|
1
|
Limketkai BN, Rau S, Fasulo C. Preventative and therapeutic potential of nutrition for inflammatory bowel diseases: A narrative review. JPEN J Parenter Enteral Nutr 2024; 48:258-266. [PMID: 38357793 DOI: 10.1002/jpen.2606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 12/10/2023] [Accepted: 01/18/2024] [Indexed: 02/16/2024]
Abstract
Diet strongly shapes the gut microbiome and metabolome, which in turn influence intestinal inflammation in patients with inflammatory bowel disease (IBD). Separate from inflammation and malnutrition, diet's direct interactions with the gastrointestinal system can also provoke or attenuate a host of nonspecific gastrointestinal symptoms. Given these multifaceted effects of diet on inflammation and symptoms, nutrition has been investigated for its potential roles in the prevention and treatment of IBD. This review presents epidemiological, observational cohort, and clinical trial evidence that underlie our current understanding of nutrition for prevention and treatment of IBD.
Collapse
Affiliation(s)
- Berkeley N Limketkai
- Vatche & Tamar Manoukian Division of Digestive Diseases, UCLA School of Medicine, Los Angeles, California, USA
| | - Sameeha Rau
- Vatche & Tamar Manoukian Division of Digestive Diseases, UCLA School of Medicine, Los Angeles, California, USA
| | - Christina Fasulo
- Vatche & Tamar Manoukian Division of Digestive Diseases, UCLA School of Medicine, Los Angeles, California, USA
| |
Collapse
|
|
2
|
Halfvarson J, Ludvigsson JF, Bresso F, Askling J, Sachs MC, Olén O. Age determines the risk of familial inflammatory bowel disease-A nationwide study. Aliment Pharmacol Ther 2022; 56:491-500. [PMID: 35460098 DOI: 10.1111/apt.16938] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Revised: 02/04/2022] [Accepted: 04/07/2022] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIMS To estimate familial aggregation of inflammatory bowel disease (IBD), we performed a nationwide, case-control study and examined the odds for patients with IBD (vs controls) to have a first-degree relative (FDR) with IBD, by age of diagnosis, type of family history and IBD subtype. To assess the incidence of future IBD in relatives of incident IBD patients, we performed a cohort study. METHODS Individuals diagnosed with IBD (N = 50,667) between 2003 and 2017 with at least one FDR were identified from Swedish national registers and compared to general population controls (N = 506,720) with at least one FDR. We used logistic regression to calculate adjusted odds ratios (ORs) and Cox regression to estimate hazard ratios (HRs). RESULTS Compared to controls, IBD cases more often had a mother (3.0% vs 0.9%, OR = 3.5; 95% CI: 3.3-3.7), father (2.9% vs 0.8%, OR = 3.5; 95% CI: 3.3-3.7), full sibling (5.3% vs 1.5%, OR = 3.6; 95% CI: 3.4-3.8) and child (2.4% vs 0.9%, OR = 2.6; 95% CI: 2.4-2.8) with IBD. The strength of association increased with the number of affected FDRs and was modified by subtype of IBD and age of diagnosis. Highest ORs were observed for paediatric IBD among paediatric-onset Crohn's disease (OR = 10.6; 95% CI: 8.2-13.5) and paediatric-onset ulcerative colitis (OR = 8.4; 95% CI: 6.4-10.9) cases. The 10-year cumulative incidence of IBD was 1.7% in full-siblings of incident IBD patients vs 0.4% among full-siblings of reference individuals. CONCLUSION The variations in the strength of familial IBD and future risk of IBD in FDRs support differences in genetic predisposition and call for targeted approaches in potential screening programmes.
Collapse
Affiliation(s)
- Jonas Halfvarson
- Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Jonas F Ludvigsson
- Department Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.,Department of Pediatrics, Örebro University Hospital, Örebro, Sweden.,Department of Medicine, Columbia University College of Physicians and Surgeons, New York City, USA
| | - Francesca Bresso
- Center for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden.,Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Johan Askling
- Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Michael C Sachs
- Department Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Ola Olén
- Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.,Sachs' Children and Youth Hospital, Stockholm South General Hospital, Stockholm, Sweden
| |
Collapse
|
|
3
|
Dipasquale V, Romano C. Genes vs environment in inflammatory bowel disease: an update. Expert Rev Clin Immunol 2022; 18:1005-1013. [PMID: 35912838 DOI: 10.1080/1744666x.2022.2108407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Inflammatory bowel diseases (IBDs) are known to be caused by a combination of genetic and environmental factors that vary in their influence on the development of the disease. Environmental exposures seem to influence IBD susceptibility, whereas genetic background is thought to modulate the impact of the environment on disease course and phenotype. AREAS COVERED A broad review of the involvement of genes and the environment in IBD pathogenesis was performed, and information regarding the main genetic and environmental factors - categorized into lifestyle factors, drugs, diet, and microbes - was updated. Monogenic very early onset IBD (VEO-IBD) was also discussed. EXPERT OPINION In the upcoming years, better understanding of gene-environment interactions will contribute to the possibility of a better prediction of disease course, response to therapy, and therapy-related adverse events with the final goal of personalized and more efficient patient management.
Collapse
Affiliation(s)
- Valeria Dipasquale
- Pediatric Gastroenterology and Cystic Fibrosis Unit, Department of Human Pathology in Adulthood and Childhood "G. Barresi", University of Messina, Messina, Italy
| | - Claudio Romano
- Pediatric Gastroenterology and Cystic Fibrosis Unit, Department of Human Pathology in Adulthood and Childhood "G. Barresi", University of Messina, Messina, Italy
| |
Collapse
|
|
4
|
Gordon H, Blad W, Trier Møller F, Orchard T, Steel A, Trevelyan G, Ng S, Harbord M. UK IBD Twin Registry: Concordance and Environmental Risk Factors of Twins with IBD. Dig Dis Sci 2022; 67:2444-2450. [PMID: 34097167 DOI: 10.1007/s10620-021-07080-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 05/26/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS Twin studies have long been used to infer heritability. Within the 'omics era, twin cohorts have even greater research potential. This study describes the formation of the UK IBD Twin Registry and analysis of concordance and environmental factors. METHOD Twin pairs with IBD were recruited by advertising via IBD charities and social media, re-tracing a dormant IBD database and clinician referral. Details of zygosity, concordance, disease history and environmental factors were assessed. Pair concordance was calculated, and environmental factors were analysed with logistic regression models adjusted for zygosity and concordance. RESULTS Ninety-one twin pairs were included in the analysis; forty-two with CD and forty-nine with UC. More MZ twin pairs with CD were concordant compared with DZ pairs, thus inferring heritability (Chi-sq. 15.6. P < 0.001). In UC, MZ concordance was also numerically greater. Cigarette smoking was predictive of CD (OR 2.66, 95% CI 1.16 to 6.07 P = 0.02); there may be an independent association with cannabis smoking (OR 2.59 95% CI 0.89 to 7.55 P = 0.08). Breastfeeding was protective against UC (OR 0.48, 95% CI 0.25-0.93, P = 0.03), but not CD. Self-reports of less occurrences of gastroenteritis than peers were protective against future UC onset (OR 0.33 95% CI 0.15 to 0.74, P = 0.01). Method of delivery, parental attitudes towards hygiene and recall of diet did not impact future IBD concordance. CONCLUSIONS This study supports the heritability of IBD. Twin study analysis was able to elucidate environmental factors associated with IBD.
Collapse
Affiliation(s)
- Hannah Gordon
- Department of Gastroenterology, Royal London Hospital, Whitechapel Rd, Whitechapel, London, E1 1FR, UK.
| | - William Blad
- Department of Gastroenterology, Royal London Hospital, Whitechapel Rd, Whitechapel, London, E1 1FR, UK
| | - Frederik Trier Møller
- Department of Gastroenterology, Royal London Hospital, Whitechapel Rd, Whitechapel, London, E1 1FR, UK
| | - Timothy Orchard
- Department of Gastroenterology, Royal London Hospital, Whitechapel Rd, Whitechapel, London, E1 1FR, UK
| | - Alan Steel
- Department of Gastroenterology, Royal London Hospital, Whitechapel Rd, Whitechapel, London, E1 1FR, UK
| | - Gareth Trevelyan
- Department of Gastroenterology, Royal London Hospital, Whitechapel Rd, Whitechapel, London, E1 1FR, UK
| | - Siew Ng
- Department of Gastroenterology, Royal London Hospital, Whitechapel Rd, Whitechapel, London, E1 1FR, UK
| | - Marcus Harbord
- Department of Gastroenterology, Royal London Hospital, Whitechapel Rd, Whitechapel, London, E1 1FR, UK
| |
Collapse
|
|
5
|
Yang J, Germano PM, Oh S, Wang S, Wang J, Lee R, Paige H, Yang S, Henning SM, Zhong J, Jacobs JP, Li Z. Pomegranate Extract Improves Colitis in IL-10 Knockout Mice Fed a High Fat High Sucrose Diet. Mol Nutr Food Res 2022; 66:e2100730. [PMID: 34932869 DOI: 10.1002/mnfr.202100730] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 11/19/2021] [Indexed: 11/10/2022]
Abstract
SCOPE The study tests the hypothesis that dietary pomegranate extract (PomX) supplementation attenuates colitis in a Western diet feed IL-10 deficient (IL-10-/-) murine model. METHODS AND RESULTS Four-week-old male IL-10-/- mice are randomly assigned to a high fat high sucrose (HFHS) diet or a HFHS diet supplement with 0.25% PomX for 8 weeks. PomX supplementation lead to significantly lower histological score for colitis (2.6 ± 0.5 vs 3.9 ± 1.0), lower spleen weight (0.11 ± 0.01 vs 0.15 ± 0.02), and lower circulating Interleukin 6(IL-6) levels (15.8±2.2 vs 29.5±5.5) compared with HFHS fed controls. RNAseq analysis of colonic tissues showed 483 downregulated and 263 upregulated genes with PomX supplementation, which are mainly associated with inflammatory responses, defenses, and neutrophil degranulation. In addition, PomX treatment affects the cecal microbiome with increased alpha diversity, altered microbial composition, and increased levels of the tryptophan-related microbial metabolite indole propionate. CONCLUSION The data demonstrate that dietary PomX supplementation ameliorated colitis and lowered inflammatory markers in HFHS fed IL-10-/- mice. These data support the anti-inflammatory effects of dietary PomX supplementation for IBD and a potential mediating role of gut microbiome, suggesting the need for future clinical studies to explore the use of PomX dietary supplementation in IBD patients.
Collapse
Affiliation(s)
- Jieping Yang
- Center for Human Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Patrizia Maria Germano
- Department of Medicine at the David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA
- Research Service Department, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, 90095, USA
| | - Suwan Oh
- Research Service Department, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, 90095, USA
| | - Sijia Wang
- Center for Human Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Jing Wang
- Center for Human Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Rupo Lee
- Center for Human Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Hayden Paige
- Center for Human Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Scarlet Yang
- Center for Human Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Susanne M Henning
- Center for Human Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Jin Zhong
- Department of Pathology and Laboratory Medicine, VA Greater Los Angeles Health Care System, Los Angeles, CA, 90095, USA
| | - Jonathan P Jacobs
- Department of Medicine at the David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA
- Department of Medicine, VA Greater Los Angeles Health Care System, Los Angeles, CA, 90095, USA
| | - Zhaoping Li
- Center for Human Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
- Department of Medicine at the David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA
- Department of Medicine, VA Greater Los Angeles Health Care System, Los Angeles, CA, 90095, USA
| |
Collapse
|
|
6
|
Bergemalm D, Andersson E, Hultdin J, Eriksson C, Rush ST, Kalla R, Adams AT, Keita ÅV, D'Amato M, Gomollon F, Jahnsen J, Ricanek P, Satsangi J, Repsilber D, Karling P, Halfvarson J. Systemic Inflammation in Preclinical Ulcerative Colitis. Gastroenterology 2021; 161:1526-1539.e9. [PMID: 34298022 DOI: 10.1053/j.gastro.2021.07.026] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 07/12/2021] [Accepted: 07/12/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Preclinical ulcerative colitis is poorly defined. We aimed to characterize the preclinical systemic inflammation in ulcerative colitis, using a comprehensive set of proteins. METHODS We obtained plasma samples biobanked from individuals who developed ulcerative colitis later in life (n = 72) and matched healthy controls (n = 140) within a population-based screening cohort. We measured 92 proteins related to inflammation using a proximity extension assay. The biologic relevance of these findings was validated in an inception cohort of patients with ulcerative colitis (n = 101) and healthy controls (n = 50). To examine the influence of genetic and environmental factors on these markers, a cohort of healthy twin siblings of patients with ulcerative colitis (n = 41) and matched healthy controls (n = 37) were explored. RESULTS Six proteins (MMP10, CXCL9, CCL11, SLAMF1, CXCL11 and MCP-1) were up-regulated (P < .05) in preclinical ulcerative colitis compared with controls based on both univariate and multivariable models. Ingenuity Pathway Analyses identified several potential key regulators, including interleukin-1β, tumor necrosis factor, interferon-gamma, oncostatin M, nuclear factor-κB, interleukin-6, and interleukin-4. For validation, we built a multivariable model to predict disease in the inception cohort. The model discriminated treatment-naïve patients with ulcerative colitis from controls with leave-one-out cross-validation (area under the curve = 0.92). Consistently, MMP10, CXCL9, CXCL11, and MCP-1, but not CCL11 and SLAMF1, were significantly up-regulated among the healthy twin siblings, even though their relative abundances seemed higher in incident ulcerative colitis. CONCLUSIONS A set of inflammatory proteins are up-regulated several years before a diagnosis of ulcerative colitis. These proteins were highly predictive of an ulcerative colitis diagnosis, and some seemed to be up-regulated already at exposure to genetic and environmental risk factors.
Collapse
Affiliation(s)
- Daniel Bergemalm
- Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
| | - Erik Andersson
- Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Johan Hultdin
- Department of Medical Biosciences, Division of Clinical Chemistry, Umeå University, Umeå, Sweden
| | - Carl Eriksson
- Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Stephen T Rush
- School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Rahul Kalla
- Medical Research Council Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Alex T Adams
- Translational Gastroenterology Unit, Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Åsa V Keita
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Mauro D'Amato
- CIC bioGUNE Basque Research and Technology Alliance and Basque Science Foundation, Bilbao, Spain; Division of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Fernando Gomollon
- Hospital Clinico Universitario Lozano Blesa, IIS Aragón, Zaragoza, Spain
| | - Jørgen Jahnsen
- Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | | | - Petr Ricanek
- Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway
| | - Jack Satsangi
- Translational Gastroenterology Unit, Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom; Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Dirk Repsilber
- School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Pontus Karling
- Department of Public Health and Clinical Medicine, Division of Medicine, Umeå University, Umeå, Sweden
| | - Jonas Halfvarson
- Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| |
Collapse
|
|
7
|
Torres J, Halfvarson J, Rodríguez-Lago I, Hedin CRH, Jess T, Dubinsky M, Croitoru K, Colombel JF. Results of the Seventh Scientific Workshop of ECCO: Precision Medicine in IBD-Prediction and Prevention of Inflammatory Bowel Disease. J Crohns Colitis 2021; 15:1443-1454. [PMID: 33730755 DOI: 10.1093/ecco-jcc/jjab048] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Inflammatory bowel disease [IBD] is a complex chronic disorder with no clear aetiology and no known cure. Despite recent advances in overall disease management and improved therapeutics, patients with IBD still experience a substantial burden. Furthermore, as the incidence continues to increase in developing areas of the world, it is expected that the burden of IBD to society will increase and exert tremendous pressure on health care systems worldwide. Therefore, new strategies to prevent the global increase of IBD are urgently required. Data are being progressively acquired on the period preceding disease diagnosis, which support the concept that IBD has a preclinical period that may reveal the triggers of disease and may be amenable to early intervention. Having a better knowledge of this preclinical period will increase the potential not only for improved understanding of disease pathogenesis and improved therapeutics, but also for disease prediction and prevention.
Collapse
Affiliation(s)
- Joana Torres
- Division of Gastroenterology, Hospital Beatriz Ângelo, Loures, Portugal.,Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Jonas Halfvarson
- Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Iago Rodríguez-Lago
- Department of Gastroenterology, Hospital de Galdakao, and Biocruces Bizkaia Health Research Institute, Bilbao, Spain
| | - Charlotte R H Hedin
- Karolinska Institutet, Department of Medicine Solna, Stockholm, Sweden.,Karolinska University Hospital, Gastroenterology unit, Department of Gastroenterology, Dermatovenereology and Rheumatology, Stockholm, Sweden
| | - Tine Jess
- Department of Epidemiology Research, Statens Serum Institut, Copenhagen S, Denmark.,PREDICT, Institute of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Marla Dubinsky
- Division of Pediatric Gastroenterology and Nutrition, Susan and Leonard Feinstein Inflammatory Bowel Disease Clinical Center, Icahn School of Medicine Mount Sinai, New York, NY, USA
| | - Kenneth Croitoru
- Center for Inflammatory Bowel Disease, Mount Sinai Hospital, Toronto, ON, Canada.,Division of Gastroenterology and Hepatology, University of Toronto, Toronto, ON, Canada
| | - Jean-Frédéric Colombel
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| |
Collapse
|
|
8
|
Hedin CRH, Sonkoly E, Eberhardson M, Ståhle M. Inflammatory bowel disease and psoriasis: modernizing the multidisciplinary approach. J Intern Med 2021; 290:257-278. [PMID: 33942408 DOI: 10.1111/joim.13282] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 01/11/2021] [Accepted: 01/18/2021] [Indexed: 12/11/2022]
Abstract
Psoriasis and inflammatory bowel disease (IBD) are immune-mediated diseases occurring in barrier organs whose main task is to protect the organism from attack. These disorders are highly prevalent especially in northern Europe where psoriasis has a prevalence of around 3-4% and IBD around 0.3%. The prevalence of IBD in North America has been estimated at around 0.4%. The total incidence rates in northern Europe have been estimated at around 6 for Crohn's disease and 11 for ulcerative colitis per 100 000 person-years, compared with an incidence rate of around 280 per 100 000 person-years for psoriasis. Both diseases are less common in countries with a lower index of development. The rise in IBD appears to occur as populations adopt a westernized lifestyle, whereas psoriasis seems more stable and prevalence differences may derive more from variation in genetic susceptibility. The gut microbiota is clearly an important driver of IBD pathogenesis; in psoriasis, changes in gut and skin microbiota have been reported, but it is less clear whether and how these changes contribute to the pathogenesis. Large studies show that most identified genes are involved in the immune system. However, psoriasis and IBD are highly heterogeneous diseases and there is a need for more precise and deeper phenotyping to identify specific subgroups and their genetic, epigenetic and molecular signatures. Epigenetic modifications of DNA such as histone modifications, noncoding RNA effects on transcription and translation and DNA methylation are increasingly recognized as the mechanism underpinning much of the gene-environment interaction in the pathogenesis of both IBD and psoriasis. Our understanding of underlying pathogenetic mechanisms has deepened fundamentally over the past decades developing hand in hand with novel therapies targeting pathways and proinflammatory cytokines incriminated in disease. There is not only substantial overlap between psoriasis and IBD, but also there are differences with implication for therapy. In psoriasis, drugs targeting interleukin-23 and interleukin-17 have shown superior efficacy compared with anti-TNFs, whilst in IBD, drugs targeting interleukin-17 may be less beneficial. The therapeutic toolbox for psoriasis is impressive and is enlarging also for IBD. Still, there are unmet needs reflecting the heterogeneity of both diseases and there is a need for closer molecular diagnostics to allow for the development of precise therapeutics.
Collapse
Affiliation(s)
- C R H Hedin
- From the, Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden.,Division of Gastroenterology, Medical Unit Gastroenterology, Dermatovenereology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden
| | - E Sonkoly
- From the, Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden.,Division of Dermatology, Medical Unit Gastroenterology, Dermatovenereology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden
| | - M Eberhardson
- From the, Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden.,Department of Gastroenterology, University Hospital in Linkoping, Linkoping, Sweden
| | - M Ståhle
- From the, Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden.,Division of Dermatology, Medical Unit Gastroenterology, Dermatovenereology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden
| |
Collapse
|
|
9
|
To Be or to Have Been Lucky, That Is the Question. PHILOSOPHIES 2021. [DOI: 10.3390/philosophies6030057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Is it possible to measure the dispersion of ex ante chances (i.e., chances “before the event”) among people, be it gambling, health, or social opportunities? We explore this question and provide some tools, including a statistical test, to evidence the actual dispersion of ex ante chances in various areas, with a focus on chronic diseases. Using the principle of maximum entropy, we derive the distribution of the risk of becoming ill in the global population as well as in the population of affected people. We find that affected people are either at very low risk, like the overwhelming majority of the population, but still were unlucky to become ill, or are at extremely high risk and were bound to become ill.
Collapse
|
|
10
|
Giudici F, Cavalli T, Luceri C, Russo E, Zambonin D, Scaringi S, Ficari F, Fazi M, Amedei A, Tonelli F, Malentacchi C. Long-Term Follow-Up, Association between CARD15/NOD2 Polymorphisms, and Clinical Disease Behavior in Crohn's Disease Surgical Patients. Mediators Inflamm 2021; 2021:8854916. [PMID: 33708009 PMCID: PMC7932801 DOI: 10.1155/2021/8854916] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 02/04/2021] [Accepted: 02/08/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND CARD15/NOD2 is the most significant genetic susceptibility in Crohn's disease (CD) even though a relationship between the different polymorphisms and clinical phenotype has not been described yet. The study is aimed at analyzing, in a group of CD patients undergoing surgery, the relationship between CARD15/NOD2 polymorphisms and the clinical CD behavior after a long-term follow-up, in order to identify potential clinical biomarkers of prognosis. METHODS 191 surgical CD patients were prospectively characterized both for the main single nucleotide polymorphisms of CARD15/NOD2 and for many other environmental risk factors connected with the severe disease form. After a mean follow-up of 7.3 years, the correlations between clinical features and CD natural history were analyzed. RESULTS CARD15/NOD2 polymorphisms were significantly associated with younger age at diagnosis compared to wild type cases (p < 0.05). Moreover, patients carrying a 3020insC polymorphism presented a larger Δ between diagnosis and surgery (p = 0.0344). Patients carrying an hz881 and a 3020insC exhibited, respectively, a lower rate of responsiveness to azathioprine (p = 0.012), but no difference was found in biologic therapy. Finally, the risk of surgical recurrence was significantly associated, respectively, to age at diagnosis, to familial CD history, to diagnostic delay, to arthritis, and to the presence of perioperative complications. CONCLUSIONS 3020insC CARD15 polymorphism is associated with an earlier CD onset, and age at CD diagnosis < 27 years was confirmed to have a detrimental effect on its clinical course. In addition, the familiarity seems to be connected with a more aggressive postoperative course. Finally, for the first time, we have observed a lower rate of responsiveness to azathioprine in patients carrying an hz881 and a 3020insC.
Collapse
Affiliation(s)
- Francesco Giudici
- Department of Clinical and Experimental Medicine, Surgical Unit, University of Florence, Italy
| | - Tiziana Cavalli
- Department of Clinical and Experimental Medicine, Surgical Unit, University of Florence, Italy
| | - Cristina Luceri
- Department of Neuroscience, Psychology, Pharmacology and Child Health (NEUROFARBA), Italy
| | - Edda Russo
- Department of Clinical and Experimental Medicine, Surgical Unit, University of Florence, Italy
| | - Daniela Zambonin
- Department of Clinical and Experimental Medicine, Surgical Unit, University of Florence, Italy
| | - Stefano Scaringi
- Department of Clinical and Experimental Medicine, Surgical Unit, University of Florence, Italy
| | - Ferdinando Ficari
- Department of Clinical and Experimental Medicine, Surgical Unit, University of Florence, Italy
| | - Marilena Fazi
- Department of Clinical and Experimental Medicine, Surgical Unit, University of Florence, Italy
| | - Amedeo Amedei
- Department of Clinical and Experimental Medicine, Surgical Unit, University of Florence, Italy
| | - Francesco Tonelli
- Department of Clinical and Experimental Medicine, Surgical Unit, University of Florence, Italy
| | - Cecilia Malentacchi
- Department of Biomedical Experimental and Clinical Sciences, “Mario Serio”, Italy
| |
Collapse
|
|
11
|
Sharifi A, Vahedi H, Honarvar MR, Alipoor B, Nikniaz Z, Rafiei H, Hosseinzadeh-Attar MJ. Vitamin D Increases CTLA-4 Gene Expression in Patients with Mild to Moderate Ulcerative Colitis. Middle East J Dig Dis 2019; 11:199-204. [PMID: 31824622 PMCID: PMC6895856 DOI: 10.15171/mejdd.2019.149] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Accepted: 08/14/2019] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Ulcerative colitis (UC) is a chronic inflammatory disorder of the large intestine. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a member of the immunoglobulin superfamily, which binds B7-1 and B7-2 on APCs (antigen-presenting cells), and induces APCs to produce an inhibitory signal to T cells. The aim of this study was to investigate the effect of vitamin D on CTLA-4 gene expression in whole blood samples of patients with UC. METHODS 90 patients with mild to moderate UC were randomized to receive either a single injection of 7.5 mg vitamin D3 or 1 mL normal saline. 90 days following the intervention fold changes in CTLA-4 mRNA expression were determined and statistical comparisons between the two groups were performed. RESULTS Serum vitamin D increased significantly only in the vitamin D group. CTLA-4 fold changes were significantly higher in the vitamin D group compared with the placebo group (median ± IQR: 1.21 ± 2.3 vs. 1.00 ± 1.5, respectively; p = 0.007). CONCLUSION The results of this study revealed that vitamin D administration in patients with UC enhances the CTLA-4 gene expression.
Collapse
Affiliation(s)
- Amrollah Sharifi
- Assistant Professor; Golestan Research Center of Gastroenterology and Hepatology (GRCGH), Faculty of health, Golestan University of Medical Sciences (GOUMS), Gorgan, Iran
| | - Homayoon Vahedi
- Associate Professor; Digestive Disease Research Center, Digestive Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Honarvar
- Assistant Professor, Health Management and Social Development Research Center, Faculty of Health, Golestan University of Medical Sciences, Gorgan, Iran
| | - Behnam Alipoor
- Assistant Professor; Department of Laboratory Sciences, Faculty of Paramedicine, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Zeinab Nikniaz
- Assistant Professor; Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hossein Rafiei
- Faculty of Health and Social Development, College of Health and Exercise Sciences, University of British Columbia Okanagan, Kelowna, BC, Canada
| | - Mohammad Javad Hosseinzadeh-Attar
- Professor; Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
12
|
Harrison CA, Laubitz D, Midura-Kiela MT, Jamwal DR, Besselsen DG, Ghishan FK, Kiela PR. Sexual Dimorphism in the Response to Broad-spectrum Antibiotics During T Cell-mediated Colitis. J Crohns Colitis 2019; 13:115-126. [PMID: 30252029 PMCID: PMC6302957 DOI: 10.1093/ecco-jcc/jjy144] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND Broad-spectrum antibiotics [Abx], including combination therapy with ciprofloxacin and metronidazole, are often prescribed during the treatment of inflammatory bowel disease [IBD] to alleviate symptoms, but with varying success. In this pilot study, we studied the effects of Abx on the course of experimental colitis, with a particular focus on sex as a determinant of the microbial and inflammatory responses. METHODS The effects of Abx were tested on colonic inflammation and microbiome in male and female Rag-/- mice, using adoptive transfer of naïve T cells to induce colitis in a short-term [2-week] and long-term [9-week] study. RESULTS We observed disparities between the sexes in both the response to adoptive T cell transfer and the effects of Abx. At baseline without Abx, female mice displayed a trend toward a more severe colitis than males. In both the short- and the long-term experiments, gut microbiota of some female mice exposed to Abx showed weak, delayed, or negligible shifts. Caecum weight was significantly lower in Abx-treated females. Abx exposure favoured a quick and persistent rise in Enterococcaceae exclusively in females. Males had higher relative abundance of Lactobacillaceae following Abx exposure relative to females. Abx-treated females trended toward higher colitis scores than Abx-treated males, and towards higher levels of IL-17A, NOS2, and IL-22. CONCLUSIONS Although preliminary, our results suggest a differential response to both inflammation and Abx between male and female mice, The findings may be relevant to current practice and also as the basis for further studies on the differential gender effects during long-term antibiotic exposure in IBD.
Collapse
Affiliation(s)
- Christy A Harrison
- Department of Pediatrics, Steele Children’s Research Center, Tucson, AZ, USA
- Department of Immunobiology, University of Arizona College of Medicine, Tucson, AZ, USA
| | - Daniel Laubitz
- Department of Pediatrics, Steele Children’s Research Center, Tucson, AZ, USA
| | | | - Deepa R Jamwal
- Department of Pediatrics, Steele Children’s Research Center, Tucson, AZ, USA
| | | | - Fayez K Ghishan
- Department of Pediatrics, Steele Children’s Research Center, Tucson, AZ, USA
| | - Pawel R Kiela
- Department of Pediatrics, Steele Children’s Research Center, Tucson, AZ, USA
- Department of Immunobiology, University of Arizona College of Medicine, Tucson, AZ, USA
| |
Collapse
|
|
13
|
Keita ÅV, Lindqvist CM, Öst Å, Magana CDL, Schoultz I, Halfvarson J. Gut Barrier Dysfunction-A Primary Defect in Twins with Crohn's Disease Predominantly Caused by Genetic Predisposition. J Crohns Colitis 2018; 12:1200-1209. [PMID: 29659773 PMCID: PMC6225972 DOI: 10.1093/ecco-jcc/jjy045] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS The aetiology of Crohn's disease is poorly understood. By investigating twin pairs discordant for Crohn's disease, we aimed to assess whether the dysregulated barrier represents a cause or a consequence of inflammation and to evaluate the impact of genetic predisposition on barrier function. METHODS Ileal biopsies from 15 twin pairs discordant for Crohn's disease [monozygotic n = 9, dizygotic n = 6] and 10 external controls were mounted in Ussing chambers to assess paracellular permeability to 51Chromium [Cr]-EDTA and trancellular passage to non-pathogenic E. coli K-12. Experiments were performed with and without provocation with acetylsalicylic acid. Immunofluorescence and ELISA were used to quantify the expression level of tight junction proteins. RESULTS Healthy co-twins and affected twins displayed increased 51Cr-EDTA permeability at 120 min, both with acetylsalicylic acid [p < 0.001] and without [p < 0.001] when compared with controls. A significant increase in 51Cr-EDTA flux was already seen at 20 min in healthy monozygotic co-twins compared with controls [p≤0.05] when stratified by zygosity, but not in healthy dizygotic co-twins. No difference in E. coli passage was observed between groups. Immunofluorescence of the tight junction proteins claudin-5 and tricellulin showed lower levels in healthy co-twins [p < 0.05] and affected twins [p < 0.05] compared with external controls, while ELISA only showed lower tricellulin in Crohn's disease twins [p < 0.05]. CONCLUSION Our results suggest that barrier dysfunction is a primary defect in Crohn's disease, since changes were predominantly seen in healthy monozygotic co-twins. Passage of E. coli seems to be a consequence of inflammation, rather than representing a primary defect.
Collapse
Affiliation(s)
- Åsa V Keita
- Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
| | - Carl Mårten Lindqvist
- Department of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Åke Öst
- Department of Pathology and Cytology, Aleris Medilab, Täby, Sweden
| | - Carlos D L Magana
- Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
| | - Ida Schoultz
- Department of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Jonas Halfvarson
- Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| |
Collapse
|
|
14
|
Goebel-Stengel M, Holtmann G, Enck P. Opportunities of twin research in gastroenterology. Nat Rev Gastroenterol Hepatol 2018; 15:325-326. [PMID: 29752456 DOI: 10.1038/s41575-018-0002-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
Affiliation(s)
- Miriam Goebel-Stengel
- Department of Internal Medicine II: Gastroenterology, Helios Clinic Rottweil, Rottweil, Germany.,Department of Internal Medicine VI: Psychosomatic Medicine and Psychotherapy, University Hospital Tübingen, Tübingen, Germany
| | - Gerald Holtmann
- Princess Alexandra Hospital, Australian GI Research Alliance (AGIRA), University of Queensland, Brisbane, Australia
| | - Paul Enck
- Department of Internal Medicine VI: Psychosomatic Medicine and Psychotherapy, University Hospital Tübingen, Tübingen, Germany.
| |
Collapse
|
|
15
|
Schultz BM, Salazar GA, Paduro CA, Pardo-Roa C, Pizarro DP, Salazar-Echegarai FJ, Torres J, Riedel CA, Kalergis AM, Álvarez-Lobos MM, Bueno SM. Persistent Salmonella enterica serovar Typhimurium Infection Increases the Susceptibility of Mice to Develop Intestinal Inflammation. Front Immunol 2018; 9:1166. [PMID: 29896196 PMCID: PMC5986922 DOI: 10.3389/fimmu.2018.01166] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Accepted: 05/09/2018] [Indexed: 12/12/2022] Open
Abstract
Chronic intestinal inflammations are triggered by genetic and environmental components. However, it remains unclear how specific changes in the microbiota, host immunity, or pathogen exposure could promote the onset and exacerbation of these diseases. Here, we evaluated whether Salmonella enterica serovar Typhimurium (S. Typhimurium) infection increases the susceptibility to develop intestinal inflammation in mice. Two mouse models were used to evaluate the impact of S. Typhimurium infection: the chemical induction of colitis by dextran sulfate sodium (DSS) and interleukin (IL)-10−/− mice, which develop spontaneous intestinal inflammation. We observed that S. Typhimurium infection makes DSS-treated and IL-10−/− mice more susceptible to develop intestinal inflammation. Importantly, this increased susceptibility is associated to the ability of S. Typhimurium to persist in liver and spleen of infected mice, which depends on the virulence proteins secreted by Salmonella Pathogenicity Island 2-encoded type three secretion system (TTSS-2). Although immunization with a live attenuated vaccine resulted in a moderate reduction of the IL-10−/− mice susceptibility to develop intestinal inflammation due to previous S. Typhimurium infection, it did not prevent bacterial persistence. Our results suggest that persistent S. Typhimurium infection may increase the susceptibility of mice to develop inflammation in the intestine, which could be associated with virulence proteins secreted by TTSS-2.
Collapse
Affiliation(s)
- Bárbara M Schultz
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Geraldyne A Salazar
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Carolina A Paduro
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Catalina Pardo-Roa
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Daniela P Pizarro
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Francisco J Salazar-Echegarai
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Javiera Torres
- Departamento de Anatomía Patológica, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Claudia A Riedel
- Millennium Institute on Immunology and Immunotherapy, Departamento de Ciencias Biológicas, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile
| | - Alexis M Kalergis
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.,Departamento de Endocrinología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Manuel M Álvarez-Lobos
- Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Susan M Bueno
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| |
Collapse
|
|
16
|
Yang WH, Heithoff DM, Aziz PV, Sperandio M, Nizet V, Mahan MJ, Marth JD. Recurrent infection progressively disables host protection against intestinal inflammation. Science 2018; 358:358/6370/eaao5610. [PMID: 29269445 DOI: 10.1126/science.aao5610] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Accepted: 11/13/2017] [Indexed: 12/15/2022]
Abstract
Intestinal inflammation is the central pathological feature of colitis and the inflammatory bowel diseases. These syndromes arise from unidentified environmental factors. We found that recurrent nonlethal gastric infections of Gram-negative Salmonella enterica Typhimurium (ST), a major source of human food poisoning, caused inflammation of murine intestinal tissue, predominantly the colon, which persisted after pathogen clearance and irreversibly escalated in severity with repeated infections. ST progressively disabled a host mechanism of protection by inducing endogenous neuraminidase activity, which accelerated the molecular aging and clearance of intestinal alkaline phosphatase (IAP). Disease was linked to a Toll-like receptor 4 (TLR4)-dependent mechanism of IAP desialylation with accumulation of the IAP substrate and TLR4 ligand, lipopolysaccharide-phosphate. The administration of IAP or the antiviral neuraminidase inhibitor zanamivir was therapeutic by maintaining IAP abundance and function.
Collapse
Affiliation(s)
- Won Ho Yang
- Center for Nanomedicine, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.,Sanford Burnham Prebys Medical Discovery Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.,Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA
| | - Douglas M Heithoff
- Center for Nanomedicine, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.,Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA
| | - Peter V Aziz
- Center for Nanomedicine, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.,Sanford Burnham Prebys Medical Discovery Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.,Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA
| | - Markus Sperandio
- Walter-Brendel-Centre for Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany
| | - Victor Nizet
- Department of Pediatrics and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA
| | - Michael J Mahan
- Center for Nanomedicine, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.,Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA
| | - Jamey D Marth
- Center for Nanomedicine, University of California, Santa Barbara, Santa Barbara, CA 93106, USA. .,Sanford Burnham Prebys Medical Discovery Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.,Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA
| |
Collapse
|
|
17
|
Salih A, Widbom L, Hultdin J, Karling P. Smoking is associated with risk for developing inflammatory bowel disease including late onset ulcerative colitis: a prospective study. Scand J Gastroenterol 2018; 53:173-178. [PMID: 29262738 DOI: 10.1080/00365521.2017.1418904] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES Life style factors have been associated with inflammatory bowel disease (IBD) but there is a lack of data on the exposure of life styles factors before the onset of IBD. Our aim was to study the association between lifestyle factors and the development of IBD in a prospective setting. MATERIALS AND METHODS We performed a case control study of 72 patients who later developed ulcerative colitis (UC), 26 patients who developed Crohn's disease (CD) and 427 healthy controls from the Västerbotten intervention project matched for gender, age, year of health survey and area of residence. At recruitment, participants completed validated lifestyle questionnaires including data on alcohol intake. Information from this was used to assess the connection between lifestyle factors and later developing IBD. RESULTS For CD and UC, the median age at diagnosis was 53 and 52 years and median time of survey was 4 and 6 years before diagnosis, respectively. Multivariate odds ratio (OR) showed an association between never smoking and not developing IBD, including both UC and CD, OR (95% CI) 0.341 (0.136-0.853) and 0.473 (0.259-0.864), respectively. Marital status, educational level, alcohol consumption, reported physical activity and use of moist smokeless tobacco (snus) did not differ between patients and controls. CONCLUSIONS Smoking proves to be a risk factor for both CD and UC in this prospective case-control study. No association was seen for snus users, implying a non-nicotine pathogenic mechanism from combusted tobacco.
Collapse
Affiliation(s)
- Abdulkadir Salih
- a Department of Public Health and Clinical Medicine, Division of Medicine , Umeå University , Umeå , Sweden
| | - Lovisa Widbom
- b Department of Medical Biosciences, Division of Clinical Chemistry , Umeå University , Umeå , Sweden
| | - Johan Hultdin
- b Department of Medical Biosciences, Division of Clinical Chemistry , Umeå University , Umeå , Sweden
| | - Pontus Karling
- a Department of Public Health and Clinical Medicine, Division of Medicine , Umeå University , Umeå , Sweden
| |
Collapse
|
|
18
|
Kelsen JR, Sullivan KE. Inflammatory Bowel Disease in Primary Immunodeficiencies. Curr Allergy Asthma Rep 2017; 17:57. [PMID: 28755025 DOI: 10.1007/s11882-017-0724-z] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW Inflammatory bowel disease is most often a polygenic disorder with contributions from the intestinal microbiome, defects in barrier function, and dysregulated host responses to microbial stimulation. There is, however, increasing recognition of single gene defects that underlie a subset of patients with inflammatory bowel disease, particularly those with early-onset disease, and this review focuses on the primary immunodeficiencies associated with early-onset inflammatory bowel disease. RECENT FINDINGS The advent of next-generation sequencing has led to an improved recognition of single gene defects underlying some cases of inflammatory bowel disease. Among single gene defects, immune response genes are the most frequent category identified. This is also true of common genetic variants associated with inflammatory bowel disease, supporting a pivotal role for host responses in the pathogenesis. This review focuses on practical aspects related to diagnosis and management of children with inflammatory bowel disease who have underlying primary immunodeficiencies.
Collapse
Affiliation(s)
- Judith R Kelsen
- Divisions of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, ARC 1216-I, 3615 Civic Center Blvd, Philadelphia, PA, 19104, USA
| | - Kathleen E Sullivan
- Allergy Immunology, The Children's Hospital of Philadelphia, ARC 1216-I, 3615 Civic Center Blvd, Philadelphia, PA, 19104, USA.
| |
Collapse
|
|
19
|
Riba A, Olier M, Lacroix-Lamandé S, Lencina C, Bacquié V, Harkat C, Gillet M, Baron M, Sommer C, Mallet V, Salvador-Cartier C, Laurent F, Théodorou V, Ménard S. Paneth Cell Defects Induce Microbiota Dysbiosis in Mice and Promote Visceral Hypersensitivity. Gastroenterology 2017; 153:1594-1606.e2. [PMID: 28865734 DOI: 10.1053/j.gastro.2017.08.044] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Revised: 08/22/2017] [Accepted: 08/24/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Separation of newborn rats from their mothers induces visceral hypersensitivity and impaired epithelial secretory cell lineages when they are adults. Little is known about the mechanisms by which maternal separation causes visceral hypersensitivity or its relationship with defects in epithelial secretory cell lineages. METHODS We performed studies with C3H/HeN mice separated from their mothers as newborns and mice genetically engineered (Sox9flox/flox-vil-cre on C57BL/6 background) to have deficiencies in Paneth cells. Paneth cell deficiency was assessed by lysozyme staining of ileum tissues and lysozyme activity in fecal samples. When mice were 50 days old, their abdominal response to colorectal distension was assessed by electromyography. Fecal samples were collected and microbiota were analyzed using Gut Low-Density Array quantitative polymerase chain reaction. RESULTS Mice with maternal separation developed visceral hypersensitivity and defects in Paneth cells, as reported from rats, compared with mice without maternal separation. Sox9flox/flox-vil-Cre mice also had increased visceral hypersensitivity compared with control littermate Sox9flox/flox mice. Fecal samples from mice with maternal separation and from Sox9flox/flox-vil-cre mice had evidence for intestinal dysbiosis of the microbiota, characterized by expansion of Escherichia coli. Daily gavage of conventional C3H/HeN adult mice with 109 commensal E coli induced visceral hypersensitivity. Conversely, daily oral administration of lysozyme prevented expansion of E coli during maternal separation and visceral hypersensitivity. CONCLUSIONS Mice with defects in Paneth cells (induced by maternal separation or genetically engineered) have intestinal expansion of E coli leading to visceral hypersensitivity. These findings provide evidence that Paneth cell function and intestinal dysbiosis are involved in visceral sensitivity.
Collapse
Affiliation(s)
- Ambre Riba
- INRA, ToxAlim (Research Centre in Food Toxicology), team Neuro-Gastroenterology and Nutrition, Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France
| | - Maïwenn Olier
- INRA, ToxAlim (Research Centre in Food Toxicology), team Neuro-Gastroenterology and Nutrition, Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France
| | - Sonia Lacroix-Lamandé
- Equipe Apicomplexes et Immunité Mucosale (AIM), UMR 1282 INRA/Université-Infectiologie et Santé Publique (ISP), Centre INRA Val de Loire, Nouzilly, France
| | - Corinne Lencina
- INRA, ToxAlim (Research Centre in Food Toxicology), team Neuro-Gastroenterology and Nutrition, Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France
| | - Valérie Bacquié
- INRA, ToxAlim (Research Centre in Food Toxicology), team Neuro-Gastroenterology and Nutrition, Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France
| | - Cherryl Harkat
- INRA, ToxAlim (Research Centre in Food Toxicology), team Neuro-Gastroenterology and Nutrition, Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France
| | - Marion Gillet
- INRA, ToxAlim (Research Centre in Food Toxicology), team Neuro-Gastroenterology and Nutrition, Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France
| | - Marine Baron
- INRA, ToxAlim (Research Centre in Food Toxicology), team Neuro-Gastroenterology and Nutrition, Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France
| | - Caroline Sommer
- INRA, ToxAlim (Research Centre in Food Toxicology), team Neuro-Gastroenterology and Nutrition, Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France
| | - Virginie Mallet
- INRA, ToxAlim (Research Centre in Food Toxicology), team Neuro-Gastroenterology and Nutrition, Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France
| | - Christel Salvador-Cartier
- INRA, ToxAlim (Research Centre in Food Toxicology), team Neuro-Gastroenterology and Nutrition, Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France
| | - Fabrice Laurent
- Equipe Apicomplexes et Immunité Mucosale (AIM), UMR 1282 INRA/Université-Infectiologie et Santé Publique (ISP), Centre INRA Val de Loire, Nouzilly, France
| | - Vassilia Théodorou
- INRA, ToxAlim (Research Centre in Food Toxicology), team Neuro-Gastroenterology and Nutrition, Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France
| | - Sandrine Ménard
- INRA, ToxAlim (Research Centre in Food Toxicology), team Neuro-Gastroenterology and Nutrition, Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France.
| |
Collapse
|
|
20
|
Santos MPC, Gomes C, Torres J. Familial and ethnic risk in inflammatory bowel disease. Ann Gastroenterol 2017; 31:14-23. [PMID: 29333063 PMCID: PMC5759609 DOI: 10.20524/aog.2017.0208] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 09/21/2017] [Indexed: 02/07/2023] Open
Abstract
Familial aggregation in inflammatory bowel disease (IBD) has been established for several decades, reflecting shared genetic and environmental susceptibility. A positive family history remains the strongest recognizable risk factor for the development of IBD and is reported in around 8-12% of IBD patients. Crohn’s disease shows a more frequent familial pattern than ulcerative colitis. The risk of developing IBD in first-degree relatives of an affected proband is increased 4- to 8-fold. The risk for twins and children born from couples who both have IBD is also substantially higher; a cumulative effect of the number of family members affected has been described, with the highest incidence being described for families with three or more affected members. Herein, we review the available evidence regarding familial IBD, and briefly discuss the variation of IBD across different races and ethnicities, hoping to provide a useful update and a practical guide that can serve clinicians as a guide for counseling.
Collapse
Affiliation(s)
- Maria Pia Costa Santos
- Gastroenterology Division, Surgical Department, Hospital Beatriz Ângelo, Loures, Portugal
| | - Catarina Gomes
- Gastroenterology Division, Surgical Department, Hospital Beatriz Ângelo, Loures, Portugal
| | - Joana Torres
- Gastroenterology Division, Surgical Department, Hospital Beatriz Ângelo, Loures, Portugal
| |
Collapse
|
|
21
|
Gut biofilm forming bacteria in inflammatory bowel disease. Microb Pathog 2017; 112:5-14. [PMID: 28942174 DOI: 10.1016/j.micpath.2017.09.041] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Revised: 09/15/2017] [Accepted: 09/18/2017] [Indexed: 12/18/2022]
Abstract
Inflammatory bowel disease (IBD) symbolizes a group of intestinal disorders in which prolonged inflammation occur in the digestive tract (esophagus, large intestine, small intestine mouth, stomach). Both genetic and environmental factors (infections, stress, diet) are involved in the development of IBD. As we know that bacteria are found in the intestinal mucosa of human and clinical observations revealed bacterial biofilms associated with patients of IBD. Various factors and microbes are found to play an essential role in biofilm formation and mucosal colonization during IBD. Biofilm formation in the digestive tract is dependent on an extracellular matrix synthesized by the bacteria and it has an adverse effect on the immune response of the host. There is no satisfactory and safe treatment option for IBD. Therefore, the current research aims to disrupt biofilm in IBD and concentrates predominantly on improving the drug. Here, we review the literature on bacterial biofilm and IBD to gather new knowledge on the current understanding of biofilm formation in IBD, host immune deregulation and dysbiosis in IBD, molecular mechanism, bacteria involved in biofilm formation, current and future regimen. It is urgently required to plan new ways to control and eradicate bacteria in biofilms that will open up novel diagnostic and therapeutic avenues for IBD. This article includes the mechanism of signaling molecules with respect to the biofilm-related genes as well as the diagnostic methods and new technologies involved in the treatment of IBD.
Collapse
|
|
22
|
Ballester MP, Martí D, Tosca J, Bosca-Watts MM, Sanahuja A, Navarro P, Pascual I, Antón R, Mora F, Mínguez M. Disease severity and treatment requirements in familial inflammatory bowel disease. Int J Colorectal Dis 2017; 32:1197-1205. [PMID: 28361220 DOI: 10.1007/s00384-017-2791-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/03/2017] [Indexed: 02/04/2023]
Abstract
PURPOSE Several studies demonstrate an increased prevalence and concordance of inflammatory bowel disease among the relatives of patients. Other studies suggest that genetic influence is over-estimated. The aims of this study are to evaluate the phenotypic expression and the treatment requirements in familial inflammatory bowel disease, to study the relationship between number of relatives and degree of kinship with disease severity and to quantify the impact of family aggregation compared to other environmental factors. METHODS Observational analytical study of 1211 patients followed in our unit. We analyzed, according to the existence of familial association, number and degree of consanguinity, the phenotypic expression, complications, extraintestinal manifestations, treatment requirements, and mortality. A multivariable analysis considering smoking habits and non-steroidal-anti-inflammatory drugs was performed. RESULTS 14.2% of patients had relatives affected. Median age at diagnosis tended to be lower in the familial group, 32 vs 29, p = 0.07. In familial ulcerative colitis, there was a higher proportion of extraintestinal manifestations: peripheral arthropathy (OR = 2.3, p = 0.015) and erythema nodosum (OR = 7.6, p = 0.001). In familial Crohn's disease, there were higher treatment requirements: immunomodulators (OR = 1.8, p = 0.029); biologics (OR = 1.9, p = 0.011); and surgery (OR = 1.7, p = 0.044). The abdominal abscess increased with the number of relatives affected: 5.1% (sporadic), 7.0% (one), and 14.3% (two or more), p=0.039. These associations were maintained in the multivariate analysis. CONCLUSIONS Familial aggregation is considered a risk factor for more aggressive disease and higher treatment requirements, a tendency for earlier onset, more abdominal abscess, and extraintestinal manifestations, remaining a risk factor analyzing the influence of some environmental factors.
Collapse
Affiliation(s)
- María Pilar Ballester
- Digestive Disease Department, University of Valencia, University Clinic Hospital of Valencia, Blasco Ibañez Av. 17, 46010, Valencia, Spain.
| | - David Martí
- Digestive Disease Department, University of Valencia, University Clinic Hospital of Valencia, Blasco Ibañez Av. 17, 46010, Valencia, Spain
| | - Joan Tosca
- Digestive Disease Department, University of Valencia, University Clinic Hospital of Valencia, Blasco Ibañez Av. 17, 46010, Valencia, Spain
| | - Marta Maia Bosca-Watts
- Digestive Disease Department, University of Valencia, University Clinic Hospital of Valencia, Blasco Ibañez Av. 17, 46010, Valencia, Spain
| | - Ana Sanahuja
- Digestive Disease Department, University of Valencia, University Clinic Hospital of Valencia, Blasco Ibañez Av. 17, 46010, Valencia, Spain
| | - Pablo Navarro
- Digestive Disease Department, University of Valencia, University Clinic Hospital of Valencia, Blasco Ibañez Av. 17, 46010, Valencia, Spain
| | - Isabel Pascual
- Digestive Disease Department, University of Valencia, University Clinic Hospital of Valencia, Blasco Ibañez Av. 17, 46010, Valencia, Spain
| | - Rosario Antón
- Digestive Disease Department, University of Valencia, University Clinic Hospital of Valencia, Blasco Ibañez Av. 17, 46010, Valencia, Spain
| | - Francisco Mora
- Digestive Disease Department, University of Valencia, University Clinic Hospital of Valencia, Blasco Ibañez Av. 17, 46010, Valencia, Spain
| | - Miguel Mínguez
- Digestive Disease Department, University of Valencia, University Clinic Hospital of Valencia, Blasco Ibañez Av. 17, 46010, Valencia, Spain
| |
Collapse
|
|
23
|
Hammer T, Lophaven SN, Nielsen KR, von Euler‐Chelpin M, Weihe P, Munkholm P, Burisch J, Lynge E. Inflammatory bowel diseases in Faroese-born Danish residents and their offspring: further evidence of the dominant role of environmental factors in IBD development. Aliment Pharmacol Ther 2017; 45:1107-1114. [PMID: 28176348 PMCID: PMC5396334 DOI: 10.1111/apt.13975] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 11/24/2016] [Accepted: 01/16/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND The incidence of inflammatory bowel disease (IBD) is record high in the Faroe Islands, and many Faroese emigrate to Denmark, where the IBD incidence is considerably lower. AIM To study the IBD incidence in first-, second- and third-generation immigrants from the Faroe Islands to Denmark to assess the extent to which the immigrants adopt the lower IBD incidence of their new home country. METHODS Data on Faroese-born Danish residents and their children were retrieved from the Danish Central Population Register for 1980-2014. Incident IBD cases were identified from the Danish National Patient Register. Standardised Incidence Ratios (SIRs) were used to compare the IBD risk in immigrants with that of Danes. 95% confidence intervals (CI) were calculated using the square-root transform. RESULTS First-generation Faroese immigrants had a higher IBD incidence than Danes, SIR 1.25 (95% CI, 0.97-1.59) for men and 1.28 (95% CI, 1.05-1.53) for women. This excess risk derived from ulcerative colitis (UC), SIR 1.44 (95% CI, 1.10-1.87) for men and 1.36 (95% CI, 1.09-1.68) for women. No excess risk was found for Crohn's disease (CD). The UC risk was nearly doubled during the immigrants' first 10 years in Denmark; SIR 2.13 (95% CI, 1.52-2.92) for men and 1.63 (95% CI, 1.19-2.18) for women. CONCLUSIONS Although some impact of genetic dilution cannot be excluded, our findings indicate importance of gene-environment interplay in UC, as the excess UC risk in Faroese immigrants to Denmark disappeared over time and over one generation in men and over two generations in women.
Collapse
Affiliation(s)
- T. Hammer
- Department of Public HealthUniversity of CopenhagenCopenhagenDenmark,Department of Occupational Medicine and Public HealthThe Faroese Hospital SystemTórshavnFaroe Islands
| | - S. N. Lophaven
- Department of Public HealthUniversity of CopenhagenCopenhagenDenmark
| | - K. R. Nielsen
- Medical CentreNational HospitalTórshavnFaroe Islands,Genetic BiobankTórshavnFaroe Islands
| | | | - P. Weihe
- Department of Occupational Medicine and Public HealthThe Faroese Hospital SystemTórshavnFaroe Islands
| | - P. Munkholm
- Department of GastroenterologyNorth Zealand HospitalCopenhagenDenmark
| | - J. Burisch
- Department of GastroenterologyNorth Zealand HospitalCopenhagenDenmark
| | - E. Lynge
- Department of Public HealthUniversity of CopenhagenCopenhagenDenmark
| |
Collapse
|
|
24
|
Melinder C, Hiyoshi A, Fall K, Halfvarson J, Montgomery S. Stress resilience and the risk of inflammatory bowel disease: a cohort study of men living in Sweden. BMJ Open 2017; 7:e014315. [PMID: 28130207 PMCID: PMC5278277 DOI: 10.1136/bmjopen-2016-014315] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE To determine if low psychosocial stress resilience in adolescence (increasing chronic stress arousal throughout life) is associated with an increased inflammatory bowel disease (IBD) risk in adulthood. Subclinical Crohn's disease (CD) and ulcerative colitis (UC) can exist over many years and we hypothesise that psychosocial stress may result in conversion to symptomatic disease through its proinflammatory or barrier function effects. DESIGN National register-based cohort study of men followed from late adolescence to middle age. SETTING A general population cohort of men in Sweden. PARTICIPANTS Swedish population-based registers provided information on all men born between 1952 and 1956 who underwent mandatory Swedish military conscription assessment (n=239 591). Men with any gastrointestinal diagnoses (except appendicitis) prior to follow-up were excluded. PRIMARY OUTCOME MEASURES An inpatient or outpatient diagnosis of CD or UC recorded in the Swedish Patient Register (1970-2009). RESULTS A total of 938 men received a diagnosis of CD and 1799 UC. Lower stress resilience in adolescence was associated with increased IBD risk, with unadjusted HRs (95% CIs) of 1.54 (1.26 to 1.88) and 1.24 (1.08 to 1.42), for CD and UC, respectively. After adjustment for potential confounding factors, including markers of subclinical disease activity in adolescence, they are 1.39 (1.13 to 1.71) and 1.19 (1.03 to 1.37). CONCLUSIONS Lower stress resilience may increase the risk of diagnosis of IBD in adulthood, possibly through an influence on inflammation or barrier function.
Collapse
Affiliation(s)
- Carren Melinder
- Department of Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro, Sweden
| | - Ayako Hiyoshi
- Department of Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro, Sweden
| | - Katja Fall
- Department of Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro, Sweden
| | - Jonas Halfvarson
- Department of Gastroenterology, School of Medical Sciences, Örebro University, Örebro, Sweden
| | - Scott Montgomery
- Department of Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro, Sweden
- Department of Epidemiology and Public Health, University College London, London, UK
- Clinical Epidemiology Unit, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
| |
Collapse
|
|
25
|
Hedin CR, van der Gast CJ, Stagg AJ, Lindsay JO, Whelan K. The gut microbiota of siblings offers insights into microbial pathogenesis of inflammatory bowel disease. Gut Microbes 2017; 8:359-365. [PMID: 28112583 PMCID: PMC5570433 DOI: 10.1080/19490976.2017.1284733] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Siblings of patients with Crohn's disease (CD) have elevated risk of developing CD and display aspects of disease phenotype, including faecal dysbiosis. In our recent article we have used 16S rRNA gene targeted high-throughput sequencing to comprehensively characterize the mucosal microbiota in healthy siblings of CD patients, and determine the influence of genotypic and phenotypic factors on the gut microbiota (dysbiosis). We have demonstrated that the core microbiota of both patients with CD and healthy siblings is significantly less diverse than controls. Faecalibacterium prausnitzii contributed most to core metacommunity dissimilarity between both patients and controls and between siblings and controls. Phenotype/genotype markers of CD risk significantly influenced microbiota variation between and within groups, of which genotype had the largest effect. Individuals with elevated CD-risk display mucosal dysbiosis characterized by reduced diversity of core microbiota and lower abundance of F. prausnitzii. The presence of this dysbiosis in healthy people at-risk of CD implicates microbiological processes in CD pathogenesis.
Collapse
Affiliation(s)
- Charlotte R. Hedin
- Department of Medicine, Karolinska University Hospital, Solna, Stockholm
| | | | - Andrew J. Stagg
- Queen Mary University of London, Centre for Immunobiology, Blizard Institute, London, UK
| | - James O. Lindsay
- Queen Mary University of London, Centre for Immunobiology, Blizard Institute, London, UK,Barts Health NHS Trust, Department of Gastroenterology, London, UK
| | - Kevin Whelan
- King's College London, Faculty of Life Sciences & Medicine, Diabetes and Nutritional Sciences Division, London, UK,CONTACT Kevin Whelan King's College London, 150 Stamford Street, London, SE1 9NH, United Kingdom
| |
Collapse
|
|
26
|
Wehkamp J, Götz M, Herrlinger K, Steurer W, Stange EF. Inflammatory Bowel Disease. DEUTSCHES ARZTEBLATT INTERNATIONAL 2017; 113:72-82. [PMID: 26900160 DOI: 10.3238/arztebl.2016.0072] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Revised: 12/14/2015] [Accepted: 12/14/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND Inflammatory bowel diseases are common in Europe, with prevalences as high as 1 in 198 persons (ulcerative colitis) and 1 in 310 persons (Crohn's disease). METHODS This review is based on pertinent articles retrieved by a search in PubMed and in German and European guidelines and Cochrane reviews of controlled trials. RESULTS Typically, the main clinical features of inflammatory bowel diseases are diarrhea, abdominal pain, and, in the case of ulcerative colitis, peranal bleeding. These diseases are due to a complex immunological disturbance with both genetic and environmental causes. A defective mucosal barrier against commensal bowel flora plays a major role in their pathogenesis. The diagnosis is based on laboratory testing, ultrasonography, imaging studies, and, above all, gastrointestinal endoscopy. Most patients with Crohn's disease respond to budesonide or systemic steroids; aminosalicylates are less effective. Refractory exacerbations may be treated with antibodies against tumor necrosis factor (TNF) or, more recently, antibodies against integrin, a protein of the cell membrane. In ulcerative colitis, aminosalicylates are given first; if necessary, steroids or antibodies against TNF-α or integrin are added. Maintenance therapy to prevent further relapses often involves immunosuppression with thiopurines and/or antibodies. Once all conservative treatment options have been exhausted, surgery may be necessary. CONCLUSION The treatment of chronic inflammatory bowel diseases requires individually designed therapeutic strategies and the close interdisciplinary collaboration of internists and surgeons.
Collapse
Affiliation(s)
- Jan Wehkamp
- Department of Internal Medicine I - Gastroenterology, Hepatology, Infectiology, University Hospital of Tübingen, Asklepios Klinik Nord - Heidberg, Hamburg, Department of Internal Medicine I (Gastroenterology, Hepatology and Endocrinology), Robert-Bosch-Krankenhaus, Stuttgart
| | | | | | | | | |
Collapse
|
|
27
|
Gabbani T, Deiana S, Annese AL, Lunardi S, Annese V. The genetic burden of inflammatory bowel diseases: implications for the clinic? Expert Rev Gastroenterol Hepatol 2016; 10:1109-1117. [PMID: 27258545 DOI: 10.1080/17474124.2016.1196131] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Inflammatory bowel diseases (IBD), which include Crohn's disease (CD) and ulcerative colitis (UC), are characterized by chronic intestinal inflammation. Their etiology is multifactorial, with complex interactions between genetic and environmental factors, which are still largely unclear. Areas covered: The influence of genetics is clearly demonstrated by important epidemiological data, including familial aggregation and concordance in twins. In 2001, the first genetic susceptibility gene for IBD, the NOD2 gene, was identified. Currently, thanks to genetic wide association studies, over 200 susceptibility genetic markers are know. Expert commentary: However, clinically highly relevant gene associations are still very limited and the usefulness of these information in the current clinical strategies for treatment and surveillance of IBD is weak. Nevertheless, the recent identification of some genetic risk variants has clarified some newbiological pathways of these diseases thus paving the way for the discoveries in the near future of new targeted therapies.
Collapse
Affiliation(s)
- Tommaso Gabbani
- a Division of Gastroenterology , AOU Careggi University Hospital , Florence , Italy
| | - Simona Deiana
- a Division of Gastroenterology , AOU Careggi University Hospital , Florence , Italy
| | - Antonio Luca Annese
- a Division of Gastroenterology , AOU Careggi University Hospital , Florence , Italy
| | - Sarah Lunardi
- b Division of Internal Medicine 4 , AOU Careggi University Hospital , Florence , Italy
| | - Vito Annese
- a Division of Gastroenterology , AOU Careggi University Hospital , Florence , Italy
| |
Collapse
|
|
28
|
Vindigni SM, Zisman TL, Suskind DL, Damman CJ. The intestinal microbiome, barrier function, and immune system in inflammatory bowel disease: a tripartite pathophysiological circuit with implications for new therapeutic directions. Therap Adv Gastroenterol 2016; 9:606-25. [PMID: 27366227 PMCID: PMC4913337 DOI: 10.1177/1756283x16644242] [Citation(s) in RCA: 140] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
We discuss the tripartite pathophysiological circuit of inflammatory bowel disease (IBD), involving the intestinal microbiota, barrier function, and immune system. Dysfunction in each of these physiological components (dysbiosis, leaky gut, and inflammation) contributes in a mutually interdependent manner to IBD onset and exacerbation. Genetic and environmental risk factors lead to disruption of gut homeostasis: genetic risks predominantly affect the immune system, environmental risks predominantly affect the microbiota, and both affect barrier function. Multiple genetic and environmental 'hits' are likely necessary to establish and exacerbate disease. Most conventional IBD therapies currently target only one component of the pathophysiological circuit, inflammation; however, many patients with IBD do not respond to immune-modulating therapies. Hope lies in new classes of therapies that target the microbiota and barrier function.
Collapse
Affiliation(s)
- Stephen M. Vindigni
- Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Timothy L. Zisman
- Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, WA, USA
| | - David L. Suskind
- Department of Pediatrics, Seattle Children’s Hospital and University of Washington, Seattle, WA, USA
| | | |
Collapse
|
|
29
|
Moller FT, Knudsen L, Harbord M, Satsangi J, Gordon H, Christiansen L, Christensen K, Jess T, Andersen V. Danish cohort of monozygotic inflammatory bowel disease twins: Clinical characteristics and inflammatory activity. World J Gastroenterol 2016; 22:5050-5059. [PMID: 27275097 PMCID: PMC4886380 DOI: 10.3748/wjg.v22.i21.5050] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Revised: 03/21/2016] [Accepted: 05/04/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To describe the establishment of a Danish inflammatory bowel diseases (IBD) twin cohort with focus on concordance of treatment and inflammatory markers.
METHODS: We identified MZ twins, likely to be discordant or concordant for IBD, by merging information from the Danish Twin Register and the National Patient Register. The twins were asked to provide biological samples, questionnaires, and data access to patient files and public registries. Biological samples were collected via a mobile laboratory, which allowed for immediate centrifugation, fractionation, and storage of samples. The mean time from collection of samples to storage in the -80 °C mobile freezer was less than one hour. The diagnoses where validated using the Copenhagen diagnostic criteria.
RESULTS: We identified 159 MZ IBD twin pairs, in a total of 62 (39%) pairs both twins agreed to participate. Of the supposed 62 IBD pairs, the IBD diagnosis could be confirmed in 54 pairs. The cohort included 10 concordant pairs, whereof some were discordant for either treatment or surgery. The 10 concordant pairs, where both pairs suffered from IBD, included eight CD/CD pairs, one UC/UC pair and one UC/IBDU pair. The discordant pairs comprised 31 UC, 5 IBDU (IBD unclassified), and 8 CD discordant pairs. In the co-twins not affected by IBD, calprotectin was above 100 μg/g in 2 participants, and above 50 μg/g in a further 5 participants.
CONCLUSION: The presented IBD twin cohorts are an excellent resource for bioinformatics studies with proper adjustment for disease-associated exposures including medication and inflammatory activity in the co-twins.
Collapse
|
|
30
|
Opstelten JL, Leenders M, Dik VK, Chan SSM, van Schaik FDM, Khaw KT, Luben R, Hallmans G, Karling P, Lindgren S, Grip O, Key TJ, Crowe FL, Boeing H, Bergmann MM, Overvad K, Palli D, Masala G, Racine A, Carbonnel F, Boutron-Ruault MC, Tjønneland A, Olsen A, Andersen V, Kaaks R, Katzke VA, Tumino R, Trichopoulou A, Siersema PD, Bueno-de-Mesquita HB, Hart AR, Oldenburg B. Dairy Products, Dietary Calcium, and Risk of Inflammatory Bowel Disease: Results From a European Prospective Cohort Investigation. Inflamm Bowel Dis 2016; 22:1403-11. [PMID: 27120568 DOI: 10.1097/mib.0000000000000798] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Dairy products may be involved in the etiology of inflammatory bowel disease by modulating gut microbiota and immune responses, but data from epidemiological studies examining this relationship are limited. We investigated the association between prediagnostic intake of these foods and dietary calcium, and the subsequent development of Crohn's disease (CD) and ulcerative colitis (UC). METHODS In total, 401,326 participants were enrolled in the European Prospective Investigation into Cancer and Nutrition cohort. At recruitment, consumption of total and specific dairy products (milk, yogurt, and cheese) and dietary calcium was measured using validated food frequency questionnaires. Cases developing incident CD (n = 110) or UC (n = 244) during follow-up were matched with 4 controls. Conditional logistic regression analyses were used to calculate odds ratios (ORs) with 95% confidence intervals (CIs), adjusted for total energy intake and smoking. RESULTS Compared with the lowest quartile, the ORs for the highest quartile of total dairy products and dietary calcium intake were 0.61 (95% CI, 0.32-1.19, p trend = 0.19) and 0.63 (95% CI, 0.28-1.42, p trend = 0.23) for CD, and 0.80 (95% CI, 0.50-1.30, p trend = 0.40) and 0.81 (95% CI, 0.49-1.34, p trend = 0.60) for UC, respectively. Compared with nonconsumers, individuals consuming milk had significantly reduced odds of CD (OR 0.30, 95% CI, 0.13-0.65) and nonsignificantly reduced odds of UC (OR 0.85, 95% CI, 0.49-1.47). CONCLUSIONS Milk consumption may be associated with a decreased risk of developing CD, although a clear dose-response relationship was not established. Further studies are warranted to confirm this possible protective effect.
Collapse
Affiliation(s)
- Jorrit L Opstelten
- 1Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, the Netherlands; 2Department of Medicine, Norwich Medical School, University of East Anglia, Norwich, United Kingdom; 3Department of Gastroenterology, Norfolk and Norwich University Hospital NHS Trust, Norwich, United Kingdom; 4Strangeways Research Laboratory, Institute of Public Health, University of Cambridge, Cambridge, United Kingdom; 5Department of Public Health and Clinical Medicine, Nutritional Research, Umeå University, Umeå, Sweden; 6Department of Public Health and Clinical Medicine, GI Unit, Umeå University, Umeå, Sweden; 7Department of Clinical Sciences, Lund University, Lund, Sweden; 8Gastroenterology-Hepatology Division, University Hospital Skane, Malmö, Sweden; 9Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom; 10Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Potsdam, Germany; 11Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark; 12Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute (ISPO), Florence, Italy; 13French Institute of Health and Medical Research (INSERM), Centre for Research in Epidemiology and Population Health, Institut Gustave Roussy, Villejuif, France; 14Université Paris Sud, Paris, France; 15Department of Gastroenterology, Bicêtre University Hospital, Assistance Publique des Hôpitaux de Paris, Paris, France; 16Diet, Genes and Environment, Danish Cancer Society Research Center, Copenhagen, Denmark; 17Institute of Regional Research, Center Sønderjylland, University of Southern Denmark, Odense, Denmark; 18Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; 19Cancer Registry and Histopathology Unit, "Civic-M.P. Arezzo" Hospital, Ragusa, Italy; 20Department of Hygiene and Epidemiology, WHO Collaborating Center for Food and Nu
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
31
|
Hedin C, van der Gast CJ, Rogers GB, Cuthbertson L, McCartney S, Stagg AJ, Lindsay JO, Whelan K. Siblings of patients with Crohn's disease exhibit a biologically relevant dysbiosis in mucosal microbial metacommunities. Gut 2016; 65:944-53. [PMID: 25856344 DOI: 10.1136/gutjnl-2014-308896] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Accepted: 03/11/2015] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To determine the existence of mucosal dysbiosis in siblings of patients with Crohn's disease (CD) using 454 pyrosequencing and to comprehensively characterise and determine the influence of genotypical and phenotypical factors, on that dysbiosis. Siblings of patients with CD have elevated risk of developing CD and display aspects of disease phenotype, including faecal dysbiosis. Whether the mucosal microbiota is disrupted in these at-risk individuals is unknown. DESIGN Rectal biopsy DNA was extracted from 21 patients with quiescent CD, 17 of their healthy siblings and 19 unrelated healthy controls. Mucosal microbiota was analysed by 16S rRNA gene pyrosequencing and were classified into core and rare species. Genotypical risk was determined using Illumina Immuno BeadChip, faecal calprotectin by ELISA and blood T-cell phenotype by flow cytometry. RESULTS Core microbiota of both patients with CD and healthy siblings was significantly less diverse than controls. Metacommunity profiling (Bray-Curtis (SBC) index) showed the sibling core microbial composition to be more similar to CD (SBC=0.70) than to healthy controls, whereas the sibling rare microbiota was more similar to healthy controls (SBC=0.42). Faecalibacterium prausnitzii contributed most to core metacommunity dissimilarity both between siblings and controls, and between patients and controls. Phenotype/genotype markers of CD risk significantly influenced microbiota variation between and within groups, of which genotype had the largest effect. CONCLUSIONS Individuals with elevated CD-risk display mucosal dysbiosis characterised by reduced diversity of core microbiota and lower abundance of F. prausnitzii. This dysbiosis in healthy people at risk of CD implicates microbiological processes in CD pathogenesis.
Collapse
Affiliation(s)
- Charlotte Hedin
- Faculty of Life Sciences & Medicine, Diabetes and Nutritional Sciences Division, King's College London, London, UK Centre for Immunology and Infectious Disease, Blizard Institute, Queen Mary University of London, London, UK
| | | | - Geraint B Rogers
- South Australian Health and Medical Research Institute, Infection and Immunity Theme, Flinders University, Adelaide, Australia
| | - Leah Cuthbertson
- NERC Centre for Ecology & Hydrology, Wallingford, Oxfordshire, UK
| | - Sara McCartney
- Centre for Gastroenterology and Nutrition, University College London, London, UK
| | - Andrew J Stagg
- Centre for Immunology and Infectious Disease, Blizard Institute, Queen Mary University of London, London, UK
| | - James O Lindsay
- Centre for Digestive Diseases, Blizard Institute, Queen Mary University of London, London, UK Department of Gastroenterology, Barts Health NHS Trust, London, UK
| | - Kevin Whelan
- Faculty of Life Sciences & Medicine, Diabetes and Nutritional Sciences Division, King's College London, London, UK
| |
Collapse
|
|
32
|
Singh VP, Proctor SD, Willing BP. Koch's postulates, microbial dysbiosis and inflammatory bowel disease. Clin Microbiol Infect 2016; 22:594-9. [PMID: 27179648 DOI: 10.1016/j.cmi.2016.04.018] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Revised: 04/16/2016] [Accepted: 04/23/2016] [Indexed: 02/07/2023]
Abstract
Over the past 20 years, a growing amount of evidence supports the role of microbes and an imbalanced microbiota in inflammatory bowel disease (IBD). While many reviews have been written on the microbiota in IBD, few have considered how they fulfil the Koch's postulates. In this review, we consider how the Koch's postulates might be modified so that they can be fulfilled for polymicrobial diseases, and we discuss the progress made to date in fulfilling them.
Collapse
Affiliation(s)
- V P Singh
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Canada; Metabolic and Cardiovascular Diseases Laboratory, Alberta Institute of Human Nutrition, University of Alberta, Edmonton, Canada
| | - S D Proctor
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Canada; Metabolic and Cardiovascular Diseases Laboratory, Alberta Institute of Human Nutrition, University of Alberta, Edmonton, Canada
| | - B P Willing
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Canada.
| |
Collapse
|
|
33
|
Kevans D, Silverberg MS, Borowski K, Griffiths A, Xu W, Onay V, Paterson AD, Knight J, Croitoru K. IBD Genetic Risk Profile in Healthy First-Degree Relatives of Crohn's Disease Patients. J Crohns Colitis 2016; 10:209-15. [PMID: 26512135 PMCID: PMC5007582 DOI: 10.1093/ecco-jcc/jjv197] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2015] [Accepted: 10/15/2015] [Indexed: 12/13/2022]
Abstract
BACKGROUND Family history provides important information on risk of developing inflammatory bowel disease [IBD], and genetic profiling of first-degree relatives [FDR] of Crohn's disease [CD]- affected individuals might provide additional information. We aimed to delineate the genetic contribution to the increased IBD susceptibility observed in FDR. METHODS N = 976 Caucasian, healthy, non-related FDR; n = 4997 independent CD; and n = 5000 healthy controls [HC]; were studied. Genotyping for 158 IBD-associated single nucleotide polymorphisms [SNPs] was performed using the Illumina Immunochip. Risk allele frequency [RAF] differences between FDR and HC cohorts were correlated with those between CD and HC cohorts. CD and IBD genetic risk scores [GRS] were calculated and compared between HC, FDR, and CD cohorts. RESULTS IBD-associated SNP RAF differences in FDR and HC cohorts were strongly correlated with those in CD and HC cohorts, correlation coefficient 0.63 (95% confidence interval [CI] 0.53 - 0.72), p = 9.90 x 10(-19). There was a significant increase in CD-GRS [mean] comparing HC, FDR, and CD cohorts: 0.0244, 0.0250, and 0.0257 respectively [p < 1.00 x 10(-7) for each comparison]. There was no significant difference in the IBD-GRS between HC and FDR cohorts [p = 0.81]; however, IBD-GRS was significantly higher in CD compared with FDR and HC cohorts [p < 1.00 x 10(-10) for each comparison]. CONCLUSION FDR of CD-affected individuals are enriched with IBD risk alleles compared with HC. Cumulative CD-specific genetic risk is increased in FDR compared with HC. Prospective studies are required to determine if genotyping would facilitate better risk stratification of FDR.
Collapse
Affiliation(s)
- David Kevans
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, ON, Canada,Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Mark S. Silverberg
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, ON, Canada,Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Krzysztof Borowski
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, ON, Canada
| | - Anne Griffiths
- Division of Gastroenterology, Hepatology and Nutrition, Department of Paediatrics, The Hospital for Sick Children, Toronto, ON, Canada
| | - Wei Xu
- Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
| | - Venus Onay
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, ON, Canada
| | - Andrew D. Paterson
- The Hospital for Sick Children Research Institute, The Hospital for Sick Children, Toronto, ON, Canada
| | - Jo Knight
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada,Institute of Medical Science, University of Toronto, Toronto, ON, Canada,Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
| | - Ken Croitoru
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, ON, Canada,Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, ON, Canada
| | | |
Collapse
|
|
34
|
Buttó LF, Schaubeck M, Haller D. Mechanisms of Microbe-Host Interaction in Crohn's Disease: Dysbiosis vs. Pathobiont Selection. Front Immunol 2015; 6:555. [PMID: 26635787 PMCID: PMC4652232 DOI: 10.3389/fimmu.2015.00555] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 10/16/2015] [Indexed: 12/11/2022] Open
Abstract
Crohn’s disease (CD) is a systemic chronic inflammatory condition mainly characterized by discontinuous transmural pathology of the gastrointestinal tract and frequent extraintestinal manifestations with intermittent episodes of remission and relapse. Genome-wide association studies identified a number of risk loci that, catalyzed by environmental triggers, result in the loss of tolerance toward commensal bacteria based on dysregulated innate effector functions and antimicrobial defense, leading to exacerbated adaptive immune responses responsible for chronic immune-mediated tissue damage. In this review, we discuss the inter-related role of changes in the intestinal microbiota, epithelial barrier integrity, and immune cell functions on the pathogenesis of CD, describing the current approaches available to investigate the molecular mechanisms underlying the disease. Substantial effort has been dedicated to define disease-associated changes in the intestinal microbiota (dysbiosis) and to link pathobionts to the etiology of inflammatory bowel diseases. A cogent definition of dysbiosis is lacking, as well as an agreement of whether pathobionts or complex shifts in the microbiota trigger inflammation in the host. Among the rarely available animal models, SAMP/Yit and TNFdeltaARE mice are the best known displaying a transmural CD-like phenotype. New hypothesis-driven mouse models, e.g., epithelial-specific Caspase8−/−, ATG16L1−/−, and XBP1−/− mice, validate pathway-focused function of specific CD-associated risk genes highlighting the role of Paneth cells in antimicrobial defense. To study the causal role of bacteria in initiating inflammation in the host, the use of germ-free mouse models is indispensable. Unraveling the interactions of genes, immune cells and microbes constitute a criterion for the development of safe, reliable, and effective treatment options for CD.
Collapse
Affiliation(s)
- Ludovica F Buttó
- Chair of Nutrition and Immunology, Technische Universität München , Freising-Weihenstephan , Germany
| | - Monika Schaubeck
- Chair of Nutrition and Immunology, Technische Universität München , Freising-Weihenstephan , Germany
| | - Dirk Haller
- Chair of Nutrition and Immunology, Technische Universität München , Freising-Weihenstephan , Germany
| |
Collapse
|
|
35
|
Michielan A, D’Incà R. Host-microbiome interaction in Crohn’s disease: A familiar or familial issue? World J Gastrointest Pathophysiol 2015; 6:159-168. [PMID: 26600974 PMCID: PMC4644880 DOI: 10.4291/wjgp.v6.i4.159] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Revised: 09/13/2015] [Accepted: 10/27/2015] [Indexed: 02/07/2023] Open
Abstract
An impaired interaction between the gut and the intestinal microbiome is likely to be the key element in the pathogenesis of Crohn’s disease (CD). Family studies have provided invaluable information on CD pathogenesis and on its etiology. Relatives share the same genetic risk of developing the disease as affected subjects. Relatives also exhibit similar features relating to their host-microbiome interaction, namely genetic variants in loci involved in detecting bacteria, a greater sero-reactivity to microbial components, and an impaired intestinal permeability. The burden of environmental factors such as cigarette smoking and dysbiosis also seems to be particularly relevant in these genetically predisposed subjects. Diet is emerging as an important factor and could account for the changing epidemiology of CD in recent years. Despite the pivotal role of genetics in the disease’s pathogenesis (especially in familial CD), screening tests in healthy relatives cannot be recommended.
Collapse
|
|
36
|
Melinder C, Hiyoshi A, Hussein O, Halfvarson J, Ekbom A, Montgomery S. Physical Fitness in Adolescence and Subsequent Inflammatory Bowel Disease Risk. Clin Transl Gastroenterol 2015; 6:e121. [PMID: 26540026 PMCID: PMC4816088 DOI: 10.1038/ctg.2015.49] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Accepted: 09/05/2015] [Indexed: 12/27/2022] Open
Abstract
OBJECTIVES: Physical fitness may reduce systemic inflammation levels relevant to the risk of symptomatic Crohn's disease (CD) and ulcerative colitis (UC); we assessed if fitness in adolescence is associated with subsequent inflammatory bowel disease (IBD) risk, independent of markers of risk and prodromal disease activity. METHODS: Swedish registers provided information on a cohort of 240,984 men (after exclusions) who underwent military conscription assessments in late adolescence (1969–1976). Follow-up started at least 4 years after the conscription assessment until 31 December 2009 (up to age 57 years). Cox's regression assessed the association of physical fitness with CD (n=986) and UC (n=1,878) in separate models, with adjustment including: socioeconomic conditions in childhood; physical fitness, height, body mass index, and erythrocyte sedimentation rate (ESR) in adolescence; and subsequent diagnoses of IBD. RESULTS: Low fitness was associated with a raised risk of IBD, with unadjusted hazard ratios (and 95% confidence intervals) of 1.62 (1.31–2.00) for CD and 1.36 (1.17–1.59) for UC. The results were attenuated by adjustment, particularly for markers of prodromal disease activity to 1.32 (1.05–1.66) and 1.25 (1.06–1.48), respectively. Raised ESR in adolescence was associated with increased risks for subsequent CD (5.95 (4.47–7.92)) and UC (1.92 (1.46–2.52)). CONCLUSIONS: The inverse association of physical fitness with IBD risk is consistent with a protective role for exercise. However, evidence of disease activity before diagnosis was already present in adolescence, suggesting that some or all of the association between fitness and IBD may be due to prodromal disease activity reducing exercise capacity and therefore fitness.
Collapse
Affiliation(s)
- Carren Melinder
- Clinical Epidemiology and Biostatistics, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Ayako Hiyoshi
- Clinical Epidemiology and Biostatistics, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Oula Hussein
- Clinical Epidemiology and Biostatistics, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Jonas Halfvarson
- Department of Gastroenterology, Faculty of Medicine and Health, School of Health and Medical Sciences, Örebro University, Örebro, Sweden
| | - Anders Ekbom
- Clinical Epidemiology Unit, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Scott Montgomery
- Clinical Epidemiology and Biostatistics, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.,Clinical Epidemiology Unit, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.,Department of Epidemiology and Public Health, University College London, London, UK
| |
Collapse
|
|
37
|
Fuhler GM, Parikh K, van der Woude CJ, Peppelenbosch MP. Linkage between genotype and immunological phenotype in Crohn's disease. ANNALS OF TRANSLATIONAL MEDICINE 2015; 3:237. [PMID: 26539454 DOI: 10.3978/j.issn.2305-5839.2015.09.28] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Understanding the mechanisms that drive uncontrolled inflammation in Crohn's disease (CD) remains one of the most pressing challenges in contemporary experimental medicine. Recently, a three-phased view on the pathogenesis of CD was proposed in which following the breakdown of intestinal epithelial barrier function, CD patients fail to clear the resulting infectious debris, provoking subsequent immune responses. This view on CD is attractive in that it is testable and allows better diagnosis of disease if proven correct, apart from opening a window on new therapeutic horizons. Here we shall argue, however, that this scheme may be an oversimplification in that it ignores the genetic diversity of CD and thus does not fully take into account the nature of the intestinal epithelium, which appears a non-passive actor in this disease.
Collapse
Affiliation(s)
- Gwenny M Fuhler
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center Rotterdam, Erasmus University of Rotterdam, Rotterdam, The Netherlands
| | - Kaushal Parikh
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center Rotterdam, Erasmus University of Rotterdam, Rotterdam, The Netherlands
| | - C Janneke van der Woude
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center Rotterdam, Erasmus University of Rotterdam, Rotterdam, The Netherlands
| | - Maikel P Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center Rotterdam, Erasmus University of Rotterdam, Rotterdam, The Netherlands
| |
Collapse
|
|
38
|
Kaunitz J, Nayyar P. Bugs, genes, fatty acids, and serotonin: Unraveling inflammatory bowel disease? F1000Res 2015; 4:F1000 Faculty Rev-1146. [PMID: 27508055 PMCID: PMC4963018 DOI: 10.12688/f1000research.6456.1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/30/2015] [Indexed: 12/13/2022] Open
Abstract
The annual incidence of the inflammatory bowel diseases (IBDs) ulcerative colitis and Crohn's disease has increased at an alarming rate. Although the specific pathophysiology underlying IBD continues to be elusive, it is hypothesized that IBD results from an aberrant and persistent immune response directed against microbes or their products in the gut, facilitated by the genetic susceptibility of the host and intrinsic alterations in mucosal barrier function. In this review, we will describe advances in the understanding of how the interaction of host genetics and the intestinal microbiome contribute to the pathogenesis of IBD, with a focus on bacterial metabolites such as short chain fatty acids (SCFAs) as possible key signaling molecules. In particular, we will describe alterations of the intestinal microbiota in IBD, focusing on how genetic loci affect the gut microbial phylogenetic distribution and the production of their major microbial metabolic product, SCFAs. We then describe how enteroendocrine cells and myenteric nerves express SCFA receptors that integrate networks such as the cholinergic and serotonergic neural systems and the glucagon-like peptide hormonal pathway, to modulate gut inflammation, permeability, and growth as part of an integrated model of IBD pathogenesis. Through this integrative approach, we hope that novel hypotheses will emerge that will be tested in reductionist, hypothesis-driven studies in order to examine the interrelationship of these systems in the hope of better understanding IBD pathogenesis and to inform novel therapies.
Collapse
Affiliation(s)
- Jonathan Kaunitz
- Medical Service, West Los Angeles VAMC, Los Angeles, CA, 90073, USA
- Department of Medicine, David Geffen School of Medicine, Los Angeles, CA, 90095, USA
- Department of Surgery, David Geffen School of Medicine, Los Angeles, CA, 90095, USA
| | - Piyush Nayyar
- Medical Service, West Los Angeles VAMC, Los Angeles, CA, 90073, USA
- Department of Medicine, David Geffen School of Medicine, Los Angeles, CA, 90095, USA
| |
Collapse
|
|
39
|
Nagy-Szakal D, Mir SAV, Harris RA, Dowd SE, Yamada T, Lacorazza HD, Tatevian N, Smith CW, de Zoeten EF, Klein J, Kellermayer R. Loss of n-6 fatty acid induced pediatric obesity protects against acute murine colitis. FASEB J 2015; 29:3151-9. [PMID: 25903104 DOI: 10.1096/fj.14-267690] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 03/31/2015] [Indexed: 12/22/2022]
Abstract
Dietary influences may affect microbiome composition and host immune responses, thereby modulating propensity toward inflammatory bowel diseases (IBDs): Crohn disease (CD) and ulcerative colitis (UC). Dietary n-6 fatty acids have been associated with UC in prospective studies. However, the critical developmental period when (n-6) consumption may induce UC is not known. We examined the effects of transiently increased n-6 consumption during pediatric development on subsequent dextran-sulfate-sodium (DSS)-induced acute murine colitis. The animals transiently became obese then rapidly lost this phenotype. Interestingly, mice were protected against DSS colitis 40 days after n-6 consumption. The transient high n-6-induced protection against colitis was fat type- and dietary reversal-dependent and could be transferred to germ-free mice by fecal microbiota transplantation. We also detected decreased numbers of chemokine receptor (Cxcr)5(+) CD4(+) T cells in the mesenteric lymph nodes (MLNs) of transiently n-6-fed mice. Further experiments revealed that anti-chemokine ligand (Cxcl)13 (the ligand of Cxcr5) antibody treatment decreased DSS colitis severity, implicating the importance of the Cxcr5-Cxcl13 pathway in mammalian colitis. Consecutively, we found elevated CXCL13 concentrations (CD: 1.8-fold, P = 0.0077; UC: 1.9-fold, P = 0.056) in the serum of untreated pediatric IBD patients. The human serologic observations supported the translational relevance of our findings.
Collapse
Affiliation(s)
- Dorottya Nagy-Szakal
- *Section of Pediatric Gastroenterology, Baylor College of Medicine, Texas Children Hospital, Houston, Texas, USA; U.S. Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center, Houston, Texas, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA; Molecular Research LP, Shallowater, Texas, USA; Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA; Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center, Houston, Texas, USA; Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado, USA; and **School of Dentistry, The University of Texas Health Science Center, Houston, Texas, USA
| | - Sabina A V Mir
- *Section of Pediatric Gastroenterology, Baylor College of Medicine, Texas Children Hospital, Houston, Texas, USA; U.S. Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center, Houston, Texas, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA; Molecular Research LP, Shallowater, Texas, USA; Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA; Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center, Houston, Texas, USA; Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado, USA; and **School of Dentistry, The University of Texas Health Science Center, Houston, Texas, USA
| | - R Alan Harris
- *Section of Pediatric Gastroenterology, Baylor College of Medicine, Texas Children Hospital, Houston, Texas, USA; U.S. Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center, Houston, Texas, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA; Molecular Research LP, Shallowater, Texas, USA; Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA; Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center, Houston, Texas, USA; Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado, USA; and **School of Dentistry, The University of Texas Health Science Center, Houston, Texas, USA
| | - Scot E Dowd
- *Section of Pediatric Gastroenterology, Baylor College of Medicine, Texas Children Hospital, Houston, Texas, USA; U.S. Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center, Houston, Texas, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA; Molecular Research LP, Shallowater, Texas, USA; Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA; Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center, Houston, Texas, USA; Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado, USA; and **School of Dentistry, The University of Texas Health Science Center, Houston, Texas, USA
| | - Takeshi Yamada
- *Section of Pediatric Gastroenterology, Baylor College of Medicine, Texas Children Hospital, Houston, Texas, USA; U.S. Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center, Houston, Texas, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA; Molecular Research LP, Shallowater, Texas, USA; Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA; Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center, Houston, Texas, USA; Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado, USA; and **School of Dentistry, The University of Texas Health Science Center, Houston, Texas, USA
| | - H Daniel Lacorazza
- *Section of Pediatric Gastroenterology, Baylor College of Medicine, Texas Children Hospital, Houston, Texas, USA; U.S. Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center, Houston, Texas, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA; Molecular Research LP, Shallowater, Texas, USA; Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA; Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center, Houston, Texas, USA; Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado, USA; and **School of Dentistry, The University of Texas Health Science Center, Houston, Texas, USA
| | - Nina Tatevian
- *Section of Pediatric Gastroenterology, Baylor College of Medicine, Texas Children Hospital, Houston, Texas, USA; U.S. Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center, Houston, Texas, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA; Molecular Research LP, Shallowater, Texas, USA; Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA; Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center, Houston, Texas, USA; Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado, USA; and **School of Dentistry, The University of Texas Health Science Center, Houston, Texas, USA
| | - C Wayne Smith
- *Section of Pediatric Gastroenterology, Baylor College of Medicine, Texas Children Hospital, Houston, Texas, USA; U.S. Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center, Houston, Texas, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA; Molecular Research LP, Shallowater, Texas, USA; Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA; Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center, Houston, Texas, USA; Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado, USA; and **School of Dentistry, The University of Texas Health Science Center, Houston, Texas, USA
| | - Edwin F de Zoeten
- *Section of Pediatric Gastroenterology, Baylor College of Medicine, Texas Children Hospital, Houston, Texas, USA; U.S. Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center, Houston, Texas, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA; Molecular Research LP, Shallowater, Texas, USA; Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA; Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center, Houston, Texas, USA; Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado, USA; and **School of Dentistry, The University of Texas Health Science Center, Houston, Texas, USA
| | - John Klein
- *Section of Pediatric Gastroenterology, Baylor College of Medicine, Texas Children Hospital, Houston, Texas, USA; U.S. Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center, Houston, Texas, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA; Molecular Research LP, Shallowater, Texas, USA; Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA; Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center, Houston, Texas, USA; Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado, USA; and **School of Dentistry, The University of Texas Health Science Center, Houston, Texas, USA
| | - Richard Kellermayer
- *Section of Pediatric Gastroenterology, Baylor College of Medicine, Texas Children Hospital, Houston, Texas, USA; U.S. Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center, Houston, Texas, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA; Molecular Research LP, Shallowater, Texas, USA; Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA; Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center, Houston, Texas, USA; Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado, USA; and **School of Dentistry, The University of Texas Health Science Center, Houston, Texas, USA
| |
Collapse
|
|
40
|
Hayes CE, Hubler SL, Moore JR, Barta LE, Praska CE, Nashold FE. Vitamin D Actions on CD4(+) T Cells in Autoimmune Disease. Front Immunol 2015; 6:100. [PMID: 25852682 PMCID: PMC4364365 DOI: 10.3389/fimmu.2015.00100] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Accepted: 02/23/2015] [Indexed: 12/11/2022] Open
Abstract
This review summarizes and integrates research on vitamin D and CD4+ T-lymphocyte biology to develop new mechanistic insights into the molecular etiology of autoimmune disease. A deep understanding of molecular mechanisms relevant to gene–environment interactions is needed to deliver etiology-based autoimmune disease prevention and treatment strategies. Evidence linking sunlight, vitamin D, and the risk of multiple sclerosis and type 1 diabetes is summarized to develop the thesis that vitamin D is the environmental factor that most strongly influences autoimmune disease development. Evidence for CD4+ T-cell involvement in autoimmune disease pathogenesis and for paracrine calcitriol signaling to CD4+ T lymphocytes is summarized to support the thesis that calcitriol is sunlight’s main protective signal transducer in autoimmune disease risk. Animal modeling and human mechanistic data are summarized to support the view that vitamin D probably influences thymic negative selection, effector Th1 and Th17 pathogenesis and responsiveness to extrinsic cell death signals, FoxP3+CD4+ T-regulatory cell and CD4+ T-regulatory cell type 1 (Tr1) cell functions, and a Th1–Tr1 switch. The proposed Th1–Tr1 switch appears to bridge two stable, self-reinforcing immune states, pro- and anti-inflammatory, each with a characteristic gene regulatory network. The bi-stable switch would enable T cells to integrate signals from pathogens, hormones, cell–cell interactions, and soluble mediators and respond in a biologically appropriate manner. Finally, unanswered questions and potentially informative future research directions are highlighted to speed delivery of etiology-based strategies to reduce autoimmune disease.
Collapse
Affiliation(s)
- Colleen Elizabeth Hayes
- Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison , Madison, WI , USA
| | - Shane L Hubler
- Department of Statistics, College of Letters and Sciences, University of Wisconsin-Madison , Madison, WI , USA
| | - Jerott R Moore
- Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison , Madison, WI , USA
| | - Lauren E Barta
- Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison , Madison, WI , USA
| | - Corinne E Praska
- Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison , Madison, WI , USA
| | - Faye E Nashold
- Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison , Madison, WI , USA
| |
Collapse
|
|
41
|
Identifying strains that contribute to complex diseases through the study of microbial inheritance. Proc Natl Acad Sci U S A 2015; 112:633-40. [PMID: 25576328 DOI: 10.1073/pnas.1418781112] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
It has been 35 y since Carl Woese reported in PNAS how sequencing ribosomal RNA genes could be used to distinguish the three domains of life on Earth. During the past decade, 16S rDNA sequencing has enabled the now frequent enumeration of bacterial communities that populate the bodies of humans representing different ages, cultural traditions, and health states. A challenge going forward is to quantify the contributions of community members to wellness, disease risk, and disease pathogenesis. Here, we explore a theoretical framework for studies of the inheritance of bacterial strains and discuss the advantages and disadvantages of various study designs for assessing the contribution of strains to complex diseases.
Collapse
|
|
42
|
Liu J, Liu YY, Liu J, Li BZ, Cen H, Xu WD, Leng RX, Pan HF, Ye DQ. Association between CARD8 rs2043211 polymorphism and inflammatory bowel disease: a meta-analysis. Immunol Invest 2015; 44:253-64. [PMID: 25564880 DOI: 10.3109/08820139.2014.988721] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVE The aim of this study was to determine whether caspase recruitment domain-containing protein 8 (CARD8) rs2043211 polymorphism was associated with susceptibility to inflammatory bowel disease (IBD). METHODS Relevant studies were searched using PubMed and Embase up to February 2014. A meta-analysis was conducted on the association between rs2043211 polymorphism and IBD using: (1) allele contrast, (2) the dominant model, (3) the recessive model, and (4) homozygote contrast. The pooled estimated of risk was obtained by random-effects model or fixed-effects model. Publication bias was assessed by Egger's test. RESULTS Eight relevant articles with a total of 10 534 IBD patients [6785 Crohn's disease (CD), 3713 ulcerative colitis (UC) and 36 indeterminate colitis (IC)] and 6755 healthy controls were included in the meta-analysis, which consisted of 12 studies, 12 for CD, 10 for UC, 2 for IC. There was no significant association between rs2043211 polymorphism and IBD, CD, and IC in overall population. However, stratified meta-analysis by ethnicity showed significant association between rs2043211 polymorphism and CD in the European population under the dominant model [odds ratio (OR) = 1.210, 95% confidence interval (CI) = 1.013-1.445, p = 0.036] and homozygote contrast (OR = 1.212, 95% CI = 1.005-1.461, p = 0.044). CONCLUSIONS Our meta-analysis results indicated significant association between rs2043211 polymorphism and the susceptibility to CD under the dominant model and homozygote contrast in the European population.
Collapse
Affiliation(s)
- Juan Liu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University , Hefei, Anhui , PR China and
| | | | | | | | | | | | | | | | | |
Collapse
|
|
43
|
Smith AM, Sewell GW, Levine AP, Chew TS, Dunne J, O'Shea NR, Smith PJ, Harrison PJ, Macdonald CM, Bloom SL, Segal AW. Disruption of macrophage pro-inflammatory cytokine release in Crohn's disease is associated with reduced optineurin expression in a subset of patients. Immunology 2015; 144:45-55. [PMID: 24943399 PMCID: PMC4264909 DOI: 10.1111/imm.12338] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2014] [Revised: 06/09/2014] [Accepted: 06/16/2014] [Indexed: 12/18/2022] Open
Abstract
Crohn's disease (CD) is a complex and highly heterogeneous chronic inflammatory disorder, primarily affecting the gastrointestinal tract. Genetic and functional studies have highlighted a key role for innate immunity in its pathogenesis. Profound systemic defects in innate immunity and acute inflammation are understood to result in markedly delayed clearance of bacteria from the tissues, leading to local chronic granulomatous inflammation and compensatory adaptive immunological changes. Macrophages, key orchestrators of acute inflammation, are likely to play an important role in the initial impaired innate immune response. Monocyte-derived macrophages from CD patients stimulated with Escherichia coli were shown to release attenuated levels of tumour necrosis factor and interferon-γ with normal secretion of interleukin-8 (IL-8), IL-10 and IL-6. In controls, the secretion of these cytokines was strongly positively correlated, which was not seen with CD macrophages. The transcriptomes of CD and control macrophages were examined in an attempt to understand the molecular basis of this defect. There were no differentially expressed genes identified between the two groups, consistent with genetic heterogeneity; however, a number of molecules were found to be under-expressed in subgroups of CD patients. The most common of these was optineurin (OPTN) which was under-expressed in approximately 10% of the CD patients. Reduced OPTN expression coincided with lower intracellular protein levels and diminished cytokine secretion after bacterial stimulation both in the patients and with small interfering RNA knockdown in THP-1 cells. Identifying and studying subgroups of patients with shared defective gene expression could aid our understanding of the mechanisms underlying highly heterogeneous diseases such as CD.
Collapse
Affiliation(s)
- Andrew M Smith
- Microbial Diseases, Eastman Dental Institute, University College London, London, UK
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
44
|
Hedin CR, McCarthy NE, Louis P, Farquharson FM, McCartney S, Taylor K, Prescott NJ, Murrells T, Stagg AJ, Whelan K, Lindsay JO. Altered intestinal microbiota and blood T cell phenotype are shared by patients with Crohn's disease and their unaffected siblings. Gut 2014; 63:1578-86. [PMID: 24398881 DOI: 10.1136/gutjnl-2013-306226] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Crohn's disease (CD) is associated with intestinal dysbiosis, altered blood T cell populations, elevated faecal calprotectin (FC) and increased intestinal permeability (IP). CD-associated features present in siblings (increased risk of CD) but not in healthy controls, provide insight into early CD pathogenesis. We aimed to (1) Delineate the genetic, immune and microbiological profile of patients with CD, their siblings and controls and (2) Determine which factors discriminate between groups. DESIGN Faecal microbiology was analysed by quantitative PCR targeting 16S ribosomal RNA, FC by ELISA, blood T cell phenotype by flow cytometry and IP by differential lactulose-rhamnose absorption in 22 patients with inactive CD, 21 of their healthy siblings and 25 controls. Subject's genotype relative risk was determined by Illumina Immuno BeadChip. RESULTS Strikingly, siblings shared aspects of intestinal dysbiosis with patients with CD (lower concentrations of Faecalibacterium prausnitzii (p=0.048), Clostridia cluster IV (p=0.003) and Roseburia spp. (p=0.09) compared with controls). As in CD, siblings demonstrated a predominance of memory T cells (p=0.002) and elevated naïve CD4 T cell β7 integrin expression (p=0.01) compared with controls. FC was elevated (>50 μg/g) in 8/21 (38%) siblings compared with 2/25 (8%) controls (p=0.028); whereas IP did not differ between siblings and controls. Discriminant function analysis determined that combinations of these factors significantly discriminated between groups (χ(2)=80.4, df=20, p<0.001). Siblings were separated from controls by immunological and microbiological variables. CONCLUSIONS Healthy siblings of patients with CD manifest immune and microbiological abnormalities associated with CD distinct from their genotype-related risk and provide an excellent model in which to investigate early CD pathogenesis.
Collapse
Affiliation(s)
- Charlotte R Hedin
- Diabetes and Nutritional Sciences Division, School of Medicine, King's College London, London, UK Centre for Digestive Diseases, Blizard Institute, Queen Mary University of London, London, UK
| | - Neil E McCarthy
- Centre for Digestive Diseases, Blizard Institute, Queen Mary University of London, London, UK
| | - Petra Louis
- Microbiology Group, Gut Health Theme, Rowett Institute of Nutrition and Health, University of Aberdeen, Bucksburn, Aberdeen, UK
| | - Freda M Farquharson
- Microbiology Group, Gut Health Theme, Rowett Institute of Nutrition and Health, University of Aberdeen, Bucksburn, Aberdeen, UK
| | - Sara McCartney
- Department for Gastroenterology and Clinical Nutrition, University College Hospitals NHS Foundation Trust, London, UK
| | - Kirstin Taylor
- Department of Medical and Molecular Genetics, King's College London, London, UK
| | - Natalie J Prescott
- Department of Medical and Molecular Genetics, King's College London, London, UK
| | - Trevor Murrells
- National Nursing Research Unit, Florence Nightingale School of Nursing and Midwifery, King's College London, London, UK
| | - Andrew J Stagg
- Centre for Immunology and Infectious Disease, Blizard Institute, Queen Mary University of London, London, UK
| | - Kevin Whelan
- Diabetes and Nutritional Sciences Division, School of Medicine, King's College London, London, UK
| | - James O Lindsay
- Centre for Digestive Diseases, Blizard Institute, Queen Mary University of London, London, UK Gastroenterology Division, Barts Health NHS Trust, London, UK
| |
Collapse
|
|
45
|
Rigoli L, Caruso RA. Inflammatory bowel disease in pediatric and adolescent patients: A biomolecular and histopathological review. World J Gastroenterol 2014; 20:10262-10278. [PMID: 25132743 PMCID: PMC4130834 DOI: 10.3748/wjg.v20.i30.10262] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2013] [Revised: 01/13/2014] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
Crohn’s disease (CD) and ulcerative colitis (UC) are the two main forms of inflammatory bowel disease (IBD) with both overlapping and distinct clinical, pathological and biomolecular features. It has been suggested that pediatric IBD is a distinct disease entity, with probably different disease subtypes.The aim of this study is to review and summarize the evolution of the current concept of pediatric IBD. The results of this review reinforce the idea that pediatric CD and UC may be further classified in various clinicopathologic entities. For clinicians and pathologists convenience, practical algorithms for the distinction of the various subphenotypes of pediatric IBD are also provided.
Collapse
|
|
46
|
Abstract
IBD is a spectrum of chronic disorders that constitute an important health problem worldwide. The hunt for genetic determinants of disease onset and course has culminated in the Immunochip project, which has identified >160 loci containing IBD susceptibility genes. In this Review, we highlight how genetic association studies have informed our understanding of the pathogenesis of IBD by focusing research efforts on key pathways involved in innate immunity, autophagy, lymphocyte differentiation and chemotaxis. Several of these novel genetic markers and cellular pathways are promising candidates for patient stratification and therapeutic targeting.
Collapse
|
|
47
|
Sobczak M, Fabisiak A, Murawska N, Wesołowska E, Wierzbicka P, Wlazłowski M, Wójcikowska M, Zatorski H, Zwolińska M, Fichna J. Current overview of extrinsic and intrinsic factors in etiology and progression of inflammatory bowel diseases. Pharmacol Rep 2014; 66:766-75. [PMID: 25149979 DOI: 10.1016/j.pharep.2014.04.005] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Revised: 03/29/2014] [Accepted: 04/09/2014] [Indexed: 12/16/2022]
Abstract
Inflammatory bowel diseases (IBD) are chronic, relapsing disorders affecting gastrointestinal (GI) tract and associated with intestinal mucosa damage and inflammation. The principal therapeutic goals in IBD include control of the intestinal inflammation and treatment of the major symptoms, mainly abdominal pain and diarrhea. Current therapeutic strategies for IBD rely on the use of non-specific anti-inflammatory agents and immunosuppressive drugs (e.g. aminosalicylates, monoclonal antibodies, and antibiotics), which cause severe side effects, and - in a significant number of patients - do not induce long-term benefits. In this review, we summarize the epidemiology and the most important risk factors of IBD, including genetic, immunological and environmental. Our main focus is to discuss pharmacological targets for current and future treatments of IBD.
Collapse
Affiliation(s)
- Marta Sobczak
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland
| | - Adam Fabisiak
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland
| | - Natalia Murawska
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland
| | - Ewelina Wesołowska
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland
| | - Paulina Wierzbicka
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland
| | - Marcin Wlazłowski
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland
| | - Marta Wójcikowska
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland
| | - Hubert Zatorski
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland
| | - Marta Zwolińska
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland
| | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland.
| |
Collapse
|
|
48
|
Chen GB, Lee SH, Brion MJA, Montgomery GW, Wray NR, Radford-Smith GL, Visscher PM. Estimation and partitioning of (co)heritability of inflammatory bowel disease from GWAS and immunochip data. Hum Mol Genet 2014; 23:4710-20. [PMID: 24728037 DOI: 10.1093/hmg/ddu174] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
As custom arrays are cheaper than generic GWAS arrays, larger sample size is achievable for gene discovery. Custom arrays can tag more variants through denser genotyping of SNPs at associated loci, but at the cost of losing genome-wide coverage. Balancing this trade-off is important for maximizing experimental designs. We quantified both the gain in captured SNP-heritability at known candidate regions and the loss due to imperfect genome-wide coverage for inflammatory bowel disease using immunochip (iChip) and imputed GWAS data on 61,251 and 38.550 samples, respectively. For Crohn's disease (CD), the iChip and GWAS data explained 19 and 26% of variation in liability, respectively, and SNPs in the densely genotyped iChip regions explained 13% of the SNP-heritability for both the iChip and GWAS data. For ulcerative colitis (UC), the iChip and GWAS data explained 15 and 19% of variation in liability, respectively, and the dense iChip regions explained 10 and 9% of the SNP-heritability in the iChip and the GWAS data. From bivariate analyses, estimates of the genetic correlation in risk between CD and UC were 0.75 (SE 0.017) and 0.62 (SE 0.042) for the iChip and GWAS data, respectively. We also quantified the SNP-heritability of genomic regions that did or did not contain the previous 163 GWAS hits for CD and UC, and SNP-heritability of the overlapping loci between the densely genotyped iChip regions and the 163 GWAS hits. For both diseases, over different genomic partitioning, the densely genotyped regions on the iChip tagged at least as much variation in liability as in the corresponding regions in the GWAS data, however a certain amount of tagged SNP-heritability in the GWAS data was lost using the iChip due to the low coverage at unselected regions. These results imply that custom arrays with a GWAS backbone will facilitate more gene discovery, both at associated and novel loci.
Collapse
Affiliation(s)
| | | | | | | | | | - Graham L Radford-Smith
- School of Medicine, The University of Queensland, Brisbane, QLD, Australia Inflammatory Bowel Disease Research Group, Immunology Division, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia Department of Gastroenterology, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia
| | - Peter M Visscher
- The Queensland Brain Institute and The University of Queensland Diamantina Institute, Brisbane, QLD, Australia
| | | |
Collapse
|
|
49
|
Huang VW, Habal FM. From conception to delivery: managing the pregnant inflammatory bowel disease patient. World J Gastroenterol 2014; 20:3495-506. [PMID: 24707132 PMCID: PMC3974516 DOI: 10.3748/wjg.v20.i13.3495] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2013] [Revised: 01/12/2014] [Accepted: 02/26/2014] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) typically affects patients during their adolescent and young adult years. As these are the reproductive years, patients and physicians often have concerns regarding the interaction between IBD, medications and surgery used to treat IBD, and reproduction, pregnancy outcomes, and neonatal outcomes. Studies have shown a lack of knowledge among both patients and physicians regarding reproductive issues in IBD. As the literature is constantly expanding regarding these very issues, with this review, we provide a comprehensive, updated overview of the literature on the management of the IBD patient from conception to delivery, and provide action tips to help guide the clinician in the management of the IBD patient during pregnancy.
Collapse
|
|
50
|
Association of CTLA-4 variants with susceptibility to inflammatory bowel disease: A meta-analysis. Hum Immunol 2014; 75:227-33. [DOI: 10.1016/j.humimm.2013.12.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2013] [Revised: 11/05/2013] [Accepted: 12/17/2013] [Indexed: 02/07/2023]
|