Sensitivity to wheat, gluten and FODMAPs in IBS: facts or fiction?

ABSTRACT
IBS is one of the most common types of functional bowel disorder. Increasing attention has been paid to the causative role of food in IBS. Food ingestion precipitates or exacerbates symptoms, such as abdominal pain and bloating in patients with IBS through different hypothesised mechanisms including immune and mast cell activation, mechanoreceptor stimulation and chemosensory activation. Wheat is regarded as one of the most relevant IBS triggers, although which component(s) of this cereal is/are involved remain(s) unknown. Gluten, other wheat proteins, for example, amylase-trypsin inhibitors, and fructans (the latter belonging to fermentable oligo-di-mono-saccharides and polyols (FODMAPs)), have been identified as possible factors for symptom generation/exacerbation. This uncertainty on the true culprit(s) opened a scenario of semantic definitions favoured by the discordant results of double-blind placebo-controlled trials, which have generated various terms ranging from non-coeliac gluten sensitivity to the broader one of non-coeliac wheat or wheat protein sensitivity or, even, FODMAP sensitivity. The role of FODMAPs in eliciting the clinical picture of IBS goes further since these short-chain carbohydrates are found in many other dietary components, including vegetables and fruits. In this review, we assessed current literature in order to unravel whether gluten/wheat/FODMAP sensitivity represent ‘facts’ and not ‘fiction’ in IBS symptoms. This knowledge is expected to promote standardisation in dietary strategies (gluten/wheat-free and low FODMAP) as effective measures for the management of IBS symptoms.

Extract from study:

WHEAT SENSITIVITY
Wheat is considered one of the foods known to evoke IBS symptoms. However, which component(s) of wheat is/are actually responsible for these clinical effects still remain(s) an unsettled issue. The two parts of wheat that are thought to have a mechanistic effect comprise proteins (primarily, but not exclusively, gluten) and carbohydrates (primarily indigestible short-chain components, FODMAPs). Two distinct views characterise the clinical debate: one line identifies wheat proteins as a precipitating/perpetuating factor leading to symptoms, while the other believes that FODMAPs are the major trigger for IBS.

The controversy over nomenclature
If gluten is a major trigger for IBS, it expands the gluten-related disorders by adding a new entity now referred to as non-coeliac gluten sensitivity (NCGS). Indeed, coeliac disease-like abnormalities were reported in a subgroup of patients with IBS many years ago. A recent expert group of researchers reached unanimous consensus attesting the existence of a syndrome triggered by gluten ingestion. This syndrome recognises a wide spectrum of symptoms and manifestations including an IBS-like phenotype, along with an extra-intestinal phenotype, that is, malaise, fatigue, headache, numbness, mental confusion (‘brain fog’), anxiety, sleep abnormalities, fibromyalgia-like symptoms and skin rash. In addition, other possible clinical features include gastroesophageal reflux disease, aphthous stomatitis, anaemia, depression, asthma and rhinitis. Symptoms or other manifestations occur shortly after gluten consumption and disappear or recur in a few hours (or days) after gluten withdrawal or challenge. A fundamental prerequisite for suspecting NCGS is to rule out all the established gluten/wheat disorders, comprising coeliac disease (CD), gluten ataxia, dermatitis herpetiformis and wheat allergy. The major issue not addressed by the consensus opinion was that gluten is only one protein contained within wheat. Other proteins, such as amylase-trypsin inhibitors (ATIs), are strong activators of innate immune responses in monocytes, macrophages and dendritic cells. Furthermore, wheat germ agglutinin, which has epithelial-damaging and immune effects at very low doses at least in vitro, might also contribute to both intestinal and extraintestinal manifestations of NCGS. Consequently, a further development of this research field led to suggestions of a broader term, non-coeliac wheat sensitivity (NCWS). The problems with this term are twofold. First, rye and barley may be inappropriately excluded. Second, the term will refer to any wheat component that might be causally related to induction of symptoms and, therefore, will also include fructans (FODMAPs). It will then have a very nonspecific connotation in IBS. A more correct term would then be non-coeliac wheat protein sensitivity (NCWPS) since this does not attribute effects to gluten without evidence of such specificity, eliminates the issue of fructan-induced symptoms and avoids the unknown contribution of rye and barley proteins to the symptoms. Both NCGS, the currently accepted term, and NCWPS will be used subsequently in this paper.

Evidence for involvement of sensitivity to wheat proteins in IBS
Due to the lack of biomarkers, the diagnosis of NCGS still challenges clinicians as it remains based only on clinical criteria. In addition, one of the major diagnostic criteria for NCGS, which is the improvement of symptoms after wheat protein/ gluten exclusion, might be influenced by a placebo effect experienced by patients after food elimination from their usual diet. This is compounded by a huge media drive, via publications, printed media, television and the internet supported strongly by celebrity endorsement where a gluten-free diet (GFD) has been embraced not only as a solution to many symptoms but also with the erroneous belief that it is healthy not to eat gluten and, even more, that GFD helps to lose weight. As a result, a high proportion of US population, for example, switched to GFD with a marked increase of the global sale of gluten-free foods. Because of these facts, it has been hypothesised that NCGS might be a false problem created by media rather than an emerging clinical entity. However, recent studies have provided strong signals that wheat protein/gluten may specifically induce GI* and extraintestinal, including psychological, symptoms in at least some patients with NCGS.

Although epidemiological data are still scanty and approximate, NCGS may be at least as common as CD (ie, occurring in ≥1% of the general population). Similarly to IBS, NCGS affects more young (third decade of life) women (F:M ratio >3:1), while, in contrast to IBS, NCGS is diagnosed more commonly in tertiary than primary care centres. According to the National Health and Nutrition Examination Survey, a primary care programme, NCGS was found in 0.6% over 7762 subjects, 41 whereas at the Celiac Disease Center (University of Maryland) 6% over 5896 subjects were identified as NCGS. In an Italian multicentre prospective survey carried out on 38 referral paediatric and adult centres for the diagnosis of glutenrelated disorders, NCGS and CD were respectively diagnosed in 391 (3.2%) and 340 (2.8%) over 12 255 patients consecutively studied in a 1-year period. Such data have to be viewed, however, in the light of the failure to actually prove specific sensitivity to gluten/wheat proteins in double-blind placebocontrolled (DBPC) cross-over studies in most patients fulfilling the criteria for NCGS.

Although still a matter of debate, several factors have been postulated to play a role in NCGS pathogenesis. First, NCGS may be an immune-mediated disorder evoked by innate immunity, as highlighted by the increased expression of toll-likereceptors (TLRs), mainly TLR2, in the intestinal mucosa. More recently, however, the evidence of an increased level of interferon-γ in small intestinal biopsies of patients with NCGS after a short (3-day) gluten challenge lends support to a possible role exerted by adaptive immunity in this syndrome. In line with the latter findings, the detection of antigliadin antibodies in >50% of patients with NCGS provides further support to adaptive immunity in NCGS pathogenesis. Second, discordant data exist on epithelial barrier dysfunction. Initial studies showed a reduced intestinal permeability in NCGS, thus suggesting an increased intestinal barrier function. This finding has been also supported by a significantly higher expression of claudin-4 mRNA, a marker of reduced permeability, in duodenal biopsies of patients with NCGS. However, more recently, some evidence for increased intestinal permeability in a subgroup of patients with IBS-D carrying the human leucocyte antigen (HLA)-DQ2+/DQ8+ was reported when consuming a gluten-containing diet compared with a GFD. Further studies are needed. Third, changes of gut microbiota, as detected in CD, might also occur in patients with NCGS. Finally, a further aspect potentially linking NCGS with IBS is that HLA-DQ8 transgenic mice sensitised by gliadin displayed an increased secretion of acetylcholine from the myenteric plexus, enhancing muscle contractility and epithelial hypersecretion. Gluten withdrawal reversed both abnormalities.

omissis Evidence from double-blind placebo-controlled trials. Consistent evidence indicates the existence of an overlap between IBS and gluten-related disorders. In fact, about 5% of patients with IBS tests positive for CD and, conversely, CD may present with typical IBS-like symptoms. Moreover, IBS-like symptoms occur in the majority of patients with NCGS, while about one-third of patients with IBS may have NCWPS. Although wheat is now established to be linked to IBS, the component(s) that actually trigger(s) symptoms remain unknown. In this line, the only way to confirm the possible role of gluten or wheat as causative factors of NCGS/NCWPS is a DBPC strategy.

…….Omissis THE ROLE OF FODMAPS IN IBS. The development of the FODMAP story.
Over many years, there have been multiple observations that ingestion of certain short-chain carbohydrates—lactose, fructose and sorbitol, and fructo-oligosaccharides and galactooligosaccharides—was able to induce IBS-like symptoms, and that their restriction in the diet was associated with apparent improvement in symptoms in some patients with IBS (as reviewed in detail). These carbohydrates have several key features in common. They are small molecules, containing only 1–10 sugars, and hence are possible osmotically active substances in the lumen of the intestine. They are slowly absorbed in the small intestine if monosaccharides are not absorbed at all if they contain more than one sugar due to lack of suitable hydrolases. Hence, they are present in the small intestinal lumen for a prolonged time and do increase the intestinal luminal water content. Their malabsorption leads to their exposure to intestinal bacteria, which rapidly ferment them to release shortchain fatty acids and gases (hydrogen, carbon dioxide and, in some people, methane). Their effects on symptoms and gas production are also additive. Two hypotheses were proposed: (1) the luminal distension evoked by FODMAPs was related to symptom generation; (2) in patients with IBS and its associated visceral hypersensitivity, reducing the intake of all those short-chain carbohydrates would optimally improve the symptom burden. This was different to previous dietary strategies in that only one or two species of those carbohydrates—for example, lactose in lactose malabsorbers, fructose alone or in combination with sorbitol or fructans in fructose malabsorbers—were restricted”.
Note:
* Gastrointestinal diseases (abbrev. GI diseases or GI illnesses) refer to diseases involving the gastrointestinal tract, namely the oesophagus, stomach, small intestine, large intestine and rectum, and the accessory organs of digestion, the liver, gallbladder, and pancreas.

Deepening
Sensitivity to wheat, gluten and FODMAPs in IBS: facts or fiction?
Roberto De Giorgio, Umberto Volta, Peter R Gibson. Published Online First 15 June 2015. Gut 2016; 65:169–178.