Nutrition and Inflammation

Overview of Inflammation

Inflammation, the immune response of body tissues to injury or infection, is an important

component of innate immunity. The inflammatory process involves a complex biological

cascade of molecular and cellular signals that alter physiological responses, ultimately

resulting in the familiar clinical symptoms of pain, swelling, heat, and redness (1, 2). At the

site of the injury, cells release molecular signals that cause a number of changes in the

affected area: vasodilation, increased blood flow, increased vascular permeability, exudation

of fluids containing proteins likeantibodies, and invasion by several different types

of leukocytes, including granulocytes, monocytes, and lymphocytes (3). Neutrophils are the

first leukocytes to appear at the injured site. These cells phagocytose and kill invading

microorganisms through the release of non-specific toxins, such as superoxide radicals,

hypochlorite, and hydroxyl radicals; these reactive oxygen species (ROS)kill pathogens as

well as adjacent cells, sick and healthy alike. Neutrophils also provide additional killing

activities by releasing antimicrobial peptides and proteins, such as defensins, cathelicidins

and iron-binding proteins, into the phagosome (4). Neutrophils also release cytokines,

including interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-alpha, gamma interferon (INF-

gamma), and others (3, 5). Such pro-inflammatory cytokines in turn induce the liver to

synthesize variousacute phase reactant proteins and also induce systemic inflammatory

responses (e.g., fever and leukocytosis—a rise in the number of white blood cells) (5).

Acute inflammation is a normal process that protects and heals the body following physical

injury or infection. However, if the agent causing the inflammation persists for a prolonged

period of time, the inflammation becomes chronic. Chronic inflammation can result from a

viral or microbial infection, environmental antigen (e.g., pollen), autoimmune reaction, or

persistent activation of inflammatory molecules. Chronic inflammation is primarily mediated

by monocytes and long-lived macrophages (3); monocytes mature into macrophages once

they leave the bloodstream and enter tissues. Macrophages engulf and digest

microorganisms and senescent cells (6). They release several different chemical mediators,

including IL-1, TNF-alpha, and prostaglandins, that perpetuate the pro-inflammatory

response. At later stages, other cells, including lymphocytes, invade the affected tissues: T

lymphocytes kill virus-infected cells and B lymphocytes produce antibodies that specifically

target the invading microorganisms for destruction (3).

Macrophages and other leukocytes release ROS and proteases that destroy the source of

inflammation; however, damage to the body's own tissues often results in chronic

inflammation. In chronic inflammation, damaged tissues are repaired through replacement

with cells of the same type or with fibrous connective tissue. Another important characteristic

of chronic inflammation is local angiogenesis—the development of new blood vessels (7). In

some instances, the body is unable to repair tissue damage, and the inflammatory cascade

continues. Chronic inflammation is abnormal and does not benefit the body; in fact, chronic

inflammation is involved in a number of disease states.

Several human diseases are inflammatory in nature, including asthma, Crohn's

disease, rheumatoid arthritis, polymyalgia rheumatica, tendonitis, bursitis, laryngitis,

gingivitis, gastritis, otitis, celiac disease, diverticulitis, and inflammatory bowel disease.

Additionally, a number of chronic diseases have inflammatory components, such

as atherosclerosis, obesity, diabetes mellitus, cancer, and perhaps even Alzheimer's disease.

The biochemical mechanisms underlying several of these diseases are unknown, and the role

of inflammation in disease pathogenesis is under investigation.

Role of Nutrition

One’s diet can affect inflammatory responses within the body; the roles of various dietary

components in inflammation are discussed below. Clinical biomarkers of inflammation are

used to study the effect of dietary constituents on inflammation.C-reactive protein (CRP),

which is an acute phase reactant protein, is a common clinical biomarker of cardiac-related

inflammation and also a general marker of inflammation. Other common clinical indicators of

inflammation are a high erythrocyte sedimentation rate (ESR), a high white blood cell count,

and a low albumin level. However, these tests are nonspecific, meaning an abnormal result

might result from a condition unrelated to inflammation. Various cytokines and adhesion

molecules are not commonly used clinically because they do not identify the source of

inflammation; rather; they are frequently used in scientific research(3, 8, 9). Some

biomarkers of inflammation are listed in the table below (10).

Biomarkers of Inflammation

Acute-phase reactant proteins (CRP, SAA, vWF antigen,

fibrinogen)

White cell count, ESR, albumin

Cytokines (IL-1 beta, IL-6, IL-18, TNF-alpha)

Adhesion molecules (E-selectin, P-selectin, ICAM-1, VCAM-1)

Abbreviations: CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; ICAM-1, intercellular adhesion molecule-1; IL,

interleukin; SAA, serum amyloid A protein; VCAM-1, vascular cell adhesion molecule-1; vWF, von Willebrand factor

In addition to specific dietary factors, achieving and/or maintaining a healthy body weight is

critical in the prevention of chronic inflammatory diseases. For instance, elevated CRP levels

have been linked to obesity, and weight loss has been shown to decrease CRP levels (11).

Obesity and abdominal obesity (also called visceral obesity) are risk factors for several

diseases associated with inflammation, i.e.,cardiovascular diseases, type 2 diabetes mellitus,

and metabolic syndrome (12, 13). The causes of these diseases are not completely

established, and the role of inflammation in disease pathogenesis is under investigation. For

example, it is known that adipose tissue secretes several inflammatory factors (known as

adipocytokines or adipokines) and that obesity is associated with macrophageinfiltration in

adipose tissue (14, 15); however, the exact role of inflammation in the pathogenesis of

obesity is currently unknown.

Dietary Fats and Cholesterol

In general, epidemiological studies have found that diets high in saturated

fat andtrans fat are pro-inflammatory in nature (reviewed in 16). In contrast, some studies

have found that adherence to a Mediterranean-style diet—a diet high in monounsaturated

fats—may help reduce inflammation (17, 18). A Mediterranean diet emphasizes olive oil,

fruits and vegetables, nuts, beans, fish, whole grains, and moderate consumption of alcohol.

Several of these foods are important sources of essential fatty acids that are involved in

inflammatory processes. Higher intakes of the omega-3 fatty acids (i.e., alpha-linolenic acid

(ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA)) have been generally

associated with decreased biomarkers of inflammation (19). Rich dietary sources of ALA

include flaxseeds and their oil, walnuts and their oil, and canola oil. EPA and DHA are found

in oily fish and fish oils (see Sources in the separate article on Essential Fatty Acids). The

ratio of omega-6 to omega-3 fatty acids in the typical Western diet is about 15-20:1, yet it is

estimated that humans evolved on a diet with an omega-6 to omega-3 fatty acid ratio of

about 1:1 (20). Decreasing this ratio will likely reduce the prevalence and severity of various

inflammatory conditions observed in Western societies (for more information on dietary fats,

see the Micronutrient Information Center article, Essential fatty acids, and the research

newsletter article, What’s Good About Dietary Fat?) (21).

Low cholesterol diets may also reduce inflammation in the body. One study found that a high

cholesterol diet (4 eggs/day for four weeks) increased levels of CRPand serum amyloid A

(SAA), two inflammatory markers, in lean (BMI <27.5 kg/m2) subjects who were insulin-

sensitive but not in lean subjects who wereinsulin-resistant or in obese (BMI >27.5 kg/m2)

individuals; individuals in these two latter groups had elevated baseline levels of CRP and

SAA (22). An 8-week intervention study in patients with primary hypercholesterolemia found

that a diet low in both cholesterol (<200 mg/day) and saturated fat (5% of dietary fat from

saturated fat) was linked to reduced inflammation, evidenced by a 39% reduction in CRP

levels (23).

Dietary Carbohydrates

Hyperglycemia can cause inflammation through varying mechanisms that result in the

production of free radicals and pro-inflammatory cytokines (19, 24). Thus, high glycemic

index and glycemic load diets may stimulate inflammation. Glycemic index is the blood

glucose-raising potential of the carbohydrates in different foods. A more accurate indicator of

the relative glycemic response to dietary carbohydrates, however, is glycemic load. Glycemic

load incorporates the relative quality of carbohydrates characterized by the glycemic index.

Consumption of high-glycemic index foods results in higher and more rapid increases in

blood glucose levels than the consumption of low-glycemic index foods. Rapid increases in

blood glucose are potent signals to the beta-cells of the pancreas to

increaseinsulin secretion, which can cause a sharp decrease in glucose levels and lead

tohypoglycemia (25). In contrast, the consumption of low-glycemic index foods results in

lower but more sustained increases in blood glucose and lower insulin demands on

pancreatic beta-cells (26).

A study in 39 overweight or obese adults found adherence to a low-glycemic index, energy-

restricted diet resulted in a 48% decrease in levels of CRP—a common clinical biomarker of

cardiac-related inflammation but also a general marker of inflammation (27). Individuals in

this study who followed a low-fat, energy-restricted diet experienced only a 5% decline in

CRP levels, despite similar weight loss and body composition changes (27). Another small

study showed that acute hyperglycemia resulted in increased levels of various pro-

inflammatory cytokines; this effect was more pronounced in individuals with

impaired glucose tolerance compared to healthy controls (24). More information on the role

of dietary carbohydrates in the prevention of chronic diseases, such as cardiovascular

disease and diabetes, is available in the article on Glycemic Index and Glycemic Load.

In addition, higher intakes of dietary fiber may protect against the development of diseases

with inflammatory components, including cardiovascular disease and type 2

diabetes (28) (see the article on Fiber).

Dietary Proteins and Amino Acids

A number of studies have evaluated the potential of soy protein in the prevention of diseases

with inflammatory components (see the separate article on Soy Isoflavones). Some clinical

trials have specifically evaluated the effects of soy protein or soy food consumption

on CRP and other inflammatory biomarkers; several such studies have reported overall null

effects (29-32).

Analysis of data collected from the Third National Health Nutrition and Examination Survey

(NHANES), a U.S. national survey, indicated higher intakes of the amino acid arginine were

associated with lower levels of CRP (33). Common sources of arginine in the American diet

include meat, poultry, fish, dairy products, eggs, and cereals (34). Nuts, especially peanuts,

are also good sources of arginine (35, 36). Regular nut consumption has been shown to be

cardioprotective (see the article onNuts).

Micronutrients

Several micronutrients are related to diseases that have inflammatory components,

e.g., cardiovascular diseases, type 2 diabetes, inflammatory bowel disease, chronic

obstructive pulmonary disease (COPD), and rheumatoid arthritis(see the Disease Index).

Some observational studies have reported dietary intake or blood levels of individual

micronutrients to be inversely associated with certainbiomarkers of inflammation,

especially CRP.

Magnesium

The National Health and Nutrition Examination Survey (NHANES) 1999-2000, a U.S. national

survey, found American adults who consumed less than the RDA ofmagnesium were 1.48 to

1.75 times more likely to have elevated CRP levels compared to those who consumed at

least the RDA (37). This survey found that 68% of the sample consumed less than the RDA

of magnesium (37).

Vitamin B6

Body status of certain vitamins may also affect inflammatory processes. The analysis of data

from a cohort of 891 elderly adults participating in the Framingham Heart Study indicated

that low vitamin B6 status was associated with higher CRP levels; this association was

independent of plasma homocysteine (38). In this study, vitamin B6 status was assessed by

measuring plasma levels of pyridoxal 5’-phosphate (PLP). PLP is the active form of the

vitamin and considered to be a good indicator of long-term body stores (39). More recently,

plasma PLP levels were inversely associated with CRP levels in a cohort of older Puerto Rican

adults (40). A low circulating level of vitamin B6 is a risk factor for cardiovascular

diseases (see the separate article on Vitamin B6), and may also be related torheumatoid

arthritis (41-43). However, a double-blind, placebo-controlled trial in 33 patients with

rheumatoid arthritis reported that supplementation with 30 mg/day of pyridoxine for 30 days

corrected the vitamin B6 deficiency but did not improve specific markers of inflammation,

including levels of certain pro-inflammatory cytokines, erythrocyte sedimentation rate, and

CRP (44). Moreover, one analysis of data from the NHANES 2003-2004 indicated that dietary

intakes at levels corresponding to the current RDA may not result in vitamin B6 adequacy, at

least in certain subgroups, such as cigarette smokers, blacks, and the elderly (39).

Vitamin C

Adequate dietary intake of the antioxidant vitamin, vitamin C, is also important because free

radicals have pro-inflammatory effects (45). Compared to its antioxidant actions,

considerably less is known about whether vitamin C has anti-inflammatory effects (46).

A cross-sectional study of 3,258 men (aged 60-79 years) participating in the British Regional

Heart Study found that both dietary intake and plasma levels of vitamin C were inversely

related to CRP levels (47). Higher vitamin C levels were also associated with lower CRP levels

in the NHANES III, which included data from 14,519 U.S. adults (48). A randomized

controlled trial in healthy nonsmokers found that vitamin C supplementation (1,000 mg/day)

for two months resulted in a 16.7% decrease in median level of CRP in those with elevated

CRP levels (= 1.0 mg/L; the level associated with a heightened risk of cardiovascular

diseases) compared to an 8.6% increase that was seen in theplacebo group (49). This trial

found no effect of vitamin C supplementation in those with baseline levels of CRP lower than

the 1.0 mg/L threshold (49). Severalepidemiological studies have examined whether dietary

intake, supplemental intake, or serum levels of vitamin C are associated with

various cardiovascular diseases and gout. Results of many of these studies have indicated

that vitamin C may help protect against coronary heart disease and gout—diseases with

inflammatory components (see Disease Prevention in the article on vitamin C for details).

Additionally, low plasma and leukocyte concentrations of vitamin C have been observed in

patients with sepsis—a clinical syndrome characterized by whole-body inflammation that can

lead to organ failure (50).

Vitamin D

Several human studies associated vitamin D deficiency or impaired vitamin D status with

various inflammatory diseases, such as Crohn’s disease and otherinflammatory bowel

diseases (55-60). Vitamin D status may also be linked tocardiovascular diseases and

certain cancers (see the separate article on Vitamin D). A role for vitamin D in inflammation

is supported by studies in laboratory animals. In particular, mice lacking the vitamin D

receptor or the vitamin D activating enzyme, 25-hydroxyvitamin D3-1-hydroxylase, have

increased susceptibility to inflammation, especially inflammation of

the gastrointestinal tract(61-63).

Vitamin E

Vitamin E has effects on inflammatory processes due to the antioxidant functions of alpha-

tocopherol (51). Alpha-tocopherol exerts anti-inflammatory effects through a number of

different mechanisms, for example, by decreasing levels ofCRP and pro-

inflammatory cytokines and by inhibiting the activity of protein kinase C, an important cell-

signaling molecule, and other enzymes, such as cyclooxygenase-2 (51, 52). For information

on the role of alpha-tocopherol in the prevention and treatment of cardiovascular diseases,

see the separate article onVitamin E. Results of some animal studies suggest that vitamin E

may also have utility in the treatment of rheumatoid arthritis, but more research in humans

is needed (51). In addition, some cell culture and animal studies indicate thatgamma-

tocopherol has anti-inflammatory activities (53, 54).

Multivitamin-mineral Supplements

Analysis of a randomized, double-blind, placebo-controlled trial in 87 healthy men and

postmenopausal women, who were recruited from the general U.S. population, found that

supplementation with a daily multivitamin-mineral for six months was associated with a 14%

decrease in CRP levels; a greater magnitude of reduction was seen in those with higher

baseline levels of CRP (64). Daily use of a multivitamin-mineral supplement may help

improve nutritional status of several micronutrients, which may be of benefit to Americans

because, according to a U.S. national survey, over 90% of the population does not meet

the EAR for vitamin E, 44% for vitamin A, 31% for vitamin C, and 14% for vitamin B6 (65).

Dietary Phytochemicals

Carotenoids

Various dietary phytochemicals could affect inflammatory processes within the

body. Carotenoids, the yellow, orange, and red pigments synthesized by plants, have a

number of different biological activities (see the article on Carotenoids). In one study, the

carotenoid beta-carotene displayed anti-inflammatory activity by inhibiting pro-

inflammatory gene expression through suppressing the activation of NFκ-B, a redox-

sensitive transcription factor (66). Specifically, a decrease in expression of various pro-

inflammatory genes was seen with beta-carotene treatment when an endotoxin was used to

induce inflammation in macrophages in vitro as well as mice in vivo (66). The carotenoids,

lycopene and astaxanthin, have also been shown to exhibit anti-inflammatory activities in

cell cultures and animal models (67-72). Sources of lycopene include tomatoes, red

grapefruit, red watermelon, and guava, while the main dietary sources of astaxanthin include

salmon, shrimp, and other seafood (73).

Additionally, the putative anti-inflammatory effect of various carotenoids has been examined

in humans. Some epidemiological studies have observed serum levels of certain carotenoids,

including alpha-carotene, beta-carotene, beta-cryptoxanthin, lycopene, lutein, and

zeaxanthin, to be inversely associated with circulating levels of CRP, a cardiovascular and

general marker of inflammation (74, 75). In a four-week randomized controlled trial in

healthy, nonsmoking men, eight daily servings of carotenoid-rich vegetables and fruit were

associated with a reduction in CRP levels; the authors of this study did not observe any

change in plasmaconcentrations of vitamins C or E over the four-week period (76).

Consumption of fruits and vegetables, in general, has been inversely associated with CRP

levels and other biomarkers of inflammation (77-79). In two small intervention trials,

consumption of tomato juice or a tomato-based soft drink was associated with decreased

markers of inflammation (80, 81), but other dietary components of tomatoes besides

lycopene, such as vitamin C, may in part be responsible for any beneficial effects on

inflammatory processes (80). Larger clinical trials are needed to determine whether lycopene

or other carotenoids help reduce inflammation and risk of associated diseases. For details on

carotenoids in the prevention ofcardiovascular diseases, see the separate article

on Carotenoids.

Flavonoids

Another class of phytochemicals with anti-inflammatory effects includes theflavonoids, a

large family of polyphenolic compounds that consists of several subclasses: flavanols,

flavonols, flavanones, flavones, isoflavones, and anthocyanidins. For information on common

dietary sources of these flavonoids, see the Table in the separate article on Flavonoids.

Several in vitro studies and a few in vivo animal studies have shown that various flavonoids,

such as quercetin, kaempferol, and genistein, possess anti-inflammatory properties

(reviewed in 51and 82); however, limited studies on the effect of flavonoid intake on

inflammatory processes are currently available in humans. In general,bioavailability of

flavonoids is relatively low due to poor absorption and rapid elimination. Once absorbed,

flavonoids are rapidly metabolized to form variousmetabolites. Therefore, in vitro studies

that use high concentrations and parent compounds (rather than the metabolites) may not

be physiologically relevant. Additionally, results of studies employing animal models may not

be directly applicable to humans.

Analysis of data from the National Health and Nutrition Examination Survey (NHANES) 1999-

2002, a cross-sectional study of U.S. adults, indicated that total flavonoid intake was

inversely related to serum concentration of CRP (83). Similar inverse associations were found

for flavonol, anthocyanidin, and isoflavone intakes as well as intake of select individual

flavonoids, including quercetin, kaempferol, genistein, diadzein, malvidin, and peonidin. All of

these associations were independent of fruit and vegetable consumption (83). However,

a prospective study in a cohort of 38,018 women participating in the Women’s Health Study,

followed for almost nine years, did not observe flavonoid intake to be related

toplasma concentrations of CRP or risk of developing type 2 diabetes mellitus (84). This

study found consumption of flavonoid-rich apples was associated with a significantly reduced

risk of type 2 diabetes (84), but such an effect might not necessarily be attributed to

flavonoids (see the LPI research newsletter, Why Apples are Healthful). Tea also contains

high levels of flavonoids, and regular consumption of tea may help prevent chronic diseases

associated with inflammation, such as cardiovascular disease and cancer (see the article

on Tea).

Other Dietary Phytochemicals

A six-week, placebo-controlled trial in 20 healthy adults associated consumption of an

extract of Polygonum cuspidatum that contained 20% resveratrol (equivalent to 40 mg/day

of trans-resveratrol) with decreased plasma levels of TNF-alpha, a pro-inflammatory

cytokine, and reduced nuclear binding of NFκB, a pro-inflammatorytranscription factor (85).

Other phytochemicals, namely curcumin and garlic-derived compounds, have been shown to

exhibit anti-inflammatory properties, mainly in cell culture or animal studies (see the

separate articles on Curcumin andGarlic). Additionally, a high dose of the spice, ginger, has

been shown to have anti-inflammatory effects in rats (86). Large-scale, randomized

controlled trials are needed to determine the effects of these phytochemicals on

inflammatory processes or diseases in humans.

Other Dietary Compounds

Alpha-lipoic acid is a naturally occurring compound that is synthesized in small amounts by

the body. It is also obtained in the diet from tomatoes, green leafy vegetables, cruciferous

vegetables, and other sources. Endogenous alpha-lipoic acid functions as

a cofactor for mitochondrial enzymes important in the generation of energy. When provided

as a dietary supplement, however, alpha-lipoic acid may display a number of other biological

activities, including antioxidant and anti-inflammatory functions. Results from studies in cell

cultures and animal models have shown the compound has anti-inflammatory properties

(reviewed in 87), but human data are extremely limited. A small placebo-controlled trial in

patients withmetabolic syndrome found that supplementation with alpha-lipoic acid (300

mg/day) for four weeks resulted in a 15% decline in plasma levels of interleukin-6, an

inflammatory marker of atherosclerosis (88).

Lifestyle Factors

Animal and human studies have found that various forms of physical activity decrease both

acute and chronic inflammation, as measured by reductions in CRPand certain pro-

inflammatory cytokines (89). Moreover, regular physical activity is important in reducing

one’s risk for obesity and chronic diseases associated with inflammation (90). However,

excessive exercise can increase systemic inflammation. For example, overtraining syndrome

in athletes is associated with systemic inflammation and suppressed immune function (91).

Several studies have shown that moderate alcohol consumption decreases risk of

cardiovascular diseases as well as all-cause mortality (see the article on Alcoholic

Beverages). Further, smoking cessation has been reported to decrease CRP and

otherbiomarkers of inflammation (92, 93).

References

Written in August 2010 by:

Victoria J. Drake, Ph.D.

Linus Pauling Institute

Oregon State University

Reviewed in August 2010 by:

Adrian F. Gombart, Ph.D.

Associate Professor

Department of Biochemistry and Biophysics

Principal Investigator, Linus Pauling Institute

Oregon State University

This article was underwritten, in part, by a grant from

Bayer Consumer Care AG, Basel, Switzerland.

Last updated 8/31/10 Copyright 2010-2015 Linus Pauling Institute