J. Nutr.-2000-Brady-410S-4S(1), ARTYKUŁY NAUKOWE (probiotyki, mikroflora, germ-free), ebook, pdf

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//-->Symposium: Probiotic Bacteria:Implications for Human HealthThe Role of Probiotic Cultures in the Prevention of Colon Cancer1,2Linda J. Brady,3Daniel D. Gallaher and Frank F. BustaDepartment of Food Science & Nutrition, University of Minnesota, St. Paul, MN 55108-6099ABSTRACT Risk factors for colon cancer include both hereditary and environmental factors. Dietary patternsrepresent controllable risk factors for the development of colon cancer. Much attention has focused on decreasingcolon cancer risk through increasing intake of dietary ﬁber; recently, this has included interest in the consumptionof prebiotics and probiotics. Because factors involved in the initiation and promotion of colon cancer might beseparated in time from actual tumor development, it is difﬁcult to choose “outcomes” or “end points” that aredeﬁnitive indicators of efﬁcacy of probiotics or prebiotics. Studies that have explored the cause-effect relationshipdirectly have used animal models. In this review, we have conﬁned our discussion to animal studies from the last10 years that have examined most directly the relationship between prebiotic and probiotic consumption and coloncancer development. To present the consensus of these studies ﬁrst, it appears that probiotics with or withoutprebiotics have an inhibitory effect on the development of aberrant crypts (precancerous lesions) and tumors inanimal models. The effect is not completely consistent and is small in some studies, but this may represent a doseor time effect. J. Nutr. 130: 410S– 414S, 2000.KEY WORDS:●Downloaded from jn.nutrition.org by guest on January 22, 2015probiotic●prebiotic●colon cancerA 1999 report on cancer statistics from the National Can-cer Institute (NCI)4was released in April 1999; it states thatfrom 1990 to 1996, four cancer sites, i.e., lung, prostate, breastand colon and rectum, accounted for more than half of all newcancer cases; these cancers were also the leading causes ofcancer deaths. Tracking trends for those primary sites showsthat rates are going down for prostate cancer incidence andmortality. Breast cancer incidence rates have shown littlechange in the 1990s, whereas breast cancer death rates havebeen declining 2%/y since 1990. Colorectal cancer inci-dence and death rates continued to decline for both men andwomen. However, even with a decrease, the NCI indicatesthat colon cancer is the second most frequently diagnosedcancer among both men and women in the United States andthe second most common cause of cancer death. Between133,000 and 160,000 new cases of colorectal cancers are di-agnosed each year, with a combined death total of 50,000 –60,000 people. Risk factors for developing cancer include bothPresented at the symposium entitled “Probiotic Bacteria: Implications forHuman Health” as part of the Experimental Biology 99 meeting held April 17–21in Washington, DC. This symposium was sponsored by the American Society forNutritional Sciences and was supported in part by an educational grant from theNational Dairy Council. The proceedings of this symposium are published as asupplement toThe Journal of Nutrition.Guest editor for this supplement wasDouglas B. DiRenzo, National Dairy Council, Rosemont, IL.2Support for this work was provided by Dairy Management, Inc., the Minne-sota-South Dakota Dairy Foods Research Center, the Minnesota AgriculturalExperiment Station, USDA-NRI and SKW (Waukesha, WI).3To whom correspondence should be addressed.4Abbreviations 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.1hereditary and environmental factors. Hereditary factors in-clude familial polyposis, hereditary nonpolyposis colon cancer,Lynch syndromes I and II, and ulcerative colitis. Environmen-tal factors, such as living in an industrialized area, physicalinactivity, exposure to certain chemicals and consumption ofa high fat, low ﬁber diet, are of greater interest because theyrepresent controllable risk factors. In particular, much atten-tion has focused on decreasing cancer risk through diet alter-ations, particularly increasing intake of dietary ﬁber (including“prebiotics”) and consumption of probiotics. A probiotic isdeﬁned as a “a viable microbial dietary supplement whichbeneﬁcially affects the host through its effects on the intestinaltract” (Gibson and Roberfroid 1995). A prebiotic is deﬁned asa “nondigestible food ingredient which beneﬁcially affects thehost by selectively stimulating the growth and/or activatingthe metabolism of one or a limited number of health promot-ing bacteria in the intestinal tract, thus improving the host’sintestinal balance” (Gibson and Roberfroid 1995).Development of colon cancer represents a sequence ofevents that, although incompletely understood, occurs in de-ﬁnable steps. First is an initiating step, in which a carcinogenproduces an alteration in the DNA. This step may be precededby a metabolic activation of a precursor to produce the car-cinogen. At present, it is believed that several mutations mustoccur for a tumor to develop. The post-initiation steps aremuch less clear, but usually involve changes in signal trans-duction pathways. The next clearly observable step is anovergrowth in the colonic crypts, which can be seen morpho-logically as an aberrant crypt. Aberrant crypts, which areconsidered preneoplastic structures, are enlarged and elevatedrelative to normal crypts, and have a serpentine growth pat-0022-3166/00 $3.00 © 2000 American Society for Nutritional Sciences.410SPROBIOTICS AND COLON CANCER411Stern. Aberrant crypts may occur singly or as groups of aberrantcrypts within a single focus. A certain small but unknownfraction of these aberrant crypts will progress to polyps andeventually to tumors.Because factors involved in initiation and postinitiationsteps might be separated in time from actual tumor develop-ment, it is difﬁcult to choose “outcomes” or “endpoints” thatare deﬁnitive indicators of efﬁcacy of a given treatment such asprobiotics. In many animal and human studies of colon cancer,investigators have measured how diets or treatments affectpredisposing factors, such as increases in enzyme activities thatactivate carcinogens, increase procarcinogenic chemicalswithin the colon or alter populations of certain bacterialgenera or species. A number of studies have now shown thatthese predisposing factors are altered favorably by consump-tion of certain probiotics or prebiotics. However, these studiesdo not demonstrate a causal relationship to development ofcolon cancer and are at best circumstantial. Studies that doexplore the cause-effect relationship directly are, by necessity,animal studies. In this review, we have conﬁned our discussionto animal studies from the last 10 years that have examinedmost directly the relationship between pre- and probioticconsumption and colon cancer development. We will notehuman studies that provide support for the conclusions drawnfrom the animal studies. To present the conclusion ﬁrst, itappears from these studies that probiotics with or withoutprebiotics have an inhibitory effect on the development ofaberrant crypts (precancerous lesions) and tumors in animalmodels. The effect is not completely consistent and is small insome studies, but this likely represents a dose effect.Animal and human studiesEarly studies examined the effects of milk fermented withlactobacilli andCandidaon tumor formation (Takano et al.1985). The investigators found that colon tumorigenesis in-duced by 1,2 dimethylhydrazine (DMH) was reduced in ratsgiven the fermented milk. Shackleford et al. (1983) studiedthe effects of milk fermented byStreptococcus thermophilusorLactobacillus bulgaricuson DMH-induced colon tumors. Sur-vival rate was greater in rats fed the fermented milk, butnumbers of colon tumors were not different among the controlskim milk group, the group givenS. thermophilus–fermentedmilk and the group givenL. bulgaricus–fermentedmilk. Ab-delali et al. (1995) studied aberrant crypt (AC) formation inrats fed skim milk, skim milk fermented withBiﬁdobacteriumsp.Bio,and the same bacteria incorporated into the diet. Thetest diets reduced the incidence of AC by 50%. There wasno difference in cecal pH, but the groups consuming thebiﬁdobacteria had decreased cecal -glucuronidase activity.Tsuda et al. (1998) actually studied the inﬂuence of lactoferrinon azoyxymethane-induced aberrant crypts, but usedBiﬁdobac-terium longum(3% of diet) as a positive control in their studies.Both lactoferrin andB. longumreduced aberrant crypt foci(ACF).Koo and Rao (1991) reported that administration of bothbiﬁdobacteria (B.pseudolongum)and 5% neosugar [fructooli-gosaccharide (FOS)] to female mice given DMH resulted in50% as many AC as in control animals at 18 and 38 wk.There were also decreased numbers of ACF at 18 and 38 wkafter DMH injection. Biﬁdobacteria in feces were measured at38 wk only; the numbers of biﬁdobacteria were slightly butsigniﬁcantly elevated (8.85 0.2 vs. 9.45 0.19) over con-trols in mice fed the treatment. The decrease in aberrantcrypts was a positive effect on the mouse host; however,several key pieces of data would have been useful. The groupsof mice were as follows: controls given the AIN-76 deﬁneddiet, mice fed DMH only and the same diet, and those givenDMHbiﬁdobacterianeosugar and the same diet. Thedesign does not allow the effects of biﬁdobacteria alone orneosugar alone to be determined. Although the differences innumbers of fecal biﬁdobacteria at wk 38 were signiﬁcant, ourexperience has been that changes in numbers of biﬁdobacteriaof less than 1 log-fold usually do not reach signiﬁcance, evenwith 15–20 animals/group. Another indicator of these smallchanges in numbers of biﬁdobacteria in relation to othergenera might be changes in the short-chain fatty acid (SCFA)proﬁle. In this study, acetic acid in the cecal contents was notsigniﬁcantly different between the DMH and DMHbi-ﬁdobacteria neosugar groups. Acetic acid and lactic acid areproduced by biﬁdobacteria, whereas butyrate and propionateare not produced; one might expect an increase in acetic acidif numbers of bacteria producing them increase signiﬁcantly. Itis important to remember, however, that concentrations ofSCFA represent both production and utilization. The inves-tigators did measure a host outcome (AC) that has beenaccepted as a predictor of the development of colon tumors.The question that remained at the closure of this study iswhether the small changes in biﬁdobacteria due to the treat-ment are responsible for the decrease in lesion formation orwhether some other factor, such as changes in other SCFA orinhibitory substances or even other groups of bacteria, playeda role.A series of studies examining the inﬂuence of biﬁdobacteriaand/or FOS and inulin on aberrant crypts or tumors waspresented 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-ami-no-3-methylimidazo[4,5-f]quinoline, a food mutagen. Bothmale and female rats were fed a high fat diet (AIN-76), withor without the mutagen and with or without the addition ofB.longumfor 58 wk. The diets were mixed weekly and kept inair-tight plastic containers. TheB. longumwas lyophilized in acryoprotectant solution containing glutamate and sucrose.The authors state that each gram of lyophilized material con-tained 2 1010live bacterial cells, but it is not clear whetherthis measurement was taken at the time of lyophilization orthe time of feeding or both. There were differences betweenmale and female rats in incidence of colon tumors. Females didnot develop colon tumors on either the diet mutagen or dietmutagen lyophilized culture. Males fed the control dietthe mutagen developed 23 tumors, whereas males fed the samediet mutagen the lyophilized culture did not develop anytumors. This study found more tumor development in liver inboth sexes than in colon, suggesting that this particular mu-tagen is not a potent inducer of colon tumors. No measure-ments of viable biﬁdobacteria in the feces or intestinal con-tents were reported for any of the groups. Similarly, therelationship between viable biﬁdobacteria and feeding of thelyophilizedB. longumis not clear, nor is the relationshipbetween live biﬁdobacteria in the colon and the presence orabsence of tumors because the biﬁdobacteria were not mea-sured.Kulkarni and Reddy (1994) induced colonic aberrant cryptsin male F344 rats by azoxymethane (AOM) treatment. At 5wk of age, groups of rats were fed either the AIN-76 diet orAIN-76 1.5 or 3.0% of lyophilized culture of biﬁdobacteriaas described above. At 10 wk of age, the rats were given theAOM injection. Six weeks later, rats were killed and AC inthe colons determined. The consumption of the lyophilizedcultures inhibited the development of AC in the colon by50%; fecal -glucuronidase was also decreased in feces of ratsDownloaded from jn.nutrition.org by guest on January 22, 2015412SSUPPLEMENTfed the cultures. Again, fecal biﬁdobacteria were not measuredin the study, and it is impossible to draw conclusions about therelationship of numbers of viable biﬁdobacteria and the out-come measured (in this case, AC). In addition, the effect ofthe addition of lyophilized culture was not linear; 1.5% wasequally as effective as 3.0% addition to the diet. This is notsurprising, considering that the absolute numbers of biﬁdobac-teria in the two groups differed by a small factor. The mea-surement of -glucuronidase represents an indirect indicator ofrisk because it is not clear which bacteria produce it andwhether 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 aspart of the AIN-76 diet to male F334 rats that were givenAOM in a design similar to the one reported above. The ratswere killed 7 wk after the last dose of AOM. Total numbers ofAC per colon were signiﬁcantly less (120 28 for control; 9228 for oligofructose; 7837 for inulin) in rats thatconsumed these prebiotics at 10% of the diet. No bacterialcultures of feces or colon contents were reported, but theauthors cited the data of other studies, which reported thatthese prebiotics increase biﬁdobacteria and decrease other lessdesirable organisms. Again, based on our own observations,the effect of these prebiotics in rats (numbers of biﬁdobacteriaand clostridia or AC) is not consistent; thus, measurement ofthe change in bacteria is critical in drawing conclusions aboutthe relationship between bacteria and aberrant crypt forma-tion. Oligofructose or inulin fed at 10% of the diet is a highamount of dietary ﬁber intake of a speciﬁc type for rats; itwould be interesting to determine whether other dietary ﬁbersat this level have similar effects or whether the effect is speciﬁcfor these two oligosaccharides. The authors refer in detail toother studies that note changes in bacteria numbers and pro-duction of SCFA, such as lactic acid and butyric acid. Theyrefer to studies in which the feeding of oligosaccharides in-creases butyrate levels in the colon as a positive outcomebecause butyrate has been associated with apoptosis and de-creased cellular proliferation. However, increased butyrateconcentration is not directly consistent with increasing num-bers of biﬁdobacteria and displacement of less desirable organ-isms such as clostridia because biﬁdobacteria do not producebutyrate, whereas clostridia do produce it.Reddy (1998) reviewed the various studies from his group.In addition to the data cited above, he presented data showingthat the colonic labeling index, ornithine decarboxylase ac-tivity, and ras-p21 oncogene activity were decreased in rats fedthe lyophilized cultures ofB. longum.These measures arethought to reﬂect cell proliferation, and correlation with ACnumbers is not surprising. However, these indices are notnecessarily indicative of a cause-effect in terms of AC or tumorformation because relatively few AC progress to tumors and wedo not understand completely the factors that inﬂuence tumorformation.Our own studies in male Wistar rats have not been consis-tent in terms of increases in numbers of biﬁdobacteria, de-creases in clostridia, or AC formation in response to feeding ofbiﬁdobacteria or FOS (Gallaher et al. 1996). We used DMH asthe carcinogen and measured the ability of probiotics and FOSto inhibit AC formation in the postinitiation phase. In ourﬁrst experiment of the series, we gavaged 109biﬁdobacteria perday and fed 2% FOS (Gallaher et al. 1996). Feeding biﬁdobac-teriaFOS inhibited AC formation in this experiment byalmost 50%, but there was not an inverse correlation of ACwith the numbers of cecal biﬁdobacteria, nor was there anycorrelation with numbers of cecalClostridium perfringens.In asecond experiment, we used a saline-gavaged control group, amilk-gavaged control group, a group gavaged with milkbiﬁdobacteria, a group gavaged with milk FOS, and a groupgavaged with milk both biﬁdobacteria and FOS. We foundno differences in AC with any treatment and no correlationswith cecal bacteria. In a third experiment, we repeated thesecond study. We found marginal decreases of ACF in the ratsgavaged with biﬁdobacteria FOS compared with control ratsgavaged with skim milk. ACF numbers did not correlate withnumbers of fecal biﬁdobacteria orC. perfringens.In anotherexperiment, we changed this design to include the following:control (rats gavaged with skim milk), rats gavaged with skimmilk FOS, rats gavaged with skim milk biﬁdobacteriaFOS, rats gavaged withLactobacillus acidophilusFOS, and agroup that was gavaged withL. acidophilus,biﬁdobacteria andFOS. We found no differences in AC numbers, but in thiscase, did ﬁnd decreased numbers of fecal clostridia in the ratsthat received biﬁdobacteria-FOS,L. acidophilus-FOS,or bi-ﬁdobacteriaL. acidophilusFOS. We found no consistentcorrelation of bacterial numbers with AC, nor did we ﬁndeffects of biﬁdobacteria or FOS on AC formation. Last, weexamined the effects of various oligosaccharides consumed inthe diet biﬁdobacteria. We found that the group of rats fedFOS and biﬁdobacteria did have signiﬁcantly decreased AC,but AC did not correlate with changes in biﬁdobacteria orclostridia. When data from all experiments were plotted as therelationship between biﬁdobacteria and clostridia, we did seean inverse relationship of biﬁdobacteria with clostridia. Wewere careful to provide for the consistent consumption ofnumbers of viable bacteria that the rats received each day. Wegavaged live cultures that were made up fresh daily and assayedfor viability randomly during the experiment from the samemix 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 thereason for differences in effects observed. However, we feltthat this level was reasonable in terms of amounts consumed.Our conclusion was that biﬁdobacteria FOS had some slighteffect on AC numbers in rat colon, but this effect was not duedirectly to numbers of culturable biﬁdobacteria in the colon.Challa et al. (1997) examined AOM-induced AC in ratsconsumingB. longumlactulose. BothB. longumand lactu-lose singly and together reduced ACF formation. The authorsconcluded that the effect ofB. longumand lactulose wasadditive, but numbers of biﬁdobacteria in gut contents werenot measured. This makes it difﬁcult to ascribe the resultsdirectly to changes in colonic biﬁdobacteria.Rowland et al. (1998) found that consumption of bi-ﬁdobacteria or inulin or both together inhibited AOM-in-duced small ACF. These treatments were also associated withdecreased -glucuronidase activity and ammonia concentra-tion in cecal contents of rats. -Glucosidase and cecal weightwere increased with these treatments. There was no measure ofnumbers of biﬁdobacteria in the colon or the feces in thisstudy. Again, the enzyme measurements suggest that somealteration in bacterial metabolism that is related to the de-creases in ACF has occurred, but do not implicate directly aparticular bacteria or suggest changes in numbers of any groupor changes in metabolite levels.Arimochi et al. (1997) studied the effect of numbers ofintestinal bacteria on AC formation with AOM as the admin-istered carcinogen. They presented very different conclusionsthan those of other investigators about the genera of bacteriathat decrease AC formation. Biﬁdobacteria had no effect,whereas bothL. acidophilusandC. perfringensdecreased ACformation signiﬁcantly. The culture supernatants were foundto mediate the effect, suggesting a metabolite product (theysuggested butyrate produced byC. perfringens).The drinksDownloaded from jn.nutrition.org by guest on January 22, 2015PROBIOTICS AND COLON CANCER413Scontaining bacterial cultures were prepared freshly each day,but there is no indication of how much the rats drank of eachsolution, even though similar numbers of each bacteria wereadded to the drinks. It is possible that bacteria exhibiteddifferential survival in the bottles before actual consumption.The authors did not ﬁnd that -glucuronidase activity wasaffected byL. acidophilus,even though AC were decreased byL. acidophilus. C. perfringenstreatment also did not increase-glucuronidase activity, as would be expected if this enzymeandC. perfringenswere positively correlated with AC devel-opment; in fact,C. perfringenswas correlated with decreasedAC development.Onoue et al. (1997) studied the effects of inoculating germ-free rats with various combinations of microbiota. Germ-freerats were givenEscherichia coli, Enterococcus faecium,and sev-eral strains ofBacteriodesandClostridiumsp. (gnotobiotic) orfeces from conventional rats. They were then given DMHinjections 3 and 4 wk later and then killed 11 or 34 wk afterthat. Addition of bacteria to germ-free rats increased both theACF with four or more AC and the mean number of AC perfocus. WhenBiﬁdobacterium brevewas added to the deﬁnedinoculation (gnotobiotic) noted above, ACF with four or moreAC per focus and crypt multiplicity were signiﬁcantly lower at11 wk, but not at 34 wk.B. breveaddition did not affect thefecal microﬂora, again making it difﬁcult to attribute thedifferences to changes in numbers of ﬂora.Goldin et al. (1996) studied the effect of dietary fat (20 and5%) and administration ofLactobacillus caseion developmentof tumors in DMH-treated Fischer 344 rats. A lyophilizedpowder of 1011viable cells/g was added at 1% of the diet. Therats consumed 2– 41010organisms/d. At 24 wk, in thehigh fat group fed the lactobacillus before, during and afterDMH injections, colon tumors numbered 24 vs. the DMHcontrol number of 74 (not signiﬁcantly different, but colontumors per tumor-bearing animal were 3.7 vs. 1.7, which wassigniﬁcantly different. There was also a signiﬁcant decrease inpercentage of rats with tumors, from 100% in the control to71% in the rats fed lactobacilli. This study highlights problemswith expression of data, when various measures that are usedto indicate development of precancerous lesions do not cor-relate. The question of the most meaningful expression of dataremains to be answered.The outcomes measured in human studies are more indirectand provide more circumstantial evidence than is offered byanimal studies, but may support or refute data from animalstudies in the host of most interest. Advantages of humanstudies are as follows:1)this is the real population target ofcolon cancer prevention and the information gained fromstudies can be applied more directly (such as efﬁcacy of variousstrains or degree of colonization);2)the variability of thepopulation plays an important role, in contrast to studies usinghomogeneous populations of animals. A few recent studiesillustrate the nature of human studies that have addressedvarious aspects of the relationships among diet, fecal bacteriaand colon cancer risk.Meijer-Severs et al. (1993) compared SCFA concentrationand selected bacteria in controls and patients with familialpolyposis before and after colectomy. Preoperative patientshad bacterial counts similar to those of controls (B.fragilisincontrol: 109; preop, 109; postop, 107; biﬁdobacteria: control,109.5; preop, 109.75; postop, 108.1). After colectomy, numbersof Bacteroides and biﬁdobacteria were decreased comparedwith preop and controls. The ratio of acetic acid to otherSCFA increased, in proportion to decreases in other SCFA.Kanazawa et al. (1996) studied control and high risk pa-tients after treatments for large bowel cancer were completedand the colon appeared normal again. Feces were collectedunder CO2and packed on ice for shipment, but were notactually cultured until 30 h. later. It is unclear whether dietaryintake was determined from only one sample taken on the daybefore the fecal sample, but analysis indicated that patientsconsumed more carbohydrate, soluble ﬁber and calcium thancontrols. Bacterial cultures revealed that the feces of patientscontained more lecithinase-negative clostridia (109.4vs.108.8), more lactobacilli (108.37vs. 106.88) and less yeast (103.32vs. 103.96). pH was signiﬁcantly higher in the patient group, aswas H2S and cresol concentration. One question not addressedby this study concerns the cause-effect timeline; did the dif-ferences reﬂect the cause of the high risk or were they theresult of the cancer?Bouhnik et al. (1996) fed 12.5 g FOS/d to 20 healthyhuman volunteers. A recent paper by the same group foundthat 5 g FOS is necessary to increase numbers of biﬁdobac-teria in humans (Bouhnik et al. 1999). Saccharose was used asthe placebo control. Consuming 12.5 g of FOS led to increasednumbers of fecal biﬁdobacteria within the 12-d feeding periodof FOS (from 107.9to 109.1), but the regimen did not signiﬁ-cantly affect any measures used to indicate risk of colon cancerdevelopment, i.e., total fecal anaerobes, pH, activities of ni-troreductase, azoreductase, and -glucuronidase, bile acids andneutral sterols. In this case, fecal samples were stored at 4°Cfor up to 12 h before analysis. The authors pointed out thepossibility that changes in metabolic parameters might takelonger to occur after the occurrence of increases in fecalbiﬁdobacteria than the 12-d measurements that were deter-mined; alternatively, a much longer sustained feeding periodmight be necessary to see effects. Obviously, these effectswould have to be correlated directly with changes in the colonto be meaningful, whatever the length of the study.Watne et al. (1976) studied fecal neutral and acid steroidsand bacterial ﬂora in patients with polyposis coli and controls.Bacterial ﬂora of patients showed an anaerobe/aerobe ratio of2.7:1 with a relative increase in clostridia and biﬁdobacteriaand decrease in eubacteria and bacteroides. After ileorectos-tomy, clostridia disappeared, along with ruminococcus, pep-tostreptococcus and fusobacteria; eubacteria and lactobacillidecreased and biﬁdobacteria and bacteroides increased. Again,these measures do not imply cause-effect of microbial changeswith tumor risk.Moore et al. (1995) did an epidemiologic study of intestinalﬂoras in population with high risks of colon cancer. The resultswere not supportive of data linking high numbers of biﬁdobac-teria with low risk for colon cancer. Fecal bacteria were com-pared in populations of polyp patients, Japanese-Hawaiians,North American Caucasians, rural native Japanese and ruralnative Africans. The polyp patients and Japanese-Hawaiianswere initially considered the high risk groups. Fifteen bacterialgroups were associated signiﬁcantly with high risk of coloncancer (among these Bacteroides and biﬁdobacteria) and ﬁvewere associated signiﬁcantly with low risk (certain lactobacillispecies andEubacterium aerofaciens).This study does not in-dicate cause-effect, but rather associations between bacteriaand risk of disease.SUMMARYAlthough research exists that links the consumption of pro-biotics and prebiotics with decreased risk of colon cancer, thestudies can be sorted into those that most directly link consump-tion inversely with aberrant crypts or tumor development (animalstudies) and those that tend to provide more circumstantialevidence. We have made the attempt in this paper to reviewDownloaded from jn.nutrition.org by guest on January 22, 2015414SSUPPLEMENTKanazawa, K., Konishi, F., Mitsuoka, T., Terada, A., Itoh, K., Narushima, S.,Kumemura, M. & Kimura, H. (1996) Factors inﬂuencing the development ofsigmoid colon cancer. Cancer 77: 1701–1706.Koo, M. & Rao, A. (1991) Long-term effect ofBiﬁdobacteriaand neosugar onprecursor lesions of colonic cancer in CF1 mice. Nutr. Cancer 16: 249 –257.Kulkarni, N. & Reddy, B. (1994) Inhibitory effect ofBiﬁdobacterium longumcultures on the azoxymethane-induced aberrant crypt foci formation and fecalbacterial -glucuronidase. Proc. Soc. Exp. Biol. Med. 207: 278 –283.Meijer-Severs, G., Cats, A., Vershueren, C., Van Santen, E. & Kleibeuker, J.(1993) Anaerobes and their fermentation products in feces of patients withfamilial adenomatous polyposis before and after subtotal colectomy andileorectal anastomosis. Eur. J. Clin. Investig. 23: 356 –360.Moore, W. E. & Moore, L. H. (1995) Intestinal ﬂoras of populations that have ahigh risk of colon cancer. Appl. Environ. Microbiol. 61: 3202–3207.Onoue, M., Kado, S., Sakaitani, Y., Uchida, K. & Morotomi, M. (1997) Speciﬁcspecies of intestinal bacteria inﬂuence the induction of aberrant crypt foci by1,2 dimethylhydrazine in rats. Cancer Lett. 113: 179 –186.Reddy, B. (1998) Prevention of colon cancer by pre- and probiotics: evidencefrom laboratory studies. Br. J. Nutr. 80: S219 –S223.Reddy, B., Hamid, R. & Rao, C. (1997) Effect of dietary oligofructose and inulinon colonic preneoplastic aberrant crypt formation. Carcinogenesis 18: 1371–1374.Reddy, B. & Rivenson, A. (1993) Inhibitory effect ofBiﬁdobacterium longumoncolon, mammary, and liver carcinogenesis induced by 2-amino-3-methylimi-dazo[4,5-f]quinoline, a food mutagen. Cancer Res. 53: 3914 –3918.Rowland, I. R., Rumney, C. J., Coutts, J. T. & Lievense, L. C. (1998) Effect ofbiﬁdobacterium longum and inulin on gut bacterial metabolism and carcino-gen-induced aberrant crypt foci in rats. Carcinogenesis 19: 281–285.Shackelford, L., Rao, D., Chawan, C. & Rulusani, S. (1983) Effect of feedingfermented milk on the incidence of chemically induced colon tumors in rats.Nutr. Cancer 5: 159 –164.Takano, T., Arai, K., Murota, I., Hayakawa, K., Mizutani, T. & Mitsuoka, T. (1985)Effects of feeding sour milk on longevity and tumorigenesis in mice and rats.Biﬁd. Microﬂora 4: 31–37.Tsuda, H., Sekine, K., Nakamura, J., Ushida, Y., Kuhara, T., Takasuka, N., Kim.,D., Asamoto, M., Baba-Toriyama, H., Moore, M., Nishino, H. & Kakizoe, T.(1998) Inhibition of azoxymethane initiated colon tumor and aberrant cryptfoci development by bovine lactoferrin administration in F344 rats. In: Ad-vances in Lactoferrin Research (Spik et al., eds.). Plenum Press, New York,NY.Watne, A., Lai, H., Mance, T. & Core, S. (1976) Fecal steroids and bacterialﬂora in patients with polyposis coli. Am. J. Surg. 131: 42– 46.Wingo, P., Ries, L., Giovino, G., Miller, D., Rosenbergy, H., Shoplad, D., Thun, M.& Edwards, B. (1999) Annual report to the nation on the status of cancer,1973–1996. J. Natl. Cancer Inst. (in press).critically those animal studies that we feel provide some directmeasure of cause and effect. In the case of human studies, we havereviewed those that link bacteria and colon cancer. The obviousassumption in the human data is that humans would react simi-larly to the animals in all respects.The major conclusion from the animal data is that thereappears to be a synergistic effect of consumption of probioticbacteria and prebiotics such as fructooligosaccharides on theattenuation of the development of colon cancer. The effect isoften not large, but it is possible that it could be beneﬁcial, incombination with other ways to reduce risk. The data also pointthe way to the opportunities for further investigation, particularlyin deﬁning and measuring outcomes/end points in humans thatare meaningful and that correlate the consumption of pro- andprebiotics with decreased risk of colon cancer development.LITERATURE CITEDAbdelali, H., Cassand, P., Soussotte, V., Daubeze, M., Bouley, C. & Narbonne, J.(1995) Effect of dairy products on initiation of precursor lesions of coloncancer in rats. Nutr. Cancer 24: 121–132.Arimochi, H., Kinouchi, T., Kataoka, K., Kuwahara, T. & Ohnishi, Y. (1997)Effect of intestinal bacteria on formation of azoxymethane-induced aberrantcrypt foci in the rat colon. Biochem. Biophys. Res. Commun. 238: 753–757.Bouhnik, Y., Flourie, B., Riottot, M., Bisetti, N., Gailing, M., Guibert, A., Bornet, F.& Rambaud, J. (1996) Effects of fructo-oligosaccharides ingestion on fecalbiﬁdobacteria and selected metabolic indexes of colon carcinogenesis inhealthy humans. Nutr. Cancer 26: 21–29.Bouhnik, Y., Vahedi, K., Achour, L., Attar, A., Salfati, J., Pochart, P., Marteau, P.,Flourie, B., Bornet, F. & Rambaud, J. (1999) Short-chain fructo-oligosac-charide administration dose-dependently increases fecal biﬁdobacteria inhealthy humans. J. Nutr. 129: 113–116.Challa, A., Rao, D., Chawan, C. & Shackleford, L. (1997)Biﬁdobacteriumlongumand lactulose suppress azoxymethane-induced colonic aberrantcrypt foci in rats. Carcinogenesis 18: 517–521.Gallaher, D., Stallings, W., Blessing, L., Busta, F. & Brady, L. (1996) Probiotics,cecal microﬂora, and aberrant crypts in the rat colon. J. Nutr. 126: 1362–1371.Gibson, G. & Roberfroid, M. (1995) Dietary modulation of the human colonicmicrobiota: introducing the concept of prebiotics. J. Nutr. 125: 1401–1412.Goldin, B., Gualtieri, L. & Moore, R. (1996) The effect ofLactobacillusGG onthe initiation and promotion of DMH-induced intestinal tumors in the rat. Nutr.Cancer 25: 197–204.Downloaded from jn.nutrition.org by guest on January 22, 2015 [ Pobierz całość w formacie PDF ]

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