Patients who report “feeling better on a gluten-free diet” have become a common presence in primary care. A meta-analysis estimated that 10.3% of the global population (95% CI, 7.0%-14.0%) reported gluten or wheat sensitivity, with 40% of these individuals already following a gluten-free diet. However, double-blind, placebo-controlled gluten challenge tests confirm specific reactivity to gluten in only a minority of cases, typically fewer than 30%.

For primary care physicians, the challenge lies between these two extremes: identifying individuals in whom suspicion is well founded, ruling out conditions with similar presentations, and avoiding unnecessary long-term elimination diets.

The classification of gluten-related disorders proposed in 2012 distinguished among celiac disease, wheat allergy, and nonceliac gluten sensitivity (NCGS). The terminology has gradually shifted toward nonceliac wheat sensitivity (NCWS) because gluten is not the only component of wheat that may trigger symptoms.

A review identified three main classes of potential molecular triggers: gluten; fermentable carbohydrates such as fructans in wheat are short-chain carbohydrates (oligosaccharides) that act as the “O” in Fermentable Oligosaccharides, Disaccharides, Monosaccharides, Polyols (FODMAP).

Amylase-trypsin inhibitors can activate innate immune responses. Fructans have also been implicated in a double-blind crossover study, in which individuals with self-reported NCGS developed more symptoms in response to fructans than to gluten.

This heterogeneity is clinically relevant because it may explain why responses to elimination diets vary and why the term “wheat sensitivity” may provide a more accurate description.

Proposed Mechanisms

Innate Immunity

Unlike celiac disease, in which the HLA-DQ2- or HLA-DQ8-restricted adaptive immune response is well characterized, NCWS may predominantly involve innate immune mechanisms. Wheat ATIs can bind to the TLR4-MD2-CD14 complex on monocytes, macrophages, and dendritic cells, activating the MyD88-NF-κB pathway and promoting the production of proinflammatory cytokines, such as TNF-alpha and interleukin-8. However, recent data suggest that some of this effect may be attributable to lipopolysaccharide copurified with ATIs rather than to the ATIs themselves.

Gut Barrier

Individuals with NCWS have been reported to have increased serum levels of lipopolysaccharide-binding protein, soluble CD14, and fatty acid-binding protein 2, markers of intestinal epithelial injury, along with greater antibody reactivity to bacterial flagellin and lipopolysaccharide. These findings correlated with one another and were partially improved after dietary exclusion, suggesting that microbial products may cross a compromised epithelial barrier. The role of zonulin remains controversial, with inconsistent findings across studies.

Neuroimmune Links

Alterations in the gut microbiota have also been described, including reductions in butyrate-producing species, such as Faecalibacterium and Roseburia. Increased proximity between mast cells and enteric nerve endings is associated with pain and bloating. A modest adaptive immune component has also been suggested by the presence of immunoglobulin (Ig)G antibodies to gliadin in approximately half of the individuals with NCWS, with levels normalizing within months of wheat exclusion.

Nocebo Effect

In blinded studies, the expectation of consuming gluten can increase symptoms more than actual gluten exposure, and many individuals cannot distinguish between gluten and placebo. This complicates the interpretation of improvements observed during open-label dietary trials and supports the use of double-blind challenge testing as the reference standard.

NCWS has no pathognomonic symptoms. Suspicion should instead arise from a characteristic cluster of symptoms with a reproducible temporal relationship with wheat consumption.

Symptoms That Should Raise Suspicion of NCWS

NCWS does not present as a single characteristic symptom. Suspicion should arise when a combination of symptoms develops consistently after wheat consumption.

Intestinal Symptoms

The presentation is typically similar to irritable bowel syndrome (IBS), with abdominal bloating, abdominal pain, and altered bowel habits including diarrhea, constipation, nausea, and epigastric pain. In a multicenter study, bloating and abdominal pain were the most commonly reported symptoms.

Extraintestinal Symptoms

Extraintestinal symptoms may provide important clues because they are less prominent in IBS alone. Common manifestations include fatigue, brain fog, headache, joint and muscle pain, mood changes, and dermatitis, while the recognized range of symptoms continues to expand.

The timing of the symptoms is important. Symptoms typically develop within several hours to 1 or 2 days after consuming wheat-containing foods, improve after wheat is eliminated, and recur when it is reintroduced. A latency of several weeks or the absence of a reproducible relationship with meals makes NCWS less likely.

Risk Factors

Individuals with confirmed NCWS had higher rates of anemia, weight loss, atopy, and a history of food allergies during childhood compared with individuals with IBS. The same group proposed that a subgroup may represent non-IgE-mediated food allergy based on positive basophil activation testing and eosinophilic infiltration of the duodenum and colon.

Red Flags

Significant unexplained weight loss, bleeding, marked iron deficiency anemia, fever, symptom onset after the age of 50 years, or a family history of cancer should prompt a different and more urgent diagnostic evaluation.

Diagnostic Sequence

Thus, NCWS remains an exclusion diagnosis. A common clinical error is performing the diagnostic steps in the wrong order.

Step 1: The Patient Should Follow a Normal Diet

The patient is required to consume a normal diet before testing. Celiac serology and biopsy lose their diagnostic value after gluten is eliminated. If an individual has already stopped eating wheat, gluten should generally be reintroduced for an adequate period, usually at least 46 weeks, before testing, or the individual should be referred to a specialist to manage reintroduction.

Step 2: Ruling Out Celiac Disease

Testing should include anti-tissue transglutaminase IgA and total IgA to identify selective IgA deficiencies. If IgA deficiency is present, anti-tissue transglutaminase IgG or anti-deamidated gliadin peptide IgG levels should be measured.

A positive serology result should prompt referral for esophagogastroduodenoscopy with multiple duodenal biopsies. HLA-DQ2 or HLA-DQ8 genotyping is not recommended as a first-line test; however, its negative predictive value can be useful in borderline cases or in individuals already following a gluten-free diet.

First-generation IgG antigliadin antibodies may be positive in about half of the individuals with NCGS. They are not diagnostic of NCWS and are nonspecific; a positive result alone does not indicate celiac disease.

Step 3: Ruling Out Wheat Allergy

Wheat allergies are another important differential diagnosis that can be overlooked. Skin-prick and wheat-specific IgE testing has limitations because aqueous extracts may underrepresent the gliadin fraction. Thus, extract-based testing can yield negative results in individuals sensitized to specific wheat components.

When symptoms suggest a wheat allergy, particularly urticaria, angioedema, respiratory symptoms, or systemic reactions after eating wheat, the medical history should also establish whether the reactions occur in connection with exercise, nonsteroidal anti-inflammatory drugs, or alcohol. In such cases, testing specific wheat allergens may be appropriate.

Testing for omega-5 gliadin (Tri a 19) and nonspecific lipid transfer protein (Tri a 14) via specific IgE blood tests helps diagnose IgE-mediated wheat allergies, childhood wheat hypersensitivity, and wheat-dependent exercise-induced anaphylaxis (WDEIA) may help identify a distinct clinical phenotype.

WDEIA can be underdiagnosed and potentially serious, with diagnostic delays reported in a multicenter study of 132 adults. Suspected cases should be referred to an allergist for proper diagnostic testing rather than relying on dietary restrictions alone.

Step 4: Ruling Out Alternative Diagnoses

Alternative diagnoses include IBS, small intestinal bacterial overgrowth, lactose intolerance, chronic inflammatory bowel disease, thyroid disorders, and iatrogenic causes. NCWS and IBS can be particularly difficult to distinguish because their symptoms often overlap.

Compared with Celiac disease, NCWS generally develops more rapidly, within hours to days rather than weeks to months. It is not associated with enteropathy or positive celiac-specific serology, including anti-tissue transglutaminase, anti-endomysial, or anti-deamidated gliadin peptide antibodies. HLA-DQ2 or HLA-DQ8 is present only slightly more often in NCWS than in the general population, at approximately 50% compared with more than 95% in celiac disease.

Compared with IgE-mediated wheat allergy, in which urticaria, angioedema, bronchospasm, or anaphylaxis typically develop within minutes to several hours and specific IgE can be detected, NCWS generally has a later onset and is not associated with acute systemic reactions.

NCWS should also be distinguished from non-IgE-mediated allergies, including eosinophilic esophagitis and eosinophilic gastroenteritis, which can cause persistent upper gastrointestinal symptoms and eosinophilic infiltration on biopsy. Such findings are not characteristic of NCWS.

Step 5: Dietary Challenge

The 2015 Salerno criteria provide the methodological standard for confirming NCWS. Symptoms are assessed using a scoring system during a 6-week elimination diet, followed by a double-blind, placebo-controlled crossover challenge with a washout period in responders.

Double-blind challenge testing is generally limited to referral centers. In primary care, a practical approach is a structured elimination trial with a symptom diary followed by reintroduction while recognizing its limitations.

Systematic reviews have shown that only a minority of individuals with suspected NCGS can confirm the diagnosis using challenge testing. A multicenter randomized controlled trial also documented a significant expectation effect independent of actual gluten intake.

Therefore, an improvement during an open-label trial does not establish causality.

Biomarker Status

Currently, no validated biomarkers are available for clinical use. A previous study demonstrated intestinal epithelial injury and systemic immune activation; however, these findings remain investigational. Basophil activation tests and mucosal eosinophil counts have been proposed for an allergic subgroup but are not part of routine clinical practice.

IgG tests for “food intolerance” marketed directly to consumers have no established diagnostic validity and should be discouraged.

Treatment Approach

Treatment involves avoiding wheat and related grains, but with two important differences from the approach used for celiac disease.

The tolerance threshold varies from person to person. Unlike celiac disease, strict avoidance of trace amounts is not necessarily required. Many patients can tolerate small amounts of gluten, although a double-blind crossover trial found that symptoms could recur after small amounts of gluten in some participants. Therefore, the individual threshold needs to be established on a case-by-case basis.

The condition may be temporary. Unlike Celiac disease, NCWS is not necessarily permanent. Reevaluation within 12-24 months, followed by gradual reintroduction of gluten when appropriate, can help determine whether continued dietary restriction is necessary.

If avoiding wheat provides only partial relief, fermentable carbohydrates, such as fructans, may also contribute to symptoms. A dietitian-guided low-FODMAP approach, followed by structured reintroduction to identify individual thresholds, may be more appropriate than further restricting gluten. A double-blind study that reported a symptomatic effect of gluten was later qualified by the same researchers, who found that reducing FODMAPs largely eliminated this effect.

A prolonged, unsupervised gluten-free diet carries potential risks, including lower intake of fiber, folate, B vitamins, iron, and zinc; higher calorie and fat intake from some substitute products; increased cost; and effects on quality of life and social interactions. Consultation with a dietitian can help ensure adequate nutrition and guide the appropriate reintroduction of gluten.

Management of Residual Symptoms

If IBS-like symptoms persist despite avoiding wheat, treatment should follow IBS management guidelines. The relationship between gastrointestinal symptoms and psychological factors is bidirectional. Recognizing the potential role of expectations does not mean that the symptoms are not real.

Five Key Considerations

1. Suspicion arises from IBS-like intestinal symptoms plus extraintestinal symptoms, such as fatigue, brain fog, or headache, with a close and reproducible temporal relationship to wheat consumption.
2. Do not start dietary restrictions before testing: Celiac disease and wheat allergy should be ruled out while the patient is following a normal diet.
3. Wheat allergy requires component-specific testing, including Tri a 19 and Tri a 14, when the medical history suggests the condition; a skin prick test using a wheat extract is not sufficient to rule it out.
4. Improvement reported in an open-label trial does not establish causality because the nocebo effect is well documented and can be significant.
5. Dietary restriction does not necessarily have to be lifelong: schedule a follow-up evaluation and consider fructans if the response is only partial.

This story was translated from Univadis Italy, part of the Medscape Professional Network.