Chronic Low-Grade Inflammation, Metabolic Syndrome & Dietary Recommendations: Implications for Physical Therapists

Inflammation is necessary for regeneration, proliferation and healing,1 especially in the acute phase of healing post-injury or surgery.2 Numerous cells within the body release inflammatory mediators, which propagate pain in joints, tendons, discs, muscles, ligaments fascia and epineurium so as to signal an immune response.  Macrophages and monocytes remove tissue debris and release cytokines, chemokines and growth factors, which propagate inflammation.3, 4 In doing so, tissue remodeling is facilitated by removing apoptotic neutrophils.4 Thus, inflammation drives both a vascular and cellular immune response so as to protect and repair compromised tissue.5

However, inflammation becomes problematic when anti-inflammatory mediators (e.g., lipoxins, aspirin-triggered lipoxins, PGE2,PGD2, glucocorticoids, resolvins, protectins, annexin-1, cyclopentenone prostaglandins)6 are not released appropriately to break the cycle. As a result, inflammatory markers (e.g., c-reactive protein, histamine, cytokines, free radicals, eicosanoids, tumor necrosis growth factor, bradykinins and interleukin-6) remain elevated, both locally and systemically, causing low-grade chronic inflammation, which is present in many degenerative conditions such as osteoarthritis, rheumatoid arthritis and various other neuromusculoskeletal pain syndromes.3, 7-12 While many patients attempt to control and break the cycle of chronic inflammation with synthetic inflammatory agents, many of these oral medicines are known to have adverse effects with long-term use.4

Chronic low-grade inflammation often accompanies metabolic syndrome and is thought to be a primary causative factor of the condition and its associated consequences.13 Metabolic syndrome describes a number of metabolic disturbances such as glucose intolerance, central obesity, hypertension and dyslipidemia and has been linked to cardiovascular disease, type-2 diabetes, stroke and cancer.14  Individuals with metabolic syndrome are also more likely to have musculoskeletal pain and tendinopathies.3, 15 For example, researchers have found a link between increased waist circumference and insulin resistance with rotator cuff tendinitis16 and Achilles tendinopathy.15

While overuse can be a causative factor for tendon related pathologies, nearly one third of tendon injuries affect sedentary, overweight individuals and have been associated with dyslipidemia, insulin resistance, hypertension and obesity.15 Insulin resistance has also been linked to fat deposits and inflammation in muscle, resulting in less force production and increased atrophy.15-18 Additionally, patients with metabolic syndrome have a higher prevalence of painful neuropathy, allodynia, and hyperalgsia.9Given the relationship between food consumption and chronic, low-grade inflammation,19 diet may be an important consideration for physical therapists attempting to optimize therapeutic outcomes. 

DIET & INFLAMMATION

According to Ann Wigmore, “The foods you eat can be either the safest and most powerful form of medicine or the slowest form of poison.”20 Moreover, 60% of the American diet comes from starches, sugars, flour and foods with a high glycemic index,21 which stimulates postprandial free radicals and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), both of which mediate inflammation.3, 16

Additionally, 30% of the American diet consists of meat and dairy products rich in omega-6 fatty acids (also referred to as linoleic acid or arachidonic acid), which significantly contributes to the membrane phospholipids of cells involved in inflammation and mediates two potent pro-inflammatory eicosanoids, prostaglandin and leukotrienes.22 Arachidonic acid, accumulates in joints due to excessive consumption,3 and has been shown to be elevated in the cartilage and synovial fluid of patients with osteoarthritis.23, 24 Although omega-3 fatty acids found in lean meats, fish, eggs, and nuts have significant anti-inflammatory benefits, the ratio of consumption of omega-6 to omega-3 fatty acids ranges between 15:1 and 20:1.25

Notably, only 10% of the American diet is comprised of fruits and vegetables, which aid in anti-inflammation.21The majority of experimental studies included in a recent systematic review found that fruits and vegetables led to increased anti-inflammatory biomarkers including high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and E-selectin along with stronger immune system activity.26 Moreover, one cohort27 and 5 cross-sectional studies28-32 reported an inverse association between fruit and vegetable intake and circulating factors of inflammation.26 Additionally, fruits and vegetables also contain antioxidants, which neutralize free radicals and limit inflammatory arachidonic acid and cytokines.33

DIET & REHABILITATION

While many post-injury nutrition strategies aim to reduce and/or abolish inflammation, it is an important aspect of wound healing, and nutritional interventions meant to drastically reduce inflammation should be avoided.34 However, small dietary changes designed to control inflammation (as described above) may facilitate recovery35 and reduce the risk for chronic dysfunction and pain.36 In addition, the following dietary recommendations may be considered during the rehabilitation of muscle, bone and connective tissue:

DIET AND MUSCLE TISSUE REPAIR

Individuals that have suffered a muscle injury should be careful not to significantly reduce their carbohydrate intake, as the healing process has been shown to result in a substantial increase in energy expenditure.37 Furthermore, additional protein is recommended to limit muscle atrophy and promote repair.38 However, the most frequently studied micronutrients to promote skeletal muscle repair are vitamin D, polyphenols, vitamin C, vitamin E, and creatine monohydrate.38, 39

Vitamin D deficiencies have been shown to impair muscle regeneration, and for individuals with limited sun exposure, 2000 to 4000 IU D3 is recommended per day.40 While polyphenols have been found to attenuate muscle damage caused by inflammation and promote free radical production, recent studies have reported limited ability for Vitamins C and E to promote repair.41 In contrast, creatine monohydrate has been found to attenuate upper arm muscle mass and lower leg muscle hypertrophy during immobilization.42  Therefore, 20g/day for 5 days followed by 5g/day thereafter is recommended to facilitate muscle healing.42

DIET AND BONE REPAIR

For bones, consumption of dairy, fruit and green, leafy vegetables are recommended, as these foods contain calcium, protein, magnesium, phosphorus, vitamin D, potassium and fluoride to support bone formation and manganese, copper, boron, iron, zinc, vitamin A, vitamin K, vitamin C and vitamin B for bone health.38, 43 Notably, a number of studies have specifically linked stress fractures to deficiencies in vitamin D, calcium and carbohydrate intake.44 While protein intake has been debated for bone strength and repair secondary to acidic load,45 recent systematic reviews46 and meta-analyses47 do still recommend a high-protein intake during recovery.38 

DIET & CONNECTIVE TISSUE REPAIR

For ligament and tendon injuries, a combination of load and nutritional interventions has been recommended to maximize healing.48 Vitamin C and copper regulate prolyl hydroxylase and lysyl oxidase activity, respectively,49, 50 which are required for collagen cross-linking and export from the endoplasmic reticulum. Supplementing high-dose vitamin C every two days has been shown to improve Achilles tendon healing due to angiogenesis and increased collagen synthesis.51 Moreover, following histological evaluations of rat Achilles tendons, a combination of high-dose vitamin C and hyaluronic acid has shown significant therapeutic effects compared to controls, particularly in the later stages of tendon healing.52

Glycine, is an amino acid, a building block for protein, and allows collagen to form a tight triple helix, which facilitates strength. Previous studies that gave rats a 5% glycine diet reported increased collagen, glycosaminoglycan, and mechanical strength 21 days after Achilles tendon injury.53 Gelatin or hydrolyzed collagen may also increase collagen synthesis and promote repair.38 Previous double-blind, placebo-controlled randomized controlled trials found that consuming 10g of hydrolyzed collagen led to improved knee pain in athletes,54 and consuming 15g resulted in double the collagen synthesis.55

Improved collagen synthesis of engineered ligaments was recently found when vitamin C induced gelatin was incorporated into an intermittent exercise program.55 Notably, Gatorade now recommends ingesting both vitamin C and gelatin to prevent connective tissue injuries and accelerate recovery following injury.56 While turmeric curcumin, taurine, arginine, bromelain and boswellic acid have all been linked to tendon and ligament health due to their ability to reduce inflammation, the role of inflammation in tendinopathy continues to be a topic of debate in the literature.38 Supplements that protect and promote connective tissue biosynthesis continue to be heavily researched by pharmaceutical powerhouses such as Ortho Molecular and Vital Proteins.57, 58 

CONCLUSIONS

While inflammation is an important aspect of tissue protection and repair following injury, chronic low-grade inflammation is a causative or contributing factor in a number of musculoskeletal disorders, degenerative diseases, and metabolic syndrome comorbidities.  Given the close relationship between food consumption, inflammation and repair rates for various tissue types (i.e., muscle, bone, tendon, ligament), physical therapists should consider diet education as part of their treatment strategy. 

AUTHORS

Raymond Butts, PhD, DPT, MSc, Dip. Osteopractic
Senior Instructor, American Academy of Manipulative Therapy
Coordinator, AAMT Fellowship in Orthopaedic Manual Physical Therapy
Louisville, KY

Benjamin England, DPT, Dip. Osteopractic, Cert. SMT, Cert. DN
Physical Therapist, Mallers & Swoverland Orthopaedic Physical Therapy
Fellow-in-Training, AAMT Fellowship in Orthopaedic Manual Physical Therapy
Fort Wayne, IN

Robin Bewley, DPT, OTR/L, OCS, Dip. Osteopractic
Fellow-in-Training, AAMT Fellowship in Orthopaedic Manual Physical Therapy
Physical Therapist & Clinic Director, Physio Whitefish
Whitefish, MT

James Dunning, PhD, DPT, MSc, FAAOMPT, Dip. Osteopractic
Director, AAMT Fellowship in Orthopaedic Manual Physical Therapy
Owner, Montgomery Osteopractic Physiotherapy & Acupuncture Clinic
Montgomery, AL

REFERENCES

1.         Kumar V, Abbas A.K, Aster J.C, Robbins S.L. Inflammation and repair. Robbins Basic Pathology. Philadelphia, London: Saunders; 2012. pp. 29–74.

2.         Julier Z, Park AJ, Briquez PS, Martino MM. Promoting tissue regeneration by modulating the immune system. Acta Biomater. 2017;53:13-28.

3.         Seaman DR. The diet-induced proinflammatory state: a cause of chronic pain and other degenerative diseases? J Manipulative Physiol Ther. 2002;25(3):168-79.

4.         Abdulkhaleq LA, Assi MA, Abdullah R, Zamri-Saad M, Taufiq-Yap YH, Hezmee MNM. The crucial roles of inflammatory mediators in inflammation: A review. Vet World. 2018;11(5):627-35.

5.         Nguyen T.T. Systems Biology Approaches to Corticosteroid Pharmacogenomics and Systemic Inflammation (Doctoral dissertation, Rutgers University-Graduate School-New Brunswick) 2012

6.         Serhan CN. Systems approach to inflammation resolution: identification of novel anti-inflammatory and pro-resolving mediators. J Thromb Haemost. 2009;7 Suppl 1:44-8.

7.         Richardson JD, Vasko MR. Cellular mechanisms of neurogenic inflammation. J Pharmacol Exp Ther. 2002;302(3):839-45.

8.         Gleeson M, Bishop NC, Stensel DJ, Lindley MR, Mastana SS, Nimmo MA. The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nat Rev Immunol. 2011;11(9):607-15.

9.         Zhang C, Ward J, Dauch JR, Tanzi RE, Cheng HT. Cytokine-mediated inflammation mediates painful neuropathy from metabolic syndrome. PLoS One. 2018;13(2):e0192333.

10.      Adam O, Beringer C, Kless T, Lemmen C, Adam A, Wiseman M, et al. Anti-inflammatory effects of a low arachidonic acid diet and fish oil in patients with rheumatoid arthritis. Rheumatol Int. 2003;23(1):27-36.

11.      Bosma-den Boer MM, van Wetten ML, Pruimboom L. Chronic inflammatory diseases are stimulated by current lifestyle: how diet, stress levels and medication prevent our body from recovering. Nutr Metab (Lond). 2012;9(1):32.

12.      Esposito K, Giugliano D. Diet and inflammation: a link to metabolic and cardiovascular diseases. Eur Heart J. 2006;27(1):15-20.

13.      Sharma P. Inflammation and the metabolic syndrome. Indian J Clin Biochem. 2011;26(4):317-8.

14.      10.      MacGill M. Metabolic syndrome: symptoms, diagnosis and causes. medicalnewstoday.com. Published May 18, 2018. Accessed June 7, 2020.

15.      Gaida JE, Alfredson L, Kiss ZS, Wilson AM, Alfredson H, Cook JL. Dyslipidemia in Achilles tendinopathy is characteristic of insulin resistance. Med Sci Sports Exerc. 2009;41(6):1194-7.

16.      Rechardt M, Shiri R, Karppinen J, Jula A, Heliovaara M, Viikari-Juntura E. Lifestyle and metabolic factors in relation to shoulder pain and rotator cuff tendinitis: a population-based study. BMC Musculoskelet Disord. 2010;11:165.

17.      Wolf R. Wired to Eat. New York, NY: Harmony Books; 2017.

18.      Addison O, LaStayo PC, Dibble LE, Marcus RL. Inflammation, aging, and adiposity: implications for physical therapists. J Geriatr Phys Ther. 2012;35(2):86-94.

19.      Minihane AM, Vinoy S, Russell WR, Baka A, Roche HM, Tuohy KM, et al. Low-grade inflammation, diet composition and health: current research evidence and its translation. Br J Nutr. 2015;114(7):999-1012.

20.      Wigmore AHNRS. The wheatgrass way to super health and vitality: it’s easy to grow your own! Health News & Review. 1992;Spring.

21.      Cordain L, Eaton SB, Sebastian A, Mann N, Lindeberg S, Watkins BA, et al. Origins and evolution of the Western diet: health implications for the 21st century. Am J Clin Nutr. 2005;81(2):341-54.

22.      Innes JK, Calder PC. Omega-6 fatty acids and inflammation. Prostaglandins Leukot Essent Fatty Acids. 2018;132:41-8.

23.      Plumb MS, Aspden RM. High levels of fat and (n-6) fatty acids in cancellous bone in osteoarthritis. Lipids Health Dis. 2004;3:12.

24.      Bonnet CS, Walsh DA. Osteoarthritis, angiogenesis and inflammation. Rheumatology (Oxford). 2005;44(1):7-16.

25.      Kohatsu W. The Aniti-inflammatory Diet. Rakel D, editor. Philadelphia: Saunders, WH; 2010.

26.      Hosseini B, Berthon BS, Saedisomeolia A, Starkey MR, Collison A, Wark PAB, et al. Effects of fruit and vegetable consumption on inflammatory biomarkers and immune cell populations: a systematic literature review and meta-analysis. Am J Clin Nutr. 2018;108(1):136-55.

27.      Romieu I, Barraza-Villarreal A, Escamilla-Nunez C, Texcalac-Sangrador JL, Hernandez-Cadena L, Diaz-Sanchez D, et al. Dietary intake, lung function and airway inflammation in Mexico City school children exposed to air pollutants. Respir Res. 2009;10:122.

28.      Holt EM, Steffen LM, Moran A, Basu S, Steinberger J, Ross JA, et al. Fruit and vegetable consumption and its relation to markers of inflammation and oxidative stress in adolescents. J Am Diet Assoc. 2009;109(3):414-21.

29.      Almeida-de-Souza J, Santos R, Lopes L, Abreu S, Moreira C, Padrao P, et al. Associations between fruit and vegetable variety and low-grade inflammation in Portuguese adolescents from LabMed Physical Activity Study. Eur J Nutr. 2018;57(6):2055-68.

30.      Hermsdorff HH, Zulet MA, Puchau B, Martinez JA. Fruit and vegetable consumption and proinflammatory gene expression from peripheral blood mononuclear cells in young adults: a translational study. Nutr Metab (Lond). 2010;7:42.

31.      Lopez-Garcia E, Schulze MB, Fung TT, Meigs JB, Rifai N, Manson JE, et al. Major dietary patterns are related to plasma concentrations of markers of inflammation and endothelial dysfunction. Am J Clin Nutr. 2004;80(4):1029-35.

32.      Root MM, McGinn MC, Nieman DC, Henson DA, Heinz SA, Shanely RA, et al. Combined fruit and vegetable intake is correlated with improved inflammatory and oxidant status from a cross-sectional study in a community setting. Nutrients. 2012;4(1):29-41.

33.      Lobo V, Patil A, Phatak A, Chandra N. Free radicals, antioxidants and functional foods: Impact on human health. Pharmacogn Rev. 2010;4(8):118-26.

34.      Tipton KD. Nutritional Support for Exercise-Induced Injuries. Sports Med. 2015;45 Suppl 1:S93-104.

35.      Owens DJ, Twist C, Cobley JN, Howatson G, Close GL. Exercise-induced muscle damage: What is it, what causes it and what are the nutritional solutions? Eur J Sport Sci. 2019;19(1):71-85.

36.      Elma O, Yilmaz ST, Deliens T, Clarys P, Nijs J, Coppieters I, et al. Chronic Musculoskeletal Pain and Nutrition: Where Are We and Where Are We Heading? PM R. 2020.

37.      Frankenfield D. Energy expenditure and protein requirements after traumatic injury. Nutr Clin Pract. 2006;21(5):430-7.

38.      Close GL, Sale C, Baar K, Bermon S. Nutrition for the Prevention and Treatment of Injuries in Track and Field Athletes. Int J Sport Nutr Exerc Metab. 2019;29(2):189-97.

39.      Close GL, Kasper AM, Morton JP. From Paper to Podium: Quantifying the Translational Potential of Performance Nutrition Research. Sports Med. 2019;49(Suppl 1):25-37.

40.      Owens BD, Williams AE, Wolf JM. Risk factors for surgical complications in rotator cuff repair in a veteran population. J Shoulder Elbow Surg. 2015;24(11):1707-12.

41.      Peeling P, Binnie MJ, Goods PSR, Sim M, Burke LM. Evidence-Based Supplements for the Enhancement of Athletic Performance. Int J Sport Nutr Exerc Metab. 2018;28(2):178-87.

42.      Johnston AP, Burke DG, MacNeil LG, Candow DG. Effect of creatine supplementation during cast-induced immobilization on the preservation of muscle mass, strength, and endurance. J Strength Cond Res. 2009;23(1):116-20.

43.      Palacios C. The Role of Nutrients and Bone Health: from A to Z. Critical Reviews in Food Sciena dn Nutrition. 2006;46:621-8.

44.      Moran DS, Heled Y, Arbel Y, Israeli E, Finestone AS, Evans RK, et al. Dietary intake and stress fractures among elite male combat recruits. J Int Soc Sports Nutr. 2012;9(1):6.

45.      Barzel US, Massey LK. Excess dietary protein can adversely affect bone. J Nutr. 1998;128(6):1051-3.

46.      Rizzoli R, Biver E, Bonjour JP, Coxam V, Goltzman D, Kanis JA, et al. Benefits and safety of dietary protein for bone health-an expert consensus paper endorsed by the European Society for Clinical and Economical Aspects of Osteopororosis, Osteoarthritis, and Musculoskeletal Diseases and by the International Osteoporosis Foundation. Osteoporos Int. 2018;29(9):1933-48.

47.      Shams-White MM, Chung M, Fu Z, Insogna KL, Karlsen MC, LeBoff MS, et al. Animal versus plant protein and adult bone health: A systematic review and meta-analysis from the National Osteoporosis Foundation. PLoS One. 2018;13(2):e0192459.

48.      Baar K. Stress relaxation and targeted nutrition to treat patellar tendinopathy. Interntional Journal of Sport Nutrition and Exercise Metabolism. 2018:1-18.

49.      Mussini E, Hutton JJ, Jr., Udenfriend S. Collagen proline hydroxylase in wound healing, granuloma formation, scurvy, and growth. Science. 1967;157(3791):927-9.

50.      Kagan HM, Li W. Lysyl oxidase: properties, specificity, and biological roles inside and outside of the cell. J Cell Biochem. 2003;88(4):660-72.

51.      Omeroğlu S, Peker T, Türközkan N, Omeroğlu H. High-dose vitamin C supplementation accelerates the Achilles tendon healing in healthy rats. Archives of orthopaedic and trauma surgery. 2008;281(6).

52.      Dincel YM, Adanir O, Arikan Y, Caglar AK, Dogru SC, Arslan YZ. Effects of High-Dose Vitamin C and Hyaluronic Acid on Tendon Healing. Acta Ortop Bras. 2018;26(2):82-5.

53.      Vieira CP, De Oliveira LP, Da Re Guerra F, Dos Santos De Almeida M, Marcondes MC, Pimentel ER. Glycine improves biochemical and biomechanical properties following inflammation of the achilles tendon. Anat Rec (Hoboken). 2015;298(3):538-45.

54.      McAlindon TE, Nuite M, Krishnan N, Ruthazer R, Price LL, Burstein D, et al. Change in knee osteoarthritis cartilage detected by delayed gadolinium enhanced magnetic resonance imaging following treatment with collagen hydrolysate: a pilot randomized controlled trial. Osteoarthritis Cartilage. 2011;19(4):399-405.

55.      Shaw G, Lee-Barthel A, Ross ML, Wang B, Baar K. Vitamin C-enriched gelatin supplementation before intermittent activity augments collagen synthesis. Am J Clin Nutr. 2017;105(1):136-43.

56.      Baar K. Training and Nutrition to Prevent Soft Tissue Injuries and Accelerate Return to Play 2015 [cited 2020 July 23]. Available from: https://www.gssiweb.org/sports-science-exchange/article/sse-142-training-and-nutrition-to-prevent-soft-tissue-injuries-and-accelerate-return-to-play.

57.      CollaGEN  [cited 2020 July 23]. Available from: https://www.orthomolecularproducts.com/assets/1/30/OMPI-CollaGEN_PDN-B3.pdf.

58.      How Much Collagen Should You Take Every Day?  [cited 2020 July 23]. Available from: https://www.vitalproteins.com/?msclkid=626e58d3c4e21425fa1a07c9f63109a4.