Inflammatory bowel disease : determinants related to gut microbiota

Inflammatory bowel disease (IBD) is a chronic and idiopathic disorder that causes inflammation in the gastrointestinal tract. Overall, it can be classified into two types: ulcerative colitis (UC) and Crohn's disease (CD). The causes of IBD have been extensively studied, with heredity, lifestyle, and environmental factors being identified as possible contributors. These factors can trigger an imbalance in the bacterial flora in the colon, which is increasingly thought to play a crucial role in the development of IBD. As dysbiosis in the gut microbiota has been frequently reported in inflammatory bowel disease, it has been proposed that both UC and CD may be caused by an auto-immune response to gut bacteria in genetically susceptible individuals. However, the exact aetiology of these diseases is still largely unknown. The aim of this thesis was to investigate epidemiological aspects of surgical abdominal procedures and possible biochemical markers associated with gut microbiota, in relation to IBD.

In Paper I, we investigated the association between juvenile appendicitis, treated with appendectomy or conservatively treated without surgery, and adult risk of IBD. This, nation-wide, population-based retrospective cohort study, based on Swedish national registers, included all individuals with a diagnosed appendicitis before the age of 16, during the time-period 1973-1996, and matched controls. The study population was followed until 2017 for any development of UC and CD. We found that childhood appendicitis with appendectomy was associated with lower risk of UC (aHR 0.30 95% CI 0.25-0.36) and CD (aHR 0.82 95% CI 0.68-0.97), whereas conservative treatment was associated with lower risk of adult UC (aHR 0.29 95% CI 0.12-0.69), only, compared to unexposed individuals. Our findings warrant further research of the appendix in relation to gut microbiota and IBD pathogenesis.

In Paper II, we investigated the association between bariatric surgery and new onset of IBD. This population-based retrospective cohort study included Swedish individuals registered in the Scandinavian Obesity Surgery Registry who underwent primary Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) during 2007 – 2018 and matched controls. The study population was followed up until 2019 to determine the development of CD and UC. We found that individuals operated on with RYGB had an increased risk of later development of CD (HR 1.8 95% CI 1.5 - 2.2) whereas individuals who underwent SG had an increased risk of UC (HR 1.8 95% CI 1.1-3.1). The findings should encourage further studies on surgical procedures for obesity and their effect on gut microbiota and development of IBD.

In Paper III, the aim was to analyse plasma concentrations of short chain fatty acids (SCFA) in relation to CD and UC and to evaluate SCFA as a potential biomarker for IBD. This cross-sectional study included 132 and 119 individuals with CD and UC respectively and 205 controls. Although we found lower plasma concentrations of succinic acid among individuals with CD and UC in comparison to controls in univariate analysis, the difference did not remain after adjusting for sex, age and dietary factors. For all other SCFA, no differences could be found between the groups. In conclusion, CD and UC were not associated with alterations in plasma SCFA concentration.

In Paper IV, we aimed to assess alterations of plasma bile acid (BA) profiles in association to CD. This cross-sectional study included 88 individuals with CD and 88 controls. CD was found to be associated with lower concentrations of most secondary BA, particularly derivatives of deoxycholic acid and lithocholic acid. Moreover, plasma concentration of secondary BA among participants with active CD was lower in comparison to participants with CD in remission. We concluded that the immune dysfunction in CD may be associated with altered bile acid composition in blood plasma.

List of scientific papers

I. Kiasat A, Ekström LD, Marsk R, Löf Granström A, Gustafsson UO. Childhood appendicitis and future risk of inflammatory bowel disease - A nationwide cohort study in Sweden 1973-2017. Colorectal Dis. 2022 Aug;24(8):975-983.
https://doi.org/10.1111/codi.16128

II. Kiasat A, Löf Granström A, Stenberg E, Gustafsson UO, Marsk R. The risk of inflammatory bowel disease after bariatric surgery. Surg Obes Relat Dis. 2022 Mar;18(3):343-350.
https://doi.org/10.1016/j.soard.2021.12.014

III. Kiasat A, Rautiainen S, Prast-Nielsen S, Engstrand L, Schuppe-Koistinen I, Gustafsson UO, Löf Granström A. Evaluation of plasma Short Chain Fatty Acid levels as markers for Inflammatory bowel disease. [Submitted]

IV. Kiasat A, Prast-Nielsen S, Rautiainen S, Engstrand L, Andersson F, Lindberg J, Schuppe-Koistinen I, Löf Granström A, Gustafsson UO. Plasma bile acids in association with Crohn’s disease. [Submitted]