Tuesday, February 3, 2015

Low Grade Inflammation and Diet

Key messages
  • There is reasonable level of evidence from 13 observational studies for an association between diets high in whole grains and lower levels of the inflammatory marker CRP.
  • There is limited evidence to indicate legumes may be beneficial in reducing low-grade inflammation.
  • There is evidence of an association between dietary fibre intake and lower levels of the markers of low-grade inflammation.
  • Studies suggest a positive relationship between higher consumption of refined grains and inflammatory diseases and inflammatory markers.
  • Whole grains may reduce low grade systemic inflammation by mediating insulin resistance, promoting weight loss or via antioxidant activity of naturally occurring key nutrients and phytochemicals.  
  • Fibre is thought to reduce inflammatory marker concentrations by mediating insulin resistance and promoting weight loss.

Low grade inflammation, also known as meta-inflammation or subclinical inflammation, is an immune system response to stimuli causing elevated pro-inflammatory markers in the bloodstream. In the hours following the consumption of a meal, there is an elevation in the concentrations of inflammatory markers in the bloodstream. However, in obese people and those with chronic disease these high levels of inflammation persist in a constant state. Low grade inflammation is different to acute/chronic inflammation where the latter is generally a response to high injury and trauma.

Researchers suggest, that just as the germ theory of the 19th Century helped us understand the case and spread of infectious disease, low grade inflammation may be the key feature underpinning a wide range of chronic diseases which plague the modern era – including type 2 diabetes and depression to heart disease, many forms of cancer, and even dementia.1 Consequently markers of low grade inflammation are beginning to be used as markers of chronic disease risk and are the targets of treatment.

Studies have established an association between lifestyle factors including diet and systemic inflammation. Among the components of a healthy diet, whole grains, vegetables, fruit, and fish are all associated with lower inflammation.2 However, proponents of the paleo diet and low carbohydrate diets suggest including grains in the diet results in a state of low grade inflammation, increasing risk of chronic disease.

What does the literature say?
Markers of low grade inflammation
Markers of low grade inflammation include C-reactive protein (CRP) and fibrogen which are markers of cardiovascular disease as well as interleukins and tumour necrosis factor alpha, indicators of higher risk of metabolic disorders including obesity and Type 2 diabetes.

Relationship between dietary whole grains, key nutrients and low grade inflammation
Evidence indicates whole grains and high fibre grains may be protective against low-grade inflammation.

A review of epidemiological and intervention studies on the effect of whole grain on low-grade inflammation concluded there is a reasonable level of evidence from 13 observational studies for an association between diets high in whole grains and lower CRP concentrations. However, the same review found intervention studies do not demonstrate a clear effect of increased whole grain consumption on CRP or other markers of inflammation. This may be explained by inconsistencies in the research methodologies in the five identified studies.3

Diets higher in refined grains, processed meats and fried foods are linked to higher levels of inflammatory markers.4 Studies conducted by Masters et al and Lu et al, showed that frequent consumption of refined grains  increased  the release of pro-inflammatory markers as opposed to a diet higher in whole grains.5,6 Similarly Liu et al reported an association between an increase in high glycemic loads and an increase in C- reactive protein, likely due to a diet high in refined foods.7

A review by Galisteo et al. of the effects of dietary fibre on metabolic syndrome outlines the evidence for the effect of fibre on inflammation.8 The review reports that an association between dietary fibre intakes and reduced levels of inflammatory markers has been shown in people with diabetes, hypertension or obesity, and an even stronger relationship among people with two or more of these conditions of metabolic syndrome.9 Two cross sectional studies and one longitudinal study indicate an association between dietary fibre intake and reduced CRP levels.10,11 A study of diabetic women found the intake of both cereal fibre, whole grains and bran to be associated with lower levels of CRP and TNF-α receptor 2 .6

Intervention trials on dietary fibre also indicate a beneficial effect on proinflammatory and anti-inflammatory cytokines and adipocytokines in adipose tissue. In one study IL-18 concentration decreased after consumption of a high-carbohydrate high-fibre meal (16.8 g fibre) in both healthy subjects and those with diabetes.12 Another study of 120 women followed for 2 years on a low energy Mediterranean-style diet including a higher intake of fibre (25 vs. 16 g/day in the control group) exhibited serum concentrations of proinflammatory markers IL-6, IL-18 and CRP.13

Relationship between dietary legumes and low grade inflammation
A meta-analysis of 17 intervention trials with a total of 2,300 people found the Mediterranean diet, characterised by high consumption of legumes, is linked to significantly increased levels of anti-inflammatory markers and significant decreases in anti-inflammatory markers.14

However a second meta-analysis of nine randomised controlled trials on the effects of legumes specifically (other than soy beans) on CRP found only a non-significant trend for the reduction of CRP with increasing legume intake. However, the study design appears to affect the results so more studies are needed to confirm the effect.15

There is no significant evidence of an effect of soy on low-grade inflammation. A review published in 2009 of 14 trials on soy foods found no significant effect on markers of inflammation.16 One large scale cohort study has reported an association between soy isoflavones and reduced CRP.17

Low-grade inflammation is a characteristic of the obese state, as obese people have higher circulating concentrations of many inflammatory markers than lean people. These markers are thought to play a role in causing insulin resistance and other metabolic disturbances. 

Higher intakes of whole grains are associated with reduction in body fat and improved insulin sensitivity, both of which are linked to reduction in inflammatory markers. It is proposed that the effect of whole grains is also likely to mediated through reduction in oxidative stress.18 Whole grains contain a range of compounds which may promote anti-inflammatory actions, preventing cellular oxidation and systemic inflammatory responses.18,19  These inclue the phyto-chemicals lignin and phyto-oestrogen as well as the nutrients vitamin E, selenium, zinc, magnesium and folate.

Phyto-chemicals in whole grains including lignans and phyto-sterols, are thought to act as antioxidants by preventing free radical damage to cells and tissues which induce an inflammatory response.20 Higher intakes of magnesium has been shown in two large studies to be linked to reduced likelihood  of inflammation.21,22 Folate, found in whole grains, has a role in folate-homocysteine regulation⁷ which in turn mediates  the release of inflammatory proteins.23

It has been suggested that the association between insoluble fibre intake and reduced risk of chronic disease may be explained in part by modulation of inflammatory markers. The effect of fibre may be as a result of aiding weight loss which is known to reduce inflammation, as a result of the role of fibre in modulating glycemic response or the production of butyrate as a result of fermentation in the gut.8

The proponents of grain avoidance suggest that grains induce inflammation by increased post-pradial insulin response which leads to fat deposition and consequently increase in inflammatory markers. In the hours following the consumption of a meal, there is an elevation in the concentrations of inflammatory mediators in the bloodstream, which is exaggerated in obese subjects and in type 2 diabetics. Both high-glucose and high-fat meals may induce postprandial inflammation.2 However, it is the quality of grain food choices that is important. Whole grain, high fibre and low GI grains reduce post-prandial glycemic response and therefore insulin levels.

The consumption of whole grains and high fibre grains is linked to reduced low-grade inflammation which may be part of the explanation for the reduced risk of chronic disease that results from a diet high in these foods. It is thought that the protective effect of whole grains and high fibre grains is as a result of the naturally occurring vitamins, minerals, fibre and phytochemicals which play a role in anti-inflammatory mechanisms.

  1. van Woudenbergh GJ, Theofylaktopoulou D, Kuijsten A, et al. Adapted dietary inflammatory index and its association with a summary score for low-grade inflammation and markers of glucose metabolism: the Cohort study on Diabetes and Atherosclerosis Maastricht (CODAM) and the Hoorn study. The American journal of clinical nutrition. 2014.
  2. Calder PC, Ahluwalia N, Brouns F, et al. Dietary factors and low-grade inflammation in relation to overweight and obesity. The British journal of nutrition. 2011;106 Suppl 3:S5-78.
  3. Lefevre M, Jonnalagadda S. Effect of whole grains on markers of subclinical inflammation. Nutrition reviews. 2012;70(7):387-396.
  4. Defagó MD, Elorriaga N, Irazola VE, Rubinstein AL. Influence of Food Patterns on Endothelial Biomarkers: A Systematic Review. The Journal of Clinical Hypertension. 2014;16(12):907-913.
  5. Masters RC, Liese AD, Haffner SM, Wagenknecht LE, Hanley AJ. Whole and Refined Grain Intakes Are Related to Inflammatory Protein Concentrations in Human Plasma. The Journal of nutrition. 2010;140(3):587-594.
  6. Qi L, van Dam RM, Liu S, Franz M, Mantzoros C, Hu FB. Whole-Grain, Bran, and Cereal Fiber Intakes and Markers of Systemic Inflammation in Diabetic Women. Diabetes care. 2006;29(2):207-211.
  7. Liu S, Manson JE, Buring JE, Stampfer MJ, Willett WC, Ridker PM. Relation between a diet with a high glycemic load and plasma concentrations of high-sensitivity C-reactive protein in middle-aged women. The American journal of clinical nutrition. 2002;75(3):492-498.
  8. Galisteo M, Duarte J, Zarzuelo A. Effects of dietary fibers on disturbances clustered in the metabolic syndrome. Journal of Nutritional Biochemistry.19(2):71-84.
  9. King DE, Mainous AG, Egan BM, Woolson RF, Geesey ME. Fiber and C-Reactive Protein in Diabetes, Hypertension, and Obesity. Diabetes care. 2005;28(6):1487-1489.
  10. King DE, Egan BM, Geesey ME. Relation of dietary fat and fiber to elevation of C-reactive protein. American Journal of Cardiology.92(11):1335-1339.
  11. Ajani UA, Ford ES, Mokdad AH. Dietary Fiber and C-Reactive Protein: Findings from National Health and Nutrition Examination Survey Data. The Journal of nutrition. 2004;134(5):1181-1185.
  12. Esposito K, Nappo F, Giugliano F, et al. Meal modulation of circulating interleukin 18 and adiponectin concentrations in healthy subjects and in patients with type 2 diabetes mellitus. The American journal of clinical nutrition. 2003;78(6):1135-1140.
  13. DJ J. Lente carbohydrate: a newer approach to the dietary management of diabetes.  . Diabetes care. 1982;5:7.
  14. Schwingshackl L, Hoffmann G. Mediterranean dietary pattern, inflammation and endothelial function: A systematic review and meta-analysis of intervention trials. Nutrition, Metabolism and Cardiovascular Diseases. 2014;24(9):929-939.
  15. Salehi-Abargouei A, Saraf-Bank S, Bellissimo N, Azadbakht L. Effects of non-soy legume consumption on C- reactive protein: a systematic review and meta-analysis. Nutrition.
  16. Beavers KM, Jonnalagadda SS, Messina MJ. Soy consumption, adhesion molecules, and pro-inflammatory cytokines: a brief review of the literature. Vol 672009.
  17. Nicastro H, Mondul A, Rohrmann S, Platz E. Associations between urinary soy isoflavonoids and two inflammatory markers in adults in the United States in 2005–2008. Cancer Causes & Control. 2013;24(6):1185-1196.
  18. Jacobs DR, Andersen LF, Blomhoff R. Whole-grain consumption is associated with a reduced risk of noncardiovascular, noncancer death attributed to inflammatory diseases in the Iowa Women's Health Study. The American journal of clinical nutrition. 2007;85(6):1606-1614.
  19. Jensen MK, Koh-Banerjee P, Franz M, Sampson L, Grønbæk M, Rimm EB. Whole grains, bran, and germ in relation to homocysteine and markers of glycemic control, lipids, and inflammation. The American journal of clinical nutrition. 2006;83(2):275-283.
  20. Slavin JL, Jacobs D, Marquart LEN, Wiemer K. The Role of Whole Grains in Disease Prevention. Journal of the American Dietetic Association. 2001;101(7):780-785.
  21. Song Y, Ridker PM, Manson JE, Cook NR, Buring JE, Liu S. Magnesium intake, C-reactive protein, and the prevalence of metabolic syndrome in middle-aged and older U.S. women. Diabetes care. 2005;28(6):1438-1444.
  22. King DE, Mainous AG, 3rd, Geesey ME, Woolson RF. Dietary magnesium and C-reactive protein levels. Journal of the American College of Nutrition. 2005;24(3):166-171.
  23. Andersson A, Tengblad S, Karlström B, et al. Whole-Grain Foods Do Not Affect Insulin Sensitivity or Markers of Lipid Peroxidation and Inflammation in Healthy, Moderately Overweight Subjects. The Journal of nutrition. 2007;137(6):1401-1407.