Abstract
Irritable Bowel Syndrome (IBS) is a functional gastrointestinal disorder (FGID) associated with reduced quality of life, significant health care costs, and has an estimated global prevalence of 11%. Due to its variable phenotype and multifactorial pathophysiology there are currently no satisfactory biomarkers for IBS diagnosis. Additionally, the current ‘gold standard’ validated clinical tool for FGID diagnosis, the Rome IV criteria, is a consensus driven criteria which do not take pathophysiology into account. Many different pathophysiologies for IBS have been intensively investigated, including aberrant sub-clinical inflammatory responses, dysbiosis, small intestinal bacterial overgrowth, genetic polymorphisms and alterations to gastrointestinal (GI) barrier permeability. However, these have historically been investigated in isolation rather than holistically. This current body of knowledge has created an extensive scientific background of inconsistent or contradictory results of the pathophysiology and treatment of IBS and other FGID.
The COMFORT (Christchurch IBS cOhort to investigate Mechanisms FOr gut Relief and improved Transit) study is an observational case-control study which recruited participants with IBS, functional constipation (FC) or diarrhoea (FD) as well as asymptomatic controls. This cohort is designed to take a ‘multi-omics’, systems biology approach to the investigation of FGID pathophysiology by collecting and integrating demographic, GI and non-GI symptoms, and a range of biological data (blood, breath, stool, urine, and colonic tissue samples). Participants also completed a three day Food And Symptoms Times (FAST) diary to investigate correlations between food consumption and the onset, duration, and severity of GI symptoms experienced over those three days.
This research aimed to investigate the association of fibre consumption with the faecal microbiota (as a proxy of the gut microbiota), subsequent butyrate production and colonic epithelial tight junction gene expression in the biological samples collected from the COMFORT study participants. Additionally, this research explores the way in which COMFORT participants cluster together without the framework of Rome IV criteria and apply these results to biological data in comparison to Rome IV diagnostic groups.
Section One provides a cohort description of the COMFORT study, and risk factors of concomitant symptomatic anxiety and depression in FGID participants. The clustering of participants using unsupervised analysis is also compared to Rome IV diagnostic criteria using faecal microbiome data in order to test the validity of applying this analysis to a biological dataset.
Section Two details the associations, captured in the FAST diary, of fibre and fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) consumption with the onset of the GI symptoms within three hours of meal consumption. This analysis provided a more nuanced understanding of the relationship between GI symptoms and two food components commonly identified to exacerbate IBS symptoms, fibre and FODMAP.
Section Three presents tight junction and Nerve Growth Factor gene expression data and faecal butyrate concentration data. These data were correlated with fibre and FODMAP consumption, GI and non-GI symptoms, faecal microbiota relative abundance, and demographics. The results were interpreted using clusters determined by unsupervised analysis.
This thesis demonstrates the biological plausibility of the relationships between diet, faecal microbiota, faecal butyrate concentration and colonic tight junction and Nerve Growth Factor gene expression. Additionally, the use of data from multiple biological systems approach outside of the Rome IV framework provides novel insights into FGID pathophysiologies.