Download PowerPoint-presentatie

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
Nutritional Immunogenomics and Depression
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
EURIMM
European Institute of Molecular Medicine
Nutritional Immunogenomics and Depression
Communication within the
“Brain / Immune Network System”
 NEUROPEPTIDES / NEUROHORMONES
 NEUROTRANSMITTORS
 CYTOKINES
EURIMM
European Institute of Molecular Medicine
Nutritional Immunogenomics and Depression
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;
EURIMM
European Institute of Molecular Medicine
Nutritional Immunogenomics and Depression
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
EURIMM
European Institute of Molecular Medicine
Nutritional Immunogenomics and Depression
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
EURIMM
European Institute of Molecular Medicine
Nutritional Immunogenomics and Depression
Chronic Immune Stimulation = Disturbed Immune Balance
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)
EURIMM
European Institute of Molecular Medicine
Nutritional Immunogenomics and Depression
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)
EURIMM
European Institute of Molecular Medicine
Nutritional Immunogenomics and Depression
Immune Balance can be Influenced by Nutrients (1)
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)
EURIMM
European Institute of Molecular Medicine
Nutritional Immunogenomics and Depression
Immune Balance can be Influenced by Nutrients (2)
I. Anti-oxidants (continued)
 By increasing the redox potential of immune cells, antioxidants inhibit activation of Nuclear Factor kappa Beta
(NFκB) system, which promotes expression of proinflammatory 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.
EURIMM
European Institute of Molecular Medicine
Nutritional Immunogenomics and Depression
Immune Balance can be Influenced by Nutrients (3)
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
EURIMM
European Institute of Molecular Medicine
Nutritional Immunogenomics and Depression
Immune Balance can be Influenced by Nutrients (4)
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 proinflammatory 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.
EURIMM
European Institute of Molecular Medicine
Nutritional Immunogenomics and Depression
Immune Balance can be Influenced by Nutrients (5)
 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 antioxidative system is concerned.
Therefore, predictive genomic testing with respect to genetic
polymorphisms involved in the “brain / immune network” is indicated.
EURIMM
European Institute of Molecular Medicine
Nutritional Immunogenomics and Depression
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.
EURIMM
European Institute of Molecular Medicine
Nutritional Immunogenomics and Depression
Predictive Genomic Testing (2)
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.
EURIMM
European Institute of Molecular Medicine
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:
– 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
EURIMM
European Institute of Molecular Medicine
Nutritional Immunogenomics and Depression
Predictive Genomic Testing (4)
“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;
EURIMM
European Institute of Molecular Medicine
Nutritional Immunogenomics and Depression
Predictive Genomic Testing (5)
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;
EURIMM
European Institute of Molecular Medicine
Nutritional Immunogenomics and Depression
Predictive Genomic Testing (6)
(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
EURIMM
European Institute of Molecular Medicine