Microbial, immunological, phenotypic and genetic markers of risk: aspects of Crohn’s disease that are shared by unaffected siblings
Crohn’s disease (CD) is an incurable intestinal disorder in which an immune response driven by commensal gut microbiota leads to chronic inflammation. Why this occurs in specific individuals is unclear; however, a genetic predisposition is fundamental and relatives of patients with CD are at enhanced risk of developing CD. Accumulating knowledge relating to the genetic loci that predispose to CD raises the possibility of disease prediction and prevention in susceptible populations. However, the genetic basis of CD is complex, and genotyping alone is likely to be insufficient to predict disease risk accurately. Specific physiological abnormalities associated with CD, such as increased intestinal permeability and raised faecal calprotectin, are also abnormal in some relatives of patients with CD. By using the combination of genotype and biomarkers models of disease prediction become a realistic possibility, and may permit intervention to prevent disease onset. Furthermore, enhanced understanding of the genotype and phenotype of the at-risk state in relatives of patients with CD also provides insights into the earliest, pre-disease stages of the pathogenesis of CD. This thesis reports a case-control study comparing 22 patients with quiescent CD with 21 of their healthy siblings and 25 healthy, unrelated controls. In addition to genotyping each participant, the CD-risk phenotype was found to encompass alterations in the intestinal microbiota, blood T-cell phenotype, concentrations of faecal calprotectin and intestinal permeability. A combination of these factors could be used to discriminate healthy siblings from healthy controls. Prior to commencement of the case-control study, a detailed survey of the prevalence of probiotic and prebiotic use in the intended patient population was carried out. Furthermore, a subset of the participants in the case-control study subsequently undertook a 3 week open-label trial of oral prebiotic oligofructose-enriched inulin in order to assess the potential of prebiotics to influence the at-risk phenotype.
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