Psychoneuroimmunology and Nutrition
Stress, Food, and Inflammation: Psychoneuroimmunology and Nutrition at the Cutting Edge JANICE K. KIECOLT-GLASER, PHD
Abstract: Inflammation is the common link among the leading causes of death. Mechanistic studies have shown how various dietary components can modulate key pathways to inflammation, including sympathetic activity, oxidative stress, transcription factor nuclear factor-�B activation, and proinflammatory cytokine production. Behavioral studies have demonstrated that stressful events and depression can also influence inflammation through these same processes. If the joint contributions of diet and behavior to inflammation were simply additive, they would be important. However, several far more intriguing interactive possibilities are discussed: stress influences food choices; stress can enhance maladaptive metabolic responses to unhealthy meals; and diet can affect mood as well as proinflammatory responses to stressors. Furthermore, because the vagus nerve innervates tissues involved in the digestion, absorption, and metabolism of nutrients, vagal activation can directly and profoundly influence metabolic responses to food, as well as inflammation; in turn, both depression and stress have well-documented negative effects on vagal activation, contributing to the lively interplay between the brain and the gut. As one example, omega-3 fatty acid intake can boost mood and vagal tone, dampen nuclear factor-�B activation and responses to endotoxin, and modulate the magnitude of inflammatory responses to stressors. A better understanding of how stressors, negative emotions, and unhealthy meals work together to enhance inflammation will benefit behavioral and nutritional research, as well as the broader biomedical community. Key words: interleukin-6; C-reactive protein; proinflammatory cytokines; depression; omega-3; polyunsaturated fatty acid.
CRP � C-reactive protein; EPA � eicosapentaenoic acid; IL � interleukin; TNF � tumor necrosis factor; LPS � lipopolysaccha- ride; n-3 � omega-3; n-6 � omega-6; NF � nuclear factor; PUFA � polyunsaturated fatty acid.
INTRODUCTION
Together, cardiovascular disease, cancer, and diabetes ac-count for almost 70% of all deaths in the United States; these diseases share inflammation as a common link (1,2). Dietary strategies clearly influence inflammation, as docu- mented through both prospective observational studies as well as randomized, controlled, feeding trials in which participants agree to eat only the food provided to them (1,3). Mechanistic studies have shown how various dietary components can mod- ulate sympathetic activity, oxidative stress, transcription fac- tor nuclear factor (NF)-�B activation, and proinflammatory cytokine production, thus modifying health risks (4).
Behavioral studies have convincingly demonstrated that stress and depression can also influence inflammation through these same pathways. Stressors—and the negative emotions they generate—can enhance sympathetic hyperactivity, pro- mote oxidative stress, augment NF-�B activation, and boost proinflammatory cytokine production (5–7).
If the joint contributions of diet and behavior to inflamma- tion were simply additive, they would certainly be important. However, after briefly reviewing the independent contribu- tions of diet and behavior to inflammation, several far more
intriguing interactive possibilities will be discussed: stress influences food choices; stress enhances maladaptive meta- bolic responses to unhealthy foods; diet can affect mood as well as proinflammatory responses to stress—and more, as illustrated in Figure 1. The evidence that vulnerabilities are not merely additive provides a window for considering new multidisciplinary prospects.
Diet and Inflammation
Diets that promote inflammation are high in refined starches, sugar, saturated and transfats, and low in omega-3 (n-3) fatty acids, natural antioxidants, and fiber from fruits, vegetables, and whole grains (1). For example, women in the Nurses’ Health Study who ate a “Westernized” diet (high in red and processed meats, sweets, desserts, French fries, and refined grains) had higher C-reactive protein (CRP), interleu- kin (IL)-6, E-selectin, soluble vascular adhesion molecule-1, and soluble intercellular adhesion molecule-1 than those with the “prudent” pattern, characterized by higher intakes of fruit, vegetables, legumes, fish, poultry, and whole grains (8).
Further work from the Nurses’ Health Study clearly linked transfatty acid consumption with higher inflammation; for exam- ple, CRP was 73% higher in women in the highest quintile of consumption compared with those in the lowest quintile, and IL-6 levels were 17% higher in the highest quintile of con- sumption compared with the lowest quintile (9). The associ- ation between transfat consumption and inflammation is a reliable finding across a number of controlled trials and ob- servational studies (3).
The antioxidant properties of vegetables and fruits are thought to be one of the fundamental mechanisms underlying their anti- inflammatory dietary contributions (1). Oxidants, such as super- oxide radicals or hydrogen peroxide, that are produced during the metabolism of food can activate the NF-�B pathway, promoting inflammation (4). Higher fruit and vegetable in- takes are associated with lower oxidative stress and inflam- mation (1,4). In fact, some evidence (1,10) suggests that the addition of antioxidants or vegetables may limit or even
From the Department of Psychiatry, The Ohio State Institute for Behavioral Medicine Research, The Ohio State University College of Medicine, Colum- bus, Ohio.
Address correspondence and reprint requests to Janice K. Kiecolt- Glaser, PhD, Institute for Behavioral Medicine Research, The Ohio State University College of Medicine, IBMR Building, 460 Medical Center Drive, Room 130C, Columbus, OH 43210-1228. E-mail: Janice. Kiecolt-Glaser@osumc.edu
Received for publication October 8, 2009; revision received February 1, 2010.
This study was supported, in part, by Grants AG029562, CA126857, CA131029, and AT003912 from the National Institutes of Health.
DOI: 10.1097/PSY.0b013e3181dbf489
C U T T I N G–E D G E R E V I E W
365Psychosomatic Medicine 72:365–369 (2010) 0033-3174/10/7204-0365 Copyright © 2010 by the American Psychosomatic Society
reverse proinflammatory responses to meals high in saturated fat.
Whole grains are healthier than refined grains, because the process of refining carbohydrates results in the elimination of much of the fiber, vitamins, minerals, phytonutrients, and essential fatty acids (1). Furthermore, refined starches and sugars can rapidly alter blood glucose and insulin levels (1), and postprandial hyperglycemia can increase production of free radicals as well as proinflammatory cytokines (11). Med- ications used to regulate postprandial glucose in diabetics also improve oxidative stress, NF-�B activation, and inflamma- tion, corroborating the relevance of this pathway (12).
Several lines of research (13,14) have implicated inflam- mation in the pathophysiology of depression. From this per- spective, inflammation-enhancing diets could fuel depressive symptoms and could, thus, boost inflammation. One recent article (15) suggested the Mediterranean dietary pattern was potentially protective for the prevention of depressive disor- ders. Thus, diet influences inflammation; dietary-related in- flammation may, in turn, promote depression; and depression can, in turn, advance inflammation.
Depression, Stress, and Inflammation
Psychosocial stress and depression contribute to a greater risk for infection, prolonged infectious episodes, and delayed wound healing—all processes that can fuel proinflammatory cytokine production (16). However, stress and depression can also directly provoke proinflammatory cytokine production in the absence of infection or injury (17,18). Additionally, both clinical depression and subsyndromal depressive symptoms may sensitize or prime the inflammatory response, thus effectively promoting larger cytokine increases in response to stressors as well as antigen challenge (19,20). Furthermore, depression and stress alter inflammation-relevant health behaviors; for example, disturbed sleep, a common response to negative emotions and emotional stress responses, promotes IL-6 pro- duction (21). Accordingly, depression and stress can effec- tively modulate secretion of proinflammatory cytokines both directly and indirectly. Through these pathways, depression and stressful experiences contribute to both acute and chronic proinflammatory cytokine production (22,23).
NF-�B seems to be a prime bridge for stress-induced in- creases in proinflammatory cytokines and the genes that control their expression (5). For example, NF-�B activity rose 341% within 10 minutes after a laboratory stressor (5). These stress- related changes in NF-�B activity are consistent with other evi- dence that stress can boost proinflammatory gene expression in peripheral blood mononuclear cells (24,25). Stress-related in- creases in norepinephrine provoke NF-�B activation, one direct route from the endocrine system to inflammation (5).
Chronic stressors can directly provoke long-term changes in proinflammatory cytokine production, as well as indirectly, by promoting oxidative stress that activates the NF-�B path- way. For example, a 6-year longitudinal study (23) showed that the average annual rate of increase in serum IL-6 was about four times as large in men and women who were chronically stressed by caregiving for a spouse with dementia compared with similar individuals with no caregiving respon- sibilities. In a sample of mothers who were caregiving for a chronically ill child as well as mothers of healthy children, higher reports of stress were associated with higher oxidative stress activity as measured by levels of F2-isoprostanes (6). Thus, stress and depression can enhance…
