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© 2007 American Society for Nutrition J. Nutr. 137:1266-1271, May 2007

Nutritional Epidemiology

Relation between Plasma Enterodiol and Enterolactone and Dietary Intake of Lignans in a Dutch Endoscopy-Based Population1,2

Ivon E. J. Milder3,4,*, Anneleen Kuijsten4,5, Ilja C. W. Arts4,6, Edith J. M. Feskens5, Ellen Kampman5, Peter C. H. Hollman4 and Pieter Van 't Veer5

3 Centre for Nutrition and Health, National Institute of Public Health and the Environment, 3720 BA Bilthoven, The Netherlands; 4 RIKILT-Institute of Food Safety, Wageningen University and Research Centre, 6700 AE Wageningen, The Netherlands; 5 Division of Human Nutrition, Wageningen University, 6700 EV Wageningen, The Netherlands; and 6 Department of Epidemiology, Maastricht University, 6200 MD Maastricht, The Netherlands

* To whom correspondence should be addressed: E-mail: ivon.milder{at}rivm.nl.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Enterolignans are phytoestrogenic compounds derived from the conversion of dietary lignans by the intestinal microflora that may be protective against cardiovascular diseases and cancer. To evaluate the use of enterolignans as biomarkers of dietary lignan intake, we studied the relation between plasma and dietary lignans. We determined the dietary intake of 4 lignans (secoisolariciresinol (SECO), matairesinol (MAT), pinoresinol, and lariciresinol) using the European Prospective Investigation into Cancer and Nutrition FFQ, and plasma enterodiol (END) and enterolactone (ENL) concentrations were determined by liquid chromatography-tandem mass spectrometry. The population consisted of 637 men and women, aged 19-75 y, participating in a case-control study on colorectal adenomas. Participants did not use antibiotics in the preceding calendar year. We found a modest association between lignan intake and plasma END (Spearman r = 0.09, P = 0.03) and ENL (Spearman r = 0.18, P <0.001). The correlation of total lignan intake with plasma enterolignans was slightly stronger than that of only SECO plus MAT. The plasma concentrations of both END and ENL were associated with intake of dietary fiber and vegetable protein but not with intake of other macronutrients. The relation between lignan intake and plasma END was modulated by age and previous use of antibiotics, whereas for ENL, it was modulated by weight, current smoking, and frequency of defecation. However, even when we included these nondietary factors in the regression models, the explained variance in plasma END and ENL remained low (2 and 13%, respectively).


   Introduction
TOP
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Lignans are biphenolic compounds in plant foods, which belong to the group of phytoestrogens. Wholegrain products, vegetables, fruits, nuts, seeds, and beverages such as tea, coffee, and wine are dietary sources of lignans (1,2). Plant lignans can be converted by intestinal bacteria into so-called enterolignans: enterodiol (END)7 and enterolactone (ENL). For about 2 decades only secoisolariciresinol (SECO) and matairesinol (MAT) were known to be precursors of enterolignans, but recently it was shown that also pinoresinol (PINO) and lariciresinol (LARI) are efficiently converted into enterolignans (3).

Enterolignans possess several biological activities by which they may reduce the risk of cancer and cardiovascular diseases. Enterolignans have weak estrogen-like activity (4), may inhibit enzymes such as aromatase and 5{alpha}-reductase, and stimulate the production of sex hormone-binding globulin (5). In addition, plant lignans, and to a lesser extent also enterolignans, have antioxidant activity (6). In epidemiological studies, some evidence for protection of lignans against hormone-related cancers and cardiovascular diseases was found, but results were not consistent (7). Enterolignan concentrations in biological fluids have been used as a biomarker for lignan intake in several of these studies.

To assess the relative validity of these exposure measures, a few studies have examined the correlation between plasma and dietary lignans. So far, these studies have found only weak to moderate associations (Spearman r = 0.08–0.19) (8–10), possibly because they only included 2 of the dietary lignan precursors (SECO plus MAT) and 1 of the metabolites (ENL). Horn-Ross et al. (11) used urinary END plus ENL as a biomarker for lignan intake and found a similar correlation with intake of SECO and MAT (Spearman r = 0.17). In 1 study, additional dietary lignans have been included, but lignan contents were only available for milk, bread, and cereal products and it did not improve the correlation with serum ENL compared with inclusion of only SECO plus MAT (12).

We recently developed and validated methods to measure 4 dietary lignans in foods and 2 enterolignans in plasma (13,14). To evaluate the use of enterolignans as biomarkers of dietary lignan intake, we studied the relation between plasma and dietary lignans in the POLIEP-study, a case-control study on colorectal adenomas. We included both plasma lignans, END and ENL, and 4 dietary lignans (LARI, PINO, SECO, and MAT). In addition, we identified other determinants of plasma lignans, which may modulate the relation between plasma and dietary lignans.


   Materials and Methods
TOP
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 LITERATURE CITED
 
Population

Subjects included in this study were men and women participating in the POLIEP study, a case-control study designed to investigate gene-environment interactions and the risk of colorectal adenomas. Participants were recruited among patients undergoing endoscopy in 10 clinics in the Netherlands between June 1997 and October 2002. The study design has previously been described in more detail (15,16). Eligible subjects were Dutch speaking, of European origin, 18–75 y old at the time of endoscopy, and had no hereditary colorectal cancer syndromes (i.e. familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer), chronic inflammatory bowel disease, history of colorectal cancer, (partial) bowel resection, or serious disabling morbidity. In the POLIEP study, cases were defined as those with at least 1 histologically confirmed colorectal adenoma. In controls, diagnosis of any type of adenoma was negative at the endoscopy and no history of any type of adenoma existed (based on medical record). The medical ethical committees of all participating hospitals and of Wageningen University approved the study protocol and all participants provided written informed consent.

Plasma was available for 1385 of a total of 1477 subjects. Before the endoscopy, subjects fasted and received medication to clean the colon. Because enterolignans are produced by intestinal bacteria, plasma enterolignan values were expected to be lower than normal at the time of endoscopy. Therefore, we excluded 350 subjects whose blood samples were drawn on the same day an endoscopy was performed. Antibiotic use can decrease enterolignan concentrations for 3–12 mo (17). We excluded an additional 397 subjects because they had taken antibiotics in the calendar year of blood sampling or because data on antibiotic use were missing. One subject was excluded because information on body weight was missing, which made it impossible to calculate the lignan dose. After these exclusions, data for 637 subjects remained in the analyses, 331 cases with adenomatous polyps and 306 endoscopy control subjects who never had polyps. The population included 355 women aged 19–75 y with a mean weight of 70 ± 13 kg, and 288 men aged 21–75 y with a mean weight of 84 ± 12 kg.

Data collection

Participants were requested to complete self-administered questionnaires on diet, medical history, and lifestyle according to habits in the year preceding their last endoscopy. Habitual physical activity was estimated using a short questionnaire (18).

    Dietary assessment. We assessed dietary intake with the validated Dutch European Prospective Investigation into Cancer and Nutrition (EPIC) FFQ (19,20). This questionnaire enables estimation of the mean daily consumption of 178 food items in the preceding year. Consumption data were converted into energy and nutrient data using the Dutch Food Composition Table (21). Lignan intake was estimated using a recently developed database (2), including contents of LARI, PINO, SECO, and MAT of commonly consumed Dutch plant foods.

    Collection of plasma samples. Venous blood samples were placed in vacuum tubes containing EDTA. Samples were taken between 0800 and 2045 on an average 4 mo after endoscopy. Subjects did not fast. Samples were transported to our laboratory at Wageningen University in a foam refrigerator at 4°C. Within 48 h they were centrifuged at 1187x g; 10 min at 4°C and then kept at –80°C until analysis.

Plasma assays

We determined plasma END and ENL using a validated isotope-dilution LC-MS/MS method (14). In brief, 13C3-labeled END and ENL were added to the samples and samples were enzymatically hydrolyzed to release aglycones from glucuronide and sulfate conjugates. Samples were extracted twice with diethyl ether, dissolved in 40% methanol/water, ether evaporated, filtered, and injected into the LC-MS/MS system. The samples were analyzed in 20 analyses over a 12-wk period. The between-assay CV was 14% for END and 10% for ENL. The limit of detection was 0.15 nmol/L for END and 0.55 nmol/L for ENL. When a plasma value was below the detection limit, we assigned to that sample a value of 0.5 times the detection limit to enable log-transformation of skewed data.

Statistical analysis

Participants were classified according to tertiles of total plasma enterolignans. To test for differences in demographic and lifestyle characteristics between tertiles, we used ANOVA for normally distributed variables, Kruskal-Wallis test for skewed variables, and the chi-square test for categorical variables.

Spearman rank order correlations were calculated for absolute lignan intake as well as lignan dose (lignan intake per kilogram body weight) with plasma enterolignan concentrations.

We used linear regression to evaluate whether the correlations between lignan intake and plasma enterolignans differed between total, incident, or prevalent cases and controls.

To identify dietary and nondietary determinants of plasma enterolignans, we used several regression models. Because the distribution of dietary and plasma lignans was skewed, log-transformed data were used. This also accounts for the apparent exponential relation between plasma and dietary lignans. First, total lignan intake, age, sex, weight, smoking, physical activity, use of antibiotics (ever), polyps (ever), indication for endoscopy, and frequency of defecation were examined as potential determinants of plasma enterolignans by fitting univariate models. Second, we constructed a full model that included all these nondietary variables. Finally, to identify dietary determinants of plasma enterolignan concentrations, we used multivariate models, including the nondietary determinants that were significant (P < 0.05) in the full model for END or ENL, and energy intake. Dietary lignans, fiber, major energy-providing nutrients, and major food sources of lignans were considered as potential dietary determinants of plasma enterolignan concentrations. We used 1 SD change in intake of potential dietary determinants to estimate the associated change in plasma enterolignan concentrations.

Statistical analyses were performed using SAS software (version 9.1, SAS Institute).

Values in the text are geometric means (95% CI) unless otherwise indicated.


   Results
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 LITERATURE CITED
 
As expected, participants in the highest tertile for total plasma enterolignans had higher intakes of all 4 dietary lignans than participants with lower plasma enterolignan concentrations, although the difference was not significant for SECO (P = 0.17) (Table 1). Participants in the highest tertile of total plasma enterolignans were on average older, more likely to be female, weighed less, less likely to smoke, and more likely to have a low frequency of defecation than participants with lower plasma enterolignan concentrations.


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  		TABLE 1 Characteristics of the study population according to tertiles of total plasma enterolignans, n = 6371

 
The plasma concentrations in the total population were 1.4 (1.3–1.6) nmol/L for END and 11.3 (10.2–12.5) nmol/L for ENL (Table 2). Six percent (n = 39) of the samples was below the detection limit of 0.15 nmol/L for END and 1% (n = 6) was below the detection limit for ENL of 0.55 nmol/L. The total lignan intake was 989 (963–1016) µg/d.


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  		TABLE 2 Spearman correlation coefficients between lignan intake and plasma lignan concentration in 637 men and women in the POLIEP-study

 
The correlation of total lignan intake with plasma END (Spearman r = 0.09, P = 0.03) was weaker than that with plasma ENL (Spearman r = 0.18, P < 0.001) (Table 2). When lignan intake was expressed per kilogram body weight (lignan dose), the correlations with plasma enterolignans were stronger than those for absolute lignan intake. Most of the correlations of plasma END and ENL with intake of the individual lignans were slightly weaker than those with total lignan intake, and the intakes of SECO and MAT were not correlated with plasma END. The correlation between total lignan intake and plasma enterolignans did not differ between total, incident, or prevalent cases and controls (P for interaction all ≥0.41, results not shown).

In the univariate models, total lignan intake, age, weight, and use of antibiotics were significantly associated with plasma END (Table 3). In the full model, only age and use of antibiotics remained significant and the total explained variance was 2.1%. Total lignan intake, age, weight, current smoking, and frequency of defecation were associated with plasma ENL in both the univariate and full model. The total explained variance of ENL concentrations was 12.7%.


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  		TABLE 3 Determinants of plasma enterolignans in 637 men and women in the POLIEP-study

 
We then further evaluated the dietary determinants of END and ENL after adjustment for age, weight, energy intake, use of antibiotics, current smoking, and frequency of defecation. Plasma ENL was associated with all 4 individual dietary lignans, whereas plasma END was only associated with intake of LARI and PINO (Table 4). The increase in plasma END and ENL associated with 1 SD increase in intake of fiber or 1 SD increase in intake of vegetable protein was larger than that associated with 1 SD increase in total lignan intake. None of the other nutrients was significantly associated with plasma enterolignan concentrations. Whole-grain wheat bread was the only lignan-containing food for which the consumption was significantly associated with plasma END. Consumption of fruits, nuts and seeds, and wine were also significantly associated with ENL plasma concentrations. Beer consumption was significantly inversely associated with plasma ENL.


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  		TABLE 4 Dietary determinants of plasma enterolignans in 637 men and women in the POLIEP study1

 

   Discussion
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
LITERATURE CITED
 
In this study, we found a modest positive association between plasma enterolignans and dietary lignan intake. The Spearman correlation coefficient of plasma END was 0.09 (P = 0.03) and was 0.18 for ENL (P < 0.001). As expected, the correlations improved (END Spearman r = 0.12, P = 0.002; ENL Spearman r = 0.24, P < 0.001) when lignan dose was used instead of lignan intake.

An important strength of our study was that we used a newly developed database (2) that included 4 major plant lignans (SECO, MAT, PINO, and LARI), whereas other studies included only SECO plus MAT. Furthermore, the lignan database was especially developed to study the Dutch population. It included all major plant foods in the Netherlands habitually processed and prepared. In addition, all values in this database were obtained using 1 analytical method (LC-MS/MS) (13) with an identical sample preparation for all food items. Lignan intake in the year preceding endoscopy was estimated based on the habitual consumption of 178 food items in the Dutch EPIC-FFQ, which had a satisfactory reproducibility and relative validity compared with 12 monthly 24-h recalls for the main food groups contributing to lignan intake (19). In addition, we have included both END and ENL to assess the internal exposure (plasma concentrations), whereas most of the previous studies included only ENL.

A drawback of our study may be that the population studied included only persons who underwent endoscopy. Both cases and controls often had bowel complaints and/or a positive (family) history of abdominal polyps or cancer. Thus, results for this population may have differed from those for a healthy population. A total of 28% of the study participants indicated that they changed their diet because of their bowel complaints, but their plasma enterolignan levels were not significantly different from those of participants who did not change their diet. In addition, plasma enterolignan concentrations did not differ between persons who underwent endoscopy, indicated by complaints, screening, or other/unknown reasons. And finally, the correlation between total lignan intake and plasma enterolignans did not differ between cases and controls. So, to the extent that we could verify this in our study, we found no evidence that the relation between plasma enterolignan levels and dietary lignan in our population differs from that in a healthy population and we have combined cases and controls in the analyses.

Vegetables, black tea, whole-grain bread, fruits, and wine were the most important lignan sources. Although vegetables and black tea both contributed >20% to the total lignan intake, they were not associated with plasma enterolignan concentrations. Consumption of whole-grain bread, fruits, nuts and seeds, and wine contributed less to the total lignan intake, but all were significantly associated with plasma enterolignan concentrations. This indicates that there are differences in the bioavailability from different foods or in the reliability of the intake measurements. Indeed, the relative validity of the EPIC-FFQ compared with 12 monthly 24-h recalls was relatively low for vegetables and higher for bread, fruits, and nuts and seeds (19).

Although the correlation of lignan intake with the intake of dietary fiber is relatively strong (Spearman r = 0.6, P < 0.001; results not shown) and the variation in intake is similar, the increase in plasma enterolignans associated with 1 SD intake in fiber was larger than that associated with 1 SD increase in total lignan intake. Perhaps fiber-rich foods also contain other enterolignan precursors such as syringaresinol (3), sesamin (22), and lignin (23) that we did not take into account but that may also be converted to enterolignans. This is supported by the fact that the association between intake of dietary fiber and ENL was only slightly attenuated from ß = 0.296 to ß = 0.215 nmol/L per SD fiber intake (P = 0.007; results not shown), i.e. it remained clearly positive when lignan intake was also included in the multivariate model.

Plasma END concentrations were positively associated with total lignan intake, age, and antibiotic use. We excluded participants who used antibiotics in the calendar year preceding the endoscopy. Therefore, it was remarkable that we found a significant positive association between plasma END and antibiotic use. Apparently, antibiotic use can have a long-term effect on plasma enterolignans and it does not affect plasma END and ENL concentrations in a similar way. A possible explanation for this finding is that the bacteria involved in the production of END and ENL from dietary precursors are not the same (24,25). So far, 1 bacterial strain capable of catalyzing the oxidation of END to ENL has been identified (26). Destruction of this strain by antibiotics may increase the relative concentration of END due to reduced conversion to ENL.

In agreement with previous studies, we found that plasma ENL concentrations were associated with age and inversely associated with weight, frequency of defecation, and current smoking. Kilkinnen et al. (27) found that serum ENL concentrations were higher in men and women with constipation. They also found that serum ENL concentrations were associated with age and inversely associated with smoking and obesity in women, but not in men. Horner et al. (28) reported that plasma ENL concentrations were associated with age and inversely associated with BMI.

The correlation between total dietary lignan intake and plasma ENL (Spearman r = 0.18, P < 0.001) was similar to correlations found previously for lignan density (SECO plus MAT/energy intake) and serum ENL concentrations [Spearman r = 0.18–0.19 (8,12)] and for the correlation between intake of SECO plus MAT and urinary END plus ENL [Spearman r = 0.17–0.25; (11)]. However, it was stronger than the correlation between SECO plus MAT estimated using 12 monthly 24-h recalls and plasma ENL reported by Bhakta et al. (10) for South Asian (Spearman r = 0.10, P = 0.1) and native British women in the UK (Spearman r = 0.08, P = 0.6).

In our study, associations between lignan intake and plasma enterolignans were stronger when we included 4 dietary lignans than when we included only SECO plus MAT. This indicates that inclusion of 4 dietary lignans better reflects the exposure to enterolignans than only SECO plus MAT. In the study of Hedelin et al. (12), 7 additional dietary lignans were included, but the correlation between lignan intake and serum ENL was not stronger than when only SECO and MAT were included. However, data on these additional lignans were available for only milk, bread, and cereal products. It should also be noted that with the inclusion of 4 dietary lignans and 2 lignan metabolites, both the dietary lignan intake and plasma enterolignan concentrations may still be underestimated, because more enterolignan precursors (3,22,23), as well as lignan metabolites (29), have been identified. In addition, the estimation the dietary lignan exposure could be improved by taking into account seasonal and varietal variation in lignan content and differences in bioavailability of lignans from different foods (30). Food processing may affect both the lignan content and bioavailability from foods, e.g. crushing or milling substantially improved the bioavailability of lignans from flaxseed (31).

We assumed that the plasma concentrations of END and ENL reflect steady-state concentrations, because enterolignans are eliminated slowly, their precursors are present in many foods and beverages, and they are eaten several times a day (32). Thus, 1 plasma sample will probably reflect exposure for a longer period. Indeed, the reliability coefficient estimated from 3 yearly serum samples was moderately high for ENL (0.55; 95% CI: 0.41–0.69), but lower for END (0.37; 95% CI: 0.21–0.53) (33).

Several researchers have pointed out the large intra- and interindividual variation in plasma enterolignan concentrations due to differences in the composition of the colonic microflora (34,35). Knowledge of the bacterial strains responsible for the conversion of dietary lignans to enterolignans is emerging (24,25), but so far it is not possible to take into account the microflora composition as a factor modulating the relation between plasma and dietary lignans. We could adjust for habitual diet composition, sex, age, previous use of antibiotics, smoking, presence of polyps, and frequency of defecation, which all may affect the composition of the microflora. However, when we included these nondietary factors in the multivariate adjusted models, the explained variance in plasma END and ENL concentrations remained low (2 and 13%, respectively).

In summary, we found a modest positive association between dietary lignan intake and plasma END and ENL. When 4 dietary lignans were included, the associations between dietary lignan intake and plasma enterolignan concentrations were stronger than when only SECO plus MAT were included. However, even when we also included age, weight, energy intake, previous use of antibiotics, current smoking, and frequency of defecation in the regression models, the explained variance in plasma END and ENL remained low.


   FOOTNOTES
 
1 Supported by the Netherlands Organisation for Health Research and Development (program Nutrition: Health, Safety and Sustainability, grant 014-12-014). Back

2 Author disclosures: I. E. J. Milder, no conflicts of interest; A. Kuijsten, no conflicts of interest; I. C. W. Arts, no conflicts of interest; E. J. M. Feskens, no conflicts of interest; E. Kampman, no conflicts of interest; P. C. H. Hollman, no conflicts of interest; and P. Van 't Veer no conflicts of interest. Back

7 Abbreviations used: END, enterodiol; ENL; enterolactone; EPIC, European Prospective Investigation into Cancer and Nutrition; LARI, lariciresinol; MAT, matairesinol; PINO, pinoresinol, SECO, secoisolariciresinol. Back

Manuscript received 30 October 2006. Initial review completed 12 December 2006. Revision accepted 7 February 2007.


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TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 

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