This document summarizes a presentation on managing chronic inflammation through modulating fatty acids like omega-3 and arachidonic acid. It discusses how inflammation contributes to diseases like cancer and dementia, and how biomarkers like the omega-3 index, omega-6/omega-3 ratio, and AA/EPA ratio can be used to personalize omega-3 dosing to reduce inflammation. Clinical evidence suggests EPA in particular may help treat inflammation and inhibit cancer progression by competing with arachidonic acid metabolism.

1. Managing chronic inflammation:
a cutting edge approach to treating chronic disease
Nina Bailey
BSc (hons) MSc PhD ANutr

2. 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

3. Inflammation
The 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 system
HPA-axis
Innate immune system
Three defined phases:
Initiation Resolution Termination

4. Exercise
High calorie diet
Muscle/fat ratio
‘New’ environmental
stressors
Reactive Hypoglycemia
Immune System
Activation
(Adapted from Bosma-den Boer et al., 2012)

5. 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

7. Inflammation – the role of fat
• Igennus is the only independent manufacturer
of specialist Fatty Acid in the UK. Based in
Cambridge the medical innovation hub for the
UK:
 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
- Seven Seas Merck Pharma Germany
- Minami Atrium Pharma Canada
- Biocare Elder Pharma India
- Eskimo 3 Bringwell Pharma Sweden
- Equizen Vifor Pharma Swiss
 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

8. • Cell fluidity
• Cell cycle control
• Metabolism
• Growth and development
• Brain structure and function
• Eicosanoid production
 Immunity
 Cardiovascular health
 Inflammation

11. Resoleomics - the process of inflammation resolution
Inflammatory response
Eicosanoid switch Stop signal
PGE2
LTB4
Pro-inflammatory reduced
Anti-inflammatory increased
Time
Initiation Resolution Termination
Source: Bosma-den Boer et al., 2012

12. Biomarkers for personalising omega-3 fatty acid dosing

13. Shifting the balance
The 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

14. The AA to EPA ratio – a biomarker of inflammatory status

15. 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

16. 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)

17. The omega-3 index – a biomarker of cardiovascular health

18. The omega-3 index: a dose response
Harris & Von Schacky, 2004

19. R² = 0.649
14
12
10
8
6
4
2
0
1 2 3 4 5 6 7 8
Omega-3 index
Omega-6 to Omega-3 ratio
R² = 0.6493
14
12
10
8
6
4
2
0
0 5 10 15 20
Omega-3 index
AA to EPA ratio
In house data n=25
A higher omega-3 index correlates with a lower AA to EPA ratio

20. Dosing with omega-3 – how much do I need?

21. 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

22. Biomarkers for personalising omega-3 fatty acid dosing
Omega-3 index
an early cardiovascular risk indicator
Omega-6 to omega-3 ratio
an established marker of long-term health and chronic illness
AA 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 4
An AA to EPA ratio of between 1.5 and 3

24. 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)

25. 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
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)

26. 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)

27. 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)

28. 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

29. 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)

30. 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

31. 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

32. 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 cancer
Plasma 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 cancer
Plasma AA to EPA ratio was 21.029+2.584 compared to 12.10+1.414 in
healthy subjects (median age 77; range 44 - 86)

33. Arachidonic acid
COX-1
Constitutive ‘gate-keeping functions’
Homeostatic function
Gastrointestinal + renal tract
Platelet function
Macrophage differentiation
COX-2
Induced
Inflammation
Phospholipase A2

34. The role of EPA as a competitive inhibitor
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

35. 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)

36. 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)

37. 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)

38. 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)

39. 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)

40. 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

41. 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)

42. 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)

43. 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)

44. 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

45. 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)

46. 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 to
kynurenine 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)
TDO: 2,3-dioxygenase; IDO: indoleamine 2-,3-dioxygenase; KMO kynurenine monoxygenase

47. 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)

48. 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)

49. 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)

50. Neurodevelopmental disorders
Deficiencies 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

51. 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)

52. 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

53. 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

54. ninab@igennus.com
www.igennus.com
drninabailey.co.uk
0044 1223 421434

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