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Department of Food Science & Nutrition, University of Minnesota, St. Paul, MN 55108-6099
3To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONAnimal and human studiesSUMMARYREFERENCES |
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KEY WORDS: • probiotic • prebiotic • colon cancer
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONAnimal and human studiesSUMMARYREFERENCES |
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). A prebiotic is
defined as a "nondigestible food ingredient which beneficially
affects the host by selectively stimulating the growth and/or
activating the metabolism of one or a limited number of health
promoting bacteria in the intestinal tract, thus improving the host’s
intestinal balance" (Gibson and Roberfroid 1995
). Development of colon cancer represents a sequence of events that, although incompletely understood, occurs in definable steps. First is an initiating step, in which a carcinogen produces an alteration in the DNA. This step may be preceded by a metabolic activation of a precursor to produce the carcinogen. At present, it is believed that several mutations must occur for a tumor to develop. The post-initiation steps are much less clear, but usually involve changes in signal transduction pathways. The next clearly observable step is an overgrowth in the colonic crypts, which can be seen morphologically as an aberrant crypt. Aberrant crypts, which are considered preneoplastic structures, are enlarged and elevated relative to normal crypts, and have a serpentine growth pattern. Aberrant crypts may occur singly or as groups of aberrant crypts within a single focus. A certain small but unknown fraction of these aberrant crypts will progress to polyps and eventually to tumors.
Because factors involved in initiation and postinitiation steps might be separated in time from actual tumor development, it is difficult to choose "outcomes" or "endpoints" that are definitive indicators of efficacy of a given treatment such as probiotics. In many animal and human studies of colon cancer, investigators have measured how diets or treatments affect predisposing factors, such as increases in enzyme activities that activate carcinogens, increase procarcinogenic chemicals within the colon or alter populations of certain bacterial genera or species. A number of studies have now shown that these predisposing factors are altered favorably by consumption of certain probiotics or prebiotics. However, these studies do not demonstrate a causal relationship to development of colon cancer and are at best circumstantial. Studies that do explore the cause-effect relationship directly are, by necessity, animal studies. In this review, we have confined our discussion to animal studies from the last 10 years that have examined most directly the relationship between pre- and probiotic consumption and colon cancer development. We will note human studies that provide support for the conclusions drawn from the animal studies. To present the conclusion first, it appears from these studies that probiotics with or without prebiotics have an inhibitory effect on the development of aberrant crypts (precancerous lesions) and tumors in animal models. The effect is not completely consistent and is small in some studies, but this likely represents a dose effect.
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Animal and human studies |
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TOPABSTRACTINTRODUCTIONAnimal and human studiesSUMMARYREFERENCES |
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). The investigators found that colon tumorigenesis
induced by 1,2 dimethylhydrazine (DMH) was reduced in rats given the
fermented milk. Shackleford et al. (1983)
studied the
effects of milk fermented by Streptococcus thermophilus or
Lactobacillus bulgaricus on DMH-induced colon tumors.
Survival rate was greater in rats fed the fermented milk, but numbers
of colon tumors were not different among the control skim milk group,
the group given S. thermophilus–fermented milk and the
group given L. bulgaricus–fermented milk. Abdelali et al. (1995)
studied aberrant crypt (AC) formation in rats fed
skim milk, skim milk fermented with Bifidobacterium sp.
Bio, and the same bacteria incorporated into the diet. The
test diets reduced the incidence of AC by ~50%. There was no
difference in cecal pH, but the groups consuming the bifidobacteria had
decreased cecal ß-glucuronidase activity. Tsuda et al. (1998)
actually studied the influence of lactoferrin on
azoyxymethane-induced aberrant crypts, but used
Bifidobacterium longum (3% of diet) as a positive control
in their studies. Both lactoferrin and B. longum reduced
aberrant crypt foci (ACF).
Koo and Rao (1991)
reported that administration of both
bifidobacteria (B. pseudolongum) and 5% neosugar
[fructooligosaccharide (FOS)] to female mice given DMH resulted in
~50% as many AC as in control animals at 18 and 38 wk. There were
also decreased numbers of ACF at 18 and 38 wk after DMH injection.
Bifidobacteria in feces were measured at 38 wk only; the numbers of
bifidobacteria were slightly but significantly elevated (8.85 ± 0.2 vs. 9.45 ± 0.19) over controls in mice fed the treatment. The
decrease in aberrant crypts was a positive effect on the mouse host;
however, several key pieces of data would have been useful. The groups
of mice were as follows: controls given the AIN-76 defined diet, mice
fed DMH only and the same diet, and those given DMH + bifidobacteria +
neosugar and the same diet. The design does not allow the effects of
bifidobacteria alone or neosugar alone to be determined. Although the
differences in numbers of fecal bifidobacteria at wk 38 were
significant, our experience has been that changes in numbers of
bifidobacteria of less than ~1 log-fold usually do not reach
significance, even with 15–20 animals/group. Another indicator of
these small changes in numbers of bifidobacteria in relation to other
genera might be changes in the short-chain fatty acid (SCFA)
profile. In this study, acetic acid in the cecal contents was not
significantly different between the DMH and DMH + bifidobacteria +
neosugar groups. Acetic acid and lactic acid are produced by
bifidobacteria, whereas butyrate and propionate are not produced; one
might expect an increase in acetic acid if numbers of bacteria
producing them increase significantly. It is important to remember,
however, that concentrations of SCFA represent both production and
utilization. The investigators did measure a host outcome (AC) that has
been accepted as a predictor of the development of colon tumors. The
question that remained at the closure of this study is whether the
small changes in bifidobacteria due to the treatment are responsible
for the decrease in lesion formation or whether some other factor, such
as changes in other SCFA or inhibitory substances or even other groups
of bacteria, played a role.
A series of studies examining the influence of bifidobacteria and/or
FOS and inulin on aberrant crypts or tumors was presented by Reddy and
colleagues (Kulkarni and Reddy 1994
, Reddy and Rivenson 1993
, Reddy et al. 1997
, Reddy 1998
). The initial study examined the induction of tumors by
2-amino-3-methylimidazo[4,5-f]quinoline, a food mutagen. Both male
and female rats were fed a high fat diet (AIN-76), with or without the
mutagen and with or without the addition of B. longum for 58
wk. The diets were mixed weekly and kept in air-tight plastic
containers. The B. longum was lyophilized in a
cryoprotectant solution containing glutamate and sucrose. The authors
state that each gram of lyophilized material contained 2 x 1010 live bacterial cells, but it is not clear
whether this measurement was taken at the time of lyophilization or the
time of feeding or both. There were differences between male and female
rats in incidence of colon tumors. Females did not develop colon tumors
on either the diet + mutagen or diet + mutagen + lyophilized culture.
Males fed the control diet + the mutagen developed 23 tumors, whereas
males fed the same diet + mutagen + the lyophilized culture did not
develop any tumors. This study found more tumor development in liver in
both sexes than in colon, suggesting that this particular mutagen is
not a potent inducer of colon tumors. No measurements of viable
bifidobacteria in the feces or intestinal contents were reported for
any of the groups. Similarly, the relationship between viable
bifidobacteria and feeding of the lyophilized B. longum is
not clear, nor is the relationship between live bifidobacteria in the
colon and the presence or absence of tumors because the bifidobacteria
were not measured.
Kulkarni and Reddy (1994)
induced colonic aberrant
crypts in male F344 rats by azoxymethane (AOM) treatment. At 5 wk of
age, groups of rats were fed either the AIN-76 diet or AIN-76 + 1.5 or
3.0% of lyophilized culture of bifidobacteria as described above. At
10 wk of age, the rats were given the AOM injection. Six weeks later,
rats were killed and AC in the colons determined. The consumption of
the lyophilized cultures inhibited the development of AC in the colon
by ~50%; fecal ß-glucuronidase was also decreased in feces of rats
fed the cultures. Again, fecal bifidobacteria were not measured in the
study, and it is impossible to draw conclusions about the relationship
of numbers of viable bifidobacteria and the outcome measured (in this
case, AC). In addition, the effect of the addition of lyophilized
culture was not linear; 1.5% was equally as effective as 3.0%
addition to the diet. This is not surprising, considering that the
absolute numbers of bifidobacteria in the two groups differed by a
small factor. The measurement of ß-glucuronidase represents
an indirect indicator of risk because it is not clear which bacteria
produce it and whether it has a direct effect on the outcome measured.
However, in this case, it correlated with the decrease in AC.
Reddy et al. (1997)
fed 10% oligofructose or 10%
inulin as part of the AIN-76 diet to male F334 rats that were given AOM
in a design similar to the one reported above. The rats were killed 7
wk after the last dose of AOM. Total numbers of AC per colon were
significantly less (120 ± 28 for control; 92 ± 28 for
oligofructose; 78 ± 37 for inulin) in rats that consumed these
prebiotics at 10% of the diet. No bacterial cultures of feces or colon
contents were reported, but the authors cited the data of other
studies, which reported that these prebiotics increase bifidobacteria
and decrease other less desirable organisms. Again, based on our own
observations, the effect of these prebiotics in rats (numbers of
bifidobacteria and clostridia or AC) is not consistent; thus,
measurement of the change in bacteria is critical in drawing
conclusions about the relationship between bacteria and aberrant crypt
formation. Oligofructose or inulin fed at 10% of the diet is a high
amount of dietary fiber intake of a specific type for rats; it would be
interesting to determine whether other dietary fibers at this level
have similar effects or whether the effect is specific for these two
oligosaccharides. The authors refer in detail to other studies that
note changes in bacteria numbers and production of SCFA, such as lactic
acid and butyric acid. They refer to studies in which the feeding of
oligosaccharides increases butyrate levels in the colon as a positive
outcome because butyrate has been associated with apoptosis and
decreased cellular proliferation. However, increased butyrate
concentration is not directly consistent with increasing numbers of
bifidobacteria and displacement of less desirable organisms such as
clostridia because bifidobacteria do not produce butyrate, whereas
clostridia do produce it.
Reddy (1998)
reviewed the various studies from his
group. In addition to the data cited above, he presented data showing
that the colonic labeling index, ornithine decarboxylase activity, and
ras-p21 oncogene activity were decreased in rats fed the lyophilized
cultures of B. longum. These measures are thought to
reflect cell proliferation, and correlation with AC numbers is not
surprising. However, these indices are not necessarily indicative of a
cause-effect in terms of AC or tumor formation because relatively
few AC progress to tumors and we do not understand completely the
factors that influence tumor formation.
Our own studies in male Wistar rats have not been consistent in terms
of increases in numbers of bifidobacteria, decreases in clostridia, or
AC formation in response to feeding of bifidobacteria or FOS
(Gallaher et al. 1996
). We used DMH as the carcinogen
and measured the ability of probiotics and FOS to inhibit AC formation
in the postinitiation phase. In our first experiment of the series, we
gavaged 109 bifidobacteria per day and fed 2% FOS
(Gallaher et al. 1996
). Feeding bifidobacteria + FOS
inhibited AC formation in this experiment by almost 50%, but there was
not an inverse correlation of AC with the numbers of cecal
bifidobacteria, nor was there any correlation with numbers of cecal
Clostridium perfringens. In a second experiment, we used
a saline-gavaged control group, a milk-gavaged control group, a
group gavaged with milk + bifidobacteria, a group gavaged with milk +
FOS, and a group gavaged with milk + both bifidobacteria and FOS. We
found no differences in AC with any treatment and no correlations with
cecal bacteria. In a third experiment, we repeated the second study. We
found marginal decreases of ACF in the rats gavaged with bifidobacteria
+ FOS compared with control rats gavaged with skim milk. ACF numbers
did not correlate with numbers of fecal bifidobacteria or C.
perfringens. In another experiment, we changed this design to
include the following: control (rats gavaged with skim milk), rats
gavaged with skim milk + FOS, rats gavaged with skim milk +
bifidobacteria + FOS, rats gavaged with Lactobacillus
acidophilus + FOS, and a group that was gavaged with L.
acidophilus, bifidobacteria and FOS. We found no differences in
AC numbers, but in this case, did find decreased numbers of fecal
clostridia in the rats that received bifidobacteria-FOS, L.
acidophilus-FOS, or bifidobacteria + L.
acidophilus + FOS. We found no consistent correlation of
bacterial numbers with AC, nor did we find effects of bifidobacteria or
FOS on AC formation. Last, we examined the effects of various
oligosaccharides consumed in the diet + bifidobacteria. We found that
the group of rats fed FOS and bifidobacteria did have significantly
decreased AC, but AC did not correlate with changes in bifidobacteria
or clostridia. When data from all experiments were plotted as the
relationship between bifidobacteria and clostridia, we did see an
inverse relationship of bifidobacteria with clostridia. We were careful
to provide for the consistent consumption of numbers of viable bacteria
that the rats received each day. We gavaged live cultures that were
made up fresh daily and assayed for viability randomly during the
experiment from the same mix as was given to rats. We also used 2% FOS
in the diets; this is less FOS than used in other studies and might be
the reason for differences in effects observed. However, we felt that
this level was reasonable in terms of amounts consumed. Our conclusion
was that bifidobacteria + FOS had some slight effect on AC numbers in
rat colon, but this effect was not due directly to numbers of
culturable bifidobacteria in the colon.
Challa et al. (1997)
examined AOM-induced AC in rats
consuming B. longum ± lactulose. Both B.
longum and lactulose singly and together reduced ACF formation.
The authors concluded that the effect of B. longum and
lactulose was additive, but numbers of bifidobacteria in gut contents
were not measured. This makes it difficult to ascribe the results
directly to changes in colonic bifidobacteria.
Rowland et al. (1998)
found that consumption of
bifidobacteria or inulin or both together inhibited AOM-induced
small ACF. These treatments were also associated with decreased
ß-glucuronidase activity and ammonia concentration in cecal contents
of rats. ß-Glucosidase and cecal weight were increased with these
treatments. There was no measure of numbers of bifidobacteria in the
colon or the feces in this study. Again, the enzyme measurements
suggest that some alteration in bacterial metabolism that is related to
the decreases in ACF has occurred, but do not implicate directly a
particular bacteria or suggest changes in numbers of any group or
changes in metabolite levels.
Arimochi et al. (1997)
studied the effect of numbers of
intestinal bacteria on AC formation with AOM as the administered
carcinogen. They presented very different conclusions than those of
other investigators about the genera of bacteria that decrease AC
formation. Bifidobacteria had no effect, whereas both L.
acidophilus and C. perfringens decreased AC
formation significantly. The culture supernatants were found to mediate
the effect, suggesting a metabolite product (they suggested butyrate
produced by C. perfringens). The drinks containing
bacterial cultures were prepared freshly each day, but there is no
indication of how much the rats drank of each solution, even though
similar numbers of each bacteria were added to the drinks. It is
possible that bacteria exhibited differential survival in the bottles
before actual consumption. The authors did not find that
ß-glucuronidase activity was affected by L.
acidophilus, even though AC were decreased by L.
acidophilus. C. perfringens treatment also did not increase
ß-glucuronidase activity, as would be expected if this enzyme and
C. perfringens were positively correlated with AC
development; in fact, C. perfringens was correlated with
decreased AC development.
Onoue et al. (1997)
studied the effects of inoculating
germ-free rats with various combinations of microbiota.
Germ-free rats were given Escherichia coli,
Enterococcus faecium, and several strains of
Bacteriodes and Clostridium sp.
(gnotobiotic) or feces from conventional rats. They were then given DMH
injections 3 and 4 wk later and then killed 11 or 34 wk after that.
Addition of bacteria to germ-free rats increased both the ACF with
four or more AC and the mean number of AC per focus. When
Bifidobacterium breve was added to the defined
inoculation (gnotobiotic) noted above, ACF with four or more AC per
focus and crypt multiplicity were significantly lower at 11 wk, but not
at 34 wk. B. breve addition did not affect the fecal
microflora, again making it difficult to attribute the differences to
changes in numbers of flora.
Goldin et al. (1996)
studied the effect of dietary fat
(20 and 5%) and administration of Lactobacillus casei
on development of tumors in DMH-treated Fischer 344 rats. A
lyophilized powder of 1011 viable cells/g was added at 1%
of the diet. The rats consumed ~2–4 x 1010
organisms/d. At 24 wk, in the high fat group fed the lactobacillus
before, during and after DMH injections, colon tumors numbered 24 vs.
the DMH control number of 74 (not significantly different, but colon
tumors per tumor-bearing animal were 3.7 vs. 1.7, which was
significantly different. There was also a significant decrease in
percentage of rats with tumors, from 100% in the control to 71% in
the rats fed lactobacilli. This study highlights problems with
expression of data, when various measures that are used to indicate
development of precancerous lesions do not correlate. The question of
the most meaningful expression of data remains to be answered.
The outcomes measured in human studies are more indirect and provide more circumstantial evidence than is offered by animal studies, but may support or refute data from animal studies in the host of most interest. Advantages of human studies are as follows: 1) this is the real population target of colon cancer prevention and the information gained from studies can be applied more directly (such as efficacy of various strains or degree of colonization); 2) the variability of the population plays an important role, in contrast to studies using homogeneous populations of animals. A few recent studies illustrate the nature of human studies that have addressed various aspects of the relationships among diet, fecal bacteria and colon cancer risk.
Meijer-Severs et al. (1993)
compared SCFA concentration
and selected bacteria in controls and patients with familial polyposis
before and after colectomy. Preoperative patients had bacterial counts
similar to those of controls (B. fragilis in control:
109; preop, 109; postop, 107;
bifidobacteria: control, 109.5; preop, 109.75;
postop, 108.1). After colectomy, numbers of Bacteroides and
bifidobacteria were decreased compared with preop and controls. The
ratio of acetic acid to other SCFA increased, in proportion to
decreases in other SCFA.
Kanazawa et al. (1996)
studied control and high risk
patients after treatments for large bowel cancer were completed and the
colon appeared normal again. Feces were collected under CO2
and packed on ice for shipment, but were not actually cultured until
30 h. later. It is unclear whether dietary intake was determined
from only one sample taken on the day before the fecal sample, but
analysis indicated that patients consumed more carbohydrate, soluble
fiber and calcium than controls. Bacterial cultures revealed that the
feces of patients contained more lecithinase-negative clostridia
(109.4 vs. 108.8), more lactobacilli
(108.37 vs. 106.88) and less yeast
(103.32 vs. 103.96). pH was significantly
higher in the patient group, as was H2S and cresol
concentration. One question not addressed by this study concerns the
cause-effect timeline; did the differences reflect the cause of the
high risk or were they the result of the cancer?
Bouhnik et al. (1996)
fed 12.5 g FOS/d to 20
healthy human volunteers. A recent paper by the same group found that
5 g FOS is necessary to increase numbers of bifidobacteria in humans
(Bouhnik et al. 1999
). Saccharose was used as the
placebo control. Consuming 12.5 g of FOS led to increased numbers
of fecal bifidobacteria within the 12-d feeding period of FOS (from
107.9 to 109.1), but the regimen did not
significantly affect any measures used to indicate risk of colon cancer
development, i.e., total fecal anaerobes, pH, activities of
nitroreductase, azoreductase, and ß-glucuronidase, bile acids and
neutral sterols. In this case, fecal samples were stored at 4°C for
up to 12 h before analysis. The authors pointed out the
possibility that changes in metabolic parameters might take longer to
occur after the occurrence of increases in fecal bifidobacteria than
the 12-d measurements that were determined; alternatively, a much
longer sustained feeding period might be necessary to see effects.
Obviously, these effects would have to be correlated directly with
changes in the colon to be meaningful, whatever the length of the
study.
Watne et al. (1976)
studied fecal neutral and acid
steroids and bacterial flora in patients with polyposis coli and
controls. Bacterial flora of patients showed an anaerobe/aerobe ratio
of 2.7:1 with a relative increase in clostridia and bifidobacteria and
decrease in eubacteria and bacteroides. After ileorectostomy,
clostridia disappeared, along with ruminococcus, peptostreptococcus and
fusobacteria; eubacteria and lactobacilli decreased and bifidobacteria
and bacteroides increased. Again, these measures do not imply
cause-effect of microbial changes with tumor risk.
Moore et al. (1995)
did an epidemiologic study
of intestinal floras in population with high risks of colon cancer. The
results were not supportive of data linking high numbers of
bifidobacteria with low risk for colon cancer. Fecal bacteria were
compared in populations of polyp patients, Japanese-Hawaiians,
North American Caucasians, rural native Japanese and rural native
Africans. The polyp patients and Japanese-Hawaiians were initially
considered the high risk groups. Fifteen bacterial groups were
associated significantly with high risk of colon cancer (among these
Bacteroides and bifidobacteria) and five were associated significantly
with low risk (certain lactobacilli species and Eubacterium
aerofaciens). This study does not indicate cause-effect,
but rather associations between bacteria and risk of disease.
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SUMMARY |
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TOPABSTRACTINTRODUCTIONAnimal and human studiesSUMMARYREFERENCES |
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The major conclusion from the animal data is that there appears to be a synergistic effect of consumption of probiotic bacteria and prebiotics such as fructooligosaccharides on the attenuation of the development of colon cancer. The effect is often not large, but it is possible that it could be beneficial, in combination with other ways to reduce risk. The data also point the way to the opportunities for further investigation, particularly in defining and measuring outcomes/end points in humans that are meaningful and that correlate the consumption of pro- and prebiotics with decreased risk of colon cancer development.
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FOOTNOTES |
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2 Support for this work was provided by Dairy Management, Inc., the Minnesota-South Dakota Dairy Foods Research Center, the Minnesota Agricultural Experiment Station, USDA-NRI and SKW (Waukesha, WI).
4 Abbreviations used: AC, aberrant crypt; ACF, aberrant crypt foci; AOM, azoxymethane; DMH, 1,2 dimethylhydrazine; FOS, fructooligosaccharide; NCI, National Cancer Institute; SCFA, short-chain fatty acids.
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TOPABSTRACTINTRODUCTIONAnimal and human studiesSUMMARYREFERENCES |
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