DRUG DEVELOPMENT RESEARCH : (2013)

DDR

Research Overview

Gut Microbiota and Probiotics: Current Status and Their Role in Cancer Therapeutics
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Abdul Arif Khan,1* Mohsin Khurshid,1 Shahanavaj Khan,1 and Aws Alshamsan1,2 Nanomedicine Research Unit, Department of Pharmaceutics, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia 2 Prince Salman Bin Abdulaziz Chair for Kidney Disease, King Saud University, Riyadh 11451, Saudi Arabia

Strategy, Management and Health Policy Enabling Technology, Genomics, Proteomics Preclinical Research Preclinical Development Toxicology, Formulation Drug Delivery, Pharmacokinetics Clinical Development Phases I-III Regulatory, Quality, Manufacturing Postmarketing Phase IV

ABSTRACT The microbiome is a collection of all microbial species that coexist with an individual. These organisms inuence several aspects of individual body functions. Probiotic organisms are generally benecial components of microora and confer normal health status. Usually, probiotics should be provided from the outside in the diet for maintaining proper health status. Probiotics can also have a signicant impact on cancer management. While the results toward cancer management with probiotics are promising, careful risk assessment of probiotics use in cancer patients, who are usually immunocompromised due to radical therapy, comes as a great demand. This article provides an overview of the current research status of probiotics use in cancer patients and discusses the role of probiotics in cancer management. Drug Dev Res : , 2013. 2013 Wiley Periodicals, Inc.
Key words: probiotics; cancer; normal microora; cancer management

INTRODUCTION

The term probiotic is derived from the Greek word pro indicating promote and biotic representing life. Probiotics are generally dened as living micro-organisms which upon ingestion in certain numbers exert health benets beyond inherent general nutrition [Rafter, 2004]. In 1907, the Russian Nobel laureate, Metchnikoff introduced the concept of probiotics and suggested that ingesting microora could be benecial for humans especially for the treatment of gastrointestinal (GI) diseases. Lilly and Stillwell [1965] were the rst to use the term probiotics for the description of substances secreted by one organism that stimulate the growth of another organism. There are a number of disparities in describing probiotics. The Food and Agriculture Organization (FAO) of the United Nations denes these as live microorganisms, which, when administered in adequate amounts, confer a health benet on the host by improving its microbial
2013 Wiley Periodicals, Inc.

balance [FAO/WHO, 2001; Reid et al., 2003]. A vast number of microbiota are closely associated with various parts of the human body including skin, mouth, and the GI tract. The microbiota comprises mainly bacteria; however, viruses, fungi, and protozoans are also present [Lederberg, 2000]. Probiotics can create a helpful impact on the host by improving the endogenous microora, and they are often used as drugs as they can confer potential health benets through the prevention and treatment of specic pathological conditions or can reduce the risk of disease [Rolfe, 2000;
*Correspondence to: Abdul Arif Khan, Nanomedicine Research Unit, Department of Pharmaceutics, College of Pharmacy, 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

KHAN ET AL.

Gionchetti et al., 2003; Shanahan, 2005; Kumar et al., 2010]. Probiotics can also alter microbial components with known benecial and advantageous functions for the human host [Preidis and Versalovic, 2009]. As their health potential is enormous, they are currently the subject of many studies. This article discusses gut microbiota and probiotics, and their potential role in cancer management.
GUT MICROFLORA AND PROBIOTICS

The normal gut microora controls several aspects of bodily function including the development of certain types of cancer [Khan et al., 2012]. Generally, probiotics are bacteria similar to those naturally inhabiting the human gut particularly those of breastfed infants that have been shown to have natural protection against several infections and diseases. Normally, high numbers of Lactobacilli are observed in the infant intestine, but they rapidly decline after infancy [Balamurugan et al., 2008]. Another common gut bacterium, Bidobacteria, is a Gram-positive, nonmotile, nonsporulating rod-shaped bacteria with varying appearance. The majority of strains are strictly anaerobic. They comprise the main part of the human normal gut microora and appear in the stool a few days after birth and subsequently rise in number [Matto et al., 2004]. The colons of young children contain high numbers of Bidobacteria, which are reduced signicantly with age [Balamurugan et al., 2008]. Different types of probiotic bacteria are present in the gut and convey varying health benets to the intestine. Probiotics must be ingested regularly for any health-promoting activity to persist. It is possible to manipulate (at least temporarily) the composition of the intestinal microora through dietary supplementation with probiotics. An ideal probiotic should possess most of the following characteristics: the ability to adhere to cells, persist, multiply, and produce hydrogen peroxide, acids, bacteriocins against pathogenic growth, be of safe, noninvasive, noncarcinogenic, nonpathogenic nature, and co-aggregate to form a normal balanced ora [Harmsen et al., 2000; Kaur et al., 2002; Lee et al., 2007; Borchers et al., 2009]. Probiotic bacteria have signicant effects on gut microora, thus modulation of gut microora through probiotics has been used as a therapeutic strategy for many clinical conditions. In a randomized, doubleblind, placebo-controlled, two-period crossover study on 38 healthy male subjects, a daily dose of probiotic bacteria including L. rhamnosus LC705 (LC705) and Propionibacterium freudenreichii ssp. shermanii JS (PJS) was given for 4 weeks. The administration of
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LC705 and PJS was followed by evaluation of harmful bacterial carcinogenic enzymes. Administration of these probiotics signicantly raised fecal counts of Lactobacilli and Propionibacteria and decreased the activity of -glucosidase with increasing counts of Propionibacteria. This intervention also reduced colorectal proliferation in the patients [Hatakka et al., 2008]. In a 12-week clinical trial [Rafter et al., 2007], polypectomized patients were treated with Lactobacillus rhamnosus GG (LGG) and B. lactis Bb12 (BB12) and oligofructose-enriched inulin. The treatment resulted in considerable alterations in fecal microora of the patients as the level of Lactobacillus and Bidobacterium increased and Clostridium perfringens decreased. In a recent study, probiotic bacteria were given perioperatively to 31 patients with colorectal carcinoma (CRC) and evaluated for their adherence to the colonic mucosa, reduction of pathogen concentration in stool, and modulation of the local immune function. The La1 strain of Lactobacilli johnsonii affected intestinal microbiota by decreasing pathogen concentration and changing the immune response of intestine [Gianotti et al., 2010]. These are just a few examples of how probiotics can play a crucial role in modulation of gut microora and how they can be used as therapeutic agents for the management of several conditions including cancer.
PROBIOTICS AS THERAPEUTIC AGENTS

Incomplete absorption of lactose results in atulence, bloating, abdominal cramps, and moderate-tosevere (watery) diarrhea. This occurs in a large number of patients and increases especially with age due to a decrease in lactase (-galactosidase) in the intestinal brush border mucosa. Several studies have demonstrated the production of lactase during the fermentative process used in the production of yogurt, which can exert its inuence in the intestinal tract [de Vrese et al., 2001]. Streptococcus salivarius subsp. thermophilus and Lactobacillus bulgaricus are the commonly used organisms in the production of yogurt [Goldin and Gorbach, 2008]. In lactose-intolerant individuals, yogurt feeding led to a marked reduction in breath hydrogen levels compared to subjects fed milk. Breath hydrogen level is indicative of the degree of lactose metabolism in the large bowel. A decrease of 67% hydrogen in the breath was noted after ingestion of 18 g of lactose in yogurt as compared with that produced by a similar dose of lactose delivered in milk. Further, signicant levels of lactase were found in aspirates obtained from the duodenum 1 h after the yogurt consumption. These studies support the practical approach for treatment of lactose malabsorption via lactase

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delivery to the intestine using lactase-producing probiotics [Goldin and Gorbach, 2008]. The use of probiotics to either treat or prevent acute diarrhea has also been reported in studies, the majority of which were done with infants or children. The probiotic Lactobacillus rhamnosus strain GG (Lactobacillus GG ATCC 53103) was used to treat diarrhea while the etiological agent was either rotavirus or unknown. Lactobacillus reuteri and Saccharomyces boulardii were also helpful for the treatment of acute gastroenteritis [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 of probiotics to reduce the frequently observed intestinal adverse effects and diarrhea associated with the clinical use of antibiotics [Marchand and Vandenplas, 2000; McFarland, 2010]. Moreover, probiotics are also helpful in the management of Clostridium difcile associated diarrhea (CDAD). The pathophysiology of CDAD is not completely clear, however, the risk factors include elderly age, renal disease and continued antibiotic therapy. The role of probiotics has been partially appraised in the prevention of CDAD. Early uncontrolled trials and a further report of a controlled trial using Lactobacillus GG suggested some benet of probiotic in recurrent CDAD [Limdi et al., 2006]. Clinical studies have demonstrated a considerable role for bacteria in the pathogenesis of inammatory bowel disease (IBD). Antimicrobial therapies have led to an improvement in Crohns disease, and have also reduced stula-related complications, postoperative pouchitis and postoperative relapse. Plymorphisms in the CARD15/NOD2 gene, an intracellular bacterial pattern recognition receptor, are of interest as risk factors for the development of Crohns disease [Limdi et al., 2006]. Thus, probiotics can help to modulate the gut microbiota and may exert possible benets in IBD management. Improved intestinal permeability, increased mucosal IgA levels, and reduced disease activity were noted after administration of Lactobacillus GG to children with Crohns disease [Gupta et al., 2000; Limdi et al., 2006]. In addition, modication of allergic reactions for atopic eczema with probiotic Lactobacillus GG has also been studied extensively [Kalliomaki et al., 2001, 2003]. There has also been a study that reported the use of Bidobacterium animalis Bb12 to reduce the severity of atopic dermatitis [Isolauri et al., 2000]. In one study, either Lactobacillus GG capsules or a placebo were given to pregnant women with a family history of atopic disease for 24 weeks before their expected delivery date [Kalliomaki et al., 2001]. The newborn infants were fed with Lactobacillus GG directly or it was given to the

breastfeeding mothers. The reduction rate in the frequency of atopic eczema was 50% during the rst two years of the childrens lives for the group given Lactobacillus GG [Kalliomaki et al., 2001]. The role of probiotics in reducing dental caries is also evident in many studies. During a randomized, double-blind, placebo-controlled study at a day care center, children who were fed with milk for 7 months with or without Lactobacillus GG were examined for dental caries and bacterial counts. A reduced oral count of Streptococcus mutans and considerably lower rates of dental caries were observed in the 34 year-old children from the Lactobacillus GG group [Nase et al., 2001]. Probiotics also play a role in the removal of nasal pathogens. In a study with 209 volunteers, the effect of probiotics on nasal bacterial ora was observed. Elimination of pathogenic bacteria from the nasal cavity was observed in those subjects who consumed a fermented milk product containing probiotics as compared to those who consumed a yogurt drink. The potentially pathogenic bacteria removed from the nasal cavity included Streptococcus pneumoniae, -hemolytic streptococci and Staphylococcus aureus. These ndings indicate a linkage between lymphoid tissue of the intestine and the upper respiratory tract and signify the potential role of probiotics in the reduction of the pathogenic bacterial load from the upper respiratory tract [Gluck and Gebbers, 2003]. From all of these examples, it can be concluded that the potential therapeutic applications of probiotics are enormous, they have the capability to alter microora, and they can also bring benecial changes to the body which can help to manage healthy condition. Figure 1 shows an example of the roles of a probiotics can play in regards to several clinical conditions. The next section of this article specically focuses on the role of probiotics in the management of cancer.
IMPLICATION OF PROBIOTICS IN CANCER THERAPEUTICS

Cancer is a serious public health issue with considerable negative impact on human health. It is a signicant factor of mortality and morbidity rates with a total of 1.6 million new cases and approximately 600 000 deaths projected to occur in the US in 2012 [Siegel et al., 2012]. The benecial effects of probiotics on cancer were recently reviewed by Kumar et al. [2010]. Probiotics can exert their anticancer effects through modulation of microbiome composition, maintenance of gut lumen epithelial barrier function, and systemic and mucosal immunomodulation [Khan et al., 2012; Kumar et al., 2013]. The following sections discuss the role of probiotics in different types of cancer.
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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 and Gorbach 2008; Hilton et al. 1997]. [Color gure can be viewed in the online issue which is available at wileyonlinelibrary.com]

Role in Colon Cancer Probiotics have substantial health benets which are not limited to anticancer activity. The colon harbours several different microbiome constituents including both benecial and harmful bacteria and the relative contribution of both types of organisms determines gut health status; however ingestion of probiotics can help to increase benecial bacteria [Isolauri et al., 2002]. These bacteria inuence carcinogenic processes through different mechanisms, and different bacterial strains have different mechanisms for their anticancer effects [Rafter, 2003]. A recent cohort study conducted over 12 years of follow-up on 45 241 volunteers found that intake of high yogurt was signicantly linked with decreased CRC risk, suggesting that administration of long-term probiotics formulations can decrease the incidence of CRC [Pala et al., 2011]. Table 1 provides detail about the role of probiotics in colon cancer.

L. plantarum enriched with selenium nanoparticles increased production of the proinammatory cytokines IFN-, TNF-, and IL-2 and natural killer cell activity [Yazdi et al., 2012]. Thus probiotics-mediated immune modulation control breast cancer through regulation of these cytokines (Table 2).

Role in Bladder Cancer Probiotics can also inuence urinary tract infections, calcium oxalate stone disease and experimentally induced bladder tumors. Oral administration of lactic acid bacteria can be effective against bladder cancer [Fischer and Altwein, 2007]. Bacillus CalmetteGuerin immunotherapy has been used for a long time to prevent recurrence of supercial bladder cancer, and this treatment strategy also suggests promise for the use of other bacterial strains in the management of bladder cancer [Borchert et al., 2008]. An epidemiological study also supports habitual intake of lactic acid bacteria to reduce bladder cancer risk [Ohashi et al., 2002]. Additionally, animal studies also demonstrated potential bladder tumor inhibitory effects of probiotics [Asano et al., 1986]. Table 2 provides details on studies related to the role of probiotics in bladder cancer.

Role in Breast Cancer Probiotics play an important role in the prevention and healing of breast cancer as shown in animals [Soltan Dallal et al., 2012; Yazdi et al., 2012] and in vitro studies [Bif et al., 1997]. It has been suggested that daily consumption of probiotic strain L. casei improves the immune response, reduces tumor growth and increases overall survival [Soltan Dallal et al., 2012]. In a case control study on breast cancer, consumption of yoghurt was negatively associated with breast cancer risk [Le et al., 1986]. Another study showed that
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Other Cancer-Related Aspects Although research for the evaluation of probiotics role in cancer prevention is in its infancy, we can speculate on the basis of our current knowledge that it is not

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TABLE 1. Some Studies Related to Probiotics Application in Colon Cancer
No. 1 Probiotic organisms Study type Study results Bacteria were able to prevent MNNG and 1,2-dimethylhydrazine (DMH)-induced genotoxicity. References

Oral administration of bacteria in rats and Lactobacillus acidophilus prevention of N-methyl-N-nitro-NL. gasseri (P79) nitrosoguanidine (MNNG) induced DNA L. confuses (DSM20196) Streptococcus thermophilus damage evaluation using comet assay. (NCIM 50083) Bidobacterium breve B. longum (from human infant stool) Lactobacillus acidophilus (Delvo Freeze-dried bacteria were added to an Pro LA-1) experimental diet based on a high-fat Lactobacillus rhamnosus (GG) semipuried (AIN-93) rodent diet. The inuence of diet was observed in the Bidobacterium animalis (CSCC1941) incidence of rats with large intestinal Streptococcus thermophilus DMH-induced tumors. (DD145) Lactobacillus acidophilus Animals belonging to different probiotic Lactobacillus rhamnosus (GG) groups were given daily Lactobacilli for Bidobacterium bidum 1 week through oral route, then weekly injections of DMH was given intraperitoneally for 6 weeks consequent with daily administration of probiotic.

[Pool-Zobel et al., 1996]

Strain of L. acidophilus supplied as freeze-dried bacteria in the diet was protective, as seen by a small but signicant inhibition of tumors within the rat colon.

[McIntosh et al., 1999]

L. casei L. rhamnosus

Bidobacterium longum

Bidobacterium longum

Bidobacterium longum

Lactobacillus acidophilus

Consumption of probiotic organisms containing food products (yoghurt) Probiotic bacteria isolated from infant feces

10

Bidobacterium bidum reduced -glucosidase activity. Furthermore, L. rhamnosus GG, L. acidophilus also reduced DMH-induced procarcinogenic fecal enzymes. It was suggested that these bacteria can be used as prophylactic agents for experimental colon carcinogenesis in Sprague Dawley rats Colon cancer cells (HCT-116) were treated Lactobacillus sp. reduces colorectal cell with cell-free supernatant from L. casei, invasion, and some >100 kDa and 50100 kDa macromolecules present L. rhamnosus, or B. thetaiotaomicron (a gut in bacterial cell-free supernatant were commensal); or with uninoculated bacterial growth media. found to be responsible for this activity. Consumption of bacterium and Raftiline HP The bacteria -inulin combination was (a derivative of inulin) and its effect on found to be a potent inhibitor of ACF azoxymethane induced colonic in comparison to either alone. aberrant crypt foci (ACF) in rats was Consumption of B. longum is evaluated. associated with benecial changes in physiology leading to reduced cancer risk and pre-neoplastic changes. Modied AIN-76A diet in male F344 rats B. longum signicantly reduces AOM was given with 0 or 2% lyophilized induced cell proliferation, ornithine cultures of B. longum. Simultaneously, decarboxylase activity, and ras-p21 carcinogen azoxymethane (AOM) was oncoprotein expression. Thus, it administered, once weekly for 2 weeks. showed strong antitumor activity. Animals were fed with high-fat, semi-puried Results indicated that B. longum inhibits diets containing 0 and 0.5% lyophilized IQ induced colon and liver tumors, cultures of B. longum and effects and to some extant mammary tumors were evaluated on 2-amino-3in F344 rats. methylimidazo[4,5-f]quinoline (IQ) induced carcinogenesis. Study involved 11 healthy human subjects Lactobacillus acidophilus reduced mutagen excretion in human. who were given fried beef patties as diet twice daily for 3 days. Additionally, ordinary Lactococcus fermented milk (phase 1) and thereafter with L. acidophilus fermented milk (phase 2) was given as food supplement, and excretion of mutagenic activity in urine and feces was determined. During this study, the diets of 746 colon Yoghurt was found protective against cancer patients were compared with those colon cancer. of 746 age, sex, race, and neighborhood matched controls. Lactic acid bacteria isolated from infant feces Out of a total of 81 bacteria isolated were applied on colon cancer cells and from infant feces, four probiotic anti-proliferative effects of bacteria were bacteria showed antiproliferation evaluated through MTT and Trypan Blue activity on colon cancer cells. exclusion assay.

[Verma and Shukla, 2013]

[Escamilla et al., 2012]

[Rowland et al., 1998]

[Singh et al., 1997]

[Reddy and Rivenson, 1993]

[Lidbeck et al., 1992]

[Peters et al., 1992]

[Thirabunyanon and Hongwittayakorn, 2013]

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TABLE 2. Some Studies Related to Probiotic Application in Breast and Bladder Cancer No. 1 Probiotic organisms L. acidophilus ATCC4356 Study type Breast tumor was transplanted in BALB/c mice and L. acidophilus ATCC4356 was administered orally 14 days before and 30 days after tumor transplantation with 3-day intervals. Female BALB/c mice were given single subcutaneous injections of tumor cells in the left mammary gland and fermented milk was given to mice for 2, 5, or 7 consecutive days before tumor injection. Several factors related to tumor development were monitored for 2 months. Direct effect of milk fermented by bacterial strains was evaluated on the MCF7 breast cancer cell line. Study results L. acidophilus ATCC4356 improved immune response by inducing production of immunomodulatory cytokine IL-12. Lactobacillus helveticus R389 reduced growth rate of mammary tumors. References [Yazdi et al., 2010]

Lactobacillus helveticus R389 (+) fermented milk

[Rachid et al., 2006]

Bidobacterium infantis Bidobacterium bidum Bidobacterium animalis Lactobacillus acidophilus Lactobacillus paracasei Lactobacillus casei + epirubicin

A prospective, randomized, controlled clinical trial with 207 supercial bladder cancer patients was performed to evaluate the effect of orally administered Lactobacillus casei with intravesical instillation of epirubicin on recurrence of bladder cancer after transurethral resection.

All fermented milks showed inhibition of breast cancer cell lines, but the B. infantis and L. acidophilus were most effective. Intravesical instillation of epirubicin combined with oral administration of Lactobacillus casei signicantly increased the survival rate.

[Bif et al., 1997]

[Naito et al., 2008]

only limited to the cancers mentioned above. Probiotics can also prevent adverse events associated with cancer chemotherapy. Consumption of Lactobacillus sp. can prevent chemotherapy-associated diarrhea and abdominal discomfort [Osterlund et al., 2007]. Development of infectious complications due to cancer chemotherapy induced febrile neutropenia (FN) generally creates life-threatening situations in cancer patients. Clinical studies with probiotic strains as an FNcontrolling agent have been conducted [Mego et al., 2006], with no satisfactory results reported. Probiotic use for cancer patients should be strictly regulated under immunocompromised conditions [Boyle et al., 2006]. Therefore, both aspects of probiotic therapy need further research and the development of regulations for its practical use in cancer therapeutics.
HOW CAN PROBIOTICS PREVENT CANCER?

Probiotics can exert their anticancer effects through several mechanisms. A variety of studies are document of their putative anticancer mechanisms. Induction of Apoptosis Bacteria generally induce apoptosis during the course of their infection, that can also have an anticancer role as veried in a study comparing apoptosis induction activity by gut bacterium Atopobium
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minutum, commensal E. coli K-12 strains, probiotics Lactobacillus rhamnosus and Bidobacterium latis and pathogenic E. coli (EPEC and VTEC) within the Caco-2 colon cancer cell line. Probiotic strains showed apoptotic effects via mitochondrial pathways on the colon cancer cell line [Altonsy et al., 2010]. In addition, Propionibacterium acidipropionici and freudenreichii also induce apoptosis in CRC cell lines through short chain fatty acids acting on mitochondria [Jan et al., 2002]. In addition to fatty acids, cell-bound exopolysaccharides from Lactobacillus acidophilus 606 also induce autophagic cell death in colon cancer cells [Kim et al., 2010]. In a study evaluating the apoptotic inducing capacity of 5- uorouracil (5-FU) in the presence of probiotics (Lactobacillus acidophilus and Lactobacillus casei) a 40% increase in 5-FU apoptosis induction activity was observed [Baldwin et al., 2010]. Although the precise mechanisms behind the anticancer activities remain unclear, current ndings clearly support the apoptosis inducing activity of probiotics. Increase in Immune Cell Activity Probiotics can regulate several aspects of natural and acquired immune response [Gill and Prasad, 2008]. Probiotic-mediated immunomodulation may have the ability to prevent cancer. As an example, Lactobacillus shirota delayed cancer onset via enhanced NK cell cytotoxicity [Takagi et al., 2001]. Inammation is a major factor in the development of cancer, with

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probiotics acting as immunomodulators to prevent IBD and reduce colon cancer risk [Sheil et al., 2007]. In a placebo-controlled trial with Lactobacillus salivarius UCC118 this bacteria reduced mucosal inammatory activity and subsequent colon cancer risk in IL-10-/- mice [OMahony et al., 2001]. In a murine breast cancer model, L. acidophilus altered cytokine production resulting in increased lymphocyte proliferation and reduced tumor growth [Maroof et al., 2012]. Probiotics (Bidobacterium longum and/or Lactobacillus gasseri) also reduce colonic mucosa cell proliferation and increase macrophage stimulation in mice, attributes responsible for the prevention of 1,2-dimethylhydrazine-induced colon cancer in mice [Foo et al., 2011].

191R and Streptococcus salivarius ssp. thermophilus CH3, can inactivate carcinogens and prevent DNA damage and resultant tumors in rat colon [Wollowski et al., 1999] while Bidobacterium adolescentis SPM0212 had anticancer activity via reduction of harmful fecal enzymes, -glucuronidase, -glucosidase, tryptophanase, and urease, in three colon cancer cell lines (HT-29, SW 480, and Caco-2) [Kim et al., 2008].

CURRENT PROBIOTICS FORMULATIONS AND THEIR USE IN CANCER

Bacterial Effects on Intestine and Gut Microbiota Dysbiosis Normal microora inuence aspects of the carcinogenic process with a shift from a normal to abnormal microbiome being a major hallmark in the development of certain tumors [Khan et al., 2012]. Probiotic bacteria inhibit some bacterial infection due to colonization resistance and promote intestinal homeostasis [Lawley and Walker, 2013]. A probiotic-induced microora shift resulted in reduced absorption and increased excretion of the mutagenic and carcinogenic agent, aatoxin [Gratz et al., 2006]. In vitro and in vivo studies demonstrtae that the probiotic itself can bind and prevent the absorption of aotoxins, thus potentially preventing hepatitis and liver cancer in humans [Haskard et al., 2000]. Probiotic bacteria bind to mutagens and inhibit their carcinogenic activity [Burns and Rowland, 2000]. Probiotic organisms can also inhibit bacterial conversion of pro-carcinogens into carcinogens [Rolfe, 2000].

Reduction of Carcinogens in Intestine The probiotic metabolome has signicant effects on the molecular and cellular processes leading to cancer development [Kumar et al., 2010, 2012]. The gut microbiota secretes metabolites including organic acids, baceriocins, peptides, and others, which inuence aspects of cell differentiation, programmed cell death, cell proliferation, angiogenesis and cancer development [Kumar et al., 2013]. Probiotic organisms also have the capability to transform toxic compounds in the gut [Cho et al., 2009]. In a study analyzing the effect of probiotics in carcinogen-mediated DNA damage, yoghurt reduced genotoxicity [Oberreuther-Moschner et al., 2004]. Lactobacillus delbrueckii ssp. bulgaricus

Although probiotics have been extensively commercialized, the market for food products with probiotics is larger than the probiotics sold in capsules, sachet, and other pharmaceutical forms. Probiotic food products include yoghurt-type drinks, probiotics fruit juices, berry soups and soy-cereal-based fermented products, and others. [Saxelin, 2008]. Milk-based probiotics are widely accepted [Castro et al., 2013] and act as buffering agents and inhibitors of digestive protease activity protecting bacteria in the GI tract [Charteris et al., 1998]. Milk sugar also provides nutrients for probiotic organisms. Freeze-dried bacteria are available as oral formulations, but require preservatives to increase their shelf life [Jalali et al., 2012]. Most commercial probiotics contain bacteria, Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus casei, Lactobacillus rhamnosus, Lactobacillus plantarum, Lactobacillus salivarius, Lactobacillus sporogenes, Bidobacterium bidum, Bidobacteria infantis, Bidobacteria longum, Streptococcus thermophilus, some Homeostatic Soil Organisms (HSOs) and also some yeast species, e.g. Saccharomyces boulardii [Ljungh and Wadstrom, 2006]. These preparations may be solitary strains or combinations of up to eight strains. The basic requirement for multiple-strain preparations is that they are active against a wide range of animal species and under multiple conditions. Other species utilized in probiotic preparations are L. helveticus, L. lactis, Enterococcus faecium, Ent. faecalis, E. coli, and others. These all are intestinal strains except for L. bulgaricus and S. thermophilus, which are considered as yoghurt starter strains [Angelakis et al., 2011]. A dose of 5 billion colony forming units (CFU) for a minimum of 5 days has been suggested for satisfactory health benets (5 109 CFU/day) [Gupta and Garg, 2009].

CONCLUSION

Animal studies as well as preliminary human studies have documented treatment of several diseases
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Borchert D, Sheridan L, Papatsoris A, Faruquz Z, Barua JM, Junaid I, Pati Y, Chinegwundoh F, Buchholz N. 2008. Prevention and treatment of urinary tract infection with probiotics: review and research perspective. Indian J Urol 24:139144. Boyle RJ, Robins-Browne RM, Tang ML. 2006. Probiotic use in clinical practice: what are the risks? Am J Clin Nutr 83:12561264; quiz 14461447. Brigidi P, Vitali B, Swennen E, Bazzocchi G, Matteuzzi D. 2001. Effects of probiotic administration upon the composition and enzymatic activity of human fecal microbiota in patients with irritable bowel syndrome or functional diarrhea. Res Microbiol 152:735741. Burns AJ, Rowland IR. 2000. Anti-carcinogenicity of probiotics and prebiotics. Curr Issues Intest Microbiol 1:1324. Castro WF, Cruz AG, Bisinotto MS, Guerreiro LM, Faria JA, Bolini HM, Cunha RL, Deliza R. 2013. Development of probiotic dairy beverages: rheological properties and application of mathematical models in sensory evaluation. J Dairy Sci 96:1625. Charteris WP, Kelly PM, Morelli L, Collins JK. 1998. Development and application of an in vitro methodology to determine the transit tolerance of potentially probiotic Lactobacillus and Bidobacterium species in the upper human gastrointestinal tract. J Appl Microbiol 84:759768. Cho KM, Math RK, Islam SM, Lim WJ, Hong SY, Kim JM, Yun MG, Cho JJ, Yun HD. 2009. Biodegradation of chlorpyrifos by lactic acid bacteria during kimchi fermentation. J Agric Food Chem 57:18821889. Cremonini F, Di Caro S, Covino M, Armuzzi A, Gabrielli M, Santarelli L, Nista EC, Cammarota G, Gasbarrini G, Gasbarrini A. 2002. Effect of different probiotic preparations on antihelicobacter pylori therapy-related side effects: a parallel group, triple blind, placebo-controlled study. Am J Gastroenterol 97:27442749. de Vrese M, Stegelmann A, Richter B, Fenselau S, Laue C, Schrezenmeir J. 2001. Probiotics compensation for lactase insufciency. Am J Clin Nutr 73(2 Suppl):421S429S. Escamilla J, Lane MA, Maitin V. 2012. Cell-free supernatants from probiotic Lactobacillus casei and Lactobacillus rhamnosus GG decrease colon cancer cell invasion in vitro. Nutr Cancer 64:871 878. FAO/WHO. 2001. Health and nutritional properties of probiotics in food including powder milk with live lactic acid bacteria. Food and Agriculture Organization of the United Nations and World Health Organization Expert Consultation Report. Fischer C, Altwein J. 2007. [Statins and probiotics in the prevention of urologic diseases]. Urologe A 46:622627. Foo NP, Ou Yang H, Chiu HH, Chan HY, Liao CC, Yu CK, Wang YJ. 2011. Probiotics prevent the development of 1,2dimethylhydrazine (DMH)-induced colonic tumorigenesis through suppressed colonic mucosa cellular proliferation and increased stimulation of macrophages. J Agric Food Chem 59:1333713345. Gianotti L, Morelli L, Galbiati F, Rocchetti S, Coppola S, Beneduce A, Gilardini C, Zonenschain D, Nespoli A, Braga M. 2010. A randomized double-blind trial on perioperative administration of probiotics in colorectal cancer patients. World J Gastroenterol 16:167175. Gill H, Prasad J. 2008. Probiotics, immunomodulation, and health benets. Adv Exp Med Biol 606:423454.

and conditions with probiotics. Animal studies have demonstrated the inhibitory function of probiotics in the initiation or progression of colon and bladder cancers. In medical practice, the use of probiotics is increasing as additional studies suggest the efcacy of probiotics. Although in some cases, such as the immunocompromised situation in cancer patients, stringent evaluation of the infection risk associated with the use of these organisms is necessary. Further evidence-based research will help to establish their medical applications and to explore additional areas in which probiotics may be useful.

ACKNOWLEDGMENT

AAK is thankful to Dr. Todd D. Taylor, Team Leader of the Laboratory for Integrated Bioinformatics at the RIKEN Center for Integrative Medical Sciences in Yokohama, Japan, for critical review and valuable suggestions during the preparation of this manuscript.

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