1. MOOD FOOD The Significance of Nutritional Immunogenomics for the Treatment of Mental Disorders Prof. Dr. Chris De Bruijn, EURIMM, Düsseldorf EURIMM European Institute of Molecular Medicine

2. Nutrition influence on gene expression related to immune function Immunology immune balance physiology (e.g. macrophage function, T-cell activity) Genomics genetic predisposition viz. regulation of immune function Nutritional Immunogenomics and Depression EURIMM European Institute of Molecular Medicine

3. Communication within the “Brain / Immune Network System” NEUROPEPTIDES / NEUROHORMONES NEUROTRANSMITTORS CYTOKINES Nutritional Immunogenomics and Depression EURIMM European Institute of Molecular Medicine

4. The Brain / Immune Network Hypothesis of Depression (1)  Hypothalamic-pituitary-adrenal (HPA axis) is activated by both external and internal stressors, leading to hypersecretion of adrenal glucocorticoids (e.g. cortisol);  Prolonged elevation of glucocorticoid levels leads to desensitisation / activation of immune cells (e.g. macrophages, Th1 cells), leading to increased expression of pro-inflammatory mediators, such as cytokines;  Certain cytokines, in turn, are known to be potent activators of the HPA axis; their release can be a consequence of infections, auto-immune phenomena and/or nutritional factors; Nutritional Immunogenomics and Depression EURIMM European Institute of Molecular Medicine

5. The Brain / Immune Network Hypothesis of Depression (2)  Hypersecretion of glucocorticoids and pro-inflammatory cytokines result in malfunctioning of noradrenergic and serotonergic neurotransmission in the brain, which is reflected in the major symptoms of depression  Depression, therefore, is a form of sickness behaviour in which the chronically unbalanced, pro-inflammatory immune function plays a dominant role;  Certain antidepressants reduce the release of pro-inflammatory cytokines from activated immune cells (e.g. macrophages), thereby facilitating the feed-back inhibition of the HPA axis: they can increase the release of cytokine antagonists, such as IL-1-receptor antagonist, and the anti-inflammatory cytokine IL-10 Nutritional Immunogenomics and Depression EURIMM European Institute of Molecular Medicine

6. The Brain / Immune Balance Hypothesis of Depression (3)  The Brain / Immune Balance Hypothesis of Depression extends the biogenic amine hypothesis of depression to take account of the changes in the endocrine and immune systems Nutritional Immunogenomics and Depression EURIMM European Institute of Molecular Medicine

7. Examples –Impaired Macrophage Function (e.g. in bacterial infections) –Hyperactive T-helper 1 cells (e.g. in auto-immune disease) –Hyperactive T-helper 2 cells (e.g. in allergic disease) –Hyperactive T-suppressor cells (e.g. in food intolerance) –Hypo-active natural killer cells (e.g. in malignant disease and depression) Chronic Immune Stimulation = Disturbed Immune Balance Nutritional Immunogenomics and Depression EURIMM European Institute of Molecular Medicine

8. Disturbed Immune Balance is causally related to Psychoneuroimmunological (PNI) Disease  Profiles of pro-inflammatory mediators (cytokines from macrophages; Th1 / Th2 cells ) can be used as an indicator of a disturbed immune balance;  Th1 / Th2 balance is typically disturbed in PNI disease;  Pro-inflammatory cytokines: Interleukin-1 (IL-1), Tumour Necrosis Factor α (TNFα) Nutritional Immunogenomics and Depression EURIMM European Institute of Molecular Medicine

9. I. Anti-oxidants –anti-oxidative vitamins (C, E, A, carotenoids) –plant-derived substances (e.g. bioflavonoids) –amino acids (e.g. N-acetyl-cysteine, taurine) –co-enzymes (e.g. lipoic acid, co-enzyme Q10) –minerals as components of anti-oxidative enzymes (e.g. selenium, zinc) Nutritional Immunogenomics and Depression Immune Balance can be Influenced by Nutrients (1) EURIMM European Institute of Molecular Medicine

10. I. Anti-oxidants (continued)  By increasing the redox potential of immune cells, anti- oxidants inhibit activation of Nuclear Factor kappa Beta (NFκB) system, which promotes expression of pro- inflammatory genes, such as IL1 and TNFα;  Down-regulation of pro-inflammatory phenotype;  Improvement of HPA axis feed-back inhibition and normalisation of biogenic amine function. Immune Balance can be Influenced by Nutrients (2) Nutritional Immunogenomics and Depression EURIMM European Institute of Molecular Medicine

11. II. Omega-6 and Omega-3 Polyunsaturated Fatty Acids (PUFA´s)  Omega-6 PUFA´s (e.g. linoleic acid) are precursors of arachidonic acid, which can be converted into certain Prostaglandins (e.g. PGE2) and Leukotrienes (e.g. LT 4);  The latter compounds stimulate the expression of pro-inflammatory mediators including IL-1, TNFα, cyclo-oxygenase (COX II) and inducible NO Synthase (iNOS);  This stimulation occurs via the NFκB system;  Omega-6 PUFA´s promote pro-inflammatory phenotype Immune Balance can be Influenced by Nutrients (3) Nutritional Immunogenomics and Depression EURIMM European Institute of Molecular Medicine

12. II. Omega-6 and Omega-3 Polyunsaturated Fatty Acids (PUFA´s)  Omega-3 PUFA´s (e.g. EPA and DHA in fish oil) compete with arachidonic acid and inhibit the NFκB-dependent expression of pro- inflammatory mediators (e.g. IL-1, TNFα, COX II, iNOS);  Counteract a pro-inflammatory phenotype, restore feed-back inhibition of HPA axis and normalise biogenic amine function. Nutritional Immunogenomics and Depression Immune Balance can be Influenced by Nutrients (4) EURIMM European Institute of Molecular Medicine

13.  Combining anti-oxidant and omega-3 strategies to improve the disturbed immune balance and HPA axis feed-back inhibition in depressed patients will lead to an evidence-based extension of the therapeutic and preventive repertoire for the treatment of depression and probably of PNI disorders in general. However, in this respect it should be realised that there are considerable individual genetic differences as far as the capacity of the anti- oxidative system is concerned. Therefore, predictive genomic testing with respect to genetic polymorphisms involved in the “brain / immune network” is indicated. Nutritional Immunogenomics and Depression Immune Balance can be Influenced by Nutrients (5) EURIMM European Institute of Molecular Medicine

14. Predictive Genomic Testing (1) Overview  All human diseases are caused by the interaction between genetic predisposition and modifiable environmental factors;  Slight variations in genetic make-up, called single nucleotide polymorphisms (SNP´s), are associated with almost all diseases;  SNP´s do generally not cause disease by themselves; rather, they influence the individual susceptibility to specific environmental factors that increase disease risk;  Predictive genomic testing provides a clinical foundation for designing comprehensive, personalised prevention and treatment plans to optimise health and reduce disease risk in patients. Nutritional Immunogenomics and Depression EURIMM European Institute of Molecular Medicine

15. Prerequisites for including specific SNP´s Relevance:the SNP exerts direct influence over specific biochemical imbalances that create known symptom clusters or diseases; Prevalence:the SNP is relatively common among the general population; Modifiable:the expression of the SNP is modifiable by environmental factors, such as nutrition, diet, toxic exposure and lifestyle; Measurable:the impact of clinical interventions to modify the expression of the SNP can be monitored by using specialised functional assessments, such as immune balance testing. Nutritional Immunogenomics and Depression Predictive Genomic Testing (2) EURIMM European Institute of Molecular Medicine

16. –Proactive Risk Assessment to provide earlier, more precise and more personalised preventive interaction; –Family History to identify inherited risks within families that can be modified by environment; –Personalised Nutritional- and Pharmacotherapy allows the development of more effective treatment options based on genetic individuality Nutritional Immunogenomics and Depression Predictive Genomic Testing (3) Clinical Applications Predictive genomic testing offers expanded clinical insight that can provide improved healthcare for all patients, especially for: EURIMM European Institute of Molecular Medicine

17. “Nutritional Immunogenomics Panel” 1) CYP1A1: detoxifies oxidative polycyclic aromatic hydrocarbons (PAH´s), present in nutrition and environment (e.g. combusted organic materials including cigarette smoke, charbroiled foods etc.; 2) CYP2A6: is responsible for detoxifying nicotine, nitrosamines (from smoked meats, vegetables containing nitrates), aflatoxin B1 (mold product found in peanuts) and numerous pharmaceutical drugs; 3) CYP2C19: detoxifies H2 blockers and many anticonvulsants; 4) CYP2D6: detoxifies antidepressants (SSRI´s, tricyclics), antipsychotics, β-blockers; Nutritional Immunogenomics and Depression Predictive Genomic Testing (4) EURIMM European Institute of Molecular Medicine

18. 5) COMT:linked to increased risk for depression; bipolar disorder, ADHD and alcoholism; 6) GSTM1 and GSTP1: protect against oxidative stress; catalyse the conjugation of oxidants with glutathione and regenerate vitamins C and E; defects in GST activity can contribute to chronic fatigue; 7) SOD2:anti-oxidant enzyme present within the mitochondria and responsible for detoxification of reactive oxygen superoxide; lowered activity may impair anti-oxidant capacity and increase oxidative stress; Nutritional Immunogenomics and Depression Predictive Genomic Testing (5) EURIMM European Institute of Molecular Medicine

19. (under development) 8)Interleukin-1-receptor antagonist: polymorphism can lead to increased stimulation of pro-inflammatory agents (e.g. COX- II, prostaglandins); 9)TNFα:polymorphisms affect cell mediated immunity, increasing production of this pro-inflammatory cytokine; 10)IL6, IL-10 and IL-13: polymorphisms increase production of cytokines that stimulate humoral immune response; enhance susceptibility for certain viral infections Nutritional Immunogenomics and Depression Predictive Genomic Testing (6) EURIMM European Institute of Molecular Medicine