managing chronic inflammation
DESCRIPTION
Managing chronic inflammation: a cutting edge approach to treating chronic diseaseTRANSCRIPT
Managing chronic inflammation: a cutting edge approach to treating chronic disease
Nina BaileyBSc (hons) MSc PhD ANutr
Talk outline
Understanding inflammation as a risk factor for disease
The significance of omega-3 and the role of fatty acids in inflammatory resoleomics
Treating inflammation through the modulation of eicosanoids
Biomarkers for personalising omega-3 fatty acid dosing The omega-3 index
AA to EPA ratio
Clinical evidence of EPA as an inflammatory modulator
InflammationThe normal response of a tissue to injury, triggered by a number of causes including infection, invading pathogens (such as bacteria or viruses) trauma or compromised blood flow
Key players:Sympathetic nervous systemHPA-axisInnate immune system
Three defined phases:Initiation Resolution Termination
‘New’ environmental stressors Reactive Hypoglycemia Immune System
Activation
(Adapted from Bosma-den Boer et al., 2012)
Exercise High calorie dietMuscle/fat ratio
In some cases, such as rheumatoid arthritis (RA), inflammatory bowel diseases (IBD) and asthma, the central role of inflammation in the pathology is well recognised
Individuals with these conditions have heavy infiltration of inflammatory cells at the site of disease activity (e.g. the joints, the intestinal mucosa, the lungs)
They have elevated concentrations of inflammatory mediators at those sites and in the systemic circulation, and they are treated with anti-inflammatory drugs with a corresponding improvement in symptoms
• Igennus is the only independent manufacturer of specialist Fatty Acid in the UK. Based in Cambridge the medical innovation hub for the UK:
- Seven Seas Merck Pharma Germany- Minami Atrium Pharma Canada- Biocare Elder Pharma India- Eskimo 3 Bringwell Pharma Sweden- Equizen Vifor Pharma Swiss
Inflammation – the role of fat
Dietary patterns high in refined starches, sugar and saturated & trans-fatty acids, poor in natural antioxidants and fibre from fruits, vegetables and whole grains, and poor in omega-3 fatty acids may cause an activation of the innate immune system, most likely by excessive production of proinflammatory cytokines associated with a reduced production of anti-inflammatory cytokines
Historically, the human diet was high in omega-3 fatty acids, with a ratio of omega-6 to omega-3 fatty acids of around 1-2:1
During the last few decades, there has been a marked increase in consumption of omega-6 and a decrease in consumption of omega-3 fatty acids
Many modern food types are ‘new’ in regard to human evolution, rich in added omega-6 and stripped of omega-3
• Cell fluidity• Cell cycle control• Metabolism• Growth and development• Brain structure and function
• Eicosanoid production Immunity Cardiovascular health Inflammation
Resoleomics - the process of inflammation resolution In
flam
mat
ory
resp
onse
Initiation Resolution Termination
PGE2
LTB4
Eicosanoid switch Stop signal
Time
Pro-inflammatory reduced
Anti-inflammatory increased
Source: Bosma-den Boer et al., 2012
Biomarkers for personalising omega-3 fatty acid dosing
Shifting the balanceThe omega-6 to omega-3 ratio is well documented as a marker of health status; however, the ratio of AA to EPA is a more accurate indicator of inflammatory status
AA and EPA contents of cell membranes can be altered through consumption of omega-3 EPA (marine products/marine oils)
Changing the fatty acid composition of cell membranes affects• changes in membrane structure• products involved in immune function and the inflammatory cascade• cell signalling• gene expression and cell cycle control
The AA to EPA ratio – a biomarker of inflammatory status
Marine omega-3 fatty acids partly inhibit a number of aspects of inflammation
Anti-inflammatory actions of omega-3 well defined in vitro and animal experiments demonstrate benefits of marine omega-3 fatty acids
Trials of marine omega-3 fish oil in patients are generally inconsistent
These conflicting results are likely due to differences in study design, sample size, sample studied, background diet, baseline levels of omega-3, omega-3 supplement choice, dose, study length, etc.
Often the most prominent outcomes are observed in those individuals with the lowest omega-3 levels and predominantly with the lowest levels of EPA
Increasing interest in the unique and individual properties associated with EPA and DHA
The omega-3 index
The omega-3 index was originally developed as an informative risk factor for developing cardiovascular disease and is defined as the content of EPA and DHA in the cell membrane of RBCs, expressed as a weight percentage of total fatty acids and reflects tissue fatty acid composition (Harris & Von Schackey 2004)
Data from epidemiological and dietary intervention studies suggest a desirable target value for the omega-3 index of more than 8%, with less than 4% recognised as an undesirable level
A low omega-3 index is also associated with numerous health conditions including neurodevelopmental and mental health disorders, with increasing interest in its use as a biomarker of mental health (Milte et al., 2009)
The omega-3 index – a biomarker of cardiovascular health
The omega-3 index: a dose response
Harris & Von Schacky, 2004
1 2 3 4 5 6 7 80
2
4
6
8
10
12
14
R² = 0.648953336648925
Omega-6 to Omega-3 ratio
Om
ega-
3 in
dex
0 2 4 6 8 10 12 14 160
2
4
6
8
10
12
14
R² = 0.649320399799339
AA to EPA ratioO
meg
a-3
inde
x
In house data n=25
A higher omega-3 index correlates with a lower AA to EPA ratio
Dosing with omega-3 – how much do I need?
Fatty acid composition of RBC is considered to be a more reliable biomarker of long-term fatty acid intake because the turnover of RBC (4 months) is slower than that of plasma or platelets
Using the model developed by Flock and colleagues (2013) it is possible to estimate the dose required to raise the omega-3 index to a desirable level
The Opti-0-3 is the only omega-3 biomarker test that offers a bespoke dosing guide to optimise omega-3 fatty acid biomarkers for optimal health
Biomarkers for personalising omega-3 fatty acid dosing
Omega-3 index an early cardiovascular risk indicatorOmega-6 to omega-3 ratio an established marker of long-term health and chronic illnessAA to EPA ratio a measure of ’silent’ or chronic inflammation
A personalised plan aims to achieve:An omega-3 index of more than 8% An omega-6 to omega-3 ratio of between 3 and 4An AA to EPA ratio of between 1.5 and 3
AA to EPA ratio in health and disease
Fasted blood samples from 1432 [Italian] subjects, who were referred by their physicians, were analysed to assess their AA to EPA and total omega-6 to omega-3 ratios in whole blood and in RBC membrane phospholipids
Individuals with no diagnosable conditions had lower AA to EPA ratios than those with diagnosable health conditions
Individuals with allergic, skin and neurodegenerative diseases had higher ratios of AA to EPA compared to the values for subjects with other pathologies, possibly due to a higher turnover of EPA
Subjects who did not take omega-3 supplements and suffered from allergic, neurodegenerative, skin and inflammatory diseases had higher values for AA to EPA ratios than those with the other diseases (heart, metabolic, cancer)
(Rizzo et al., 2010)
Subjects who did not take omega-3 supplements and suffered from allergic, neurodegenerative, skin and inflammatory diseases had higher values for AA to EPA ratios than those with the other diseases (heart, metabolic, cancer)
AA to EPA ratios of patients grouped according to their specific conditions. The horizontal line indicates the mean value for healthy subjects not
supplementing with omega-3
(Rizzo et al., 2010)
Obesity, insulin resistance and the metabolic syndrome
Subjects with metabolic syndrome have been shown to possess tissue and plasma fatty acid profiles characterised by a relative predominance of saturated fatty acids and omega-6 polyunsaturated fatty acids, with corresponding low levels of long-chain omega-3 polyunsaturated fatty acids
Levels of saturated fatty acids are significantly higher and EPA levels significantly lower in obese subjects both with and without insulin resistance compared to controls (p<0.001 for both) (Gunes et al., 2014)
This fatty acid pattern appears to confer a higher risk of both diabetes and coronary heart disease (CHD) events (Nigam et al., 2013)
AA to EPA ratio and the metabolic syndrome
High AA to EPA ratio associated with insulin resistance
Age and visceral fat accumulation correlated significantly with serum AA to EPA ratio
Subjects with visceral fat accumulation ≥100 cm2 had higher serum AA to EPA ratio (but not DHA to AA or [EPA+DHA] to AA) and more likely to have metabolic syndrome and history of coronary artery disease, compared to those with visceral fat accumulation <100 cm2 (Inoue et al., 2013)
“The balance of AA to EPA by lifestyle modification and medication (such as EPA-based medications) could be useful in reducing the prevalence of the metabolic syndrome and atherosclerosis” (Inoue et al., 2013)
Cancer – an inflammatory disease?
A high rate of cell proliferation and a low rate of apoptosis are the hallmark of abnormal cell growth
The link between non-resolving inflammation and cancer is well documented, with epidemiological evidence supporting that approximately 25% of all human cancer worldwide is caused by non-resolving inflammation
Inflammatory cells are found in the microenvironment of most, if not all tumours
High AA content of cells indicates a pro-inflammatory microenvironment
Products derived from inflammatory cells influence almost every aspect of cancer
Vendramini-Costa & Carvalho 2012
AA, EPA and the cell cycle
Inflammation creates the ideal ‘tumour microenvironment’ and is now widely recognised as an enabling characteristic of cancer in regard to enhanced cell proliferation, cell survival, cell migration and angiogenesis
AA and EPA have opposing effects on the proliferation, differentiation and apoptosis of genetically altered cells and therefore the disposal/accumulation of DNA damaged tissue (Cathcart et al, 2011)
The anti-proliferative effects of EPA combined with the ability to induce programmed cell death suggests that EPA supplementation may have a significant impact on halting disease progression (Hawcroft et al., 2010; Hawcroft et al., 2012)
Modulation of angiogenesis by AA and EPA
The formation of new blood vessels (angiogenesis), a critical process that affects tumour growth and dissemination (Szymczak et al., 2008)
EPA inhibits and AA stimulates major pro-angiogenic processes in human endothelial cells:
angiopoietin-2 (Ang-2) vascular endothelial growth factor (VEGF) basic fibroblast growth factor (bFGF) insulin-like growth factor-1 matrix metalloproteases (MMPs) that degrade the extracellular matrix,
and play an important role in the migration of endothelial cells during angiogenesis
Arachidonic acid and eicosapentaenoic acid metabolism contribute to cancer risk and progression through pro-and anti-inflammatory lipid metabolites that influence cell proliferation, angiogenesis and migration
Azrad et al., 2013
A new biomarker in cancer patients: the AA to EPA ratio Aim To evaluate the potential value of tumour risk assessment in colon and breast
cancer patients by determining the AA to EPA ratio in plasma in a case-control study against healthy patients (Garassino et al., 2006)
Findings Colorectal cancerPlasma AA to EPA ratio was 22.232+1.852 compared to 14.25+1.083 for healthy subjects (median age 70; range 53 - 81) Breast cancerPlasma AA to EPA ratio was 21.029+2.584 compared to 12.10+1.414 in healthy subjects (median age 77; range 44 - 86)
Arachidonic acid
COX-1
Constitutive ‘gate-keeping functions’Homeostatic function
Gastrointestinal + renal tract
Platelet function
Macrophage differentiation
COX-2
InducedInflammation
Phospholipase A2
High arachidonic acid levels
Pro-inflammatory ‘cancer driving’ prostaglandins COX-2
Increased EPA lowers arachidonic acid levels
Anti-inflammatory ‘cancer-suppressing’
prostaglandins COX-2
Increased EPA lowers arachidonic acid levels
Anti-inflammatory ‘cancer-suppressing’
prostaglandins
EPA competes with AA for COX-2
The role of EPA as a competitive inhibitor
Changes in omega fatty acids within the mucosa of CRC patients
Patients with CRC have shown increased concentrations of AA and AA-derived prostaglandins within the tumoural mucosa (Bennett et al, 1987)
Phospholipase A2 and prostaglandin E2 (potent tumour promoter) have been shown to be increased in human CRC tissue (Soydan et al., 1996) Patients with CRC have shown increased concentrations of AA and DHA (Neoptolemos et al., 1991)
Unlike EPA, DHA may have detrimental effects on CRC by accelerating dysplastic tissue transformation (Woodworth et al., 2010)
EPA has been shown in studies to be significantly more effective than DHA in reducing tumourigenesis in animal models of CRC, with some indication that DHA may actually accelerate dysplastic tissue transformation (Petrick et al., 2000; Woodworth et al., 2010)
Increasing numbers of studies are focusing on pure EPA as a safe and potentially viable chemopreventative agent for the treatment of CRC
EPA has been shown to reduce intestinal adenoma multiplicity by 79% in animal models of familial adenomatous polyposis (FAP) (Fini et al., 2010)
In humans, the effects of EPA (2g daily for 6 months) on rectal polyp growth in patients with FAP produced a 22.4% decrease in adenoma numbers and a 29.8% reduction in adenoma size (West et al., 2010)
Incremental increases in the dietary intake of EPA results in a dose-dependent decrease in pro-inflammatory PGE2 concentrations (Jiang et al., 2014)
The seAFOod Polyp Prevention Trial (Hull et al., 2013)
The seAFOod Polyp Prevention Trial is a randomised, double-blind, placebo-controlled, 2×2 factorial ‘efficacy’ study, which will determine whether EPA prevents colorectal adenomas, either alone (1 g twice daily) or in combination with aspirin (300mg daily)
Aspirin irreversibly acetylates the COX enzymes, leading to conversion of EPA to 18R-hydroxyeicosapentaenoic acid (18R-HEPE) and then trihydroxy-EPA, also known as resolvin E1, which has potent anti-inflammatory activity
Participants are 55–73 year-old patients, who have been identified as ‘high risk’ (detection of ≥5 small adenomas or ≥3 adenomas with at least one being ≥10 mm in diameter) at screening colonoscopy in the English Bowel Cancer Screening Programme (BCSP)
EPA and and aspirin lead to the production of different bioactive lipid mediators, including PGE3 and 15R-HETE (resolvin E1)
Inflammation and dementia
Inflammation factors are known to be associated with a higher risk for Alzheimer's disease and cognitive decline (Halliday et al., 2000)
Two large-scale prospective studies showed baseline blood levels of inflammatory markers are associated with higher risk of incident Alzheimer's disease (Schmidt et al., 2002; Engelhart et al., 2004)
Omega-3 and dementia
The physiological roles of omega-3 PUFAs in the brain include regulation of cell membrane fluidity, dopaminergic and serotonergic transmission, regulation of cellular signal transduction, brain glucose metabolism, eicosanoid synthesis, gene expression and cell cycle control
Deficiencies in omega-3 fatty acids are observed in dementia patients (Lopes da Silva et al., 2013)
High AA to EPA and omega-6 to omega-3 is associated with an increased risk of dementia, whereas a higher EPA concentration is associated with a lower risk of dementia (Samieri et al, 2008)
2012 meta-analysis of 10 studies (including 2,280 subjects)
- EPA and total n-3 PUFAs were decreased in patients with dementia
- levels of EPA, but not DHA or other PUFAs, were significantly lower in patients with pre-dementia syndrome
- EPA may act as a disease-state marker AND a risk factor for cognitive impairment (Lin et al, 2012)
EPA intake is more advantageous than DHA in reducing "brain effort" relative to cognitive performance (in young adults) (Bauer et al., 2014)
40
Omega-3 and cardiovascular health
Numerous studies have been conducted that highlight the importance of omega-3 to support cardiovascular health
(i.e., DART studies, GISSI, JELIS,…)
Omega-3 fatty acid therapy shows great promise in both primary and secondary prevention of cardiovascular diseases (Peter et al., 2013)
Significant reductions in total mortality and sudden cardiac death to the extent of 20% to 50% have been found in studies using doses ranging from 0.85 to 4.0 grams daily (Artham et al., 2008)
EPA (not DHA) is associated with a lower risk of cardiovascular disease events and of all-cause death (Chien et al., 2013)
The Japan EPA Lipid Intervention Study (JELIS) has established the clinical efficacy of EPA for CVD, with higher levels of blood EPA, not DHA, found to be associated with a lower incidence of major coronary events:
EPA ‘gold standard’ for preventing recurrent coronary events
Supplementing with 1.8g/day recommended for women with raised cholesterol and triglycerides
Supplementation with EPA and statins in hypercholesterolaemia patients resulted in a significant reduction of coronary events when the AA to EPA ratio was <1.34 (HR:0.83, p = 0.031)
(Yokoyama et al, 2003; Yokoyama et al, 2007; Yamanouchi & Komori 2010; Ohnishi & Saito 2013)
EPA as a therapeutic tool
In 2012 the FDA approved a high purity EPA product for use in treating hypertriglyceridaemia
Products containing a combination of EPA and DHA, including dietary supplements, are more likely to raise LDL than EPA-only products, especially for those not on statin therapy (Ballantyne et al., 2013)
A systematic review of 22 RCTs of EPA and/or DHA reported increased LDL-C in 71% of studies of DHA monotherapy (Jacobson et al., 2012; Wei & Jacobson 2011)
Patients who are switched from EPA/DHA-containing products to pure EPA show substantial improvements in lipid profiles (Hilleman & Malesker 2014)
Inflammation and mood disorders
There is now an extensive body of data showing that depression is associated with both a chronic low-grade inflammatory response, and activation of cell-mediated immunity
Early research on the role of inflammation in major depression centred on the observation that some people with depression show elevated levels of pro-inflammatory cytokines; recent reviews and pooled analyses have found general immune dysregulation and/or positive associations between depression and various cytokines including : IL-1, IL-6, and C-reactive protein & TNF-α
Howren et al., 2009; Dowlati et al., 2010; Berk et al., 2013
High AA to EPA ratio and high levels of pro-inflammatory cytokines are directly correlated with severity of depression, lower RBC membrane omega-3 and especially EPA are associated with the severity of depression (Adams et al., 1996; Conklin et al., 2007) and distinguish between anxious and non-anxious forms of major depressive disorder (Liu et al., 2013)
Depression [in the elderly] is characterised by very low levels of omega-3, in particular of EPA, in RBC membranes and a high AA to EPA ratio compared to healthy subjects (Rizzo et al., 2012)
Omega-3 intervention lowers AA to EPA ratio and is correlated with improved scores on the Geriatric Depression Scale (GDS) (Rizzo et al., 2012)
Omega-3 Index (mean, 3.9% vs 5.1%) and individual omega-3 fatty acids were significantly lower in major depressive disorder patients. An Omega-3 Index < 4% was associated with high concentrations IL-6 (indicative of an elevated cardiovascular risk profile (Baghai et al., 2011)
TDO: 2,3-dioxygenase; IDO: indoleamine 2-,3-dioxygenase; KMO kynurenine monoxygenase
The kynurenine (KYN)/tryptophan ratio, serotonin and depression
Activation of tryptophan 2,3-dioxygenase (TDO), present in liver and brain, is up regulated by cortisol and cytokines activate indoleamine 2-,3-dioxygenase (IDO), and kynurenine monooxygenase (KMO) (Oxenkrug 2010)
The shift of tryptophan metabolism from serotonin tokynurenine formation is observed in depression, with a high K/T ratio significantly associated with symptoms (Swardfager 2009)
Activation of KMO decreases the production of the NMDA antagonist kynurenic acid and increases the production of quinolinic acid, an excitotoxic NMDA receptor agonist (Heyes et al., 1992)
Changes in brain structure in mood disorders
MRI shows structural brain grey matter abnormalities in major depression, bi-polar and schizophrenia (Kempton et al., 2011)
Elevated quinolinic acid has the potential to cause neuronal damage and accumulation in certain areas of the brain tissue has been reported in depressed patients (Steiner et al., 2012)
Furthermore, serotonin transporter activity (involved in recycling serotonin for reuse) is increased by certain pro-inflammatory cytokines, thus reducing overall serotonin activity (Jazayeri et al., 2010; Song et al., 2007)
The depletion of tryptophan and subsequent decrease in serotonin production is a well-established feature of mood disorders pathophysiology (Oxenkrug 2010)
Omega-3 intervention studies meta-analysis findings
Fish oil studies produce conflicting and often contradictory findings
2009 meta-analysis (28 studies) clarified ‘EPA but not DHA to be responsible for the efficacy of omega-3 long-chain polyunsaturated fatty acid supplementation in depression’ (Martins 2009)
Only those supplements containing EPA ≥ 60% of total EPA + DHA, in a dose range of 200 to 2,200 mg/d of EPA in excess of DHA, were effective against primary depression (Sublette et al., 2011)
It is the EPA in excess of DHA within a supplement that exerts therapeutic effects (Sublette et al., 2011)
1g pure EPA more effective than 1g DHA in treating depressive symptoms (Mozaffari-Khosravi et al., 2012)
The effect of EPA supplements on cortisol and cytokine levels
EPA treatment (1g/daily 8 weeks) as effective as 20 mg fluoxetine in treating depressive symptoms (Jazayeri et al., 2008)
EPA supplementation decreases the AA to EPA ratio and increases IL-10, an anti-inflammatory cytokine associated with decreased depressive-like behaviour (Satoh- Asahara et al., 2012)
EPA may exert its therapeutic effects through its ability to reduce cortisol (Jazayeri et al., 2008) and TNF-a and IL-B1 (Caughey et al., 1996)
EPA rather than DHA exerts therapeutic effects in the prevention of IFN- a induced depression (therapy for chronic hepatitis C virus infection) (Su et al., 2014)
Neurodevelopmental disordersDeficiencies or imbalances in the long-chain highly unsaturated omega-3 fatty acids have been implicated in the predisposition and development of neurodevelopmental disorders (Richardson & Ross 2000; Richardson 2000)
AA to EPA ratio correlates with ADHD symptoms (Germano et al., 2007)
In ADHD, callous-unemotional (CU) traits are significantly negatively related to both EPA and total omega-3 (Gow et al., 2013)
Omega-3 fatty acids related to abnormal emotion processing in adolescent boys with attention deficit hyperactivity disorder (Gow et al., 2013)
Correlation between AA to EPA ratio and physical aggression (Itomura et al., 2005
Omega-3 intervention studies and ADHD
Fish oil studies produce conflicting and often contradictory findings!
Pure DHA has no benefits in the treatment of ADHD (Voigt 2001)
Pure EPA improves symptoms in ADHD diagnosed children, with changes in AA to EPA ratio related to clinical improvement (Gustafsson et al., 2010)
Meta-analysis of 10 dietary omega-3 supplementation trials (699 children with ADHD) showed EPA-rich preparations were significantly associated with clinical efficacy (Bloch & Qawasmi 2011)
Summary
Western dietary and lifestyle factors, particularly those that create an inflammatory environment, contribute significantly to inflammatory related disorders
Diets that are high in omega-6 increase ‘risk’, whilst diets that are rich in long-chain omega-3 may reduce the ‘risk’
Specifically, a high AA to EPA ratio and low EPA [rather than DHA] appears to be associated with many inflammatory conditions
Modifying the diet can reduce systemic inflammation by manipulating the AA to EPA ratio
Summary
Human intervention studies show inconsistent findings – is there a need for personalising omega-3 fatty acid dosing for clinical outcomes?
Not all ‘fish oils’ are the same – acknowledge the significance of the EPA to DHA ratio
Pure EPA is a safe adjunctive therapy for inflammatory disorders
Evidence suggests that the presence of DHA within the therapeutic oil may be [in some conditions] undesirable
Pure EPA, because of its safety and known anti-cancer benefits, is now entering phase III human trials as a chemopreventive agent
Pure EPA is recognised for its cardiovascular health benefits
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