Beyond omega-3: managing the many faces of inflammation


Figure 1: the many players in the inflammatory process. Click to enlarge

Unresolved or exaggerated inflammation is the hallmark of chronic disease and targeting key regulators of inflammatory mechanisms is essential for successful therapeutic intervention.  Whilst the omega-6 and omega-3 fatty acids AA, EPA and DHA play key and distinct roles in regulating inflammatory pathways, inflammation is itself a complex and multisystem process (figure 1). Understanding that there are multiple systems and mechanisms that regulate inflammation is therefore vital for a holistic approach to managing western disease.   Anti-inflammatory diets focus on the importance of nutrient combinations to effectively target the multitude of pro-inflammatory ‘players’; similarly, supplemental intervention also needs to take into consideration the client’s individual requirements.  Restoring an appropriate balance of omega-6 to omega-3 (and in particular AA to EPA) with potent EPA-rich omega-3 supplements is a good place to start and is extremely effective in managing several aspects of the inflammatory process. Optimal results are likely to be achieved by adopting a more comprehensive anti-inflammatory protocol and utilising additional antioxidants, probiotics and/or other specific nutrients that will address a number of different inflammatory pathways.

Targeting nuclear factor NF-kB

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.  NF-κB activation is therefore widely implicated in inflammatory diseases and much attention has focused on the development of both anti-inflammatory drugs and nutrients targeting NF-κB. Under normal conditions, NF-kB is present within the cytoplasm as an inactive Ikk-B-bound complex. When a cell receives an extracellular signal, the Ikk-B fraction of the complex is removed, thereby activating and allowing NF-kB to enter the nucleus where it is free to induce gene expression.  Inducers of NF-kB are numerous (over 200 physiological stimuli are known to activate NF-kB), [1] with key triggers that include oxidative stress, microbial products (via Toll-like microbial pattern recognition receptors [TLRs]) and proinflammatory cytokines such as TNF-α and IL-1.  The major cellular targets of NF-kB are chemokines, immune receptors, adhesion molecules and stress response genes, regulators of apoptosis, transcription factors, growth factors, enzymes and cell cycle regulators.   Thus, the inappropriate or over activation of NF-kB can be linked to numerous health conditions, with NF-κB known to be highly activated at sites of inflammation.  In rheumatoid arthritis, for example, NF-κB is over expressed in the inflamed synovium with its increased activity enhancing the recruitment of inflammatory cells that then result in the subsequent production of proinflammatory mediators including IL-1, IL-6, IL-8, and TNF-α. [2] The role of NF-kB in carcinogenesis is particularly significant, as it will activate key genes that regulate proliferation, apoptosis, angiogenesis, invasion, inflammation and metastasis. [3]

Using antioxidants to reduce oxidative stress

Low antioxidant status leads to increased free radical generation, and with oxidative stress (an important inducer of NF-kB) the use of antioxidants can be a useful and highly effective way to manage or block NF-kB activity.  Numerous nutrients with antioxidant activity have been shown to reduce inflammation via the targeting of NF-kB; these include­­ lipoic acid, vitamin C, vitamin E, CoQ10 (ubiquinol), numerous polyphenols (resveratrol, curcumin, EGCG, quercetin), carotene (beta carotene, lycopene) and xanthophylls (astaxanthin, lutein, zeaxanthin).  [4] Increasing dietary intake of antioxidants (such as tomatoes, dark green and allium vegetables, spices, green tea, dark chocolate, berries – to name a few) can play a major role in reducing the impact of free radicals, whilst supplements (such as curcumin, ubiquinol and resveratrol) can offer concentrated and highly bioavailable sources of specific compounds that may offer superior benefits over raw foods.  Curcumin is a classic example and as the most active constituent of turmeric (50-60%) has been shown to exhibit potent antioxidant and anti-inflammatory properties; however, studies regarding absorption, transportation, assimilation and elimination of curcumin have revealed low absorption and coupled with its rapid metabolism and short half life leads to relatively low bioavailability.  After absorption, curcumin undergoes conjugations like sulfation and glucuronidation and when metabolised in the liver, the major metabolic products of curcumin are glucuronides of tetrahydrocurcumin (THC) and hexahydrocurcumin (HHC) which are inactive compared to curcumin itself and so when metabolised the activity of curcumin seems to be lost.  The development of nanotechnology methods to overcome the bioavailability issues associated with curcumin has led to the production of a number of highly absorbable, and therefore effective, curcumin supplements that can be used to complement numerous therapeutic interventions. [5] Similar technology can be applied to other poorly absorbed nutrients such as ubiquinol, and by adopting VESIsorb technology to this potent antioxidant (which effectively shuttles ubiquinol across the gut barrier and into the enterocytes of the gut) significantly improves its ability to raise blood levels effectively for maximum antioxidant and anti-inflammatory benefits. [6]

Managing dysbiosis – an early trigger of inflammation

The gut microbiota (which plays a number of essential roles in the maintenance of the health of the host) is constantly exposed to and affected by numerous external factors (such as diet, medication, stress and so on) and alterations in the composition and/or function of the microbiota have been described in several disease states including depression, diabetes and disorders of the GI tract (such as colorectal cancer and inflammatory bowel diseases, to name but a few). [7]. A common factor in all these conditions is a change in the balance of Firmicutes and Bacteroidetes. Toll-like receptors (TLRs) are membrane-bound sensors that function to detect and respond to microbial infection and thus the family of Toll-like receptors play a crucial role in the detection of microbial infection and the appropriate induction of immune and inflammatory responses.  Lipopolysaccharides (LPS) are endotoxins found as a major component of the outer membrane of gram-negative bacteria.  LPS function to activate TLRs such as Toll-like 4 receptors (TLR4) and the increased number of Firmicutes associated with many western conditions significantly contributes to increased LPS activity of TLR4, resulting in the up-regulation of  the expression of a number of pro-inflammatory cytokines, nitric oxide, and pro-inflammatory eicosanoids associated with the inflammatory cascade.   It has (unsurprisingly) been suggested that dysbiosis could be the link through a molecular crosstalk of the multiple inflammatory pathways linked to inflammatory conditions.   High fat diets, common to westernised populations, affect the composition of the gut flora resulting in an increase in Firmicutes and a reduction in both Bacteroidetes and Bifidobacterium.  With the recent 180 degree ‘turnaround’ of dietary advice regarding the role of high fat diets and cardiovascular disease risk, it should not be forgotten that 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.  Intestinal microbes altered by a 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. This in turn has the potential to lead to an increased risk of obesity, metabolic syndrome and type II diabetes. [8]  As with many dietary factors, the ‘facts’ are not black or white and dietary advice should be reflective of this; however, manipulating the gut flora via the consumption of fermented foods like sauerkraut, kimchi, yogurt or kefir can have huge benefits for the client.  Additional supplementation with probiotics (such as Bifidobacteria, Lactobacilli and Saccharomyces) in combination with prebiotics (short-chain non-digestible carbohydrates) can offer additional benefits.  The inulin-type fructans, fructo-oligosaccharides (FOS) and galacto-oligosaccharides (GOS) are the quintessential prebiotics (occurring naturally in cereals, fruits and vegetables) as they directly target bacterial groups such as Bifidobacterium and Lactobacillus.  Dysbiosis is a growing problem of western dietary behaviours and is associated with numerous health conditions.  Identifying and managing dysbiosis, or encouraging the client to adopt a ‘healthier’ gut flora can have wide implications on their general health.

 

Nutrient Interventions/conditions Suggested dose range
Epigallocatechin gallate (EGCG) [10,11] Metabolic syndrome, obesity, type II diabetes, cancer and cardiovascular health 200-300mg daily
Resveratrol [12] Cardiovascular health, neurodegenerative diseases and cancer 100-500mg daily
Curcumin [13] Arthritis, cardiovascular health,  neurodegenerative diseases, metabolic and autoimmune disease, cancer, liver disease and general inflammatory conditions ≥200mg daily
Ubiquinol  [14,15,16] Parkinson’s disease, fertility 100-200mg daily
Lycopene [17, 18, 19] Age-related eye diseases, cancer, cardiovascular health, benign prostatic hypertrophy (BPH) 10-75mg daily
Multi strain probiotic Digestive integrity, autoimmune conditions, general inflammatory support  Min. 5 billion CFU

Table 1.  Examples of anti-inflammatory nutrients often used as add-ons for the management of inflammatory-related conditions.

Summary

Inflammation has many players and contributors, with some working in isolation and other working in a cross-talking fashion.  From transcription factors (of which NF-kB is just one example), to transcription factor activator proteins, to the toll-like receptors, protein kinases, the peroxisome proliferator-activated receptors (that, in addition to regulating inflammation, also regulate carbohydrate and lipid metabolism) – the list is not exhaustive.  Different ‘nutrients’ act on different ‘players’, with some more effective at dampening the inflammatory response than others.  The combination of an anti-inflammatory diet approach which is coupled with nutrient combinations such as EPA, ubiquinol and additional micronutrients/nutrients (Table 1) can help to modulate inflammation more effectively than single nutrients alone.

References

[1] Tergaonkar V.  NFkappaB pathway: a good signaling paradigm and therapeutic target. Int J Biochem Cell Biol. 2006;38(10):1647-53.

[2] Simmonds REFoxwell BM. Signalling, inflammation and arthritis: NF-kappaB and its relevance to arthritis and inflammation. Rheumatology (Oxford). 2008 May;47(5):584-90.

[3] Ben-Neriah YKarin M. Inflammation meets cancer, with NF-κB as the matchmaker. Nat Immunol. 2011 Jul 19;12(8):715-23.

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

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

[6] Liu ZX, Artmann C: Relative bioavailability comparison of different coenzyme Q10 formulations with a novel delivery system. Alternative therapies in health and medicine 2009, 15:42-46.

[7]  Jurjus A, Eid A, Al Kattar S, Zeenny MN, Gerges-Geagea A, Haydar H, Hilal A, Oueidat D, Matar M, Tawilah J, Hussein IH, Schembri-Wismayer P, Cappello F, Tomasello G, Leone A, Jurjus RA. Inflammatory bowel disease, colorectal cancer and type 2 diabetes mellitus: The links. BBA Clin. 2015 Nov 5;5:16-24.

[8] 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. S.

[9] Conlon MA, Bird AR. The impact of diet and lifestyle on gut microbiota and human health. Nutrients. 2014 Dec 24;7(1):17-44.

[10]  Zaveri NT. Green tea and its polyphenolic catechins: medicinal uses in cancer and noncancer applications. Life Sci. 2006 Mar 27;78(18):2073-80. Epub 2006 Jan 30. Review.

[11]  Chacko SM, Thambi PT, Kuttan R, Nishigaki I. Beneficial effects of green tea: a literature review. Chin Med. 2010 Apr 6;5:13.

[12] Kuršvietienė L, Stanevičienė I, Mongirdienė A, Bernatonienė J.Multiplicity of effects and health benefits of resveratrol. Medicina (Kaunas). 2016;52(3):148-55. doi: 10.1016/j.medici.2016.03.003. Epub 2016 Apr 7. Review.

[13] Aggarwal BB, Harikumar KB.Potential therapeutic effects of curcumin, the anti- inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. Int J Biochem Cell Biol. 2009 Jan;41(1):40-59.

[14] 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.

[15] Thakur AS, Littarru GP, Funahashi I, Painkara US, Dange NS, Chauhan P. Effect of Ubiquinol Therapy on Sperm Parameters and Serum Testosterone Levels in Oligoasthenozoospermic Infertile Men. J Clin Diagn Res. 2015 Sep;9(9):BC01-3

[16] Safarinejad MR, Safarinejad S, Shafiei N, Safarinejad S Effects of the reduced form of coenzyme Q10 (ubiquinol) on semen parameters in men with idiopathic infertility: a double-blind, placebo controlled, randomized study..J Urol. 2012 Aug;188(2):526-31.

[17] Lycopene and Risk of Prostate Cancer: A Systematic Review and Meta-Analysis. Chen P, Zhang W, Wang X, Zhao K, Negi DS, Zhuo L, Qi M, Wang X, Zhang X. Medicine (Baltimore). 2015 Aug;94(33):e1260.

[18] Ilic D.  Lycopene for the prevention and treatment of prostate disease. Recent Results Cancer Res. 2014;202:109-14.

[19] Selvan VK, Vijayakumar A, Kumar S & Singh GN.  Lycopene’s Effects on Health and Diseases. Natural Medicine Journal. March 2011 Vol. 3 Issue 3

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Coenzyme Q10 and neurodegenerative conditions
Safe support for clients with cancer

Dr Nina Bailey

About Dr Nina Bailey

Nina is a leading expert in marine fatty acids and their role in health and disease. Nina holds a master’s degree in Clinical Nutrition and received her doctorate from Cambridge University. Nina’s main area of interest is the role of essential fatty acids in inflammatory disorders. She is a published scientist and regularly features in national health publications and has featured as a nutrition expert on several leading and regional radio stations including SKY.FM, various BBC stations and London’s Biggest Conversation. Nina regularly holds training workshops and webinars both with the public and health practitioners.