Gluten Wars: No smoke without fire.
Chapter 7 of Professor David Sanders new book, ‘Gluten Attack’, is entitled Sheffield: Centre of The Gluten Universe. The Royal Hallamshire Hospital accommodates the Sheffield Institute of Gluten Related Disorders, dedicated to the investigation of the role of gluten, not only in Coeliac Disease and IBS, but also in a range of neurological, dermatological and psychological disorders. Sheffield has long been a centre for gastroenterology, but research has moved on apace since I posted on the door of my laboratory some 30 years ago the notice: ‘Harwich for the Continent. Sheffield for the Incontinent’.
Gluten Free: Food fad or Treatment.
Between 15% to 20% of people living in the UK are on a gluten free diet these days, but only 1% of the population have coeliac disease. So is gluten free the latest food fad, a manifestation of ‘orthorexia nervosa’ or might there be something in the idea of gluten playing a pivotal role in a number of diseases. Sanders makes a powerful case for the latter.
What is Gluten and what does it do?
Gluten is a mixture of two proteins, gliadin and glutenin, which surround the starch granules in the endosperm. It is a storage protein which resists digestion by insects and protects the stores of starch. Its sticky qualities are highly valued in breadmaking as this binds the starch together with water and traps gas bubbles, which allow bread to rise.
Gluten Toxicity
But for David Sanders and his team and for many people with Coeliac Disease and other disorders of gluten sensitivity, gluten is toxic. Human beings can only partially digest it, but the gliadin sub-units bind to specific histocompatibility antigens present on the surface of the intestinal cells to attract white blood cells called lymphocytes that attack those cells. They also increase the production of a protein known as zonulin that loosens the tight junctions between adjacent cells. This allows the gliadin to penetrate the intestinal barrier, where it reacts with histo-compatibility antigens on macrophages marshalling special forces of lymphocytes targeted to any cells targeted with those specific proteins. 99% of people with Coeliac Disease have the particular histo-compatibility antigens (DQ2 or DQ8) that bind to gliadin. Thus when coeliacs ingest gluten, it can initiate a particularly destructive inflammatory reaction that results in a flat intestinal epithelium and malabsorption.
If DQ2 and DQ8 are so potentially harmful for our nutrition and health, we might wonder why these genes have survived. In ‘Gluten Attack’, Sanders suggests this may be because these same antigens seemed to protect against tooth decay and would therefore have conferred a greater evolutionary advantage before the days of dental care.
But although the right genetic configuration is clearly crucial for the pathogenesis of coeliac disease, there is also some evidence that the combination of Canadian wheat and the Chorleywood Process seems to produce a gluten enriched bread that is much more toxic. Other cultivars of wheat, spelt, for example, are better tolerated and the sourdough process seems to reduce the toxicity of wheat (as well as denaturing the fructans).
Undiagnosed Coeliac Disease.
David Sanders and his colleagues had observed that it was not just his patients with Coeliac Disease (CD) who seemed to respond to a gluten free diet, many of his patients with IBS did as well. He wondered if some might actually have CD. The results were surprising: CD was four times as common in his IBS patients as it was in the general population1. It was this study that led to the current advice from NICE and Coeliac UK that people with IBS should always be tested for CD.
Non-Coeliac Gluten Sensitivity
Since that study was published, research from Germany showed that a much larger subgroup of patients with IBS diarrhea not only had the right genetic background for CD, they also had intestinal inflammation, antigliadin antibodies, but no villous atrophy. Patients reported that their symptoms also improved with a gluten free diet2. They made a presumptive diagnosis of ‘non celiac gluten sensitivity’ (NCGS), whereby gluten causes an inflammatory response that may sensitise the gut but does not have the same destructive consequences as Coeliac Disease. There is, however, no definitive test for NCGS; the diagnosis can only be established with any degree of certainty by means of a randomized double-blind placebo-controlled gluten challenge.
This was conducted by Professor Peter Gibson’s team in Monash University, Melbourne3. 34 patients with IBS, who were stabilized on a gluten free diet and relatively symptom free, were randomized to receive muffins and bread containing gluten (16g/day) and a gluten-free muffins and bread every day for six weeks. When the data were analysed, 68% percent of patients given gluten developed all their original symptoms, but 40% of the group on placebo also developed symptoms while 32% remained symptom free throughout. So, in effect, only 28% of the patients in this study reacted to the bread. Ignoring the possibility that patients may have guessed by the texture of the bread and muffins whether they were eating gluten or not, it was not clear whether it was the gluten that was causing the problem or something in the wheat4, perhaps the antitrypsins formed to protect the wheat from insects or the fructo-oligosaccharides, a component of FODMAPs.
Not so much Gluten, but FODMAPs
Undeterred, the Monash team were conducted out a more definitive study to test the concept of gluten sensitivity. This was a three-way, cross-over double-blind, placebo-controlled challenge5. The investigators controlled all the food that was eaten thoughout the study and after stabilizing on a gluten free, low FODMAP diet, each patient consumed in random order 2g gluten a day for a week, 16g gluten a day of gluten a day for a week and no gluten for a week. All three groups developed symptoms and there was no significant difference in the results between the different diets. On the basis of this, the Monash team concluded that it was not so much the gluten but the additional FODMAPs in the wheat that were causing the symptoms.
Since then there have been a number of additional studies, but no concensus. This might suggest that the components of wheat acted synergistically. Could, for example, gluten have caused an inflammatory response in the intestine that made it sensitive to fructans? This was the scenario I mapped out in a previous post: Food Allergy and Food Intolerance: are they closer than we think?
More questions than answers
So gluten sensitivity remains a somewhat controversial diagnosis, yet as David Sanders points out, it is somewhat of a paradox that doctors accept the existence of IBS on the basis of no hard evidence, yet do not accept the existence of gluten sensitivity. Perhaps the notion of a syndrome leaves the door open for clarification, while the more definitive diagnosis of gluten sensitivity requires greater proof. Gluten is unlikely to be the only antigen that can interact with histo-compatibility antigens and affect gastrointestinal permeability; other food antigens may be implicated, not to mention specific bacterial and yeast antigens. Maybe the time is ripe for a reappraisal of the candida hypothesis. Alcohol and stress are also known to make the gut leaky and may open the doors to hitherto unsuspected allergens.
The essence of a good book is that it leaves you with more questions than it answers. Gluten Attack covers a wide range of neurological, dermatological, immunological and even psychological conditions where there is some tantalizing evidence that gluten (and by implication other food and microbial antigens) might be involved. I have the impression that this is just the beginning.
Watch this space.
References
- Sanders DS, Carter MJ, Hurlstone DP et al. Association of adult celiac disease with Irritable Bowel Syndrome: a case control study in patients fulfilling ROME II criteria referred to secondary care. Lancet 2001; 358: 1504-1508.
- Wahnschaffe U, Schulzke JD, Zeitz M, Ullrich. Predictors of clinical response to gluten free diet in patients diagnosed with diarrhea-predominant irritable bowel syndrome. Gastroenterol. Hepatol. 2007; 106: 508-514.
- Biesiekierski JR, Newnham ED, Irving PM et al. Gluten causes gastroentintestinal symptomsin subject without coeliac disease: a double-blind, randomized, placebo-controolled trial. J. Gastroenterol. 2011; 106:508-514.
- Carroccio A, Mansueto P, Iacono G. et al. Non-coeliac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: exploring a new clinical entity. Am. J. Gastroenterol 2012; 107: 1898-1906.
- Biesiekierski JR, Peters SL, Newnham ED. et al. No effects of gluten in patients with self-reported non-coeliac gluten sensitivity after dietary reduction of fermentable, poorly-absorbed, short-chain carbohydrates. Gastroenterology 2013; 145: 320-328.
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The Sensitive Gut 