of simple elements of "association" to the identification of elements of real "causality" allowing to provide a mechanistic approach to the exploration of the development of CIDs.This can only be done when these diseases are studied as complex biological networks. In this chapter we discuss the current knowledge regarding the contribution of the microbiome to CID in childhood, focusing on celiac disease and inflammatory bowel disease, with the overall aim of identifying pathways to shift research from descriptive to mechanistic approaches. We then examine how some components of the microbiota, through epigenetic reprogramming, can start the march from genetic predisposition to clinical expression of CIDs, thus opening up new possibilities for intervention, through microbiota therapy targeting the manipulation of the composition and function of the microbiota, for future applications of precision medicine and primary prevention.
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Affiliation(s)
- Alessio Fasano
- Research Centre for Immunology and Mucosal Biology and Division of Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital for Children - Harvard Medical School, Boston, USA, MA.
- Mucosal Immunology and Biology Research Center and Division of Pediatric Gastroenterology and Nutrition, Mass General for Children - Harvard Medical School, Boston, MA, USA.
| | - Mariarosaria Matera
- Neonatologist, Neurodevelopmental Clinics and Pediatric Clinical Microbiomic - Misericordia Hospital, Grosseto, Italy
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12
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Stahl M, Koletzko S, Andrén Aronsson C, Lindfors K, Liu E, Agardh D. Coeliac disease: what can we learn from prospective studies about disease risk? THE LANCET. CHILD & ADOLESCENT HEALTH 2024; 8:63-74. [PMID: 37972632 PMCID: PMC10965251 DOI: 10.1016/s2352-4642(23)00232-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 09/01/2023] [Accepted: 09/06/2023] [Indexed: 11/19/2023]
Abstract
Paediatric prospective studies of coeliac disease with longitudinal collection of biological samples and clinical data offer a unique perspective on disease risk. This Review highlights the information now available from international paediatric prospective studies on genetic and environmental risk factors for coeliac disease. In addition, recent omics studies have made it possible to study complex interactions between genetic and environmental factors and thereby further our insight into the causes of the disease. In the future, paediatric prospective studies will be able to provide more detailed risk prediction models combining genes, the environment, and biological corroboration from multiomics. Such studies could also contribute to biomarker development and an improved understanding of disease pathogenesis.
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Affiliation(s)
- Marisa Stahl
- Pediatric Gastroenterology, Hepatology, and Nutrition, Digestive Health Institute, Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
| | - Sibylle Koletzko
- Department of Pediatrics, Dr von Hauner Kinderspital, LMU University Hospital, LMU Munich, Munich, Germany; Department of Pediatrics, Gastroenterology and Nutrition, School of Medicine Collegium Medicum University of Warmia and Mazury, Olsztyn, Poland
| | - Carin Andrén Aronsson
- Unit of Celiac Disease and Diabetes, Department of Clinical Sciences, Lund University, Malmö, Sweden
| | - Katri Lindfors
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Edwin Liu
- Pediatric Gastroenterology, Hepatology, and Nutrition, Digestive Health Institute, Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Daniel Agardh
- Unit of Celiac Disease and Diabetes, Department of Clinical Sciences, Lund University, Malmö, Sweden
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13
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Besser HA, Khosla C. Celiac disease: mechanisms and emerging therapeutics. Trends Pharmacol Sci 2023; 44:949-962. [PMID: 37839914 PMCID: PMC10843302 DOI: 10.1016/j.tips.2023.09.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 09/14/2023] [Accepted: 09/20/2023] [Indexed: 10/17/2023]
Abstract
Celiac disease (CeD) is a widespread, gluten-induced, autoimmune disorder that lacks any medicinal therapy. Towards the goal of developing non-dietary treatments for CeD, research has focused on elucidating its molecular and cellular etiology. A model of pathogenesis has emerged centered on interactions between three molecular families: specific class II MHC proteins on antigen-presenting cells (APCs), deamidated gluten-derived peptides, and T cell receptors (TCRs) on inflammatory CD4+ T cells. Growing evidence suggests that this pathogenic axis can be pharmacologically targeted to protect patients from some of the adverse effects of dietary gluten. Further studies have revealed the existence of additional host and environmental contributors to disease initiation and tissue damage. This review summarizes our current understanding of CeD pathogenesis and how it is being harnessed for therapeutic design and development.
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Affiliation(s)
- Harrison A Besser
- Department of Chemistry, Stanford University, Stanford, CA 94305, USA; Stanford Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Chaitan Khosla
- Department of Chemistry, Stanford University, Stanford, CA 94305, USA; Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA; Sarafan ChEM-H (Chemistry, Engineering and Medicine for Human Health), Stanford University, Stanford, CA 94305, USA.
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14
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Aparicio A, Sun Z, Gold DR, Litonjua AA, Weiss ST, Lee-Sarwar K, Liu YY. Genotype-microbiome-metabolome associations in early childhood, and their link to BMI and childhood obesity. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.11.13.23298467. [PMID: 38014043 PMCID: PMC10680902 DOI: 10.1101/2023.11.13.23298467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2023]
Abstract
The influence of genotype on defining the human gut microbiome has been extensively studied, but definite conclusions have not yet been found. To fill this knowledge gap, we leverage data from children enrolled in the Vitamin D Antenatal Asthma Reduction Trial (VDAART) from 6 months to 8 years old. We focus on a pool of 12 genes previously found to be associated with the gut microbiome in independent studies, establishing a Bonferroni corrected significance level of p-value < 2.29 × 10 -6 . We identified significant associations between SNPs in the FHIT gene (known to be associated with obesity and type 2 diabetes) and obesity-related microbiome features, and the children's BMI through their childhood. Based on these associations, we defined a set of SNPs of interest and a set of taxa of interest. Taking a multi-omics approach, we integrated plasma metabolome data into our analysis and found simultaneous associations among children's BMI, the SNPs of interest, and the taxa of interest, involving amino acids, lipids, nucleotides, and xenobiotics. Using our association results, we constructed a quadripartite graph where each disjoint node set represents SNPs in the FHIT gene, microbial taxa, plasma metabolites, or BMI measurements. Network analysis led to the discovery of patterns that identify several genetic variants, microbial taxa and metabolites as new potential markers for obesity, type 2 diabetes, or insulin resistance risk.
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Belei O, Jugănaru I, Basaca DG, Munteanu AI, Mărginean O. The Role of Intestinal Microbiota in Celiac Disease and Further Therapeutic Perspectives. Life (Basel) 2023; 13:2039. [PMID: 37895421 PMCID: PMC10608277 DOI: 10.3390/life13102039] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 10/01/2023] [Accepted: 10/04/2023] [Indexed: 10/29/2023] Open
Abstract
Celiac disease (CD) is an immune-mediated enteropathy caused by exposure to gluten and related prolamins in genetically susceptible individuals. It is a complex genetic disorder with multiple contributing genes. Linkage studies have identified several genomic regions that probably contain CD susceptibility genes. The most important genetic factors are HLA-DQ2 and DQ8. Several known environmental triggers promote the onset of CD at any age after gluten introduction in individuals with a genetic background, such as viral infections and intestinal dysbiosis. Recent publications have described the interference of the intestinal microbiome in gluten metabolism, modulation of local immune reactions, and in maintaining normal gut permeability. These results have promoted further lines of research on the benefit of probiotic administration to prevent disease onset or alleviate clinical symptoms along with a gluten-free diet (GFD). The relationship between gut microbiome changes and the onset of CD is incompletely understood, still being the subject of current research. This narrative review analyzes the interplay between environmental factors, intestinal microbiome alterations, and the course of CD. Furthermore, this review sets out to discuss if modulation of intestinal microflora with pre- and probiotics along with a GFD could represent a reliable therapeutic target for celiac patients.
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Affiliation(s)
- Oana Belei
- First Pediatric Clinic, Disturbances of Growth and Development on Children Research Center, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timișoara, Romania; (O.B.); (D.-G.B.); (A.I.M.); (O.M.)
- First Pediatric Clinic, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timișoara, Romania
| | - Iulius Jugănaru
- First Pediatric Clinic, Disturbances of Growth and Development on Children Research Center, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timișoara, Romania; (O.B.); (D.-G.B.); (A.I.M.); (O.M.)
- First Pediatric Clinic, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timișoara, Romania
| | - Diana-Georgiana Basaca
- First Pediatric Clinic, Disturbances of Growth and Development on Children Research Center, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timișoara, Romania; (O.B.); (D.-G.B.); (A.I.M.); (O.M.)
- First Pediatric Clinic, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timișoara, Romania
| | - Andrei Ioan Munteanu
- First Pediatric Clinic, Disturbances of Growth and Development on Children Research Center, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timișoara, Romania; (O.B.); (D.-G.B.); (A.I.M.); (O.M.)
- First Pediatric Clinic, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timișoara, Romania
| | - Otilia Mărginean
- First Pediatric Clinic, Disturbances of Growth and Development on Children Research Center, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timișoara, Romania; (O.B.); (D.-G.B.); (A.I.M.); (O.M.)
- First Pediatric Clinic, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timișoara, Romania
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Jenickova E, Andrén Aronsson C, Mascellani Bergo A, Cinek O, Havlik J, Agardh D. Effects of Lactiplantibacillus plantarum and Lacticaseibacillus paracasei supplementation on the faecal metabolome in children with coeliac disease autoimmunity: a randomised, double-blinded placebo-controlled clinical trial. Front Nutr 2023; 10:1183963. [PMID: 37485388 PMCID: PMC10359497 DOI: 10.3389/fnut.2023.1183963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 06/08/2023] [Indexed: 07/25/2023] Open
Abstract
Introduction Coeliac disease is a lifelong immune-mediated enteropathy manifested as gluten intolerance in individuals carrying specific human leukocyte antigen (HLA) molecules. Other factors than genetics and gluten intake, however, may play a role in triggering the disease. The gut internal environment is thought to be one of these potential contributing factors, and it can be influenced throughout life. Methods We examine the impact of Lactiplantibacillus plantarum HEAL9 and Lacticaseibacillus paracasei 8700:2 supplementation on the faecal metabolome in genetically predisposed children having tissue transglutaminase autoantibodies, i.e., coeliac disease autoimmunity. Probiotic strains were selected based on their beneficial properties, including mucosal permeability and immune modulation effects. The intervention group (n = 40) and control group (n = 38) took the probiotics or placebo daily for 6 months in a double-blinded randomised trial. Faecal samples were collected at baseline and after 3 and 6 months and analysed using the 1H NMR for metabolome. The incorporation of 16S rRNA sequencing as a supportive dataset complemented the analysis of the metabolome data. Results During the 6 months of intervention, the stool concentrations of 4-hydroxyphenylacetate increased in the intervention group as compared to controls, whereas concentrations of threonine, valine, leucine, isoleucine, methionine, phenylalanine, aspartate, and fumarate decreased. Additionally, a noteworthy effect on the glycine, serine, and threonine metabolic pathway has been observed. Conclusion The findings suggest a modest yet significant impact of the probiotics on the faecal metabolome, primarily influencing proteolytic processes in the gut. Clinical trial registration ClinicalTrials.gov, NCT03176095.
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Affiliation(s)
- Eliska Jenickova
- Department of Food Science, Czech University of Life Sciences Prague, Prague, Czechia
| | | | - Anna Mascellani Bergo
- Department of Food Science, Czech University of Life Sciences Prague, Prague, Czechia
| | - Ondrej Cinek
- Department of Pediatrics and Department of Medical Microbiology, Charles University in Prague and University Hospital Motol, Prague, Czechia
| | - Jaroslav Havlik
- Department of Food Science, Czech University of Life Sciences Prague, Prague, Czechia
| | - Daniel Agardh
- Department of Clinical Sciences, Lund University, Malmö, Sweden
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17
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González-García BP, Marí S, Cilleros-Portet A, Hernangomez-Laderas A, Fernandez-Jimenez N, García-Santisteban I, Bilbao JR. Two-Sample Mendelian Randomization detects bidirectional causality between gut microbiota and celiac disease in individuals with high genetic risk. Front Immunol 2023; 14:1082862. [PMID: 37457693 PMCID: PMC10347381 DOI: 10.3389/fimmu.2023.1082862] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 06/07/2023] [Indexed: 07/18/2023] Open
Abstract
Background Celiac Disease (CeD) is an autoimmune disorder triggered by gluten intake in genetically susceptible individuals. Highest risk individuals are homozygous for the Human Leucocyte Antigen (HLA) DQ2.5 haplotype or DQ2.5/DQ2.2 heterozygous. Both the HLA-DQ2-positive high genetic risk individuals and those that have developed the disease have altered intestinal microbiota, but it remains unclear whether these alterations are a cause or a consequence of CeD. Objective To investigate a potential bidirectional causality between gut microbiota (GM) and CeD in HLA-DQ2 high genetic risk individuals. Materials and Methods We performed a bidirectional Two-Sample Mendelian Randomization (2SMR) test using summary statistics from the largest publicly available Genome-Wide Association Study (GWAS) of GM and the summary statistics of the Immunochip CeD study of those individuals with the HLA-DQ2 high-risk haplotype. To test whether changes in GM composition were causally linked to CeD, GM data were used as exposure and CeD data as outcome; to test for reverse causation, the exposure and outcome datasets were inverted. Results We identified several bacteria from Ruminococcaceae and Lachnospiraceae families of the Firmicutes phylum as potentially causal in both directions. In addition, our results suggest that changes in the abundance of Veillonellaceae family might be causal in the development of CeD, while alterations in Pasteurellaceae family might be a consequence of the disease itself. Conclusion Our results suggest that the relationship between GM and HLA-DQ2 high risk individuals is highly complex and bidirectional.
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Affiliation(s)
- Bárbara P. González-García
- Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU) and Biocruces Bizkaia Health Research Institute, Leioa, Spain
| | - Sergi Marí
- Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU) and Biocruces Bizkaia Health Research Institute, Leioa, Spain
| | - Ariadna Cilleros-Portet
- Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU) and Biocruces Bizkaia Health Research Institute, Leioa, Spain
| | - Alba Hernangomez-Laderas
- Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU) and Biocruces Bizkaia Health Research Institute, Leioa, Spain
| | - Nora Fernandez-Jimenez
- Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU) and Biocruces Bizkaia Health Research Institute, Leioa, Spain
| | - Iraia García-Santisteban
- Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU) and Biocruces Bizkaia Health Research Institute, Leioa, Spain
| | - Jose Ramon Bilbao
- Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU) and Biocruces Bizkaia Health Research Institute, Leioa, Spain
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
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18
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Martín-Masot R, Jiménez-Muñoz M, Herrador-López M, Navas-López VM, Obis E, Jové M, Pamplona R, Nestares T. Metabolomic Profiling in Children with Celiac Disease: Beyond the Gluten-Free Diet. Nutrients 2023; 15:2871. [PMID: 37447198 DOI: 10.3390/nu15132871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 06/20/2023] [Accepted: 06/22/2023] [Indexed: 07/15/2023] Open
Abstract
Celiac disease (CD) is included in the group of complex or multifactorial diseases, i.e., those caused by the interaction of genetic and environmental factors. Despite a growing understanding of the pathophysiological mechanisms of the disease, diagnosis is still often delayed and there are no effective biomarkers for early diagnosis. The only current treatment, a gluten-free diet (GFD), can alleviate symptoms and restore intestinal villi, but its cellular effects remain poorly understood. To gain a comprehensive understanding of CD's progression, it is crucial to advance knowledge across various scientific disciplines and explore what transpires after disease onset. Metabolomics studies hold particular significance in unravelling the complexities of multifactorial and multisystemic disorders, where environmental factors play a significant role in disease manifestation and progression. By analyzing metabolites, we can gain insights into the reasons behind CD's occurrence, as well as better comprehend the impact of treatment initiation on patients. In this review, we present a collection of articles that showcase the latest breakthroughs in the field of metabolomics in pediatric CD, with the aim of trying to identify CD biomarkers for both early diagnosis and treatment monitoring. These advancements shed light on the potential of metabolomic analysis in enhancing our understanding of the disease and improving diagnostic and therapeutic strategies. More studies need to be designed to cover metabolic profiles in subjects at risk of developing the disease, as well as those analyzing biomarkers for follow-up treatment with a GFD.
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Affiliation(s)
- Rafael Martín-Masot
- Pediatric Gastroenterology and Nutrition Unit, Hospital Regional Universitario de Malaga, 29010 Málaga, Spain
- Institute of Nutrition and Food Technology "José MataixVerdú" (INYTA), Biomedical Research Centre (CIBM), University of Granada, 18071 Granada, Spain
| | - María Jiménez-Muñoz
- Pediatric Gastroenterology and Nutrition Unit, Hospital Regional Universitario de Malaga, 29010 Málaga, Spain
| | - Marta Herrador-López
- Pediatric Gastroenterology and Nutrition Unit, Hospital Regional Universitario de Malaga, 29010 Málaga, Spain
| | - Víctor Manuel Navas-López
- Pediatric Gastroenterology and Nutrition Unit, Hospital Regional Universitario de Malaga, 29010 Málaga, Spain
| | - Elia Obis
- Department of Experimental Medicine, Lleida Biomedical Research Institute (IRBLleida), University of Lleida (UdL), 25198 Lleida, Spain
| | - Mariona Jové
- Department of Experimental Medicine, Lleida Biomedical Research Institute (IRBLleida), University of Lleida (UdL), 25198 Lleida, Spain
| | - Reinald Pamplona
- Department of Experimental Medicine, Lleida Biomedical Research Institute (IRBLleida), University of Lleida (UdL), 25198 Lleida, Spain
| | - Teresa Nestares
- Institute of Nutrition and Food Technology "José MataixVerdú" (INYTA), Biomedical Research Centre (CIBM), University of Granada, 18071 Granada, Spain
- Department of Physiology, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain
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19
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Rossi RE, Dispinzieri G, Elvevi A, Massironi S. Interaction between Gut Microbiota and Celiac Disease: From Pathogenesis to Treatment. Cells 2023; 12:823. [PMID: 36980164 PMCID: PMC10047417 DOI: 10.3390/cells12060823] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 12/24/2022] [Accepted: 01/01/2023] [Indexed: 03/09/2023] Open
Abstract
Celiac disease (CD) is a common systemic disorder that results from an abnormal response of human immunity to gluten intake, affecting the small intestine. In individuals who carry a genetic susceptibility, CD is triggered by environmental factors, including viral infections and dysbiosis of the gut microbiota. The gut microbiome is essential in controlling the immune system, and recent findings indicate that changes in the gut microbiome may contribute to various chronic immune disorders, such as CD through mechanisms that still require further exploration. Some bacteria exhibit epitopes that mimic gliadin and may enhance an immune response in the host. Other bacteria, including Pseudomonas aeruginosa, may work in conjunction with gluten to trigger and escalate intestinal inflammation. The microbiota may also directly influence antigen development through the production of immunogenic or tolerogenic gluten peptides or directly influence intestinal permeability through the release of zonulin. Finally, the gut microbiome can impact intestinal inflammation by generating proinflammatory or anti-inflammatory cytokines and metabolites. It is crucial to consider the impact of genetic factors (specifically, HLA-DQ haplotypes), perinatal elements such as birth mode, type of infant feeding, and antibiotic and infection exposure on the composition of the early intestinal microbiome. According to the available studies, the gut microbiome alterations associated with CD tend to exhibit a decreased presence of beneficial bacteria, including some anti-inflammatory Bifidobacterium species. However, some controversy remains as some reports have found no significant differences between the gut microbiomes of individuals with and without CD. A better understanding of the gut microbiome's role in the development of CD would greatly benefit both prevention and treatment efforts, especially in complicated or treatment-resistant cases. Here, we have attempted to summarize the available evidence on the relationship between the gut microbiota and CD, with a particular focus on potential therapeutic targets.
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Affiliation(s)
- Roberta Elisa Rossi
- Gastroenterology and Endoscopy Unit, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy
| | - Giulia Dispinzieri
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca and European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Via Pergolesi 33, 20900 Monza, Italy
| | - Alessandra Elvevi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca and European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Via Pergolesi 33, 20900 Monza, Italy
| | - Sara Massironi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca and European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Via Pergolesi 33, 20900 Monza, Italy
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20
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Alkhiari R, Adler JR. Psychiatric and Neurological Manifestations of Celiac Disease in Adults. Cureus 2023; 15:e35712. [PMID: 36875248 PMCID: PMC9984242 DOI: 10.7759/cureus.35712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/03/2023] [Indexed: 03/06/2023] Open
Abstract
Celiac disease (CD), a chronic inflammatory disorder of the intestines, affects 0.7% to 1.4% of the world's population. CD causes diarrhea, abdominal discomfort, bloating, flatulence, and, in rare cases, constipation in the digestive tract. Since the identification of gluten as the disease-causing antigen, CD patients have been treated with a gluten-free diet, which is advantageous but has limitations for certain patient groups. CD is associated with mood disorders, such as manic-depressive disease, schizophrenia, and bipolar disorder, as well as other disorders such as depression and anxiety. The relationship between CD and psychological issues is not entirely understood. Here, we look at the most recent psychiatric data as they pertain to CD, as well as the relevant psychiatric manifestations that have been associated with this condition. Clinicians should examine mental health factors when a CD diagnosis is established. More research is needed to understand the pathophysiology of CD's psychiatric manifestations.
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Affiliation(s)
| | - John R Adler
- Department of Medicine, Qassim University, Qassim, SAU
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21
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Molaaghaee-Rouzbahani S, Asri N, Sapone A, Baghaei K, Yadegar A, Amani D, Rostami-Nejad M. Akkermansia muciniphila exerts immunomodulatory and anti-inflammatory effects on gliadin-stimulated THP-1 derived macrophages. Sci Rep 2023; 13:3237. [PMID: 36828897 PMCID: PMC9958093 DOI: 10.1038/s41598-023-30266-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 02/20/2023] [Indexed: 02/26/2023] Open
Abstract
Macrophages (MQs) pro-inflammatory phenotype is triggered by gliadin peptides. Akkermansia muciniphila (A. muciniphila) showed to enhance the anti-inflammatory phenotype of MQs. This study aimed to investigate the anti-inflammatory effects of A. muciniphila, on gliadin stimulated THP-1 derived macrophages. THP-1 cell line monocytes were differentiated into MQs by phorbol 12-myristate 13-acetate (PMA). MQs were treated with A. muciniphila before and after stimulation with gliadin (pre- and post-treat). CD11b, as a marker of macrophage differentiation, and CD206 and CD80, as M1 and M2 markers, were evaluated by flow cytometry technique. The mRNA expression of TGF-β, IL-6, and IL-10 and protein levels of IL-10 and TNF-α were measured by RT-PCR and ELISA techniques, respectively. Results show an increased percentage of M1 phenotype and release of proinflammatory cytokines (like TNF-α and IL-6) by macrophages upon incubation with gliadin. Pre- and post-treatment of gliadin-stimulated macrophages with A. muciniphila induced M2 phenotype associated with decreased proinflammatory (IL-6, TNF-α) and increased anti-inflammatory (IL-10, TGF-β) cytokines expression relative to the group that was treated with gliadin alone. This study suggests the potential beneficial effect of A. muciniphila on gliadin-stimulated MQs and the importance of future studies focusing on their exact mechanism of action on these cells.
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Affiliation(s)
- Sara Molaaghaee-Rouzbahani
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nastaran Asri
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Anna Sapone
- Center for Celiac Research and Treatment, Massachusetts General Hospital, Boston, MA, 02114, USA.
| | - Kaveh Baghaei
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abbas Yadegar
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davar Amani
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, 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.
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22
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Girdhar K, Dogru YD, Huang Q, Yang Y, Tolstikov V, Raisingani A, Chrudinova M, Oh J, Kelley K, Ludvigsson JF, Kiebish MA, Palm NW, Ludvigsson J, Altindis E. Dynamics of the gut microbiome, IgA response, and plasma metabolome in the development of pediatric celiac disease. MICROBIOME 2023; 11:9. [PMID: 36639805 PMCID: PMC9840338 DOI: 10.1186/s40168-022-01429-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 11/16/2022] [Indexed: 06/17/2023]
Abstract
BACKGROUND Celiac disease (CD) is an autoimmune disorder triggered by gluten consumption. Almost all CD patients possess human leukocyte antigen (HLA) DQ2/DQ8 haplotypes; however, only a small subset of individuals carrying these alleles develop CD, indicating the role of environmental factors in CD pathogenesis. The main objective of this study was to determine the contributory role of gut microbiota and microbial metabolites in CD onset. To this end, we obtained fecal samples from a prospective cohort study (ABIS) at ages 2.5 and 5 years. Samples were collected from children who developed CD after the final sample collection (CD progressors) and healthy children matched by age, HLA genotype, breastfeeding duration, and gluten-exposure time (n=15-16). We first used 16S sequencing and immunoglobulin-A sequencing (IgA-seq) using fecal samples obtained from the same children (i) 16 controls and 15 CD progressors at age 2.5 and (ii) 13 controls and 9 CD progressors at age 5. We completed the cytokine profiling, and plasma metabolomics using plasma samples obtained at age 5 (n=7-9). We also determined the effects of one microbiota-derived metabolite, taurodeoxycholic acid (TDCA), on the small intestines and immune cell composition in vivo. RESULTS CD progressors have a distinct gut microbiota composition, an increased IgA response, and unique IgA targets compared to healthy subjects. Notably, 26 plasma metabolites, five cytokines, and one chemokine were significantly altered in CD progressors at age 5. Among 26 metabolites, we identified a 2-fold increase in TDCA. TDCA treatment alone caused villous atrophy, increased CD4+ T cells, Natural Killer cells, and two important immunoregulatory proteins, Qa-1 and NKG2D expression on T cells while decreasing T-regulatory cells in intraepithelial lymphocytes (IELs) in C57BL/6J mice. CONCLUSIONS Pediatric CD progressors have a distinct gut microbiota composition, plasma metabolome, and cytokine profile before diagnosis. Furthermore, CD progressors have more IgA-coated bacteria and unique targets of IgA in their gut microbiota. TDCA feeding alone stimulates an inflammatory immune response in the small intestines of C57BJ/6 mice and causes villous atrophy, the hallmark of CD. Thus, a microbiota-derived metabolite, TDCA, enriched in CD progressors' plasma, has the potential to drive inflammation in the small intestines and enhance CD pathogenesis. Video Abstract.
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Affiliation(s)
- Khyati Girdhar
- Boston College Biology Department, Chestnut Hill, MA, 02467, USA
| | | | - Qian Huang
- Boston College Biology Department, Chestnut Hill, MA, 02467, USA
| | - Yi Yang
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 06510, USA
| | | | - Amol Raisingani
- Boston College Biology Department, Chestnut Hill, MA, 02467, USA
| | | | - Jaewon Oh
- Boston College Biology Department, Chestnut Hill, MA, 02467, USA
| | - Kristina Kelley
- Boston College Biology Department, Chestnut Hill, MA, 02467, USA
| | - Jonas F Ludvigsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Department of Paediatrics, Örebro University Hospital, Örebro, Sweden
| | | | - Noah W Palm
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 06510, USA
| | - Johnny Ludvigsson
- Crown Princess Victoria Children's Hospital, Division of Pediatrics, Department of Biomedical and Clinical Sciences, Linköping University, 58185, Linköping, SE, Sweden
| | - Emrah Altindis
- Boston College Biology Department, Chestnut Hill, MA, 02467, USA.
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23
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Masucci L, D’Ippolito S, De Maio F, Quaranta G, Mazzarella R, Bianco DM, Castellani R, Inversetti A, Sanguinetti M, Gasbarrini A, Scambia G, Di Simone N. Celiac Disease Predisposition and Genital Tract Microbiota in Women Affected by Recurrent Pregnancy Loss. Nutrients 2023; 15:221. [PMID: 36615877 PMCID: PMC9823693 DOI: 10.3390/nu15010221] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/28/2022] [Accepted: 12/28/2022] [Indexed: 01/04/2023] Open
Abstract
The incidence of Idiopathic Recurrent Pregnancy Loss (RPL) is doubled in patients suffering from Celiac Disease (CD) compared to healthy populations. CD genetic components are HLA class II genes known as HLA-DQ2 and DQ8. Genetically susceptible women can remain asymptomatic even though they are exposed to a doubled risk of RPL compared to the general population. Furthermore, CD has been associated with microbiota alterations. The aim of this study is to evaluate endometrial and vaginal microbiota in HLA-DQ2/DQ8 positive and negative RPL patients compared to healthy pregnant women. Endometrial and vaginal microbiota of 3 subgroups were evaluated: 15 HLA-DQ2/DQ8 positive RPL women, 25 HLA DQ2/DQ8 negative RPL women (for a total of 40 RPL women) and 7 healthy fertile controls with previous uncomplicated pregnancies (all HLA-DQ2/DQ8 negative). The 2 RPL subgroups (HLA-DQ2/DQ8 positive and negative) showed a different endometrial and vaginal composition in the Lactobacillacae family compared to controls: Lactobacillus acidophilus was absent both in the vaginal and endometrial samples of RPL women, while Lactobaciluus iners, which can favor a less stable vaginal microbiota, was found only in RPL women (26.4% in HLA DQ2/DQ8 positive and 22.1% HLA DQ2/DQ8 negative) in both the vaginal and endometrial districts. In conclusion, both HLA DQ2/DQ8 positive-RPL and HLA DQ2/DQ8 negative-RPL women showed different endometrial and vaginal microbiota composition compared to healthy controls.
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Affiliation(s)
- Luca Masucci
- Dipartimento di Scienze Biotecnologiche Di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Dipartimento Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (I.R.C.C.S.), 00168 Rome, Italy
| | - Silvia D’Ippolito
- Dipartimento di Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (I.R.C.C.S.), 00168 Rome, Italy
| | - Flavio De Maio
- Dipartimento Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (I.R.C.C.S.), 00168 Rome, Italy
| | - Gianluca Quaranta
- Dipartimento Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (I.R.C.C.S.), 00168 Rome, Italy
| | - Roberta Mazzarella
- Dipartimento di Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (I.R.C.C.S.), 00168 Rome, Italy
| | - Delia Mercedes Bianco
- Dipartimento di Scienze Biotecnologiche Di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Roberta Castellani
- Dipartimento di Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (I.R.C.C.S.), 00168 Rome, Italy
| | - Annalisa Inversetti
- Humanitas University Department of Biomedical Sciences, Humanitas University, via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy
- IRCCS Humanitas Research Hospital, via Manzoni 56, Rozzano, 20089 Milan, Italy
| | - Maurizio Sanguinetti
- Dipartimento di Scienze Biotecnologiche Di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Dipartimento Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (I.R.C.C.S.), 00168 Rome, Italy
| | - Antonio Gasbarrini
- CEMAD Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Giovanni Scambia
- Dipartimento di Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (I.R.C.C.S.), 00168 Rome, Italy
- Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Nicoletta Di Simone
- Humanitas University Department of Biomedical Sciences, Humanitas University, via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy
- IRCCS Humanitas Research Hospital, via Manzoni 56, Rozzano, 20089 Milan, Italy
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24
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Szajewska H, Shamir R, Stróżyk A, Chmielewska A, Zalewski BM, Auricchio R, Koletzko S, Korponay-Szabo IR, Mearin ML, Meijer C, Ribes-Koninckx C, Troncone R. Systematic review: early feeding practices and the risk of coeliac disease. A 2022 update and revision. Aliment Pharmacol Ther 2023; 57:8-22. [PMID: 36411726 DOI: 10.1111/apt.17290] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 10/07/2022] [Accepted: 10/23/2022] [Indexed: 11/24/2022]
Abstract
BACKGROUND The effects of early feeding practices on the risk of coeliac disease (CD) remain debated. AIMS To update evidence on these practices on the risk of CD and/or CD-related autoimmunity (CDA), defined as anti-transglutaminase or anti-endomysial antibody positivity METHODS: We searched MEDLINE, EMBASE and the Cochrane Library to May 2022 for randomised controlled trials (RCTs) and observational studies. RESULTS We included 36 publications (30 studies). In the population at genetic risk of developing CD (HLA DQ2/DQ8-positive), exclusive or any breastfeeding and longer breastfeeding duration did not reduce the risk of developing CD/CDA during childhood. While a meta-analysis of four case-control studies showed a decreased risk for CD when gluten was introduced during breastfeeding, this was not shown in RCTs and cohort studies. Age at gluten introduction was not associated with cumulative CD/CDA risk, although two RCTs suggested that earlier gluten introduction was associated with earlier CDA appearance. Evidence from six observational studies suggests that consumption of a higher amount of gluten at weaning and/or thereafter may increase CD risk. There is insufficient evidence to determine the amount of gluten associated with an increased CD/CDA risk. Regarding whether infant feeding practices modulate the risk conferred by different HLA genotypes results were inconsistent. CONCLUSIONS For the population at genetic risk of CD, breastfeeding and age at gluten introduction have no effect on its cumulative incidence during childhood. There is some evidence for an effect of the amount of gluten consumed at weaning and/or thereafter on CD/CDA risk.
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Affiliation(s)
- Hania Szajewska
- Department of Paediatrics, The Medical University of Warsaw, Warsaw, Poland
| | - Raanan Shamir
- Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Agata Stróżyk
- Department of Paediatrics, The Medical University of Warsaw, Warsaw, Poland
| | - Anna Chmielewska
- Department of Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden
| | | | - Renata Auricchio
- Department of Translation Medical Science, Pediatric Section European Laboratory for the Investigation of Food Induced Disease (ELFID), University Federico II, Naples, Italy
| | - Sibylle Koletzko
- Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, LMU Munich, Munich, Germany
- School of Medicine Collegium Medicum, Department of Pediatrics, Gastroenterology and Nutrition, University of Warmia and Mazury, Olsztyn, Poland
| | - Ilma R Korponay-Szabo
- Department of Pediatrics, Faculty of Medicine and Clinical Center, University of Debrecen, Debrecen, Hungary
- Celiac Disease Center, Heim Pál National Paediatric Institute, Budapest, Hungary
| | - M Luisa Mearin
- Willem Alexander Children's Hospital, Leiden University Medical Center, Leiden, The Netherlands
| | - Caroline Meijer
- Willem Alexander Children's Hospital, Leiden University Medical Center, Leiden, The Netherlands
| | - Carmen Ribes-Koninckx
- Pediatric Gastroenterology and Hepatology & Instituto de Investigacion Sanitaria, La Fe University Hospital, Valencia, Spain
| | - Riccardo Troncone
- Department of Translation Medical Science, Pediatric Section European Laboratory for the Investigation of Food Induced Disease (ELFID), University Federico II, Naples, Italy
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25
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Andrén Aronsson C, Agardh D. Intervention strategies in early childhood to prevent celiac disease-a mini-review. Front Immunol 2023; 14:1106564. [PMID: 36911718 PMCID: PMC9992640 DOI: 10.3389/fimmu.2023.1106564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 02/08/2023] [Indexed: 02/24/2023] Open
Abstract
A higher intake of gluten during childhood is associated with increased risk of celiac disease, and the incidence of celiac disease peaks shortly after the time point when associations with higher gluten intake during the second and third year of life occur. Additional environmental factors are most likely necessary for celiac disease to develop. It is hypothesized that gastrointestinal infections increase gut permeability and exposure to gluten. Alternatively, infections may lead to gut dysbiosis and chronic inflammation, with leakage of self-antigens that mimic gluten peptides that leads to an autoimmune-like response. Different gluten interventions to prevent celiac disease have been proposed. Early clinical studies suggested an optimal time point introducing gluten between 4 and 6 months of age while the infant is being breastfed. However, later clinical trials on reduced gluten intake given to infants have shown no protection from celiac disease if gluten introduction was delayed or if gluten was introduced in small amounts during the child's first year of life. Still, more randomized clinical trials (RCTs) are warranted to answer the question if a reduced amount of gluten, not only at the time of introduction during infancy but also in a longer time frame, will prevent children at genetic risk from having lifelong celiac disease. It needs to be clarified whether dietary interventions are effective strategies to be proposed as future prevention of celiac disease in the general population. The present mini-review provides an overview of ongoing or completed RCTs that have focused on interventions during early childhood with the aim of preventing celiac disease.
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Affiliation(s)
| | - Daniel Agardh
- Department of Clinical Sciences, Lund University, Malmö, Sweden
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26
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Ayariga JA, Ibrahim I, Gildea L, Abugri J, Villafane R. Microbiota in a long survival discourse with the human host. Arch Microbiol 2022; 205:5. [PMID: 36441284 DOI: 10.1007/s00203-022-03342-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Revised: 11/14/2022] [Accepted: 11/16/2022] [Indexed: 11/29/2022]
Abstract
The relationship between human health and gut microbiota is becoming more apparent. It is now widely believed that healthy gut flora plays a vital role in the overall well-being of the individual. There are spatial and temporal variations in the distribution of microbes from the esophagus to the rectum throughout an individual's lifetime. Through the development of genome sequencing technologies, scientists have been able to study the interactions between different microorganisms and their hosts to improve the health and disease of individuals. The normal gut microbiota provides various functions to the host, whereas the host, in turn, provides nutrients and promotes the development of healthy and resilient microbiota communities. Thus, the microbiota provides and maintains the gut's structural integrity and protects the gut against pathogens. The development of the normal gut microbiota is influenced by various factors. Some of these include the mode of delivery, diet, and antibiotics. In addition, the environment can also affect the development of the gut microbiota. For example, one of the main concerns of antibiotic use is the alteration of the gut microbiota, which could lead to the development of multidrug-resistant organisms. When microbes are disturbed, it can potentially lead to various diseases. Depending on the species' ability to adapt to the human body's environment, the fate of the microbes in the host and their relationship with the human body are decided. This review aims to provide a comprehensive analysis of microbe, microbes-host immune interactions, and factors that can disturb their interactions.
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Affiliation(s)
- Joseph A Ayariga
- Department of Biological Sciences, Microbiology PhD. Program, College of Science, Technology, Engineering and Mathematics (C-STEM), Alabama State University, 1627 Hall Street Montgomery, Montgomery, AL, 36104, USA.
| | - Iddrisu Ibrahim
- Department of Biological Sciences, Microbiology PhD. Program, College of Science, Technology, Engineering and Mathematics (C-STEM), Alabama State University, 1627 Hall Street Montgomery, Montgomery, AL, 36104, USA
| | - Logan Gildea
- Department of Biological Sciences, Microbiology PhD. Program, College of Science, Technology, Engineering and Mathematics (C-STEM), Alabama State University, 1627 Hall Street Montgomery, Montgomery, AL, 36104, USA
| | - James Abugri
- Department of Biochemistry and Forensic Sciences, School of Chemical and Biochemical Sciences, C. K. Tedam University of Technology and Applied Sciences, Navrongo, Ghana.
| | - Robert Villafane
- Department of Biological Sciences, Microbiology PhD. Program, College of Science, Technology, Engineering and Mathematics (C-STEM), Alabama State University, 1627 Hall Street Montgomery, Montgomery, AL, 36104, USA
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27
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Arcila-Galvis JE, Loria-Kohen V, Ramírez de Molina A, Carrillo de Santa Pau E, Marcos-Zambrano LJ. A comprehensive map of microbial biomarkers along the gastrointestinal tract for celiac disease patients. Front Microbiol 2022; 13:956119. [PMID: 36177469 PMCID: PMC9513315 DOI: 10.3389/fmicb.2022.956119] [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] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Accepted: 08/11/2022] [Indexed: 11/13/2022] Open
Abstract
Dysbiosis of the microbiome has been related to Celiac disease (CeD) progress, an autoimmune disease characterized by gluten intolerance developed in genetically susceptible individuals under certain environmental factors. The microbiome contributes to CeD pathophysiology, modulating the immune response by the action of short-chain fatty acids (SCFA), affecting gut barrier integrity allowing the entrance of gluten-derived proteins, and degrading immunogenic peptides of gluten through endoprolyl peptidase enzymes. Despite the evidence suggesting the implication of gut microbiome over CeD pathogenesis, there is no consensus about the specific microbial changes observed in this pathology. Here, we compiled the largest dataset of 16S prokaryotic ribosomal RNA gene high-throughput sequencing for consensus profiling. We present for the first time an integrative analysis of metataxonomic data from patients with CeD, including samples from different body sites (saliva, pharynx, duodenum, and stool). We found the presence of coordinated changes through the gastrointestinal tract (GIT) characterized by an increase in Actinobacteria species in the upper GIT (pharynx and duodenum) and an increase in Proteobacteria in the lower GIT (duodenum and stool), as well as site-specific changes evidencing a dysbiosis in patients with CeD' microbiota. Moreover, we described the effect of adherence to a gluten-free diet (GFD) evidenced by an increase in beneficial bacteria and a decrease in some Betaproteobacteriales but not fully restoring CeD-related dysbiosis. Finally, we built a Random Forest model to classify patients based on the lower GIT composition achieving good performance.
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Affiliation(s)
- Juliana Estefanía Arcila-Galvis
- Computational Biology Group, Precision Nutrition, and Cancer Research Program, IMDEA Food Institute, Madrid, Spain.,Computational Epigenomics Laboratory, Faculty of Medical Sciences, Newcastle University, Newcastle, United Kingdom
| | - Viviana Loria-Kohen
- Nutrition and Clinical Trials Unit, GENYAL Platform IMDEA-Food Institute, Madrid, Spain.,Departamento de Nutrición y Ciencia de los Alimentos, Faculty of Pharmacy, Universidad Complutense de Madrid, Madrid, Spain
| | - Ana Ramírez de Molina
- Nutrition and Clinical Trials Unit, GENYAL Platform IMDEA-Food Institute, Madrid, Spain
| | | | - Laura Judith Marcos-Zambrano
- Computational Biology Group, Precision Nutrition, and Cancer Research Program, IMDEA Food Institute, Madrid, Spain
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28
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Vacca M, Porrelli A, Calabrese FM, Lippolis T, Iacobellis I, Celano G, Pinto D, Russo F, Giannelli G, De Angelis M. How Metabolomics Provides Novel Insights on Celiac Disease and Gluten-Free Diet: A Narrative Review. Front Microbiol 2022; 13:859467. [PMID: 35814671 PMCID: PMC9260055 DOI: 10.3389/fmicb.2022.859467] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 05/27/2022] [Indexed: 12/12/2022] Open
Abstract
Celiac disease (CD) is an inflammatory autoimmune disorder triggered by the ingestion of gluten from wheat and other cereals. Nowadays, its positive diagnosis is based on invasive approaches such as the histological examination of intestinal biopsies and positive serology screening of antibodies. After proven diagnosis, the only admissible treatment for CD individuals is strict life-long adherence to gluten-free diet (GFD), although it is not a conclusive therapy. Acting by different mechanisms and with different etiologies, both CD and GFD have a great impact on gut microbiota that result in a different taxa composition. Altered production of specific metabolites reflects these microbiota changes. In this light, the currently available literature reports some suggestions about the possible use of specific metabolites, detected by meta-omics analyses, as potential biomarkers for a CD non-invasive diagnosis. To highlight insights about metabolomics application in CD study, we conducted a narrative dissertation of selected original articles published in the last decade. By applying a systematic search, it clearly emerged how the metabolomic signature appears to be contradictory, as well as poorly investigated.
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Affiliation(s)
- Mirco Vacca
- Department of Soil, Plant and Food Science, University of Bari Aldo Moro, Bari, Italy
| | - Annalisa Porrelli
- Department of Soil, Plant and Food Science, University of Bari Aldo Moro, Bari, Italy
| | - Francesco Maria Calabrese
- Department of Soil, Plant and Food Science, University of Bari Aldo Moro, Bari, Italy
- *Correspondence: Francesco Maria Calabrese,
| | - Tamara Lippolis
- National Institute of Gastroenterology “S. de Bellis,” Institute of Research, Castellana Grotte, Italy
| | - Ilaria Iacobellis
- Department of Soil, Plant and Food Science, University of Bari Aldo Moro, Bari, Italy
| | - Giuseppe Celano
- Department of Soil, Plant and Food Science, University of Bari Aldo Moro, Bari, Italy
| | - Daniela Pinto
- Human Microbiome Advanced Project-HMPA, Giuliani SpA, Milan, Italy
| | - Francesco Russo
- National Institute of Gastroenterology “S. de Bellis,” Institute of Research, Castellana Grotte, Italy
| | - Gianluigi Giannelli
- National Institute of Gastroenterology “S. de Bellis,” Institute of Research, Castellana Grotte, Italy
| | - Maria De Angelis
- Department of Soil, Plant and Food Science, University of Bari Aldo Moro, Bari, Italy
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Fornasaro S, Esposito A, Florian F, Pallavicini A, De Leo L, Not T, Lagatolla C, Mezzarobba M, Di Silvestre A, Sergo V, Bonifacio A. Spectroscopic investigation of faeces with surface-enhanced Raman scattering: a case study with coeliac patients on gluten-free diet. Anal Bioanal Chem 2022; 414:3517-3527. [PMID: 35258650 PMCID: PMC9018641 DOI: 10.1007/s00216-022-03975-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 02/07/2022] [Accepted: 02/10/2022] [Indexed: 11/06/2022]
Abstract
Surface-enhanced Raman scattering (SERS) spectra of faecal samples can be obtained by adding AuNP to their methanol extracts according to the reported protocol, and display bands that are due to bilirubin-like species but also to xanthine and hypoxanthine, two metabolic products secreted by gut bacteria. A total of 27 faecal samples from three different groups, i.e. coeliac patients (n = 9), coeliac patients on gluten-free diet (n = 10) and a control group (n = 8), were characterized with both SERS spectroscopy and 16S rRNA sequencing analysis. Significant differences are present between SERS spectra of coeliac patients and those on gluten-free diet, with a marked increase in the relative intensity of both xanthine and hypoxanthine for the latter. Interestingly, these differences do not correlate with bacterial composition as derived from 16S rRNA sequencing.
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Affiliation(s)
- Stefano Fornasaro
- Raman Spectroscopy Laboratory, Department of Engineering and Architecture, University of Trieste, P.le Europa 1, 34100, Trieste, Italy
| | - Alessandro Esposito
- Raman Spectroscopy Laboratory, Department of Engineering and Architecture, University of Trieste, P.le Europa 1, 34100, Trieste, Italy
| | - Fiorella Florian
- Department of Life Sciences, University of Trieste, Via Edoardo Weiss 2, 34128, Trieste, TS, Italy
| | - Alberto Pallavicini
- Department of Life Sciences, University of Trieste, Via Edoardo Weiss 2, 34128, Trieste, TS, Italy
| | - Luigina De Leo
- Institute for Maternal Child Health-IRCCS "Burlo Garofolo" Trieste, via dell'Istria 65/1, 34100, Trieste, Italy
| | - Tarcisio Not
- Institute for Maternal Child Health-IRCCS "Burlo Garofolo" Trieste, via dell'Istria 65/1, 34100, Trieste, Italy
| | - Cristina Lagatolla
- Department of Life Sciences, University of Trieste, Via Edoardo Weiss 2, 34128, Trieste, TS, Italy
| | - Marica Mezzarobba
- Department of Life Sciences, University of Trieste, Via Edoardo Weiss 2, 34128, Trieste, TS, Italy
| | - Alessia Di Silvestre
- Raman Spectroscopy Laboratory, Department of Engineering and Architecture, University of Trieste, P.le Europa 1, 34100, Trieste, Italy
| | - Valter Sergo
- Raman Spectroscopy Laboratory, Department of Engineering and Architecture, University of Trieste, P.le Europa 1, 34100, Trieste, Italy
| | - Alois Bonifacio
- Raman Spectroscopy Laboratory, Department of Engineering and Architecture, University of Trieste, P.le Europa 1, 34100, Trieste, Italy.
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Kociszewska D, Vlajkovic SM. The Association of Inflammatory Gut Diseases with Neuroinflammatory and Auditory Disorders. Front Biosci (Elite Ed) 2022; 14:8. [PMID: 35730449 DOI: 10.31083/j.fbe1402008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 02/11/2022] [Accepted: 02/24/2022] [Indexed: 11/06/2022]
Abstract
Disorders such as inflammatory bowel disease (IBD) and celiac disease (CeD) result in intestinal hyperpermeability or 'leaky' gut. The increased permeability of the intestinal barrier allows microbial metabolites, toxins, and pathogens to infiltrate the bloodstream and extraintestinal tissues, causing systemic inflammation. Despite differences in aetiology and pathophysiology, IBD and CeD share several extraintestinal manifestations such as neuroinflammation, neurological and psychiatric manifestations, and sensorineural hearing loss (SNHL). This narrative review focuses on the association between intestinal hyperpermeability with the brain and inner ear diseases. We postulate that the microbial metabolites and pathogens released from the gut increase the permeability of natural barriers, such as the blood-brain barrier (BBB) and blood-labyrinth barrier (BLB). The barrier breakdown allows the spreading of inflammatory processes to the brain and inner ear, leading to disease.
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Affiliation(s)
- Dagmara Kociszewska
- Department of Physiology and The Eisdell Moore Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, 1142 Auckland, New Zealand
| | - Srdjan M Vlajkovic
- Department of Physiology and The Eisdell Moore Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, 1142 Auckland, New Zealand
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31
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Singh A, Kaur H, Midha V, Sood A. Microorganisms in the Pathogenesis and Management of Celiac Disease (CeD). ROLE OF MICROORGANISMS IN PATHOGENESIS AND MANAGEMENT OF AUTOIMMUNE DISEASES 2022:287-307. [DOI: 10.1007/978-981-19-4800-8_15] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Preserved central cholinergic functioning to transcranial magnetic stimulation in de novo patients with celiac disease. PLoS One 2021. [PMID: 34914787 DOI: 10.1371/journal.pone.0261373.] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Celiac disease (CD) is now viewed as a systemic disease with multifaceted clinical manifestations. Among the extra-intestinal features, neurological and neuropsychiatric symptoms are still a diagnostic challenge, since they can precede or follow the diagnosis of CD. In particular, it is well known that some adults with CD may complain of cognitive symptoms, that improve when the gluten-free diet (GFD) is started, although they may re-appear after incidental gluten intake. Among the neurophysiological techniques, motor evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) can non-invasively probe in vivo the excitation state of cortical areas and cortico-spinal conductivity, being also able to unveil preclinical impairment in several neurological and psychiatric disorders, as well as in some systemic diseases affecting the central nervous system (CNS), such as CD. We previously demonstrated an intracortical disinhibition and hyperfacilitation of MEP responses to TMS in newly diagnosed patients. However, no data are available on the central cholinergic functioning indexed by specific TMS measures, such as the short-latency afferent inhibition (SAI), which might represent the neurophysiological correlate of cognitive changes in CD patients, also at the preclinical level. METHODS Cognitive and depressive symptoms were screened by means of the Montreal Cognitive Assessment (MoCA) and the 17-item Hamilton Depression Rating Scale (HDRS), respectively, in 15 consecutive de novo CD patients and 15 healthy controls. All patients were on normal diet at the time of the enrolment. Brain computed tomography (CT) was performed in all patients. SAI, recorded at two interstimulus intervals (2 and 8 ms), was assessed as the percentage amplitude ratio between the conditioned and the unconditioned MEP response. Resting motor threshold, MEP amplitude and latency, and central motor conduction time were also measured. RESULTS The two groups were comparable for age, sex, anthropometric features, and educational level. Brain CT ruled out intracranial calcifications and clear radiological abnormalities in all patients. Scores at MoCA and HDRS were significantly worse in patients than in controls. The comparison of TMS data between the two groups revealed no statistically significant difference for all measures, including SAI at both interstimulus intervals. CONCLUSIONS Central cholinergic functioning explored by the SAI of the motor cortex resulted to be not affected in these de novo CD patients compared to age-matched healthy controls. Although the statistically significant difference in MoCA, an overt cognitive impairment was not clinically evident in CD patients. Coherently, to date, no study based on TMS or other diagnostic techniques has shown any involvement of the central acetylcholine or the cholinergic fibers within the CNS in CD. This finding might add support to the vascular inflammation hypothesis underlying the so-called "gluten encephalopathy", which seems to be due to an aetiology different from that of the cholinergic dysfunction. Longitudinal studies correlating clinical, TMS, and neuroimaging data, both before and after GFD, are needed.
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Lanza G, Fisicaro F, D’Agate CC, Ferri R, Cantone M, Falzone L, Pennisi G, Bella R, Hadjivassiliou M, Pennisi M. Preserved central cholinergic functioning to transcranial magnetic stimulation in de novo patients with celiac disease. PLoS One 2021; 16:e0261373. [PMID: 34914787 PMCID: PMC8675755 DOI: 10.1371/journal.pone.0261373] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 11/30/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Celiac disease (CD) is now viewed as a systemic disease with multifaceted clinical manifestations. Among the extra-intestinal features, neurological and neuropsychiatric symptoms are still a diagnostic challenge, since they can precede or follow the diagnosis of CD. In particular, it is well known that some adults with CD may complain of cognitive symptoms, that improve when the gluten-free diet (GFD) is started, although they may re-appear after incidental gluten intake. Among the neurophysiological techniques, motor evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) can non-invasively probe in vivo the excitation state of cortical areas and cortico-spinal conductivity, being also able to unveil preclinical impairment in several neurological and psychiatric disorders, as well as in some systemic diseases affecting the central nervous system (CNS), such as CD. We previously demonstrated an intracortical disinhibition and hyperfacilitation of MEP responses to TMS in newly diagnosed patients. However, no data are available on the central cholinergic functioning indexed by specific TMS measures, such as the short-latency afferent inhibition (SAI), which might represent the neurophysiological correlate of cognitive changes in CD patients, also at the preclinical level. METHODS Cognitive and depressive symptoms were screened by means of the Montreal Cognitive Assessment (MoCA) and the 17-item Hamilton Depression Rating Scale (HDRS), respectively, in 15 consecutive de novo CD patients and 15 healthy controls. All patients were on normal diet at the time of the enrolment. Brain computed tomography (CT) was performed in all patients. SAI, recorded at two interstimulus intervals (2 and 8 ms), was assessed as the percentage amplitude ratio between the conditioned and the unconditioned MEP response. Resting motor threshold, MEP amplitude and latency, and central motor conduction time were also measured. RESULTS The two groups were comparable for age, sex, anthropometric features, and educational level. Brain CT ruled out intracranial calcifications and clear radiological abnormalities in all patients. Scores at MoCA and HDRS were significantly worse in patients than in controls. The comparison of TMS data between the two groups revealed no statistically significant difference for all measures, including SAI at both interstimulus intervals. CONCLUSIONS Central cholinergic functioning explored by the SAI of the motor cortex resulted to be not affected in these de novo CD patients compared to age-matched healthy controls. Although the statistically significant difference in MoCA, an overt cognitive impairment was not clinically evident in CD patients. Coherently, to date, no study based on TMS or other diagnostic techniques has shown any involvement of the central acetylcholine or the cholinergic fibers within the CNS in CD. This finding might add support to the vascular inflammation hypothesis underlying the so-called "gluten encephalopathy", which seems to be due to an aetiology different from that of the cholinergic dysfunction. Longitudinal studies correlating clinical, TMS, and neuroimaging data, both before and after GFD, are needed.
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Affiliation(s)
- Giuseppe Lanza
- Department of Surgery and Medical-Surgical Specialties, University of Catania, Catania, Italy
- Clinical Neurophysiology Research Unit, Oasi Research Institute-IRCCS, Troina, Italy
| | - Francesco Fisicaro
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Carmela Cinzia D’Agate
- Gastroenterology and Endoscopy Unit, University Hospital Policlinico “G. Rodolico-San Marco”, Catania, Italy
| | - Raffaele Ferri
- Clinical Neurophysiology Research Unit, Oasi Research Institute-IRCCS, Troina, Italy
| | - Mariagiovanna Cantone
- Department of Neurology, Sant’Elia Hospital, ASP Caltanissetta, Caltanissetta, Italy
| | - Luca Falzone
- Epidemiology and Biostatistics Unit, Instituto Nazionale Tumori-IRCCS “Fondazione G. Pascale, Napoli, Italy
| | - Giovanni Pennisi
- Department of Surgery and Medical-Surgical Specialties, University of Catania, Catania, Italy
| | - Rita Bella
- Department of Medical and Surgical Sciences and Advanced Technologies, University of Catania, Catania, Italy
| | - Marios Hadjivassiliou
- Academic Department of Neurosciences, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield, United Kingdom
| | - Manuela Pennisi
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
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Mohamed Qadir R, Assafi MS. The association between body mass index and the oral Firmicutes and Bacteroidetes profiles of healthy individuals. MALAYSIAN FAMILY PHYSICIAN : THE OFFICIAL JOURNAL OF THE ACADEMY OF FAMILY PHYSICIANS OF MALAYSIA 2021; 16:36-43. [PMID: 34938391 PMCID: PMC8680938 DOI: 10.51866/oa1129] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
INTRODUCTION Microbiome status is considered an important factor that contributes to obesity. Investigations have shown that the oral microbiome comprises a vast array of bacterial species that can influence human health. OBJECTIVE To determine the association between the presence of the bacterial phyla Firmicutes and Bacteroidetes and the body mass index (BMI) status of normal, overweight and obese subjects in Duhok, Iraq. Additionally, to investigate the composition of oral Firmicutes and Bacteroidetes profiles for individuals with different BMI statuses. METHODS A total of 155 saliva samples were collected from participants in Duhok, Iraq. Bacterial genomic DNA was then extracted from the collected saliva. The presence of Firmicutes and Bacteroidetes phyla was detected via polymerase chain reaction. RESULTS Firmicutes and Bacteroidetes were detected in 63.2 and 37.4% of the population, respectively. Differences in the carriage rates of oral Firmicutes in overweight (78%) and obese individuals (83%) were statistically significant when compared to normal weight individuals (36%) (P<0.0001). The percentage rates of Bacteroidetes in obese individuals (26.4%) was statistically significant when compared to normal weight individuals (50.8%) (P=0.0078). The Firmicutes/ Bacteroidetes ratios (obese=3.1, overweight= 2.5 and normal weight=0.7) were higher with increasing BMI. CONCLUSION This study provides evidence of the Firmicutes/Bacteroidetes ratio growing with increasing BMI. High rates of Firmicutes could serve a role in the development of obesity. Further studies are required to clarify the exact relationship between oral bacteria and obesity, which could lead to a promising therapeutic method for improving the physical health of humans.
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Affiliation(s)
- Roshna Mohamed Qadir
- MSc, Department of Biology, College of Science, University of Duhok, Duhok Kurdistan Region, Iraq
| | - Mahde Saleh Assafi
- PhD, Department of Biology, College of Science, University of Duhok, Duhok Kurdistan Region, Iraq,
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Verdu EF, Schuppan D. Co-factors, Microbes, and Immunogenetics in Celiac Disease to Guide Novel Approaches for Diagnosis and Treatment. Gastroenterology 2021; 161:1395-1411.e4. [PMID: 34416277 DOI: 10.1053/j.gastro.2021.08.016] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 08/10/2021] [Accepted: 08/10/2021] [Indexed: 12/14/2022]
Abstract
Celiac disease (CeD) is a frequent immune-mediated disease that affects not only the small intestine but also many extraintestinal sites. The role of gluten proteins as dietary triggers, HLA-DQ2 or -DQ8 as major necessary genetic predisposition, and tissue transglutaminase (TG2) as mechanistically involved autoantigen, are unique features of CeD. Recent research implicates many cofactors working in synergism with these key triggers, including the intestinal microbiota and their metabolites, nongluten dietary triggers, intestinal barrier defects, novel immune cell phenotypes, and mediators and cytokines. In addition, apart from HLA-DQ2 and -DQ8, multiple and complex predisposing genetic factors and interactions have been defined, most of which overlap with predispositions in other, usually autoimmune, diseases that are linked to CeD. The resultant better understanding of CeD pathogenesis, and its manifold manifestations has already paved the way for novel therapeutic approaches beyond the lifelong strict gluten-free diet, which poses a burden to patients and often does not lead to complete mucosal healing. Thus, supported by improved mouse models for CeD and in vitro organoid cultures, several targeted therapies are in phase 2-3 clinical studies, such as highly effective gluten-degrading oral enzymes, inhibition of TG2, cytokine therapies, induction of tolerance to gluten ingestion, along with adjunctive and preventive approaches using beneficial probiotics and micronutrients. These developments are supported by novel noninvasive markers of CeD severity and activity that may be used as companion diagnostics, allow easy-to perform and reliable monitoring of patients, and finally support personalized therapy for CeD.
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Affiliation(s)
- Elena F Verdu
- Division of Gastroenterology, Department of Internal Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Canada
| | - Detlef Schuppan
- Institute of Translational Immunology,Research Center for Immune Therapy and Celiac Center, University Medical Center, Johannes Gutenberg University, Mainz, Germany; Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
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36
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Reply to Chen and Vitetta: Unraveling the complex interactions among organisms in the microbiome is necessary to identify unique signatures predicting CD onset. Proc Natl Acad Sci U S A 2021; 118:2114053118. [PMID: 34607963 DOI: 10.1073/pnas.2114053118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/11/2021] [Indexed: 11/18/2022] Open
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Oreshko LS, Bakulin IG, Avalueva EB, Semenova EA, Sitkin SI. Modern understanding of adult celiac disease. EXPERIMENTAL AND CLINICAL GASTROENTEROLOGY 2021:84-95. [DOI: 10.31146/1682-8658-ecg-188-4-84-95] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/26/2023]
Abstract
The article presents a modern view of celiac disease within the framework of the classification concept of gluten- associated disorders. The prevalence of the disease, the modern model of the etiopathogenesis of celiac disease, clinical manifestations, and the possibilities of differential diagnosis are discussed. According to the European guidelines, a strategy for monitoring outpatients with celiac disease is presented, based on baseline characteristics of the disease, regular doctor- patient interaction, and prevention of gluten- associated disorders.
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Affiliation(s)
- L. S. Oreshko
- North- Western State Medical University named after I. I. Mechnikov, Ministry of Health of Russian Federation
| | - I. G. Bakulin
- North- Western State Medical University named after I. I. Mechnikov, Ministry of Health of Russian Federation
| | - E. B. Avalueva
- North- Western State Medical University named after I. I. Mechnikov, Ministry of Health of Russian Federation
| | - E. A. Semenova
- North- Western State Medical University named after I. I. Mechnikov, Ministry of Health of Russian Federation
| | - S. I. Sitkin
- North- Western State Medical University named after I. I. Mechnikov, Ministry of Health of Russian Federation;
Federal State Budgetary Institution “Almazov National Medical Research Centre” of the Ministry of Health of the Russian Federation
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Leonard MM, Valitutti F, Karathia H, Pujolassos M, Kenyon V, Fanelli B, Troisi J, Subramanian P, Camhi S, Colucci A, Serena G, Cucchiara S, Trovato CM, Malamisura B, Francavilla R, Elli L, Hasan NA, Zomorrodi AR, Colwell R, Fasano A. Microbiome signatures of progression toward celiac disease onset in at-risk children in a longitudinal prospective cohort study. Proc Natl Acad Sci U S A 2021; 118:e2020322118. [PMID: 34253606 PMCID: PMC8307711 DOI: 10.1073/pnas.2020322118] [Citation(s) in RCA: 95] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Other than exposure to gluten and genetic compatibility, the gut microbiome has been suggested to be involved in celiac disease (CD) pathogenesis by mediating interactions between gluten/environmental factors and the host immune system. However, to establish disease progression markers, it is essential to assess alterations in the gut microbiota before disease onset. Here, a prospective metagenomic analysis of the gut microbiota of infants at risk of CD was done to track shifts in the microbiota before CD development. We performed cross-sectional and longitudinal analyses of gut microbiota, functional pathways, and metabolites, starting from 18 mo before CD onset, in 10 infants who developed CD and 10 matched nonaffected infants. Cross-sectional analysis at CD onset identified altered abundance of six microbial strains and several metabolites between cases and controls but no change in microbial species or pathway abundance. Conversely, results of longitudinal analysis revealed several microbial species/strains/pathways/metabolites occurring in increased abundance and detected before CD onset. These had previously been linked to autoimmune and inflammatory conditions (e.g., Dialister invisus, Parabacteroides sp., Lachnospiraceae, tryptophan metabolism, and metabolites serine and threonine). Others occurred in decreased abundance before CD onset and are known to have anti-inflammatory effects (e.g., Streptococcus thermophilus, Faecalibacterium prausnitzii, and Clostridium clostridioforme). Additionally, we uncovered previously unreported microbes/pathways/metabolites (e.g., Porphyromonas sp., high mannose-type N-glycan biosynthesis, and serine) that point to CD-specific biomarkers. Our study establishes a road map for prospective longitudinal study designs to better understand the role of gut microbiota in disease pathogenesis and therapeutic targets to reestablish tolerance and/or prevent autoimmunity.
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Affiliation(s)
- Maureen M Leonard
- Division of Pediatric Gastroenterology and Nutrition, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA 02114
- Mucosal Immunology and Biology Research Center, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA 02129
- Celiac Research Program, Harvard Medical School, Boston, MA 02114
| | - Francesco Valitutti
- European Biomedical Research Institute of Salerno, 84125 Salerno, Italy
- Pediatric Unit, Maternal and Child Health Department, Azienda Ospedaliera Universitaria San Giovanni di Dio e Ruggi d'Aragona, 84125 Salerno, Italy
| | | | | | - Victoria Kenyon
- Mucosal Immunology and Biology Research Center, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA 02129
- Celiac Research Program, Harvard Medical School, Boston, MA 02114
| | | | - Jacopo Troisi
- European Biomedical Research Institute of Salerno, 84125 Salerno, Italy
- Theoreo srl, University of Salerno, 20851 Salerno, Italy
- Department of Medicine, Surgery and Dentistry, Scuola Medica Salernitana, University of Salerno, 84090 Salerno, Italy
| | | | - Stephanie Camhi
- Mucosal Immunology and Biology Research Center, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA 02129
- Celiac Research Program, Harvard Medical School, Boston, MA 02114
| | - Angelo Colucci
- Theoreo srl, University of Salerno, 20851 Salerno, Italy
- Department of Medicine, Surgery and Dentistry, Scuola Medica Salernitana, University of Salerno, 84090 Salerno, Italy
| | - Gloria Serena
- Division of Pediatric Gastroenterology and Nutrition, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA 02114
- Mucosal Immunology and Biology Research Center, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA 02129
- Celiac Research Program, Harvard Medical School, Boston, MA 02114
| | | | | | - Basilio Malamisura
- Pediatric Unit, Maternal and Child Health Department, Azienda Ospedaliera Universitaria San Giovanni di Dio e Ruggi d'Aragona, 00185 Salerno, Italy
| | | | - Luca Elli
- Center for Prevention and Diagnosis of Celiac Disease, Fondazione Department and University Hospital (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, 70126 Milan, Italy
| | | | - Ali R Zomorrodi
- Division of Pediatric Gastroenterology and Nutrition, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA 02114
- Mucosal Immunology and Biology Research Center, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA 02129
- Celiac Research Program, Harvard Medical School, Boston, MA 02114
| | - Rita Colwell
- CosmosID Inc., Rockville, MD 84100;
- Center for Bioinformatics and Computational Biology, University of Maryland, College Park, MD 20122
| | - Alessio Fasano
- Division of Pediatric Gastroenterology and Nutrition, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA 02114;
- Mucosal Immunology and Biology Research Center, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA 02129
- Celiac Research Program, Harvard Medical School, Boston, MA 02114
- European Biomedical Research Institute of Salerno, 84125 Salerno, Italy
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Up-Regulation of Specific Bioactive Lipids in Celiac Disease. Nutrients 2021; 13:nu13072271. [PMID: 34209150 PMCID: PMC8308317 DOI: 10.3390/nu13072271] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 06/12/2021] [Accepted: 06/25/2021] [Indexed: 12/29/2022] Open
Abstract
Celiac disease (CD) is an autoimmune enteropathy linked to alterations of metabolism. Currently, limited untargeted metabolomic studies evaluating differences in the plasma metabolome of CD subjects have been documented. We engage in a metabolomic study that analyzes plasma metabolome in 17 children with CD treated with a gluten-free diet and 17 healthy control siblings in order to recognize potential changes in metabolic networks. Our data demonstrates the persistence of metabolic defects in CD subjects in spite of the dietary treatment, affecting a minor but significant fraction (around 4%, 209 out of 4893 molecular features) of the analyzed plasma metabolome. The affected molecular species are mainly, but not exclusively, lipid species with a particular affectation of steroids and derivatives (indicating an adrenal gland affectation), glycerophospholipids (to highlight phosphatidic acid), glycerolipids (with a special affectation of diacylglycerols), and fatty acyls (eicosanoids). Our findings are suggestive of an activation of the diacylglycerol-phosphatidic acid signaling pathway in CD that may potentially have detrimental effects via activation of several targets including protein kinases such as mTOR, which could be the basis of the morbidity and mortality connected with untreated CD. However, more studies are necessary to validate this idea regarding CD.
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Torun A, Hupalowska A, Trzonkowski P, Kierkus J, Pyrzynska B. Intestinal Microbiota in Common Chronic Inflammatory Disorders Affecting Children. Front Immunol 2021; 12:642166. [PMID: 34163468 PMCID: PMC8215716 DOI: 10.3389/fimmu.2021.642166] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 05/24/2021] [Indexed: 12/12/2022] Open
Abstract
The incidence and prevalence rate of chronic inflammatory disorders is on the rise in the pediatric population. Recent research indicates the crucial role of interactions between the altered intestinal microbiome and the immune system in the pathogenesis of several chronic inflammatory disorders in children, such as inflammatory bowel disease (IBD) and autoimmune diseases, such as type 1 diabetes mellitus (T1DM) and celiac disease (CeD). Here, we review recent knowledge concerning the pathogenic mechanisms underlying these disorders, and summarize the facts suggesting that the initiation and progression of IBD, T1DM, and CeD can be partially attributed to disturbances in the patterns of composition and abundance of the gut microbiota. The standard available therapies for chronic inflammatory disorders in children largely aim to treat symptoms. Although constant efforts are being made to maximize the quality of life for children in the long-term, sustained improvements are still difficult to achieve. Additional challenges are the changing physiology associated with growth and development of children, a population that is particularly susceptible to medication-related adverse effects. In this review, we explore new promising therapeutic approaches aimed at modulation of either gut microbiota or the activity of the immune system to induce a long-lasting remission of chronic inflammatory disorders. Recent preclinical studies and clinical trials have evaluated new approaches, for instance the adoptive transfer of immune cells, with genetically engineered regulatory T cells expressing antigen-specific chimeric antigen receptors. These approaches have revolutionized cancer treatments and have the potential for the protection of high-risk children from developing autoimmune diseases and effective management of inflammatory disorders. The review also focuses on the findings of studies that indicate that the responses to a variety of immunotherapies can be enhanced by strategic manipulation of gut microbiota, thus emphasizing on the importance of proper interaction between the gut microbiota and immune system for sustained health benefits and improvement of the quality of life of pediatric patients.
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Affiliation(s)
- Anna Torun
- Chair and Department of Biochemistry, Medical University of Warsaw, Warsaw, Poland
| | - Anna Hupalowska
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, United States
| | - Piotr Trzonkowski
- Department of Medical Immunology, Medical University of Gdansk, Gdansk, Poland
| | - Jaroslaw Kierkus
- Department of Gastroenterology, Hepatology, Feeding Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Beata Pyrzynska
- Chair and Department of Biochemistry, Medical University of Warsaw, Warsaw, Poland
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Celiac Disease and the Thyroid: Highlighting the Roles of Vitamin D and Iron. Nutrients 2021; 13:nu13061755. [PMID: 34064075 PMCID: PMC8224353 DOI: 10.3390/nu13061755] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 05/17/2021] [Accepted: 05/17/2021] [Indexed: 02/07/2023] Open
Abstract
Celiac disease (CD) and autoimmune thyroid diseases (AITD) like Hashimoto’s thyroiditis (HT) and Graves’ disease (GD) frequently coexist, entailing numerous potential impacts on diagnostic and therapeutic approaches. Possible correlations might exist through gut microbiota, regulating the immune system and inflammatory responses, promoting autoimmune diseases, as well as shared cytokines in pathogenesis pathways, cross-reacting antibodies or malabsorption of micronutrients that are essential for the thyroid like iron or vitamin D. Vitamin D deficiency is a common finding in patients with AITD, but might protect from autoimmunity by wielding immunoregulatory and tolerogenic impacts. Additionally, vitamin D is assumed to be involved in the onset and progression of CD, presumably plays a substantial protective role for intestinal mucosa and affects the thyroid via its immunomodulatory effects. Iron is an essential micronutrient for the thyroid gland needed for effective iodine utilization by the iron-dependent enzyme thyroid iodine peroxidase (TPO). Despite being crucial for thyroid hormone synthesis, iron deficiency (ID) is a common finding in patients with hypothyroidism like HT and is frequently found in patients with CD. A literature research was conducted to examine the interplay between CD, AITD, vitamin D and iron deficiency. This narrative review highlights the relevant correlation of the two disease entities CD and AITD, their reciprocal impact and possible therapeutic options that should be further explored by future studies.
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Investigating colonization patterns of the infant gut microbiome during the introduction of solid food and weaning from breastmilk: A cohort study protocol. PLoS One 2021; 16:e0248924. [PMID: 33798237 PMCID: PMC8018627 DOI: 10.1371/journal.pone.0248924] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 03/02/2021] [Indexed: 12/21/2022] Open
Abstract
The first exposures to microbes occur during infancy and it is suggested that this initial colonization influences the adult microbiota composition. Despite the important role that the gut microbiome may have in health outcomes later in life, the factors that influence its development during infancy and early childhood have not been characterized fully. Guidelines about the introduction of solid foods and cessation of breastfeeding, which is thought to have a significant role in the transition to a more adult-like microbiota, are not based on microbiome research. There is even less understanding of approaches used to transition to solid food in the preterm population. The purpose of this study is to identify the impact of early life dietary events on gut microbiome community structures and function among infants born at term and pre-term. We plan to prospectively monitor the gut microbiome of infants during two critical timepoints in microbial development: the introduction of solid foods and cessation from breastmilk. A total of 35 participants from three primary observational birth cohorts (two full-term cohorts and one pre-term cohort) will be enrolled in this sub-study. Participants will be asked to collect stool samples and fill out a study diary before, during and after the introduction of solids and again during weaning from breastmilk. We will use frequent fecal sampling analyzed using 16S rRNA gene profiling, metagenomics, metabolomics, and targeted bacterial culturing to identify and characterize the microbial communities, as well as provide insight into the phenotypic characteristics and functional capabilities of the microbes present during these transitional periods of infancy. This study will provide a comprehensive approach to detailing the effects of dietary transition from breastmilk to a more adult-like solid food diet on the microbiome and in doing so will contribute to evidence-based infant nutrition guidance.
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Contribution of Infectious Agents to the Development of Celiac Disease. Microorganisms 2021; 9:microorganisms9030547. [PMID: 33800833 PMCID: PMC8001938 DOI: 10.3390/microorganisms9030547] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 02/28/2021] [Accepted: 03/02/2021] [Indexed: 02/07/2023] Open
Abstract
The ingestion of wheat gliadin (alcohol-soluble proteins, an integral part of wheat gluten) and related proteins induce, in genetically predisposed individuals, celiac disease (CD), which is characterized by immune-mediated impairment of the small intestinal mucosa. The lifelong omission of gluten and related grain proteins, i.e., a gluten-free diet (GFD), is at present the only therapy for CD. Although a GFD usually reduces CD symptoms, it does not entirely restore the small intestinal mucosa to a fully healthy state. Recently, the participation of microbial components in pathogenetic mechanisms of celiac disease was suggested. The present review provides information on infectious diseases associated with CD and the putative role of infections in CD development. Moreover, the involvement of the microbiota as a factor contributing to pathological changes in the intestine is discussed. Attention is paid to the mechanisms by which microbes and their components affect mucosal immunity, including tolerance to food antigens. Modulation of microbiota composition and function and the potential beneficial effects of probiotics in celiac disease are discussed.
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Jia M, Sangwan N, Tzeng A, Eng C. Interplay Between Class II HLA Genotypes and the Microbiome and Immune Phenotypes in Individuals With PTEN Hamartoma Tumor Syndrome. JCO Precis Oncol 2021; 5:PO.20.00374. [PMID: 34250407 DOI: 10.1200/po.20.00374] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 12/12/2020] [Accepted: 12/22/2020] [Indexed: 12/31/2022] Open
Abstract
We evaluate potential contributors to the development of autoimmunity and other phenotypes consistent with immune dysregulation in individuals with germline mutations in the tumor suppressor gene PTEN in this observational report. MATERIALS AND METHODS Illumina sequencing of bacterial and fungal microbes was carried out on patient-donated fecal samples in a cohort of 67 patients with pathogenic germline PTEN mutations, including 41 individuals with autoimmunity and/or phenotypes consistent with immune dysregulation (cases) and 26 individuals without (controls). From these data, we measured differences in alpha and beta diversity between cases and controls and identified differentially abundant bacterial and fungal taxa using phyloseq and MicrobiomeSeq packages in R. We analyzed correlations between these taxa and specific HLA genotypes, along with correlations between HLA diversity and microbial diversity, by conducting high-resolution HLA genotyping at four class II loci (DRB1, DRB345, DQA1, and DQB1). RESULTS We found that alpha diversity distributions for both bacterial and fungal genera were statistically different between cases and controls. We identified differentially abundant bacterial and fungal taxa between cases and controls. Network analysis of differentially abundant bacterial taxa revealed some co-varying bacterial genera. We additionally found significant correlations between certain HLA genotypes and certain taxa and significant correlations between HLA diversity and alpha diversity. CONCLUSION PTEN-associated immune phenotypes might be influenced by the gut microbiome, and class II HLA molecules, in part, crosstalk with the gut microbiome. These preliminary observations should lay the groundwork for future studies to ultimately derive clinical measures, which could use gut microbiome and HLA molecule biomarkers to predict, and perhaps prevent, immunity and inflammation in patients predisposed to cancer because of germline PTEN mutations.
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Affiliation(s)
- Margaret Jia
- Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH
| | - Naseer Sangwan
- Center for Microbiome in Health and Disease, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
| | - Alice Tzeng
- Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH.,Cleveland Clinic Lerner College of Medicine, Cleveland, OH
| | - Charis Eng
- Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH.,Cleveland Clinic Lerner College of Medicine, Cleveland, OH.,Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH.,Center for Personalized Genetic Healthcare, Cleveland Clinic Community Care and Population Health, Cleveland, OH.,Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH.,Germline High Risk Cancer Focus Group, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH
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D'Avino P, Serena G, Kenyon V, Fasano A. An updated overview on celiac disease: from immuno-pathogenesis and immuno-genetics to therapeutic implications. Expert Rev Clin Immunol 2021; 17:269-284. [PMID: 33472447 DOI: 10.1080/1744666x.2021.1880320] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Celiac disease (CD) is an autoimmune enteropathy triggered by ingestion of gluten. While presenting many similarities with other autoimmune diseases, celiac disease is unique in that the external trigger, gluten, and the genetic background necessary for disease development (HLA DQ2/DQ8) are well described. The prevalence of celiac disease is dramatically increasing over the years and new epidemiologic data show changes regarding age of onset and symptoms. A better understanding of CD-pathogenesis is fundamental to highlight the reasons of this rise of celiac diagnoses. AREAS COVERED In this review we describe CD-pathogenesis by dissecting all the components necessary to lose tolerance to gluten (ingestion of gluten, genetic predisposition, loss of barrier function and immune response). Additionally, we also highlight the role that microbiome plays in celiac disease as well as new proposed therapies and experimental tools. EXPERT OPINION Prevalence of autoimmune diseases is increasing around the world. As a result, modern society is strongly impacted by a social and economic burden. Given the unique characteristics of celiac disease, a better understanding of its pathogenesis and the factors that contribute to it may shed light on other autoimmune diseases for which external trigger and genetic background are not known.
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Affiliation(s)
- Paolo D'Avino
- Division of Pediatric Gastroenterology and Nutrition, Mass General Hospital for Children, Harvard Medical School, Boston, MA, USA.,Mucosal Immunology and Biology Research Center, Mass General Hospital for Children, Harvard Medical School, Boston, MA, USA.,Celiac Research Program, Harvard Medical School, Boston, MA, USA.,Vita-Salute San Raffaele University, Milan, Italy
| | - Gloria Serena
- Division of Pediatric Gastroenterology and Nutrition, Mass General Hospital for Children, Harvard Medical School, Boston, MA, USA.,Mucosal Immunology and Biology Research Center, Mass General Hospital for Children, Harvard Medical School, Boston, MA, USA.,Celiac Research Program, Harvard Medical School, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA
| | - Victoria Kenyon
- Division of Pediatric Gastroenterology and Nutrition, Mass General Hospital for Children, Harvard Medical School, Boston, MA, USA.,Mucosal Immunology and Biology Research Center, Mass General Hospital for Children, Harvard Medical School, Boston, MA, USA.,Celiac Research Program, Harvard Medical School, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA
| | - Alessio Fasano
- Division of Pediatric Gastroenterology and Nutrition, Mass General Hospital for Children, Harvard Medical School, Boston, MA, USA.,Mucosal Immunology and Biology Research Center, Mass General Hospital for Children, Harvard Medical School, Boston, MA, USA.,Celiac Research Program, Harvard Medical School, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA.,European Biomedical Research Institute of Salerno (EBRIS), Salerno, Italy
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Gholam-Mostafaei FS, Didari T, Ramandi M, Vafaee R, Rostami-Nejad M. Gut microbiota, angiotensin-converting enzyme, celiac disease, and risk of COVID-19 infection: a review. GASTROENTEROLOGY AND HEPATOLOGY FROM BED TO BENCH 2021; 14:S24-S31. [PMID: 35154599 PMCID: PMC8817746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Accepted: 08/11/2021] [Indexed: 11/24/2022]
Abstract
Celiac disease (CD) is an autoimmune disorder of the gastrointestinal tract in a genetically susceptible person. Gluten is the most crucial trigger factor for CD, and environmental factors such as microbiota and opportunistic infection risk its pathogenesis. Coronavirus disease 19 (COVID-19) spread rapidly and became a problem for healthcare systems worldwide. Little is known about the risk of severe COVID-19 and the role of dysbiosis among patients with CD. There is also a lack of knowledge about the effects of CD gut microbiota on COVID-19 infection. Therefore, the current review discusses the relationship between CD and risk factors such as microbiota for susceptibility to COVID-19.
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Affiliation(s)
- Fahimeh Sadat Gholam-Mostafaei
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Tina Didari
- Pharmaceutical Products Technology Development Center, Tehran University of Medical Sciences, Tehran, Iran,Co-first author
| | - Marzieh Ramandi
- Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Reza Vafaee
- Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, 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
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Olshan KL, Leonard MM, Serena G, Zomorrodi AR, Fasano A. Gut microbiota in Celiac Disease: microbes, metabolites, pathways and therapeutics. Expert Rev Clin Immunol 2020; 16:1075-1092. [PMID: 33103934 DOI: 10.1080/1744666x.2021.1840354] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Current evidence supports a vital role of the microbiota on health outcomes, with alterations in an otherwise healthy balance linked to chronic medical conditions like celiac disease (CD). Recent advances in microbiome analysis allow for unparalleled profiling of the microbes and metabolites. With the growing volume of data available, trends are emerging that support a role for the gut microbiota in CD pathogenesis. AREAS COVERED In this article, the authors review the relationship between factors such as genes and antibiotic exposure on CD onset and the intestinal microbiota. The authors also review other microbiota within the human body (like the oropharynx) that may play a role in CD pathogenesis. Finally, the authors discuss implications for disease modification and the ultimate goal of prevention. The authors reviewed literature from PubMed, EMBASE, and Web of Science. EXPERT OPINION CD serves as a unique opportunity to explore the role of the intestinal microbiota on the development of chronic autoimmune disease. While research to date provides a solid foundation, most studies have been case-control and thus do not have capacity to explore the mechanistic role of the microbiota in CD onset. Further longitudinal studies and integrated multi-omics are necessary for investigating CD pathogenesis.
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Affiliation(s)
- Katherine L Olshan
- Division of Pediatric Gastroenterology and Nutrition, MassGeneral Hospital for Children, Harvard Medical School , Boston, MA, USA.,Mucosal Immunology and Biology Research Center, MassGeneral Hospital for Children, Harvard Medical School , Boston, MA, USA.,Celiac Research Program, Harvard Medical School , Boston, MA, USA
| | - Maureen M Leonard
- Division of Pediatric Gastroenterology and Nutrition, MassGeneral Hospital for Children, Harvard Medical School , Boston, MA, USA.,Mucosal Immunology and Biology Research Center, MassGeneral Hospital for Children, Harvard Medical School , Boston, MA, USA.,Celiac Research Program, Harvard Medical School , Boston, MA, USA
| | - Gloria Serena
- Division of Pediatric Gastroenterology and Nutrition, MassGeneral Hospital for Children, Harvard Medical School , Boston, MA, USA.,Mucosal Immunology and Biology Research Center, MassGeneral Hospital for Children, Harvard Medical School , Boston, MA, USA.,Celiac Research Program, Harvard Medical School , Boston, MA, USA
| | - Ali R Zomorrodi
- Division of Pediatric Gastroenterology and Nutrition, MassGeneral Hospital for Children, Harvard Medical School , Boston, MA, USA.,Mucosal Immunology and Biology Research Center, MassGeneral Hospital for Children, Harvard Medical School , Boston, MA, USA.,Celiac Research Program, Harvard Medical School , Boston, MA, USA
| | - Alessio Fasano
- Division of Pediatric Gastroenterology and Nutrition, MassGeneral Hospital for Children, Harvard Medical School , Boston, MA, USA.,Mucosal Immunology and Biology Research Center, MassGeneral Hospital for Children, Harvard Medical School , Boston, MA, USA.,European Biomedical Research Institute of Salerno (EBRIS) , Salerno, Italy
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Alterations in One-Carbon Metabolism in Celiac Disease. Nutrients 2020; 12:nu12123723. [PMID: 33276620 PMCID: PMC7761552 DOI: 10.3390/nu12123723] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 11/29/2020] [Accepted: 11/30/2020] [Indexed: 12/19/2022] Open
Abstract
Celiac disease (CD) is an autoimmune enteropathy associated with alterations of metabolism. Metabolomics studies, although limited, showed changes in choline, choline-derived lipids, and methionine concentrations, which could be ascribed to alterations in one-carbon metabolism. To date, no targeted metabolomics analysis investigating differences in the plasma choline/methionine metabolome of CD subjects are reported. This work is a targeted metabolomic study that analyzes 37 metabolites of the one-carbon metabolism in 17 children with CD, treated with a gluten-free diet and 17 healthy control siblings, in order to establish the potential defects in this metabolic network. Our results demonstrate the persistence of defects in the transsulfuration pathway of CD subjects, despite dietary treatment, while choline metabolism, methionine cycle, and folate cycle seem to be reversed and preserved to healthy levels. These findings describe for the first time, a metabolic defect in one-carbon metabolism which could have profound implications in the physiopathology and treatment of CD.
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Akobeng AK, Singh P, Kumar M, Al Khodor S. Role of the gut microbiota in the pathogenesis of coeliac disease and potential therapeutic implications. Eur J Nutr 2020; 59:3369-3390. [PMID: 32651763 PMCID: PMC7669811 DOI: 10.1007/s00394-020-02324-y] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Accepted: 07/01/2020] [Indexed: 12/17/2022]
Abstract
PURPOSE Although genetic predisposition and exposure to dietary gluten are considered necessary triggers for the development of coeliac disease, alterations in the gut microbial composition may also contribute towards the pathogenesis of coeliac disease. This review aims to provide an overview of the available data on the potential mechanisms through which the gut microbiota plays a role in the causation of coeliac disease and to discuss the potential therapeutic strategies that could diminish the consequences of microbial dysbiosis. METHOD A search of the literature was performed using the PubMed, Embase, and JSTOR databases; relevant articles were included. RESULTS Recent studies in patients with coeliac disease have reported an increase in the relative amounts of gram negative bacterial genera such as Bacteroides, Prevotella, and Escherichia, and reduced amounts of protective anti-inflammatory bacteria such as Bifidobacteria and Lactobacilli. Dysbiotic microbiota may lead to a dysregulated immune response that may contribute to the pathogenesis of coeliac disease. In infancy, antibiotic use and certain infant feeding practices may lead to alterations in the developing gut microbiota to influence the immune maturation process and predispose to coeliac disease. CONCLUSION The induction of the intestinal immune system and gluten intolerance may be influenced by the relative abundance of certain microbiota. Factors such as infant feeding practices, diet, antibiotics, and infections, may be involved in the development of coeliac disease due to their influence on gut microbial composition. The efficacy of potential modulators of the gut microbiota such as probiotics, prebiotics, and fecal microbial transplant as adjunctive treatments to gluten-free diet in coeliac disease is unproven and requires further investigation.
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Affiliation(s)
- Anthony K Akobeng
- Division of Gastroenterology, Hepatology, and Nutrition, Sidra Medicine, Doha, Qatar
- Weill Cornell Medicine, Cornell University, Doha, Qatar
| | - Parul Singh
- Research Department, Sidra Medicine, Doha, Qatar
| | - Manoj Kumar
- Research Department, Sidra Medicine, Doha, Qatar
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García-Santisteban I, Romero-Garmendia I, Cilleros-Portet A, Bilbao JR, Fernandez-Jimenez N. Celiac disease susceptibility: The genome and beyond. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2020; 358:1-45. [PMID: 33707051 DOI: 10.1016/bs.ircmb.2020.10.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Celiac Disease (CeD) is an immune-mediated complex disease that is triggered by the ingestion of gluten and develops in genetically susceptible individuals. It has been known for a long time that the Human Leucocyte Antigen (HLA) molecules DQ2 and DQ8 are necessary, although not sufficient, for the disease development, and therefore other susceptibility genes and (epi)genetic events must participate in CeD pathogenesis. The advances in Genomics during the last 15 years have made CeD one of the immune-related disorders with the best-characterized genetic component. In the present work, we will first review the main Genome-Wide Association Studies (GWAS) carried out in the disorder, and emphasize post-GWAS discoveries, including diverse integrative strategies, SNP prioritization approaches, and insights into the Microbiome through the host Genomics. Second, we will explore CeD-related Epigenetics and Epigenomics, mostly focusing on the emerging knowledge of the celiac methylome, and the vast but yet under-explored non-coding RNA (ncRNA) landscape. We conclude that much has been done in the field although there are still completely unvisited areas in the post-Genomics of CeD. Chromatin conformation and accessibility, and Epitranscriptomics are promising domains that need to be unveiled to complete the big picture of the celiac Genome.
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Affiliation(s)
- Iraia García-Santisteban
- Department of Genetics, Physical Anthropology and Animal Physiology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU) and Biocruces-Bizkaia Health Research Institute, Leioa, Spain
| | - Irati Romero-Garmendia
- Department of Genetics, Physical Anthropology and Animal Physiology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU) and Biocruces-Bizkaia Health Research Institute, Leioa, Spain
| | - Ariadna Cilleros-Portet
- Department of Genetics, Physical Anthropology and Animal Physiology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU) and Biocruces-Bizkaia Health Research Institute, Leioa, Spain
| | - Jose Ramon Bilbao
- Department of Genetics, Physical Anthropology and Animal Physiology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU) and Biocruces-Bizkaia Health Research Institute, Leioa, Spain; Spanish Biomedical Research Center in Diabetes and associated Metabolic Disorders, CIBERDEM, Madrid, Spain
| | - Nora Fernandez-Jimenez
- Department of Genetics, Physical Anthropology and Animal Physiology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU) and Biocruces-Bizkaia Health Research Institute, Leioa, Spain.
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