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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
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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