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Gluten and The Brain

By Casey Thaler, B.A., NASM-CPT, FNS
June 16, 2014
Gluten and The Brain image

With the plethora of benefits supported by scientific evidence,1 Gluten-free diets have been gaining in popularity in recent years.2 Studies range from gastrointestinal symptom improvement,3 to possible correlations with autism,4 and diabetes.5 However, there may not be a more fascinating area of gluten study than how the protein composite can be related to cognitive function.6 One study shows large changes in brain tissue, specifically, white matter, in those who are sensitive to gluten.7

Gluten and The Brain image

Why is this an important discovery? White matter is actively involved in neurogenesis, or "the growth of new neurons."8, 9, 10 If gluten is possibly disrupting this process, like chemotherapy has been studied to do,11 then its effects may not be just temporary and transient. Instead they may be both long lasting and potentially damaging.12

Stress, sleep disruption, exercise and inflammation have all been linked with regulating hippocampal neurogenesis and implicated in the pathophysiology of mood disorders.13 But can gluten be linked to mood disorders? The science says yes.14

Many reports evidence unexpected resolution of long-term schizophrenic symptoms, when eliminating gluten from the diet.15 Interestingly, one study of Pacific Islanders who consumed almost no grains (or dairy) showed that only 2 in 65,000 subjects presented with overtly psychotic cases of schizophrenia.16, 17 However, since there are oftentimes confounding variables in these studies, it is not yet mechanistically clear on what may be causing remission of symptoms.18

In regards to cognitive function, as far back as 2004, scientists have shown improvements in the frontal region of the brain, in subjects consuming a gluten-free diet.19 Other research shows gluten’s effects are clearly not limited to gastrointestinal issues alone.20

Gluten and The Brain image
Proposed algorithm for the differential diagnosis of gluten-related disorders, including celiac disease, gluten sensitivity and wheat allergy.
Proposed algorithm for the differential diagnosis of gluten-related disorders, including celiac disease, gluten sensitivity and wheat allergy.

To whom does this apply21 and how exactly does gluten cause cognitive impairment? Definitively, we can seem to say that removing gluten from the diet improves cognitive functioning in many individuals.22, 23 Gluten elicits an adaptive Th1-mediated immune response in individuals carrying HLA-DQ2 or HLA-DQ8 genes.24

The "foggy brain" symptoms, as reported by non-celiac disease subjects, are intriguing. In these subjects, we see an up-regulation of claudin-4, which is associated with an increased expression of toll-like receptor-2 and a significant reduction of the T-regulatory cell marker FoxP3.25 This is part of why an innate immune system response seems to be involved in these subjects, rather than an adaptive immune system response.

Gluten sensitivity as a neurological illness
Gluten sensitivity as a neurological illness

However, individuals diagnosed with celiac disease, α-amylase/trypsin inhibitors (ATIs) are strong activators of innate immune system responses in macrophages, monocytes and dendritic cells, via toll-like receptor-4.26 Despite these details, however, we cannot yet definitively say that gluten causes cognitive impairment,27, 28 no matter how likely it may seem in the scientific literature.

Brain MRI of a patient with gluten ataxia showing rapid onset of cerebellar atrophy over a period of 15 months before the diagnosis of gluten ataxia.
Brain MRI of a patient with gluten ataxia showing rapid onset of cerebellar atrophy over a period of 15 months before the diagnosis of gluten ataxia.

The distinction is very important. A much-publicized study29 from early 2014 suggested it might not be gluten itself that causes issues, but instead it may agglutinins, FODMAPs, prodynorphins, deamidated gliadin and/or gliadorphins.

These findings illustrate more studies need to be done in order to show, mechanistically, what is causing physiologic disruptions, changes in white matter. Furthermore, research may determine distinct populations that should avoid gluten, if indeed the protein composite is causing these issues.

"Early diagnosis and removal of the trigger factor, by the introduction of a gluten-free diet, is a promising therapeutic intervention," said researchers in a study published in the Journal of Neurology.30 A promising intervention – that needs much more research.31

I do not dismiss anecdotal improvements seen in individuals adopting gluten-free diets, such as the Paleo Diet. And with that said, we need instead maintain scientific rigor and provide the best, most accurate, recommendations possible.

The negative effects of gluten and other gluten-like compounds have been well-documented for many years.32, 33, 34, 35 Just because a specific mechanism for neurologic dysfunction hasn’t yet been identified - doesn’t mean gluten is doing anyone any favors.36, 37

We must also remember that although the human genome has remained primarily unchanged since the agricultural revolution 10,000 years ago, our diet and lifestyle have become progressively more divergent from those of our ancient ancestors.38, 39 A Paleo Diet still provides the best defense against neurologic impairment, as well as providing favorable changes in risk factors, such as weight, waist circumference, C-reactive protein, glycated haemoglobin (HbAlc), blood pressure, glucose tolerance, insulin secretion, insulin sensitivity and lipid profiles.40


1. Soares FL, De oliveira matoso R, Teixeira LG, et al. Gluten-free diet reduces adiposity, inflammation and insulin resistance associated with the induction of PPAR-alpha and PPAR-gamma expression. J Nutr Biochem. 2013;24(6):1105-11.

2. Available at: // Accessed August 3, 2014.

3. Murray JA, Watson T, Clearman B, Mitros F. Effect of a gluten-free diet on gastrointestinal symptoms in celiac disease. Am J Clin Nutr. 2004;79(4):669-73.

4. Buie T. The relationship of autism and gluten. Clin Ther. 2013;35(5):578-83.

5. Sildorf SM, Fredheim S, Svensson J, Buschard K. Remission without insulin therapy on gluten-free diet in a 6-year old boy with type 1 diabetes mellitus. BMJ Case Rep. 2012;2012

6. Hu WT, Murray JA, Greenaway MC, Parisi JE, Josephs KA. Cognitive impairment and celiac disease. Arch Neurol. 2006;63(10):1440-6.

7. Hadjivassiliou M, Grünewald RA, Lawden M, Davies-jones GA, Powell T, Smith CM. Headache and CNS white matter abnormalities associated with gluten sensitivity. Neurology. 2001;56(3):385-8.

8. Liu XS, Chopp M, Kassis H, et al. Valproic acid increases white matter repair and neurogenesis after stroke. Neuroscience. 2012;220:313-21.

9. Takemura NU. Evidence for neurogenesis within the white matter beneath the temporal neocortex of the adult rat brain. Neuroscience. 2005;134(1):121-32.

10. Gould E, Reeves AJ, Graziano MS, Gross CG. Neurogenesis in the neocortex of adult primates. Science. 1999;286(5439):548-52.

11. Nokia MS, Anderson ML, Shors TJ. Chemotherapy disrupts learning, neurogenesis and theta activity in the adult brain. Eur J Neurosci. 2012;36(11):3521-30.

12. Lichtwark IT, Newnham ED, Robinson SR, et al. Cognitive impairment in coeliac disease improves on a gluten-free diet and correlates with histological and serological indices of disease severity. Aliment Pharmacol Ther. 2014;40(2):160-70.

13. Lucassen PJ, Meerlo P, Naylor AS, et al. Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation: Implications for depression and antidepressant action. Eur Neuropsychopharmacol. 2010;20(1):1-17.

14. Dickerson F, Stallings C, Origoni A, et al. Markers of gluten sensitivity and celiac disease in bipolar disorder. Bipolar Disord. 2011;13(1):52-8.

15. Kraft BD, Westman EC. Schizophrenia, gluten, and low-carbohydrate, ketogenic diets: a case report and review of the literature. Nutr Metab (Lond). 2009;6:10.

16. Dohan FC, Harper EH, Clark MH, Rodrigue RB, Zigas V. Is schizophrenia rare if grain is rare?. Biol Psychiatry. 1984;19(3):385-99.

17. Dohan FC. Genetic hypothesis of idiopathic schizophrenia: its exorphin connection. Schizophr Bull. 1988;14(4):489-94.

18. Di sabatino A, Corazza GR. Nonceliac gluten sensitivity: sense or sensibility?. Ann Intern Med. 2012;156(4):309-11.

19. Usai P, Serra A, Marini B, et al. Frontal cortical perfusion abnormalities related to gluten intake and associated autoimmune disease in adult coeliac disease: 99mTc-ECD brain SPECT study. Dig Liver Dis. 2004;36(8):513-8.

20. Hadjivassiliou M, Grünewald RA, Davies-jones GA. Gluten sensitivity: a many headed hydra. BMJ. 1999;318(7200):1710-1.

21. Troncone R, Jabri B. Coeliac disease and gluten sensitivity. J Intern Med. 2011;269(6):582-90.

22. Genuis SJ, Lobo RA. Gluten sensitivity presenting as a neuropsychiatric disorder. Gastroenterol Res Pract. 2014;2014:293206.

23. Bürk K, Bösch S, Müller CA, et al. Sporadic cerebellar ataxia associated with gluten sensitivity. Brain. 2001;124(Pt 5):1013-9.

24. Junker Y, Zeissig S, Kim SJ, et al. Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4. J Exp Med. 2012;209(13):2395-408.

25. Sapone A, Bai JC, Ciacci C, et al. Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Med. 2012;10:13.

26. Laparra, M., Zevallos, V. and Schuppan, D. (n.d.). Influence of faecal contents from a gluten-free vs. gluten-containing diet on alpha-amylase/trypsin inhibitor-mediated inflammation. Zeitschrift fur Gastroenterologie, 50(08), p.174.

27 Poloni N, Vender S, Bolla E, Bortolaso P, Costantini C, Callegari C. Gluten encephalopathy with psychiatric onset: case report. Clin Pract Epidemiol Ment Health. 2009;5:16.

28 Gluten sensitivity as a neurological illness. Journal of Neurology, Neurosurgery & Psychiatry. 2002;72(5):560.

29. Biesiekierski JR, Peters SL, Newnham ED, Rosella O, Muir JG, Gibson PR. No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates. Gastroenterology. 2013;145(2):320-8.e1-3.

30. Gluten sensitivity as a neurological illness. Journal of Neurology, Neurosurgery & Psychiatry. 2002;72(5):560.

31. Biesiekierski JR, Muir JG, Gibson PR. Is gluten a cause of gastrointestinal symptoms in people without celiac disease?. Curr Allergy Asthma Rep. 2013;13(6):631-8.

32. Norström F, Sandström O, Lindholm L, Ivarsson A. A gluten-free diet effectively reduces symptoms and health care consumption in a Swedish celiac disease population. BMC Gastroenterol. 2012;12:125.

33. Gasbarrini G, Mangiola F. Wheat-related disorders: A broad spectrum of 'evolving' diseases. United European Gastroenterol J. 2014;2(4):254-62.

34. Paoloni M, Tavernese E, Ioppolo F, Fini M, Santilli V. Complete remission of plantar fasciitis with a gluten-free diet: Relationship or just coincidence?. Foot (Edinb). 2014;

35. Cordain L. Cereal grains: humanity's double-edged sword. World Rev Nutr Diet. 1999;84:19-73.

36. Lachance LR, Mckenzie K. Biomarkers of gluten sensitivity in patients with non-affective psychosis: a meta-analysis. Schizophr Res. 2014;152(2-3):521-7.

37. Catassi C, Bai JC, Bonaz B, et al. Non-Celiac Gluten sensitivity: the new frontier of gluten related disorders. Nutrients. 2013;5(10):3839-53.

38. O'keefe JH, Cordain L. Cardiovascular disease resulting from a diet and lifestyle at odds with our Paleolithic genome: how to become a 21st-century hunter-gatherer. Mayo Clin Proc. 2004;79(1):101-8.

39. Cordain L, Eaton SB, Sebastian A, et al. Origins and evolution of the Western diet: health implications for the 21st century. Am J Clin Nutr. 2005;81(2):341-54.

40. Kowalski LM, Bujko J. [Evaluation of biological and clinical potential of paleolithic diet]. Rocz Panstw Zakl Hig. 2012;63(1):9-15.

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