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Commonwealth Scientific and Industrial Research Organisation, Human Nutrition, Adelaide, SA, Australia 5000
2To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • aleurone flour • folic acid • bioavailability • wheat bran • humans
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, Saxelby and Venn-Brown 1980
). The phytochemicals, vitamins, and
minerals in aleurone cells may be lost when wheat grain is refined. A
unique and commercially viable milling process that enables the
isolation of the aleurone cell layer and at the same time splits the
cell walls to release the contents of these cells has recently been
developed (by Goodman Fielder Pty. Ltd., Australia) (Stenvert 1995 and 1997
). A schematic representation of the isolation of
aleurone is shown in Fig. 1
. The sheared aleurone cells together with a small amount of wheat germ
was formulated into a novel aleurone flour
(ALF)3
. The aleurone flour described in this study was available commercially
in Australia and internationally for more than 12 months and is sold
widely as a major ingredient of bread and pasta. One of the most
notable features of the composition of this product is the high level
of folate that is present, a concentration between 400 and 600 µg per
100 g wet ALF. This natural level of folate is higher than that
observed in wheat bran, fruits, and vegetables (usually between 20 and
200 µg/100 g wet) (Bailey 1995
, Subar et al. 1989
) and is comparable to folate/folic acid levels in
fortified flour and cereal that provide 50% Recommended Dietary Intake
(RDI) per serve (assuming an RDI of 400 µg and a serving size
of 40 g wet weight) (Crane et al. 1995
).
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, Medical Research Council Vitamin Study Research
Group 1991
). There is also increasing evidence that an above
average intake of folate may help reduce plasma homocysteine, a risk
factor for cardiovascular disease (Boushey et al. 1995
,
Kang et al. 1992
), and DNA damage, a risk factor for
cancer (Blount et al. 1997
, Fenech 1996
,
Ma et al. 1997
). There is some concern that eating foods
that are naturally rich in folate may not provide for a large enough
and reliable intakeof folate required to prevent spina bifida
(Cuskelly et al. 1996
). Therefore, it is
important to identify novel, naturally rich sources of folate and to
test that dietary strategies based on such foods may be effective for
the optimization of tissue folate in the general population. To assess the potential of ALF as a source of folate, it is necessary to measure how much folate actually appears in the blood after ingesting foods rich in this ingredient. To achieve, this we performed a randomized, controlled intervention trial to compare the change in plasma folate after consumption of 1) a cereal made from ALF, 2) a cereal made from wheat bran (WB), and 3) a tablet containing 0. 5 mg folic acid that was taken together with WB cereal.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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There were 7 d between each intervention round to allow
sufficient time for plasma folate to return to baseline before the next
round. On the day prior to each intervention round, volunteers were
required to refrain from drinking alcohol and to fast overnight. On the
following morning volunteers donated a fasted blood sample after which
they ate 100 g of cereal with 250 ml fresh milk (containing 1.5
g/100 g fat) over a period of 30 min. The folic acid tablet was taken
while the WB cereal was being ingested. Further blood samples were
collected at 1, 2, 4, and 7 h after commencing cereal intake. During
the course of the day, volunteers were provided with light snacks that
were poor in folate (as estimated from food composition tables,
Holland et al. 1995
), and they were not allowed to eat
any other foods. The level of folate in the milk was 0.6 µg/L. The
texture and color of the ALF and WB cereals was clearly different, but
the volunteers were not informed which of the cereals was made from
ALF.
Plasma from coded blood samples collected in EDTA was isolated immediately, snap frozen in liquid nitrogen, and stored at -80°C. Plasma folate was measured using radioimmunoassay (BioRad Quantaphase II kit, Bio-Rad Laboratories Pty. Ltd. North Ryde, NSW, Australia). Plasma vitamin B-12 measurements using radioimmunoassay (BioRad Quantaphase II kit; Bio-Rad Laboratories Pty. Ltd. North Ryde, NSW, Australia) were also made as an internal analytical control. Samples were analyzed within 2–4 wk after collection. Under our conditions of frozen storage, there is no decline in plasma folate for up to 8 mo of storage (data not shown). The assays for folate and vitamin B-12 were performed in a single analysis on the same day, and the intra-assay coefficients of variation were 5.5 and 4.8%, respectively.
Coded samples of the ALF cereal, WB cereal, and tablets were sent to
the Australian Government Analytical Laboratories (South Melbourne,
Victoria) to measure the level of folate. The method used was a
modification of the standard Association of Official Analytical
Chemists microbiological assay with or without conjugase treatment
(Cunniff 1996
, Scheelings 1996
). Briefly
the samples were milled in a Cyclotec Sample Mill to a mesh size of
<0.5 mm. The samples were then autoclaved in a phosphate buffer at
100°C for 5 min and then cooled and filtered prior to deconjugation
for 3 h at pH 4.5 with human plasma (enzyme source) at 37°C. The
enzyme reaction was halted by boiling, the pH adjusted to 6.0, and an
aliquot of the filtrate was bioassayed with Lactobacillus casei
var. rhamnosis as the culture.
Proximate analyses of wheat bran and aleurone flour were performed.
Total starch was analyzed using the method of McCleary et al. (1994)
. Total dietary fiber was determined by the gravimetric
method of Prosky et al. (1985)
. Fat extraction was done according to
the method of Daugherty and Lento (1983)
, using Clarase digestion
followed by homogenization and extraction with
chloroform/methanol/water. The total nitrogen level was determined
using the method of Kirsten and Hesselius (1983)
and a Carlo Erba
Nitrogen Analyser (Carlo Erba Strumentazione, Rodano, Milan).
Free sugars were extracted with 80% aqueous methanol according
to the method of Theander and Westerlund (1986)
, and then
quantified by HPLC using acetonitrile:water 75:25 as the mobile phase,
a Polyamine-Bonded polymeric gel column, and a refractive
index detector. Ash was measured by igniting the samples in
preweighed borosilicate glass crucibles in a muffle furnace at 515°C
for 12 h and then cooled in a desiccator prior to weighing; the
percentage ash weight was calculated by difference. The dry matter of
the samples was determined by drying the samples to constant weight at
110°C; they were then cooled in a desiccator prior to weighing and
moisture loss was calculated by difference.
The statistical significance of the changes in plasma folate following ingestion of the WB and ALF cereals and the folic acid tablet was determined using nonparametric, repeated measures ANOVA (Friedman test). The area under the plasma folate concentration versus time curve [area under the curve (AUC)] was measured for each individual and for each group at each intervention round using plasma folate measured at 0 h as the baseline value. The significance of differences in the AUC values was also estimated using nonparametric, repeated measures ANOVA and Dunn's multiple comparison test. All statistical analyses including measurements of AUC were performed using PRISM software (GraphPad, San Diego, CA). All quoted P-values are for two-tailed tests, unless otherwise indicated. Differences were considered significant if P < 0. 05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Proximate analyses of the aleurone and wheat bran flour indicated a
higher starch and protein content and a lower fiber content in aleurone
flour when compared to wheat bran flour (Table 1
). The total folate level per 100 g in the WB cereal and the ALF cereals
was 94 ± 4 µg (n = 2) and 515 ± 7 µg
(n = 2), respectively; the folic acid in each tablet
was 526 ± 24 µg (n = 3). The proportion of folate in
the tablet, ALF cereal, and WB cereal that could be detected without
prior treatment with folate conjugase was 100, 81, and 32%,
respectively.
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None of the volunteers were folate deficient (plasma folate < 3.4
nmol/L). All volunteers completed the intervention successfully. The
results for plasma folate at each time-point for each intervention
round for males and females are shown in Table 2
, and the mean values (± SEM) for the combined results for
males and females are shown graphically in Fig. 2
. There was a significant, positive correlation between individual
base-line data from each intervention round (R = 0.69–0.78, P < 0.001).
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|
. The
increase in plasma folate following consumption of ALF cereal was also
significant in both males and females (P = 0.0001) and
appeared to be of the same magnitude as that observed after the
ingestion of 0.5 mg folic acid supplement with WB cereal, with a steady
increase in plasma folate during the first 2 h from a
base-line of 13.9 nmol/L to a peak at 2 h of 23.5 nmol/L and a
decline down to baseline by 7 h (Fig. 2)
. However, the time
response following ALF cereal showed significant increments in plasma
folate at 2 and 4 h after ingestion of the cereal. This suggested
a slower rate of appearance of folate into the plasma compared to the
results for the folic acid tablet with WB cereal, which showed
significant increments in plasma folate at 1 and 2 h following
ingestion (Table 2)
. Analysis of the combined male and female data
showed that the observed increments in plasma folate following intake
of ALF cereal or folic acid tablet with WB cereal were significant
(P < 0.0001), but there was no change following ingestion
of the WB cereal.
To assess the extent of net folate appearance in the blood we also
measured the area under the plasma folate concentration versus time
curve for each individual for each intervention round. The folate AUC
measured in the blood of all subjects did not differ following
ingestion of 100 g ALF cereal [41.8 ± 6.2 (nmol/L)h] or
ingestion of the 0.5 mg folic acid tablet with 100 g WB cereal
[42.9 ± 7.0 (nmol/L)h]; these results were more than four times
greater than the AUC measured following the WB cereal intake [6.8
± 2.4 (nmol/L)h] (Fig. 3
). The same conclusions were reached when the data for male
(n = 8, P < 0.01) and female
(n = 8, P < 0.05) volunteers are
analyzed separately; no significant effect of gender on the AUC was
detected for any treatment (Table 2)
.
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The individual AUC following ingestion of the ALF cereal were not correlated with those observed after intake of the tablet supplement with WB cereal, but they were positively correlated with the AUC observed following intake of the WB cereal (R = 0.41, P = 0.055, one-tailed test).
Significant positive correlations were observed between an
individual's mean baseline value of plasma folate measured before each
intervention round and the AUC following ingestion of the WB cereal or
the ALF cereal (R = 0.53, P = 0.03)
(Fig. 4
). However, this particular relationship was not significant for AUC
data from the folic acid tablet intervention even though the
correlation factor was positive (R = 0.33, P
= 0.212). When the data for the ALF cereal intervention were
combined with the data for the tablet intervention, the correlation
coefficient was 0.427 (P = 0.014).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). In contrast, a
randomized, placebo-controlled trial designed to identify the
minimum effective dose for food fortification to prevent neural tube
defects found that a supplement of 200 µg/d synthetic folic acid was
sufficient to raise red blood cell folate level above the 400 µg/L
threshold (measured by microbiological bioassay) required for
minimization of spina bifida risk (Daly et al. 1997
). In
a similar study, it was shown that 200 µg/d of synthetic folic acid
appeared to be as effective as 400 µg/d with regard to lowering
plasma homocysteine in apparently normal subjects (Ward et al. 1997
). An increase of 100 µg/d of synthetic folic acid intake
was shown by both these studies to be relatively ineffective in terms
of adequately reducing folate-related risk factors for spina bifida
and cardiovascular disease. The results from our study on cereal made from aleurone flour show quite clearly that this natural source of folate can make a significant difference in blood folate concentration. Of main interest was 1) the much greater capacity for ALF cereal, relative to WB cereal, to increase plasma levels of folate and 2) that the increase in plasma folate following ingestion of 100 g of ALF cereal was the same as that observed following intake of 500 µg synthetic folic acid with 100 g WB cereal. Our data indicate that it is the higher content of aleurone flour rather than increased bioavailability of folate from this product that gives it value as a folate source in the diet.
Bailey et al. (1988)
compared the bioavailability of monoglutamyl
folate and polyglutamyl folate when ingested with bran cereal and found
that monoglutamyl folate bioavailability is unaffected by dietary
fiber, but wheat bran fiber appeared to marginally inhibit the uptake
of polyglutamyl folate. Using a dual-label, stable isotope
protocol, Pfeiffer et al. (1997)
showed that consuming folic acid with
a light breakfast meal only produced a small reduction in folic acid
absorption (15%, P > 0.05) relative to a control
without food. Thus the comparison, in our study, between the AUC
estimates following ingestion of ALF cereal and folic acid in a tablet
taken with wheat bran cereal may have been influenced only to a limited
extent by fiber because 1) the tablet contained monoglutamyl
folate, and wheat bran only contributed a small percentage of folate;
and 2) the folate in the ALF cereal appeared to be in a
relatively unconjugated form, and the level of fiber in the ALF cereal
was almost half that of the wheat bran cereal (Table 1)
.
The short-term, nonisotopic type of bioavailability study used is
very similar to that reported by Keagy et al. (1988)
and Bailey et al. (1988)
. In accordance with the recommendations from these studies,
multiple samples were taken over a 7-h period to avoid errors in
bioavailability estimation occurring because of different rates of
absorption. Bailey et al. (1988)
, who measured plasma folate by
microbiological assay, also reported that with such a protocol it was
only possible to obtain consistent responses with doses of folic acid
above 250 µg—the folic acid/folate levels in the tablet with WB
cereal and the ALF cereal were well above this level. The WB cereal,
which contained only 92 µg folate, produced a significant increment
in plasma folate only in males, suggesting that such a level of
ingested folate produces a change in plasma folate that is at the limit
of detection of the system used. Consequently, the AUC measurement with
the WB cereal may, therefore, be considered less accurate than those
obtained for the ALF cereal and the folic acid tablet with WB cereal.
The apparent relative bioavailability of monoglutamyl and polyglutamyl
folates varies according to the protocol used (Gregory 1995
). For example, protocols with nonlabeled folates
quantified by urinary excretion suggest a mean bioavailability of
85–90% for tri- and hepta-glutamyl folate relative to folic acid
(Tamura and Stokstad 1973
). Protocols with nonlabeled
folate quantified by AUC of plasma folate concentration found
equivalent bioavailability for 750 µg folic acid and the molar
equivalent of heptaglutamyl folate, but the bioavailability of the
latter was reduced when given with bran cereal but not spinach
(Bailey et al. 1988
). It is possible that in certain
cases the reported lower bioavailability of polyglutamyl folate could
have been caused by specific conjugase inhibitors and not the extent of
folate polyglutamation (Rosenberg and Godwin 1971
). Our
results, obtained with similar techniques, for wheat bran and aleurone
flour, suggest no difference between the bioavailability of folate in
these products and that for folic acid in a tablet. Bioavailability of
folate in the WB and ALF flours may have been overestimated if the
folate level measured in the flours was underestimated by the
single-enzyme (conjugase) method used. However, it was shown that
for ready-to-eat cereals including wheat bran cereal, the level of
folate measured using the single-enzyme (conjugase) method is the
same as that measured by the tri-enzyme method involving
-amylase, folate conjugase, and protease (Rader et al.
1998
). For other foods the tri-enzyme method yields a total
folate value that may be up to 30% higher than that determined by
using conjugase alone (Rader et al. 1988
).
The microbiological analyses in our study have shown that, unlike
folate in wheat bran, most of the folate in aleurone flour could be
detected without pretreatment with folate deconjugase enzyme. The
reason for this difference is not known, but it is possible that in the
process of shearing aleurone cells endogenous folate deconjugases are
released and activated. The shearing of aleurone cells may increase the
bioavailability of folate from this natural ingredient, particularly in
those individuals who have difficulty in digesting the thick cell walls
of aleurone cells. The apparent deconjugation of polyglutamate folate
may make folate more available to people who have limited deconjugase
activity in the small intestine, possibly because of suboptimal pH
levels, which may occur in conditions such as atrophic gastritis,
resulting in reduced gastric acid secretion (Gregory 1995
). Our estimates based on the ratio of folate
increments in the blood and ingested level of folate suggest, however,
that bioavailability of folate from ALF cereal was not significantly
greater than the bioavailability of folate from WB cereal or synthetic
folic acid from a tablet.
The results from this study give some indication that individuals with
low baseline plasma folate seem to have lower AUC for plasma folate
than individuals with higher initial plasma levels. The correlation
factors suggest that between 9 and 25% of the observed variation in
the AUC measurements could be explained by baseline levels of plasma
folate. The low plasma folate and AUC levels may indicate either
reduced gut absorption or increased tissue uptake of folate from
plasma. Suboptimal jejunal pH may explain inefficient absorption of
folate in some cases (Gregory 1995
, Russel et al. 1986
). It may, therefore, be useful in future studies to verify
that blood folate levels can be optimized by different strategies in
those subjects with an impaired capacity to absorb folate.
The time-related increment in plasma folate during the initial
2 h occurred more rapidly following the ingestion of the folic
acid tablet with WB cereal than it did following ingestion of ALF
cereal. A conceivable explanation for the slower uptake of folate from
ALF cereal relative to folic acid from the tablet is the necessity of
folate deconjugation for the aleurone source of folate. An alternative
explanation could be that folate from the ALF cereal was mainly
absorbed by the jejunal, pH-dependent, and saturable transport
process, while absorption of folic acid from the tablet may have partly
involved a nonsaturable mechanism, such as passive diffusion
(Gregory 1995
, Halsted 1990
, Mason 1990
, Shoda et al. 1993
, Strum 1979
). It was reported that the latter mechanism may operate
when a bolus of synthetic folic acid of between 400 and 800 µg is
ingested by humans and could result in substantial amounts of
unmetabolized folic acid appearing in plasma and urine (Gregory 1995
, Kelly et al. 1997
, Lucock et al. 1989
). In contrast, physiological uptake by the saturable
mechanism into jejunal mucosal cells ensures that monoglutamyl folate
is reduced and methylated to form 5-methyltetrahydrofolate, the major
cytosolic folate in mammalian tissues, before transport into the blood
(Shane 1995
). Therefore, it may be worthwhile in future
studies to compare the ratio of unmetabolized folic acid and
5-methyltetrahydrofolate in plasma following ingestion of ALF cereal
and a bolus of synthetic folic acid possibly using established HPLC
methods (Kelly et al. 1997
, Lucock et al. 1995
).
Although the results from this study indicate that ALF cereal is an
important source of folate, long-term studies are required to
establish the extent to which folate from aleurone flour may reduce
plasma homocysteine and increase the level of red cell folate, which is
considered to be a reliable biomarker of tissue folate stores. Such
studies are currently underway in our laboratory. Longer-term
studies are also important because aleurone flour increases the rate of
fermentation of bacteria in the large bowel (Cheng et al. 1987
). If ALF cereal is favorable to the increase of
folate-producing bacteria such as Bifidobacteria
(Krause et al. 1996
), then there may be an additional
folate contribution via this route because recent studies with rats and
organ-cultured biopsies of human colon suggest that folate can be
absorbed across the large bowel epithelium (Rong et al. 1991
, Zimmerman 1990
). These series of potential
events may explain the apparent positive association between fiber
intake and blood folate (Houghton et al. 1997
). The
significant contribution of folate from aleurone cells may also explain
in part why an increased intake of whole-grain foods confers
lowered risk for various digestive tract cancers (Jacobs et al. 1998
).
In conclusion, this study has shown that cereal made from wheat aleurone flour is a significant source of natural, bioavailable folate that can make an effective contribution to increasing blood folate concentration. This effect is of a similar magnitude to that observed following ingestion of 500 µg synthetic folic acid given with wheat bran cereal. These results suggest that inclusion of foods made from wheat aleurone flour in the diet can be considered as an alternative, important strategy for increasing folate intake in the general population.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: ALF, aleurone flour; AUC,
area the curve; RDI, recommended dietary intake; WB, wheat bran.
Manuscript received December 7, 1998. Initial review completed January 21, 1999. Revision accepted February 26, 1999.
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