The role of FODMAPs in gastrointestinal disorders

Functional gastrointestinal symptoms such as abdominal pain, bloating and altered bowel habits are common in gastrointestinal disorders. Treatment is generally unsatisfactory, but two new therapeutic targets – poorly absorbed short-chain carbohydrates (FODMAPs) and small intestinal bacterial overgrowth (SIBO) - offer new avenues of treatment. Refining dietary therapy and developing new approaches to SIBO requires a better understanding of the underlying pathophysiology related to symptom induction, intestinal fermentation patterns, and dietary habits. The overall aim of the work in this thesis was to address these issues by performing four distinct, but interrelated studies. First, the mechanism of how dietary FODMAPs influence intestinal contents delivered to the colon was examined in twelve ileostomates who undertook two four-day dietary periods (high vs low FODMAP). Ileal effluent was collected on day four of each diet with FODMAP intake and output analysed. The results demonstrated that a high FODMAP diet increased ileal output weight by 22% (95%CI 5-39%;p=0.01), water volume by 20% (2-38%;p=0.013) and dry weight by 24% (4-43%;p=0.028). Of the ingested FODMAPs, 34% (19-48%) were recovered. Secondly, the prevalence of early rise in breath hydrogen after lactulose (ERBHAL) - a putative marker of SIBO - and fructose and lactose malabsorption – important in the design of therapeutic diets - was determined using consistent hydrogen breath testing methodologies across consecutive patients with functional gastrointestinal disorders (n=201), coeliac disease (treated, 57; untreated, 79), ulcerative colitis (56), Crohn’s disease (92), and in healthy volunteers (71). Prevalence of all three end-points were similar across all groups with the main exception being Crohn’s disease where fructose and lactose malabsorption were 2-3 times as common. 62% of subjects with ERBHAL had fructose malabsorption, compared to 36% of those without (p<0.001). This association was seen across all groups, except Crohn’s disease (72% with vs 59% without ERBHAL;p=0.4). Thirdly, eighteen IBS subjects with ERBHAL consumed 56ml of Lactobacillus casei Shirota strain (Yakult®) daily for six weeks. Lactulose breath testing was repeated, impact on intestinal permeability measured, and symptom severity rated. Of 14 patients completing the study, nine (64%) had reversal of ERBHAL, with the median time of first rise increasing from 45 to 75 minutes (p=0.03). There was no significant change in intestinal permeability, but symptoms trended to improve in those with reversal of ERBHAL. Finally, a FODMAP-specific food frequency questionnaire (FFQ) was developed and completed by 100 participants. Results were compared with four one-week food diaries over a 12-month period, with the FFQ repeated at the end. The FFQ consistently overestimated intake, but validity for all major FODMAPs was established; Spearman’s correlation coefficient >0.5, acceptable Bland-Altman limits of agreement (0.02-2.07), weighted Kappa >0.4 and appropriate classifications. The FFQ was reproducible, with intraclass correlation coefficients of 0.73-0.9. These findings demonstrate that FODMAPs increase delivery of water and fermentable substrate to the proximal colon, providing theoretical evidence for the symptomatic improvement noted when IBS and IBD subjects restrict FODMAPs. Fructose and lactose malabsorption and ERBHAL are normal physiological phenomena without disease-related association, except for Crohn’s disease where FODMAPs might play a pathogenic role. The positive effects of Yakult® on ERBHAL and possibly gut symptoms provides the basis for a future double blind, randomised, controlled trial. The validation of the FFQ enables its application to population and disease research and to patient management