The many faces of inflammation: nutritional protocols for supporting inflammation-based illness

Nina Bailey
BSc (Hons) MSc PhD ANutr
Modulating inflammation by targeting NFkB

Mozaffarian D & Wu JH. Omega-3 Fatty Acids and Cardiovascular Disease: Effects on Risk Factors, Molecular Pathways, and Clinical Events J Am Coll Cardiol.
2011;58(20):2047-2067.
© CNELM

An omega-3 dose 1 g/d, (as Omacor) in the study
by Rupp et al, increased omega-3 index from a
mean of 3.6 % to 5.4 % but approximately 16 % of
the subjects achieved an EPA + DHA blood level
less than 4.8 %.
The AA to EPA ratio was reduced from 20 to 7.2
This is clinically relevant since it has been noted
that an omega-3 index > 5 % is the range in which
dramatic reduction in sudden coronary death
reduction can be observed
Rupp H, Wagner D, Rupp T, Schulte LM, Maisch B. Risk stratification by the
“EPA + DHA level” and the “EPA/AA ratio” Herz. 2004;29:673–685.

The role of transcription factors in health and disease
 Inflammation is a complex and multisystem event affecting a wide range of cells, tissues and
organs
 Numerous mediators, like leukocyte adhesion molecules (ICAM-1 & VCAM-1), various
proinflammatory cytokines (TNF & IL-1b), chemokines (such as IL-8 and monocyte
chemoattractant protein-1 - MCP-1)), and reactive oxygen species (ROS, such as superoxide
and peroxynitrite) are involved in both the generation and propagation of the inflammatory
response
 The transcription factors activator protein-1 (AP1) and nuclear factor-kappaB (NFkB) play key
roles in the expression of immuno-modulatory genes and whose activity and expression are
elevated in inflammatory conditions
 These transcription factors regulate gene expression in response to a variety of stimuli,
including cytokines, growth factors, stress and bacterial and viral infections

IL-1, TNFα,
LPS
Two signalling pathways lead to the
activation of NF-κB, known as the
classical (canonical) pathway and the
alternative (non-canonical) pathway
The common regulatory step in both
of these cascades is activation of an
IκB kinase (IKK)

The role of transcription factors in health and disease
 NF-κB is one of the principal inducible transcription factors whose modulation triggers
a cascade of signalling events involving an integrated sequence of protein-regulated
steps, some of which are potential key targets for intervention in treating inflammatory
conditions
 The ‘canonical’ pathway is triggered by microbial products (via Toll-like microbial
pattern recognition receptors [TLRs]) and proinflammatory cytokines such as TNFα and
IL-1
• IL-1 and TNFα represent the archetypal proinflammatory cytokines that are
rapidly released on tissue injury or infection
• Endogenous ligands may trigger TLRs during tissue injury and certain disease
states, which may act to promote inflammation in the absence of infection
 NF-κB activation is widely implicated in inflammatory diseases and much attention has
focused on the development of anti-inflammatory drugs targeting NF-κB

NF-kB
Inflammation
TNF, IL-1,
chemokines
Angiogenesis
VEGF, TNF, IL-
1, IL-8
Metastasis
ICAM-1, VCAM,
ELAM-1
Tumour promotion
COX-2 iNOS, MMP-9
Anti-
apoptosis/survival
Bcl-xl, cIAP, XIAP,
cFLIP
Proliferation
TNF, IL-1, IL-6
cyclin D1, cMyc
NF-kB in carcinogenesis

Toll-like receptors (TLRs) are membrane-bound sensors that detect and respond
to microbial infection
The survival of multicellular organisms is dependent on their ability to recognise invading microbial
pathogens and to induce a variety of defence reactions
The family of Toll-like receptors play a crucial role in the detection of microbial infection and the
induction of immune and inflammatory responses
TLRs recognise highly conserved structural motifs known as pathogen-associated microbial patterns
(PAMPs), which are exclusively expressed by microbial pathogens, or danger-associated molecular
patterns (DAMPs) that are endogenous molecules released from necrotic or dying cells
Medzhitov R. Toll-like receptors and innate immunity.
Nat Rev Immunol. 2001 Nov;1(2):135-45. Review.
PAMPs include various bacterial cell wall
components such as lipopolysaccharide
(LPS), peptidoglycan (PGN) and lipopeptides,
as well as flagellin, bacterial DNA and viral
double-stranded RNA
DAMPs include intracellular proteins such as
heat shock proteins as well as protein
fragments from the extracellular matrix

The TLR4 signalling pathway culminates in
activation of the transcription factor nuclear
factor-kappaB (NF-kB)
NF-kB controls the expression of an array of
inflammatory cytokine genes
TLR4 agonists:
• Lipopolysaccharide (LPS)
gram negative bacteria
• Saturated fat/high fat diets
• Palmitic acid
• Stearic acid
Rocha DM, Caldas AP, Oliveira LL, Bressan J, Hermsdorff HH. Saturated fatty acids trigger TLR4-
mediated inflammatory response. Atherosclerosis. 2016 Jan;244:211-5.
Elevated LPS is directly related to increased intestinal permeability
This phenomenon occurs due to reduced expression and activity of tight junction proteins, such as
zonula occludens-1 (ZO-1) and occludin, that, together with gut epithelial cells, create a barrier that
separates the intestinal lumen and its bacterial population and products from peritoneal tissues

SFA SFA Omega-3 Omega-3 Omega-3
Palmitic Stearic EPA DPA DHA
16:0 18:0 20:5 22:5 22:6
g/100g lipid
Cross bred steers Grass 18.42 17.54 2.23 2.56 0.2
Grain 20.79 14.96 0.47 0.91 0.11
g/100g lipid
Mixed cattle Grass 26.9 17.0 0.31 0.24 n/a
Grain 26.3 13.2 0.19 0.06 n/a
mg/100g muscle tissue
Angus steers Grass 508 273 24.5 36.5 4.2
Grain 899 463 13.1 31.6 3.7
% total fat
Crossbred steers Grass 22.0 19.1 tr 0.6 tr
Grain 25.0 18.2 tr 0.4 tr
% fatty acid within intramuscular fat
Hereford steers Grass 21.61 17.74 0.96 1.04 0.09
Grain 24.26 15.77 0.3 0.56 0.09
Daley CA, Abbott A, Doyle PS, Nader GA, Larson S. A review of fatty acid profiles and antioxidant content in grass-fed and grain-fed beef Nutr J. 2010; 9: 10.

DISRUPTED
METHYLATION/SULFATION
GENETICS
ANTIBIOTICSVACCINATIONS
INFLAMMATION
GUT PERMEABILITY
GUT DYSBIOSIS
TOXICITY
Gluten/Casein
(opiates)
Food sensitivities
(endorphins)
Gut inflammation
Toxins
(bacterial/yeast)
Compromised
detoxification
Compromised
digestion
Dysregulated immune
function
Heavy metal toxicity Increased virus
exposure
DIET (i.e. high fat)
LPS

 The pro-inflammatory effect of a high-fat diet has mainly been attributed to the
inflammatory properties of dietary fatty acids (e.g. palmitic acid)
 Recently, it has been proposed that such fatty acids trigger an inflammatory response
by acting via LPS receptor (Toll-like receptor-4 [TLR-4]) signalling in adipocytes and
macrophages, which might contribute to the inflammation of adipose tissue in
obesity
 High fat diets affect the composition of the gut flora with an increase
in Firmicutes and a reduction in both Bacteroidetes and Bifidobacterium
 Therefore excess dietary fat not only increases systemic exposure to potentially pro-
inflammatory free fatty acids (e.g. palmitic acid) but also facilitates the development
of metabolic endotoxaemia ( increased plasma LPS) triggering systemic low grade
inflammatory responses in a range of tissues
Conlon MA, Bird AR. The impact of diet and lifestyle on gut microbiota and human health. Nutrients. 2014 Dec
24;7(1):17-44.

Intestinal microbes altered by
high-fat diet suppress fasting
induced adipose factor
(Fiaf) expression,
promoting lipoprotein lipase
(Lpl), a regulatory enzyme that
enhances the absorption of fatty
acid and the build-up of
adipocyte triglyceride thereby
increasing fat storage
https://microbewiki.kenyon.edu/index.php/Gut_Microbiota_and_Obesity
An increase in glucagon-like
peptide-2 (GLP-2) increases
gut permeability
Firmicutes significantly
contribute to increased LPS
activate TLR4 and upregulate
the expression of pro-
inflammatory cytokines
As obesity is considered a
chronic inflammatory disease,
the increased production of
pro-inflammatory cytokines will
trigger an inflammatory
response that ultimately leads
to weight gain

Lactobacillus rhamnosus - helps repair leaky gut, reduces candida cell numbers
Lactobacillus reuteri reduces candida cell numbers
Lactobacillus plantarum reduces gut wall permeability. This bacterium adheres to
reinforce the barrier function of the intestinal mucosa, thus preventing the attachment
of the pathogenic bacteria to the intestinal wall
Lactobacillus fermentum - antimicrobials that inhibits the growth of some harmful
pathogens
Lactobacillus bulgaricus and lactobacillus breve ferment sugars into lactic acid, thereby
increasing the acidity of the intestine, inhibiting the reproduction of harmful microbes
(e.g. candida, that prefers an alkaline environment) and strains with known microbial
activity
http://www.probiotic.org

Probiotic treatment reduces epithelial barrier dysfunction
Commensal and probiotic strains modulate the amount of tight junction proteins at
the cell boundaries and can prevent or reverse adverse effects of pathogens
 Several probiotic strains such as Lactobacillus Bacteroides thetaiotaomicron,
Bifidobacterium longum and Lactobacillus rhamnosus, Bifidobacterium infantis,
Lactobacillus plantarum shown to have beneficial impacts on tight junction- and
intestinal barrier function
 Increasing zonula occludens-1 (ZO-1)
 increased transcription of occludin and cingulin genes
 decreased faecal zonulin levels (a marker indicating enhanced gut
permeability)
 Decreased proinflammatory cytokines
Ulluwishewa D, Anderson RC, McNabb WC, Moughan PJ, Wells JM, Roy NC
Regulation of tight junction permeability by intestinal bacteria and dietarycomponents. Nutr. 2011 May;141(5):769-76.
Lamprecht M, Bogner S, Schippinger G, Steinbauer K, Fankhauser F, Hallstroem S, Schuetz B, Greilberger JF
Probiotic supplementation affects markers of intestinal barrier, oxidation, and inflammationin trained men; a randomized, double-blinded, placebo-
controlled trial. J Int Soc Sports Nutr. 2012 Sep 20;9(1):45.

 Beneficial bacteria favour an acidic environment of pH5.9 to 6.9 (the
ascending colon) whilst less beneficial bacteria create an alkaline environment
and are most active at pH 7.1 to 7.9 (descending colon)
 Some genera of bacteria, such as Bacteroides and Clostridium, have been
associated with an increase in colonic tumour growth rate, while other genera
like Lactobacillus and Bifidobacterium are known to prevent tumour formation
 Bifidobacterium are associated with reduced cell proliferation and a reduction
in carcinogenic-promoting substances such as ammonia and faecal pH
 Lactobacillus can decrease cresol and bile levels, decrease urinary and faecal
mutagenicity as well as carcinogen-promoting enzymes
 Lactobacillus are also associated with the modification of the immune system
Guarner F, Malagelada JR Gut flora in health and disease. Lancet. 2003
8:512-9. Review.

Beneficial bacteria favour an acidic environment of pH5.9 to 6.9 (the ascending
colon) whilst less beneficial bacteria create an alkaline environment and are most
active in at pH 7.1 to 7.9 (descending colon)
Guarner F, Malagelada JR Gut flora in health and disease. Lancet. 2003
8:512-9. Review.

Valdés L, Cuervo A, Salazar N, Ruas-Madiedo P, Gueimonde M, González S.
The relationship between phenolic compounds from diet and microbiota: impact on human health.
Food Funct. 2015 Aug;6(8):2424-39.

Improving gut health
 Probiotics from the following three families have been found to be beneficial
for gut function:
Bifidobacteria, Lactobacilli, and Saccharomyces
 Short-chain non-digestible carbohydrates (inulin-type fructans, fructo-
oligosaccharides (FOS) and galacto-oligosaccharides (GOS)) are the
quintessential prebiotics (occurring naturally in cereals, fruits and vegetables)
and the target bacterial groups are typically Bifidobacterium and Lactobacillus
 Fermented foods like sauerkraut, kimchi, yogurt, kefir

Free radical
damage and
oxidative stressSkin
Lungs
Inflammation
Cardiovascular
Brain
Immunity
Organs
Oxidative stress/ROS/free radicals is an important inducer of NF-kB
Low antioxidant status leads to increased free radical generation

Numerous antioxidants have been shown to reduce inflammation via NF-kB
 Lipoic acid, vitamin c, vitamin E
 CoQ10 (ubiquinol)
 Polyphenols (resveratrol, curcumin, EGCG, quercetin)
 Carotene (beta carotene, lycopene)
 Xanthophylls (astaxanthin, lutein, zeaxanthin)

Martin KR. Targeting apoptosis with dietary bioactive agents.
Exp Biol Med (Maywood). 2006 Feb;231(2):117-29. Review.

Kundu JK, Surh YJ. Cancer chemopreventive and therapeutic potential
of resveratrol: mechanistic perspectives.
Cancer Lett. 2008 Oct 8;269(2):243-61.
Resveratrol!

Kundu JK, Surh YJ. Cancer chemopreventive and therapeutic potential of resveratrol: mechanistic
perspectives. Cancer Lett. 2008 Oct 8;269(2):243-61.

A free radical has an electron
missing from its outer shell
X
Ubiquinol donates an
electron to a free radical
X
Ubiquinol donates
electrons to other
antioxidants
‘Recharged’ antioxidants
(i.e. vitamins C & E, lipoic acid) can
donate electrons to free radical
Ubiquinol –
the antioxidant/antioxidant recycler

Bioavailability of CoQ10 supplements depends on the formulation taken
Ubiquinol is more bioavailable than ubiquinone
The addition of two hydrogen atoms increases the polarity, making
ubiquinol more water-soluble and therefore more bioavailable than
ubiquinone
Bhagavan HN, Chopra RK. Coenzyme Q10: absorption, tissue uptake, metabolism and pharmacokinetics.
Free Radic Res. 2006 40:445-53.

• Absorption occurs in the small intestine directly into the lymphatic
system followed by absorption into the bloodstream
• Absorption is generally poor (large lipophilic molecule) and fat soluble
molecules must cross the ‘unstirred’ water layer for effective uptake
• ~60% of oral supplements may be excreted via the faeces
• High variability with absorption depending on the dosage form
• Higher bioavailability when taken with lipid-containing food but need to
increase bioavailability!

Liu ZX, Artmann C.Relative bioavailability comparison of different coenzyme Q10
formulations with a novel delivery system. Altern Ther Health Med. 2009 15:42-6.
VESIsorb® is a novel delivery technology that
mimics this natural absorption process to
improve bioavailability of large lipophilic
molecules

Ubiquinol studies coming out on top!
Supplementation with 150 mg/ day ubiquinol for 14 days reduces inflammatory processes via
gene expression
Oral intake of ubiquinol increased its proportion significantly (P < 0.001), with the highest
increase in those persons having a low basal serum ubiquinol content (<92.3%)
Ubiquinol status significantly correlated to the concentration of the inflammation marker
monocyte chemotactic protein 1 (involved in the accumulation of inflammatory cells).
CoQ10 redox state predicts the concentration of C-reactive protein (CRP)
People with lower ubiquinol status, higher BMI, and low grade inflammation may benefit from
ubiquinol supplementation
Fischer A1, Onur S1, Niklowitz P2, Menke T2, Laudes M3, Döring F1. Coenzyme Q10 redox state predicts the concentration of c-reactive protein in a large
caucasian cohort. Biofactors. 2016 Feb 23. doi: 10.1002/biof.1269. [Epub ahead of print]
Fischer A, Onur S, Schmelzer C, Döring F. Ubiquinol decreases monocytic expression and DNA methylation of the pro-inflammatory chemokine ligand 2 gene
in humans. BMC Res Notes. 2012 Oct 1;5:540. doi: 10.1186/1756-0500-5-540.

Ubiquinol not ubiquinone for Parkinson’s
Parkinson’s disease is a progressive disease, and established drug treatments can slow but not halt disease
process.
In 2002, a small study (n=80) published findings suggesting that taking 1,200 mg/day of CoQ10 (as oxidised
ubiquinone) may benefit those with early Parkinson’s disease
Less disability developed in subjects assigned to CoQ10 than in those assigned to placebo
This study gathered much excitement, resulting in a follow on phase III trial that recruited more than 600
participants who were randomly assigned to receive placebo, or CoQ10 at doses 1200 mg/d or 2400 mg/d.
However the trial was stopped early because although CoQ10 levels increased, there was some worsening of
symptom severity
The findings of this latter study were finally published in 2014 with two additional, relatively small studies published
in the interim also failing to report any significant benefit from ubiquinone intervention in early Parkinson’s disease
In contrast, more recent evidence suggests that the reduced, ubiquinol form of CoQ10 may offer benefits for
Parkinson’s patients
Yoritaka A, Kawajiri S, Yamamoto Y, Nakahara T, Ando M, Hashimoto K, Nagase M, Saito Y, Hattori N. Randomized, double-blind,
placebo-controlled pilot trial of reduced coenzyme Q10 for Parkinson's disease. Parkinsonism Relat Disord. 2015 Aug;21(8):911-6. May
29.

• 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
VESIsorb® Ubiquinol-QH
VESIsorb® Ubiquinol-QH is the most bioavailable source of the
activated form of coenzyme Q10 (CoQ10). The patented VESIsorb®
delivery system provides colloidal, highly solubilised ubiquinol that
passes easily through the water layer barrier in the gut and into the
bloodstream for unprecedented absorption, optimal blood CoQ10
levels and sustained action.
 'Bioactive’ form of CoQ10 with dual benefits
as a coenzyme and antioxidant
 Solubilised ubiquinol improves absorption and
uptake
 Patented VESIsorb® delivery system mimics
the natural transport of the intestine, pre-
digesting and emulsifying the ubiquinol into
microscopic water-soluble particles that are
easily absorbed into the bloodstream for
optimal tissue distribution
 Pre-digested ubiquinol is absorbed faster,
reaches higher blood plasma
concentrations & offers sustained action
over oil-based forms
 Unprecedented bioavailability
 1-a-day dosing offers therapeutic benefits
 Offers benefits for cardiovascular health,
energy production within the heart, brain
& muscles and protection from free
radicals

Shanmugam MK, Rane G, Kanchi MM, Arfuso F, Chinnathambi A, Zayed ME, Alharbi SA, Tan BK, Kumar AP, Sethi G.
The multifaceted role of curcumin in cancer prevention and treatment. Molecules. 2015 Feb 5;20(2):2728-69.

Curcumin
 Curcumin is the most active constituent of turmeric (50-60%) and it has
been shown to exhibit antioxidant and anti-inflammatory properties
 However, studies regarding absorption, transportation, assimilation and
elimination of curcumin have revealed low absorption and its rapid
metabolism and short half life which leads to relatively low bioavailability
 After absorption, curcumin undergoes conjugations like sulfation and
glucuronidation
 When metabolised in the liver, the major metabolic products of curcumin
are glucuronides of Tetrahydrocurcumin (THC) and Hexahydrocurcumin
(HHC)
 Studies have shown that these metabolites are actually less active
compared to curcumin itself and so when metabolised the activity of
curcumin seems to be lost

Ghalandarlaki N, Alizadeh AM, Ashkani-Esfahani S: Nanotechnology-applied curcumin for different
diseases therapy. BioMed research international 2014, 2014:394264.

Ghalandarlaki N, Alizadeh AM, Ashkani-Esfahani S: Nanotechnology-applied curcumin for different diseases
therapy. BioMed research international 2014, 2014:394264.

Ghalandarlaki N, Alizadeh AM, Ashkani-Esfahani S: Nanotechnology-applied curcumin for different diseases therapy. BioMed research
international 2014, 2014:394264.
 To improve the bioavailability of curcumin, numerous approaches have been undertaken
including:
• use of adjuvant that interferes with glucuronidation
 Piperine (black pepper extract)
• Inclusion of turmeric volatile oils
 BCM-95®
• nanoformulations (liposomes, micelles, etc)
 Novasol®
 Longvida®
• the use of curcumin phospholipid complex
 Meriva-SR®
 Micelles and phospholipid complexes increase the absorption resulting in higher blood
plasma concentration and lower elimination thus increasing the bioavailability

Shanmugam MK, Rane G, Kanchi MM, Arfuso F, Chinnathambi A, Zayed ME, Alharbi SA, Tan BK, Kumar
AP, Sethi G. The multifaceted role of curcumin in cancer prevention and treatment. Molecules. 2015 Feb
5;20(2):2728-69.

Peroxisome proliferator-activated receptors
(PPARs) are activated by fatty acids and
eicosanoids and are the target for drugs
such as fibrates (PPARa; lipid
lowering) thiazolidinediones (PPARg;
diabetes) and NSAIDs
After activation by ligand binding, PPARs
heterodimerize with retinoid X receptor
(RXR) and bind to specific PPAR response
elements (PPRE) on the promoter of target
genes to regulate glucose and lipid
metabolism (right)
This aspect of PPAR-α and PPAR-γ action
has cardiovascular protective effects
through effects on atherosclerosis and
diabetes
PPAR-α and PPAR-γ also interact with different transcription factors to repress proinflammatory genes
(left)
Inflammatory regulation
via PPARs
Schiffrin EL. Peroxisome proliferator-activated receptors and cardiovascular remodeling.
Am J Physiol Heart Circ Physiol. 2005 Mar;288(3):H1037-43. Epub 2004 Sep 16. Review.

Down regulate the expression of membrane
receptors (5)
Increase IΚBα expression (4)
Inhibition translocation of NF-kB to the nucleus (3)
Decrease transcription factor expression levels (2)
Interfere with the activation of the transcription
initiation complex (1)
Omega-3
Zambon, A., P. Gervois, et al. (2006). "Modulation of hepatic inflammatory risk markers of cardiovascular diseases by PPAR-alpha activators: clinical
and experimental evidence." Arteriosclerosis, thrombosis, and vascular biology 26(5): 977-986.
Omega-3 and NF-κB!
Omega-3 inhibits the activity of NF-κB by
attenuating phosphorylation and degradation
of the inhibitory factor, IκB

Inflammtory regulating pathways, cell proliferation, differentiation and apoptosis are
modified by components of diet

Reactive oxygen species
(ROS), such as superoxide
and peroxynitrite
Activation of AP-1
(TPA-response
element) and NF-κB
(IκB kinase, PKC, ROS)
The MAPK kinase signalling
cascades
(ERKs, JNK, SAPKs, p38 kinases)
COX & LOX
enzymes
c-Jun, c-Fos, c-Myc,
Bax, and Cdks
(oncogene activation)
p53, Rb, Bcl-2, p21,
and p27
(tumour suppressor
inactivation)
PKC, calcium release,
and calcium channel
activation
Toll-like
receptors
PPARs
NF-kB & AP1
Adhesion molecules
(ICAM-1 & VCAM-1)
Inflammatory
regulation
Cytokines (such as TNF & IL-1b),
chemokines (such as IL-8 and MCP-1)

Therapeutic
Wellbeing
Additional nutrients
Our products range

Education Technical
Sophie Tully
Nutrition Education Manager
sophiet@igennus.com
Dr Nina Bailey
Head of Nutrition
ninab@igennus.com
Twitter @DrNinaBailey

An inflammatory reaction can be regulated in a number of different ways…
 The detection and interpretation of inflammatory signals
 The response of the activated immune cells (such as cytokine release)
 The reaction of the surrounding tissue to inflammatory agents and to immune
mediators as well as the resolution/repair phase
These are all targets of intervention

The many faces of inflammation: nutritional protocols for supporting inflammation-based illness

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