Uccello et al. BMC Surgery 2012, 12(Suppl 1):S35
`http://www.biomedcentral.com/1471-2482/12/S1/S35
`
`R ES EA R C H AR T I C LE
`Open Access
`Potential role of probiotics on colorectal cancer
`prevention
`Mario Uccello1, Giulia Malaguarnera2, Francesco Basile3, Velia D’agata4, Michele Malaguarnera2*, Gaetano Bertino5,
`Marco Vacante1, Filippo Drago2, Antonio Biondi3
`
`From XXV National Congress of the Italian Society of Geriatric Surgery
`Padova, Italy. 10-11 May 2012
`
`Abstract
`
`Background: Colorectal cancer represents the most common malignancy of the gastrointestinal tract. Owing to
`differences in dietary habits and lifestyle, this neoplasm is more common in industrialized countries than in
`developing ones. Evidence from a wide range of sources supports the assumption that the link between diet and
`colorectal cancer may be due to an imbalance of the intestinal microflora.
`Discussion: Probiotic bacteria are live microorganisms that, when administered in adequate amounts, confer a
`healthy benefit on the host, and they have been investigated for their protective anti-tumor effects. In vivo and
`molecular studies have displayed encouraging findings that support a role of probiotics in colorectal cancer
`prevention.
`Summary: Several mechanisms could explain the preventive action of probiotics against colorectal cancer onset.
`They include: alteration of the intestinal microflora; inactivation of cancerogenic compounds; competition with
`putrefactive and pathogenic microbiota; improvement of the host’s immune response; anti-proliferative effects via
`regulation of apoptosis and cell differentiation; fermentation of undigested food; inhibition of tyrosine kinase
`signaling pathways.
`
`Background
`Colorectal cancer [CRC] is one of the major health pro-
`blems in the world, representing the most common malig-
`nancy of the gastrointestinal [GI] tract. CRC is more
`frequent in industrialized countries than in developing
`ones with a four times higher incidence [1]. Differences in
`dietary habits and lifestyle rather than racial factors may
`explain this gap as it has been demonstrated by studies on
`migrants. The diet is likely to play a key role in the patho-
`genesis of CRC. Epidemiological studies have shown that
`the consumption of red meat and animal fat is associated
`with an increased risk for CRC development [2], whereas
`a diet rich in fruits and vegetables appears to be protective
`against CRC [3]. Evidence from a wide range of sources
`supports the assumption that the link between diet and
`
`* Correspondence: m.malaguarnera@email.it
`2International PhD programme in Neuropharmacology, University of Catania,
`Italy
`Full list of author information is available at the end of the article
`
`CRC may be due to an imbalance of the intestinal micro-
`flora [4]. At birth, the GI tract is colonized by microbes
`and remains the home for several populations of microor-
`ganisms throughout the life of the host. The ‘normal’ gut
`microflora consists of bacterial species with morphologi-
`cal, physiological and genetic features that let it to colonize
`and multiply under particular conditions at certain sites,
`coexist with other colonizing microorganisms and compe-
`titively inhibit the growth of pathogenic bacteria. Never-
`theless, some environmental factors such as diet and drugs
`can alter the composition of the resident microbiota, with
`consequent dysmicrobia and negative implications for the
`health of the individual. The colonic microflora is very
`rich and dominated by strict anaerobic bacteria such as
`Bacteroides spp., Fusobacterium spp., Clostridium spp, and
`many others [5]. Probiotic bacteria may be defined as ‘live
`microorganisms which when administered in adequate
`amounts confer a health benefit on the host’ [6], and they
`most frequently belong to the lactic acid bacteria [LAB]
`
`© 2012 Uccello et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
`Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
`any medium, provided the original work is properly cited.
`
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`category, such as Lactobacillus spp. and Bifidobacterium
`spp. LAB are widely available, for instance, in yogurts and
`other functional foods such as cheese, fermented and
`unfermented milks, juices, smoothies, cereal, nutrition
`bars and infant/toddler formula [7]. A number of studies
`in animal models and in human population have demon-
`strated that the consumption of probiotics is effective in
`various medical conditions such as lactose intolerance,
`antibiotic-induced diarrhea, gastroenteritis, constipation,
`and genitourinary tract infections [8]. Moreover, accumu-
`lating evidence suggests that the ingestion of probiotics
`may be able to play a preventive role in the onset of CRC
`[4]. This observation seems to be very interesting as it
`would make possible an effective strategy for CRC primary
`prevention. This review is merely intended at providing an
`outline of the possible mechanisms whereby probiotics
`may exert their beneficial effects for CRC prevention. We
`have given greater emphasis on those novel mechanisms,
`such as the inhibition of tyrosine kinase signaling path-
`ways and anti-proliferative effects, that have not been
`thoroughly discussed yet.
`
`Discussion
`Mechanisms of CRC prevention exerted by probiotics
`Despite the great number of studies in the literature, the
`precise mechanisms by which probiotics may prevent
`CRC still remain not perfectly clear. However, it is con-
`ceivable that they include: alteration of the intestinal
`microflora; inactivation of cancerogenic compounds;
`competition with putrefactive and pathogenic microbiota;
`improvement of the host’s immune response; anti-prolif-
`erative effects via regulation of apoptosis and cell differ-
`entiation; fermentation of undigested food; inhibition of
`tyrosine kinase signaling pathways. The coadministration
`of probiotics with prebiotics [which are defined as ‘selec-
`tively fermented ingredients that allow specific changes,
`both in the composition and/or activity in the gastroin-
`testinal microflora that confer benefits upon host well-
`being and health’ [9], the so-called synbiotics, can
`increase the effectiveness of these anti-cancer mechan-
`isms [10,11]. Moreover, the acidification of pH, although
`not considered as a distinct mechanism of action, is an
`intrinsic and fundamental feature whereby many probio-
`tics carry out their metabolic activities [12,13]. These
`potential mechanisms will be discussed individually now.
`
`Alteration of the intestinal microflora metabolism
`Glucuronide conjugation is one of the major metabolic
`processes occurring in the liver. It is critical to metabolize
`hormones, and also to inactivate toxic and carcinogenic
`compounds of endogenous and exogenous origin. The
`conjugation with glucuronic acid results in polar metabo-
`lites that are efficiently eliminated in the bile [14]. The
`
`deconjugation of these glucuronides in the intestine by
`bacterial b-glucuronidase leads to the release of aglycones
`that are potentially carcinogenic substances [15]. There
`are other fecal bacterial enzymes, including azoreductase
`and nitroreductase, which catalyze the liberation of pro-
`carcinogenic substances in the intestine [16,17]. The
`alteration of the intestinal metabolism by modulating the
`activity of these bacterial enzymes may be one of the pos-
`sible mechanisms by which probiotics may reduce the risk
`for the onset of CRC [18]. It has been demonstrated that a
`yogurt feeding can reduce the levels of b-glucuronidase
`and nitroreductase contained in the large intestine of mice
`bearing colon cancer [19]. Goldin and Gordbach [18]
`reported a decrease in fecal bacterial enzyme activity after
`a Lactobacillus acidophilus feeding in animal models. The
`same authors [20] recruited 21 young healthy subjects for
`a study aimed at investigating the effect of L. acidophilus
`oral supplements on the enzyme activity of b-glucuroni-
`dase, nitroreductase and azoreductase. Both two strains of
`L. acidophilus used in the study [N-2 and NCFM] caused
`a significant decrease in the activities of the three fecal
`enzymes after a ten-days lactobacilli feeding. Having
`stopped the bacterial feedings, fecal enzyme levels
`returned to normal after four weeks, suggesting that con-
`tinuous ingestion of these organisms is required for these
`enzyme effects to be maintained in the microflora. How-
`ever, apparently ambiguous or discordant results have
`been shown by most human studies designed to investi-
`gate the effects of probiotics supplementation on fecal
`enzyme bacterial activity [21-26]. For example, Marteau et
`al. [24] reported a decrease only in nitroreductase activity
`after a three weeks-period of ingesting a fermented dairy
`product containing L. acidophilus, Bifidobacterium bifi-
`dum, and mesophilic cultures [Streptococcus lactis and
`Streptococcus cremoris] while b-glucuronidase and azore-
`ductase activities did not change. Indeed, these findings
`suggest that the capability of modulating fecal enzymes
`bacteria activity is a strain-specific characteristic for pro-
`biotics. The duration and amount of probiotic intake are
`other considerable factors. Moreover, the degree of rela-
`tionship between the ability of probiotics to influence the
`bacterial metabolism and the prevention of CRC has to be
`better clarified.
`
`Inactivation of cancerogenic compounds
`A meta-analysis of 15 prospective studies showed a rela-
`tive risk of developing CRC of 1.28 for subjects with a
`higher consumption of red meat, when compared with
`people who eat red meat in lower quantities [2]. Several
`hypotheses have been proposed to explain this relation-
`ship. Heterocyclic aromatic amines [HCA], formed as a
`result of cooking meat at high temperatures, are among
`the substances called into question [27,28]. Intestinal
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`microbiota can activate HCA to their active derivatives
`such as the mutagenic pyrolyzates 3-amino-1,4-dimethyl-
`5H-pyrido-[4,3-b]indole [Trp-P-1], 3-amino-1-methyl-5H-
`pyrido-[4,3-b]indole [Trp-P-2], 2-amino-3-methylimidazo
`[4,5-f]quinoline [IQ], 2-amino-1-methyl-6-phenylimidazo
`[4,5-b]pyridine [PhIP], 2-amino-3,4-dimethylimidazo[4,5-f]
`quinoline [MeIQ], and 2-amino-3,8-dimethylimidazo[4,5-
`f]quinoxaline [MeIQx] [29,30]. Such powerful mutagenic
`substances may act with the colonic mucosa, causing
`tumorigenic mutations [30]. LAB and other commensal
`bacteria have been found to bind or metabolize several
`carcinogens, including HCA and N-nitroso compounds.
`Binding and/or degradation well correlates with the reduc-
`tion in mutagenicity observed after exposure of HCA to
`the bacterial strains [31-33]. According to the literature,
`the binding or degradation of HCA by probiotics could be
`one of the main mechanisms of removing carcinogens out
`of the human body. Orrhage et al. [32] studied the in vitro
`capacity of some LAB to bind mutagenic HCA formed
`during the cooking of protein-rich food. The binding of
`the mutagens Trp-P-2, PhIP, IQ and MeIQx by the bacter-
`ial strains was analyzed by HPLC. Trp-P-2 was almost
`completely and irreversibly bound while the binding of
`PhIP, a major mutagen in the western diet, reached about
`50%. IQ and MeIQx were slightly less well bound. Sreeku-
`mar and Hosono [34,35] demonstrated that different
`strains of Lactobacillus gasseri and Bifidobacterium
`longum strongly bound Trp-P-1 and Trp-P-2. Oral supple-
`mentation with L. acidophilus NCFB1748 and B. longum
`BB536 decreased the bioavailability of Trp-P-2 in the GI
`tract and other several tissues in mice [36]. Cell fractions
`of L. acidophilus and Bifidobacterium spp. have been
`found to bind Trp-P-1 and decrease its genotoxicity [37].
`Most data suggest that the binding of mutagens could be
`due to the bacterial cell wall [32,37,38] though the anti-
`mutagenic effect of Lactobacillus plantarum KLAB21 is
`mediated by three extracellular glycoproteins [39]. Challa
`et al. [40] demonstrated that a B. longum and lactulose
`feeding in rats significantly increased the activity of colonic
`glutathione S-transferase, which is one of the Phase II
`enzymes involved in the detoxification of toxic metabolites
`and carcinogens, and suppressed azoxymethane [AOM]-
`induced colonic aberrant crypt foci [ACF] that are preneo-
`plastic markers. More recently, Lactobacillus casei
`DN 114001 has been shown to grow and survive in the
`presence of IQ, MelQx and PhIP and to decrease their
`concentrations [12].The probiotic ability to bind or meta-
`bolize toxic compounds depends on pH and other physi-
`cochemical conditions [12,32,33]. All these results indicate
`that the detoxification of cooked food mutagenic com-
`pounds, commonly found in the western meat-rich diet,
`may be one of the main mechanisms by which LAB antag-
`onize the onset of CRC.
`
`Competition with putrefactive and pathogenic microbiota
`The GI tract, particularly the colon, is very heavily popu-
`lated with bacteria. Although most gut bacteria are
`benign, some species are pathogenic and may be involved
`in the onset of acute and chronic disorders, including
`CRC [41]. It is established that a diet rich in animal fat
`stimulates the growth of secondary bile salt-producing
`bacteria and further studies have shown that secondary
`bile salts are cytotoxic and carcinogenic [42,43]. A diet
`rich in red meat also facilitates the growth of sulfate-
`reducing bacteria producing hydrogen sulfide which
`experimentally is known to be genotoxic [44-46]. Putre-
`factive intestinal microbiota such as Bacteroides spp. and
`Clostridium spp. have been implicated in the pathogen-
`esis of CRC [47] while numerous LAB have been shown
`to possess cancer-preventing attributes [31]. Rafter et al.
`[48] found that the synbiotic combination of a specific
`oligofructose-enriched inulin with probiotics on the fecal
`flora of polyp and colon cancer patients caused an
`increase in the number of some groups of LAB [Bifido-
`bacterium in both groups and Lactobacillus in polyp
`patients], whereas the number of Clostridium perfringens
`in polyp patients significantly decreased. The consump-
`tion of probiotics alone have also proved effectiveness to
`cause changes in GI microflora, with a significant reduc-
`tion of fecal putrefactive bacteria, such as coliforms, and
`an increase of LAB [49,50]. These effects may be
`mediated by adherence to enterocytes and the pH lower-
`ing [13,51]. Furthermore, O’Mahony et al. reported that
`the enteric flora modification in interleukin-10 [IL-10]
`knockout mice by probiotic Lactobacillus salivarius
`UCC118 resulted in a reduced prevalence of colon cancer
`[49]. Thus, probiotics may counteract CRC development
`also through a mechanism of competition with patho-
`genic intestinal microbiota.
`
`Improvement of the host’s immune response
`The immune system plays an important role in the con-
`trol of tumor promotion and progression. The close
`interaction of several elements of the immune system,
`such as antigen-presenting cells [APCs], and different
`subsets of T cells, B cells and natural killer [NK] cells, is
`critical for the generation of an effective anti-tumour
`immune response [52]. Besides other potential effects in
`the prevention of cancer, probiotics have been suggested
`to enhance the mucosal and system immune response
`[53]. In 1981, Yokokura [54] screened 26 strains of 14
`different species of LAB for in vivo anti-tumor activities
`against a transplantable mouse sarcoma, and noticed that
`some of these strains had potent anti-tumor effects.
`Among them, especially Lactobacillus casei Shirota [LcS]
`showed a high potential. Since such strain is not directly
`cytotoxic to tumor cells in vitro, it has been postulated
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`that its anti-tumor effects may be mediated by the
`enhancement of the host’s immune system [55]. This
`hypothesis has elicited further investigations on the anti-
`tumor and immunoregulatory action of LcS in various
`experimental models [56-58]. Oral administration of LcS
`has exhibited beneficial effects in both humans and ani-
`mals as well as anti-tumor activity against human bladder
`cancer cells in clinical trials [59,60]. LcS has been shown
`to possess powerful anti-tumor and anti-metastatic
`effects on transplantable tumor cells and to suppress che-
`mically-induced carcinogenesis in rodents. In particular,
`It has been noted that the intrapleural administration of
`LcS into tumor-bearing mice has induced the production
`of several cytokines, such as Interferon-g [IFN-g], inter-
`leukin-b [IL-1b] and tumor necrosis factor-a [TNF-a],
`leading to the inhibition of tumor growth and to an
`increased survival [58,61]. After LcS is ingested by the
`host, it is incorporated into M cells in Peyer’s patches
`and digested to form active components. In Peyer’s
`patches, macrophages or dendritic cells [DCs], after pha-
`gocytosing LcS, become able to produce several cyto-
`kines, especially TNF-a. Then, the components of LcS
`digested in Peyer’s patches are recognized through toll-
`like receptor 2 in APCs, and lead to the production of
`several cytokines that stimulate different responses in
`host immune cells [62]. Lcs has also exhibited a strong
`anti-tumor effect in mice by regulating the host immune
`response in a 3-methylcholanthrene [MC]-induced carci-
`nogenesis model [63] that has been used to induce many
`tumors, including colon cancer model [64,65]. An LcS
`oral feeding of mice is likely to counteract MC-induced
`tumorigenesis by ameliorating the host
`immune
`responses which have been disrupted during MC carci-
`nogenesis. A possible mechanism of carcinogenesis pre-
`vention is the proliferation and activation of NK cells
`[66]. NK cells are large granular lymphocytes derived
`from bone marrow, and have a critical role in immune
`surveillance against tumor development [67]. Other pos-
`sible effector cells that may respond to LcS and other
`probiotics are DCs [62,68]: they represent important
`types of cells involved in the presentation of several anti-
`gens and in the production of cytokines [69]. In addition,
`oral administration of LcS has been shown to stimulate
`type 1 helper T cells, activate the cellular immune sys-
`tem, and inhibit the incidence of tumors and IgE produc-
`tion in mice [70]. More recently, it has been reported
`that LcS has suppressed murine tumorigenesis with
`potent elicitation to produce interleukin-12 [IL-12] by
`bone marrow-derived cells in vitro [71] and to inhibit of
`interleukin-6 [IL-6] production in the colonic mucosa
`[72]. In numerous studies, other probiotic strains have
`shown remarkable immunoprotective properties through
`the increase of specific and non-specific mechanisms that
`have anti-tumor effects. For instance, Lee et al. [73]
`
`reported that the administration for four weeks of
`L. acidophilus SNUL, L. casei YIT9029 and B. longum
`HY8001, for instance, increased the survival rate of mice
`injected with tumor cells. The increase of survival was
`correlated with an increase in cellular immunity as
`reflected by an augmentation in the number of total
`T cells, NK cells and MHC class II+ cells, and CD4−CD8+
`T cells in flow cytometry analysis. These findings suggest
`that the treatment with probiotics has the potential to
`prevent CRC by modulation of the host’s immune sys-
`tem, specifically cellular immune responses.
`
`Anti-proliferative effects via regulation of apoptosis and
`cell differentiation
`Apoptosis is a genetically determined mode of cell death
`playing a key role in the regulation of cell numbers. In
`many types of cancer, a reduced ability to trigger apoptosis
`is an important pathogenetic event that is accompanied by
`alteration of control processes of cell proliferation [74].
`The regulation of cell survival and death with molecules
`acting on the apoptotic process can have a huge chemo-
`preventive and therapeutic potential [75]. There is much
`evidence that probiotics can have a role in the regulation
`of cell proliferation and apoptosis which are potentially
`crucial mechanisms in the prevention of CRC. Iyer et al.
`[76] found that Lactobacillus reuteri suppressed TNF-
`induced NF-B activation in a dose and time-dependent
`manner. L. reuteri may regulate cell proliferation by pro-
`moting apoptosis of activated immune cells via inhibition
`of IkBa ubiquitination and enhancing pro-apoptotic mito-
`gen activated protein kinase [MAPK] signaling. The pro-
`biotic mixture VSL#3 has been reported to suppress the
`COX-2 expression in Colo320 and SW480 intestinal
`epithelial cells [77]. The expression of COX-2 is increased
`in colorectal tumors [78], and this elevation can protect
`intestinal epithelial cells from apoptosis [79,80]. Recently,
`rodent studies have demonstrated that the synbiotic com-
`bination of resistant starch and Bifidobacterium lactis has
`exerted a pro-apoptotic action in response to the carcino-
`gen, AOM [10,81]. Other studies have postulated that pro-
`biotics possess CRC-protective effects by altering the
`differentiation process of tumor cells. Using a cultured
`human colon cancer cell line [HT-29], Baricault et al. [82]
`studied the effect of fermented milks on colon cancer cell
`proliferation and growth. Milks were fermented by one of
`the following bacterial populations: Lactobacillus helveti-
`cus, Bifidobacterium, L. acidophilus or a mix of Streptococ-
`cus thermophilus and Lactobacillus bulgaricus. After
`HT-29 cells were added to the fermented milk, only
`L. acidophilus was found to have no effects on both cell
`growth and differentiation while the three other bacterial
`strains induced a significant, although variable, reduction
`in the growth rate of HT-29 cells, which resulted in a
`10-50% decrease in the cell number at steady-state.
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`Concomitantly, the specific activities of dipeptidyl pepti-
`dase IV, which is a sensitive and specific marker of HT-29
`cell differentiation, and those of three other brush border
`enzymes [sucrase, aminopeptidase N and alkaline phos-
`phatase] were significantly increased, thus suggesting that
`these cells may have entered a differentiation process.
`Moreover, the combination of Bifidobacterium breve
`R0070 + Lactobacillus lactis R1058 + oligoalternan inhib-
`ited the proliferation of HT-29 cells in absence of cytotoxic
`effect [83]. This could be explained by the induction from
`an undifferentiated phenotype to a more differentiated
`one. In fact, the results showed that cancerous HT-29
`cells treated with the synbiotic, when compared with the
`differentiated ones, reached the same rate expression of
`intestinal alkaline phosphatase, a biomarker of colic differ-
`entiation [84]. Singh et al. [85] demonstrated that a dietary
`administration in rats of lyophilized cultures of B. longum
`resulted in a significant suppression of colon tumor inci-
`dence and tumor multiplicity, and it also reduced the
`tumor volume. Analyses on intermediate biomarkers also
`revealed that the ingestion of B. longum inhibited AOM-
`induced cell proliferation through a reduction in ornithine
`decarboxylase [ODC] activity. ODC is involved in the bio-
`synthesis of polyamines that cause cell proliferation and
`differentiation of the colonic mucosa [86]. According to
`these data, an improved understanding of LAB-mediated
`effects on apoptosis and differentiation signalling pathways
`may facilitate the development of future probiotics-based
`regimens for the prevention of CRC.
`
`Fermentation of undigested food
`The bacterial transformation of dietary components in the
`intestinal lumen may be associated with the production of
`cancer-preventive agents and may therefore be another
`mechanism whereby probiotics can influence CRC risk.
`The bacterial fermentation of indigestible carbohydrates
`generates short-chain fatty acids [SCFA] and gas; while
`the gas is eliminated in the feces, SCFA [mainly acetate,
`propionate and butyrate] represent nutrients and growth
`signals for the intestinal mucosa and may play a role in
`CRC prevention [87]. They reduce, for instance, the con-
`centration of secondary bile salts. Butyrate, that is the
`most widely studied of these SCFA, is a preferred energy
`source for colonocytes and is likely to promote a normal
`phenotype in these cells. In CRC cell lines, butyrate
`enhances cellular differentiation and reduces proliferation
`[88,89]. In human studies, butyrate and the associated low-
`ering of luminal pH are correlated with a reduced risk of
`CRC [90,91]. A specific strain [MDT-1] of the ruminal
`bacterium Butyrivibrio fibrisolvens has been evaluated for
`use as a probiotic to prevent CRC cancer since it produces
`high amounts of butyrate [92]. Using a mouse model of
`colon cancer, the administration of MDT-1 has reduced
`the number of ACF and the percentage of mice with an
`
`increased proportion of ACF. Furthermore, the human
`probiotic Propionibacterium spp. has been shown to kill
`CRC cells through apoptosis in vitro via its metabolites,
`the SCFA, acetate and propionate [93,94]. However, syn-
`biotics would be more active than probiotics alone in
`increasing the production of SCFA and consequently pro-
`tect against CRC onset [10,95]. A possible explanation is
`that the interaction of the immunomodulating properties
`of probiotic bacteria and butyrate, which is more produced
`via fermentation of prebiotics, results in an upregulation of
`apoptosis [10,11]. In addition to SCFA, probiotics are
`involved in the production of another group of fatty acids,
`termed conjugated linoleic acids [CLAs]. These are a
`group of isomers of linoleic acid that have been shown to
`exert numerous health benefits, including anti-inflamma-
`tory and anti-carcinogenic effects [96,97]. In rodent stu-
`dies CLA has been shown to reduce the incidence of
`colonic tumors [98,99]. Using animal models, Ewaschuk
`et al. [100] demonstrated that the probiotic strains in the
`mixture VSL#3 are able to convert linoleic acid into CLA,
`inducing the upregulation of PPARg, a reduction in colo-
`nic tumor cells viability, and the induction of apoptosis.
`These studies support a role for supplemental probiotics
`as a strategy for preventing CRC by fermentation of indi-
`gestible food, but further investigations are needed.
`
`Inhibition of tyrosine kinase signaling pathways
`Signaling pathways are represented by a series of biochem-
`ical events whereby a cell communicates with the extracel-
`lular environment. Signaling pathways are activated by
`receptors or cytoplasmic proteins with tyrosine kinase
`activity and play a critical role in carcinogenesis [101].
`Saccharomyces boulardii [Sb] is a safety probiotic agent
`used to prevent or treat a wide variety of human GI disor-
`ders [102,103]. It has been reported that Sb acts through
`modulation of the host signaling pathways that regulate
`the intestinal mucosal inflammatory response. In particu-
`lar, Sb down-regulates MAPK signaling pathways
`[104,105] that are located downstream of many growth-
`factor receptors, including the epidermal growth factor
`receptor [EGFR]. The EGF receptor family consists of four
`members: ErbB1/EGFR/HER1, ErbB2/HER2/Neu, ErbB3/
`HER-3 and ErbB4/HER-4 that are important for cancer
`development [106]. Chen et al. [107] wanted to examine
`the effects of Sb on tumor development in ApcMin mice,
`an animal model used for quantitative and mechanistic
`studies of the induction of intestinal tumors [108]. Sb pre-
`vented cancer cell colony formation, reduced EGF-
`mediated cell proliferation, and increased apoptosis. Both
`in vitro and in vivo effects were consistent with inhibition
`of the EGFR and Akt pathways. Furthermore, a laboratory
`study by Ma et al. [109] demonstrated that the probiotic
`Bacillus polyfermenticus suppressed colon cancer cells
`growth in vitro and colon cancer tumor growth in vivo.
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`Bacillus polyfermenticus exerted its anticancer effect
`through the reduction of ErbB2 and ErbB3 and their
`downstream signaling molecules E2F-1 and cyclin D1.
`Thus, in addition to the other anti-tumorigenic effects,
`probiotics may inhibit EGFR and other tyrosine kinase sig-
`naling pathways and thereby may also serve a novel thera-
`peutic or prophylactic role in intestinal malignancies.
`
`Conclusions
`Although a wide range of studies have brought to grow-
`ing remarkable findings in recent years, it has not still
`been possible to obtain conclusive clinical evidence sup-
`porting the role of probiotics in CRC prophylaxis. Since
`CRC is an impractical endpoint in terms of numbers of
`subjects, cost, study duration and ethical considerations,
`probiotic intervention studies often use recurrence of
`preneoplastic lesions or intermediate biomarkers of can-
`cer as an endpoint [110,111]. Several mechanisms could
`explain the preventive action of probiotics against CRC
`onset. All of the CRC-preventing mechanisms previously
`discussed are supported in varying degrees from in vitro
`and animal model studies, some of them even from
`human clinical studies. We are not still able to deter-
`mine which mechanisms are most effective. Most likely
`distinct strains of probiotics operate with specific
`mechanisms. Further investigations are strongly required
`in order to establish the impact of each mechanism and
`the real usefulness of probiotics in CRC prevention.
`
`Acknowledgements
`MM was supported by the International PhD programme in
`Neuropharmacology, University of Catania. The authors wish to thank Alessia
`Trovato for carefully editing the manuscript and contributing to language
`revision.
`This article has been published as part of BMC Surgery Volume 12 Supplement 1,
`2012: Selected articles from the XXV National Congress of the Italian Society of
`Geriatric Surgery. The full contents of the supplement are available online at
`http://www.biomedcentral.com/bmcsurg/supplements/12/S1.
`
`Author details
`1Department of Senescence, Urological and Neurological Sciences,
`Cannizzaro Hospital Via Messina 829, 95125, University of Catania, Italy.
`2International PhD programme in Neuropharmacology, University of Catania,
`Italy. 3Department of General Surgery, Section of General Surgery and
`Oncology, Vittorio Emanuele Hospital, Via Plebiscito 628 University of
`Catania, 95123 Catania, Italy. 4Department of Biomedical Sciences, Via S.
`Sofia, 87, 95123, University of Catania, Italy. University of Catania, Italy.
`5Department of Medical and Pediatric Sciences Via S. Sofia, 87, 95123,
`University of Catania, Italy.
`
`Authors’ contributions
`MU: conception and design, drafting the manuscript, given final approval of
`the version to be published; GM, VDA, MM, MV: drafting the manuscript,
`given final approval of the version to be published; FB, GB, FD, AB: critical
`revision, given final approval of the version to be published.
`
`Competing interests
`The authors declare that they have no competing interests.
`
`Published: 15 November 2012
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