Gluten is a complex mix of proteins, mainly gliadin and glutenin, found in wheat, and collectively refers to similar proteins that also exist in barley, rye, and wheat-contaminated oats. Widespread application of a gluten-free diet has been fuelled by celebrity and media endorsements and presumed benefits for cognitive function and weight loss. The term non-coeliac gluten sensitivity, or more accurately non-coeliac wheat sensitivity, has been coined to describe a cluster of gut and other symptoms in the absence of genetic, immune, and serological biomarkers of coeliac disease or wheat allergy that appear to resolve in response to a gluten-free diet.
More than 20% of the general population follow a gluten-free diet, and more than half of these people are motivated to do so because they believe it is a healthier alternative. Many others do it for weight loss. This means many more individuals are following a gluten-free diet than need to because of a diagnosis of coeliac disease (1%), and more follow a gluten-free diet than profess to have non-coeliac wheat sensitivity (10%). Although gluten-free diet adherence figures are likely to be an overestimation given the lack of diet analysis to confirm dietary composition, the potential repercussions associated with unnecessary dietary restriction remain a concern.
Why is an unnecessary gluten-free diet a potential safety hazard? This comes down to the risk of nutritional inadequacy from eliminating gluten-containing grains and the wide range of food products containing wheat as a minor ingredient. Despite the potential for a gluten-free diet to result in a greater consumption of wholefoods (including fruit, vegetables, and pulses that are naturally gluten-free) and lower intake of processed products in some people, overall the research suggests the gluten-free diet leads to compromised intake of dietary fibre, B vitamins, and mineral micronutrients (eg, iron, zinc). The notion that gluten-free packaged foods are more nutritious than their gluten-containing counterparts is also unfounded. Adding to this, low gluten consumption has been associated with a higher risk of coronary heart disease, potentially attributable to limited intake of wholegrains. Furthermore, the psychological stress associated with adhering to a strict diet cannot be ignored.
Among the scientific community, non-coeliac wheat sensitivity, particularly in people with irritable bowel syndrome, has divided opinion and remains a controversial diagnosis. Several research issues so far have limited progress towards a consensus. First, there is large heterogeneity in design of gluten challenge trials, including the dose and duration of the gluten challenge protocol. Second, and crucially, very few trials (<20%) robustly demonstrate gluten-specific induction of symptoms in people with suspected non-coeliac wheat sensitivity. In fact, recent trials that are relatively small but incorporate the gold standard study design (double-blind, placebo-controlled crossover challenge), suggest that gut symptom improvement in response to a gluten-free diet is instead due to an inherent reduction in other food components known to irritate the gut (eg, fructans) and perhaps gluten is an innocent bystander. A strong nocebo response is also a substantial hindrance—it is supremely difficult to achieve statistically reliable effects or interpret results when this is present. Finally, there is the complex clinical profile of many people with suspected non-coeliac wheat sensitivity, including the myriad of presenting symptoms. A range of manifestations including fatigue, headache, muscle pain, skin rash, depression, and anaemia have been reported along with an irritable gut, with few clinical trials evaluating this range of symptoms. The lack of reproducible results, and perhaps more crucially, the absence of a diagnostic biomarker, drive the continuing divided opinion about non-coeliac wheat sensitivity.
Defining mechanistic pathways that lead to the development of non-coeliac wheat sensitivity would help to convince the wider scientific community. Systemic immune activation via intestinal barrier dysfunction and microbial translocation and proteolytic activity of certain small intestinal bacteria have been implicated as important mechanistic pathways. Intestinal barrier dysfunction has also been implicated in non-coeliac wheat sensitivity fatigue, which may enhance gluten transport across the blood–brain barrier and lead to neuroinflammation or modulation of the opioid system and other neurotransmission systems. An outstanding challenge is testing these mechanistic findings in human studies, and importantly, to correlate postulated mechanisms with gluten-specific symptomatic response.
Clinical diagnosis of suspected non-coeliac wheat sensitivity remains a challenge. Coeliac disease should be excluded and double-blind crossover dietary challenge with fructan-deplete gluten or placebo should be the basis of non-coeliac wheat sensitivity diagnosis. Realistically, this will rarely occur in clinical practice and formal diagnosis will probably remain difficult unless a biomarker is identified. Given the current state of the evidence, outside of coeliac disease the gluten-free diet should remain a last resort and clinicians should prioritise monitoring nutritional and psychosocial health, and trial other measures for symptom control. Failing this, gluten exclusion followed by reintroduction should be used as a crude test of exclusion success.
By Jessica R Biesiekierski, Heidi M Staudacher
Source: The Lancet
