Gluten Intolerance: Symptoms, Causes, Testing, Treatment

Gluten intolerance refers to a broad spectrum of disorders associated with the consumption of gluten, a protein primarily found in wheat, barley, and rye. While celiac disease is the most well-known form of intolerance, recent years have seen growing interest in non-celiac gluten-related disorders, such as non-celiac gluten sensitivity (NCGS) and wheat allergy.

Gluten intolerance often remains undiagnosed for extended periods, as symptoms may be mild, vague, or mistakenly attributed to other conditions such as irritable bowel syndrome, chronic fatigue, or autoimmune diseases. Furthermore, the clinical presentation can vary substantially across individuals, making diagnosis complex and multifactorial.

Accurate identification of gluten intolerance is crucial, as prolonged exposure can lead to serious complications such as malabsorption of nutrients, anemia, osteoporosis, neurological problems, and an increased risk for autoimmune diseases.

This article presents detailed information on the epidemiology, symptoms, underlying causes, available diagnostic tests (including those offered by Functional Medicine), and therapeutic approaches to help both patients and healthy individuals understand and manage the condition more effectively. It is addressed to individuals experiencing relevant symptoms as well as those seeking preventive assessment of their intestinal and immune function.

Epidemiological Data

Gluten intolerance, whether in the form of celiac disease or non-celiac gluten sensitivity, is now a significant public health issue, with its prevalence rising in recent years. The development of diagnostic tools, increased awareness among healthcare professionals, and greater patient education have contributed to the identification of more cases.

Celiac disease, an autoimmune reaction to gluten, affects approximately 1% of the global population. However, in many countries, including Greece, diagnosis remains lower than expected, with estimates suggesting that only 1 in 5 individuals with the condition receives an official diagnosis.

According to epidemiological data from studies conducted in Europe and North America, non-celiac gluten sensitivity (NCGS) is believed to affect 3% to 6% of the population, although this varies widely due to the absence of specific biomarkers. Diagnosis typically relies on symptom improvement following a gluten-free diet.

In Greece, although epidemiological data remain limited, recent reports suggest a rise in diagnosed cases of celiac disease, especially in pediatric populations. Greece's participation in European studies, such as the CELIAC-EU Consortium, has provided valuable insights into the nationwide distribution and characteristics of the condition. Interest is also growing in the role of gluten in disorders such as irritable bowel syndrome, dysbiosis, and chronic inflammation.

Of particular interest is the genetic predisposition in the Greek population. Approximately 30%-40% of Greeks carry HLA-DQ2 and/or HLA-DQ8 alleles, which are associated with an increased risk of celiac disease but are not diagnostic on their own.

The rising prevalence, multifactorial origins, and diversity of symptoms underscore the need for thorough investigation using modern, reliable, and functional tools. Early diagnosis can reduce the risk of complications and significantly improve patients' quality of life.

Symptoms and Signs of Gluten Intolerance

Gluten intolerance does not always present with characteristic symptoms, making diagnosis difficult. Symptoms are generally categorized as gastrointestinal or extraintestinal, with intensities ranging from mild to severe, and may appear immediately or be delayed after gluten consumption.

Gastrointestinal Symptoms. The most common clinical manifestations include:

• Bloating and excessive gas: Often due to inflammation or changes in the gut microbiota balance.
• Abdominal pain: Typically localized in the epigastric or central abdominal region, often worsened after meals.
• Diarrhea or constipation: Frequent alternation between these symptoms is typical and suggests functional bowel disturbance.
• Malabsorption: Poor nutrient absorption, such as iron, folic acid, and vitamin B12, can lead to chronic anemia and fatigue.
   

Extraintestinal Symptoms. Gluten intolerance can affect multiple systems in the body, causing:

• Chronic fatigue: Due to ongoing immune system activation and nutrient malabsorption.
• Arthralgia and myalgia: Often attributed to chronic inflammatory load.
• Neurological symptoms: Including mood disturbances, irritability, depression, concentration difficulties ("brain fog"), and peripheral neuropathy.
• Skin conditions: Dermatitis herpetiformis is a specific manifestation of celiac disease, though other rashes or eczema may also be associated with gluten sensitivity.
• Immunological phenomena: Frequently coexists with other autoimmune disorders such as Hashimoto’s thyroiditis, type 1 diabetes, and rheumatoid arthritis.
   

Atypical and Subclinical Manifestations. A significant proportion of patients do not display clear symptoms but may present with:

• Iron-deficiency anemia resistant to treatment
• Unexplained osteopenia or osteoporosis
• Infertility or recurrent miscarriages
• Mild hepatic dysfunction

These forms of intolerance are often discovered incidentally during preventive screenings or through specialized functional medicine testing. The variety of symptoms highlights the need for a holistic diagnostic approach that aims not only to confirm the diagnosis but also to elucidate the underlying mechanisms underlying the individual's symptom profile.

Underlying Causes of Gluten Intolerance

Gluten intolerance is not merely the result of an allergic response or isolated immune error. It is a multifactorial condition involving genetic, immunological, environmental, and microbial factors. Understanding these underlying causes is crucial for accurate diagnosis and personalized treatment planning. Below is a presentation of the primary causes with detailed explanations:

1. Genetic Predisposition. The presence of HLA-DQ2 and HLA-DQ8 alleles is a major predisposing factor for celiac disease. Although their presence is not diagnostic on its own, they are present in more than 90% of individuals with celiac disease. Their presence increases the likelihood of a pathological immune reaction to gluten by activating the adaptive immune system. Genetic predisposition is a necessary but not sufficient condition; additional factors must be present for the disease to manifest.
2. Autoimmune Dysfunction. In celiac disease, gluten consumption triggers an immune response that leads to the production of anti-tissue transglutaminase (tTG) antibodies, targeting an enzyme in enterocytes. This reaction damages the small intestine's mucosa, leading to malabsorption, inflammation, and disrupted homeostasis. This immune response may extend to other organs, which is why celiac disease often coexists with autoimmune conditions such as Hashimoto’s thyroiditis, type 1 diabetes, and some autoimmune liver diseases.
3. Increased Intestinal Permeability (Leaky Gut). Increased intestinal permeability, known as leaky gut syndrome, allows partially digested gluten peptides to pass into the bloodstream. This leads to systemic immune activation, chronic inflammation, autoimmunity, and even neurological symptoms. Zonulin, a protein that regulates intestinal tight junctions, has been found elevated in individuals with gluten intolerance, indicating activation of this pathological mechanism.
4. Dysbiosis of the Gut Microbiome. A balanced gut microbiome plays a crucial role in immune tolerance. Microbial imbalances (dysbiosis) can exacerbate inflammatory responses to gluten, impair protein breakdown, and facilitate the entry of immunoreactive peptides into the circulation. Studies show that individuals with celiac disease often have reduced levels of probiotic bacteria (e.g., Bifidobacterium and Lactobacillus) and elevated levels of pathogenic microbes, underscoring the importance of maintaining a balanced microbiome for the management of the condition.
5. Environmental Factors and Early Childhood Diet. Early or delayed exposure to gluten in infancy is considered a risk factor, especially in genetically predisposed children. Additionally, gastrointestinal infections, antibiotic use, or breastfeeding during the early months may affect immune tolerance to gluten-containing foods. Excessive consumption of processed gluten-containing products further increases the gut’s inflammatory burden, raising the risk of immune system activation.

Laboratory Tests for Investigating Gluten Intolerance

Diagnosing and understanding gluten intolerance requires a combination of conventional laboratory tests, functional medicine assessments, and, in certain cases, imaging techniques. The selection of appropriate tests depends on medical history, symptom presentation, and the goals of the diagnostic evaluation.

(a) Conventional Laboratory Tests

• Anti-Tissue Transglutaminase Antibodies (anti-tTG IgA): The most essential test for celiac disease. Detects autoantibodies against tissue transglutaminase with high sensitivity and specificity.
• Anti-Endomysial Antibodies (EMA IgA): A confirmatory test for celiac disease. Highly specific but slightly less sensitive than anti-tTG.
• Total Immunoglobulin A (IgA): Performed to rule out IgA deficiency, which may cause false-negative results in the above antibody tests.
• Genetic Testing for HLA-DQ2/DQ8: Used to exclude celiac disease. The absence of both genes makes the diagnosis highly unlikely.
• Iron, Ferritin, Vitamin B12, Folic Acid: Useful in assessing malabsorption and related anemia that may accompany gluten-related disorders.
   

(b) Functional Medicine Assessments

• Comprehensive Gluten Sensitivity Profile: A complete blood test designed to investigate all gluten-related disorders (celiac disease, wheat allergy, and non-autoimmune gluten sensitivity), aiming at early diagnosis and proper clinical guidance. Specifically, it includes total and specific IgA, IgG, and IgE antibodies against gluten, wheat, barley, and rye, as well as anti-endomysial antibodies (EMA IgA), anti–tissue transglutaminase (tTG), and anti–deamidated gliadin peptide (aDGP) antibodies.
• EnteroScan® - Functional Stool Analysis: A valuable diagnostic tool for patients with chronic gastrointestinal symptoms. It provides information on digestive function, presence of inflammation, gut microbiota composition, and detection of pathogenic microorganisms. It is particularly important in the evaluation of dysbiosis, which is closely associated with gluten sensitivity.
• Leaky Gut Test: Measures the levels of both intestinal fatty acid binding protein 2 (FABP2) and serum zonulin. Valuable diagnostic markers for intestinal permeability, since elevated levels indicate damage in the intestinal epithelium.
• MetaBolomiX™ - Organic Acids in Urine: Analyzes multiple organic acids, including metabolites associated with dysbiosis, yeast overgrowth, neurological dysfunction, and vitamin deficiencies. Ideal for evaluating systemic effects of gluten intolerance.
• SIBO Breath Test: Detects small intestinal bacterial overgrowth (SIBO).
   

(c) Other Diagnostic Tests & Imaging Techniques
In more specialized and selected cases, additional laboratory and imaging investigations may be required, such as:

• Small Intestine Biopsy: Gold standard for confirming celiac disease through histological examination.
• Superior Mesenteric Artery Duplex (Triplex): Used in differential diagnosis of ischemic enteropathy.
• Brain MRI: For evaluating neurological manifestations.
• Abdominal Ultrasound (Liver and Spleen): For detecting hepatosplenomegaly as part of systemic involvement.

Therapeutic Approaches to Gluten Intolerance

The treatment of gluten intolerance depends on the type, celiac disease, non-celiac gluten sensitivity, or wheat allergy, and on the severity of symptoms and the presence of complications. The therapeutic strategy focuses both on immediate symptom relief and long-term support of the organism’s physiological systems.

(a) Conventional Therapies
The cornerstone and irreplaceable treatment for both celiac disease and non-celiac gluten sensitivity is lifelong strict avoidance of gluten. Although no medication currently “cures” gluten intolerance, certain clinical interventions can be beneficial. For example:

• Supplementation with essential nutrients, especially iron, calcium, vitamin D, folic acid, and B12, in cases of malabsorption.
• Management of relevant complications, such as osteoporosis with antiresorptive therapy or immunomodulators for coexisting autoimmune conditions.
• Antihistamines or corticosteroids may be used symptomatically for wheat allergy or dermatitis herpetiformis.
• Experimental drugs. Some enzymes (e.g., ALV003) and zonulin inhibitors are under clinical investigation but have not yet received regulatory approval.
   

(b) Natural and Functional Approaches
Functional Medicine provides a personalized framework for treatment, focusing on restoring the physiological function of the gastrointestinal and immune systems through diet, supplementation, and lifestyle adjustments.

Diet
A gluten-free diet involves more than simply avoiding wheat. It requires a holistic restructuring of dietary habits with the goal of nourishing and repairing the intestinal mucosa:

• Avoidance: Wheat, barley, rye, oats (unless certified gluten-free), and all processed foods containing traces of gluten.
• Dietary enhancement with:
  • Naturally gluten-free grains (quinoa, amaranth, millet, rice)
  • Dietary fiber (vegetables, legumes)
  • Probiotic foods (kefir, fermented vegetables)
  • Antioxidants (berries, olive oil, turmeric)

Proper guidance from a qualified nutritionist is essential to avoid nutrient deficiencies and support mucosal healing.

Lifestyle Modifications
Lifestyle changes play a key role in modulating the immune response:

• Stress reduction: Chronic stress exacerbates inflammation and disrupts the microbiome. Mindfulness, gentle exercise, and psychotherapy can support recovery.
• Quality sleep: Adequate rest (7–8 hours/night) regulates immune activity and cytokine production.
• Toxin avoidance: Reducing intake of processed foods, additives, and pesticides minimizes intestinal irritation and immune burden.
   

Supplements and Herbal Remedies
Certain natural substances and supplements are scientifically supported in managing gluten-related conditions:

• Probiotics (Lactobacillus, Bifidobacterium): Support microbiota balance and reduce inflammatory responses. Recommended usage: 8–12 weeks.
• L-Glutamine: An amino acid that supports regeneration of the intestinal lining. Dose: 5g daily on an empty stomach for 4–6 weeks.
• Curcumin: Anti-inflammatory and antioxidant properties. Dose: 500–1000 mg daily. Caution in patients with gallstones.
• Zinc and Vitamin A: Promote intestinal healing and strengthen immune defense.
• Digestive enzymes: Especially DPP-IV enzymes, which may help break down small amounts of gluten in accidental exposure.

All interventions should be implemented under medical supervision, as unsupervised use may be ineffective or potentially harmful.

Next Steps

If you suspect you may be suffering from gluten intolerance or are experiencing persistent, non-specific symptoms, it is important not to rely on self-diagnosis or adopt a gluten-free diet without guidance. A comprehensive diagnostic approach, particularly using Functional Medicine diagnostic tools, can provide clear and actionable insights to support recovery, while in consultation with your healthcare provider.

References

1. Sergi, C., Villanacci, V. & Carroccio, A. Non-celiac wheat sensitivity: rationality and irrationality of a gluten-free diet in individuals affected with non-celiac disease: a review. BMC Gastroenterol 21, 5 (2021). https://doi.org/10.1186/s12876-020-01568-6
2. Piotin, A., de Blay, F. Investigating Non-celiac Wheat Sensitivity: A Comprehensive Review of Pathophysiology Underlying Clinical Implications. Clinic Rev Allerg Immunol 68, 94 (2025). https://doi.org/10.1007/s12016-025-09106-6
3. Roszkowska, A.; Pawlicka, M.; Mroczek, A.; Bałabuszek, K.; Nieradko-Iwanicka, B. Non-Celiac Gluten Sensitivity: A Review. Medicina 2019, 55, 222. https://doi.org/10.3390/medicina55060222
4. Uhde M, Ajamian M, Caio G, et alIntestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease. Gut 2016;65:1930-1937. https://doi.org/10.1136/gutjnl-2016-311964
5. Leonard MM, Sapone A, Catassi C, Fasano A. Celiac Disease and Nonceliac Gluten Sensitivity: A Review. JAMA. 2017;318(7):647–656. doi:10.1001/jama.2017.9730
6. Fasano, A., Sapone, A., Zevallos, V., & Schuppan, D. (2015). Nonceliac gluten sensitivity. Gastroenterology, 148(6), 1195-1204. https://doi.org/10.1053/j.gastro.2014.12.049