Exploring colonic fermentation and new technical applications for understanding functional & inflammatory bowel disease
2017-04-19T02:09:37Z (GMT) by
The colonic microbiota has major functions in the fermentation and metabolism of undigested dietary substrates. Abnormalities in these metabolic functions have been implicated in the pathogenesis of functional bowel disorders (FBD) and ulcerative colitis (UC). Restoration of these functions could potentially provide an opportunity for formulating new therapies. However, research is currently hampered by physical inaccessibility of colonic contents and inaccurate measurements of highly volatile metabolites such as hydrogen sulphide (H<sub>2</sub>S). Biomarkers to target and measure success of therapy are also lacking. <br> <br> This thesis aims to investigate the utility of new systems that profile the modulation of bacterial metabolites in a series of studies. These included (i) breath hydrogen testing in the management of FBD patients, (ii) a novel faecal gas-profiling system in the modulation of H<sub>2</sub>S and nitric oxide for ulcerative colitis, (iii) an ingestible pH-motility capsule in assessing colonic fermentation and regional pH profiles with regards to pH-dependent drug delivery systems; and (iv) a novel ingestible gas-sensing capsule in assessing colonic gas production in response to dietary manipulation of fermentable fibre. <br> <br> Findings from a retrospective evaluation of FBD patients with repeated lactulose and fructose breath hydrogen tests demonstrated poor test-retest reproducibility of testing outcomes and a poor ability to predict gastrointestinal symptoms. Hence, routine use of lactulose and fructose breath tests to guide clinical management of these patients was not recommended. <br> <br> Investigation of the newly developed faecal-gas profiling system in a proof-of-concept study was successful in producing reliable and accurate real-time measurements of faecal gas production, specifically H<sub>2</sub>S. Subsequently, assessment of H<sub>2</sub>S modulation <i>in vitro </i>identified that faecal H<sub>2</sub>S production was altered in a small cohort of UC patients, effectively suppressed by readily fermentable carbohydrates, vigorously stimulated by sulphur amino acids but minimally affected by 5-aminosalicylic acid and inorganic sulphur. These results have implications for the future design of dietary therapies to reduce excessive colonic H<sub>2</sub>S production implicated in UC and the utility of the technology as a biomarker for monitoring treatment success. <br> <br> The results of a randomised, double-blind, cross-over intervention study in patients with clinically quiescent UC documented features of reduced carbohydrate fermentation in comparison to healthy volunteers using the ingestible pH-motility capsule. A proportion of patients with UC also had colonic pH profiles that were sub-optimal for the activation of pH-dependent drug delivery systems. Acute supplementation of fermentable and slowly fermentable carbohydrates improved pH profiles in the proximal colon and normalised colonic transit but did not correct for impaired fermentative activity in the distal colon. <br> <br> In another proof-of-concept trial, divergent patterns of intestinal carbon dioxide production were detected in real time by the gas-sensing capsule following dietary interventions with high and low fermentable fibre content in a pig model. However, further animal trials are needed to improve its operation and safety before use in human trials. <br> <br> In conclusion, accurate and reliable systems are now available to measure the functional capacity of the colonic microbiota and create new frontiers in nutrition and gastroenterology research. These systems enabled identification of pathological and regional differences in the function of the microbiota in UC compared to health that will have implications in the design of new dietary therapies and drug delivery systems in UC. Further work is needed to expand on these preliminary findings.