Tag Archives: celiac disease

Wheat: Opening the Barrier to Poor Gut Health | The Paleo Diet

Did you miss The Wheat Series Part 1: Wheat and the Immune System? Read it HERE.

It was a comment I’ve heard too many times. I was watching tennis with a friend who knew me as a cyclist, not as someone who researches nutrition. The commentators were discussing world No. 1 ranked tennis player Novak Djokovic’s newfound success since going on a gluten-free diet. My friend got noticeably irritated and finally blurted “I’m tired of this gluten-free fad! There’s not a scrap of evidence it makes a difference unless you have celiac disease.” As much as I wanted to, I chose not to respond, but thought to myself, “The bottom drawer of my research cabinet is awfully heavy for not having a scrap of anything in it.

This viewpoint that the health benefits of a gluten-free diet are more fad than science is a pervasive one. But what has led so many, including doctors and scientists, to say the research doesn’t exist?

Certainly the science is extensive for celiac disease where the role of gluten is indisputable. Gliadin, a protein in gluten, binds to a molecule in our bodies called tissue transglutaminase. In celiac patients it’s this new, combined molecule that sets off the inappropriate immune response.1, 2, 3

Without gluten, celiac disease couldn’t exist.

Recently other gluten-related disorders like gluten allergies and gluten ataxia have been identified.4, 5  But admittedly, these conditions affect only about 2% – 10% of the population. Outside of these diseases my friend has a point; research showing gluten having a direct pathogenic role, as it does in celiac disease, isn’t there.

But perhaps this is where the disconnect exists.

While a great deal of published research is showing that wheat and gluten can promote a large range of chronic conditions4, 6, 7, 8, gluten’s role is not so direct. Instead, gluten may breakdown the body’s natural defenses, setting up an inflammatory environment. This environment is highly conducive to a variety of chronic diseases in those of us who are unfortunate enough to have the wrong genetics.9, 10 Gluten sets the stage.

Looking at gluten this way, the bottom drawer of my cabinet suddenly gets a lot heavier. I hope to share a few posts on the ways in which wheat can set the stage for unwanted inflammation and disease. Let’s start with a surprising function that came out of celiac research.


One of the most important roles of our gut, beside processing nutrients and hosting a rich microflora, is to provide a barrier blocking the entry of unwanted particles. Fortunately tight junctions (TJ) between the epithelial cells of our intestine carefully regulate entry of all but a few small molecules and essential nutrients.

Over the last 20 years, Dr. Alessio Fasano at the University of Maryland has researched breakdowns in this barrier, ultimately identifying a molecule produced in our guts called zonulin.14 Zonulin has the unique ability to dissolve the occludins, claudins, zonular occluden, and ZO-1 proteins that make up the structural cytoskeletons of our tight junctions.6, 15, 16, 17, 18

Put simply, zonulin can breakdown our barrier and increase intestinal permeability. An effect that’s often referred to around the web as “leaky gut.” It is rapid, reproducible, and fortunately, reversible.16

To date, two powerful triggers for zonulin have been identified.

The first trigger is exposure to bacteria in the intestine. Interestingly, infection by both pathogenic and “healthy” bacteria can have a triggering effect. However, it’s amplified with the “bad guys” as we can see from the chart below on the left.19

Wheat: Opening the Barrier to Poor Gut Health | The Paleo Diet
Wheat: Opening the Barrier to Poor Gut Health | The Paleo Diet
It is believed that zonulin evolved to protect us against bacterial colonization in the gut.6, 17, 19 When there’s an overload of bacteria in an otherwise healthy digestive tract, zonulin opens up the tight junctions allowing fluid to rush into the gut and flush out microorganisms.

The second powerful activator of the zonulin system is gliadin.

Gliadin fragments bind to the CXCR3 receptor on the epithelial cells of the gut. Then through a MyD88 signaling process, these epithelial cells release zonulin and cause an opening of tight junctions.6, 15, 17, 20, 21

It’s a complex process, but all you need to know is that gliadin can do this from inside the gut. It doesn’t have to get into our systems. More importantly, gluten is inappropriately high jacking a powerful defense mechanism designed to handle bacterial contamination.17

In the above right figure, we can see from Dr. Fasano’s research how gliadin’s ability to stimulate zonulin can be as powerful as bacterial triggers.6

Finally, while gliadin’s effect is much stronger in individuals with celiac disease, gliadin does not discriminate, and it happens in all peoples guts.6, 17


With a healthy gut barrier, large molecules are degraded before entering the body and are well tolerated by the immune system.12 Intestinal permeability caused by gluten and bacteria allows these large molecules to get into circulation and act as antigens (activators) for the immune system.15, 17, 22

This becomes a real concern considering gluten is normally consumed with a meal. Its rapid effect on gut permeability happens at the same time that the gut is being hit by a large number of foreign antigens.


Wheat: Opening the Barrier to Poor Gut Health | The Paleo Diet

Dr. Fasano and his group proposed that once these antigens gain entry, they can be misinterpreted by the immune system in genetically susceptible individuals. The result is an inappropriate immune response that ultimately leads to chronic illness.6, 12, 15, 23, 24, 25In a healthy gut, these antigens would never gain access to the immune system.

The image above provides a nice representation of how gluten can open tight junctions and lead to diseases such as celiac disease and type 1 diabetes.6


So, what does this all amount to? Intestinal permeability caused by either bacterial overgrowth or gluten (both of which are heavily influenced by diet) may be a key early step to set the body up for many chronic illness.

But is there any research? Fortunately, this is where I have to start using more drawers in my research cabinet.

Higher zonulin levels and intestinal permeability have been associated with and often precede many autoimmune conditions including type 1 diabetes,16, 30, 3132, 33celiac disease,17, 28, 34 multiple sclerosis,35, 36 rheumatoid arthritis,37, 38ankylosing spondylitis,37, 39 and Crohn’s disease.40, 41Eating wheat has been directly linked to diabetes.31, 42, 43, 44

A popular theory of autoimmune disease – called the molecular mimicry theory – proposed that autoimmune disease is initiated by viruses that mimic our bodies.26, 27 Dr. Fasano and his group suggested instead that dietary antigens passing through a leaky gut may be the environmental trigger. To test their theory, they were able to use a zonulin inhibitor to reduce the severity of celiac disease symptoms in humans 28 and the incidence of type 1 diabetes in mice.29

Intestinal permeability isn’t just associated with autoimmune conditions. Permeability may affect asthmatics by increasing their exposure to allergens.45, 46 Elevated zonulin levels have been found in irritable bowel disease 47, 48 and cancer.4950Even schizophrenia has recently been linked to gluten consumption and zonulin levels.51, 52

But a final question remains.

In a world where most people reach for a bagel and toast as soon as they get out of bed, intestinal permeability may just be a part of western life that gets an unfair rap by association. In other words, is it too easy to just link permeability with chronic disease? Does it really play a role?

In his 2011 review of zonulin and disease, Dr. Fasano addressed this question pointing out a number of studies where symptoms and incidence rates were reduced when gluten was removed from the diet or when zonulin’s effects were blocked.6

Wheat, a no-no for any good Paleo dieter, was clearly opening doors.

Read The Wheat Series Part 3: Setting Off the Bacterial Alarm Bells – With or Without the Bacteria HERE


[1]Dieterich, W., et al., Identification of tissue transglutaminase as the autoantigen of celiac disease. Nature Medicine, 1997. 3(7): p. 797-801.

[2]Molberg, O., et al., Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nature Medicine, 1998. 4(6): p. 713-717.

[3]Plenge, R.M., Unlocking the pathogenesis of celiac disease. Nat Genet, 2010. 42(4): p. 281-2.

[4]Sapone, A., et al., Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Med, 2012. 10: p. 13.

[5]Hadjivassiliou, M., et al., Gluten ataxia in perspective: epidemiology, genetic susceptibility and clinical characteristics. Brain, 2003. 126(Pt 3): p. 685-91.

[6]Fasano, A., Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer. Physiol Rev, 2011. 91(1): p. 151-75.

[7]Biesiekierski, J.R., et al., Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial. Am J Gastroenterol, 2011. 106(3): p. 508-14; quiz 515.

[8]Bernardo, D., et al., Is gliadin really safe for non-coeliac individuals? Production of interleukin 15 in biopsy culture from non-coeliac individuals challenged with gliadin peptides. Gut, 2007. 56(6): p. 889-890.

[9]Palova-Jelinkova, L., et al., Gliadin fragments induce phenotypic and functional maturation of human dendritic cells. J Immunol, 2005. 175(10): p. 7038-45.

[10]De Palma, G., et al., Effects of a gluten-free diet on gut microbiota and immune function in healthy adult human subjects. Br J Nutr, 2009. 102(8): p. 1154-60.

[11]Yu, Q.H. and Q. Yang, Diversity of tight junctions (TJs) between gastrointestinal epithelial cells and their function in maintaining the mucosal barrier. Cell Biol Int, 2009. 33(1): p. 78-82.

[12]Fasano, A., Physiological, Pathological, and Therapeutic Implications of Zonulin-Mediated Intestinal Barrier Modulation Living Life on the Edge of the Wall. American Journal of Pathology, 2008. 173(5): p. 1243-1252.

[13]Shen, L. and J.R. Turner, Role of epithelial cells in initiation and propagation of intestinal inflammation. Eliminating the static: tight junction dynamics exposed. Am J Physiol Gastrointest Liver Physiol, 2006. 290(4): p. G577-82.

[14]Di Pierro, M., et al., Zonula occludens toxin structure-function analysis. Identification of the fragment biologically active on tight junctions and of the zonulin receptor binding domain. J Biol Chem, 2001. 276(22): p. 19160-5.

[15]Sander, G.R., et al., Rapid disruption of intestinal barrier function by gliadin involves altered expression of apical junctional proteins. FEBS Lett, 2005. 579(21): p. 4851-5.

[16]Visser, J., et al., Tight junctions, intestinal permeability, and autoimmunity: celiac disease and type 1 diabetes paradigms. Ann N Y Acad Sci, 2009. 1165: p. 195-205.

[17]Drago, S., et al., Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. Scand J Gastroenterol, 2006. 41(4): p. 408-19.

[18]Fasano, A., et al., Zonula occludens toxin modulates tight junctions through protein kinase C-dependent actin reorganization, in vitro. J Clin Invest, 1995. 96(2): p. 710-20.

[19]El Asmar, R., et al., Host-dependent zonulin secretion causes the impairment of the small intestine barrier function after bacterial exposure. Gastroenterology, 2002. 123(5): p. 1607-15.

[20]Lammers, K.M., et al., Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology, 2008. 135(1): p. 194-204 e3.

[21]Clemente, M.G., et al., Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function. Gut, 2003. 52(2): p. 218-23.

[22]Fasano, A., Intestinal zonulin: open sesame! Gut, 2001. 49(2): p. 159-62.

[23]Cereijido, M., et al., New diseases derived or associated with the tight junction. Arch Med Res, 2007. 38(5): p. 465-78.

[23]Fasano, A., Surprises from celiac disease. Sci Am, 2009. 301(2): p. 54-61.

[24]Mowat, A.M., Anatomical basis of tolerance and immunity to intestinal antigens. Nat Rev Immunol, 2003. 3(4): p. 331-41.

[25]Oldstone, M.B.A., MOLECULAR MIMICRY AND AUTOIMMUNE-DISEASE. Cell, 1987. 50(6): p. 819-820.


[27]Paterson, B.M., et al., The safety, tolerance, pharmacokinetic and pharmacodynamic effects of single doses of AT-1001 in coeliac disease subjects: a proof of concept study. Aliment Pharmacol Ther, 2007. 26(5): p. 757-66.

[28]Watts, T., et al., Role of the intestinal tight junction modulator zonulin in the pathogenesis of type I diabetes in BB diabetic-prone rats. Proc Natl Acad Sci U S A, 2005. 102(8): p. 2916-21.

[29]Bosi, E., et al., Increased intestinal permeability precedes clinical onset of type 1 diabetes. Diabetologia, 2006. 49(12): p. 2824-7.

[30]Mojibian, M., et al., Diabetes-specific HLA-DR-restricted proinflammatory T-cell response to wheat polypeptides in tissue transglutaminase antibody-negative patients with type 1 diabetes. Diabetes, 2009. 58(8): p. 1789-96.

[31]Sapone, A., et al., Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives. Diabetes, 2006. 55(5): p. 1443-1449.

[32]De Magistris, L., et al., Altered mannitol absorption in diabetic children. Ital J Gastroenterol, 1996. 28(6): p. 367.

[33]De Palma, G., et al., Intestinal dysbiosis and reduced immunoglobulin-coated bacteria associated with coeliac disease in children. BMC Microbiol, 2010. 10: p. 63.

[34]Westall, F.C., Abnormal hormonal control of gut hydrolytic enzymes causes autoimmune attack on the CNS by production of immune-mimic and adjuvant molecules: A comprehensive explanation for the induction of multiple sclerosis. Med Hypotheses, 2007. 68(2): p. 364-9.

[35]Yacyshyn, B., et al., Multiple sclerosis patients have peripheral blood CD45RO+ B cells and increased intestinal permeability. Dig Dis Sci, 1996. 41(12): p. 2493-8.

[36]Smith, M.D., R.A. Gibson, and P.M. Brooks, Abnormal bowel permeability in ankylosing spondylitis and rheumatoid arthritis. J Rheumatol, 1985. 12(2): p. 299-305.

[37]Edwards, C.J., Commensal gut bacteria and the etiopathogenesis of rheumatoid arthritis. J Rheumatol, 2008. 35(8): p. 1477-14797.

[38]Liu, J., et al., Identification of disease-associated proteins by proteomic approach in ankylosing spondylitis. Biochem Biophys Res Commun, 2007. 357(2): p. 531-6.

[39]D’Inca, R., et al., Increased intestinal permeability and NOD2 variants in familial and sporadic Crohn’s disease. Aliment Pharmacol Ther, 2006. 23(10): p. 1455-61.

[40]Irvine, E.J. and J.K. Marshall, Increased intestinal permeability precedes the onset of Crohn’s disease in a subject with familial risk. Gastroenterology, 2000. 119(6): p. 1740-4.

[41]Maurano, F., et al., Small intestinal enteropathy in non-obese diabetic mice fed a diet containing wheat. Diabetologia, 2005. 48(5): p. 931-7.

[42]Ziegler, A.G., et al., Early infant feeding and risk of developing type 1 diabetes-associated autoantibodies. JAMA, 2003. 290(13): p. 1721-8.

[43]Funda, D.P., et al., Gluten-free but also gluten-enriched (gluten+) diet prevent diabetes in NOD mice; the gluten enigma in type 1 diabetes. Diabetes-Metabolism Research and Reviews, 2008. 24(1): p. 59-63.

[44]Knutson, T.W., et al., Effects of luminal antigen on intestinal albumin and hyaluronan permeability and ion transport in atopic patients. J Allergy Clin Immunol, 1996. 97(6): p. 1225-32.

[45]Hijazi, Z., et al., Intestinal permeability is increased in bronchial asthma. Arch Dis Child, 2004. 89(3): p. 227-9.

[46]Arrieta, M.C., et al., Reducing small intestinal permeability attenuates colitis in the IL10 gene-deficient mouse. Gut, 2009. 58(1): p. 41-8.

[47]Weber, C.R. and J.R. Turner, Inflammatory bowel disease: is it really just another break in the wall? Gut, 2007. 56(1): p. 6-8.

[48]Lai, C.H., et al., Proteomics-based identification of haptoglobin as a novel plasma biomarker in oral squamous cell carcinoma. Clin Chim Acta, 2010. 411(13-14): p. 984-91.

[50]Dowling, P., et al., 2-D difference gel electrophoresis of the lung squamous cell carcinoma versus normal sera demonstrates consistent alterations in the levels of ten specific proteins. Electrophoresis, 2007. 28(23): p. 4302-10.

[51]Wan, C., et al., Abnormal changes of plasma acute phase proteins in schizophrenia and the relation between schizophrenia and haptoglobin (Hp) gene. Amino Acids, 2007. 32(1): p. 101-8.

[52]Kalaydjian, A.E., et al., The gluten connection: the association between schizophrenia and celiac disease. Acta Psychiatr Scand, 2006. 113(2): p. 82-90.

Celiac Disease, Gluten, and Children

Researchers posit introducing gluten at specific points of time during infancy development might be the key to celiac disease prevention. A few recent studies tested the hypothesis on an infant population who were genetically at risk for developing the disease.1

Celiac Disease - Diagram 1

Di Sabatino A, Corazza GR. Coeliac disease. Lancet. 2009;373:1480–1493.

For those unfamiliar, celiac disease is (very simply) defined as an autoimmune disorder, which is caused by a reaction to gliadin.2 Gliadin is a prolamine protein, which is found in wheat.3 Those with celiac disease are usually also sensitive to other proteins, which are chemically similar in structure.4, 5

Celiac Disease - Diagram 2

World J Gastroenterol. Nov 14, 2012; 18(42): 6036–6059.

Surprisingly, the researchers’ hypothesis was disproved.6 The studies exhibited that children developed the disease equally, regardless of the time frame of gluten introduction. Perhaps most surprisingly, breastfeeding didn’t seem to provide any protective benefits either, which is seemingly contradictory to earlier scientific findings.7

Celiac Disease - Diagram 3

BMC Pediatr. 2011; 11: 46.

Children with chronic illnesses are known to be more predisposed to emotional and behavioral problems.8 The above chart (MASC Tscore Mean) shows the increased rate of emotional and behavioral problems in children with celiac disease.9 Since the topic of gluten, celiac disease and children is a somewhat sensitive one, it is important for us to look at the likely cause of the disease.10 Causative, not correlative, mechanisms and reasons are, at the end of the day, what’s really important about scientific findings.11 What we seem to have learned from these very well conducted studies, is that celiac disease may be caused almost entirely by genetics.12

Celiac Disease Table 1

World J Gastroenterol. 2012 November 14; 18(42): 6036–6059.

Almost all people with celiac disease have one of 2 genes, DQ2 or DQ8.13 The above table shows the worldwide frequency and distribution of the genes.14 However, interestingly, about 33% of the population also has one of these genes – but they never develop the disease.15 This leads researchers to think that perhaps there are lifestyle and/or epigenetic factors at play, as well.16

Celiac Disease Diagram 3

J Clin Invest. 2011;121(6):2126-2132. doi:10.1172/JCI58109.

Genetic and diet-induced obesity are associated with alterations of (i) the composition and (ii) the functional properties of the gut microbiota. (A) Leptin-deficient ob/ob mice rapidly gain weight. Development of obesity correlates with a shift in the abundance of the 2 dominating divisions, the Bacteroidetes and the Firmicutes. Compared to lean ob/+ or +/+ littermates, obesity was associated with a 50% reduction in Bacteroidetes and a proportional division-wide increase in Firmicutes. Moreover, ob/ob mice showed an increase in environmental gene tags that matched Archaea, methanogenic microorganisms that might promote bacterial fermentation by removing one of its end products, namely hydrogen (H2). The metagenomic analysis of the obese gut microbiome revealed an increase in glycoside hydrolases, capable of breaking down otherwise indigestible alimentary polysaccharides. Furthermore, the obese microbiome showed enrichment for transport proteins and fermentation enzymes further processing breakdown products. As a consequence, ob/ob mice have an increased capacity to harvest energy from their diet. (B) The interrelationship between diet, intestinal microbial ecology, and energy homeostasis was investigated in a mouse model of diet-induced obesity.28 The microbiota of mice fed a high-fat/high-sugar prototypic Western diet was compared with the microbiota of mice receiving a low-fat/high-polysaccharide diet. Again, as in the ob/ob model, the Western diet was associated with an increased body weight, a lower relative abundance of Bacteroidetes, and a higher relative abundance of Firmicutes. However, unlike in the ob/ob model this shift was not division-wide. The overall diversity of the Western diet-associated gut microbiota dropped dramatically. The reason was a bloom in a single class of the Firmicutes—the Mollicutes. The Western diet gut microbiome was enriched for genes involved in import and fermentation of simple sugars and host glycans, enriched for genes for beta-fructosidases, and depleted for genes involved in motility. Gastroenterology Volume 136, Issue 5, Pages 1476–1483, May 2009 .

Tilg, Herbert et al. Gastroenterology. Volume 136 , Issue 5 , 1476 – 1483

One hypothesis is that changes may occur, in gut bacteria, before the disease develops.17 This means that things such as antibiotics, refined sugar, artificial colors, gluten and other artificial food elements may be causing detrimental changes in the microbiome.18 This would also mean that intervening with a probiotic might be one possible “fix.”19, 20 Above, we can see how changes in microbiota, sometimes brought upon by diet, affect many changes and processes in the body.21, 22

Prevalence of celiac disease worldwide. N/A: Not available.   World J Gastroenterol. Nov 14, 2012; 18(42): 6036–6059.

World J Gastroenterol. Nov 14, 2012; 18(42): 6036–6059.

Hypothetically, it would make sense that the recent rise in celiac disease could be due to our massive shift in diet.23 We have changed our diet, almost totally and completely, since the 1970s.24, 25 Obviously, our genome has not really had much time to adapt to these changes.26

Another interesting factor that has also changed since the 1970s is that children are exposed to fewer germs – and parents are much more vigilant about cleanliness.27 This theory of disease is nicknamed the “hygiene hypothesis.”28 With decreased exposure to harmful environmental elements, which our body then learns to defend itself against, children’s immune systems may be turning inward – attacking the body’s own tissue, instead.29, 30

Though the cause of celiac disease may be genetic, the only cure, as has long been known, is a gluten-free diet.31 On the diet, the small intestinal mucosal injury heals and gluten-induced symptoms and signs disappear.32 If you have children, the best course of action is a screening, to see if they may be at risk for celiac disease.33 This goes doubly if any family members have the disease, as the genetic risk factor makes the likelihood increase.34

However, regardless of your children’s potential risk for developing celiac disease, it is not a good idea to be eat gluten.35, 36 There are many downsides to gluten, and it has many negative effects on the body and mind.37, 38, 39, 40 In fact, one study showed that removing gluten from the diet reduced adiposity, inflammation and insulin resistance.41

Other studies have shown that in some individuals, gluten sensitivity was shown to manifest solely with neurological dysfunction, though this point is somewhat debatable.42, 43, 44 What is interesting, however we previously detailed, is that schizophrenics among others with mental disorders, seem to respond positively to the removal of gluten from the diet.45

As should be obvious by now, you can see the benefits in removing gluten and gluten-like compounds from your children’s diet. Therefore, a Paleo Diet, which is rich in nutrients and avoids problematic proteins like gluten, is the best course of action to take – for both children and adults. You will likely see a decrease in your blood pressure, improve your glucose tolerance and your lipid profile.46 These are all healthy, positive changes – whether you’re young or old.


1. Lionetti E, Castellaneta S, Francavilla R, et al. Introduction of gluten, HLA status, and the risk of celiac disease in children. N Engl J Med. 2014;371(14):1295-303.

2. Rubio-tapia A, Murray JA. Celiac disease. Curr Opin Gastroenterol. 2010;26(2):116-22.

3. Thompson T. Wheat starch, gliadin, and the gluten-free diet. J Am Diet Assoc. 2001;101(12):1456-9.

4. Troncone R, Auricchio S, De vincenzi M, Donatiello A, Farris E, Silano V. An analysis of cereals that react with serum antibodies in patients with coeliac disease. J Pediatr Gastroenterol Nutr. 1987;6(3):346-50.

5. Hollén E, Högberg L, Stenhammar L, Fälth-magnusson K, Magnusson KE. Antibodies to oat prolamines (avenins) in children with coeliac disease. Scand J Gastroenterol. 2003;38(7):742-6.

6. Available at: //www.bostonglobe.com/lifestyle/health-wellness/2014/10/05/studies-find-tactics-prevent-celiac-disease-newborns-don-work/zsbjwMAjdYOPFzRsDhriuO/story.html. Accessed October 12, 2014.

7. Norris JM, Barriga K, Hoffenberg EJ, et al. Risk of celiac disease autoimmunity and timing of gluten introduction in the diet of infants at increased risk of disease. JAMA. 2005;293(19):2343-51.

8. Hysing M, Elgen I, Gillberg C, Lundervold AJ. Emotional and behavioural problems in subgroups of children with chronic illness: results from a large-scale population study. Child Care Health Dev. 2009;35(4):527-33.

9. Mazzone L, Reale L, Spina M, et al. Compliant gluten-free children with celiac disease: an evaluation of psychological distress. BMC Pediatr. 2011;11:46.

10. Niewinski MM. Advances in celiac disease and gluten-free diet. J Am Diet Assoc. 2008;108(4):661-72.

11. Verhulst B, Eaves LJ, Hatemi PK. Correlation not causation: the relationship between personality traits and political ideologies. Am J Pol Sci. 2012;56(1):34-51.

12. Monsuur AJ, Wijmenga C. Understanding the molecular basis of celiac disease: what genetic studies reveal. Ann Med. 2006;38(8):578-91.

13. Castro-antunes MM, Crovella S, Brandão LA, Guimaraes RL, Motta ME, Silva GA. Frequency distribution of HLA DQ2 and DQ8 in celiac patients and first-degree relatives in Recife, northeastern Brazil. Clinics (Sao Paulo). 2011;66(2):227-31.

14. Gujral N, Freeman HJ, Thomson AB. Celiac disease: prevalence, diagnosis, pathogenesis and treatment. World J Gastroenterol. 2012;18(42):6036-59.

15. Szałowska-woźniak DA, Bąk-romaniszyn L, Cywińska-bernas A, Zeman K. Evaluation of HLA-DQ2/DQ8 genotype in patients with celiac disease hospitalised in 2012 at the Department of Paediatrics. Prz Gastroenterol. 2014;9(1):32-7.

16. Alegría-torres JA, Baccarelli A, Bollati V. Epigenetics and lifestyle. Epigenomics. 2011;3(3):267-77.

17. Nistal E, Caminero A, Herrán AR, et al. Differences of small intestinal bacteria populations in adults and children with/without celiac disease: effect of age, gluten diet, and disease. Inflamm Bowel Dis. 2012;18(4):649-56.

18. Kau AL, Ahern PP, Griffin NW, Goodman AL, Gordon JI. Human nutrition, the gut microbiome and the immune system. Nature. 2011;474(7351):327-36.

19. Tillisch K, Labus J, Kilpatrick L, et al. Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology. 2013;144(7):1394-401, 1401.e1-4.

20. Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. 2012;13(10):701-12.

21. Tilg H, Moschen AR, Kaser A. Obesity and the microbiota. Gastroenterology. 2009;136(5):1476-83.

22. Tilg H, Kaser A. Gut microbiome, obesity, and metabolic dysfunction. J Clin Invest. 2011;121(6):2126-32.

23. Brown K, Decoffe D, Molcan E, Gibson DL. Diet-induced dysbiosis of the intestinal microbiota and the effects on immunity and disease. Nutrients. 2012;4(8):1095-119.

24. Hurt RT, Kulisek C, Buchanan LA, Mcclave SA. The obesity epidemic: challenges, health initiatives, and implications for gastroenterologists. Gastroenterol Hepatol (N Y). 2010;6(12):780-92.

25. 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.

26. Tännsjö T. Should we change the human genome?. Theor Med. 1993;14(3):231-47.

27. Okada H, Kuhn C, Feillet H, Bach JF. The ‘hygiene hypothesis’ for autoimmune and allergic diseases: an update. Clin Exp Immunol. 2010;160(1):1-9.

28. Rook GA. Review series on helminths, immune modulation and the hygiene hypothesis: the broader implications of the hygiene hypothesis. Immunology. 2009;126(1):3-11.

29. Bloomfield SF, Stanwell-smith R, Crevel RW, Pickup J. Too clean, or not too clean: the hygiene hypothesis and home hygiene. Clin Exp Allergy. 2006;36(4):402-25.

30. Romagnani S. The increased prevalence of allergy and the hygiene hypothesis: missing immune deviation, reduced immune suppression, or both?. Immunology. 2004;112(3):352-63.

31. See J, Murray JA. Gluten-free diet: the medical and nutrition management of celiac disease. Nutr Clin Pract. 2006;21(1):1-15.

32. Mäki M. Celiac disease treatment: gluten-free diet and beyond. J Pediatr Gastroenterol Nutr. 2014;59 Suppl 1:S15-7.

33. Aggarwal S, Lebwohl B, Green PH. Screening for celiac disease in average-risk and high-risk populations. Therap Adv Gastroenterol. 2012;5(1):37-47.

34. Rubio-tapia A, Van dyke CT, Lahr BD, et al. Predictors of family risk for celiac disease: a population-based study. Clin Gastroenterol Hepatol. 2008;6(9):983-7.

35. Biesiekierski JR, Newnham ED, Irving PM, et al. Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial. Am J Gastroenterol. 2011;106(3):508-14.

36. Marziali M, Venza M, Lazzaro S, Lazzaro A, Micossi C, Stolfi VM. Gluten-free diet: a new strategy for management of painful endometriosis related symptoms?. Minerva Chir. 2012;67(6):499-504.

37. Drago S, El asmar R, Di pierro M, et al. Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. Scand J Gastroenterol. 2006;41(4):408-19.

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

39. Hadjivassiliou M, Grünewald RA, Kandler RH, et al. Neuropathy associated with gluten sensitivity. J Neurol Neurosurg Psychiatr. 2006;77(11):1262-6.

40. 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.

41. 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.

42. Hadjivassiliou M, Sanders DS, Grünewald RA, Woodroofe N, Boscolo S, Aeschlimann D. Gluten sensitivity: from gut to brain. Lancet Neurol. 2010;9(3):318-30.

43. Nijeboer P, Mulder C, Bouma G. [Non-coeliac gluten sensitivity: hype, or new epidemic?]. Ned Tijdschr Geneeskd. 2013;157(21):A6168.

44. 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.

45. Kraft BD, Westman EC. Schizophrenia, gluten, and low-carbohydrate, ketogenic diets: a case report and review of the literature. Nutr Metab (Lond). 2009;6(1):10.

46. Frassetto LA, Schloetter M, Mietus-synder M, Morris RC, Sebastian A. Metabolic and physiologic improvements from consuming a paleolithic, hunter-gatherer type diet. Eur J Clin Nutr. 2009;63(8):947-55.

Gluten & the Brain | The Paleo Diet

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 MRI

Gluten and White Matter in the Brain

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

Mapping of α-gliadin motifs


Gluten-Related Algorithm

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

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: 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: //www.cbsnews.com/news/gluten-free-diet-more-popular-than-ever-but-who-really-needs-it/. 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.

Celiac Disease | The Paleo Diet

Hi Loren,
I recently started the paleo diet for a few reasons:  health, weight loss, and an answer as to whether or not I have celiac disease.

Question:   Is it okay to take vitamins and supplements, especially if they contain gluten, some form of sugar, etc?  I realize that my sleeping habits may improve, but right now I am taking easy to dissolve melatonin and ZMA to help me sleep.  I have had leg cramps for 51 years and have found that C Q-10 has given me relief.

Thanks for your book and suggestions.



Dr. Cordain’s Response:

Hi Emily,
Good to hear from you and thanks for your interest in The Paleo Diet.  Indeed, this lifetime way of eating will improve your overall health and help to promote weight loss.  Elimination of glutien containing grains (wheat, rye, and barley) will cause an end to symptoms you may have experienced relating to celiac disease.  Further a  dairy free, grain free, legume free and processed food free diet will also improve overall GI tract function, and you may also experience freedom from a variety of health issues that formerly may have afflicted you.  Definitely, read all labels in supplements and try to avoid any supplements containing wheat, soy, corn, yeast or any other grain, legume or food additive.

In regards to sleep, melatonin supplements may be helpful at first, but again make sure they are free of wheat, soy and other additives that are non-Paleo.  A long term strategy to improve sleep will not require melatinin supplements, as you body will naturally manufacture sufficient melatonin to elicit peaceful, long and uninterrupted sleep. Key dietary factors to promote restful sleep are theses: 1) eliminate/reduce salt from your diet in all forms 2) eliminate/reduce alcohol from your diet– particularly 3 hrs before you sleep, 3) eliminate milk/dairy/cheese from your diet, and 4) eliminate proceessed foods (refined grains, refined sugars, refined oils or combinations of these foods from your diet.  Finally, hard exercise (aerobic, weight lifting or otherwise) a few hours before you retire will defnitely promote peaceful sleep.


Loren Cordain, Ph.D., Professor Emeritus

Affiliates and Credentials