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Putting the Whole Grain Puzzle Together: Health Benefits Associated with Whole Grains-Summary of American Society for Nutrition 2010 Satellite Symposium1-3 - The Journal of Nutrition

Abstract

The symposium 'Putting the Whole Grain Puzzle Together: Health Benefits Associated with Whole Grains' sponsored by the ASN brought together researchers to review the evidence regarding the health benefits associated with whole grains. Current scientific evidence indicates that whole grains play an important role in lowering the risk of chronic diseases, such as coronary heart disease, diabetes, and cancer, and also contribute to body weight management and gastrointestinal health. The essential macroand micronutrients, along with the phytonutrients present in whole grains, synergistically contribute to their beneficial effects. Current evidence lends credence to the recommendations to incorporate whole grain foods into a healthy diet and lifestyle program. The symposium also highlighted the need for further research to examine the role of whole grain foods in disease prevention and management to gain a better understanding of their mechanisms of action. J. Nutr. 141: 1011S-1022S, 2011.

Introduction

On April 23, 2010, at the Experimental Biology Annual Meeting, the ASN, through an unrestricted education grant from the General Mills Bell Institute of Health and Nutrition, sponsored a satellite symposium on 'Putting the Whole Grain Puzzle Together: Health Benefits Associated with Whole Grain.' The symposium brought together researchers who reviewed the evidence associated with whole grain health benefits in the areas of: whole grain phytonutrients, weight management, cardiovascular disease (CVD),11 diabetes, digestive health, and ways to help improve whole grain dietary intake assessment. This paper briefly summarizes the evidence reviewed during the symposium and the recommendations for future research on the health benefits of whole grains.

Whole grains

Whole grains are defined by the American Association of Cereal Chemists International and the FDA as consisting of the 'intact, ground, cracked or flaked fruit of the grain whose principal components, the starchy endosperm, germ and bran, are present in the same relative proportions as they exist in the intact grain (1,2).' Whole grain foods that undergo processing and reconstitution must deliver the same proportion of bran, germ, and endosperm as that of the original grain to be considered whole grains (1,2). The outer bran layer is composed of nondigestible, mainly insoluble, poorly fermentable carbohydrates (such as cellulose, hemicelluloses, arabinoxylan), and the inner germ and starchy endosperm contain viscous soluble fibers, fermentable oligosaccharides, resistant starch (RS), lignans, vitamins, minerals, polyphenols, oils, and other phytonutrients (3). During the refining of whole grains into white flour, rhe outer bran and inner germ layers are removed and the remaining endosperm is processed into flour. Thus, compared with refined grains, whole grains are inherently richer in dietary fiber, containing ~80% more dietary fiber than refined grains (3,4). Furthermore, as a consequence of the refining process, there are substantial losses in essential minerals, vitamins, and phytonutrients (3,4).

The 2005 Dietary Guidelines for Americans recommend that individuals should 'consume 3 or more ounce-equivalents of whole grain products per day, with the rest of the recommended grains coming from enriched or whole-grain products. In general, at least half of the grains should come from whole grains (5).' The 2010 Dietary Guidelines for Americans continues to support this guidance (6).

Despite the current dietary guidelines recommending that individuals consume at least one-half of all their grains as whole grains (i.e. 3 servings/d; 1 serving = 16 g), dietary intake data from the Continuing Survey of Food Intakes and the NHANES indicate that the average whole grain intake is 1 serving/d, with 95% of Americans not meeting their whole grain daily intake recommendations (7,8). There is some evidence that, since the 2005 Dietary Guidelines for Americans, consumers have increased purchases of whole grain foods, particularly ready-toeat breakfast cereals, breads, and pasta, which may in part be due to more products with whole grains being available on supermarket shelves (9).

In 2001-2002, the leading food sources of whole grains in the American diet were ready-to-eat cereal (28.7%), yeast breads (25.3%), hot cereals (13.7%), popcorn (12.4%), and crackers (6.4%), with these food categories accounting for close to 90% of all whole grains consumed (10). The most common types of whole grains in the American diet are wheat, corn, oats, barley, and rice, with wheat being the most prominent grain consumed on a daily basis. Table 1 shows the common whole grains and examples of food products and Table 2 shows the macronutrient composition of the common grains (4).

Whole grain foods can contain the intact whole grain or be reconstituted in that they have components of the whole grains recombined to the relative proportion as naturally occurring in the grain kernel (1,2). The majority of products found on retail store shelves would be considered reconstituted whole grain products (11).

Whole grain dietary intake assessment

Estimation of an individual's whole grain intake can be obtained in a variety of ways, such as 24-h dietary intake recalls, food records, and FFQ, with the latter being the most common method used in epidemiological studies. In all of these dietary intake assessment methods, the definition of whole grain food is important to clearly understand. Definitions of whole grain foods have varied from study to study and nutrient Intake database to database. In early studies, whole grain foods included whole grain breakfast cereals (containing ≥25% of whole grain content), dark bread, brown rice, oatmeal, and other specific individual foods such as wild rice, whole wheat crackers, and bran muffins (see Tables 3 and 4 for individual studies). In addition, added bran and added germ were included in the whole grain category. Thus, based on the definition of what is considered a whole grain food, whole grain intake can be either under- or overestimated. This calls for the need for standardizing dietary intake assessment methods to better quantify whole grain intake.

There are a number of methodological challenges to developing a standardized approach to accurately quantify consumption of whole grain foods. The greatest challenge may be coping witJt foods that contain a combination of whole and nonwhole grain ingrethents. It is a methodological issue that must be addressed, because a growing number of partial whole grain foods appear to be entering the marketplace. The proliferation of partial whole grain foods is likely occurring for various reasons, such as technical feasibility, shelf-life stability, taste, acceptance, and cost. For example, with respect to taste and acceptance, Sadeghi and Marquait (12) showed that graham crackers that were partially whole grains (5 g/serving) had a higher rate of acceptance by elementary school children compared with 100% whole grain graham crackers (26 g/serving).

Foods that are partially whole grains are methodologically problematic, because often the relative proportion of whole and nonwhole grain ingrethents in the product is unknown and is proprietary formulation information of the food manufacturers. What is known about these products is the rank order of grain ingrethents as provided on the FDA required ingrethent statement on product packaging. From the ingrethent statement, clues are provided as to the relative proportion of whole and nonwhole grain ingrethents. As an example, if the first ingrethent listed on the product packaging of a cracked wheat bread product is enriched wheat flour and the second and only other grain ingrethent listed is whole wheat flour, it may be surmised that the product contains more nonwhole grain than whole grain ingrethents. What is unknown is the exact relative proportion. In this example, the proportion of grains in the cracked wheat bread that is whole grain could be anywhere from 49 to 1%, thus qualifying it to be considered a whole grain food.

In consideration of the lack of detailed information about the quantity of whole and nonwhole grain ingrethents in many partial whole grain food products, there are several approaches that may be considered for quantifying the contribution of partial whole grain foods to whole grain intake. One potential simplistic option is to count a food as whole grain only if all the grain ingrethents are whole, but if the total grain amount in the food is minimal, then it could result in an over/estimation of whole grain contribution. Conversely, a rule could be established whereby a food would be considered a whole grain if it contained 1 or more whole grain ingrethents (any whole grain). The primary shortcoming of this type of approach is that whole grain intake is apt to be underestimated or overestimated, with the misclassification particularly acute among those who regularly consume partial whole grain foods.

Another more complex option is to consider a food as whole grain if the first ingrethent is whole grain, partial whole grain if whole grains are not the first ingrethent, and not a whole grain food if there are no whole grain ingrethents (13). Although this option tries to account for the varying levels of whole grain composition of food products, it is hard to interpret and quantify the partial whole grain classification. For example, using this approach, a summary measure of servings of whole grains cannot be calculated without assumptions being made about the relative contribution of partial whole grain servings.

A more complex but potentially more accurate method of determining whole grain intake is to estimate the relative proportion of whole grain and nonwhole grains components, which is the approach used by the MyPyramid equivalent database (11). This approach relies on breaking down the food to its recipe and individual ingrethent level. Although this approach provides a more precise estimate, it is complicated to implement and assumptions must be made about commercial products whose recipes (ingrethents and the amount of each ingrethent) are not readily available, thus threatening the validity of the estimated whole grain content of a food product.

To evaluate the validity of the more complex approach just described, researchers at the University of Minnesota Nutrition Coordinating Center (NCC) identified products from the bread, cracker, ready-to-eat cereal, and snack chip aisles of chain supermarkets that had grams of whole grains per serving specified on product packaging (« = 54) (14). These values served as a criterion measure of whole grain composition. Using the ingrethent statement and nutrition facts panel information on the product packaging, an NCC database scientist unaware of the grams of whole grain information developed a recipe for each product. Recipes were developed using a food calculation software application routinely used at NCC to create formulations for commercial food products. The software, using a linear optimization algorithm, estimates the amount of each ingrethent needed to produce a product with a nutrient profile close to that indicated on the nutrition facts panel. Because the ingrethent statement lists ingrethents in descending order of content in the product, the linear optimization algorithm in the software places this constraint on solutions derived for ingrethent amounts. After the recipes were completed, the grams of whole grains in each product were estimated and compared with the labeled whole grain content (criterion measure). Results of this comparison indicated that the estimated values were close to the labeled values (± 4 g) for most of the products examined (45 of 52). Furthermore, the correlation between labeled and estimated values was very high (r = 0.95) ( 14). These results suggest it may be possible to estimate whole grain content of commercial food products with reasonable accuracy; however, the accuracy of this method needs to be tested with more complex foods.

Thus, ongoing efforts are necessary to more accurately estimate whole grain intake to gain a better representation of population and individual intakes and to more accurately substantiate their association with health and chronic disease risk reduction.

Whole grain phytonutrients

Whole grains are rich sources of vitamins, minerals, dietary fiber, lignans, /3-glucan, inulin, numerous phytochemicais, phytosterols, phytin, and sphingolipids (3,15). The bran is the multi-layered outer skin of the grain that protects the germ and the endosperm from damage, such as sunlight, pests, water, and disease. The bran contains phenolic compounds, vitamins, minerals, and fiber. The endosperm is the largest component of the whole grain; it contains carbohydrates (starch), protein, vitamins, and minerals and serves as the food supply for the germ and provides energy for the rest of the plant. The germ refers to the embryo, the part that forms the new plant, and contains vitamins, some protein, minerals, and fat.

Dietary phytochemicais are defined as bioactive, non-nutrient plant compounds that are associated with reduced risk of chronic diseases (15). Adorn et al. (16) reported that the majority of the beneficial phytochemicais are present in the bran and germ fractions of whole grains. Prospective cohort studies consistently suggest that when consumed in whole foods, these phytochemicais may contribute to important protection against chronic diseases, such as CVD and certain cancers (3). The additive and synergistic effects of these bioactive phytochemicais found in whole grains may be responsible for the health benefits associated with whole grains; additionally, the whole grain phytochemicais complement those in fruits and vegetables when consumed together (3,15,16).

Plant phenolic acids provide chemical defense to the plant against pathogens, parasites, and predators (15). There are various classes of phenolic compounds in whole grains, including derivatives of benzoic and cinnamic acids, namely ferulic acid, vanillic acid, caffeic acid, syringic acid, p-coumaric acid, anthocyanidins, quinines, flavonols, chalones, flavones, flavanones, and amino phenolic compounds (3,16). These phenolic acids are present in soluble-conjugated (bound) and free form in the whole grains (17). Ferulic acid is one of the most studied whole grain phenolic acids (3,16-19). Ferulic acid is most abundant in the aleurone, pericarp, and embryo cell walls of the whole grains and occurs only Ln trace amounts in the endosperm. Ferulic acid can exist in the free, soluble-conjugated, and insoluble bound forms in whole grains, with the bound form being the most predominant form (93% of total), than free and soluble-conjugated forms, in corn, wheat, oats, and rice (16-1 9). Food processing, such as thermal processing and milling, can help release these phytochemicais, making them more bioaccessible. Additionally, colonic digestion results in release of the bound phenolic compounds, thus enabling them to exert their health effects both locally and systemically upon absorption. Andreasen et al. (20) showed that human gastrointestinal esterase, from the intestinal mucosa and intestinal microbiota, can release ferulic acid and diferulics from cereal bran, thereby potentially contributing to the lower risk of certain cancers, such as colon cancer, that have been associated with whole grain consumprion (21).

In wheat kernels, ferulic acid and other phenolic acids provide protection by generating physical and chemical barriers through cross-linking with carbohydrates, antioxidant activities to combat destructive radicals, and astringency that deters consumption by insects and animals (3,16,17). The whole grain phenolic compounds in the body function as antioxidants by donating hydrogen atoms to free radicals (3,17). The total phenolic acid concentration of whole grains corresponds to their total antioxidant capacities. Corn has the highest phenolic acid content, followed by wheat, oats, and rice, with 265, 136, 111, and 95 mg gallic acid equivalents/100 g, respectively (17). Miller et al. (22) reported the antioxidant capacity of whole grain breakfast cereals to range from 2200 to 3500 Trolox equivalents (TE). In comparison, antioxidant capacity of fruits generally ranged from 600 to 1700 TE, with a high of 2200 TE for red plums and 3600 TE for berries, and vegetables averaged 450 TE, with a high of 1400 TE for red cabbage. A 41 -g average serving of ready-to-eat whole grain breakfast cereal had an antioxidant capacity of 1120 TE compared with 380 and 1020 TE in an average 85-g serving of vegetables and fruits, respectively.

Carotenoids are another group of compounds found Ln whole grains (3,16). Lutein, zeaxanthin, 0-cryptoxanthin, /3-carotene, and a-carotène are the most common carotenoids and are commonly concentrated in the bran or germ portion of whole grains (3,16). In addition to providing pigmentation, they play an important role in reproduction and protection of the whole grains, while also acting as antioxidants and having provitamin A activity (β-crytoxanthin, β-carotene, and a-carotene) in the body.

Whole grains also contain tocotrienols, tocopherols, and oryzanols (3). Vitamin E, as tocopherols and tocotrienols, is found in whole grains in varying proportions and is concentrated in the germ fraction of the grain (3). β-Tocotrienol is the predominant form of vitamin E in whole wheat grain (3). An important function of vitamin E in the body is its antioxidant activity and maintenance of cellular membrane integrity. Whole grains also contain unsaturated fatty acids, mainly oleic and linoleic acid, both of which have been suggested to lower blood cholesterol levels.

Whole grains also contain fiber, RS, oligosaccharides, and lignans, which have important biological activities and functions (3,23). For example, the dietary fiber, RS, and oligosaccharides in whole grains may contribute to cholesterol reduction, healthy blood glucose and insulin concentrations, improved digestive health, and lower risk of certain gastrointestinal cancers (23). Lignans found Ln whole grains have strong antioxidant and phytoestrogenic effects. Intestinal microflora play a role in converting these plant lignans into the mammalian lignans, enterolactone and enterodiol, which may provide protection against chronic diseases such as hormone-related cancers, diabetes, and heart disease (3,23).

Plant sterols and stands are also found in whole grains, the type and amount varying by the type of whole grain and the whole grain component. They are known to inhibit cholesterol absorption and increase its excretion, thereby playing a role in regulating blood cholesterol levels. Increased whole grain consumption may be associated with increased phytosterol intake, thus potentially contributing to cholesterol reduction and cardioprotection (3).

Antinutrients such as phytic acid, tannins, and enzyme inhibitors are also present in whole grains and may contribute to their overall protective effects (3,23). Phytic acid forms chelates with various metals suppressing iron-catalyzed redox reactions and associated oxidative damage. Likewise, phytic acid can suppress the oxidant damage associated with the oxygen radicals produced by the colonic bacteria, thereby protecting the intestinal epithelium. Protease inhibitors, phytic acid, phenolic acids, and saponins present in whole grain have also been suggested to lower the risk of certain cancers, such as colon cancer and breast cancer. Phytic acid, lectins, phenolic acids, amylase inhibitors, and saponins have also been shown to lower plasma glucose, insulin, and/or plasma cholesterol and TG levels (23).

In summary, whole grains have higher phytonutrient content and antioxidant activity than refined grains. Refined wheat flour loses 83% of total phenolic acids, 79% of total flavonoids, 93% of ferulic acid, 78% of total zeaxanthin, 51% of total lutein, and 42% of total β-cryptoxanthin compared with whole wheat flour (16). Further research on the health benefits of whole grain phytochemicais, their bioavailability, effects of processing on their physiological effects, and amounts in whole grain products is warranted.

Whole grains and weight management

Cross-sectional and prospective epidemiological studies indicate that consuming whole grains is associated with reduced risk of obesity and weight gain (24). To date, 14 cross-sectional studies, the majority of which were conducted in the US, have found that higher intake of whole grains (a daily intake of ~3 servings) is associated with lower BMI (kg/m^sup 2^) in adults; 3 studies observed that adults who consumed higher intakes of whole grains had smaller waist circumferences (25-38) (Table 3). McKeown et al. (25) in the Framingham Offspring Study and Newby et al. (31) in the Baltimore Longitudinal Study of Aging observed an inverse association between whole grain consumption and BMI, waistmip ratio, and waist circumference. Generally, an ~l-unit difference in BMI is observed between the highest and lowest whole grain intakes. More recently, McKeown et al. (35) also showed that higher intakes of whole grain foods were associated, in a dose-dependent manner, with lower abdominal fat (43.0 vs. 39.4%; P-trend = 0.02), as measured by dual-energy X-ray absorptiometry, among older adults. In this study, whole grain intake Ln the top quintile was 3 servings/d compared with <0.5 servings/d in the lowest quintile. In contrast, no significant relationship was observed with refined-grain intake. Likewise, McKeown et al. (38) showed that whole grain consumption was inversely associated with subcutaneous and visceral adipose tissue volume among the Framingham Offspring cohort; visceral adipose tissue volume was 10.7% lower among individuals consuming 3 or more ounce-equivalent servings of whole grains per day compared with no whole grain consumption.

Prospective studies suggest that weight gain and increases in abdominal adiposity over time are lower in people who consume more whole grains. Analyses of the Physicians' Health Study (27) and the Nurses' Health Study (26) showed that those who consumed more whole grain foods consistently weighed less than those who consumed fewer whole grain foods at each follow-up period of the study. Koh-Banerjee et al. (27) estimated that for every 40-g increase in daily whole grain intake, the 8-y weight gain was lower by 1.1 kg.

In a recent cross-sectional study of adults in the UK, Thane et al. (37), using 7-d food records and defining whole grain intake as foods containing >10% whole grains, observed that higher intake was inversely associated with the percentage of men classified as obese based on BMI, independent of other factors, and intake was not associated with body weight or prevalence of overweight. Harland and Garton (24), in a systematic review of the evidence, showed modest reduction in BMI (0.63 kg/m^sup 2^) and waist circumference (2.7 cm) with the consumption of 3 servings/d of whole grains. A mean difference in BMI of -0.5 kg/m^sup 2^ at the population level translates into a 5% increase in the rate of coronary events. The consistency of the observational studies lends credence to an important relationship observed between whole grain intake and body weight management.

Intervention studies on the effects of whole grains on body weight and obesity-related metabolic risk factors have yielded inconsistent results, potentially because of the use of hypocaioric diet programs as part of the intervention. Katcher et al. (39) observed similar weight loss with a whole grain hypocaioric diet compared with a refined grain hypocaioric diet, but observed a greater decrease in percent abdominal body fat in the whole grain group compared with the refined grain group (-2.2 vs. -0.9%, respectively; P = 0.03). Interestingly, Kallio et al. (40) showed a 21 % decrease in adipocyte size, in the absence of body weight changes, after the consumption of a rye pasta diet for 12 wk. However, more recently, Brownlee et al. (41), in a 16-wk dietary intervention study in healthy, overweight individuals consuming a weight maintenance diet, did not observe any changes in body weight or measures of body composition with a whole grain dietary intervention [3 servings/d (60 g/d) and 6 servings/d (120 g/d)]. The authors attributed their null findings to the nature of the intervention, the addition vs. substitution of whole grain foods into the diets, increased energy intake, and participant characteristics, among other factors (42). These intervention studies, combined with the observational studies, suggest that inclusion of whole grain foods into the diet may alter body fat distributions independently of changes in overall body weight; however, their mechanism of action still needs to be elucidated.

Several mechanisms have been suggested to explain why whole grain intake may play a role in body weight management. Fiber content of whole grain foods may influence food volume and energy density, gastric emptying, and glycémie response. Whole grains has also been proposed to play an important role in promoting satiety; individuals who eat more whole grain foods may eat less because they feel satisfied with less food. Some studies comparing feelings of fullness or actual food intake after ingestion of certain whole grains, such as barley, oats, buckwheat, or quinoa, compared with refined grain controls indicated a trend toward increased satiety with whole grains (43-45). These data are in accordance with analyses determining the satiety index of a large number of foods, which showed that the satiety index of traditional white bread was lower than that of whole grain breads (45). However, in general, these satiety studies have not observed a reduction in energy intake; hence, further research is needed to better understand the satiety effects of whole grains and their impact on weight management. Whole grains, in some studies, have also been observed to

lower the glycémie and insulin responses, affect hunger hormones, and reduce subsequent food intake in adults (46-48). Ingestion of specific whole grains has been shown to influence hormones that affect appetite and fullness, such as ghrelin, peptide YY, glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and cholecystokinin (46-48). Whole grain foods with fiber, such as wheat bran or functional doses of high molecular weight /3-glucans, compared with lower fiber Or refined counterparts have been observed to alter gastric emptying rates. Although it is likely that whole grains and dietary fiber may have similar effects on satiety, fullness, and energy intake, further research is needed to elucidate how, and to what degree, short-term satiety influences body weight in all age groups.

Differences in particle size of whole grain foods may have an effect on satiety, glycémie response, and other metabolic and biochemical (leptin, insulin, etc.) responses. Additionally, whole grains have been suggested to have prebiotic effects. For example, the presence of oligosaccharides, RS, and other fermentable carbohydrates may increase the number of fecal bifidobacteria and lactobacilli (49), thus potentially increasing the SCFA production and thereby potentially altering the metabolic and physiological responses that affect body weight regulation.

In summary, the current evidence among a predominantly Caucasian population suggests that consuming 3 or more servings of whole grains per day is associated with lower BMI, lower abdominal adiposity, and trends toward lower weight gain over time. However, intervention studies have been inconsistent regarding weight loss. As recommendations are made to incorporate whole grain foods into the diet, it will be important to emphasize replacing refined grain foods with nutrient-dense, whole grain foods rather than adding more food; this will ensure that energy balance is maintained. Further research is needed to examine the relationship between whole grain intake and abdominal adiposity or weight gain in ethnic minority groups, children, and adolescents. Additionally, there is a need for longer term dietary intervention and metabolic studies in both healthy and obese adults to better understand the mechanisms of action and relationships among whole grain intake, regulation of body weight, and adiposity.

Whole grains and CVD

Epidemiological studies from North American and European cohorts have consistently shown that consumption of whole grains is associated with reduced risk of CVD (50) (Table 4). Jacobs et al. (60) observed an inverse association between whole grain intake and risk of death from ischemic heart disease in the Iowa Women's Health Study, even after adjustment for potentially confounding factors and adjustment for total dietary fiber intake (RR = 0.70; 95% CI = 0.50-0.98 for highest quintile of whole grain intake). Liu et ai. (61) in the Nurses' Health Study also observed a strong inverse association between whole grain intake and risk of coronary heart disease (CHD) (RR = 0.51; 95% CI = 0.41-0.64) for women in the highest quintile of whole grain consumption compared with those in the lowest quintile. Steffen et al. (58) in the Atherosclerosis Risk in Communities study observed that 3 servings of whole grain foods per day was associated with a 28% lower risk of coronary artery disease, whereas Nettleton et al. (63) observed a 7% lower risk of incident heart failure in the same cohort. In a meta-analysis by Anderson et al. (64), which included 12 studies, data showed there was a significant inverse association between whole grain consumption and reduced risk of CHD (RR = 0.74; 95% CI = 0.64-0.84) after adjustment for primary and secondary risk factors. Additionally, the impact of whole grains on CHD risk reduction was stronger than the impact of cereal fiber alone; it was also stronger than the effect of total dietary fiber or that from fruits and vegetables. A more recent meta-analysis of 7 prospective cohort studies by Mellen et al. (65) estimated a 21 % lower risk of CVD events with greater whole grain intake (2.5 servings/d vs. 0.2 servings/d); additionally, the authors recommended that, 'In light of this consistent evidence, policy makers, scientist and clinicians should redouble efforts to incorporate clear messages on the beneficial effects of whole grains into public health and clinical practice endeavors.'

A number of mechanisms have been suggested for the CHD risk reduction associated with whole grains. These mechanisms include: the soluble fiber component that is associated with increased fecal excretion of cholesterol and bile acid; the antioxidant and antiinflammatory properties, possibly due to the presence of polyphenolics and other phytonutrients in whole grains; the fermentation of whole grain polysaccharides in the large bowel resulting in SCFA production, in particular propionate, which can inhibit cholesterol synthesis; and the increased serum enterolactone concentrations from fermentation of plant lignans by thé gut microflora (3,23,50). Other potential mechanisms include modulating blood glucose and insulin responses, improving vascular function and blood pressure, and weight control. Cochrane Review investigated the effects of whole grains on CHD risk in participants with preexisting CHD or 1 preexisting risk factor; they concluded that there is weak evidence for the LDL-cholesterol reduction potential of whole grains (66). However, it is unclear if LDL-cholesterol lowering is the sole mechanism of action for whole grains with regards to CHD risk reduction. It is also important to note that this review focused on studies where oats were the grain used in the intervention studies. Given the variation in the active cholesterollowering components (i.e. soluble fiber, β-gluean, and phytonutrients such as phytosterols) of different grains, the conclusions of Kelly et al. (66) need to be interpreted cautiously.

Higher whole grain intake has been associated with reduced risk of hypertension in prospective epidemiological and intervention studies. Wang et al. (54) in the Health Professionals' Study observed a 23% less likelihood of having hypertension among men who reported consuming at least 4 daily servings of whole grain foods compared with those who consumed less than one-half serving per day. In a recent intervention study, Tigne et al. (67) reported 6- and 3-mra Hg reductions in systolic blood pressure and pulse pressure, respectively, among middle-aged healthy individuals consuming 3 servings of whole grain foods per day compared with individuals consuming refined grains. This observed decrease in systolic blood pressure is estimated to lower the risk of coronary artery disease and stroke by 2:15 and 225%, respectively (67). In addition to fiber, whole grains contribute nutrients such as protein, magnesium, and potassium, which have been shown to play a role in blood pressure reduction. Additionally, the antiinflammatory effects of whole grains may also contribute to lower blood pressure and CVD risk (23,42,50,65).

Mellen et al. (68) and Erkkila et al. (69) both observed a positive association between whole grain intake and improvements in coronary artery intima thickness and diameter, a measure of progression of coronary artery atherosclerosis, after adjustments for CVD, blood pressure, and other confounding factors. These studies suggest that high whole grain intake is associated with less atherosclerotic progression, among individuals of multiple ethnicities and with varying cardiovascular risk profiles; this could be attributed to the plethora of beneficial components present in whole grains. These observations need to be confirmed in other studies and, if possible, the bioactive components responsible for these effects should be identified.

The role of whole grains in lowering blood lipids and lipoproteins is less clear, and the results from randomized intervention studies are variable. The evidence regarding the efficacy of oat and barley /3-glucan in lowering, blood lipids is well substantiated. On the other hand, the effect of whole grain foods prepared from other cereal grains in lowering blood lipids is less consistent. Brownlee et al. (41) reported the results of a randomized controlled intervention trial, which showed that whole grain foods (60 and 120 g/d) had no impact on plasma LDL-cholesterol levels of overweight but otherwise healthy adults. Furthermore, Brownlee et al. (41) observed no changes in insulin sensitivity, endothelial function, inflammatory markers, or anthropometric measures with the whole grain intervention. In contrast, Ciacco et al. ..(70) reported a significant reduction (5%) in fasting and postprandial plasma LDL-cholesterol with the consumption of wholemeal wheat foods. Similarly, the CHEWit Study (71 ) and the GrainMark Study (72) both showed significant reductions in systolic blood pressure and LDLcholesterol with higher whole grain intake. Haldar et al. (72) also reported that rye^based whole grain foods (48 g/d for 4 wk followed by 9.6 g/d for another 4 wk) were more effective in lowering blood cholesterol levels compared with wheat-based foods, which may be attributed to the higher soluble fiber content of rye compared with wheat. Discrepancies in these studies could be due to the fact that whole grain foods were potentially added to the diet rather than substituted for refined grain foods, as intended in the Brownlee study, because an increase in energy intake was observed in the intervention group compared with the control group and participants, although overweight, did not have elevated blood lipid concentrations at the start of the study. Overall, these intervention studies raise several important issues, namely, conducting randomized controlled intervention studies is challenging and changing diets in free-living intervention studies is not easy, particularly with complex food-based systems, wherein the benefits and interactions of the different components are still not well understood. Compliance with dietary interventions will always be an issue and biomarkers of intake are critical to enable better quantification of intake, importantly, the study by Brownlee et al. (41) raises the question about the use of volunteers who are at risk compared with healthy individuals in regards to the study objectives and expected outcomes.

C-reaetive protein (CRP), an acute-phase protein that is a sensitive marker of subclinical inflammation, has been shown to be strongly associated with risk of CVD, type 2 diabetes, and cancer (73,74). Whole grain intake has been associated with lower concentrations of CRP in epidemiological arid intervention studies. Qi et al. (75) in the Nurses' Health Study observed that whole grain intake was associated with improved inflammatory status among women with type 2 diabetes and the highest whole grain intake was associated with lower CRP and TNFa levels compared with the lowest whole grain intake. Similar observations were made in the Insulin Resistance Atherosclerosis Study (76). The Multi-Ethnic Study of Atherosclerosis (30) and the Nurses' Health Study (5L) reported significant inverse associations between whole grain intake and CRP concentrations even after adjustment for several confounding factors; similar associations were more recently observed among younger women (77). In a controlled weight loss intervention study, Katcher et al. (39) observed a 38% reduction in CRP concentrations among obese individuals consuming a whole grain hypocaioric diet compared with a refined grain hypocaioric diet. These effects of whole grains have been attributed to the synergistic, antiinflammatory effects of the dietary fiber, minerals, antioxidants, polyphenols, and other phytonutrients present in whole grain.

Preliminary studies also suggest that whole grain intake may be associated with improvements in insulin sensitivity (30,78), a risk factor associated with CHD. It was reported that habitual consumers of primarily whole grain flour products had lower fasting insulin concentrations than habitual refined grain flour consumers. Pereira et al. (78) observed that fasting insulin was 10% lower during consumption of the whole grain diet than during consumption of the refined grain diet (mean difference: - 15 ± 5.5 pmol/L; P = 0.03) and the area under the 2-h insulin curve tended to be lower than after the refined grain diet. The higher fiber and indigestible carbohydrate content in many whole grain foods may be fermented by colonic bacteria, which may produce SCFA that enter the portal circulation and influence hepatic glucose oxidation, decrease fatty acid release, and increase insulin clearance, thereby improving insulin sensitivity. Pereira et al. (78) also suggested that a high-whole grain, high-fiber diet could improve insulin receptor sensitivity through a chronic lowering of the overall dietary glycémie index and related insulin secretion as well as through SCFA production, leading to enhanced hepatic glucose oxidation and insulin clearance.

Based on the existing evidence, there are 4 consensus authoritative statements from national organizations, namely the U.S. FDA (79), the U.K. Joint Health Claims Initiative (80), and the Sweden (81) and Danish Dietary Recommendations (82) that link consumption of whole grains with improved heart health. Dietary guidelines around the world emphasize the importance of grain foods, particularly whole grains in the diet. For example, U.K. products composed of >51% whole grains can claim, 'People with a healthy heart tend to eat more whole grains foods as part of a healthy lifestyle.' In Sweden, products with at least 50% whole grains can state, 'A healthy lifestyle and a balanced diet rich in whole grains products reduce the risk of heart disease. Product X is rich in whole grains.'

In summary, the current scientific evidence is strong and consistent to suggest that whole grains have a beneficial effect on CVD risk reduction. Further research is needed to better understand the mechanism of action and the impact of the various components of whole grains on CVD risk reduction.

Whole grains and type 2 diabetes

Type 2 diabetes is an epidemic that affects an ever-increasing proportion of the U.S. and global population. The interactions among genes, environment, diet, and lifestyle all play an important role in insulin resistance and the subsequent multifactorial pathogenesis of diabetes. Lifestyle modification and weight control are major factors in the prevention and treatment of diabetes. Gross et al. (83) suggested that increased intake of refined carbohydrates, along with decreased intake of fiber, contributes to the increasing prevalence of type 2 diabetes in the US.

Evidence from epidemiological studies shows an inverse association between whole grain consumption and risk of type 2 diabetes. In a prospective cohort study, Liu et al. (84) found that increased intake of whole grains significantly lowered the risk of type 2 diabetes, after adjusting for age and energy intake, when comparing the highest quintile of whole grain intake to rhe lowest quintile (RR = 0.62; 95% CI = 0.53-0.71). An examination of dietary patterns revealed that a prudent diet, characterized by high consumption of whole grains, legumes, fruits, vegetables, seafood, white meat, nuts, and vegetable oils, was inversely associated with risk of type 2 diabetes, whereas a Western diet, characterized by high consumption of refined grains, red meat, processed meat, potatoes, and food high in saturated fat, cholesterol, and trans fat, was positively associated with risk of type 2 diabetes (85). A recent meta-analysis by de Munter et al, (86) showed that a 2-serving/d increase in whole grain consumption is associated with a 21% (95% CI = 13-28%) decrease in risk of type 2 diabetes after adjustment for potential confounders and BMI.

Gross et al. (83) suggested that the beneficial effects may be due to the structure of whole grains and the nutrients found in whole grains such as dietary magnesium and antioxidants like vitamin E, phytic acid, and selenium. Whole grain particle size influences rate of digestion and consequent metabolic effects and thus affects the etiology and management of diabetes. An in vitro study by Heaton et al. (87) showed step-wise increases in insulin responses based on the nature of the whole grains: whole grains < cracked grains < coarse flour < fine flour. Among overweight and obese individuals, Pereira et al. (78) observed 10% lower fasting insulin and 13% lower measures of insulin resistance after 6 wk of consumption of a whole grain diet compared with a refined grain diet, thus suggesting improved insulin sensitivity.

In summary, dietary patterns characterized by refined carbohydrates may adversely affect metabolic intermediates and such a diet may increase the risk of vascular diseases, such as diabetes and CHD, especially among individuals prone to insulin resistance. To lower disease risk and improve vascular health outcomes, it is imperative to replace refined grains with whole grains to improve glucose homeostasis. Future research needs to examine the interactions not only among different dietary factors but also between diet and genetic predisposition and between diet and metabolic determinants, such as physical activity. It will he important to conduct randomized intervention trials of sufficient size and length to further elucidate the role of whole grains and associated components in diabetes risk reduction.

Whole grains and gastrointestinal health

Gastrointestinal health is characterized as maintenance of homoeostasis of gastrointestinal function by promoting efficient digestion, optimal gut immune responses, minimal inflammation, and the absence of disease. However, given the continuous and regular exposure of the gastrointestinal tract to pathogens and toxins frorii the external environment, it is challenging to maintain homeostasis and gastrointestinal health. Prevalence data show that gastrointestinal diseases have significantly risen (>30%) between 1992 and 2004, contributing to $142 billion in total medical costs (88). Colorectal cancer is the 4th most common type of cancer, contributing to 53% of all gastrointestinal cancers (89). Current prevalence data suggest that there are many factors affecting gastrointestinal health, including, lifestyle, diet, environment, genetics, and age.

Epidemiological studies have shown an inverse association between whole grain consumption and relative risk of certain cancers (21). Observational studies in the US and Europe suggest a strong inverse association between whole grain consumption and gastrointestinal cancers, certain hormone-related cancers and pancreatic cancer. In prospective studies, Larsson et al. (90), in the Swedish Mammography cohort, reported a 24% lower risk of colorectal cancer in the highest quintile of whole grain intake compared with the lowest quintile, and Schatzkin et al. (91 ), in the NIH-AARP Diet and Health Study cohort, observed a 21% reduction in risk of colorectal cancer in the highest quintile of whole grain intake compared with the lowest quintile. In a recent meta-analysis, Haas et ai. (92) observed an inverse relationship between consumption of whole grains and risk of developing colorectal cancer; further work is needed to better understand this association.

Many dietary components can positively affect gastrointestinal health, including fiber, RS, oligosaccharides, phytochemicais, antioxidant vitamins, and minerals. Of the myriad of foods available, whole grains provide most of these beneficial components. Whole grains play an important role in digestive health and this is attributed to not only the fiber component but also the other nutrients and phytonutrients present in the whole grains. Whole grains contain a significantly higher proportion of nutrients than their refined grain counterparts (3). The dietary fi ber components of whole grains vary from one grain to another (Table 2) (93), with the whole grain version having higher proportions than the refined grain version. Additionally, different grains have different proportions of soluble and insoluble fibers, with whole grain wheat being lower in soluble fiber compared with whole grain oats, rye, and barley.

The fiber components of whole grains include fermentable carbohydrates, namely soluble and insoluble dietary fiber, RS, and oligosaccharides. Two types of oligosaccharides exist in cereal grains, galactosyl dérivâtes of sucrose (stachyose and raffinose) and fructosyl dérivâtes of sucrose (fructooligosaccharides) (94), which are present in the bran and germ components of the whole grain. Some dietary fibers play a role in maintaining gastrointestinal health by increasing fecal bulk, increasing transit time, increasing removal of carcinogenic compounds, increasing binding to mutagens, increasing SCFA production, and lowering colonic pH (95). Coarse wheat bran has a greater fecal bulking effect than finely ground wheat bran when fed at the same dosage (96), suggesting that particle size of the whole grain is an important factor in determining its physiological effect. Mclntyer et al. (97) suggested that the coarse nature of whole grain compared with refined grain results in a unique physiological effect beyond compositional differences between whole and refined grains.

There is considerable evidence regarding the fermentable carbohydrates in whole grains and their role in gastrointestinal function and health. Disruption of cell walls increases fermentability of the dietary fiber in the whole grains and the release of phytonutrients, which, in combination, can aid in digestive health. Undigested carbohydrate that reaches the colon may be fermented by intestinal microbiota to SCFA, including acetate, propionate, and butyrate. These SCFA, namely butyrate, serve as energy sources for the colonic mucosal cells and the gut microbiota, while also influencing other systemic metabolic and physiological processes such as the role of propionate in hepatic lipid metabolism.

Whole grains are also a concentrated source of RS. There are 4 main types of RS: RSl, which is the physically inaccessible starch present in whole or partly milled grain; RS2, which is the large resistant granule present in high amylose-contaimng grains, raw potatoes, and green bananas; RS3, which is the retrograded starch present in cooked and cooled grain and breads; and RS4, which is the chemically modified form present inesterified or cross-bonded starch. The RS content of raw whole grains varies; e.g., in vitro studies in canine models indicate that corn contains 31%, wheat 27%, and barley 33% (93), with the respective flours having considerably lower amounts. RS has been proposed to play a role in gastrointestinal health by increasing fecal bulk by ~ 1-1.7 g additional feces/g of RS consumed, increasing microbial mass, and increasing prebiotic effects, thereby increasing beneficial bacteria and decreasing pathogens, increasing SCFA production, especially butyrate, and decreasing production of toxic metabolites such as ammonia and deoxycholic acid (98).

The SCFA butyrate is the primary metabolic fuel for the colonic epithelial cells and is essential for maintaining epithelial health. Butyrate may contribute to gastrointestinal health by lowering inflammation, oxidative stress, and diarrhea and increasing barrier function, mineral absorption, and detoxifying enzyme activities (98). Hernot et al. (99) showed that butyrate production is proportional to the RS content of whole grains, with wheat and corn being rhe highest producers, followed by barley and oats, and rice being the lowest butyrate producer. It has been suggested that the insoluble fiber content of whole grains may aid in the fermentation of RS in the distal colon, thus allowing for a more uniform production of butyrate and a potential protective mechanism against tumor development and growth.

A prebiotic is defined as 'a selectively fermented ingrethent that allows specific changes, both in the composition and/or activity in the gastrointestinal microbiota that confers benefits upon host well-being and health' (100). Whole grains have been suggested to have prebiotic effects. The oligosaccharides and the RS present in whole grains qualify for this prebiotic status. These prebiotics selectively increase beneficial bacteria in the gut, mainly bifidobacteria and lactobacilli. By altering this beneficial gut microbiota, the fermentable carbohydrates can influence host immune response, specifically by influencing the gutassociated lymphoid tissue. In vitro studies by Karppinen et al. (101) showed that inulin, a fructose polymer, was fermented faster than the more complex carbohydrates in cereal bran. Oat bran, rich in ß-glucan, was fermented faster than rye and wheat brans, which are rich in arabinoxylans. Costabile et al. (49) conducted a double-blind, randomized crossover study of whole grain wheat and wheat bran in 31 human participants. After 3 wk of each dietary intervention, fecal bifidobacteria and lactobacilli were significantly higher with whole grain wheat consumption compared with wheat bran consumption; this prebiotic activity may contribute to the beneficial physiological effects of whole grain wheat. However, there were no significant differences in fecal SCFA production with ingestion of either whole grain or wheat bran. Hernot et al. (99) examined the fermentation profiles of native whole grains (barley, corn, oat, rice, and wheat) and their processed and bran components. Processing of most substrates resulted in higher dry matter and starch digestibility and lower RS concentrations. Dietary fiber composition varied among substrates with processing. Digestion profiles for most of the whole grains and their processed and bran components correlated well with their chemical composition. Corn bran and rice substrates were the least fermentable; extrusion rendered barley, corn, and wheat more hydrolytically digestible, and barley and oat more fermentatively digestible, which can thus affect their physiological functions such as cholesterol reduction vs. intestinal barrier protection. Except for corn bran, all components had greater or equal fermentability compared with their native whole grain.

Micronutrients such as folate and vitamin B-6, polyphenols, and antioxidant compounds, along with prebiotics such as inulin, oligosaccharides and immune modulators such as 0-glucan, present in whole grains potentially work synergistically to lower oxidative stress, inflammation, and pathogen load. Thus, it is the sum of the parts of whole grains that likely maintain gastrointestinal health.

In summary, whole grains provide the gastrointestinal tract with more than fiber, thus contributing to their role in maintaining gastrointestinal funcrion and protection against disease. The various components present in whole grains may act synergistically to help improve bowel function and provide protection against gastrointestinal cancers, inflammation, and other disease states while strengthening barrier function and providing immune support. Increasing intake of whole grains is highly recommended for improving gastrointestinal health. Future research is needed to better understand the mechanism of action of whole grains in gastrointestinal health.

Summary and Conclusions

Existing evidence indicates that whole grains have a beneficial health effect; much of the evidence comes from observational studies that have demonstrated an association between whole grain intake and disease risk reduction. Evidence from intervention studies is variable. There is consistent epidemiological evidence that whole grain foods substantially lower the risk of chronic diseases such as CHD, diabetes, and cancer and also play a role in body weight management and digestive health. The essential macro- and micronutrients along with the phytonutrients present in whole grains synergistically contribute to their beneficial effects. Current evidence lends credence to the recommendations to incorporate whole grain foods into a healthy diet and lifestyle program. Future research needs to examine the role of whole grain foods in disease prevention and management to gain a better understanding of their mechanisms of action. Given the current evidence, the importance of whole grains in the diet of individuals is best summarized by Dr. Chris Seal, who very elegantly states, 'When shopping in a supermarket there will be a range of healthy, nutritious whole grains foods, be sure to get them and beware of spurious imitations. After a little time their taste grows on you and refined foods will no longer satisfy you. Soon, only the ill-informed will avoid whole grains foods. Whole grains are not a luxury, and no house is complete unless they are provided at every meal (Dr. Chris Seal, Newcastle University, personal communication).'

Acknowledgments

We thank Dr. Chris Seal, Newcastle University, for his contribution in translating the evidence for the consumers. All authors were speakers at the symposium and contributed to the writing of their individual sections as follows: S.S.J, contributed to the overall content and coordinated the writing of the manuscript; L.H. was responsible for whole grain and whole grain dietary intake assessment; R-H. L. was responsible for whole grain phytonutrients; N.M.K. was responsible for whole grain and weight management; CS. was responsible for whole grain and CVD; S.L. was responsible for whole grain and diabetes; and G.C.F. was responsible for whole grain and gastrointestinal health. AU authors read and approved the final manuscript.

1 Published in a supplement to The Journal of Nutrition, Presented at the American Society for Nutrition's Satellite Symposium 'Putting the Whole Grain Puzzle Together: Health Benefits Associated with Whole Grain' held in Anaheim, CA, April 23. 2010. The supplement coordinator for this supplement was Satya S. Jonnalagadda. Supplement Coordinator disclosures: Satya S. Jonnalagadda is an employee of the General Mills Bell Institute of Health and Nutrition. The supplement is the responsibility of the Guest Editor to whom the Editor of The Journal of Nutrition has delegated supervision of both technical conformity to the published regulations of The Journal of Nutrition and general oversight of the scientific merit of each article. The Guest Editor for this supplement was Julie Miller Jones. Guest Editor disclosure: Julie Miller Jones had no conflicts to declare. Publication costs for this supplement were defrayed in part by the payment of page charges. This publication must therefore be hereby marked 'advertisement' in accordance with 18 USC section 1734 solely to indicate this fact. The opinions expressed in this publication are those of the authors and are not attributable to the sponsors or the publisher, Editor, or Editorial Board of The Journal of Nutrition.

2 The symposium was funded through an unrestricted education grant from the General Mills Bell Institute of Health and Nutrition, Minneapolis. MN. All symposium speakers were paid a speaker honorarium. Corresponding author is an employee of General Mills Bell Institute of Health and Nutrition, Minneapolis, MN.

3 Author disclosures: N. McKeown, S. Liu, and G. C. Fahey received research grant funding from General Mills Inc. S. S. Jonnalagadda is an employee of General Mills Inc. L. Harnack, R.-H. Uu, and C. Seal, no conflicts of interest.

11 Abbreviations used: CHD, coronary heart disease; CRP, C-reactive protein; CVD, cardiovascular disease; NCC, Nutrition Coordinating Center; RS, resistant starch; TE. Trolox equivalent.

[Reference]

Literature Cited

1. American Association of Cereal Chemists International. AACC members agree on definition of whole grain [cited 2010 Jun I]. Available from: http://www.aaccnet.org/news/pdfs/wgPR.pdf.

2. United States FDA. FDA provides guidance on 'Whole Grain' for manufacturers [cited 2010 Jun I]. Available from: http://www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/2006/ucml08598.htm.

3. Okarter N, Liu RH. Health benefits of whole grain phytochemicais. Crit Rev Food Sci Nutr. 2010;50:193-208.

4. USDA, Agricultural Research Service. USDA National Nutrient Database for Standard Reference, Release 22. Nutrient Data Laboratory Home Page; 2009 [cited 2010 Jun I]. Available from: hnp://www,ars. usda.gov/ba/bhnrc/ndl.

5. The Report of the Dietary Guidelines Advisory Committee on Dietary Guidelines for Americans. Office of Disease Prevention and Health Promorion, U.S. Department of Health and Human Services; 2005 [cited 2010 Jun I]. Accessible from: hnp;//www.health.gov/DietaryGuideIines/ dga2005/report/.

6. Dietary Guidelines for Americans; 2010 [cited 2011 January 31 1. Available from: hn^^/www.cnpp.usda.gov/DGAs2010-PolicyDocument.htm.

7. Cleveland LE, Moshfegh AJ, Albertson AM, Goldman JD. Dietary intake of whole grains. J Am Coll Nutr. 2000;19:5331-8.

8. Good CK, Holschuh NM, Albertson AM, Eldridge AL. Whole grain consumption and body mass index in adult women: an analysis of NHANES 1999-2000 and the USDA Pyramid Serving Database. J Am Coll Nutr. 2008;27:80-7.

9. Mancino L, Kuchler F, Leibtag E. Getting consumers to eat more whole-grains: rhe role of policy, information, and food manufacturers. Food Policy. 2008;33:489-96.

10. Bachman JL, Reedy K, Subar AF, Krebs-Smith SM. Sources of food group intakes among the US population, 2001-2002. J Am Diet Assoc. 2008;108:804-14.

11. Bowman SA, Friday JF, Mosbfegh A. MyPyramid Equivalents Database, 2.0 for USDA Survey Foods, 2003-2004. Food Surveys Research Group. Beltsville Human Nutrition Research Center, Agricultural Research Service, USDA, Beltsville, MD; 2008 [cited 2010 Jun I]. Available from: http^/www.ars.usda.gov/Services/docs.hrm?docid=17558.

12. Sadeghi L, Marqua« L. Whole grain snack intake in an after-school snack program: a pilot study. J Foodservice. 2009;20:71-80.

13. University of Minnesota Nutrition Data System for Research [cited 2010 Jun I]. Available from: http://www.ncc.urrm.edu/index.hnnl.

14. Harnack L, Cordy D, Zeug-Shell R, Pettir J, King D. Accuracy of whole grain composition estimates derived from formulations created for a sample of whole grain containing commercial food products. Presented at the 34th National Nutrient Databank Conference, July 12-14, 2010.

15. Liu RH. Potential synergy of phytochemicais in cancer prevention: mechanism of action. J Nutr. 2004;134:S3479-85.

16. Adorn KK, Sorrells ME, Liu RH. Phytochemicais and antioxidant activity of milled fractions of different wheat varieties. J Agrie Food Chem. 2005;53:2297-306.

17. Adorn KK, Liu RH. Antioxidant activity of grains. J Agrie Food Chem. 2002;50:6182-7.

18. Smith MM, Hartley RD. Occurrence and nature of ferulic acid substitution of cell wall polysaccharides in gramineous plants. Carbohydr Res. 1983;118:65-80.

19. Klepacka J, Fornai L. Ferulic acid and its position among the phenolic compounds of wheat. Crit Rev Food Sci Nutr. 2006;46:639-47. PubMed

20. Andreasen MF, Kroon PA, Williamson G, Garcta-Conesa MT. Intestinal release and uptake of phenolic antioxidant diferulic acids. Free Radie Biol Med. 2001;31:304-314.

21. Chatenoud L, Tavni A, La Vecchia C, Jacobs D Jr, Negri E. Whole grain food intake and cancer risk. Int J Cancer. 1998;77:24-8.

22. Miller HE, Rigelhof F, Marquait L, Prakash A, Kanter M. Antioxidant content of whole grain breakfast cereals, fruits and vegetables. J Am Coll Nutr, 2000;19:S312-9.

23. Slavin J. Whole grains and human health. Nutr Res Rev. 2004; 1 7:99-110.

24. Harland JI, Garton LE. Whole-grain intake as a marker of healthy body weight and adiposity. Public Health Nutr. 2008;11:554-63.

25. McKeown NM, Meigs JB, Liu S, Wjlson PWF, Jacques PF. Whole-grain intake is favorably associated with metabolic risk factors for type 2 diabetes and cardiovascular disease in the Framingham Offspring Study. Am J Clin Nutr. 2002;76:390-8.

26. Liu S, Willett WC, Manson JE, Hu FB, Rosner B, Colditz G. Relation between changes in intakes of dietary fiber and grain products and changes in weight and development of obesity among middle-aged women. Am J Clin Nutt. 2003;78:920-7.

27. Koh-Banerjee P, Franz M, Sampson L, Liu S, Jacobs DR Jr, Spiegelman D, Willett W, Rimm E. Changes in whole-grain, bran, and cereal fiber consumption in relation to 8-y weight gain among men. Am J Clin Nutr. 2004;80:1237-45.

28. Bazzano LA, Song Y, Bubes V, Good CK, Manson JE, Liu S. Dietary intake of whole and refined grain breakfast cereals and weight gain in men. Obes Res. 2005;13:1952-60.

29. Sahyoun NR, Jacques PF, Zhang XL, Juan W, McKeown NM. Wholegrain intake is inversely associated with the metabolic syndrome and mortality in older adults. Am J Clin Nutr. 2006;83:124-31.

30. Lutsey PL, Jacobs DR, Kori S, Mayer-Davis E, Shea S, Steffen LM, Szklo M, Tracy R. Whole grain inrake and its cross-sectional association with obesity, insulin resistance, inflammation, diabetes and subclinical CVD: The MESA Study. Br J Nutr. 2007;98:397-405.

31. Newby PK, Maras J, Bakun P, Müller D, Ferrucci L, Tucker KL. Intake of whole grains, refined grains, and cereal fiber measured with 7-d diet records and associations with risk factors for chronic disease. Am J Clin Nutr. 2007;86:1745-53.

32. Rose N, Hosig K, Davy B, Serrano E, Davis L. Whole-grain intake is associated with body mass index in college students. J Nutr Educ Behav. 2007;39:90-4.

33. McKeown NM, Yoshida M, Shea MK, Jacques PF, Lichtenstein AH, Rogers G, Booth SL, Saltzman E. Whole-grain intake and cereal fiber are associated with lower abdominal adiposity in older adults. J Nutr. 2009;139:1950-5.

34. Esmaillzadeh A, Mirmiran P, Azizi F. Whole-grain consumption and the metabolic syndrome: a favorable association in Tehtanian adults. Eur J Clin Nutr. 2005;59:353-62.

35. Esmaillzadeh A, Mirmiran P, Azizi F. Whole-grain intake and the prevalence of hypertriglyceridemic waist phenotype in Tehranian adults. Am J CHn Nutr. 2005;81:55-63.

36. van de Vijver LP, van den Bosch LM, van den Brandt PA, Goldbohm RA. Whole-grain consumption, dietary fibre intake and body mass index in the Netherlands cohort study. Eur J Clin Nutr. 2009;63:31-8.

37. Thane CW, Stephen AM, Jebb SA. Whole grains and adiposity: little association among British adults. Eur J Clin Nutr. 2009;63:229-37.

38. McKeown NM, Troy LM, Hoffmann U, O'Donneli CJ, Liu E, Rogers G, Jacques PF, Fox C. Whole- and refined-grain intakes are differentially associated with abdominal visceral and subcutaneous adiposity in healthy adults: the Framingham Heart Study. Am J Clin Nutr. 2010;92:1165-71.

39. Katcher Hl, Legro RS, Ktiriselman AR, Gillies PJ, Demers LM, Bagshaw DM, Kris-Etherton PM. The effects of a whole grain-enriched hypocaioric diet on cardiovascular disease risk factors in men and women with metabolic syndrome. Am J Clin Nutr. 2008;87:79-90.

40. Kall io P, Kölehmainen M, Laaksonen DE, Kekäläinen J, Salopuró T, Sivenius K, Pùlkkinén L, Mykkänen HM, Niskanen L, et al. Dietary carbohydrate modification induces alterations in gene expression in abdominal subcutaneous adipose tissue in persons with the metabolic syndrome: the FUNGENUT Study. Am J Clin Nutr, 2007;85:1417-27.

41. Brownlee IA, Moore C, Chatfield M, Richardson DP, Ashby P, Kuznesof SA, Jebb SA, Seal CJ. Markers of cardiovascular risk axe not changed by increased whole-grain intake: the WHOLEheart study, a randomised, controlled dietary intervention. Br J Nutr. 2010; 104: 125-34.

42. McKeown NM, Jacobs DR Jr. In defense of phvtochemieal-rich dietary patterns. BrJ Nutr: 2010;104:1-3.

43. Schroeder N, Gallaher DD, Arndt EA, Marquait L. Influence of whole grain barley, whole grain wheat, and refined rice-based foods on shortterm satiety and energy intake. Appetite.

44. Berti C, Riso P, Brusamolinp. A» Por rini M- Effect on appetite control of minor cereal and pseudocereal products. Br J Nutr. 2005;94:850-8.

45. Holt SH, Brand-Miller JC, Stitt PA. The effects of equal-energy portions of different breads on blood glucose levels, feelings of fullness and subsequent food intake. J Am Diet Assoc. 2001;101:767-73.

46. Juntuntn KS, Niskanen LK, Liukkonen KH, Poutanen KS4 Hoist JJ, Mykkänen HM. Postprandial glucose, insulin, and incferin responses to grain products in healthy subjects. AmJ Clin Nutr. 2002;75:254-62.

47. Juvonen KR, Purhonen AK, SalmenkallioJvlarttila M, Lähteenmäki L, Laaksonen DE, Herzig KH, Uusitupa MI, Poutanen KS1 Karhunen LJ. Viscosity of oat bran-enriched beverages influences gastrointestinal hormonal responses in healthy humans. J Nntr. 2009sl39:461-6.

48. Bourdon I, Yokoyama W, Davis P, Hudson C, Backus R, Richter D3 Knuckles B, Schneeman BO, Postprandial lipid, glucose, insulin, and cholecystokinin responses in men fed barley pasta enriched with betaglucán. Am J Clin Nutr. 1999;69:5 5-63.

49. Costatole A, Klinder A, Fava F, Napolitano A, Fogliano V, Leonard C, Gibson GRj Tuohy KM. Whole-grain wheat breakfast cereal has a prebiotic effect on the human gut microbiota: a double-blind, placebocontrolled, crossover study. BrJ Nutr, 2008;99:110-20.

50. Seal CJ, Brownlee IA. Whole grains and health, evidence from observational and intervention studies. Cereal Chem. 2010;87:167-74.

51. Jensen MK, Koh-Banerjee P, Franz M, Sampson L, Gronbaek M, Rimm EB. Whole grains, bran, and germ in relation to homocysteine and markers of glycemic control, lipids, and inflammation 1. Am J Clin Nutr. 2006;83275-83

52. He J, Klag MJ, Wheiton PK, Mo JP, Chen JY, Qian MC, Mo PS, He GQ. OaK and buckwheat intakes and cardiovascular disease risk factors in an ethnic minority of China. Arri J Clin Nutr. 1995;61:366-72.

53. Flint AJ, Hu FB, Glynn RJ, Jensen MK, Franz M, Sampson L, Rimm EB. Whole grains and incident hypertension in men. Am J Clin Nutr. 2009;90:493-8.

54. Wang L, Gaziano JM, LiU S, Manson JE, Buring JE, Sesso HD. Wholeand refined-grain intakes and the risk of hypertension in women. Am J Clin Nutr, 2007;86:472-9.

55. Steffen LM, Kroenke CH, Yu X, Pereira MA, Slattery ML, Van Horn L, Gross MD, Jacobs DR Jr. Associations of plant food, dairy product, and meat intakes with 15-y incidence of elevated blood pressure in young black and white adults: the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Am J Clin Nutr. 2005;82:1169-77.

56. Jensen MK, Koh-Banerjee, Hu FB, Franz M, Sampson L, Gronbaek M, Rimm EB. Intakes of whole grains, bran, and germ and rhe risk of coronary heart disease in men. Am J Clin Nutr. 2004;80:1492-9.

57. Liu S, Sesso HD, Manson JE, Willett WC, Buring JE. Is intake of breakfast cereals related to total and cause-specific mortality in men? Am J Clin Nutr. 2003;77:594-9.

58. Steffen LM, Jacobs DR Jr, Stevens J, Shahar E, Carithers T, Folsom AR. Associations of whole-grain, refined-grain, and fruit and vegetable consumption with risks of ali-cause mortality and incident coronary artery disease and ischemic stroke; the Atherosclerosis Risk in Communities (ARIC) Study. Am J Clin Nutr. 2003;78:383-90.

59. Liu S, Manson JE, Stampfer MJ, Rexrode KM, Hu FB, Rimm EB, Willett WC. Whole grain consumption and risk of ischemic stroke in women: a prospective study. JAMA. 2OQ0;284:1534r-40.

60. Jacobs DR, Meyer KA, Kushi LH, Folsom AR. Whole-grain intake may reduce the risk of ischemic heart disease death in postmenopausal women: the Iowa Women's Health Study. Am J Clin Nutr. 1998;68: 248-57.

61. Liu S, Stampfer MJ, Hu FB; Giovannucci E, Rimm E, Manson JE, Hennekens CH, Willett WC. Whole-grain consumption and risk of coronary heart disease: results from die Nurses' Health Study. Am J CKn Nutr. 1999;70:412-9.

62. Fraser GE, Sabate J, Beeson WL, Strahan TM. A possible protective effect of nut consumption on risk of coronary heart disease. The Adventist Health Study. Arch Intero Med. 1992;152:1416-24.

63. Nettleton JA, Steffen LM, Loehr- LR, Rosamond WD, Folsom AR. Incident heart failure is associated with lower whole-grain intake and greater high-fat dairy and egg intake in the Atherosclerosis Risk .in Communities (ARIC) study. J Am Diet Assoc. 2008;108:1881-7.

64. Anderson JW. Whole grains protect against atherosclerotic cardiovascular disease. Proc Nutr Soc. 2003i62: 135-42.

65. Mellen PB, Walsh TF, Herrington DM. Whole grain intake and cardiovascular disease: a meta-analysis. Nutr Metab Cardiovasc Dis. 2008;18:283-90.

66. Kelly SAH Summerbell CD, Brynes A, Whirtaker V, Frost G. Wholegrain cereals for coronary heart disease. Cochrane Database Syst Rev. 2007;CD00505t.

67. Tighe P, Duthie G, Vaughan N, Brittenden J, Simpson WG, Duihie S, Mutch W, Wahle K, Horgan G, et ai. Effect of increased consumption of whole-grain foods on blood pressure and other cardiovascular risk markers in healthy middle-aged persons: a randomized controlled trial. AmJ Clin Nutr. 2010;92:733-40.

68. Mellen PB, Liese AD, Tooze JA, Vítolins MZ, Wagenkneeht LE, Herrington DM. Whole-grain intake and carotid artery atherosclerosis in a multiethnic cohort: the Insulin Resistance Atherosclerosis Study. Am J Clin Nutr, 2007;85:1495-502.

69. Erkkila AT, Herrington DM, Mozaffarian D, Lichtenstein AH. Cereal fiber and whole-grain intake are associated with reduced progression of coronary-artery atherosclerosis in postmenopausal women with coronary artery disease. Am Heart J. 2005;150:94-101.

70. Giacco R, Clemene G, Cipriano D, Luongo D* Viseovo D, Patti L, DiMarino L, Ciacco A, Naviglio D, et al. Effects of the regular consumption of wholemeal wheat foods on cardiovascular risk factors in healrhy people. Nutr Metab Cardiovasc Dis. 2010,20: 186-94.

71. Jones AR-. Attitudinal and physiological responses to the consumption of wholegrain foods [.thesis]. Newcastle (UK): Newcastle University; 2006.

72. Haldar S, BaI W, Brandt K, Seal C. Effect of consumption of either whole grain or rye as the sole whole grain source on plasma lipid profiles in healthy volunteers (the GrainMàrk Study). Presented at C&E Spring Meeting 2009~3rd Whole Grain Global Summit, Newcastle (UK).

73. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342:836-43.

74. Heikkilä K, Harris R, Lowe G, Rumley A, Yametf J, Gallaeher J, BenShlomo Y, Shah E, Lawlor DA. Associations of circulating C-reactive protein and interleukin-6 with cancer risk: findings from two prospective cohorts and a meta-analysis. Cancer Causes Control. 2009;20:I526.

75. Qi L, van Dam RM, Liu S, Franz M, Mantzoros C, Hu FB. Wholegrain, bran, and cereal fiber intakes and markers of systemic inflammation in diabetic women. Diabetes Care. 2006;29:207-11.

76. Masters RC, Liese AD, Haffner SM, Wagenknecht LE, Hanley AJ. Whole and refined grain intakes are related to inflammatory protein concentrations in human plasma. J Nutr. 2010;140:587-94.

77. Gaskins AJ, Mumford SL, Rovner AJ, Zhang C, Chen L, WactawskiWende J, Perkins NJ, Schisterman EF, for the BieÇycle Study Group. Whole grains are associated with serum concentrations of high sensitivity C-reactive protein among premenopausal women. J Nutr. 2010;140:1669-76.

78. Pereira MA, Jacobs DR, Pins JJ, R-aatz S, Gross M, SIa vin J, Seaquisr E. The effect of whole grains on insulin sensitivity in overweight hyperinsulinemic adults, Am J Clin Nutn 2002;75:848-55.

79. FDA. Whole-grain foods aurhoritative statement claim notification. Docket 99P-2209. Washington, DC; July 1999.

80. TJK Joint Health Claims Initiative. Health claims valid until 2010 [cited 2010 Jun 1]. Available from: www.jhci.co.uk.

81. Swedish Nutrition Foundation health claims lcited 2010 Jun I]. Available from: http://www.snf.ideon.se/snf/en/rh/Healh_eiaims_FF. htm.

82. National Food Institute, Technical University of Denmark, Wholegram: definition and scientific background for recommendations of wholegrain intake in Denmark. May 2008; [cited 20 10 Jun I]. Available from: www.fooddtu.dk.

83. Gross LS;, Li L, Ford ES, Liu S. Increased consumption of refined carbohydrates and rhe epidemic of type 2 diabetes in the United States: an ecologie assessment. Am J Clin Nutr. 2004;79:774-9.

84. Liu S. intake of refined carbohydrates and whole grain foods in relation to risk of type 2 diabetes mellitus and coronary heart disease. J Arri Coll Nutr. 2002;21:298-306.

85. van Dam RM, Rimm EB, Willett WC, Stampfer MJ, Hu FB. Dietary patterns and risk for type 2 diabetes mellitus in U.S. men. Ann Intern Med. 2002;136:201-9.

86. de Munter JS, Hu FB, Spiegelman D, Franz M, van Dam RM. Whole grain, bran, and germ intake and risk of type 2 diabetes: a prospective cohort study and systematic review, PLoS Med. 2007;4:e261.

87. Heaton KW, Marcus SN, Emmett PM Bolton CH. Particle size of wheat, maize, and oat test meals: effects on plasma glucose and insulin responses and on the rate of starch digestion in vitro. Am J Clin Nutr. 1988;47:675-82.

88. Everhart JE, editor. The Burden of Digestive Diseases in die United States. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases, U.S. Department of Health and Human Services; 2008 lcited 2010 Jun I]. NIH Publication 09-6433. Available from: http://digesti ve.n iddk. nih.gov/statistics/sta tistics.htm # 1.

89. Altekruse SF, Kosary CL1 Krapcho M, Neyman N, Aminou R, Waldron W, Rubi J, Howlader N, Tatalovich Z, et al., editors. SEER Cancer Statistics Review, 1975-2007, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/e5r/1975_2007/, based on November 2009 SEER data submission, posted to the SEER Web site; 2010 [cited 2010 Jun I]. http://seer.cancengov/statfacts/litml/coIorect.html#prevalence.

90. Larsson SC, Giovannucci E, Bergkvist L, WoIk A. Whole grain consumption and risk of colorectal cancer: a population-based cohort of 60,000 women. BrJ Cancer. 2005;92:1803-7.

91. Schatzkin A, Mouw T, Park Y, Subar AF, Kipnis V, Hollenbeck A, Leirzmann MF, Thompson FE. Dietary fiber ad whole grain consumption in relation to colorectal cancer. AmJ Clin Nutr. 2007;85:1353-60.

92. Haas P, Machado MJ, Anton AA, Silva AS, De Francisco A. Effectiveness of whole grain consumption in the prevention of colorectal cancer: meta-analysis of cohort studies. Int j Food Sci Nutr. 2009:1-13.

93. Bednar GE, Patii AR, Murray SM, Grieshop CM, Merchén NR, Fahey GC Jr. Starch and fiber fractions in selected food and feed ingrethents affect their small intestinal digestibility and fermentabiliry and their large bowel fcnnentability in vitro in a canine model. J Nutr. 2001;133:276-86.

94. Henry RJ, Saini HS. Characterization of cereal sugars and oligosaccharides. Cereal Chem. 1989;66:362-365.

95. Sengupta S, Tjandra JJ, Gibson PR. Dietary fiber and colorectal neoplasia. Dis Colon Rectum. 2001;44:1016-33. PubMed

96. Slavin J. Why whole grains are protective: biological mechanisms. Proc Nutr Soc. 2003;62:129-34.

97. Melntyre A, Vincent RM, Perkins AC, Spiller RC. Effect of bran, ispaghula, and inert plastic particles on gastric emptying and small bowel transit in humans: the role of physical factors. Gut. 1 997;40:223-7.

98. Topping DL, Cl i fron PM. Short-chain fatty acids and human colonic function: roles of resistant starch and nonstarch polysaccharides. Physiol Rev. 2001;81:1031-64.

99. Hernot DC, Boileau TW, Bauer LL, Swanson KS, Fahey GC Jr. In vitro digestion characteristics of unprocessed and processed whole grains and their components. J Agrie Food Chem. 2008;56:10721-6.

100. Gibson GR, Probert HM, Loo JV, Rastall RA, Roberfroid MB. Dietary modulation of the human colonic microbiota: updating the concept of prebiotics. Nutr Res Rev. 2004;17:259-75.

101. Karppinen S, Liukkonen K, Aura AM, Foriseli P, Poutanen K. In u'ttro fermentation of polysaccharides of rye, wheat and oat brans and inulin by human faecal bacteria. J Sci Food Agrie. 2000;80:1469-76.

[Author Affiliation]

Satya S. Jonnalagadda,4* Lisa Harnack,5 Rui Hai Liu,6 Nicola McKeown,7 Chris Seal,8 Simin Liu,9 and George C. Fahey10

4 General Mills Bell Institute of Health and Nutrition, Gulden Valley, MN, 55427; 5 Division of Epidemiology and Community Health,

School of Public Health, University of Minnesota, Minneapolis, MN 55454; 6 Department of Food Science, Cornell University, Ithaca, NY

14853; 7 Nutridon Epidemiology Program, Jean Mayer USDA HNRCA at Tufts University, Boston, MA 021 1 1; 8 Human Nutrition

Research Centre, New Castle University, Newcastle upon Tyne, NF.17RU UK; 9 Program on Genomics and Nutrition, University of

California, Los Angeles, CA, 90095; and 10 Department of Animal Sciences, University of Illinois, Urbana, IL 61801

[Author Affiliation]

* To whom correspondence should be addressed. E-mail: satya.jonnalagadda@ genmills.com.