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American Health Foundation, Valhalla, NY 10595
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONInhibitory activity of...Inhibitory activity of culutres...Possible mechanisms of colon...Possible mechanism of colon...CONCLUSIONREFERENCES |
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KEY WORDS: • colon cancer • oligofructose • inulin • Bifidobacterium longum
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONInhibitory activity of...Inhibitory activity of culutres...Possible mechanisms of colon...Possible mechanism of colon...CONCLUSIONREFERENCES |
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).
Epidemiologic studies suggest that increased consumption of fruits and
vegetables and high total dietary fiber reduce the risk of development
of colon cancer (Howe et al. 1992
, Steinmetz and Porter 1991
). Human metabolic and laboratory animal model
studies indicate that beneficial effects of dietary fiber in relation
to colon cancer development depend on the composition and physical
properties of the fiber (Reddy et al. 1992
,
Reddy, 1995
).
Among the types of dietary fiber, inulin and oligofructose, which
occur in common food stuffs such as chicory, leeks, garlic, onion,
artichoke and asparagus at high levels, are ß (2
1)D
fructans. They are fermented by colonic microflora and behave as
soluble fibers (Gibson and Roberfroid 1995
). It is of
great interest that they selectively stimulate the growth of
bifidobacteria at the expense of bacteriodes, clostridia or coliforms,
which are maintained at low levels (Gibson and Roberfroid 1995
, Gibson et al. 1995
). Bacterial
fermentation of these prebiotics produces short-chain fatty acids
(SCFA)2in the colon, including a small amount of butyric acid (Campbell et al. 1997
, Gibson and Roberfroid 1995
), which
has been shown to increase apoptosis in the colon (Hague et al. 1993
). Of special interest are the beneficial effects of
certain lactic acid–producing enterobacterial food supplements,
probiotics, in the prevention of cancer (Hitchins and McDonough 1989
, Le et al. 1986
). The lactic cultures,
which are primarily used for fermentation of milk and other dairy
products, have also been shown to possess antimutagenic and
anticarcinogenic properties (Bodana and Rao 1990
,
Goldin and Gorbach 1980
, Lidbeck et al. 1992
). Furthermore, there are studies to demonstrate that
cultures of bifidobacteria increase the host's immune response
(Sekine et al. 1995
). These observations raise the
possibility that selective fermentable, nondigestible oligosaccharides
that enhance the growth of bifidobacteria in the gut and cultures of
lactic acid–producing bacteria could potentially inhibit colon
carcinogenesis. It was, therefore, of interest to evaluate the
inhibitory properties and modes of action of prebiotics such as
oligofructose and inulin, and probiotics, including bifidobacteria,
against colon carcinogenesis.
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Inhibitory activity of oligofructose and inulin against colon carcinogenesis |
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TOPABSTRACTINTRODUCTIONInhibitory activity of...Inhibitory activity of culutres...Possible mechanisms of colon...Possible mechanism of colon...CONCLUSIONREFERENCES |
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, Pretlow et al. 1992
). ACF also express
mutations in the APC gene and ras oncogene that
are involved in colon cancer development (Vivona et al. 1993
). Aberrant crypts are putative precursor lesions from
which adenomas and carcinomas may develop in the colon. Several
inhibitors of ACF formation have been shown to reduce the incidence of
colon tumors in laboratory animals (Wargovich et al. 1996
), suggesting that ACF induction can be used to evaluate
novel agents for their potential chemopreventive properties against
colon cancer.
Studies were conducted in our laboratory to determine the
potential inhibitory properties of oligofructose (Raftilose) and inulin
(Raftiline) on azoxymethane (AOM)-induced colon carcinogenesis in male
F344 rats using colonic aberrant crypt foci (ACF) as end points
(Reddy et al. 1997
). In this study, groups of 7-wk-old
male F344 rats were fed the AIN-76A (control) and the experimental
diets containing 10% oligofructose (Raftilose P95) or inulin
(Raftiline HP). All rats received a subcutaneous injection of the
colon-specific carcinogen, AOM, dissolved in normal saline at a
dose rate of 15 mg/kg body weight, once weekly for 2 wk. The animals
were necropsied 7 wk later, and the ACF were visualized under light
microscopy in the formalin-fixed, unsectioned methylene
blue-stained colons. ACF were distinguished by their increased
size, more prominent epithelial cells and pericryptal space. AOM
treatment induced on the average ~120 ACF per colon (Table 1); ACF were observed predominantly in the distal colon. Efficacy
end points used in this study were inhibition of the total number of
ACF per colon as well as the reduction of the number of multicrypt
clusters (
2) of aberrant crypts per focus. As summarized in Table 1
,
administration of oligofructose or inulin in the diet significantly
suppressed the total number of ACF per colon compared with the control
diet; the degree of inhibition was more pronounced in rats fed inulin
(P < 0.0006) than in those fed oligofructose
(P < 0.02). Crypt multiplicity in terms of two or
three aberrant crypts per focus were also inhibited significantly in
rats fed inulin (P < 0.02–0.0001) and oligofructose
(P < 0.04–0.01). These findings indicate that dietary
oligofructose and inulin inhibit ACF formation, an early preneoplastic
marker of malignant potential in the process of colon carcinogenesis,
suggesting that these agents may suppress colon tumorigenesis.
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Inhibitory activity of culutres of B. longum against colon carcinogenesis |
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TOPABSTRACTINTRODUCTIONInhibitory activity of...Inhibitory activity of culutres...Possible mechanisms of colon...Possible mechanism of colon...CONCLUSIONREFERENCES |
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Studies were also conducted to evaluate the inhibitory properties of
lyophilized cultures of B. longum against AOM-induced
colonic ACF development (Kulkarni and Reddy 1994
). The
results indicate that dietary administration of lyophilized cultures of
B. longum at 1.5 and 3.0% levels significantly inhibited
the total ACF formation and crypt multiplicity (two, three, or four or
more crypts per focus). The results of this study provide evidence for
potential colon tumor-inhibitory properties of B.
longum.
Effect on AOM-induced colon tumorigenesis.
Because the lyophilized cultures of B. longum inhibited the
preneoplastic lesions in the colon, studies were conducted to determine
the colon tumor inhibitory properties of B. longum
(Singh et al. 1997
). Male F344 rats were fed the
modified AIN-76A diet containing 0 or 2% lyophilized cultures of
B. longum and subcutaneously administered AOM dissolved in
normal saline at a dose rate of 15 mg/kg body weight, once weekly, for
2 wk. Vehicle controls received subcutaneously an equal volume of
normal saline. Animals were maintained on control or experimental diets
until termination of the study at 40 wk after last AOM treatment.
Table 2 summarizes the AOM-induced tumors in the colon in terms of
tumor incidence (percentage of animals with tumors) and colon tumor
multiplicity (number of tumors per animal). Dietary administration of
B. longum cultures significantly inhibited the incidence of
colon adenocarcinomas (P < 0.05) and colon tumor
multiplicity in terms of tumors per animal (P < 0.001)
and tumors per tumor-bearing animal (P < 0.01).
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The formation of mutagens upon broiling fish and meat was first
discovered by Sugimura et al. (1977)
. IQ, a heteroxyclic
aromatic amine produced from food pyrolysis, was first isolated from
broiled fish. Subsequently, it was isolated from a variety of broiled
or cooked fish and meat (Kasai et al. 1980
). IQ has a
multitarget organospecificity with specific cancer induction in the
Zymbal gland, skin, colon, oral cavity and mammary gland of rodents
(Sugimura et al. 1991
). Although it is not clear whether
these heterocyclic amines may contribute to human cancer development,
it is certain that these compounds are present in cooked foods and pose
a credible risk to humans.
Because IQ induces colon tumors in male and female rats and mammary
tumors in female rats, and bacterial cultures that ferment milk possess
anticarcinogenic properties, the possibility exists that these
bacterial cultures may prevent IQ-induced carcinogenesis.
Accordingly the inhibitory effect of lyophilized cultures of B.
longum on IQ-induced carcinogenesis was investigated in male
and female F344 rats (Reddy and Rivenson 1993
).
Beginning at 5 wk of age, male and female rats were divided into
various experimental groups and fed one of the high fat, semipurified
diets containing 0 and 0.5% lyophilized cultures of B.
longum with or without 125 ppm IQ. All rats were continued on this
regimen until the termination of the study at wk 58. The results
indicated that lyophilized cultures of B. longum
significantly inhibited the IQ-induced incidence (percentage of
animals with tumors) of colon tumors (100% inhibition) and
multiplicity of colon tumors (tumors per animal) in male rats (Table 2)
. In female rats, dietary supplement of B. longum cultures
also suppressed the IQ-induced mammary carcinogenesis to 50% of
that observed in animals fed the control diet. Mammary tumor
multiplicity (tumors per animal) was significantly (P
< 0.05) inhibited in female rats fed the diet containing B.
longum cultures. These findings suggest that dietary
bifidobacterium supplements inhibit IQ-induced colon tumors and to
a lesser extent mammary tumors in F344 rats.
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Possible mechanisms of colon cancer inhibition by prebiotics |
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TOPABSTRACTINTRODUCTIONInhibitory activity of...Inhibitory activity of culutres...Possible mechanisms of colon...Possible mechanism of colon...CONCLUSIONREFERENCES |
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, Gibson et al. 1995
) in the colon. In vitro
studies showed that incubation of fecal bacterial cultures with
oligofructose and inulin selectively stimulated the growth of
bifidobacteria while maintaining the Escherichia coli or
clostridia at low levels (Wang and Gibson 1993
). In diet
intervention studies, Gibson et al. (1995)
demonstrated
that dietary administration of oligofructose or inulin significantly
increased fecal bifidobacteria, whereas bacteriodes, clostridia and
fusobacteria and/or gram-positive cocci were decreased on total
fecal bacterial count. These bifidobacteria, colonizing at the expense
of enteropathogens, may bind the ultimate carcinogen by physically
removing it via feces. The colonizing cells of bifidobacteria also
produce lactic acid, thereby lowering the intestinal pH to create a
bacteriocidal environment for putative enteropathogens such as E.
coli and Clostridium perfringens, thus developing a
favorable microenvironment. This favorable microenvironment may also
involve the modulation of bacterial enzymes such as ß-glucuronidase
that can convert procarcinogens to proximate carcinogens
(Kulkarni and Reddy 1994
). In addition to selective
modulation of bifidobacteria, oligofructose and inulin increase the
production of SCFA, especially butyrate, in the colon by microbial
fermentation (Gibson and Roberfroid 1995
). Although the
production of butyrate is ~5% of total SCFA, it is of particular
interest because it inhibits proliferation of a number of cell types in
vitro and induces a more differentiated phenotype, including colorectal
tumor cells (Gamet et al. 1992
). Butyrate analogs are
being evaluated for their potential antineoplastic agents
(Newmark et al. 1994
). Although this is by no means the
only mechanism by which oligofructose and inulin might inhibit ACF, it
could explain in part why these agents appear to be protective. |
Possible mechanism of colon cancer inhibition by B. longum |
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TOPABSTRACTINTRODUCTIONInhibitory activity of...Inhibitory activity of culutres...Possible mechanisms of colon...Possible mechanism of colon...CONCLUSIONREFERENCES |
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,
Singh et al. 1992
), in dysplastic polyps vs.
nondysplastic polyps (Luk and Baylin 1984
) and also in
noninvolved mucosa from polyposis patients vs. noninvolved mucosa from
normal individuals (Luk et al. 1989
). Similarly, ODC
activity has been found to be consistently higher in colon
adenocarcinomas compared with the adjacent mucosa. Evidence that
enhanced ODC activity may play an important role in colon tumor
development is provided by the observation that
difluoromethylornithine, a highly specific and irreversible inhibitor
of ODC, suppressed colon tumor development in a time-dependent
manner in carcinogen-treated rodents (Singh et al. 1992
). Studies conducted in our laboratory demonstrate that the
colon tumor inhibitory property of lyophilized cultures of B.
longum was associated with the inhibition of colonic mucosal cell
proliferation and with suppression of ODC activity in the colonic
mucosa and tumors compared with that in control diet (Table 2)
.
Biasco et al. (1991)
observed a significant decrease in
mucosal cell proliferation in upper colonic crypts of patients with
colon adenomas after the administration of Lactobacillus
acidophilus and B. bifidus cultures. We also observed
elevated levels of ODC activity in both colon tumors and uninvolved
colonic mucosa of AOM-treated animals (Singh et al. 1997
). In addition, ODC activity was significantly decreased in
colonic mucosa as well as in colon tumors of AOM-treated animals
administered lyophilized cultures of B. longum. Although the
precise mechanism of inhibition of ODC activity by dietary B.
longum cultures is not clear, it is likely that these effects may
proceed through diverse physiologic and metabolic alterations.
Ras activation represents one of the earliest and most
frequently occurring genetic alterations associated with human cancers,
especially the cancer of the colon (Barbacid 1990
).
Elevated levels of ras-p21 have been correlated with
increased cell proliferation, histologic grade, nuclear anaplasia and
degree of undifferentiation (Kotsinas et al. 1993
). In
experiments in which mutated ras genes are selectively
inactivated, the preexisting tumor phenotype reverts to a more normal
form, indicating that activated ras may be necessary for the
maintenance of malignant behavior (Mukhopadhyay et al. 1991
). We also analyzed the modifying effects of
B. longum cultures on ras p-21 expression to
determine whether the inhibition of colon tumorigenesis is associated
with the modulation of ras p-21 activity. The results
summarized in Table 3 demonstrate that dietary B. longum cultures
significantly suppressed the expression of total and mutated
ras p-21 in the colonic mucosa and tumors compared with the
control diet. This inhibitory effect of B. longum cultures
on ras p-21 expression was again strongly correlated with
colon tumor outcome. As regards the mechanism of inhibition of
ras activation afforded by B. longum
cultures, it is likely that bifidobacterial cells, as a biological
response modifier, modulate the induction of the methylguanine repair
protein, O6-methylguanine DNA methyltransferase,
which acts as a suicide enzyme that stoichiometrically accepts a methyl
group onto itself, restoring the original guanine in DNA by in situ
demethylation (Pegg and Dolan 1989
). To our knowledge,
no other data exist pertaining to the modulation of ras
function by lactic cultures. It is clear from these results that
B. longum–augmented suppression of AOM-induced
ras activity may interfere with the progression of events
leading to colon tumor development.
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, Sekine et al. 1995
). For example, the administration of viable or nonviable
intestinal bacteria to germ-free mice has been shown to enhance
intestinal production of immunoglobulin A plasmacytes (George 1994
). Kohwi et al. (1978)
demonstrated that
repeated intralesional injections of Bifidobacterium
inhibited the growth of Meth-A tumor cells transplanted
subcutaneously into syngeneic BALB/c mice. Furthermore, Sekine et al. (1995)
and Okawa et al. (1993)
demonstrated that a water-soluble cell fraction, WPG, of
bifidobacteria induces an antitumor effect and plays an important role
as an immunomodulator in the intestines of humans and animals. |
CONCLUSION |
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TOPABSTRACTINTRODUCTIONInhibitory activity of...Inhibitory activity of culutres...Possible mechanisms of colon...Possible mechanism of colon...CONCLUSIONREFERENCES |
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FOOTNOTES |
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2 Abbreviations used: ACF, aberrant crypt foci;
AOM, azoxymethane; IQ, 2-amino-3-methylimidazo[4,5-f]quinoline; ODC,
ornithine decarboxylase; SCFA, short-chain fatty acids.
|
REFERENCES |
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]quinoline (IQ)-induced colon
carcinogenesis in F344 rats