Understanding gluten sensitivity: the role of gluten and dietary carbohydrates in the genesis of gastrointestinal symptoms in individuals who do not have coeliac disease
thesisposted on 06.02.2017 by Biesiekierski, Jessica Rose
In order to distinguish essays and pre-prints from academic theses, we have a separate category. These are often much longer text based documents than a paper.
Despite worldwide increased prescription of a gluten-free diet (GFD) for gastrointestinal (GI) and other symptoms in individuals who do not have coeliac disease, there is minimal evidence that suggests gluten is a trigger. It is not known whether it is the removal of protein (gluten) or the carbohydrate (fructan) component in wheat responsible, given fructans are capable of provoking GI symptoms themselves. A series of studies were undertaken to provide an evidence-base for this so-called non-coeliac gluten sensitivity (NCGS) and make sense of the increasing avoidance of gluten- and wheat-containing products. The objectives of this thesis were: to evaluate the content of poorly absorbed, short-chain carbohydrates (termed FODMAPs) in a variety of grains and processed cereal products; to characterise patients who believed they have NCGS; and, to evaluate the effects of gluten in patients with irritable bowel syndrome (IBS) in who coeliac disease was excluded (histology or gene typing) and who were symptomatically controlled on a GFD in three randomised, placebo-controlled, double-blind trials on GI symptoms, fatigue and markers of potential mechanism. Carbohydrate analysis of 55 commonly consumed grain and cereal products found fructans to be the most common FODMAP present, further developing the FODMAP composition tables and expanding our understanding of natural food sources of prebiotics (galacto- and fructo-oligosaccharides). Many high FODMAP-containing products were gluten-containing, and conversely many low FODMAP products were gluten-free, which may help explain the symptom improvement that individuals with IBS experience whilst following a GFD. A survey of 132 people who believe they had NCGS found the practice of initiation of a GFD without adequate exclusion of coeliac disease is common and nearly 25% believed that they were gluten-sensitive despite having uncontrolled symptoms. The results from the initial double-blind, randomised, placebo-controlled trial provided for the first time, high-quality evidence that gluten itself may trigger GI symptoms and fatigue in individuals who do not have coeliac disease (termed NCGS). A second trial used a cross-over design, controlling for other dietary triggers of symptoms, FODMAPs, and investigated more sensitive markers of possible immune mechanisms. Very limited evidence of gluten specificity was observed, but FODMAP restriction uniformly reduced residual symptoms. A strong nocebo response and an order effect were found. No clues to the mechanism were elucidated in either trial. The third trial invited previous participants to complete a rechallenge and did not show any protein specific changes in GI symptoms. Gluten did, however influence current feelings of depression, but had no influence on depression as a personality trait. A very high nocebo response was again found regardless of all background dietary triggers being controlled and reproducibility of symptom induction to gluten was poor. Either the patients did not have NCGS as self-reported or the trial design precluded its recognition because of a high nocebo effect. Clarification of the phenotype of NCGS patients, the mechanism(s) by which gluten induces symptoms and clinical significance is required. Standardised guidelines into the design and conduct of IBS dietary studies are needed. Patients who believe they have NCGS are likely to benefit from lowering their dietary intake of FODMAPs.