Gluten as an Endocrine Disruptor

General Overview

An endocrine disruptor such as gluten can cause significant interference to normal physiological processes, through invasive adaptation of hormone function. Gluten, a key component in wheat, can also be found in grains, such as barley, rye and oats. Glutenin and gliadin are the main protein building blocks of wheat gluten (7). These molecules are of exogenous origin to our immune system and cause adverse effects in genetically susceptible people. Studies show the significant role gluten contributes to intestinal and extra-intestinal diseases. Effects from gluten can be instant or develop over a period of time depending on the quantity intake or patients sensitivity. Digestion of gluten occurs in the gastrointestinal tract. In coeliac disease (CD) patients, gluten elicits an immune response which leads to inflammation and destruction of villi and crypt cells of the small intestines (3). Evidence of exogenous opioid activity from gluten demonstrates gluten to be a versatile group of proteins with deleterious effects (9).

Prolactin and Gluten

Prolactin is a peptide hormone, which has a distinct relationship with the proteins contained in gluten. Prolactin’s primary roles include: reproduction, calcium metabolism, osmoregulation and maternal behaviour (11). Gluten acts as an endocrine disruptor in this case, by elevating the levels of prolactin in the body, causing significant physiological changes as a result. The primary reason for the increase in prolactin levels is said to be the increase in production of inflammatory cytokines (3). Prolactin plays a profound role in the immune response against gluten in a CD patient’s intestines; regulating through both innate and adaptive immunity. A recent study found an important correlation between the level of prolactin and the number of CD4+ T and B lymphocytes (7).

It has been suggested that removing wheat or gluten from the diet can improve conception chances (13). This is due to the disruption prolactin can cause to important reproductive hormones such as testosterone (sperm abnormalities, decrease in libido). Autoimmune diseases involving hyperprolactinaemia and gluten disruption, such as CD have been found to be more commonly seen in females. Mostly due to hormonal changes around time of sexual maturity and pregnancy.

Hyperprolactinaemia

Several recent studies have demonstrated a strong link between hyperprolactinaemia and CD, in patients consuming gluten in their diet (3,7,11). Normal hyperprolactinemia levels in a population should be between 0.4 – 3% on average (11). The quantity of prolactin produced in the body has shown positive correlation with degree of intestinal damage (7). Therefore hyperprolactinaemia has been mentioned as a possible biomarker for autoimmune activity, which could hugely benefit immune/endocrinology studies in the future. Prolactin is unable to initiate an immune response alone but acts more as a modulator. Its modulatory roles include: interference with B cell tolerance induction, inhibiting apoptosis, enhancing antigen presentation, upregulating cytokine production and increasing antibody production (3).

Immune response: thymus

One way prolactin influences the immune response is through the thymus. Epithelial cells of the thymus are known to have a high expression of prolactin receptors, which allows prolactin to directly influence the immune response (11). This reaction can then in turn induce interleukin-2 receptors on lymphocytes and also, growth factors for lymphocytes (11). Prolactin receptors can also be found on monocytes, macrophages, T and B lymphocytes, natural killer cells and granulocytes (11). Interestingly, hyperprolactinemia is more commonly observed in CD children/adolescents consuming gluten, than adult CD patients, who are also consuming gluten. This may be due to the fact that the thymus undergoes thymic involution with age, which would in turn decrease the expression of prolactin receptor cells.

Gluten as an Exogenous Opioid

Gliadin, can additionally be degraded into a group of opioid-like polypeptides called exorphins. Opioid peptides are both of endogenous and exogenous origin. In the brain, endogenous opioid peptides attach to opioid receptors. This connection helps stimulate motivation, emotion, attachment behavior, response in stress and pain and control of food intake. Exogenous opioids or exorphins can be of food origin and have proven endogenous-opioid like activity (9). Gluten exorphins mask the gastrointestinal effects in patients suffering with CD (9). This phenomenon is termed asymptomatic coeliac disease (ACD) (9). Studies show ACD affects patients suffering from other diseases such as diabetes mellitus type 1, psoriasis,depression, autism,schizophrenia and irritable bowel syndrome (6,9).

Competition for Binding Site

Opioid activity is stimulated upon enzymatic interaction. Dipeptidyl peptidase IV (DPP IV) is a major antigenic enzyme necessary for normal cellular metabolism. DPP IV is involved in the final breakdown reaction of gliadin into small digestible amino acids. These amino acids inhibit the presence of gluten epitopes that are notorious at eliciting a pro-inflammatory immune response in genetically susceptible people. However, gluten is not the only source of exorphins in the diet. Other exorphins include, casein from dairy, vegetable proteins and other carbohydrate polypeptides. In particular, gliadin and casein display elevated substrate specificity for DPP IV compared to endogenous DPP IV substrates such as, substance P and glucagon-like peptide-1 (9).

Outcome of Binding

Studies have shown that increase levels of gliadin in the body causes inactivation of DPP IV (9). Therefore, an increase occurs in non-metabolized gliadin molecules with opioid activity. Inhibition of DPP IV leads to several intestinal and extra-intestinal effects. The neurotransmitter substance P is dependent on DPP IV activity in order to exert its effects. High levels of substance P in the gut not only causes intestinal pain and discomfort, it also induces adverse mood and depression (9). A decreased level of serum DPP IV is an important indicator for diagnosing depression (4). Inhibition of DPP IV leads to high expression of the complement protein C1Q and intense C1Q expression has been detected in patients suffering from alzheimer, autism and schizophrenia (9).

Gluten and Diabetes Mellitus Type 1

The pancreas is an endocrine organ that secretes insulin into the blood stream. Diabetes type 1 (T1DM) is a disease of the pancreas in which normal production of insulin is disrupted. Although T1DM is a multifactorial disease, studies have shown that altering the diet of an individual genetically predisposed to or already suffering from T1DM can influence the development of the disease (1, 2).

Gluten and Gut Permeability

Several studies have explored the theory of how decreasing gluten intake in an individual’s diet can have a diminutive effect on the proliferation of T1DM, especially in those individuals already suffering from gluten sensitivities, intolerances or gluten sensitive chronic enteropathy disease such as CD (5, 8). This is particularly critical in young children, as the onset of T1DM is accelerated in those patients with CD. Autoimmune disease such as CD and T1DM are linked because they share the same HLA pattern (HLA-DQ2/or 8). This makes individuals more likely to develop either disease, or both in conjunction (8).

In CD the gut becomes increasingly permeable, tight junction barriers are often damaged resulting in enteropathy. This was found in both animal and human studies with very consistent time frames. Increased permeability makes it possible for gluten proteins to pass through enterocytes and into the bloodstream. In CD this can result in an immune response following an increase in the pro inflammatory cytokine profile within the intestines (1, 10). This immune response leads to the attack on pancreatic beta cells causing cytokine production with insulin resistance, thus resulting in the onset of T1DM (2). The unbalanced cytokine profile induced by gluten could have a serious impact on the development of T1DM and CD because it is this balance that determines the inflammatory responses within the body (1).

This outlines that not only is gluten a disease initiating factor in CD, but it also has an effect on the diabetogenesis within CD patients (1). T1DM occurs more frequently in CD patients than in the general population (8).

Gluten Free Diet

The figure below compares results of three separate studies on the effect of a Gluten Free Diet (GFD) versus a Standard Gluten Diet (STD) in both mice animal models and a human study on Sicilian children (5, 8, 10)

Removing gluten from the diet has a positive effect on the individuals health, not only because the harmful effects are avoided but also because a GFD actually has a protective function. The GFD can have a profound effect on the bacterial microflora within the gut, promoting the growth of akkermansia (1). Akkermansia has been shown to induce a thicker colonic mucous layer providing a protective function over gut permeability. Early intervention is critical in individuals predisposed to autoimmune diseases. While the gut microflora and the immunity are developing, a STD could have the most negative repercussions in disease development (1).

The method to prevent gluten acting as an endocrine disruptor, is simply to cut gluten out of the diet. Within a six month period of a GFD, it is hypothesized to reduce or even completely alleviate the symptoms once shown before. Symptoms such as lesions in the gut lining of CD patients consuming gluten can normalise after it is excluded from the diet (6,7,9).

References

* 1. Antvorskov, J.C., Fundova, P., Buschard, K. and Funda, D.P., 2013. Dietary gluten alters the balance of pro‐inflammatory and anti‐inflammatory cytokines in T cells of BALB/c mice. Immunology, 138(1), pp.23-33.

* 2. De Kort, S., Keszthelyi, D. and Masclee, A.A.M., 2011. Leaky gut and diabetes mellitus: what is the link?. Obesity Reviews, 12(6), pp.449-458.

* 3. Delvecchio, M., Faienza, M.F., Lonero, A., Rutigliano, V., Francavilla, R. and Cavallo, L., 2014. Prolactin may be increased in newly diagnosed celiac children and adolescents and decreases after 6 months of gluten-free diet.Hormone Research in Paediatrics, 81(5), pp.309-313.

* 4. Deng, J., Lamb, J.R., Mckeown, A.P., Miller, S., Muglia, P., Guest, P.C., Bahn, S., Domenici, E.H. and Rahmoune, H., 2013. Identification of altered dipeptidyl-peptidase activities as potential biomarkers for unipolar depression. Journal of affective disorders, 151(2), pp.667-672.

* 5. Hansen, C.H.F., Krych, Ł., Buschard, K., Metzdorff, S.B., Nellemann, C., Hansen, L.H., Nielsen, D.S., Frøkiær, H., Skov, S. and Hansen, A.K., 2014. A maternal gluten-free diet reduces inflammation and diabetes incidence in the offspring of NOD mice. Diabetes, 63(8), pp.2821-2832.

* 6. Jackson, Jessica, et al. "A gluten-free diet in people with schizophrenia and anti-tissue transglutaminase or anti-gliadin antibodies." Schizophrenia research 140 (2012): pp.262-263.

* 7. Lauret, E. and Rodrigo, L., 2013. Celiac disease and autoimmune-associated conditions. Bio Med research international, 2013:127589. doi: 10.1155/2013/127589.

* 8. Marchese, A., Lovati, E., Biagi, F. and Corazza, G.R., 2013. Coeliac disease and type 1 diabetes mellitus: epidemiology, clinical implications and effects of gluten-free diet. Endocrine, pp.1-2.

* 9. Pruimboom, L. and de Punder, K., 2015. The opioid effects of gluten exorphins: asymptomatic celiac disease. Journal of Health, Population and Nutrition, 33(1), p.1.

* 10. Sapone, A., Lammers, K.M., Casolaro, V., Cammarota, M., Giuliano, M.T., De Rosa, M., Stefanile, R., Mazzarella, G., Tolone, C., Russo, M.I. and Esposito, P., 2011. Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity. BMC medicine, 9(1), p.23.

* 11. Shelly, S., Boaz, M. and Orbach, H., 2012. Prolactin and autoimmunity. Autoimmunity reviews, 11(6), pp.A465-A470.

Websites

* 12. http://highline.huffingtonpost.com/miracleindustry/americas-most-admired-lawbreaker/chapter-7.html

* 13. http://www.greenmedinfo.com/blog/wheat-making-you-wait-babies-gluten-infertility-link