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CSIRO Health Sciences and Nutrition, Adelaide, SA 5000, Australia
1To whom correspondence should be addressed at P.O. Box 10041. E-mail: graeme.mcintosh{at}hsn.csiro.au
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-cellulose as the source of dietary fiber (5 g/100 g of diet) in a
semipurified high fat (20 g/100 g of as 1:1 lard/sunflower seed oil)
diet fed to male Sprague-Dawley rats in which intestinal tumors
were induced using azoxymethane (AOM). WAF at 33 g/100 g of diet
(WAF33) and WB at 16 g/100 g of diet (WB16) increased the weight of
feces and produced significantly higher concentrations in the cecum of
the short-chain fatty acid butyrate (P < 0.001) than did no fiber (NF) and WAF added at only 10 g/100 g (1.5 g
of dietary fiber) (WAF10). Cecal and fecal pH were both significantly
lower in the WAF33 and WB16 treatments relative to control and no fiber
treatments (P < 0.001). The intestinal tumors in
the rats were assessed at 6 mo after the study began, and the WAF33- or
WB16-fed rats showed a trend (P = 0.06) with 43%
fewer colon adenomas relative to control. There was a significant
inverse relationship between ß-glucuronidase activity and colon
adenomas in the rat colon (r2 = 0.37, P = 0.001). WAF fiber influenced some
metabolic markers of fermentation in the colon in a manner similar to
that of WB, which, independent of the bulking effect, was associated
with a trend to reduced colon adenomas. Significantly increased cecal
ß-glucuronidase activity and/or butyrate concentrations may have
protective influences in this context by mechanisms not yet fully
elucidated.
KEY WORDS: • azoxymethane • colon tumors • wheat aleurone flour • ß-glucuronidase • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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2
3
4)
. Other
components of the fiber-rich outer layers of wheat have also been
proposed as having a protective role, e.g., phytate, phenolics,
lignans, phytosterols and vitamins such as E and the B group
(5
6
7
, 35
). Wheat aleurone flour (WAF) is a
product of milling and processing that represents primarily the
aleurone layer of wheat but also some germ, which accounts for 6–7%
of the kernel. It is an excellent source of DF, proteins and some
minerals and vitamins, as well as phenolic compounds
(8
, 9
).
It often is not possible to investigate the influence of dietary
components on colon cancer risk in humans through human intervention
studies. Animal studies of chemically induced colon cancer may provide
a useful lead in identifying potentially preventative dietary
strategies and in helping to clarify likely mechanisms by which
protection might be achieved. The rat azoxymethane (AOM) model of colon
cancer is used experimentally for this purpose (10
,
11
). AOM is a metabolite of the procarcinogen
1,2-dimethylhydrazine and is one metabolic step closer to the proximate
carcinogen capable of inducing colon tumors (adenomas and
adenocarcinomas).
WAF was tested in this model along with WB, -cellulose and a
no-fiber (NF) treatment to assess its protective potential. AIN-93
diet is regularly used in such cancer studies (7)
. High
fat diets (20 g/100 g) increase tumor expression in this experimental
model (12
, 13
). Previous studies have
established that 5% DF should be sufficient to prevent the promotional
influence of a high fat diet (7)
. WAF was provided at two
concentrations of DF (1.5 and 5 g/100 g) to evaluate its effect against
induced colon tumorigenesis.
Potential mechanisms of protection could involve the fermentation in
the cecum and colon of DF to produce potentially antineoplastic
products. For example, high concentrations of butyrate in the colon may
offer protection (4
, 13
). This and lowered pH
are potentially useful markers of fermentation (4
,
14
), whereas ß-glucuronidase activity is a marker of
enzyme activity that may release from bound form (diglycosides) factors
such as lignans (diphenolics), which are potentially protective
(15
, 16
). These biomarkers have therefore
been included in this study, along with other measures routinely used
in this type of tumor end point study.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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WAF (WAF-Nature’s Gold; Goodman Fielder, Sydney, New South Wales,
Australia) was assayed for composition and used as the DF source in
comparison with WB and -cellulose (C-8002; Sigma Chemicals
Australia, Sydney, New South Wales, Australia) when supplied at 5 g of DF/100 g of diet. The WAF and WB were supplied by the Milling and
Baking Group of Goodman Fielder, New South Wales. On analysis, the
composition of WAF was found to be 15.4 g of DF (as non–starch
polysaccharide)/100 g, 23.6 g of protein/100 g, 36.5 g of
starch/100 g, 6.5 g of fat/100 g, 5.1 g of moisture/100 g of
and 2.36 g of phytate/100 g. The composition of WB was 31.6 g
of DF/100 g, 17.8 g of protein/100 g, 21.6 g of starch/100 g,
5.2 g of fat/100 g, 10.4 g of moisture/100 g of and 1.96 g of phytate/100 g.
WAF was mixed into a semipurified diet based on AIN-93 formulation,
modified to contain high fat (20 g/100 g of as equal parts lard and
sunflower seed oil), DL-methionine in place of
L-cystine at 0.3 g/100 g of and no added ultra trace
elements (AIN-93G). The experimental diets were as follows:
1) the control diet contained 5 g of
-cellulose/100 g of as fiber source, 2) NF with extra
corn starch in place of fiber, 3) WAF (WAF10) contained
10 g of WAF/100 g of diet, which provided 1.5% DF,
4) WAF33 (33 g of WAF/100 g of diet), which provided 5%
of DF and 5) WB16 (16 g of WB/100 g of diet), which
provided 5% DF. All diets were equally balanced for the levels of
protein, fiber, fat, energy and the proportionally larger
micronutrients such as calcium, phosphate, iron and sodium. The full
compositions of the diets are shown in Table 1
.
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Weanling specific-pathogen–free male Sprague-Dawley rats were supplied by the Animal Resource Center (Murdoch University, Perth, Western Australia). They were housed in the small animal colony facility at CSIRO Health Sciences and Nutrition (Adelaide, South Australia) in stainless steel wire cages and were maintained in an air-conditioned environment at 23°C with a 12-h light/dark cycle. One hundred rats were divided into five groups matched for body weight and consumed ad libitum the experimental diets in powdered form. All procedures used in this study were reviewed and approved by the Animal Experimentation Ethics Committee before commencement and met the principles of the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes (AGPS, Canberra, Australia).
Gastrointestinal tumors were induced by subcutaneously injecting AOM in saline adjusted to pH 7. In this experiment, two doses of AOM at 20 mg/kg body were administered 1 week apart to the rats 4 wk after they were established on the experimental diets. Daily food intakes and fecal outputs were measured midway through the experiment by placing the rats in metabolism cages for two 24-h periods.
Body weights were measured weekly throughout the experiment (6 mo), and
with five rats per cage, any potential competition for feed was
minimized. At the end of the experiment, signs of tumors appeared, and
the rats were anesthetized with halothane. Blood samples were removed
via exsanguination from abdominal aorta, and the rats subsequently
killed. Tissue and blood samples were stored at -20°C for subsequent
biochemical analysis. Tumors were assessed for malignancy using
Dukes’ classification (17)
, after being fixed and
processed for histopathological assessment. The tumors were categorized
into adenomas (or polyps) and adenocarcinomas (malignant tumors). Tumor
mass index was assessed as the log transformed summed area of colon
tumors in each rat. Other indices used were colon tumors/rat (burden)
and percentage of rats with total intestinal and colonic tumors
(incidence).
The biochemical assays used in this study have been previously
published (7)
. Short-chain fatty acids (SCFA) were
assayed by gas chromatography, and ß-glucuronidase was assayed
according to the method of Goldin and Gorbach (18)
as
modified by Jenab and Thompson (17)
but with 0.3 mol
trichloroacetic acid/L excluded in the final step, before
phenolphthalein color development and spectrophotometric assay.
The pH of fecal samples taken from the rectum at autopsy and cecal samples were measured by homogenizing samples in pure water and measuring with a calibrated pH meter. The results are expressed as mg phenolphthalein released/(g cecal contents · h).
Statistical analysis.
Tumor incidence and burden data (adenomas and adenocarcinomas per
treatment group) were analyzed by 
2 test. Tumor
incidence was calculated as contingency tables for the total number of
rats with colon tumors. This was tested for differences in counts using
a generalized linear model with binomial error distribution. A
generalized linear model with a Poisson distribution of errors was used
to analyze the differences between the diets using the number of colon
tumors observed in each rat, as well as the number of adenomas and
adenocarcinomas. A log transformation was required for
ß-glucuronidase to obtain homogeneity, because non-normality was
observed, with the error proportional to the mean. Back-transformed
values were corrected for bias by multiplying the back-transformed
mean by the correction
e1/2
2
(31
,32
). The relationship between the
number of colon adenomas and ß-glucuronidase activity was examined
using regression analysis. The other biochemical data were analyzed by
parametric analysis with ANOVA and post hoc Tukey’s multiple
comparisons. P-values for ANOVA of differences between
means of each treatment are shown in tables, with significant
difference at P < 0.05, unless otherwise
indicated. Values are given as means ± SEM.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The incidence of rats with small and large intestinal tumors did not
differ between treatments, with 80–90% of rats being affected
(Table 2
). The incidence of rats with colon tumors fed the WAF33 diet tended to
be lower than the control group (P = 0.10). Tumor
burden (adenomas/group and adenomas/rat) for WAF33 rats tended to be
lower than the control (P = 0.06 and P
= 0.07, respectively).
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Fecal weights were significantly (P < 0.001) greater
in control (-cellulose), WAF33 and WB16 groups than in WAF10 and NF
groups (Table 3
). That is, there was a significant fecal bulking effect evident with
the addition of 5% DF, whether as -cellulose, WAF or WB. There were
no significant differences in weight of cecal contents among groups.
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3-fold.
The influence of dietary treatments on ß-glucuronidase activity
[µmol phenolphthalein released/(h · g cecal contents)] in cecal
contents were measured. There was a significantly higher activity
(P < 0.001) in the WB16 and WAF33 groups relative to
control and NF groups. A similar result was observed when the
ß-glucuronidase activity was expressed relative to cecal protein
content (data not shown). An assessment of ß-glucuronidase activity
relative to colon adenomas showed that they were inversely correlated
(r2 = 0.37, P < 0.05)
(see Fig. 1
). The lowest numbers of adenomas were associated with the highest
activity of the cecal enzyme. An analysis of the individual rat data
showed a significant (P < 0.05) inverse relationship
existed between cecal butyrate concentration and adenocarcinomas; rats
with higher cecal butyrate concentrations had fewer adenocarcinomas
(P < 0.05) (Table 4
).
|
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). The difference in size and shape of fibers can be seen for
-cellulose relative to WAF and WB. WB fibers were coarser in texture
than for WAF and -cellulose. Cereal fiber was virtually absent from
the feces of NF rats. Protein levels (observed histologically as
Ponceau red–stained material) were also assessed in the cross sections
of feces of rats fed the various diets but showed no differences.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-cellulose) and NF dietary
treatments. Previous studies have shown that a 5–6% cereal DF
addition to a high fat diet was sufficient to produce a significant
tumor reduction in this model, when added as wheat, rice or barley bran
(7
,19
, 20
). Reduction in the
barley study by commercial barley bran was relative to other byproducts
of barley processing added at the same fiber level as in this study.
Although previous research has shown that -cellulose was protective
(21)
, the fact that these results were obtained relative
to a -cellulose control somewhat strengthens the evidence for
protection shown by the cereal fiber sources tested. Others have added
higher percentages of cereal fiber (8–12% DF) to demonstrate a
significant effect in these animal cancer models (13
,
22
, 23
,33
,34
). The
source of cereal DF is important, because some sources, such as oat
bran, with a high proportion of soluble fiber do not offer protection
with this cancer model (24
, 25
). It is
possible that a greater addition of WAF (e.g., 10% DF) could have
enhanced the present findings. However, this would have involved more
than half of the diet as wheat aleurone, whereas the level used here
translates in human diet terms to an equivalent intake of 25 g DF,
a recommended human intake. WB usually has a higher concentration of DF
(48–50 g/100 g) than the source used here, and it may be that the
lower dietary fiber product (less than one third) used here diminished
its effectiveness in this context.
Other significant functional effects in the colon were observed in the
WAF33 and WB16 groups that are considered beneficial in terms of bowel
health. These included a significant reduction in fecal and cecal pH
evident with WB and WAF at the 5% added fiber level, an effect
associated with reduced tumorigenesis (26)
. The elevated
cecal (but not fecal) butyrate concentrations in the rats fed WAF and
WB suggested a possible protective influence of the butyrate generated
in the cecum and proximal colon, as has been reported previously
(4
, 7
, 13
, 27
). The
experimental evidence in this study and elsewhere (36)
that adenocarcinomas were significantly fewer in rats with high cecal
butyrate concentrations deserves more investigation as to its
relevance. In addition, the cecal ß-glucuronidase activity was
inversely proportional to the number of colonic adenomas. The potential
for a higher ß-glucuronidase activity to enhance protectiveness by
release of certain phytochemicals from conjugated form (e.g. lignans)
in the colon lumen was proposed by Jenab and Thompson
(15)
. Others (14
, 28
,
29
) have proposed or inferred the opposite: that increased
colonic ß-glucuronidase activity is associated with a Western diet
(high meat and fat) and possibly reflects an undesirable influence on
colonic health, by releasing toxic or mutagenic compounds. More work is
needed to elucidate the nature and relevance of this observation.
In conclusion, WAF when added at a 5% DF level to a high fat rat diet produces some significant changes that were associated with a trend for tumor burden reduction. Given the relatively low fiber content (it contained DF at approximately half the concentration of WB), further concentration of the fiber in such a product may improve its functionality with regard to reducing colon cancer risk. However, the possibility that other associated factors contributed to this response leaves the question open for further investigation. WAF appears to be a desirable food component for improving bowel health, equivalent to WB, with fermentable DF and possible associated factors capable of offering protective effects.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Manuscript received May 15, 2000. Initial review completed July 20, 2000. Revision accepted October 20, 2000.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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