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Biomarkers in inflammatory bowel diseases:Current status and proteomics identification strategies

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World Journal of Gastroenterology 2014年第12期20卷 3231-3244页

作者： Tue Bennike Svend Birkelund Allan Stensballe vibeke andersen Department of Health Science and Technology Aalborg University Institute of Regional Health Research University of Southern Denmark Organ Center Hospital of Southern Jutland

Unambiguous diagnosis of the two main forms of inflammatory bowel diseases (IBD): Ulcerative colitis (UC) and Crohn’s disease (CD), represents a challenge in the early stages of the diseases. The diagnosis may be established several years after the debut of symptoms. Hence, protein biomarkers for early and accurate diagnostic could help clinicians improve treatment of the individual patients. Moreover, the biomarkers could aid physicians to predict disease courses and in this way, identify patients in need of intensive treatment. Patients with low risk of disease flares may avoid treatment with medications with the concomitant risk of adverse events. In addition, identification of disease and course specific biomarker profiles can be used to identify biological pathways involved in the disease development and treatment. Knowledge of disease mechanisms in general can lead to improved future development of preventive and treatment strategies. Thus, the clinical use of a panel of biomarkers represents a diagnostic and prognostic tool of potentially great value. The technological development in recent years within proteomic research (determination and quantification of the complete protein content) has made the discovery of novel biomarkers feasible. Several IBD-associated protein biomarkers are known, but none have been successfully implemented in daily use to distinguish CD and UC patients. The intestinal tissue remains an obvious place to search for novel biomarkers, which blood, urine or stool later can be screened for. When considering the protein complexity encountered in intestinal biopsy-samples and the recent development within the field of mass spectrometry driven quantitative proteomics, a more thorough and accurate biomarker discovery endeavor could today be performed than ever before. In this review, we report the current status of the proteomics IBD biomarkers and discuss various emerging proteomic strategies for identifying and characterizing nove

关键词： Inflammatory bowel disease, Biomarker, Proteomics, Citrullination, Ulcerative colitis, Crohn’ s disease, Posttranslational modification

Polymorphisms in NF-κB,PXR,LXR,PPARγ and risk of inflammatory bowel disease

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World Journal of Gastroenterology 2011年第2期17卷 197-206页

作者： vibeke andersen Jane Christensen Anja Ernst Bent A Jacobsen Anne Tjφnneland Henrik B Krarup Ulla Vogel Department of Medical Viborg Regional Hospital Institute of Cancer Epidemiology Danish Cancer Society Department of Clinical Biochemistry Aarhus University Hospital Department of Medical Gastroenterology Aarhus University Hospital National Food Institute Technical University of Denmark Institute for Science Systems and ModelsUniversity of Roskilde National Research Centre for the Working Environment

AIM:To investigate the contribution of polymorphisms in nuclear receptors to risk of inflammatory bowel disease(IBD) . METHODS:Genotypes of nuclear factor(NF) -κB(NFKB1) NFκB-94ins/del(rs28362491) ;peroxisome proliferatoractivated receptor(PPAR) -γ(PPARγ) PPARγPro12Ala(rs1801282) and C1431T(rs 3856806) ;pregnane X receptor(PXR) (NR1I2) PXR A-24381C(rs1523127) ,C8055T(2276707) ,and A7635G(rs 6785049) ;and liver X receptor(LXR) (NR1H2) LXR T-rs1405655-C and T-rs2695121-C were assessed in a Danish case-control study of 327 Crohn's disease patients,495 ulcerative colitis(UC) patients,and 779 healthy *** ratio(OR) and 95%CI were estimated by logistic regression models. RESULTS:The PXR A7635G variant,the PPARγPro12Ala and LXR T-rs2695121-C homozygous variant genotypes were associated with risk of UC(OR:1.31,95% CI:1.03-1.66,P=0.03,OR:2.30,95%CI:1.04-5.08,P=0.04,and OR:1.41,95%CI:1.00-1.98,P=0.05,respectively) compared to the corresponding homozygous wild-type *** never smokers,PXR A7635G and the LXR T-rs1405655-C and T-rs2695121-C variant genotypes were associated with risk of IBD(OR:1.41,95%CI:1.05-1.91,P=0.02,OR:1.63,95%CI:1.21-2.20,P=0.001,and OR:2.02,95%CI:1.36-2.99,P=0.0005,respectively) compared to the respective homozygous variant *** A7635G(rs6785049) variant genotype was associated with a higher risk of UC diagnosis before the age of 40 years and with a higher risk of extensive disease(OR:1.34,95%CI:1.03-1.75 and OR:2.49,95%CI:1.24-5.03,respectively) . CONCLUSION:Common PXR and LXR polymorphisms may contribute to risk of IBD,especially among never smokers.

关键词： Crohn's disease Genetic susceptibility Single nucleotide polymorphisms Smoking status Transcription factors Ulcerative colitis

Danish cohort of monozygotic inflammatory bowel disease twins: Clinical characteristics and inflammatory activity

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World Journal of Gastroenterology 2016年第21期22卷 5050-5059页

作者： Frederik Trier Moller Lina Knudsen Marcus Harbord Jack Satsangi Hannah Gordon Lene Christiansen Kaare Christensen Tine Jess vibeke andersen Research Unit for Molecular Diagnostics Hospital of Southern Jutland Institute of Regional Health Research University of Southern Denmark Division of Epidemiology and Disease Surveillance Statens Serum Institut Department of Gastro-enterology Chelsea and Westminster Hospital Centre for Molecular Medicine University of Edinburgh Western General Hospital Danish Ageing Research Centre Institute of Public Health University of Southern Denmark Department of Clinical Medicine University of Aalborg

AIM: To describe the establishment of a Danish inflammatory bowel diseases (IBD) twin cohort with focus on concordance of treatment and inflammatory ***: 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 ***: 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 ***: 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.

关键词： Digestive system diseases Inflammatory bowel diseases Crohn’ s disease Ulcerative colitis Epidemiologic studies Twins Biobank

Novel understanding of ABC transporters ABCB1/MDR/P-glycoprotein, ABCC2/MRP2, and ABCG2/BCRP in colorectal pathophysiology

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World Journal of Gastroenterology 2015年第41期21卷 11862-11876页

作者： vibeke andersen Katrine Svenningsen Lina Almind Knudsen Axel Kornerup Hansen Uffe Holmskov Allan Stensballe Ulla Vogel Molecular Diagnostic and Clinical Health Research Unit Hospital of Southern Jutland Institute of Regional Health Research-Centre S?nderjylland University of Southern Denmark Medical Department Regional Hospital Viborg Experimental Animal Models University of Copenhagen Department of Cancer and Inflammation Research University of Southern Denmark Department of Health Science and Technology Aalborg University National Research Centre for the Working Environment

AIM: To evaluate ATP-binding cassette(ABC) transporters in colonic pathophysiology as they had recently been related to colorectal cancer(CRC) development. METHODS: Literature search was conducted on Pub Med using combinations of the following terms: ABC transporters, ATP binding cassette transporter proteins, inflammatory bowel disease, ulcerative, colitis, Crohns disease, colorectal cancer, colitis, intestinal inflammation, intestinal carcinogenesis, ABCB1/P-glycoprotein(P-gp/CD243/MDR1), ABCC2/multidrug resistance protein 2(MRP2) and ABCG2/breast cancer resistance protein(BCRP), Abcb1/Mdr1 a, abcc2/Mrp2, abcg2/Bcrp, knock-out mice, tight junction, membrane lipid function. RESULTS: Recently, human studies reported thatchanges in the levels of ABC transporters were early events in the adenoma-carcinoma sequence leading to CRC. A link between ABCB1, high fat diet and gut microbes in relation to colitis was suggested by the animal studies. The finding that colitis was preceded by altered gut bacterial composition suggests that deletion of Abcb1 leads to fundamental changes of hostmicrobiota interaction. Also, high fat diet increases the frequency and severity of colitis in specific pathogenfree Abcb1 KO mice. The Abcb1 KO mice might thus serve as a model in which diet/environmental factors and microbes may be controlled and investigated in relation to intestinal inflammation. Potential molecular mechanisms include defective transport of inflammatory mediators and/or phospholipid translocation from one side to the other of the cell membrane lipid bilayer by ABC transporters affecting inflammatory response and/or function of tight junctions, phagocytosis and vesicle trafficking. Also, diet and microbes give rise to molecules which are potential substrates for the ABC transporters and which may additionally affect ABC transporter function through nuclear receptors and transcriptional regulation. Another critical role of ABCB1 was suggested by the finding that ABCB1 expr

关键词： ATP-binding cassette transporters Colorectal cance

First attempt to produce experimental Campylobacter concisus infection in mice

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World Journal of Gastroenterology 2008年第45期14卷 6954-6959页

作者： Rune Aabenhus Unne Stenram Leif Percival andersen Henrik Permin sa Ljungh Department of Clinical Microbiology National University Hospital (Rigshospitalet) Department of Pathology University of Lund Department of Infectious Control and Prevention National University Hospital (Rigshospitalet) Department of Internal Medicine Bispebjerg Hospital Department of Medical Microbiology Dermatology and Infection Lund University

AIM： TO infect mice with atypical Campylobacter concisus （C. concisus） for the first time. METHODS： Three separate experiments were conducted in order to screen the ability of five clinical C. concisus isolates of intestinal origin and the ATCC 33237 type strain of oral origin to colonize and produce infection in immunocompetent BALB/cA mice. The majority of the BALB/cA mice were treated with cyclophosphamide prior to C. concisus inoculation to suppress immune functions. Inoculation of C. conc/sus was performed by the gastric route. RESULTS： C. concisus was isolated from the liver, ileum and jejunum of cyclophosphamide-treated mice in the first experiment. No C. concisus strains were isolated in the two subsequent experiments. Mice infected with C. concisus showed a significant loss of body weight from day two through to day five of infection but this decreased at the end of the first week. Histopathological examination did not consistently find signs of inflammation in the gut, but occasionally microabscesses were found in the liver of infected animals. CONCLUSION： Transient colonization with C. concisus was observed in mice with loss of body weight. Future studies should concentrate on the first few days after inoculation and in other strains of mice.

关键词： Animal model BALB/cA mice Campylobacter concisus Colonization Infection