Non-Celiac Gluten Sensitivity: A Complex Diagnosis

The ingestion of gluten has been linked to several clinical disorders, including celiac disease (CD), wheat allergy, and non-celiac gluten sensitivity (NCGS). Celiac disease (CD) affects approximately 1.4% of the global population, based on serologic results, and approximately 0.7% of the global population, based on biopsy-confirmed results.¹ Prevalence estimations of NCGS are variable in many regions around the world due to the self-reporting nature of NCGS and the lack of clear diagnostic biomarkers.^2,3 Yet in the US, some reporting suggests that up to 6% of the population may be affected by this disorder.⁴ Specific to NCGS, what has research revealed about how this condition relates to extra-intestinal symptomatology, gut health, and the immune response? How can the functional medicine approach help patients with NCGS? 

(Video Time: 2 minutes) Functional medicine expert and IFM educator Kristi Hughes, ND, IFMCP, discusses the spectrum of reactivity to gluten, the importance of understanding that spectrum to enhance the clinical assessment of patients, and the known prevalence of non-celiac gluten sensitivity. 

Symptoms & Diagnosis of Non-Celiac Gluten Sensitivity (NCGS)

CD, an autoimmune reaction, and wheat allergy, an antibody-mediated inflammatory response, have been studied extensively, but the pathogenesis and molecular mechanisms of NCGS are not as well understood.^2,5 While potential antigens and biomarkers that may lead to the onset of NCGS are still under investigation, the clinical presentation of NCGS includes a wide range of gastrointestinal (GI) and extra-intestinal symptoms, including the following:^5-7

• Abdominal pain
• Bloating
• Altered bowel function
• Weight loss
• Fatigue 
• Headache
• Difficulty concentrating or forgetfulness
• Joint and muscle pain
• Mood disorders
• Skin manifestations such as rash or eczema 

Symptoms may occur within hours to days following ingestion of gluten and reportedly dissipate upon the withdrawal of gluten.^2,4

THE IMMUNE RESPONSE

As listed, a wide range of extra-intestinal symptoms have been associated with NCGS, suggesting systemic manifestations of the condition. According to recent reporting, NCGS is considered an immune system–related disease, and its link to autoimmune diseases has been hypothesized and investigated.^2,8 The most frequently mentioned autoimmune diseases associated with NCGS are reportedly Hashimoto’s thyroiditis, dermatitis herpetiformis, psoriasis, and rheumatologic diseases.⁸ In addition, innate immunity activation may trigger the inflammatory response noted in NCGS clinical presentation.^2,8

While there is no specific NCGS biomarker or test, clinical diagnosis is characterized by the following:²

• Intestinal and extra-intestinal symptoms related to gluten ingestion
• An absence of celiac disease and wheat allergy
• Confirmation by gluten withdrawal and blinded placebo challenges

Triggers, Intestinal Permeability, & the Gut

Studies have demonstrated the role of gluten as a trigger for NCGS gastrointestinal symptoms.^2,9 In addition, studies investigating the mechanisms leading to bowel dysfunctions suggest that gluten may not be the only trigger of NCGS gastrointestinal symptoms. Fermentable oligo-, di-, and monosaccharides and polyols (FODMAPs) are other components of gluten-containing grains that may play a role.^2,9

INTESTINAL PERMEABILITY & GI FUNCTION

Regardless of the specific trigger, resulting NCGS symptoms may include an impairment of the epithelial barrier and GI function. While dysfunction of the mucosal barrier of the small intestine has been observed in NCGS,² a 2019 article reviewed investigations into the involvement of the epithelial barrier in the development of non-celiac gluten/wheat sensitivity.¹⁰ The review found conflicting data on whether the epithelial barrier is a pathogenic co-factor for the development of non-celiac gluten/wheat sensitivity;¹⁰ however, one reviewed study suggested that the intestinal epithelial barrier impairment and permeability may lead to increased microbial translocation and systemic immune responses,¹¹ which in turn may contribute to the pathophysiology of NCGS.¹⁰ 

Changes in the gut microbiome after gluten consumption have also been suggested to play a role in NCGS pathophysiology due to resulting gut dysbiosis with increased intestinal permeability and a potential increase in GI and systemic inflammation, helping to explain the wide variety of NCGS clinical presentations.^4,12

Clinical Applications: The Functional Medicine Approach

Understanding the differences and overlaps between the gluten-dependent diseases and other GI disorders is pertinent for accurate diagnosis and effective personalized treatment. In addition, knowledge of potential immune responses triggered by NCGS may assist in uncovering this issue among patients.

Identifying and treating inflammatory environmental triggers that create or perpetuate gastrointestinal imbalances, inflammation, and permeability can be challenging due to the range of potential symptoms. A wide range of gastrointestinal symptoms and conditions can be treated with IFM’s 5R framework (i.e., Remove, Replace, Repopulate, Repair, and Rebalance). This framework helps to support and heal the digestive tract. Functional medicine tools such as the matrix and timeline are also used to map out the patient’s health journey, organize their clinical imbalances, and help develop a personalized treatment strategy. These strategies may include the removal of potential triggers, the use of therapeutic food plans and nutraceuticals, and addressing modifiable lifestyle factors for an overall healthy lifestyle change. 

For food reactions, specifically, dietary triggers may be highly specific to the individual and include compounding variables such as cross-reactivity. In addition, if a patient restricts certain foods such as gluten without proper nutritional counseling, this may lead to an imbalanced diet with less than optimal nutrient density and exacerbate health concerns. Clinicians trained in functional medicine commonly use IFM’s Elimination Diet to identify food triggers. This short-term nutrition program requires the patient to remove specific foods and categories of foods from their diet. A careful reintroduction of foods can identify previously hidden food triggers that may have been contributing to illness. If appropriate for an individual patient, a gluten-free diet is the standard treatment for diseases linked to ingestion of gluten. One recent observational study found that patients with NCGS (n=125) who closely followed a gluten-free diet reported better quality of life and sleep than those who did not avoid gluten as often.¹³ Functional medicine provides the tools to manage any potential nutritional issue that may arise from following a gluten-free diet by guiding patients through the process, highlighting nutrients of concern, and addressing how patients can access specific nutrients through food or supplementation. 

Learn more about gluten sensitivities and supporting a healthy gastrointestinal tract at IFM’s GI Advanced Practice Module (APM).