Gluten Revealed

Today’s Objectives

• Gluten Overview

• Health Impact

• Biochemical/Physiological Mechanisms

• Associated Neurological Conditions

What is Gluten?

• Gluten means “Glue”

Toxic Gluten Proteins

• Gliadin (soluble) and Glutenin (insoluble)

• Gives bread the elasticity to rise

Sapone A et al. Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Medicine. 20012; 10:13.

Physiological Response to Gluten

Sapone et al. Spectrum of gluten mrelated disorders:consesnus of new nomenclature and classification. BMC Medicine. 2012; 10:13.

• Celiac Disease – T-cell mediated reaction. Autoimmune disorder. Antibodies are produced. Intestinal lining damage.

• Wheat Allergy – T-cell mediated reaction. (IgE) Triggers chemical mediators (Such as histamine.) Instestinal Lining damage.

• Gluten Sensitivity – Not autoimmune or allergy related. No intestinal damage, yet patient develop adverse reactions.

Sapone et al. Spectrum of gluten related disorders:consesus of new nomenclature and classification. BMC Medicine. 2012; 10:13.

Clinical Presentation Varies

• Gastrointestinal distress, chronic diarrhea, weight loss

• Ashma related issues (Induced by exercise)

• Rhinitis –inflammation of nose membranes

• Dermatitis Herpetiformis – blistering rash

• And, many other symptoms

Sapone et al. Spectrum of gluten mrelated disorders:consesnus of new nomenclature and classification. BMC Medicine. 2012; 10:13.

The Central Idea

Increased Gut Permeability

Increased Passage of Antigens(Food, Bacteria, or Viruses)

Faulty Immune Response

(Inflammation)

Autoimmune Dysfunction

Inflammation

Sapone et al. Spectrum of gluten related disorders:consensus of new nomenclature and classification. BMC Medicine. 2012; 10:13.

A Few Associated Heath Conditions

• Celiac Disease

• Multiple Schlerosis

• Type 1 Diabetes

• Psoriasis

• Immunoglobulin (Ig)A nephropathy

• Rhematoid Arthritis

• Neurological Conditions (Depression and Schizophrenia)

Carrera-Bastos P et al. The western diet and lifestyle and diseases of civilization. Res Rep Clin Cardiol. 2011;2:15-35

Diagnostic Criteria for Celiac Disease

1) Typical Gastrointestinal Symptoms of Celiac Disease

2) Positive for IgA class autoantibodies

3) HLA-DQ2 and/or HLA DQ8 genotypes

4) Celiac enteropathy found on small bowel biopsy

5) Response to a Gluten Free Diet

Sapone et al. Spectrum of gluten related disorders:consesus of new nomenclature and classification. BMC Medicine. 2012; 10:13.

Conclusion: The data provide evidence that dietary modification may be of clinical benefit for certain RA patients, and that this benefit may be related to a reduction in immunoreactivity to food antigens eliminated by change in diet.

Hafstrom I et al. A vegan diet free of gluten improved signs and symptoms of arthritis correlate with a reduction in antibodies to food antigens. Rheumatology. 2001; 40:1175-1179

Gluten Biochemistry

• cvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvv

The most toxic fragment of gliadin the 33-mer peptide is from a2-gliadin.

Shun-Zi J et al. A study of circulating gliadin antibodies in schizophrenia among a Chinese population. Schizophr Bull. 2012; 38(3): 514-518.

Gliadin Protein Increases Gut Permeability By Zonulin Production

• Gluten increases production of Zonulins

• Zonulins directly affect tight junction (paracellular) intestinal permeability

• Increase in zolulins increases overall permeability

Vanuytsel T et al. The role of Haptoglobin and its related protein, Zonulin, in inflammatory bowel disease. Tissue Barriers. 2013; 1(5)

Lipopolysacchardies (LPS)

Lipid + Polysaccharide

Found in Gram-Negative Bacteria

Creates A Strong Immune Response

Maes M et al. The gut-brain barrier in major depression:intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Neuroendocrinol Lett2008; 29(1):117–12

LPS Mechanism of Inflammation

Genes

Maes M et al. The gut-brain barrier in major depression:intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Neuroendocrinol Lett2008; 29(1):117–12

Intestinal Barrier Dysfunction

LPS Endotoxin

Inflammatory EnzymesProinflammatory CytokinesCell Adhesion MoleculesAntiapoptotic proteinsNitric Oxide SynthaseMatrix-degrading enzymes

Maes M et al. The gut-brain barrier in major depression:intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Neuroendocrinol Lett2008; 29(1):117–12

Gluten and The Brain

The results of the present study provide clear evidence of high

prevalence of cortical perfusion abnormality in adult coeliac

patients, up to 71% displaying brain perfusion defects.

Usai P et al. Frontal cortical perfusion abnormalities related to gluten intake and associated autoimmune disease in adult coeliac disease:99m Tc-ECD brain SPECT study. Digestive and Liver Disease. 2004; 36:513-518

Associated Neurological Conditions

• Anxiety Disorders

• Depressive and Mood Disorders

• Attention Deficit Hyperactivity Disorder

• Autism Spectrum Disorder

• SchizophreniaJackson J et al. Neurological and psychiatric manifestations of celiac disease and gluten sensitivity. Psychiatr Q. 2012; 83: 91-102

We found that the values for serum IgM and IgA

agaisnt LPS of enterobacteria to be significantly

greater in patients with major depressive disorder

than in normal volunteers.

Maes M et al. The gut-brain barrier in major depression:intestinal mucosal dysfunction with an increased translocation of LPS from gram negatieve enterobacteria (leaky but) plays a role in the inflammatory pathophysiology of depression. Neuroendocrinol Lett2008; 29(1):117–12

Main Idea Behind This Article

• Major depression is accompanied by activation of the inflammatory response system (IRS) and that pro-inflammatory cytokines and lipopolysaccharides (LPS) may induce depressive symptoms.

• This theory is called the “cytokine hypothesis of depression.”

• This study is testing the correlation between antibody production and depressive symptoms.

Maes M et al. The gut-brain barrier in major depression:intestinal mucosal dysfunction with an increased translocation of LPS from gram negatieve enterobacteria (leaky but) plays a role in the inflammatory pathophysiology of depression. Neuroendocrinol Lett2008; 29(1):117–12

Maes M et al. The gut-brain barrier in major depression:intestinal mucosal dysfunction with an increased translocation of LPS from gram negatieve enterobacteria (leaky but) plays a role in the inflammatory pathophysiology of depression. Neuroendocrinol Lett2008; 29(1):117–12

27.1% of patients were positive for IgA antibodies compared with 17.7% of control subjects.

Shun-Zi J et al. A study of circulating gliadin antibodies in schizophrenia among Chinese population. Schizophr Bull. 2012; 38(3): 514–518

473 Patients with Schizophrenia. 478 Control SubjectsPositive for IgA Antibody

Patients with Schizophrenia 27.1 %Control Subjects 17.8 %Difference of 9.3 %

Women Patients with Schizophrenia 27.6 %Women Control Subjects 13.9 %Difference of 13.7 %

Men Patients with Schizophrenia 26.4%Men Control Subjects 19.8 %Difference of 6.6 %

Shun-Zi J et al. A study of circulating gliadin antibodies in schizophrenia among a Chinese population. Schizophr Bull. 2012; 38(3): 514–518

Presentation Questions1. Which gliadin causes the most destructive autoimmune reaction in the human body?

a) Alpha-gliadin

b) Beta-Gliadin

c) Gamma-Gliadin

2. Lipopolysacchardies (LPS) has been directly linked to what neurological disorder?

a) Attention deficit disorder

b) Depression

c) Alzheimer’s

3. Zonulin proteins effect __________ which have a direct impact on intestinal permeability?

a) Cell membranes

b) Endoplasmic reticulum

c) Tight junctions

4. Gluten has been shown to ________ bloodflow to the brain.

a) Increase

b) Decrease

c) Not affect

5. Many health conditions that relate to gluten, often have increased levels of ___________ in the blood.

a) Immunoglobulins

b) Cholesterol

c) Bacteria

References

1. Carrera-Bastos P et al. The western diet and lifestyle and diseases of

civilization. Res Rep Clin Cardiol. 2011;2:15-35

2. Jackson J et al. Neurological and psychiatric manifestations of celiac disease and gluten sensitivity. Psychiatr Q. 2012; 83: 91-102

3. Hafstrom I et al. A vegan diet free of gluten improved signs and symptoms of arthritis correlate with a reduction in antibodies to food antigens. Rheumatology. 2001; 40:1175-1179

4. Maes M et al. The gut-brain barrier in major depression:intestinalmucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Neuroendocrinol Lett 2008; 29(1):117–12

5. Sapone A et al. Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Medicine. 20012; 10:13.

6. Shun-Zi J et al. A study of circulating gliadin antibodies in schizophrenia among Chinese population. Schizophr Bull. 2012; 38(3): 514–518

References Cont.

7. Vanuytsel T et al. The role of Haptoglobin and its related protein, Zonulin, in inflammatory bowel disease. Tissue Barriers. 2013; 1(5)

8. Usai P et al. Frontal cortical perfusion abnormalities related to gluten intake and associated autoimmune disease in adult coeliac disease:99m Tc-ECD brain SPECT study. Digestive and Liver Disease. 2004; 36:513-518