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Lifestyle, biomarkers and the risk of developing inflammatory bowel disease
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.ORCID iD: 0000-0003-0787-3368
2023 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Livsstil, biomarkörer och risken att utveckla inflammatorisk tarmsjukdom (Swedish)
Abstract [en]

Introduction: Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a chronic disease causing inflammation in the gut mucosa. The pathogenesis involves alteration in gut microbiota and in the intestinal barrier due to genetic factors, environmental exposure and dysregulation of the immune response. Several environmental risk factors and risk genes have been identified, but still, the pathogenesis is not fully understood. 

Methods: Included papers are all case-control studies based on previously collected data stored with the biobank in Umeå, Sweden. Cases are individuals that participated in the Northern Sweden Health and Disease Study (NSHDS) at least one year before developing IBD. Information was available for all cases regarding age, time and place for inclusion in NSHDS, height and weight, sex and tobacco use. Part of the cases also had available data from a detailed food-frequency questionnaire. For each available case, controls matched for age, sex and time and place were selected. Analysed factors included tobacco use, with smoking and snuff use analysed separately), cotinine (a metabolite of nicotine), iron status (including ferritin, iron, transferrin and transferrin saturation), B-vitamins and tryptophan metabolites. 

Results: Smoking was associated with an increased risk of developing IBD both based on questionnaire data and using cotinine as a marker for exposure. Snuff use was not associated with risk for developing IBD. A lower ferritin was associated with an increased risk of developing IBD, whereas no association was seen for other iron status analytes. When analysing iron deficiency based on ferritin and CRP, it was shown that iron deficiency was more common among men before onset of IBD, whereas no difference was seen for women. Active vitamin B6 was lower among cases compared to controls, as well as an index indicating functional B6 deficiency. Kynurenic acid and xanthurenic acid, both tryptophan metabolites with immunomodulatory properties, were lower among cases than controls. For CD only, picolinic acid was lower among cases later developing IBD.

Discussion: Smoking increases the risk of developing both UC and CD. Snuff use did not increase the risk for IBD, indicating that tobacco exposure is not the reason for increased IBD risk. Low ferritin indicates an early pathological process affecting iron storage unrelated to inflammation. Changes in vitamin B6 and tryptophan metabolites might indicate early pathological processes possibly related to gut microbiota changes. 

To conclude, this dissertation shows that multiple differences between individuals later developing IBD and controls can be seen years before IBD diagnosis. Some of which give insight to early pathophysiology in IBD.

Place, publisher, year, edition, pages
Umeå: Umeå University , 2023. , p. 86
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2247
Keywords [en]
Inflammatory bowel disease, ulcerative colitis, Crohn's disease, smoking, cotinine, iron deficiency, ferritin, pyridoxal-5-phosphate, kynurenine pathway
National Category
Clinical Medicine
Research subject
Clinical Chemistry; Internal Medicine
Identifiers
URN: urn:nbn:se:umu:diva-208115ISBN: 978-91-8070-035-1 (electronic)ISBN: 978-91-8070-034-4 (print)OAI: oai:DiVA.org:umu-208115DiVA, id: diva2:1755885
Public defence
2023-06-02, Betula, Byggnad 6M, Norrlands universitetssjukhus, Umeå, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2023-05-12 Created: 2023-05-09 Last updated: 2023-05-10Bibliographically approved
List of papers
1. Smoking is associated with risk for developing inflammatory bowel disease including late onset ulcerative colitis: a prospective study
Open this publication in new window or tab >>Smoking is associated with risk for developing inflammatory bowel disease including late onset ulcerative colitis: a prospective study
2018 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 53, no 2, p. 173-178Article in journal (Refereed) Published
Abstract [en]

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 Vasterbotten 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.

Place, publisher, year, edition, pages
Taylor & Francis, 2018
Keywords
alcohol, Crohn's disease, inflammatory bowel disease, tobacco, smoking, ulcerative colitis
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:umu:diva-144849 (URN)10.1080/00365521.2017.1418904 (DOI)000423621300010 ()29262738 (PubMedID)2-s2.0-85038615320 (Scopus ID)
Available from: 2018-02-23 Created: 2018-02-23 Last updated: 2025-02-11Bibliographically approved
2. Elevated plasma cotinine is associated with an increased risk of developing IBD, especially among users of combusted tobacco
Open this publication in new window or tab >>Elevated plasma cotinine is associated with an increased risk of developing IBD, especially among users of combusted tobacco
Show others...
2020 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 15, no 7, article id e0235536Article in journal (Refereed) Published
Abstract [en]

Objective: Smoking has previously been associated with inflammatory bowel disease (IBD), but no study has reported on cotinine, an objective, biochemical measure of tobacco use. We aimed at testing the hypothesis that cotinine levels among healthy subjects are associated with an increased risk of developing IBD in later life.

Design: We analysed plasma cotinine and evaluated corresponding lifestyle questionnaires that included tobacco habits in subjects (n = 96) who later developed late-onset IBD (70 ulcerative colitis (UC) and 26 Crohn’s disease (CD)) and in sex and age-matched controls (n = 191).

Results: Patients who later developed IBD had significantly higher plasma cotinine levels compared to controls. In multivariable analysis, higher log-cotinine was associated with a higher risk of developing IBD (OR 1.34 (95% CI 1.01–1.63)). After stratifying for time to diagnosis, the association was only significant in subjects with shorter time (< 5.1 years) to diagnosis (OR 1.45 (1.09–1.92)). The findings were similar for UC- and CD-cases, but did not reach statistical significance in CD-cases. Although plasma cotinine concentrations were higher in snuff users compared to combusted tobacco users, no increase in the risk of IBD and lower risk of developing IBD among subjects with shorter time (< 5.1 years) to diagnosis was seen among snuff users.

Conclusions: Cotinine, a biomarker of tobacco use, is associated with increased risk of developing late-onset IBD in general, and UC in particular. No increased risk among snuff users indicates that other components in combusted tobacco than nicotine may be involved in the pathogenesis of IBD among smokers.

Place, publisher, year, edition, pages
Public Library of Science (PLOS), 2020
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:umu:diva-173880 (URN)10.1371/journal.pone.0235536 (DOI)000549913100038 ()32614903 (PubMedID)2-s2.0-85087472900 (Scopus ID)
Funder
Region Västerbotten, VLL-678111Region Västerbotten, VLL-582981Swedish Research Council, VR 2017-00650
Available from: 2020-08-06 Created: 2020-08-06 Last updated: 2025-02-11Bibliographically approved
3. Patients developing inflammatory bowel disease have iron deficiency and lower plasma ferritin years before diagnosis: a nested case-control study
Open this publication in new window or tab >>Patients developing inflammatory bowel disease have iron deficiency and lower plasma ferritin years before diagnosis: a nested case-control study
2020 (English)In: European Journal of Gastroenterology and Hepathology, ISSN 0954-691X, E-ISSN 1473-5687, Vol. 32, no 9, p. 1147-1153Article in journal (Refereed) Published
Abstract [en]

Background: Iron deficiency is common among inflammatory bowel disease (IBD) patients, generally reported without comparisons with controls. The aim of this study was to analyse if iron deficiency was more common among those later developing IBD compared to matched controls in a prospective setting.

Methods: We included 96 healthy subjects later developing IBD and 191 matched controls from the Northern Sweden Health and Disease Study. We analysed iron, ferritin, transferrin, and calculated transferrin saturation in plasma sampled at least 1 year prior to IBD diagnosis. Iron deficiency was defined as plasma ferritin <30 µg/L if C-reactive protein (CRP) was <3 mg/L. When CRP was >3 mg/L, iron deficiency could not be excluded if ferritin was <100 µg/L.

Results: Iron deficiency could not be excluded among more male cases vs controls (25.0% vs 2.2%; P < 0.001), whereas with no differences for women (39.6% vs 35.3%; P = 0.538). Ferritin was lower among male IBD cases (P = 0.001) and for ulcerative colitis (P = 0.016 for males and 0.017 for females), but not for Crohn's disease. Ferritin was associated with a lower risk for IBD and in the ulcerative colitis subgroup when using sex-based z-scores. Ferritin quartiles 2–4 had a 65% lower odds ratio for all IBD, ulcerative colitis, and Crohn's disease in multivariable analysis.

Conclusions: Lower ferritin was associated with higher risk for developing IBD in a prospective setting. Iron deficiency was more common among healthy males years later developing IBD compared to matched controls, but not among women.

Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2020
Keywords
Crohn's disease, epidemiology, inflammatory bowel disease, iron deficiency, nutrition, ulcerative colitis
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:umu:diva-174854 (URN)10.1097/MEG.0000000000001816 (DOI)000562738600011 ()32541236 (PubMedID)2-s2.0-85089128561 (Scopus ID)
Available from: 2020-09-18 Created: 2020-09-18 Last updated: 2025-02-11Bibliographically approved
4. Tryptophan metabolism and vitamin B6 status are associated with the risk of developing inflammatory bowel diseases in a prospective study
Open this publication in new window or tab >>Tryptophan metabolism and vitamin B6 status are associated with the risk of developing inflammatory bowel diseases in a prospective study
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-208113 (URN)
Available from: 2023-05-09 Created: 2023-05-09 Last updated: 2023-05-09

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