Improving tolerance for FODMAPs using modified celluloses: defining the role of gelation in reducing gas production in vitro and in vivo

Although fibre is known to be an important part of our diet, we eat too little for our health. In part, this is because of the discomfort that can arise from consuming it, including bloating as a result of gas build up in the bowel. A group of dietary carbohydrates called FODMAPs are rapidly fermented in the large bowel (colon) producing gases as we have shown recently using MRI (Magnetic Resonance Imaging). Low FODMAP diets improve IBS symptoms but such diets are difficult to follow and may have undesirable effects on gut bacteria. Psyllium, a commonly prescribed fibre improves IBS patients' symptoms and reduces the rise in colonic gas volumes after consuming a commonly dietary FODMAP called inulin. Psyllium is a dietary fibre which forms a gel when added to water but exactly how psyllium alters colonic fermentation is unknown.

We have developed a laboratory model colon which simulates conditions in the colon and allows us to measure the breakdown products of inulin including gas, something very difficult / impossible in actual patients because the colon is so inaccessible. We believe that psyllium acts by forming a gel, trapping inulin thereby excluding colonic bacteria and hence slowing and redirecting colonic fermentation to produce less gas but more short chain fatty acids (SCFAs). This could retain the metabolic benefits associated with SCFAs (reducing obesity / type II diabetes) while reducing adverse effects associated with excessive gas. Celluloses are safe, inexpensive dietary fibres, already widely used in the food industry which can be modified to vary viscosity and the ability to form gels to allow us to compare the effect of viscosity (resistance to flow) with that of gel formation using chemically similar substances. Gels are likely to exclude bacteria in a way that increased viscosity alone will not do.

STUDY 1A: We will initially confirm our original findings that psyllium reduces breath hydrogen response after 20g inulin and then see if a cellulose mix of equal viscosity has a similar effect and how this compares to a cellulose preparation of equal viscosity that also gels at body temperature. We will do this by giving healthy volunteers 500ml of water and 20g inulin to which is added either a) psyllium b) cellulose mix of viscosity equal to psyllium c) cellulose of equal viscosity but modified to form a gel or d) inulin alone. We believe that high viscosity alone will not produce the effect but gelation will. If true we will then use the gelling cellulose to do STUDY 1B to work out the optimum dose to use in subsequent studies. STUDY 2: This will use our colonic model to assess the effect of the different cellulose preparations on fermentation pathways in the laboratory. STUDY 3: Will use stool samples from Study 1 subjects in our laboratory model colon to correlate gas production with other break down products of inulin including SCFAs to see how these alter with differing gas production. STUDY 4: These MRI studies will measure how the most effective cellulose from Studies 1 alters flow of inulin into the colon and gas production. We will also measure acidity in the colon in response to inulin and how the cellulose mix changes it, using a 'Smart pH pill' (a swallowed pill which passes through the gut emitting a radio signal indicating acidity). STUDY 5: Will use the results from Study 4 to accurately model flow rates, acidity and concentrations in our colonic model and measure the changes in SCFA production caused by the cellulose. STUDY 6: We will give the cellulose with inulin daily for 3 weeks to IBS patients before assessing gas and colonic volumes using MRI, relevant bowel symptoms (gas, pain, bloating) and stool fermentation pathways using our model colon. If our studies are successful celluloses could be easily added to ready prepared foods to allow consumption of large molecular weight FODMAPs without causing adverse symptoms. They could also be prescribed as a treatment.

Low FODMAP (fermentable, oligo-di-mono-saccharides and polyhydric alcohols) diets have revolutionised management of irritable bowel syndrome (IBS). FODMAPs cause abdominal discomfort, bloating and flatulence by their rapid colonic fermentation which produces gas and distends the colon. Low FODMAP diets, although widely adopted, are expensive, inconvenient and may have negative effects on health by excluding high fibre foods (HFF) that protect against obesity-related diseases and colon cancer.

This project aims to use modified celluloses to trap FODMAPs in a gel, thereby limiting bacterial access and modifying fermentation to produce less gas. We have shown this in IBS patients by co-administered psyllium, a viscous and gel forming fibre, with the FODMAP, inulin.

Initial experiments in healthy volunteers (HVs) using breath hydrogen response to inulin as the endpoint, will co-administer modified celluloses to define the relative importance of gelation versus viscosity and the optimum cellulose for subsequent use. A model of colonic fermentation using stool samples from the HVs will measure gas and short chain fatty acid (SCFA) production to a) characterise the response to increased viscosity and gelation b) define the variation in SCFA production associated with the wide range of gas production observed in vivo. Subsequent HV studies will use MRI and the pH-sensitive SmartPill to measure the effect of cellulose on key parameters (flow rate of inulin into colon, colon volume, pH). The effect of these changes will be measured in the model colon, validated by comparison of in vitro and in vivo results. They will also inform a clinical trial of 3 week of cellulose treatment in IBS patients with endpoints including MRI colonic gas volumes, symptoms, microbiota and SCFAs. This new understanding of the relationship between fermentation and symptoms could lead to inexpensive treatments for IBS and functional foods to improve population tolerance of beneficial HFFs.