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As a lifestyle change, eliminating gluten seems to have helped many patients recover from longstanding health issues. More and more Americans are choosing not to consume gluten,¹ and 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.

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.² In the United States specifically, approximately 1% of the population has a CD diagnosis.³ In addition, reports suggest that up to 6% of the United States population may be affected by NCGS;³ however, prevalence estimations tend to be variable due to the self-reporting nature of the condition and the lack of clear diagnostic biomarkers.^4,5

CD, an autoimmune reaction, and wheat allergy, an antibody-mediated inflammatory response, have been studied more extensively, but the pathogenesis and molecular mechanisms of NCGS are not as well understood.^4,6

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:^6-8

• Abdominal pain
• Bloating
• Altered bowel function
• Weight loss
• Fatigue
• Headache
• Difficulty concentrating or forgetfulness
• 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.³

While there is no specific NCGS biomarker or test, clinical diagnosis is characterized by the following:⁹

• 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.

Triggers, Immune Responses, & the Gut

According to a 2018 review, studies have demonstrated the role of gluten as a trigger for NCGS gastrointestinal symptoms.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.⁹ A 2018 investigation suggested that fructan, specifically, as a component of FODMAPs, induced NCGS symptoms during their study rather than gluten.¹⁰

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.¹¹ The review found conflicting data on whether the epithelial barrier is a pathogenic co-factor for the development of non-celiac gluten/wheat sensitivity;¹¹ however, one reviewed study suggested that the intestinal epithelial barrier impairment may lead to increased microbial translocation and systemic immune responses,¹² which in turn may contribute to the pathophysiology of NCGS.¹¹

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.^3,13,14

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.¹⁵

Extra-Intestinal SymptomS

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.¹⁶ The most frequently mentioned autoimmune diseases associated with NCGS are reportedly Hashimoto’s thyroiditis, dermatitis herpetiformis, psoriasis, and rheumatologic diseases.¹⁶ In addition, innate immunity activation may trigger the inflammatory response noted in NCGS clinical presentation.¹⁶

Treatment Considerations

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.

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. While this intervention has been beneficial for disease management, without professional guidance, there may be obstacles, including adherence and risk for nutritional imbalance. Recent research 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.^5,17

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. The personalized assessment and treatment tools available in the functional medicine 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.

In addition, a wide range of gastrointestinal symptoms and conditions can be treated with IFM’s 5R framework (i.e., Remove, Replace, Re-inoculate, Repair, and Rebalance). This framework helps to support and heal the digestive tract. Learn more about gluten sensitivities and supporting a healthy gastrointestinal tract at IFM’s GI Advanced Practice Module (APM).

Rates of Celiac Disease Continue to Rise Worldwide

The Microbiome and Immune-Related Diseases

References

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. 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
3. 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
4. Cárdenas-Torres FI, Cabrera-Chávez F, Figueroa-Salcido OG, Ontiveros N. Non-celiac gluten sensitivity: an update. Medicina (Kaunas). 2021;57(6):526. doi:3390/medicina57060526
5. Rej A, Potter MDE, Talley NJ, Shah A, Holtmann G, Sanders DS. Evidence-based and emerging diet recommendations for small bowel disorders. Am J Gastroenterol. 2022;117(6):958-964. doi:14309/ajg.0000000000001764
6. Taraghikhah N, Ashtari S, Asri N, et al. An updated overview of spectrum of gluten-related disorders: clinical and diagnostic aspects. BMC Gastroenterol. 2020;20(1):258. doi:1186/s12876-020-01390-0
7. Bell KA, Pourang A, Mesinkovska NA, Cardis MA. The effect of gluten on skin and hair: a systematic review. Dermatol Online J. 2021;27(4):13030/qt2qz916r0. doi:5070/D3274053148
8. Edwards George JB, Aideyan B, Yates K, et al. Gluten-induced neurocognitive impairment: results of a nationwide study. J Clin Gastroenterol. 2022;56(7):584-591. doi:1097/MCG.0000000000001561
9. 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
10.  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
11.  Cardoso-Silva D, Delbue D, Itzlinger A, et al. Intestinal barrier function in gluten-related disorders. Nutrients. 2019;11(10):E2325. doi:3390/nu11102325
12.  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
13.  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
14.  Transeth EL, Dale HF, Lied GA. Comparison of gut microbiota profile in celiac disease, non-celiac gluten sensitivity and irritable bowel syndrome: a systematic review. Turk J Gastroenterol. 2020;31(11):735-745. doi:5152/tjg.2020.19551
15.  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
16.  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
17.  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:10.3389/fped.2019.00414