Non-Celiac Immune Responses to Gluten

Rejecting bread due to gluten sensitivity

As a lifestyle change, eliminating gluten seems to have helped many patients recover from longstanding health issues. Perhaps as a result, more and more Americans are choosing not to consume gluten.1 Despite some high-profile commentaries to the contrary,2 many clinicians continue to demonstrate positive results when patients eliminate gluten from their diets. It’s clear why this works for those diagnosed with celiac disease, but the mechanisms are somewhat less clear for patients with gluten sensitivity, as well as for those with no known gluten reactions.

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.

Spectrum of Adverse Gluten Responses

The ingestion of gluten has been linked to several clinical disorders, including celiac disease (CD), wheat allergy, and non-celiac gluten sensitivity (NCGS). Celiac 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.3 In the United States specifically, approximately 1% of the population has a CD diagnosis.4 In addition, reports suggest that up to 6% of the United States population may be affected by non-celiac gluten sensitivity.4

CD, an autoimmune reaction, and wheat allergy, an antibody-mediated inflammatory response, have been studied more extensively, but the pathogenesis and mechanisms of NCGS are not as well understood.5

Symptoms & Diagnosis of Non-Celiac Gluten Sensitivity

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 systemic symptoms, including the following:5

  • Abdominal pain
  • Bloating
  • Altered bowel function
  • Fatigue
  • Headache
  • Joint or bone pain
  • Mood disorders
  • Skin manifestations such as rash or eczema

These symptoms may occur within hours to days following ingestion of gluten and reportedly dissipate upon the withdrawal of gluten.4

Clinical diagnosis of NCGS is characterized by the following:6

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

While diagnosis of NCGS is based on exclusion of other diseases, distinguishing NCGS from a functional GI disease, such as irritable bowel syndrome (IBS), can be a challenge without clear diagnostic markers.6

Triggers, Immune Responses, & Autoimmune Links

According to a 2018 review, studies have demonstrated the role of gluten as a trigger for NCGS gastrointestinal symptoms.6 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 mono-saccharides and polyols (FODMAPs) are other components of gluten-containing grains that may play a role.6 A 2018 investigation suggested that fructan, specifically, as a component of FODMAPs, induced NCGS symptoms during their study rather than gluten.7

Intestinal Barrier and 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, a 2019 article reviewed investigations into the involvement of the epithelial barrier in the development of non-celiac gluten/wheat sensitivity.8 The review found conflicting data on whether the epithelial barrier is a pathogenic co-factor for the development of non-celiac gluten/wheat sensitivity;8 however, one reviewed study suggested that the intestinal epithelial barrier impairment may lead to increased microbial translocation and systemic immune responses,9 which in turn may contribute to the pathophysiology of NCGS.8 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.4,10

A study from the lab of famed celiac disease researcher Alessio Fasano, MD, explored the effects of the protein gliadin on the integrity of the intestinal barrier. Gliadin is a component of gluten that triggers immune responses in some patients. Researchers took duodenal biopsies from four populations: patients with active celiac disease, patients with celiac in remission, patients with gluten sensitivity, and patients with no known gluten reactions. In all of the groups, intestinal permeability was significantly increased by exposure to gliadin. Altered gut barrier function was especially pronounced for those with active celiac disease and those with gluten sensitivity.11

Dr. Fasano has posited that many autoimmune diseases develop in the presence of three factors: genetic predisposition, environmental trigger, and intestinal permeability.12 If this research proves to be correct, eating gluten could increase the risk of autoimmune disease for all patients who have a genetic susceptibility, not just those with gluten intolerance.

Extra-Intestinal Symptoms and Autoimmune Stigma

A wide range of extra-intestinal symptoms have been associated with non-celiac gluten/wheat sensitivity, from headache and fatigue to depression and dermatitis, suggesting systemic manifestations of the disease.

According to a 2018 narrative review that summarized these extra-intestinal manifestations, NCGS is considered an immune system–related disease, and its link to autoimmune diseases has been hypothesized and investigated.13 One review found evidence that innate immunity activation may trigger the inflammatory response noted in NCGS clinical presentation, and based on their review,

…an autoimmune stigma in NCGS is strongly supported.13

The review found the most frequently mentioned autoimmune diseases associated with NCGS were Hashimoto’s thyroiditis, dermatitis herpetiformis, psoriasis, and rheumatologic diseases.13 In one reviewed retrospective study of 131 patients diagnosed with non-celiac wheat sensitivity, 29% of those patients developed an autoimmune disorder compared to 21% of 101 patients with celiac disease and 4% of 50 patients with IBS.14 The primary autoimmune disease developed was Hashimotos’s thyroiditis. In addition, 46% of patients with non-celiac wheat sensitivity tested positive for anti-nuclear antibody (ANA), a marker for autoimmune reaction, compared to 24% of patients with celiac disease and 2% of patients with IBS.14

Treatment Considerations

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

A gluten-free diet is the standard treatment for diseases linked to ingestion of gluten. While this intervention has been beneficial for disease management, without professional guidance, there may be obstacles, including adherence and risk for nutritional imbalance. A recent article reviewing the nutritional profiles of gluten-free foods and gluten-free diets suggested potential deficiencies in certain nutrients such as fiber, protein, folate, iron, potassium, and zinc, while fat, sugars, FODMAPs, and sodium amounts were higher.15

Food can be medicine, or it can undermine health.

Gluten sensitivity may lead to detrimental health effects, yet gluten restriction without proper nutritional counseling may lead to an unbalanced diet with less than optimal nutrient density. Functional Medicine (FM) 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. The personalized assessment and treatment tools available in the FM model, such as the GOTOIT framework, the timeline and matrix, and the numerous food plans that can be adjusted for a gluten-free lifestyle, empower the patient-practitioner team to develop an effective, sustainable intervention for every patient.

At IFM’s Immune Advanced Practice Module (APM), an expert team of clinicians presents several clinical strategies for assessing and treating intestinal permeability as a way to prevent or improve autoimmune conditions, as well as a host of other extra-intestinal issues.

For more information on gluten-dependent diseases and a nutrient-dense diet, please read the following IFM-authored articles.

Learn More About Immune Imbalance

Study Linked Maternal Gluten Intake to Type 1 Diabetes in Children

Rates of Celiac Disease Continue to Rise Worldwide

Rise of Autoimmune Disease Linked to Intestinal Permeability


  1. Choung RS, Unalp-Arida A, Ruhl CE, Brantner TL, Everhart JE, Murray JA. Less hidden celiac disease but increased gluten avoidance without a diagnosis in the United States: findings from the National Health and Nutrition Examination Surveys from 2009 to 2014. Mayo Clin Proc. 2017;92(1):30-38. doi:1016/j.mayocp.2016.10.012
  2. Velasquez-Manoff M. The myth of big, bad gluten. New York Times Sunday Review. Published July 4, 2015. Accessed January 15, 2020.
  3. Singh P, Arora A, Strand TA, et al. Global prevalence of celiac disease: systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2018;16(6):823-836.e2. doi:1016/j.cgh.2017.06.037
  4. Igbinedion SO, Ansari J, Vasikaran A, et al. Non-celiac gluten sensitivity: all wheat attack is not celiac. World J Gastroenterol. 2017;23(40):7201-7210. doi:3748/wjg.v23.i40.7201
  5. Elli L, Branchi F, Tomba C, et al. Diagnosis of gluten related disorders: celiac disease, wheat allergy and non-celiac gluten sensitivity. World J Gastroenterol. 2015;21(23):7110-7119. doi:3748/wjg.v21.i23.7110
  6. Barbaro MR, Cremon C, Stanghellini V, Barbara G. Recent advances in understanding non-celiac gluten sensitivity. F1000Res. 2018;7(F1000 Faculty Rev):1631. doi:12688/f1000research.15849.1
  7. Skodje GI, Sarna VK, Minelle IH, et al. Fructan, rather than gluten, induces symptoms in patients with self-reported non-celiac gluten sensitivity. Gastroenterology. 2018;154(3):529-539.e2. doi:1053/j.gastro.2017.10.040
  8. Cardoso-Silva D, Delbue D, Itzlinger A, et al. Intestinal barrier function in gluten-related disorders. Nutrients. 2019;11(10):E2325. doi:3390/nu11102325
  9. Uhde M, Ajamian M, Caio G, et al. Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease. Gut. 2016;65(12):1930-1937. doi:1136/gutjnl-2016-311964
  10. Morris G, Berk M, Carvalho AF, Caso JR, Sanz Y, Maes M. The role of microbiota and intestinal permeability in the pathophysiology of autoimmune and neuroimmune processes with an emphasis on inflammatory bowel disease type 1 diabetes and chronic fatigue syndrome. Curr Pharm Des. 2016;22(40):6058-6075. doi:2174/1381612822666160914182822
  11. Hollon J, Puppa EL, Greenwald B, Goldberg E, Guerrerio A, Fasano A. Effect of gliadin on permeability of intestinal biopsy explants from celiac disease patients and patients with non-celiac gluten sensitivity. Nutrients. 2015;7(3):1565-1576. doi:3390/nu7031565
  12. Fasano A. Leaky gut and autoimmune diseases. Clin Rev Allergy Immunol. 2012;42(1):71-78. doi:1007/s12016-011-8291-x
  13. Losurdo G, Principi M, Iannone A, et al. Extra-intestinal manifestations of non-celiac gluten sensitivity: an expanding paradigm. World J Gastroenterol. 2018;24(14):1521-1530. doi:3748/wjg.v24.i14.1521
  14. Carroccio A, D’Alcamo A, Cavataio F, et al. High proportions of people with nonceliac wheat sensitivity have autoimmune disease or antinuclear antibodies. Gastroenterology. 2015;149(3):596-603.e1. doi:1053/j.gastro.2015.05.040
  15. Lerner A, O’Bryan T, Matthias T. Navigating the gluten-free boom: the dark side of gluten free diet. Front Pediatr. 2019;7:414. doi:3389/fped.2019.00414

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