Optimal DX Supplement Series: Inflammation Management

Inflammation is a normal and protective response involving immune and non-immune cell activation in response to an insult. These insults may include infection, a toxin, damaged cells, or irradiation.The inflammatory response aims to support removing offending substances and restoring tissue homeostasis (Oronsky 2022). Inflammation is a complex process involving a series of mediators involved in its initiation, regulation, and resolution (Ahmed 2011). Sometimes, the inflammation extends beyond usefulness.

Chronic inflammation is inflammation without normal and healthy resolution. When inflammation turns chronic, it can be harmful. In fact, non-resolving inflammation is a major driver for disease, contributing significantly to conditions such as atherosclerosis, obesity, cancer, chronic obstructive pulmonary disease, asthma, inflammatory bowel disease, neurodegenerative disease, multiple sclerosis, and rheumatoid arthritis (Nathan 2010).

Nutrition supplementation can help reduce inflammation by intervening with pathways that generate pro-inflammatory compounds. For example, mechanisms of action for supplements commonly used to manage rheumatoid arthritis include (Fares 2024):

Curcumin

• Inhibits inflammatory cytokines TNF-alpha, IL-1, IL-6 and signaling pathways involving NF-kB and JNK
• Inhibits activation and differentiation of inflammatory immune cells, including macrophages, dendritic cells, and T cells
• Significantly reduced ESR, HOMA-IR, hs-CRP, triglycerides, body weight, and waist circumference in a double-blind, placebo-controlled study of women with rheumatoid arthritis

Ginger

• Blocks inflammatory pathway enzymes and cytokines, including cyclooxygenase-1, cyclooxygenase-2, 5-lipooxygenase, and IL-1, IL-12, IL-B1, IL-6, TNF-alpha, and pro-inflammatory chemokines in LPS-induced macrophages

Green tea polyphenols    

• Inhibit TNF-alpha, IL-1B, IL-6, IL-8, and NF-kB
• Neutralized reactive oxygen species that contribute to inflammation
• Doses above 800 mg/day may contribute to liver toxicity
• Ideally, choose extracts standardized to 70-80% polyphenols
• Epigallocatechin gallate (EGCG) is one of the most commonly supplemented green tea polyphenols

Omega-3 fatty acids

• Modulate immune cell function and cytokine production
• Improve cell membrane fatty acid composition
• Interfere with lipid rafts
• Prevent activation of pro-inflammatory NFkB
• Stimulates anti-inflammatory PPAR-gamma
• Compete with potentially pro-inflammatory omega-6 fatty acids
• Preformed EPA and DHA may be preferred to their precursor alpha-linolenic acid from flax, chia, and walnuts due to low conversion to EPA and DHA.
• Fish oil supplements generally comprise a total of 20-40% EPA and DHA

Quercetin

• Present in many fruits, vegetables, and grains
• Reduces pro-inflammatory cytokines
• Inhibits the production of reactive oxygen species
• Balances immune cell activity
• Inhibits invasion of fibroblast-like synoviocytes
• Restrains osteoclastogenesis

Vitamin D

• Modulates T cell populations
• Suppresses pro-inflammatory Th17 cells that promote rheumatoid arthritis pathogenesis
• Interacts with vitamin D receptors to reduce IL-17 and TNF-alpha and increases anti-inflammatory IL-10.
• Doses as high as 60,000 IU/week for six weeks and then monthly for 12 weeks yielded positive results in rheumatoid arthritis patients.
• Note: Serum vitamin D and calcium levels should be monitored, and supplementation should be adjusted accordingly with high-dose vitamin D.

Willow bark

• Suppresses TNF-alpha, COX-2, and NF-kB nuclear migration
• Contains salicin, a precursor to salicylic acid, which possesses antioxidant, analgesic, antipyretic, and anti-inflammatory properties
• A dose of 240 mg/day of salicin for six weeks is commonly used for rheumatoid arthritis

The complex pathophysiology of rheumatoid arthritis (RA) includes a network of immune, molecular, and cellular interactions leading to chronic inflammation and joint destruction

Source: Fares, Saliba et al. “Over-the-Counter Anti-inflammatory Supplements for Adjunctive Rheumatoid Arthritis Therapy: A Comprehensive Narrative Review.” Aging and disease, 10.14336/AD.2024.0131. 3 Feb. 2024, doi:10.14336/AD.2024.0131 This is an open-access article distributed under the terms of the Creative Commons Attribution License

Supplement dosing to manage inflammation

Omega-3 polyunsaturated fatty acids (PUFAs)

1.25 to 2.5 g/d of PUFAs for 12 weeks (Kiecolt-Glaser 2011 & 2012) or 3,000 mg/d of EPA and DHA (Murray 2012)

• Four months of 1.25 to 2.5 g/d n-3 PUFAs reduced serum inflammatory mediators (interleukin-6 and tumor necrosis factor alpha) in overweight, sedentary, middle-aged adults (Kiecolt-Glaser 2012).
• 5 g/d PUFAs with 2,085 mg eicosapentaenoic acid (EPA) and 348 mg docosahexaenoic acid (DHA) for 12 weeks resulted in a 14% decrease in lipopolysaccharide (LPS) stimulated interleukin 6 (IL-6) production and a 20% reduction in anxiety symptoms in medical students (Kiecolt-Glaser 2011).
• Individualized dosing of 27-54 mg/kg EPA and 18-36 mg/kg DHA over 30 weeks had anti-inflammatory effects and improved joint counts and pain in rheumatoid arthritis patients (Fares 2024).
• Specialized pro-resolving mediators (SPMs) derived from PUFAs are thought to be the mechanism by which PUFAs reduce inflammation.

Curcumin (Curcuma longa)

300 to 4,000 mg/d of curcumin (Examine.com)

• Combining curcumin with piperine or lipids is a common way to overcome curcumin’s poor bioavailability.
• 500 mg of BCM-95® (curcumin with turmeric essential oil) three times per day for 28 days had similar efficacy to diclofenac (NSAID) in osteoarthritis patients (Shep 2019).
• 500 mg/d of Curene® (curcumin with Aquasome® technology) for 60 days resulted in a statistically significant and clinically meaningful reduction in pain, stiffness, and improvement in physical functioning in subjects suffering from knee osteoarthritis (Panda 2018).
• Curcumin dosed at 500 mg/d for eight weeks significantly reduced ESR, HOMA-IR, hs-CRP, triglycerides, body weight, and waist circumference in a double-blind, placebo-controlled study of 48 women with rheumatoid arthritis. Notably, the placebo group significantly increased triglycerides and HOMA-IR values (Fares 2024).

Ginger (Zingiber officinale)

1 to 2 g of dried ginger root powder two to three times daily (Stengler 2016)

• Bioactive compounds of ginger, such as 6-shogaol, zingerone, and 8-shogaol, reduce pro-inflammatory molecules by inhibiting cyclooxygenase (COX) and lipoxygenase (LOX) enzymes (Mutthuraj 2020, Ballester 2022).
• A systematic review and meta-analysis of randomized, controlled trials demonstrates a significant impact of ginger in lowering circulating inflammatory mediators (e.g., CRP, TNF-alpha) (Morvaridzadeh 2020).

Boswellia (Boswellia serrata)

338 to 3,600 mg/d of standardized extract (Majeed 2019)

• Boswellia is one of the most ancient and valued herbs in Ayurveda (Siddiqui 2011).
• In vitro studies demonstrate that boswellic acids are direct 5-LOX inhibitors that efficiently suppress inflammatory 5-LOX products (Siddiqui 2011).
• 338 mg of Boswellin® (6 mg of total β-boswellic acids per day) for 120 days significantly improved the physical function of arthritis patients, reducing pain, stiffness, and serum levels of high-sensitive C-reactive protein (Majeed 2019).

Quercetin

500 to 2,272 mg/d (Examine.com, Mohammadi-Sartang 2017)

• C-reactive protein (CRP) is a sensitive inflammatory biomarker. In a systematic review and meta-analysis of randomized controlled trials, quercetin supplementation significantly affected CRP, predominantly at doses above 500 mg/day in patients with CRP >3 mg/l (Mohammadi-Sartang 2017).
• Eight-week supplementation with 500 mg quercetin-vitamin C in athletes effectively reduced oxidative stress and inflammatory biomarkers, including CRP and IL-6 (Askari 2012).
• A double-blind, placebo-controlled study of 50 women with rheumatoid arthritis found that 500 mg/day of quercetin for eight weeks significantly improved morning stiffness, pain, disease activity scores, health assessment scoring, and TNF-alpha levels. Improvements were also observed in erythrocyte sedimentation rate, swollen joint scores, and physical global assessment compared to placebo (Fares 2024).

References

Ahmed, Afsar U. "An overview of inflammation: mechanism and consequences." Frontiers in Biology 6.4 (2011): 274-281.

Askari, Gholamreza et al. “The effect of quercetin supplementation on selected markers of inflammation and oxidative stress.” Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences vol. 17,7 (2012): 637-41.

Ballester, Pura et al. “Effect of Ginger on Inflammatory Diseases.” Molecules (Basel, Switzerland) vol. 27,21 7223. 25 Oct. 2022, doi:10.3390/molecules27217223

Curcumin. Examine.com. Accessed July 15, 2024. https://examine.com/supplements/curcumin/#dosage-information

Fares, Saliba et al. “Over-the-Counter Anti-inflammatory Supplements for Adjunctive Rheumatoid Arthritis Therapy: A Comprehensive Narrative Review.” Aging and disease, 10.14336/AD.2024.0131. 3 Feb. 2024, doi:10.14336/AD.2024.0131

Kiecolt-Glaser, Janice K et al. “Omega-3 supplementation lowers inflammation and anxiety in medical students: a randomized controlled trial.” Brain, behavior, and immunity vol. 25,8 (2011): 1725-34. doi:10.1016/j.bbi.2011.07.229

Kiecolt-Glaser, Janice K et al. “Omega-3 supplementation lowers inflammation in healthy middle-aged and older adults: a randomized controlled trial.” Brain, behavior, and immunity vol. 26,6 (2012): 988-95. doi:10.1016/j.bbi.2012.05.011

Majeed, Muhammed, et al. "A pilot, randomized, double‐blind, placebo‐controlled trial to assess the safety and efficacy of a novel Boswellia serrata extract in the management of osteoarthritis of the knee." Phytotherapy Research 33.5 (2019): 1457-1468.

Mohammadi-Sartang, M., et al. "Effects of supplementation with quercetin on plasma C-reactive protein concentrations: a systematic review and meta-analysis of randomized controlled trials." European journal of clinical nutrition 71.9 (2017): 1033-1039.

Morvaridzadeh, Mojgan, et al. "Effect of ginger (Zingiber officinale) on inflammatory markers: A systematic review and meta-analysis of randomized controlled trials." Cytokine 135 (2020): 155224.

Murray, Michael and Pizzorno, Joseph. (2012). The Encyclopedia of Natural Medicine (Rev. 3rd ed.). Atria Books.

Mutthuraj, D., et al. "Inhibition of pro-inflammatory molecules by ginger (zingiber officinale roscoe) and its anti-inflammatory effects on arthritis patients." Journal of Drug Delivery and Therapeutics 10.2-s (2020): 125-139.

Nathan, Carl, and Aihao Ding. "Nonresolving inflammation." Cell 140.6 (2010): 871-882.

Quercetin. Examine.com. Accessed July 16, 2024. https://examine.com/supplements/quercetin/

S-adenosylmethionine. Examine.com. Accessed July 16, 2024. https://examine.com/supplements/s-adenosyl-methionine/#dosage-information

Shep, Dhaneshwar et al. “Safety and efficacy of curcumin versus diclofenac in knee osteoarthritis: a randomized open-label parallel-arm study.” Trials vol. 20,1 214. 11 Apr. 2019, doi:10.1186/s13063-019-3327-2

Siddiqui, M Z. “Boswellia serrata, a potential antiinflammatory agent: an overview.” Indian journal of pharmaceutical sciences vol. 73,3 (2011): 255-61. doi:10.4103/0250-474X.93507

Stengler M, et al. Prescription for Natural Cures: A Self-care Guide for Treating Health Problems With Natural Remedies Including Diet, Nutrition, Supplements, and Other Holistic Methods. Third ed. Turner Publishing Co, 2016.

Oronsky, Bryan et al. “What Exactly Is Inflammation (and What Is It Not?).” International journal of molecular sciences vol. 23,23 14905. 28 Nov. 2022, doi:10.3390/ijms232314905

Panda, Sanjib Kumar et al. “A Randomized, Double Blind, Placebo Controlled, Parallel-Group Study to Evaluate the Safety and Efficacy of Curene® versus Placebo in Reducing Symptoms of Knee OA.” BioMed research international vol. 2018 5291945. 25 Oct. 2018, doi:10.1155/2018/5291945