Research Overview

Gut Microbiota and Probiotics: Current Status and TheirRole in Cancer Therapeutics

Abdul Arif Khan,1* Mohsin Khurshid,1 Shahanavaj Khan,1 and Aws Alshamsan1,2

1Nanomedicine Research Unit, Department of Pharmaceutics, College of Pharmacy, King SaudUniversity, PO Box 2457, Riyadh 11451, Saudi Arabia

2Prince Salman Bin Abdulaziz Chair for Kidney Disease, King Saud University, Riyadh 11451,Saudi Arabia

Strategy, Management and Health Policy

EnablingTechnology,Genomics,Proteomics

PreclinicalResearch

Preclinical DevelopmentToxicology, FormulationDrug Delivery,Pharmacokinetics

Clinical DevelopmentPhases I-IIIRegulatory, Quality,Manufacturing

PostmarketingPhase IV

ABSTRACT The microbiome is a collection of all microbial species that coexist with an individual. Theseorganisms influence several aspects of individual body functions. Probiotic organisms are generallybeneficial components of microflora and confer normal health status. Usually, probiotics should beprovided from the outside in the diet for maintaining proper health status. Probiotics can also havea significant impact on cancer management. While the results toward cancer management withprobiotics are promising, careful risk assessment of probiotics use in cancer patients, who are usuallyimmunocompromised due to radical therapy, comes as a great demand. This article provides an overviewof the current research status of probiotics use in cancer patients and discusses the role of probiotics incancer management. Drug Dev Res 74 : 365–375, 2013. © 2013 Wiley Periodicals, Inc.

Key words: probiotics; cancer; normal microflora; cancer management

INTRODUCTION

The term probiotic is derived from the Greekword “pro” indicating “promote” and “biotic” represent-ing “life.” Probiotics are generally defined as “livingmicro-organisms which upon ingestion in certainnumbers exert health benefits beyond inherent generalnutrition” [Rafter, 2004]. In 1907, the Russian Nobellaureate, Metchnikoff introduced the concept ofprobiotics and suggested that ingesting microflora couldbe beneficial for humans especially for the treatment ofgastrointestinal (GI) diseases. Lilly and Stillwell [1965]were the first to use the term probiotics for the descrip-tion of substances secreted by one organism that stimu-late the growth of another organism. There are anumber of disparities in describing probiotics. TheFood and Agriculture Organization (FAO) of theUnited Nations defines these as “live microorganisms,which, when administered in adequate amounts, confera health benefit on the host by improving its microbial

balance” [FAO/WHO, 2001; Reid et al., 2003]. A vastnumber of microbiota are closely associated withvarious parts of the human body including skin, mouth,and the GI tract. The microbiota comprises mainly bac-teria; however, viruses, fungi, and protozoans are alsopresent [Lederberg, 2000]. Probiotics can create ahelpful impact on the host by improving the endog-enous microflora, and they are often used as drugs asthey can confer potential health benefits through theprevention and treatment of specific pathological con-ditions or can reduce the risk of disease [Rolfe, 2000;

*Correspondence to: Abdul Arif Khan, NanomedicineResearch Unit, Department of Pharmaceutics, College ofPharmacy, King Saud University, PO Box 2457, Riyadh 11451,Saudi Arabia.E-mail: abdularifkhan@gmail.com

Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ddr.21087

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Gionchetti et al., 2003; Shanahan, 2005; Kumar et al.,2010]. Probiotics can also alter microbial componentswith known beneficial and advantageous functions forthe human host [Preidis and Versalovic, 2009]. As theirhealth potential is enormous, they are currently thesubject of many studies. This article discusses gutmicrobiota and probiotics, and their potential role incancer management.

GUT MICROFLORA AND PROBIOTICS

The normal gut microflora controls severalaspects of bodily function including the developmentof certain types of cancer [Khan et al., 2012]. Gener-ally, probiotics are bacteria similar to those naturallyinhabiting the human gut particularly those ofbreastfed infants that have been shown to have naturalprotection against several infections and diseases. Nor-mally, high numbers of Lactobacilli are observed inthe infant intestine, but they rapidly decline afterinfancy [Balamurugan et al., 2008]. Another commongut bacterium, Bifidobacteria, is a Gram-positive,nonmotile, nonsporulating rod-shaped bacteria withvarying appearance. The majority of strains are strictlyanaerobic. They comprise the main part of the humannormal gut microflora and appear in the stool a fewdays after birth and subsequently rise in number[Matto et al., 2004]. The colons of young childrencontain high numbers of Bifidobacteria, which arereduced significantly with age [Balamurugan et al.,2008].

Different types of probiotic bacteria are presentin the gut and convey varying health benefits to theintestine. Probiotics must be ingested regularly for anyhealth-promoting activity to persist. It is possible tomanipulate (at least temporarily) the composition of theintestinal microflora through dietary supplementationwith probiotics. An ideal probiotic should possess mostof the following characteristics: the ability to adhere tocells, persist, multiply, and produce hydrogen peroxide,acids, bacteriocins against pathogenic growth, be ofsafe, noninvasive, noncarcinogenic, nonpathogenicnature, and co-aggregate to form a normal balancedflora [Harmsen et al., 2000; Kaur et al., 2002; Lee et al.,2007; Borchers et al., 2009].

Probiotic bacteria have significant effects on gutmicroflora, thus modulation of gut microflora throughprobiotics has been used as a therapeutic strategy formany clinical conditions. In a randomized, double-blind, placebo-controlled, two-period crossover studyon 38 healthy male subjects, a daily dose of probioticbacteria including L. rhamnosus LC705 (LC705) andPropionibacterium freudenreichii ssp. shermanii JS(PJS) was given for 4 weeks. The administration of

LC705 and PJS was followed by evaluation of harmfulbacterial carcinogenic enzymes. Administration ofthese probiotics significantly raised fecal counts ofLactobacilli and Propionibacteria and decreased theactivity of β-glucosidase with increasing counts ofPropionibacteria. This intervention also reducedcolorectal proliferation in the patients [Hatakkaet al., 2008]. In a 12-week clinical trial [Rafter et al.,2007], polypectomized patients were treated withLactobacillus rhamnosus GG (LGG) and B. lactis Bb12(BB12) and oligofructose-enriched inulin. The treat-ment resulted in considerable alterations in fecalmicroflora of the patients as the level of Lactobacillusand Bifidobacterium increased and Clostridiumperfringens decreased. In a recent study, probiotic bac-teria were given perioperatively to 31 patients withcolorectal carcinoma (CRC) and evaluated for theiradherence to the colonic mucosa, reduction of patho-gen concentration in stool, and modulation of the localimmune function. The La1 strain of Lactobacillijohnsonii affected intestinal microbiota by decreasingpathogen concentration and changing the immuneresponse of intestine [Gianotti et al., 2010]. These arejust a few examples of how probiotics can play a crucialrole in modulation of gut microflora and how they canbe used as therapeutic agents for the management ofseveral conditions including cancer.

PROBIOTICS AS THERAPEUTIC AGENTS

Incomplete absorption of lactose results in flatu-lence, bloating, abdominal cramps, and moderate-to-severe (watery) diarrhea. This occurs in a large numberof patients and increases especially with age due to adecrease in lactase (β-galactosidase) in the intestinalbrush border mucosa. Several studies have demon-strated the production of lactase during the fermenta-tive process used in the production of yogurt, which canexert its influence in the intestinal tract [de Vrese et al.,2001]. Streptococcus salivarius subsp. thermophilusand Lactobacillus bulgaricus are the commonly usedorganisms in the production of yogurt [Goldin andGorbach, 2008]. In lactose-intolerant individuals,yogurt feeding led to a marked reduction in breathhydrogen levels compared to subjects fed milk. Breathhydrogen level is indicative of the degree of lactosemetabolism in the large bowel. A decrease of 67%hydrogen in the breath was noted after ingestion of 18 gof lactose in yogurt as compared with that produced bya similar dose of lactose delivered in milk. Further,significant levels of lactase were found in aspiratesobtained from the duodenum 1 h after the yogurt con-sumption. These studies support the practical approachfor treatment of lactose malabsorption via lactase

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delivery to the intestine using lactase-producingprobiotics [Goldin and Gorbach, 2008].

The use of probiotics to either treat or preventacute diarrhea has also been reported in studies, themajority of which were done with infants or children.The probiotic Lactobacillus rhamnosus strain GG(Lactobacillus GG ATCC 53103) was used to treat diar-rhea while the etiological agent was either rotavirusor unknown. Lactobacillus reuteri and Saccharomycesboulardii were also helpful for the treatment of acutegastroenteritis [Goldin and Gorbach, 2008].

Antibiotic-associated diarrhea occurs in up to 39%of antibiotic-treated hospitalized patients [Hickson,2011]. A number of studies have proven the ability ofprobiotics to reduce the frequently observed intestinaladverse effects and diarrhea associated with the clinicaluse of antibiotics [Marchand and Vandenplas, 2000;McFarland, 2010]. Moreover, probiotics are alsohelpful in the management of Clostridium difficileassociated diarrhea (CDAD). The pathophysiology ofCDAD is not completely clear, however, the risk factorsinclude elderly age, renal disease and continued antibi-otic therapy. The role of probiotics has been partiallyappraised in the prevention of CDAD. Early uncon-trolled trials and a further report of a controlled trialusing Lactobacillus GG suggested some benefit ofprobiotic in recurrent CDAD [Limdi et al., 2006].

Clinical studies have demonstrated a considerablerole for bacteria in the pathogenesis of inflammatorybowel disease (IBD). Antimicrobial therapies have ledto an improvement in Crohn’s disease, and have alsoreduced fistula-related complications, postoperativepouchitis and postoperative relapse. Plymorphisms inthe CARD15/NOD2 gene, an intracellular bacterialpattern recognition receptor, are of interest as riskfactors for the development of Crohn’s disease [Limdiet al., 2006]. Thus, probiotics can help to modulatethe gut microbiota and may exert possible benefits inIBD management. Improved intestinal permeability,increased mucosal IgA levels, and reduced diseaseactivity were noted after administration of LactobacillusGG to children with Crohn’s disease [Gupta et al.,2000; Limdi et al., 2006]. In addition, modification ofallergic reactions for atopic eczema with probioticLactobacillus GG has also been studied extensively[Kalliomaki et al., 2001, 2003]. There has also been astudy that reported the use of Bifidobacterium animalisBb12 to reduce the severity of atopic dermatitis[Isolauri et al., 2000]. In one study, either LactobacillusGG capsules or a placebo were given to pregnantwomen with a family history of atopic disease for 2–4weeks before their expected delivery date [Kalliomakiet al., 2001]. The newborn infants were fed withLactobacillus GG directly or it was given to the

breastfeeding mothers. The reduction rate in the fre-quency of atopic eczema was 50% during the first twoyears of the children’s lives for the group givenLactobacillus GG [Kalliomaki et al., 2001]. The role ofprobiotics in reducing dental caries is also evident inmany studies. During a randomized, double-blind,placebo-controlled study at a day care center, childrenwho were fed with milk for 7 months with or withoutLactobacillus GG were examined for dental caries andbacterial counts. A reduced oral count of Streptococcusmutans and considerably lower rates of dental carieswere observed in the 3–4 year-old children from theLactobacillus GG group [Nase et al., 2001].

Probiotics also play a role in the removal of nasalpathogens. In a study with 209 volunteers, the effect ofprobiotics on nasal bacterial flora was observed. Elimi-nation of pathogenic bacteria from the nasal cavity wasobserved in those subjects who consumed a fermentedmilk product containing probiotics as compared tothose who consumed a yogurt drink. The potentiallypathogenic bacteria removed from the nasal cavityincluded Streptococcus pneumoniae, β-hemolyticstreptococci and Staphylococcus aureus. These findingsindicate a linkage between lymphoid tissue of the intes-tine and the upper respiratory tract and signify thepotential role of probiotics in the reduction of thepathogenic bacterial load from the upper respiratorytract [Gluck and Gebbers, 2003]. From all of theseexamples, it can be concluded that the potential thera-peutic applications of probiotics are enormous, theyhave the capability to alter microflora, and they can alsobring beneficial changes to the body which can help tomanage healthy condition. Figure 1 shows an exampleof the roles of a probiotics can play in regards to severalclinical conditions. The next section of this article spe-cifically focuses on the role of probiotics in the man-agement of cancer.

IMPLICATION OF PROBIOTICS INCANCER THERAPEUTICS

Cancer is a serious public health issue with consid-erable negative impact on human health. It is a signifi-cant factor of mortality and morbidity rates witha total of 1.6 million new cases and approximately600 000 deaths projected to occur in the US in 2012[Siegel et al., 2012]. The beneficial effects of probioticson cancer were recently reviewed by Kumar et al.[2010]. Probiotics can exert their anticancer effectsthrough modulation of microbiome composition, main-tenance of gut lumen epithelial barrier function, andsystemic and mucosal immunomodulation [Khan et al.,2012; Kumar et al., 2013]. The following sections discussthe role of probiotics in different types of cancer.

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Role in Colon Cancer

Probiotics have substantial health benefits whichare not limited to anticancer activity. The colon har-bours several different microbiome constituents includ-ing both beneficial and harmful bacteria and therelative contribution of both types of organisms deter-mines gut health status; however ingestion of probioticscan help to increase beneficial bacteria [Isolauri et al.,2002]. These bacteria influence carcinogenic processesthrough different mechanisms, and different bacterialstrains have different mechanisms for their anticancereffects [Rafter, 2003]. A recent cohort study conductedover 12 years of follow-up on 45 241 volunteers foundthat intake of high yogurt was significantly linked withdecreased CRC risk, suggesting that administration oflong-term probiotics formulations can decrease theincidence of CRC [Pala et al., 2011]. Table 1 providesdetail about the role of probiotics in colon cancer.

Role in Breast Cancer

Probiotics play an important role in the preven-tion and healing of breast cancer as shown in animals[Soltan Dallal et al., 2012; Yazdi et al., 2012] and in vitrostudies [Biffi et al., 1997]. It has been suggested thatdaily consumption of probiotic strain L. casei improvesthe immune response, reduces tumor growth andincreases overall survival [Soltan Dallal et al., 2012]. Ina case control study on breast cancer, consumption ofyoghurt was negatively associated with breast cancerrisk [Le et al., 1986]. Another study showed that

L. plantarum enriched with selenium nanoparticlesincreased production of the proinflammatory cytokinesIFN-γ, TNF-α, and IL-2 and natural killer cell activity[Yazdi et al., 2012]. Thus probiotics-mediated immunemodulation control breast cancer through regulation ofthese cytokines (Table 2).

Role in Bladder Cancer

Probiotics can also influence urinary tract infec-tions, calcium oxalate stone disease and experimentallyinduced bladder tumors. Oral administration of lacticacid bacteria can be effective against bladder cancer[Fischer and Altwein, 2007]. Bacillus Calmette–Guerinimmunotherapy has been used for a long time toprevent recurrence of superficial bladder cancer, andthis treatment strategy also suggests promise for the useof other bacterial strains in the management of bladdercancer [Borchert et al., 2008]. An epidemiological studyalso supports habitual intake of lactic acid bacteria toreduce bladder cancer risk [Ohashi et al., 2002]. Addi-tionally, animal studies also demonstrated potentialbladder tumor inhibitory effects of probiotics [Asanoet al., 1986]. Table 2 provides details on studies relatedto the role of probiotics in bladder cancer.

Other Cancer-Related Aspects

Although research for the evaluation of probioticsrole in cancer prevention is in its infancy, we can specu-late on the basis of our current knowledge that it is not

Fig. 1. Application of the probiotic lactic acid bacilli (LAB) to various medical conditions. 1[Gluck and Gebbers 2003]; 2[Hatakka et al. 2001];3[Kalliomaki et al. 2001; Kalliomaki et al. 2003; Rautava et al. 2002];[Nase et al. 2001]; 5[Goldin and Gorbach 2008]; 6[Brigidi et al. 2001;Guslandi et al. 2000]; 7[Allen et al. 2004; Limdi et al. 2006; Szajewska et al. 2001]; 8[Armuzzi et al. 2001; Cremonini et al. 2002]; 9[Goldin andGorbach 2008; Hilton et al. 1997]. [Color figure can be viewed in the online issue which is available at wileyonlinelibrary.com]

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TABLE 1. Some Studies Related to Probiotics Application in Colon Cancer

No. Probiotic organisms Study type Study results References

1 Lactobacillus acidophilusL. gasseri (P79)L. confuses (DSM20196)Streptococcus thermophilus

(NCIM 50083)Bifidobacterium breveB. longum (from human infant

stool)

Oral administration of bacteria in rats andprevention of N-methyl-N’-nitro-N-nitrosoguanidine (MNNG) induced DNAdamage evaluation using comet assay.

Bacteria were able to prevent MNNGand 1,2-dimethylhydrazine(DMH)-induced genotoxicity.

[Pool-Zobel et al.,1996]

2 Lactobacillus acidophilus (DelvoPro LA-1)

Lactobacillus rhamnosus (GG)Bifidobacterium animalis

(CSCC1941)Streptococcus thermophilus

(DD145)

Freeze-dried bacteria were added to anexperimental diet based on a high-fatsemipurified (AIN-93) rodent diet. Theinfluence of diet was observed in theincidence of rats with large intestinalDMH-induced tumors.

Strain of L. acidophilus supplied asfreeze-dried bacteria in the diet wasprotective, as seen by a small butsignificant inhibition of tumors withinthe rat colon.

[McIntosh et al.,1999]

3 Lactobacillus acidophilusLactobacillus rhamnosus (GG)Bifidobacterium bifidum

Animals belonging to different probioticgroups were given daily Lactobacilli for1 week through oral route, then weeklyinjections of DMH was givenintraperitoneally for 6 weeks consequentwith daily administration of probiotic.

Bifidobacterium bifidum reducedβ-glucosidase activity. Furthermore,L. rhamnosus GG, L. acidophilus alsoreduced DMH-inducedprocarcinogenic fecal enzymes. Itwas suggested that these bacteria canbe used as prophylactic agents forexperimental colon carcinogenesis inSprague Dawley rats

[Verma andShukla, 2013]

4 L. caseiL. rhamnosus

Colon cancer cells (HCT-116) were treatedwith cell-free supernatant from L. casei,L. rhamnosus, or B. thetaiotaomicron (a gutcommensal); or with uninoculatedbacterial growth media.

Lactobacillus sp. reduces colorectal cellinvasion, and some >100 kDa and50–100 kDa macromolecules presentin bacterial cell-free supernatant werefound to be responsible for thisactivity.

[Escamilla et al.,2012]

5 Bifidobacterium longum Consumption of bacterium and Raftiline HP(a derivative of inulin) and its effect onazoxymethane induced colonicaberrant crypt foci (ACF) in rats wasevaluated.

The bacteria -inulin combination wasfound to be a potent inhibitor of ACFin comparison to either alone.Consumption of B. longum isassociated with beneficial changes inphysiology leading to reduced cancerrisk and pre-neoplastic changes.

[Rowland et al.,1998]

6 Bifidobacterium longum Modified AIN-76A diet in male F344 ratswas given with 0 or 2% lyophilizedcultures of B. longum. Simultaneously,carcinogen azoxymethane (AOM) wasadministered, once weekly for 2 weeks.

B. longum significantly reduces AOMinduced cell proliferation, ornithinedecarboxylase activity, and ras-p21oncoprotein expression. Thus, itshowed strong antitumor activity.

[Singh et al.,1997]

7 Bifidobacterium longum Animals were fed with high-fat, semi-purifieddiets containing 0 and 0.5% lyophilizedcultures of B. longum and effectswere evaluated on 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)induced carcinogenesis.

Results indicated that B. longum inhibitsIQ induced colon and liver tumors,and to some extant mammary tumorsin F344 rats.

[Reddy andRivenson,1993]

8 Lactobacillus acidophilus Study involved 11 healthy human subjectswho were given fried beef patties as diettwice daily for 3 days. Additionally,ordinary Lactococcus fermented milk(phase 1) and thereafter with L. acidophilusfermented milk (phase 2) was given asfood supplement, and excretion ofmutagenic activity in urine and feces wasdetermined.

Lactobacillus acidophilus reducedmutagen excretion in human.

[Lidbeck et al.,1992]

9 Consumption of probioticorganisms containing foodproducts (yoghurt)

During this study, the diets of 746 coloncancer patients were compared with thoseof 746 age, sex, race, and neighborhoodmatched controls.

Yoghurt was found protective againstcolon cancer.

[Peters et al.,1992]

10 Probiotic bacteria isolated frominfant feces

Lactic acid bacteria isolated from infant feceswere applied on colon cancer cells andanti-proliferative effects of bacteria wereevaluated through MTT and Trypan Blueexclusion assay.

Out of a total of 81 bacteria isolatedfrom infant feces, four probioticbacteria showed antiproliferationactivity on colon cancer cells.

[ThirabunyanonandHongwittayakorn,2013]

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only limited to the cancers mentioned above. Probioticscan also prevent adverse events associated with cancerchemotherapy. Consumption of Lactobacillus sp.can prevent chemotherapy-associated diarrhea andabdominal discomfort [Osterlund et al., 2007]. Devel-opment of infectious complications due to cancer che-motherapy induced febrile neutropenia (FN) generallycreates life-threatening situations in cancer patients.Clinical studies with probiotic strains as an FN-controlling agent have been conducted [Mego et al.,2006], with no satisfactory results reported. Probioticuse for cancer patients should be strictly regulatedunder immunocompromised conditions [Boyle et al.,2006]. Therefore, both aspects of probiotic therapyneed further research and the development of regula-tions for its practical use in cancer therapeutics.

HOW CAN PROBIOTICS PREVENT CANCER?

Probiotics can exert their anticancer effectsthrough several mechanisms. A variety of studies aredocument of their putative anticancer mechanisms.

Induction of Apoptosis

Bacteria generally induce apoptosis during thecourse of their infection, that can also have an antican-cer role as verified in a study comparing apoptosisinduction activity by gut bacterium Atopobium

minutum, commensal E. coli K-12 strains, probioticsLactobacillus rhamnosus and Bifidobacterium latis andpathogenic E. coli (EPEC and VTEC) within theCaco-2 colon cancer cell line. Probiotic strains showedapoptotic effects via mitochondrial pathways on thecolon cancer cell line [Altonsy et al., 2010]. In addition,Propionibacterium acidipropionici and freudenreichiialso induce apoptosis in CRC cell lines through shortchain fatty acids acting on mitochondria [Jan et al.,2002]. In addition to fatty acids, cell-bound exopoly-saccharides from Lactobacillus acidophilus 606 alsoinduce autophagic cell death in colon cancer cells [Kimet al., 2010]. In a study evaluating the apoptotic induc-ing capacity of 5- fluorouracil (5-FU) in the presence ofprobiotics (Lactobacillus acidophilus and Lactobacilluscasei) a 40% increase in 5-FU apoptosis induction activ-ity was observed [Baldwin et al., 2010]. Although theprecise mechanisms behind the anticancer activitiesremain unclear, current findings clearly support theapoptosis inducing activity of probiotics.

Increase in Immune Cell Activity

Probiotics can regulate several aspects of naturaland acquired immune response [Gill and Prasad, 2008].Probiotic-mediated immunomodulation may have theability to prevent cancer. As an example, Lactobacillusshirota delayed cancer onset via enhanced NK cellcytotoxicity [Takagi et al., 2001]. Inflammation is amajor factor in the development of cancer, with

TABLE 2. Some Studies Related to Probiotic Application in Breast and Bladder Cancer

No. Probiotic organisms Study type Study results References

1 L. acidophilus ATCC4356 Breast tumor was transplanted in BALB/c mice andL. acidophilus ATCC4356 was administeredorally 14 days before and 30 days after tumortransplantation with 3-day intervals.

L. acidophilus ATCC4356improved immune responseby inducing production ofimmunomodulatorycytokine IL-12.

[Yazdi et al.,2010]

2 Lactobacillus helveticusR389 (+) fermented milk

Female BALB/c mice were given singlesubcutaneous injections of tumor cells in the leftmammary gland and fermented milk was givento mice for 2, 5, or 7 consecutive days beforetumor injection. Several factors related to tumordevelopment were monitored for 2 months.

Lactobacillus helveticus R389reduced growth rate ofmammary tumors.

[Rachid et al.,2006]

3 Bifidobacterium infantisBifidobacterium bifidumBifidobacterium animalisLactobacillus acidophilusLactobacillus paracasei

Direct effect of milk fermented by bacterial strainswas evaluated on the MCF7 breast cancer cellline.

All fermented milks showedinhibition of breast cancercell lines, but the B. infantisand L. acidophilus weremost effective.

[Biffi et al.,1997]

4 Lactobacilluscasei + epirubicin

A prospective, randomized, controlled clinical trialwith 207 superficial bladder cancer patientswas performed to evaluate the effect of orallyadministered Lactobacillus casei with intravesicalinstillation of epirubicin on recurrence ofbladder cancer after transurethral resection.

Intravesical instillation ofepirubicin combined withoral administration ofLactobacillus caseisignificantly increased thesurvival rate.

[Naito et al.,2008]

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probiotics acting as immunomodulators to preventIBD and reduce colon cancer risk [Sheil et al., 2007].In a placebo-controlled trial with Lactobacillussalivarius UCC118 this bacteria reduced mucosalinflammatory activity and subsequent colon cancer riskin IL-10-/- mice [O’Mahony et al., 2001]. In a murinebreast cancer model, L. acidophilus altered cytokineproduction resulting in increased lymphocyte proli-feration and reduced tumor growth [Maroof et al.,2012]. Probiotics (Bifidobacterium longum and/orLactobacillus gasseri) also reduce colonic mucosa cellproliferation and increase macrophage stimulation inmice, attributes responsible for the prevention of1,2-dimethylhydrazine-induced colon cancer in mice[Foo et al., 2011].

Bacterial Effects on Intestine andGut Microbiota Dysbiosis

Normal microflora influence aspects of the carci-nogenic process with a shift from a normal to abnormalmicrobiome being a major hallmark in the developmentof certain tumors [Khan et al., 2012]. Probiotic bacteriainhibit some bacterial infection due to colonizationresistance and promote intestinal homeostasis [Lawleyand Walker, 2013]. A probiotic-induced microflora shiftresulted in reduced absorption and increased excretionof the mutagenic and carcinogenic agent, aflatoxin[Gratz et al., 2006]. In vitro and in vivo studiesdemonstrtae that the probiotic itself can bind andprevent the absorption of aflotoxins, thus potentiallypreventing hepatitis and liver cancer in humans[Haskard et al., 2000]. Probiotic bacteria bind to muta-gens and inhibit their carcinogenic activity [Burns andRowland, 2000]. Probiotic organisms can also inhibitbacterial conversion of pro-carcinogens into carcino-gens [Rolfe, 2000].

Reduction of Carcinogens in Intestine

The probiotic metabolome has significant effectson the molecular and cellular processes leading tocancer development [Kumar et al., 2010, 2012]. Thegut microbiota secretes metabolites including organicacids, baceriocins, peptides, and others, which influ-ence aspects of cell differentiation, programmed celldeath, cell proliferation, angiogenesis and cancer devel-opment [Kumar et al., 2013]. Probiotic organisms alsohave the capability to transform toxic compounds in thegut [Cho et al., 2009]. In a study analyzing the effect ofprobiotics in carcinogen-mediated DNA damage,yoghurt reduced genotoxicity [Oberreuther-Moschneret al., 2004]. Lactobacillus delbrueckii ssp. bulgaricus

191R and Streptococcus salivarius ssp. thermophilusCH3, can inactivate carcinogens and prevent DNAdamage and resultant tumors in rat colon [Wollowskiet al., 1999] while Bifidobacterium adolescentisSPM0212 had anticancer activity via reduction ofharmful fecal enzymes, α-glucuronidase, α-glucosidase,tryptophanase, and urease, in three colon cancer celllines (HT-29, SW 480, and Caco-2) [Kim et al., 2008].

CURRENT PROBIOTICS FORMULATIONS ANDTHEIR USE IN CANCER

Although probiotics have been extensively com-mercialized, the market for food products withprobiotics is larger than the probiotics sold in capsules,sachet, and other pharmaceutical forms. Probiotic foodproducts include yoghurt-type drinks, probiotics fruitjuices, berry soups and soy-cereal-based fermentedproducts, and others. [Saxelin, 2008]. Milk-basedprobiotics are widely accepted [Castro et al., 2013] andact as buffering agents and inhibitors of digestiveprotease activity protecting bacteria in the GI tract[Charteris et al., 1998]. Milk sugar also providesnutrients for probiotic organisms. Freeze-dried bacteriaare available as oral formulations, but require pre-servatives to increase their shelf life [Jalali et al., 2012].Most commercial probiotics contain bacteria,Lactobacillus acidophilus, Lactobacillus bulgaricus,Lactobacillus casei, Lactobacillus rhamnosus, Lacto-bacillus plantarum, Lactobacillus salivarius, Lacto-bacillus sporogenes, Bifidobacterium bifidum,Bifidobacteria infantis, Bifidobacteria longum, Strep-tococcus thermophilus, some Homeostatic Soil Organ-isms (HSOs) and also some yeast species, e.g.Saccharomyces boulardii [Ljungh and Wadstrom,2006]. These preparations may be solitary strains orcombinations of up to eight strains. The basic require-ment for multiple-strain preparations is that they areactive against a wide range of animal species and undermultiple conditions. Other species utilized in probioticpreparations are L. helveticus, L. lactis, Enterococcusfaecium, Ent. faecalis, E. coli, and others. These allare intestinal strains except for L. bulgaricus andS. thermophilus, which are considered as yoghurtstarter strains [Angelakis et al., 2011]. A dose of 5 billioncolony forming units (CFU) for a minimum of 5 dayshas been suggested for satisfactory health benefits (5 ×109 CFU/day) [Gupta and Garg, 2009].

CONCLUSION

Animal studies as well as preliminary humanstudies have documented treatment of several diseases

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and conditions with probiotics. Animal studies havedemonstrated the inhibitory function of probiotics inthe initiation or progression of colon and bladdercancers. In medical practice, the use of probiotics isincreasing as additional studies suggest the efficacy ofprobiotics. Although in some cases, such as theimmunocompromised situation in cancer patients,stringent evaluation of the infection risk associated withthe use of these organisms is necessary. Furtherevidence-based research will help to establish theirmedical applications and to explore additional areas inwhich probiotics may be useful.

ACKNOWLEDGMENT

AAK is thankful to Dr. Todd D. Taylor, TeamLeader of the Laboratory for Integrated Bioinformaticsat the RIKEN Center for Integrative Medical Sciencesin Yokohama, Japan, for critical review and valuablesuggestions during the preparation of this manuscript.

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