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© 2004 The American Society for Nutritional Sciences J. Nutr. 134:2691-2697, October 2004

Nutritional Epidemiology

Intake of Whole Grains and Vegetables Determines the Plasma Enterolactone Concentration of Danish Women1

Nina F. Johnsen*,{dagger},2, Helene Hausner*,{dagger}, Anja Olsen*, Inge Tetens{dagger}, Jane Christensen*, Knud Erik Bach Knudsen**, Kim Overvad{ddagger} and Anne Tjønneland*

* Institute of Cancer Epidemiology, The Danish Cancer Society, Copenhagen, Denmark; {dagger} Department of Human Nutrition, Royal Veterinary and Agricultural University, Copenhagen, Denmark; ** Department of Animal Nutrition and Physiology, Research Centre Foulum, Foulum, Denmark; and {ddagger} Department of Clinical Epidemiology, Aalborg Hospital and Aarhus University Hospital, Aalborg, Denmark

2To whom correspondence should be addressed. E-mail: nina{at}cancer.dk.


   ABSTRACT
TOP
 ABSTRACT
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 LITERATURE CITED
 
The mammalian lignan enterolactone (ENL), which is produced from dietary plant-lignan precursors by the intestinal microflora, may protect against breast cancer and other hormone-dependent cancers. This cross-sectional study examined which variables related to diet and lifestyle were associated with high plasma concentrations of ENL in Danish postmenopausal women. Plasma ENL was measured by time-resolved fluoroimmunoassay in 857 Danish women aged 50–64 y who participated in a prospective cohort study. Diet was assessed using a semiquantitative FFQ, and background information on lifestyle was collected using a self-administered questionnaire. Multiple analyses of covariance were completed in two steps. The median plasma ENL concentration was 27 nmol/L (range 0–455 nmol/L). In covariance analyses, positive associations were found between consumption of cereals, vegetables, and beverages and plasma ENL concentration. When analyzing subgroups of these food groups, the associations were confined to whole-grain products, cabbage, leafy vegetables, and coffee. For fat and the nondietary variables, negative associations between BMI, smoking, and frequency of bowel movements and plasma ENL concentration were observed. These data show that foods high in ENL precursors are associated with high concentrations of ENL. Furthermore, smoking, frequent bowel movements, and consumption of fat seems to have a negative affect on the ENL concentration. In conclusion, whole grains and vegetables are the most important dietary providers of plant lignans for the concentration of ENL in Danish postmenopausal women, and if ENL is found to protect against cancer or heart disease, the intake of whole grains and vegetables should be increased.

KEY WORDS: • lignans • intestinal microflora • whole grains

Lignans are biphenolic compounds found ubiquitously in foods of plant origin. Early investigations showed a lower urinary lignan excretion in breast cancer patients and omnivores than in vegetarians with a lower risk of breast cancer (1). Lignans are included in the group of phytoestrogens, and because of their antioxidative and possible antiestrogen properties, they might reduce the risk of breast cancer (2–4), other hormone-dependent cancers (5,6), and cardiovascular diseases (7).

Plant lignans occur as glycosides in the fiber layer of plants (8). Nuts, seeds, berries, and whole grains are especially rich sources, but fruits, vegetables, and beverages such as coffee, tea, and wine also contain plant lignans (9,10). In the colon, plant lignans are converted to the mammalian lignans, enterodiol and enterolactone (ENL), by the intestinal microflora (11). ENL is the primary lignan in human blood and urine (12), and the concentration of ENL is thought to reflect recent and habitual intake of dietary plant lignans (13,14) in addition to the capacity and function of the intestinal microflora (15).

Two studies investigating determinants of ENL concentrations have been published. In a cross-sectional study that included a random sample of 1168 men and 1212 women from five areas in Finland, constipation was positively associated with serum ENL in both sexes (16). In women, smoking and obesity were negatively associated with serum ENL concentrations, and intake of vegetables was positively associated with serum ENL. In men, consumption of whole grains and berries and fruits was positively associated with serum ENL (16). In an American study, which included 115 women and 78 men, coffee, tea, and alcohol consumption in addition to dietary fiber consumption were positively associated with plasma ENL (17). In neither of the studies had the participants taken any antibiotics within the last 3 mo.

The objective of this study was to investigate associations between consumption of lignan-containing foods, lifestyle, and plasma ENL concentration in Danish postmenopausal women.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 LITERATURE CITED
 
    Study population. A population of 857 postmenopausal women from a nested case-control study in the prospective cohort, "Diet, Cancer and Health," were selected for the study.

"Diet, Cancer and Health" was established with the primary aim of investigating the role of diet on cancer risk. A total of 79,729 women aged 50–64 y were invited to participate if they were born in Denmark, lived in the Copenhagen or Aarhus areas, and were not at the time of invitation registered with a previous diagnosis of cancer in the Danish Cancer Registry. About 37% of the women invited (29,875 women), were enrolled in the cohort. "Diet, Cancer and Health" and the present substudy were approved by the regional Ethical Committees on Human Studies in Copenhagen and Aarhus, and by the Danish Data Protection Agency.

All participants attended 1 of the 2 established study centers. The participants, who were not fasting, had a blood sample taken and filled in a 192-item FFQ and a lifestyle questionnaire, which they received by mail before visiting 1 of the 2 study clinics. Development and validation of the FFQ was described previously (18–21). Briefly, the participants were asked to report their average intake of different food and beverage items over the previous 12 mo within 12 possible categories ranging from never to ≥8 times/d. To adjust for a possible overestimation, questions on the frequency of intake of fruits and vegetables were complemented by 3 additional questions on the overall intake of these food items. The intake of each type of fruit and vegetable was weighted in accordance with the answers to these additional questions. Daily intakes of specific foods and nutrients were calculated for each participant by the software program Food Calc (22), using specially developed standardized recipes and portion sizes.

The lifestyle questionnaire included questions about reproductive factors, health status, social factors, and lifestyle habits. From this questionnaire, information about smoking, number of bowel movements per week [reflecting intestinal transit time (23)], and time since last meal was obtained. Anthropometrical measurements were carried out by professional staff members, and the BMI was calculated as weight (kg) divided by height squared (m2).

During follow-up (mean 4.7 y), a total of 434 women were diagnosed with breast cancer. These cases were matched with 434 controls by postmenopausal status (known/probably postmenopausal), use of hormone replacement therapy (current/former/never), and age (0.5-y intervals) at entrance to the study. Blood samples from 423 of the cases and the 434 controls were analyzed for plasma ENL using time-resolved fluoroimmunoassay (11 cases were excluded due to lack of blood sample or problems with the biological analyses), and a total of 857 women were included in the statistical analyses.

    Analytical method. The standard analytical procedure for time-resolved fluoroimmunoassay (DELFIA research kits from Wallac) was used for determinations of ENL concentrations in plasma (24,25). Fluorescence was read in the DELFIA Victor multilabel counter (Wallac Oy). Duplicate internal control plasma samples were carried through the procedure for each batch and placed in the beginning and end of the plates. The concentration of ENL in the control plasma was 19.7 nmol/L and the intra- and interassay CVs were <10%. Results from a previous study (Bach Knudsen, unpublished) further showed that the CVs for the assays were virtually independent of the concentration of ENL in the plasma in the range from 0 to 140 nmol/L.

    Statistical strategy. Because half of the women developed breast cancer within 5 y of follow-up, a covariance analysis was performed to test whether a later diagnosis affected the determinants of plasma ENL concentration. Furthermore, it was tested whether a diagnosis within the first 1 or 2 y of follow-up affected the determinants of plasma ENL concentration. This was not the case, and all of the women were included in the statistical analyses. The women were grouped in quartiles according to their ENL concentrations and the distribution of selected dietary and nondietary (lifestyle-related) variables was calculated.

Determinants of plasma ENL concentration were identified by analyses of covariance. Only food items known to contain plant lignans were selected as variables for the statistical analysis. Quantitative variables entered the models linearly after linearity was tested in linear spline models. First, a univariate analysis was completed for all variables. Second, all variables were included in the model followed by stepwise backward elimination of the nonsignificant variables. P < 0.10 was chosen as the level of significance for variables in the final model so as not to be too "restrictive" and thereby exclude potentially important factors.

The statistical analyses were carried out in two steps, i.e., one step with groups of food items (cereals, vegetables, potatoes, fruit, beverages) and a second step comprising subgroups of the same variables. Potatoes were included separately because they are regarded as basic food components in Denmark and not as vegetables. In the second step, cereals were divided into the subgroups whole grains and refined grains. Vegetables were divided into the botanical groups leafy vegetables, stalk vegetables, fruiting vegetables, cabbage, root vegetables other than potatoes, mushrooms, onions, legumes, and vegetable juice. Fruit was divided into citrus fruits, other fruits, fruit juice, and stewed fruit, and beverages into coffee, tea, wine, and beer. For whole grains, a third step was created to identify the important subcomponents of this group. The subcomponents of whole grains were oatmeal, rye bread, whole-grain wheat bread, crisp bread, and corn.

Variables were scaled to reflect realistic and practical increments in the daily intake of the food items. For most dietary variables, an increment of 100 g/d was considered realistic, but when the 95th percentile of intake was <50 g, an increment of only 10 g/d was chosen.

In the multiple regression models, the associations between foods and plasma ENL were adjusted for BMI, smoking, frequency of bowel movements, and consumption of fat (g/d). The distribution of plasma ENL was skewed toward higher values and ENL data were log2-transformed. The estimates were subsequently back-transformed to illustrate the percentage increase in ENL concentration. SAS version 8 for Unix (SAS Institute) was used for the statistical analyses and a standard F-test was used to test the possible determinants.


   RESULTS
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 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 LITERATURE CITED
 
Baseline characteristics of the women were calculated according to quartiles of ENL concentrations in plasma (Table 1). The mean concentration was 38.0 nmol/L (SD 40.5 nmol/L); the median was 27.2 nmol/L, and the range was 0–455 nmol/L. The median age was identical in all 4 quartiles, but women with a high concentration of ENL had lower BMI, lower body weight, higher intake of whole-grain products, vegetables, and dietary fiber than women with lower plasma concentrations. Additionally, their intake of refined cereals and potatoes was less than for women with lower ENL concentrations. Furthermore, fewer smokers were seen among women with high ENL concentrations.


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  		TABLE 1 Baseline characteristics according to quartiles of enterolactone concentration for 857 postmenopausal women in the nested, case-control study: Diet, Cancer and Health1

 
In the first step of the analyses, daily intakes of cereals, vegetables, and beverages were significant determinants of plasma ENL, whereas smoking, more frequent bowel movements, and higher BMI were associated with lower concentrations of ENL. In the final model, a 100 g/d higher intake of cereals was associated with an almost 37% higher concentration of ENL (Table 2). A similar higher intake of vegetables or beverages was associated with higher concentrations of ENL of 6.3 and 2.2%, respectively. The nondietary variables, smoking, frequency of bowel movements, and higher BMI were associated with lower concentrations of ENL of 29, 16, and 4.1%, respectively. This model explained 13% of the variation in ENL concentration.


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  		TABLE 2 Covariance analysis of groups of food items for 857 postmenopausal women in the nested, case-control study: Diet, Cancer and Health

 
In the second step of covariance analysis, whole grains, leafy vegetables, cabbage, and coffee were significant determinants of ENL concentrations and again, smoking, more frequent bowel movements, and higher BMI were associated with lower concentrations of ENL (Table 3). In this analysis, an additional daily intake of 100 g of whole-grain products, leafy vegetables, cabbage, and coffee was related to 42, 6.7, 6.2, and 2.5% higher concentrations of ENL, respectively. This model explained 16% of the variation in ENL concentration.


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  		TABLE 3 Covariance analysis of subgroups of food items for 857 postmenopausal women in the nested, case-control study: Diet, Cancer and Health

 
The third step of covariance analysis showed that the food items responsible for the significant effect of the whole grains were oatmeal, rye bread, whole-grain wheat bread, and crisp bread (Table 4). Rye bread was an especially strong determinant of plasma ENL because a 100-g higher intake of rye bread was associated with a 42% higher ENL concentration. Higher intakes of whole-grain wheat bread, crisp bread, and oatmeal were associated with higher ENL concentrations of 37, 7.6, and 5.1%, respectively.


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  		TABLE 4 Covariance analysis of whole-grain products for 857 postmenopausal women in the nested, case-control study: Diet, Cancer and Health

 

   DISCUSSION
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
LITERATURE CITED
 
In this sample of Danish postmenopausal women, the range of plasma ENL concentrations was wide (from 0 to 455 nmol/L). Using a covariance model with validated dietary data and linear variables, whole-grain products and especially rye bread and whole-grain wheat bread were identified as the most important determinants of ENL concentration. An additional daily intake of 100 g rye bread corresponded to a 42% higher ENL concentration, whereas an additional intake of whole-grain wheat bread corresponded to a 37% higher ENL concentration.

The association between daily intake of vegetables for ENL concentration could be explained by the intake of leafy vegetables and cabbage. Cabbage is a good source of plant lignans (12) and has a high content of soluble fiber, which may facilitate the production of ENL by stimulating the intestinal microflora (26).

Among the nondietary variables, smoking was most important because current smokers had 30% lower ENL concentrations than nonsmokers. This effect may be explained by the antioxidative properties of ENL and other phenols (27–29) and may reflect a higher turnover of antioxidants in smokers (16). Furthermore, smoking may alter steroid metabolism (30) and may similarly alter the metabolism of ENL. Another important nondietary variable was the number of weekly bowel movements, reflecting transit time through the intestines (23). A faster transit through the colon is assumed to reduce the time of fermentation of fiber components. This leads to less complete liberation, conversion, and absorption of lignans and consequently, a higher loss of ENL through the fecal route (16). Body size was critical for the concentration of ENL, and the lower ENL concentrations associated with higher BMI may be explained by a dilution of the ENL pool because of a greater blood volume or because the amphiphile nature of ENL allows it to pass through cell membranes and be trapped in the greater fat mass. The observed association could also be explained by selective overreporting of "healthy" (and lignan-rich) foods by overweight women.

A high intake of fat was significantly associated with lower concentrations of ENL. This effect may be caused by a direct, inhibitory effect of fat on the microflora, leading to a higher loss of ENL by the feces, or a higher intake of fat may be associated with a lower intake of foods rich in plant lignans. In rats, fat reduced the absorption and recirculation of lignans (31). Therefore, it seems likely that a high intake of fat, because of its physical presence in the large intestine, leads to withholding of ENL in the fecal mass or reduces the capacity of the microflora to convert plant lignans to ENL. Statistical analyses on associations between food items and ENL should therefore be adjusted for the intake of dietary fat.

Potatoes, mushrooms, and stewed fruit were associated with lower concentrations of ENL. These foods contain small amounts of lignans and cannot be expected to reduce the concentration or production of ENL. A high intake of potatoes probably indicates a lower intake of cabbage and other vegetables, and because these foods were also included in the covariance analysis, the most likely explanation is small errors in the registration of diet.

In this study, half of the women developed breast cancer during 5 y of follow-up, and although women with undiagnosed breast cancer do not normally feel ill, it cannot be excluded that a latent breast cancer might affect dietary habits or the metabolism of ENL. Because ENL concentrations did not differ between those who were later diagnosed as cases and their "always healthy" controls (36.4 vs. 39.5 nmol/L), and because blood samples as well as information about diet and lifestyle were collected before diagnosis, the sampling procedure is not considered important for the determinants of this study.

The ENL concentrations measured in the present study were higher than the concentrations measured in Finnish and American women (16,17) using the same method to measure ENL in plasma or serum. However, they are lower than the concentrations measured in another group of Danish, postmenopausal women (32). The higher concentrations measured in the present study may be explained by a smaller proportion of subjects eating few vegetables, a generally higher intake of plant products, and possibly a lower intake of fat. Alternatively, part of the concentration differences could be due to unexplained variation (>80%) caused by unknown factors (genetic or environmental) that differ among the 3 populations.

Our results support the 2 previous observational studies because similar determinants was found for both men and women in the study of Kilkkinen et al. (16) in which BMI, constipation, and smoking in addition to consumption of whole-grain products, vegetables, and fruit and berries were determinants of serum ENL. Intervention studies also found that increased intake of vegetables, fruit, rye bread, and flaxseed raised ENL concentrations (33–38). As judged from dietary surveys in Finland and Denmark, dietary habits in these countries can be expected to be similar because rye bread and whole-grain products comprise traditional foods (39,40). This may explain the similar determinants in the present study and that of Kilkkinen et al. (16).

The 2 previous studies on determinants for ENL (16,17) did not adjust for energy intake in the multiple analyses. Energy adjustment was evaluated in the present study but did not influence the results (results not shown).

Similar to the study by Horner et al. (17), coffee was associated with the concentration of ENL but in contrast to the present study, dietary fiber was included in the covariance models. When dietary fiber was included in the second step of the covariance analysis, the importance of both whole-grain products and vegetables decreased considerably, indicating that the importance of these foods may be explained by their dietary fiber component and that dietary fiber is a good marker for the intake of these foods. Inclusion of dietary fiber in the American study may therefore explain the different determinants.

It was possible to explain only 13 and 16% of the variation in steps 1 and 2 of the covariance analyses, respectively. This is in accordance with similar studies (16,17) explaining 22 and 14% of the variation. The unexplained variation may be due to several unknown factors relevant to the production and metabolism of ENL. First, the lignan contents of foods are known to vary with season and species; furthermore, the bioavailability of food items can be highly variable (41,42). Second, the blood-samples were taken from nonfasting subjects, which may enhance the intraindividual variation and add to the unexplained variation. New data indicate that significant intraindividual variations in ENL concentrations exist in humans, both within and between days (32). These variations can cause error and lead to unexplained variation. Adjusting for the time since the last meal did not change the present results, however. Third, it was not possible to include information about recent use of antibiotics nor was it possible to exclude women with recent use of antibiotics. It is estimated that ~5% of the women could be affected by the use of antibiotics (43) and these women may have been misclassified because of unnaturally low concentrations of ENL. It is possible that some of the unexplained variation is due to this type of misclassification. Finally, the importance of the microflora in the metabolism of ENL is well known (11); by adding a measure of the capacity and function of the microflora into the equations, a greater part of the total variation could potentially be explained. Examples could be the production of SCFA (acetate, propionate, butyrate), pH in the colon, or enzymatic activity (e.g., ß-glucuronidase).

Our results emphasize that not only are whole-grain products good sources of ENL precursors, but they are also important contributors to the blood concentration of ENL. Furthermore, this study shows that although vegetables are not rich in ENL precursors, this food group still adds to the concentration of ENL if consumption is adequate. Lignan-containing beverages may also be important contributors to the concentration of ENL.

Identifying the determinants of plasma ENL concentration is important if ENL is found to protect against cancer or heart disease. This study supports current recommendations of an increased intake of whole grains and vegetables. Although it is not possible to deduce how changes in food consumption actually affect plasma ENL, it adds to the research on the most important sources of plant lignans. Further studies should focus on the factors determining lignan excretion and on the gut environment, facilitating the production of ENL.


   ACKNOWLEDGMENTS
 
We gratefully acknowledge Connie Stripp (dietician, Danish Cancer Society) for assistance with scaling of the dietary variables and Katja Boll (programmer, Danish Cancer Society) and Jytte Fogh (secretary, Danish Cancer Society) for their contribution in the collection and handling of the data. We thank Winnie Østergaard Thomsen and Hanne Purup (laboratory technicians, Danish Institute of Agricultural Sciences) for excellent technical assistance with the determinations of ENL.


   FOOTNOTES
 
1 Supported by grants from the Danish Cancer Society and Europe Against Cancer: European Prospective Investigation into Cancer and Nutrition (EPIC). Back

Manuscript received 24 February 2004. Initial review completed 14 April 2004. Revision accepted 5 July 2004.


   LITERATURE CITED
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 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 LITERATURE CITED
 

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