Cellular and molecular mechanisms of probiotics effects on colorectal cancer

Journal of Functional Foods 18 (2015) 463–472

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Cellular and molecular mechanisms of probiotics effects on colorectal cancer Zeinab Faghfoori a,b, Bahram Pourghassem Gargari c,d,*, Amir Saber Gharamaleki c,d, Hassan Bagherpour e, Ahmad Yari Khosroushahi e,f,** a

Tuberculosis & Lung Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Student Research Committee, Faculty of Nutrition, Tabriz University of Medical Sciences, Tabriz, Iran c Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran d Department of Biochemistry and Diet Therapy, Nutrition Research Center, Faculty of Nutrition, Tabriz University of Medical Sciences, Tabriz, Iran e Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran f Department of Pharmacognosy, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran b

A R T I C L E

I N F O

A B S T R A C T

Article history:

Colorectal cancer is the most common malignancy of the gastrointestinal tract and it seems

Received 29 November 2014

the colonic microbiota plays a significant role in the aetiology of colorectal cancer because

Received in revised form 18 August

it can influence many aspects of intestinal tract health including its physiology, metabo-

2015

lism, development, and immune homeostasis. Hence, all factors modulating the gut microflora

Accepted 18 August 2015

and their metabolism are very interesting in cancer prevention. Probiotic bacteria have been

Available online

examined for anti-cancer effects and different mechanisms were suggested about their antitumour functions. This study reviewed some of the possible cellular and molecular

Keywords:

mechanisms of probiotics such as influencing intestinal microbial composition and patho-

Colorectal cancer

genic bacteria, the production of biological substance like short chain fatty acids and

Microbiota

conjugated linoleic acid, inactivation of carcinogenic compounds especially those derived

Diet

from food, improvement of intestinal barrier function, modulation of immune responses,

Probiotic bacteria

apoptosis and anti-proliferative effects and antioxidant function. © 2015 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3.

Introduction ...................................................................................................................................................................................... 464 Probiotics, microbial composition, and CRC ................................................................................................................................ 464 Probiotics, pathogenic bacteria and CRC ..................................................................................................................................... 465

* Corresponding author. Faculty of Nutrition, Tabriz University of Medical Sciences, Daneshgah Street, Tabriz P.O.Box 51664-14766, Iran. Tel.: +98 41 3337 6228; fax: +98 41 3334 0634. E-mail address: [email protected] (B. Pourghassem Gargari). ** Corresponding author. Faculty of Pharmacy, Tabriz University of Medical Sciences, Daneshgah Street, Tabriz, P.O.Box 51664-14766, Iran. Tel.: +98 41 33372250 1; fax +98 41 33344798. E-mail address: [email protected] (A. Yari Khosroushahi). http://dx.doi.org/10.1016/j.jff.2015.08.013 1756-4646/© 2015 Elsevier Ltd. All rights reserved.

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4.

5. 6. 7. 8. 9. 10. 11. 12.

1.

Journal of Functional Foods 18 (2015) 463–472

Probiotics, biological substances and CRC ................................................................................................................................... 4.1. Short chain fatty acids ......................................................................................................................................................... 4.2. Conjugated linoleic acid ....................................................................................................................................................... Probiotic, intestinal barrier function and CRC ............................................................................................................................ Probiotic, carcinogenic compounds, potential mutagens and CRC ......................................................................................... Probiotics, bile acids and CRC ........................................................................................................................................................ Probiotics, immune system and CRC ............................................................................................................................................ Probiotics, oxidative stress and CRC ............................................................................................................................................. Probiotics, cell proliferation, apoptosis and CRC ........................................................................................................................ Probiotics, neuromodulation and CRC .......................................................................................................................................... Conclusion and future prospective ............................................................................................................................................... Ethical issues .................................................................................................................................................................................... Conflict of interest statement ........................................................................................................................................................ Acknowledgements ......................................................................................................................................................................... References .........................................................................................................................................................................................

Introduction

Colorectal cancer (CRC), the most common malignancy of the gastrointestinal tract, is the third most common cancer accounting for about 9.5% of all new malignant diseases and the fourth leading cause of cancer death worldwide (Siegel, Naishadham, & Jemal, 2012; Uccello et al., 2012; Wu et al., 2013). The number of new cases is rising rapidly, both due to the expansion of the elderly population as well as an increase in the prevalence of risk factors like inflammatory bowel disease (IBD) and the change in dietary habits (Konstantinov, Kuipers, & Peppelenbosch, 2013; Pericleous, Mandair, & Caplin, 2013). The colonic microbiota is involved in the aetiology of CRC and can impress multiple processes that affect cancer risk such as controlling epithelial proliferation and differentiation, influencing the immune system and protecting against pathogens (Zhu, Gao, Wu, & Qin, 2013). Some studies have indicated that the composition of the gut microbiome is different in CRC patients from healthy controls. The human intestinal tract contains approximately 1000 species and about 1014 bacteria that influence all over physiology, metabolism, development, and immune homeostasis (Turner, Ritchie, Bresalier, & Chapkin, 2013; Wu et al., 2013). Some strains of bacteria have been associated with the pathogenesis of cancer, such as Streptococcus bovis, Bacteroides, Clostridium, and Helicobacter pylori and some strains including Lactobacillus acidophilus and Bifidobacterium longum inhibited carcinogen-induced colon tumour development (Zhu et al., 2013). The comparison of the composition of the human intestinal microbiota between CRC patients and healthy subjects showed significant elevation of several bacterial groups, such as Bacteroides and Fusobacterium species and significant reduction of butyrate-producing bacteria in the gut microbiota of CRC patients (Wu et al., 2013). A positive correlation was also observed between the abundance of Bacteroides species and CRC disease status. Chen and colleagues reported that the structures of the intestinal lumen microbiota and mucosa-adherent microbiota were different in CRC patients compared to matched microbiota in healthy individuals (Chen, Liu, Ling, Tong, & Xiang, 2012b).

465 465 466 466 467 467 467 468 468 468 469 469 469 469 469

However, the exact composition of intestinal microbiota and its function in the CRC progression remain unknown but it seems that an imbalance between beneficial and pathological species of bacteria may be involved in cancer. By using pyrosequencing technique, colon cancer is linked with dysbiosis mainly due to a change in dominant and subdominant species (Sobhani et al., 2011). These results have led to an interest in factors that can modulate the gut microflora and their metabolism (Rafter, 2004). Probiotic bacteria are defined as “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host” (Hill et al., 2014). They usually comprise lactic acid producing bacteria (LAB) of the genera Lactobacillus and Bifidobacterium and are widely available, for instance, in yogurts and other functional foods such as cheese, fermented and unfermented milks (Burns & Rowland, 2004; Uccello et al., 2012). Despite numerous studies that have been done in this area, the exact mechanisms that probiotics can affect colorectal cancer are unknown. In the same vein, the great number of studies show that probiotics may prevent cancer initiation or its development via alteration of intestinal microbial composition, protection of host from pathogenic bacteria and fungi, the production of biological substance like short chain fatty acid and conjugated linoleic acid, inactivation of carcinogenic compounds, improvement of intestinal barrier function, modulation of immune responses, apoptosis and anti-proliferative effects and anti-oxidant function (Chen et al., 2012b; Uccello et al., 2012). Therefore, this study aimed to review the impacts of probiotics mechanisms on inhibiting colorectal cancer that were summarized in Fig. 1.

2.

Probiotics, microbial composition, and CRC

The intestinal microbiota participates in a symbiotic relationship with their host and has a major role in the health of colon by preventing overgrowth of pathogens, extracting nutrients and energy from diet and contributing to normal immune function (Chen et al., 2012a; Lozupone, Stombaugh, Gordon, Jansson, & Knight, 2012). The potential pathways linking between microbiota and the host are signalling cascades, the immune

Journal of Functional Foods 18 (2015) 463–472

Probiotics (Live microorganisms that, when administered in adequate amounts, confer a health benefit on the host) 2) Production of biological substance (SCFA & CLA)

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1) Alterations of microbiota And Prevention of Pathogenic bacteria colonization 3) Inactivation of carcinogenic compounds

5) Modulation of immune

4) Improvement of intestinal barrier function 7) Anti-oxidant 6) Apoptotic and anti-proliferative effects 8) Neuromodulation

Reduce colorectal cancer risk

Fig. 1 – Cellular and molecular mechanisms of probiotics effects on colorectal cancer.

system, the host metabolism, and the regulation of gene transcription (Turner et al., 2013). The alteration in the normal homeostasis of the gut microbiota, termed intestinal dysbiosis, may contribute to disease development (Arthur et al., 2013). The analysis of CRC patients’ microbiota indicates the remarkable change in concentrations/strains of bacteria in these patients’ gut microbiota (Zhu et al., 2013). Ohigashi et al. 2013 showed the significant difference in counts of total bacteria and 5 groups of obligate anaerobe, and 2 groups of facultative anaerobes were significantly lower in the CRC patients than in the healthy control group. The comparison of microbiota in the health and colon cancer patient’s individuals illustrated the remarkable differences in the distribution of bacterial genera especially the significant elevation of the Bacteroides/Prevotella population in cancer patients versus those with a normal colonoscopy (Sobhani et al., 2011). A positive correlation was previously reported between the abundance of S. bovis and Bacteroides and CRC disease which indicated these specific microorganisms carcinogenicity (Gold, Bayar, & Salem, 2004; Wu et al., 2013). Probiotics modify microbial composition/homeostasis in gut and thus their consumption could significantly reduce faecal coliform and enterococci levels in IL-10 knockout mice (O’Mahony et al., 2001). Probiotic administration also modulated the changes in the faecal anaerobic bacterial flora in mice administered dextran sodium sulphate (Nanda Kumar et al., 2008). The L. paracasei subsp. paracasei LC01 (LC01) consumption in healthy young adults significantly decreased Escherichia coli and increased Lactobacillus, Bifidobacterium, and Roseburia intestinalis population (Zhang et al., 2013). Four-week commercial yogurt consumption supplemented with B. animalis subsp. lactis (BB-12) and L. acidophilus (LA-5) significantly increased the faecal numbers of Bifidobacteria and Lactobacilli and decreased counts of faecal Enterococci (Savard et al., 2011). Thus, there are significant differences in the intestinal environment such as alterations of microbiota in CRC patients and probiotics may alter intestinal microbiota composition and reduce incidence of colonic adenocarcinoma.

3.

Probiotics, pathogenic bacteria and CRC

The pathobionts are resident microbes with pathogenic potential under certain conditions like environmental and genetic alteration which may be involved in CRC and IBD pathologies (Chow, Tang, & Mazmanian, 2011; Konstantinov et al., 2013). Some of pathobionts bacteria like H. hepaticus, Enterococcus faecalis, Proteus mirabilis and Klebsiella pneumonia can initiate colitis and large bowel carcinoma (Erdman et al., 2009; Garrett et al., 2009). E. coli have also been linked to colitis-associated CRC (Konstantinov et al., 2013). In addition, under dysbiosis condition, Faecalibacterium prausnitzii (a tolerogenic bacterium) might also be reduced (Sokol et al., 2008). The concomitant increase in pathogenic bacteria and the decrease in tolerogenic bacteria can lead to inflammatory responses and risk of IBD and CRC (Konstantinov et al., 2013). The commensal bacteria in gastrointestinal tract and some probiotics protect the host from pathogenic bacteria and fungi. These bacteria are able to adhere to the gastrointestinal mucosa and colonize and thus inhibit pathogens adhesion, because the pathogenic adhesion and colonization are important steps in pathogenic infection (Collado, Jalonen, Meriluoto, & Salminen, 2006). Probiotics also exclude pathogens through the secretion of potent anti-microbial peptides (AMPs) such as the bacteriocins and microsins which suppress pathogenic growth (Hardy, Harris, Lyon, Beal, & Foey, 2013). Therefore, probiotics can compete with pathogenic bacteria that are involved in procarcinogenic and mutagenic pathways via adhesion and prevention of their colonization and release of antimicrobial substance.

4.

Probiotics, biological substances and CRC

4.1.

Short chain fatty acids

Ohigashi et al. (2013) study showed that the concentrations of short chain fatty acids (SCFAs) significantly decreased while

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the pH increased in the CRC patients’ faeces. The complex carbohydrates such as cellulose, lignin and pectin escape from digestion in the small intestine and undergo bacterial fermentation and the destination of this fermentation depends on the colonic microbiota and the features of these carbohydrates (Zeng, Lazarova, & Bordonaro, 2014). SCFAs which include acetate (C2), propionate (C3) and butyrate (C4) are the end product of fermentation by the anaerobic intestinal microbiota (den Besten et al., 2013). The probiotics can influence colon health through increasing the SCFA production where these fatty acids act as messengers between colonic bacteria and the host (Ganapathy, Thangaraju, Prasad, Martin, & Singh, 2013; Sakata, Kojima, Fujieda, Takahashi, & Michibata, 2003; Sanders, 2011). The precise mechanisms of cancer inhibition by butyrate is unclear, but in vitro evaluations illustrated the butyrate anticarcinogenic effects via the induction of apoptosis, and the inhibition of proliferation/differentiation in cancer cells (Hamer et al., 2008). Butyrate inhibits histone deacetylase activity that leads to hyperacetylation of histones. The histone hyperacetylation can result in silencing/upregulation of different genes involving in the control of cell cycle progression, differentiation, apoptosis, and cancer development. The p21 gene was upregulated by the histone hyperacetylation that induce G1 cell cycle arrest. Besides, butyrate affects the regulation of Bcl2 family proteins, and triggers apoptosis via the upregulation of BAK and the down regulation of BclxL genes (Canani et al., 2011). In addition, butyrate decreases the expression of cyclin D1 and c-myc genes (essential for intestinal tumour development) through the transcriptional attenuation in SW837 human colorectal adenocarcinoma cells (Daroqui & Augenlicht, 2010). Propionate and butyrate can also modulate autophagy, and type II programmed cell death in human colon cancer cells (Tang, Chen, Jiang, & Nie, 2011).

4.2.

Conjugated linoleic acid

Conjugated linoleic acid (CLA), a fatty acid with 18 carbons and conjugated double bound, mainly includes cis-9, trans-11 and trans-10, and cis-12-octadecadienoic acid (Ogawa et al., 2005). CLA possesses the multiple potential benefits especially anticarcinogenic properties (De la Torre et al., 2005; Palombo, Ganguly, Bistrian, & Menard, 2002). CLA inhibits the cell proliferation and stimulates apoptosis by decreasing ErbB3 gene expression and downregulating the PI3-kinase/Akt pathway (Cho et al., 2003, 2005). Also, CLA upregulates the caspase 3 and caspase 9, and reduces the expression of bcl-2 gene (Beppu et al., 2006; Miller, Stanton, & Devery, 2002). Besides, CLA has inhibited the cell proliferation and has induced apoptosis in HT-29 human colon cancer cells by decreasing insulin-like growth factor-II synthesis and downregulating IGF-IR signalling (Kim et al., 2003). Moreover, CLA inhibits the cell growth in colon cancer cells through the induction of G1 cell cycle arrest (Cho et al., 2006). The milk fat and the meat of ruminant animals are main source of CLA in nature (Huang, Zhong, Cao, & Chen, 2007). However, several strains of probiotic bacteria such as Lactobacilli and Bifidobacteria can convert linoleic acid (LA) to CLA (Ewaschuk, Walker, Diaz, & Madsen, 2006). Some probiotic bacteria produce the CLA. The probiotic strains in VSL3 including

L. bulgaricus and S. thermophilus have illustrated the highest and L. acidophilus has shown the lowest capacity to convert LA to CLA in vitro and in vivo in mice and CLA produced by probiotic could upregulate the PPARγ gene, can induce the apoptosis, and reduce the cell viability in cancerous cells (Ewaschuk et al., 2006). These results suggest that probiotic bacteria may induce apoptosis and inhibit cell proliferation in human colon cancer cells by production of some compounds.

5. Probiotic, intestinal barrier function and CRC The human intestine functions as a barrier that limits the exposure of the intestinal epithelial cells to intra luminal toxins, bacteria, and antigens (Ulluwishewa et al., 2011). The intestinal mucosa, a single-cell layer and semi-permeable barrier, includes the different types of cells like the absorptive cells (enterocytes) and the secretory cells and extracellular components such as a layer of mucins (Jeon, Klaus, Kaemmerer, & Gassler, 2013; Shen, Su, & Turner, 2009). The adjacent cells in the intestinal epithelium joined together by intercellular junctional complexes are composed of tight junctions (TJ), adherens junctions, and desmosomes that the tight junctions take part at the forming of the paracellular barrier and they are the primary determinant of mucosal permeability and adherens junctions and desmosomes have structural and signalling roles (Shen et al., 2009). The tight junctions are composed of over 50 proteins such as occludin, the claudin family of proteins, junctional adhesion molecules (JAM), and plaque proteins including the zonula occludens proteins (ZOP) (Ulluwishewa et al., 2011). The intestinal permeability increased in some conditions such as autoimmune, inflammatory, and atopic diseases (Ulluwishewa et al., 2011). The analysis of TJ permeability in human and rat colon tumours showed that TJs are highly permeable and also colon polyps with more permeable TJs resulted in more frequent cancer development (Soler et al., 1999). Therefore, the maintenance of intestinal barrier integrity may prevent cancer development where some probiotic bacteria can affect intestinal barrier function (Ramakrishna, 2009). L. plantarum increased integrity of tight junctions across Caco-2 cell layers and could enhance the expression of genes encoding occludin or tubulin involved in tight junction function (Anderson et al., 2010). The probiotics consumption in 6 days preoperatively and 10 days postoperatively in patients with colorectal carcinoma increased trans-epithelial resistance and reduced transmucosal permeation of horseradish peroxidase and lactulose/ mannitol ratio. It also reduced bacterial translocation, and enhanced mucosal tight junction protein expression (Liu et al., 2011). L. plantarum significantly increased zonula occludens (ZO)-1 and trans-membrane protein occludin in healthy subjects (Karczewski et al., 2010). Probiotic mixture, VSL#3, protects the epithelial barrier by preventing the expression reduction tight junction proteins occludin, zonula occludens-1, and claudin-1, -3, -4, and -5 in acute colitis (Mennigen et al., 2009). The exact mechanisms regarding the probiotics protection of intestinal barrier and the upregulation of tight junction proteins are unknown but it seems that probiotics can activate some intracellular signalling pathways such as MAPK or

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by bacteriocin production (Dai, Zhao, & Jiang, 2012; Miyauchi et al., 2012).

6. Probiotic, carcinogenic compounds, potential mutagens and CRC Exposure to carcinogens and mutagens especially those derived from food such as heterocyclic amines (HAs), aromatic amines (AAs) and polycyclic aromatic hydrocarbons (PAHs) may be an important risk factor for colorectal cancer (Sachse et al., 2002). Some compositions such as HAs and/or polycyclic aromatic hydrocarbons (PAHs) and N-nitroso compounds during frying, grilling and broiling of meat and fish or cooking on cool are formed that are potentially carcinogens (Kim, Coelho, & Blachier, 2013). Also, PAHs are derived from vegetable oils (Kassie et al., 2001). Epidemiological studies proved a positive association between red and processed meat consumption with colorectal cancer (Abid, Cross, & Sinha, 2014). In a meta-analysis of 22 cohort and case-control studies, it was shown that red meat consumption over 50 g/day has a positive relationship with colon cancer (relative risk 1.21, 1.07–1.37) (Smolinska & Paluszkiewicz, 2010). One of the possible mechanisms for this relationship is the production of mentioned compounds during cooking (Kim et al., 2013). There is limited evidence about the impact of intestinal microflora on the carcinogenic effects of these compounds, but it seems some species in gut microbiota such as Bacteroides, Clostridium, Eubacterium and E. coli can activate them to their active derivatives. On the other hand, lactic acid bacteria existing in the colon may bind heterocyclic amines and decrease their mutagenic effects (Kassie et al., 2001; Nowak & Libudzisz, 2009; Uccello et al., 2012). Anti-mutagenic properties of probiotic bacteria have been investigated in several studies. Nowak and Libudzisz indicated that L. casei DN 114001 is able to bind three heterocyclic aromatic amines (IQ, MelQx and PhIP) in vitro and decrease concentration and genotoxicity of HCA (Nowak & Libudzisz, 2009). Fuchs et al. (2008) studied the removal of the two mycotoxins including ochratoxin A (OTA) and patulin (PAT), frequently found in human foods, by lactic acid bacteria (LAB). The findings showed that some strains of LABs could detoxify these two toxins. Bacterial enzymes such as β-glucuronidase, nitroreductase, and azoreductase metabolize ingested foreign compounds. These enzymes are important in the pathogenesis of colon cancer and converting pro-carcinogens to carcinogens. Previous studies have reported that lactic acid bacteria may decrease the level of bacterial enzymes (Aranganathan, Selvam, & Nalini, 2008; Kumar et al., 2010; Lee do et al., 2009). Therefore, the binding of probiotics to mutagens and elimination of them from body and prevention of the activation of them by bacterial enzymes is one of the mechanisms for decreasing of the carcinogenicity of such mutagens.

7.

Probiotics, bile acids and CRC

The primary bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA) are synthesized from cholesterol in the liver and then stored in the gall bladder. After a meal, especially rich in

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fat, these bile acids release into the duodenal lumen and act as detergents for absorption lipids and lipid-soluble vitamins. The bile salts are then absorbed in the distal ileum and about 15% of them reach the colon. In the colon, the secondary bile acids such as deoxycholic acid (DCA) and lithocholic acid (LCA) are formed through biotransformation by intestinal anaerobic bacteria (Barrasa, Olmo, Lizarbe, & Turnay, 2013; Debruyne et al., 2001; Ridlon, Kang, & Hylemon, 2006). This modification increases the probability of harmful effects of bile acids such as carcinogenicity and cholesterol gallstone disease. Elevated secondary bile acid concentrations enhance the cell proliferation. Besides, when the conditions of biotransformation like microbiota and diet are changed, the composition of the bile acids pool will alter (Degirolamo, Modica, Palasciano, & Moschetta, 2011; Martinez-Augustin & Sanchez de Medina, 2008). Epidemiological studies indicate an association between bile acids and colon cancer. Several reasons were suggested for this association including higher concentration of steroid in faecal sample in areas with high incidence of colon cancer, higher concentration of secondary bile acids and higher faecal LCA/ DCA ratio in faecal specimens in people with colorectal cancer compared to healthy volunteers. High percentage of bile acidspecific binding sites have been observed in mouse and human colorectal cancers not in normal colonic mucosa (Debruyne et al., 2001). Based on animal studies’ findings, bile acids act as tumour promoters not mutagens although recent studies offer the carcinogenic potential of DCA (Bernstein et al., 2011; Debruyne et al., 2001). The consumption of L. casei Zhang (LcZ), isolated from fermented milk (10.6 log10 cfu LcZ daily for a continuous period of 28 days), in Chinese subjects of different ages reduced total bile acids in faecal samples (Wang et al., 2014). The oral consumption of probiotic L. planatarum P-8 decreased the faecal total bile acids significantly and reached the lowest level on week 5 (Wang et al., 2014).

8.

Probiotics, immune system and CRC

There is an established relationship between inflammation and colorectal cancer (Djaldetti & Bessler, 2014).The immune system possesses an important role in the control of tumour promotion and progression in colon (Uccello et al., 2012). The several elements of the immune system play a crucial role in the tumourigenesis, development and migration of tumour cells. Besides, the production of anti-inflammatory cytokines in the affected colonic mucosa will cause delay, or even stop the malignant expansion.Therefore, altering cytokine secretion towards increased anti-inflammatory cytokines can be a strategy for the treatment of malignant diseases (Djaldetti & Bessler, 2014). Enormous investigation findings show the ability of probiotic bacteria in the enhancement of the mucosal and systemic immune responses (Ashraf & Shah, 2014). The interaction of probiotic bacteria with intestinal cells initiates a host response and produces various immunomodulatory molecules (Delcenserie et al., 2008). Probiotics can influence innate defence mechanisms such as phagocytosis and adaptive immunity. For the induction of the local immune response in the gut, there are different pathways. After the interaction with the epithelial cells and internalization of probiotic bacteria or their

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fragments, the first cells that interact with them are macrophages and/or dendritic cells (DCs) associated with the lamina propria of the gut. Macrophages and dendritic cells phagocytose the probiotic bacteria or their fragments that induces to produce cytokines such as TNF-α and IFN-γ. These interactions result in increasing epithelial cell stimulation and initiate the cross talk between all the associated immune cells (Galdeano, de Moreno de LeBlanc, Vinderola, Bonet, & Perdigon, 2007). Dendritic cells (DCs), macrophages and monocytes provide an interface between the innate and adaptive immune systems. They act as professional “antigen-presenting cells” (APCs) that are crucial in initiating the adaptive immune response (Delcenserie et al., 2008). DC maturation by probiotic organisms results in the development of Treg cells. These Treg cells produced increased levels of IL-10. IL-10 has an anti-inflammatory effect and inhibits the Th1 response (pro-inflammatory cytokines. Also, probiotics induce an anti-inflammatory response on the intestinal mucosal immune system by suppressing T cell proliferation. This effect could be induced by products generated as the probiotics break down intestinal content. Also, probiotic bacteria induce systemic immune response by interaction with the immune cells of Peyer’s patches. Many probiotics stimulate the production of IgA by B cells, which help maintain intestinal humoural immunity by binding to antigens, therewith limiting their access to the epithelium (Ashraf & Shah, 2014; Delcenserie et al., 2008; Forsythe & Bienenstock, 2010; Galdeano et al., 2007). Probiotics mediate the cytokine secretion through signalling pathways such as NFκB and MAPKs, which can also affect proliferation and differentiation of immune cells (such as T cells) or epithelial cells (Hemarajata & Versalovic, 2013). However, probiotics act in strain-specific and dose-dependent manner. L. plantarum attenuates intestinal inflammation and chronic inflammation but some specific strains of Lactobacillus can induce pro-inflammatory cytokines production such as interleukin (IL)-1, IL-6 and IL-12, as well as the ant-inflammatory cytokine IL-10 (Paolillo, Romano Carratelli, Sorrentino, Mazzola, & Rizzo, 2009). The chronic inflammation is a key predisposing factor of CRC in IBD. Pretreatment with the probiotic VSL#3 attenuated some inflammatory-associated parameters and delayed transition from inflammation to cancer in a rat model of colitisassociated cancer (Appleyard et al., 2011). The VSL#3 probiotic bacteria suppressed colon carcinogenesis by targeting regulatory mucosal CD4 + T cell responses in mouse models of inflammation-driven colorectal cancer (Bassaganya-Riera, Viladomiu, Pedragosa, De Simone, & Hontecillas, 2012). So, it seems that probiotics can play a significant role in prevention of cancer development and progression by reducing inflammatory responses to gut flora and enhancing the mucosal and systemic immunity.

9.

(Stone, Krishnan, Campbell, & Palau, 2014). The production of free radicals in excessive amounts is caused to react with macromolecules, such as lipids, proteins, and DNA and can influence gene expression (Perse, 2013). In addition, probiotics possess antioxidant effects on administered individuals. L. acidophilus administration in Sprague–Dawley rats with dimethylhydrazine dihydrochloride-induced colon carcinogenesis decreased malondialdehyde and increased levels of the antioxidants, glutathione reductase, superoxide dismutase, and glutathione peroxidase (Verma & Shukla, 2014). The administration of milk fermented with probiotic L. rhamnosus in 16 month old mice increased the activity of antioxidant enzymes like glutathione reductase (Sharma, Kapila, Dass, & Kapila, 2014). L. fermentum ME-3 improved the total anti-oxidative activity/status indices in healthy volunteers (Songisepp et al., 2005). Probiotics exert anti-oxidative is affected by different mechanisms such as Exopolysaccharides production which are long-chain, high molecular-mass polymers. Bacillus coagulans RK-02 synthesizes an Exopolysaccharides, a heteropolymer composed of four monosaccharides, had significant antioxidant and free radical scavenging activities (Kodali & Sen, 2008).

10. Probiotics, cell proliferation, apoptosis and CRC Resistance to apoptosis and uncontrolled proliferation of the cells are the main features of many cancer types including colorectal cancer. Apoptosis is programmed cell death that plays an important role in controlling cell numbers. Therefore, the regulation of cell proliferation and death can be one of cancer treatment strategies (Zhong, Zhang, & Covasa, 2014). Probiotic bacteria can regulate cell apoptosis and proliferation. Lactic acid bacteria isolated from infant faeces inhibited colon cancer cell proliferation through direct adhesion to cancer cells and production of SCFA (Thirabunyanon & Hongwittayakorn, 2013). The anti-proliferative effect of L. acidophilus and L. plantarum on colon cancer cells via induction of apoptosis has been previously reported by several researchers (Chen et al., 2012a; Nami et al., 2014; Thirabunyanon, Boonprasom, & Niamsup, 2009). The viable or heat-killed cells of L. paracasei IMPC2.1 and L. rhamnosus GG inhibited the growth and induced the apoptosis in DLD-1 colon cell line (Orlando et al., 2012). The supernatants obtained from L. delbrueckii fermentation arrested the proliferation of colon cancer SW620 cells in the G1 phase and induced apoptosis through the intrinsic caspase 3-dependent pathway by decreasing the BcL-2 expression. The activity of matrix metalloproteinase 9 was also reduced by probiotic treatment (Wan et al., 2014). Bacillus polyfermenticus inhibited ErbB2 and ErbB3 protein expression at mRNA levels in HT-29 human colon cancer cells (Ma et al., 2010). According to these findings, probiotics are able to suppress the CRC development via the inhibition of cell proliferation and the induction of apoptosis by influencing different signalling pathways.

Probiotics, oxidative stress and CRC 11.

Oxidative stress is an imbalance between pro-oxidant and antioxidant factors.The reactive oxygen species (ROS) are genotoxic and may have an important role in colon cancer pathogenesis

Probiotics, neuromodulation and CRC

The human gastrointestinal tract contains a complex neural network called the enteric nervous system (ENS) whose regulate

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the physiological functions of the gut. The brain–gut axis communicates between the central nervous system (CNS) and the ENS and moderates the endocrine and immune systems involved in maintaining gut function (Saulnier et al., 2013). The gut microbiota has an impact on the brain–gut axis and exerts multiple effects on the intestinal neuroimmune system via production of neuroactive and neuroendocrine molecules such as serotonin, GABA, histamine, noradrenaline and adrenaline which influence a variety of host functions including metabolic activity, immune response and physiological function (Hemarajata & Versalovic, 2013). The interactions between intestinal microbes and the enteric nervous system may modulate immunologic responses in the intestine and extraintestinal sites. The ENS is protected from the luminal content by the intestinal barrier. The gut microbiota and certain probiotics can promote the development of the intestinal barrier through alteration of the expression of tight junction proteins, increased IgA production, mucin expression, prevention of intestinal epithelial cell apoptosis, inhibition of colonization by enteric pathogens and the immune response. Also, probiotics or their products directly target intestinal sensory nerves (Saulnier et al., 2013). The communication between the immune and the nervous system cytokines play important roles in brain–gut communications. Probiotic treatment resulted in normalization of the immune response, reversal of behavioural deficits peripheral interleukin-6 release and amygdala corticotrophin-releasing factor mRNA level and restoration of basal noradrenaline concentrations in the brainstem (Desbonnet et al., 2010). This area is novel insights for improved understanding of the potential role of gut microbiota and new opportunity for interventions with pro- and prebiotics.

12.

Conclusion and future prospective

Although a wide range of studies were carried out regarding the effects of probiotic on colorectal cancer, its exact mechanism is not precisely clear. Several evidence has recently been explained regarding the effects of probiotics cellular and molecular mechanisms on CRC such as (I) modification of gut microbial composition/homeostasis, (II) competition with pathogens, (III) production of active compounds against human colon cancer cells, (IV) protection of intestinal barrier, (V) binding to mutagens and elimination of them from body, (VI) decreasing harmful effects of bile acids, (VII) enhancement of the mucosal and system immune responses, (VIII) anti-oxidant effect and controlling cell proliferation and apoptosis. Furthermore, the claimed health benefits of probiotic bacteria are strain specific and there is no universal strain that would yield all these benefits thus each strain can exert its effects through its special mechanisms. Besides, most studies were performed experimentally on animal models while large clinical studies are required to determine probiotics’ exact effects on cancer. In addition, further investigations are strongly required to establish the impact of each mechanism and the actual usefulness in CRC prevention or control and the duration, kind, and amount of probiotic consumption must be specified to obtain desirable and beneficial effects. However,

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even with the limited number of human studies available, the use of probiotics for human cancer suppression especially CRC is interesting, holds promise and is worthy more investigation.

Ethical issues No ethical issues to be promulgated.

Conflict of interest statement The authors declare that there are no conflicts of interests.

Acknowledgements The financial support of the Tabriz University of Medical Sciences, Tabriz, Iran is gratefully acknowledged.

REFERENCES

Abid, Z., Cross, A. J., & Sinha, R. (2014). Meat, dairy, and cancer. The American Journal of Clinical Nutrition, 100(Suppl. 1), 386S– 393S. Anderson, R. C., Cookson, A. L., McNabb, W. C., Park, Z., McCann, M. J., Kelly, W. J., & Roy, N. C. (2010). Lactobacillus plantarum MB452 enhances the function of the intestinal barrier by increasing the expression levels of genes involved in tight junction formation. BMC Microbiology, 10, 316. Appleyard, C. B., Cruz, M. L., Isidro, A. A., Arthur, J. C., Jobin, C., & De Simone, C. (2011). Pretreatment with the probiotic VSL#3 delays transition from inflammation to dysplasia in a rat model of colitis-associated cancer. American Journal of Physiology. Gastrointestinal and Liver Physiology, 301(6), G1004– G1013. Aranganathan, S., Selvam, J. P., & Nalini, N. (2008). Effect of hesperetin, a citrus flavonoid, on bacterial enzymes and carcinogen-induced aberrant crypt foci in colon cancer rats: A dose-dependent study. The Journal of Pharmacy and Pharmacology, 60(10), 1385–1392. Arthur, J. C., Gharaibeh, R. Z., Uronis, J. M., Perez-Chanona, E., Sha, W., Tomkovich, S., & Jobin, C. (2013). VSL#3 probiotic modifies mucosal microbial composition but does not reduce colitis-associated colorectal cancer. Science Reports, 3, 2868. Ashraf, R., & Shah, N. P. (2014). Immune system stimulation by probiotic microorganisms. Critical Reviews in Food Science and Nutrition, 54(7), 938–956. Barrasa, J. I., Olmo, N., Lizarbe, M. A., & Turnay, J. (2013). Bile acids in the colon, from healthy to cytotoxic molecules. Toxicology in Vitro: An International Journal Published in Association With BIBRA, 27(2), 964–977. Bassaganya-Riera, J., Viladomiu, M., Pedragosa, M., De Simone, C., & Hontecillas, R. (2012). Immunoregulatory mechanisms underlying prevention of colitis-associated colorectal cancer by probiotic bacteria. PLoS ONE, 7(4), e34676. Beppu, F., Hosokawa, M., Tanaka, L., Kohno, H., Tanaka, T., & Miyashita, K. (2006). Potent inhibitory effect of trans9, trans11 isomer of conjugated linoleic acid on the growth of human colon cancer cells. The Journal of Nutritional Biochemistry, 17(12), 830–836.

470

Journal of Functional Foods 18 (2015) 463–472

Bernstein, C., Holubec, H., Bhattacharyya, A. K., Nguyen, H., Payne, C. M., Zaitlin, B., & Bernstein, H. (2011). Carcinogenicity of deoxycholate, a secondary bile acid. Archives of Toxicology, 85(8), 863–871. Burns, A. J., & Rowland, I. R. (2004). Antigenotoxicity of probiotics and prebiotics on faecal water-induced DNA damage in human colon adenocarcinoma cells. Mutation Research, 551(1–2), 233–243. Canani, R. B., Costanzo, M. D., Leone, L., Pedata, M., Meli, R., & Calignano, A. (2011). Potential beneficial effects of butyrate in intestinal and extraintestinal diseases. World Journal of Gastroenterology, 17(12), 1519–1528. Chen, C. C., Lin, W. C., Kong, M. S., Shi, H. N., Walker, W. A., Lin, C. Y., & Lin, T. Y. (2012a). Oral inoculation of probiotics Lactobacillus acidophilus NCFM suppresses tumour growth both in segmental orthotopic colon cancer and extra-intestinal tissue. The British Journal of Nutrition, 107(11), 1623–1634. Chen, W., Liu, F., Ling, Z., Tong, X., & Xiang, C. (2012b). Human intestinal lumen and mucosa-associated microbiota in patients with colorectal cancer. PLoS ONE, 7(6), e39743. Cho, H. J., Kim, E. J., Lim, S. S., Kim, M. K., Sung, M. K., Kim, J. S., & Park, J. H. (2006). Trans-10,cis-12, not cis-9,trans-11, conjugated linoleic acid inhibits G1-S progression in HT-29 human colon cancer cells. The Journal of Nutrition, 136(4), 893– 898. Cho, H. J., Kim, W. K., Jung, J. I., Kim, E. J., Lim, S. S., Kwon, D. Y., & Park, J. H. (2005). Trans-10,cis-12, not cis-9,trans-11, conjugated linoleic acid decreases ErbB3 expression in HT-29 human colon cancer cells. World Journal of Gastroenterology, 11(33), 5142–5150. Cho, H. J., Kim, W. K., Kim, E. J., Jung, K. C., Park, S., Lee, H. S., & Park, J. H. (2003). Conjugated linoleic acid inhibits cell proliferation and ErbB3 signaling in HT-29 human colon cell line. American Journal of Physiology. Gastrointestinal and Liver Physiology, 284(6), G996–G1005. Chow, J., Tang, H., & Mazmanian, S. K. (2011). Pathobionts of the gastrointestinal microbiota and inflammatory disease. Current Opinion in Immunology, 23(4), 473–480. Collado, M. C., Jalonen, L., Meriluoto, J., & Salminen, S. (2006). Protection mechanism of probiotic combination against human pathogens: In vitro adhesion to human intestinal mucus. Asia Pacific Journal of Clinical Nutrition, 15(4), 570–575. den Besten, G., van Eunen, K., Groen, A. K., Venema, K., Reijngoud, D. J., & Bakker, B. M. (2013). The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. Journal of Lipid Research, 54(9), 2325– 2340. Dai, C., Zhao, D. H., & Jiang, M. (2012). VSL#3 probiotics regulate the intestinal epithelial barrier in vivo and in vitro via the p38 and ERK signaling pathways. International Journal of Molecular Medicine, 29(2), 202–208. Daroqui, M. C., & Augenlicht, L. H. (2010). Transcriptional attenuation in colon carcinoma cells in response to butyrate. Cancer Prev Res (Phila), 3(10), 1292–1302. De la Torre, A., Debiton, E., Durand, D., Chardigny, J. M., Berdeaux, O., Loreau, O., & Gruffat, D. (2005). Conjugated linoleic acid isomers and their conjugated derivatives inhibit growth of human cancer cell lines. Anticancer Research, 25(6B), 3943–3949. Debruyne, P. R., Bruyneel, E. A., Li, X., Zimber, A., Gespach, C., & Mareel, M. M. (2001). The role of bile acids in carcinogenesis. Mutation Research, 480–481, 359–369. Degirolamo, C., Modica, S., Palasciano, G., & Moschetta, A. (2011). Bile acids and colon cancer: Solving the puzzle with nuclear receptors. Trends in Molecular Medicine, 17(10), 564–572. Delcenserie, V., Martel, D., Lamoureux, M., Amiot, J., Boutin, Y., & Roy, D. (2008). Immunomodulatory effects of probiotics in the intestinal tract. Current Issues in Molecular Biology, 10(1–2), 37– 54.

Desbonnet, L., Garrett, L., Clarke, G., Kiely, B., Cryan, J. F., & Dinan, T. G. (2010). Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression. Neuroscience, 170(4), 1179–1188. Djaldetti, M., & Bessler, H. (2014). Modulators affecting the immune dialogue between human immune and colon cancer cells. World Journal of Gastrointestinal Oncology, 6(5), 129– 138. Erdman, S. E., Rao, V. P., Poutahidis, T., Rogers, A. B., Taylor, C. L., Jackson, E. A., & Fox, J. G. (2009). Nitric oxide and TNF-alpha trigger colonic inflammation and carcinogenesis in Helicobacter hepaticus-infected, Rag2-deficient mice. Proceedings of the National Academy of Sciences of the United States of America, 106(4), 1027–1032. Ewaschuk, J. B., Walker, J. W., Diaz, H., & Madsen, K. L. (2006). Bioproduction of conjugated linoleic acid by probiotic bacteria occurs in vitro and in vivo in mice. The Journal of Nutrition, 136(6), 1483–1487. Forsythe, P., & Bienenstock, J. (2010). Immunomodulation by commensal and probiotic bacteria. Immunological Investigations, 39(4–5), 429–448. Fuchs, S., Sontag, G., Stidl, R., Ehrlich, V., Kundi, M., & Knasmuller, S. (2008). Detoxification of patulin and ochratoxin A, two abundant mycotoxins, by lactic acid bacteria. Food and Chemical Toxicology: An International Journal Published for the British Industrial Biological Research Association, 46(4), 1398– 1407. Galdeano, C. M., de Moreno de LeBlanc, A., Vinderola, G., Bonet, M. E., & Perdigon, G. (2007). Proposed model: Mechanisms of immunomodulation induced by probiotic bacteria. Clinical and Vaccine Immunology, 14(5), 485–492. Ganapathy, V., Thangaraju, M., Prasad, P. D., Martin, P. M., & Singh, N. (2013). Transporters and receptors for short-chain fatty acids as the molecular link between colonic bacteria and the host. Current Opinion in Pharmacology, 13(6), 869–874. Garrett, W. S., Punit, S., Gallini, C. A., Michaud, M., Zhang, D., Sigrist, K. S., & Glimcher, L. H. (2009). Colitis-associated colorectal cancer driven by T-bet deficiency in dendritic cells. Cancer Cell, 16(3), 208–219. Gold, J. S., Bayar, S., & Salem, R. R. (2004). Association of Streptococcus bovis bacteremia with colonic neoplasia and extracolonic malignancy. Archives of Surgery (Chicago, Ill.: 1960), 139(7), 760–765. Hamer, H. M., Jonkers, D., Venema, K., Vanhoutvin, S., Troost, F. J., & Brummer, R. J. (2008). Review article: The role of butyrate on colonic function. Alimentary Pharmacology and Therapeutics, 27(2), 104–119. Hardy, H., Harris, J., Lyon, E., Beal, J., & Foey, A. D. (2013). Probiotics, prebiotics and immunomodulation of gut mucosal defences: Homeostasis and immunopathology. Nutrients, 5(6), 1869–1912. Hemarajata, P., & Versalovic, J. (2013). Effects of probiotics on gut microbiota: Mechanisms of intestinal immunomodulation and neuromodulation. Therapy Advanced Gastroenterology, 6(1), 39–51. Hill, C., Guarner, F., Reid, G., Gibson, G. R., Merenstein, D. J., Pot, B., & Sanders, M. E. (2014). Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nature Reviews. Gastroenterology & Hepatology, 11(8), 506–514. Huang, G., Zhong, X., Cao, Y., & Chen, Y. (2007). Antiproliferative effects of conjugated linoleic acid on human colon adenocarcinoma cell line Caco-2. Asia Pacific Journal of Clinical Nutrition, 16(Suppl. 1), 432–436. Jeon, M. K., Klaus, C., Kaemmerer, E., & Gassler, N. (2013). Intestinal barrier: Molecular pathways and modifiers. World Journal of Gastrointestinal Pathophysiology, 4(4), 94–99.

Journal of Functional Foods 18 (2015) 463–472

Karczewski, J., Troost, F. J., Konings, I., Dekker, J., Kleerebezem, M., Brummer, R. J., & Wells, J. M. (2010). Regulation of human epithelial tight junction proteins by Lactobacillus plantarum in vivo and protective effects on the epithelial barrier. American Journal of Physiology. Gastrointestinal and Liver Physiology, 298(6), G851–G859. Kassie, F., Rabot, S., Kundi, M., Chabicovsky, M., Qin, H. M., & Knasmuller, S. (2001). Intestinal microflora plays a crucial role in the genotoxicity of the cooked food mutagen 2-amino-3-methylimidazo [4,5-f]quinoline. Carcinogenesis, 22(10), 1721–1725. Kim, E., Coelho, D., & Blachier, F. (2013). Review of the association between meat consumption and risk of colorectal cancer. Nutrition Research (New York, N.Y.), 33(12), 983–994. Kim, E. J., Kang, I. J., Cho, H. J., Kim, W. K., Ha, Y. L., & Park, J. H. (2003). Conjugated linoleic acid downregulates insulin-like growth factor-I receptor levels in HT-29 human colon cancer cells. The Journal of Nutrition, 133(8), 2675–2681. Kodali, V. P., & Sen, R. (2008). Antioxidant and free radical scavenging activities of an exopolysaccharide from a probiotic bacterium. Biotechnology Journal, 3(2), 245–251. Konstantinov, S. R., Kuipers, E. J., & Peppelenbosch, M. P. (2013). Functional genomic analyses of the gut microbiota for CRC screening. Nature Reviews. Gastroenterology & Hepatology, 10(12), 741–745. Kumar, M., Kumar, A., Nagpal, R., Mohania, D., Behare, P., Verma, V., & Yadav, H. (2010). Cancer-preventing attributes of probiotics: An update. International Journal of Food Sciences and Nutrition, 61(5), 473–496. Lee do, K., Jang, S., Baek, E. H., Kim, M. J., Lee, K. S., Shin, H. S., & Ha, N. J. (2009). Lactic acid bacteria affect serum cholesterol levels, harmful fecal enzyme activity, and fecal water content. Lipids in Health and Disease, 8, 21. Liu, Z., Qin, H., Yang, Z., Xia, Y., Liu, W., Yang, J., & Zheng, Q. (2011). Randomised clinical trial: The effects of perioperative probiotic treatment on barrier function and post-operative infectious complications in colorectal cancer surgery – A double-blind study. Alimentary Pharmacology and Therapeutics, 33(1), 50–63. Lozupone, C. A., Stombaugh, J. I., Gordon, J. I., Jansson, J. K., & Knight, R. (2012). Diversity, stability and resilience of the human gut microbiota. Nature, 489(7415), 220–230. Ma, E. L., Choi, Y. J., Choi, J., Pothoulakis, C., Rhee, S. H., & Im, E. (2010). The anticancer effect of probiotic Bacillus polyfermenticus on human colon cancer cells is mediated through ErbB2 and ErbB3 inhibition. International Journal of Cancer, 127(4), 780–790. Martinez-Augustin, O., & Sanchez de Medina, F. (2008). Intestinal bile acid physiology and pathophysiology. World Journal of Gastroenterology, 14(37), 5630–5640. Mennigen, R., Nolte, K., Rijcken, E., Utech, M., Loeffler, B., Senninger, N., & Bruewer, M. (2009). Probiotic mixture VSL#3 protects the epithelial barrier by maintaining tight junction protein expression and preventing apoptosis in a murine model of colitis. American Journal of Physiology. Gastrointestinal and Liver Physiology, 296(5), G1140–G1149. Miller, A., Stanton, C., & Devery, R. (2002). Cis 9, trans 11- and trans 10, cis 12-conjugated linoleic acid isomers induce apoptosis in cultured SW480 cells. Anticancer Research, 22(6C), 3879–3887. Miyauchi, E., O’Callaghan, J., Butto, L. F., Hurley, G., Melgar, S., Tanabe, S., & O’Toole, P. W. (2012). Mechanism of protection of transepithelial barrier function by Lactobacillus salivarius: Strain dependence and attenuation by bacteriocin production. American Journal of Physiology. Gastrointestinal and Liver Physiology, 303(9), G1029–G1041. Nami, Y., Abdullah, N., Haghshenas, B., Radiah, D., Rosli, R., & Khosroushahi, A. Y. (2014). Assessment of probiotic potential

471

and anticancer activity of newly isolated vaginal bacterium Lactobacillus plantarum 5BL. Microbiology and Immunology, 58(9), 492–502. Nanda Kumar, N. S., Balamurugan, R., Jayakanthan, K., Pulimood, A., Pugazhendhi, S., & Ramakrishna, B. S. (2008). Probiotic administration alters the gut flora and attenuates colitis in mice administered dextran sodium sulfate. Journal of Gastroenterology and Hepatology, 23(12), 1834–1839. Nowak, A., & Libudzisz, Z. (2009). Ability of probiotic Lactobacillus casei DN 114001 to bind or/and metabolise heterocyclic aromatic amines in vitro. European Journal of Nutrition, 48(7), 419–427. Ogawa, J., Kishino, S., Ando, A., Sugimoto, S., Mihara, K., & Shimizu, S. (2005). Production of conjugated fatty acids by lactic acid bacteria. Journal of Bioscience and Bioengineering, 100(4), 355–364. Ohigashi, S., Sudo, K., Kobayashi, D., Takahashi, O., Takahashi, T., Asahara, T., & Onodera, H. (2013). Changes of the intestinal microbiota, short chain fatty acids, and fecal pH in patients with colorectal cancer. Digestive Diseases and Sciences, 58(6), 1717–1726. O’Mahony, L., Feeney, M., O’Halloran, S., Murphy, L., Kiely, B., Fitzgibbon, J., & Collins, J. K. (2001). Probiotic impact on microbial flora, inflammation and tumour development in IL-10 knockout mice. Alimentary Pharmacology and Therapeutics, 15(8), 1219–1225. Orlando, A., Refolo, M. G., Messa, C., Amati, L., Lavermicocca, P., Guerra, V., & Russo, F. (2012). Antiproliferative and proapoptotic effects of viable or heat-killed Lactobacillus paracasei IMPC2.1 and Lactobacillus rhamnosus GG in HGC-27 gastric and DLD-1 colon cell lines. Nutrition and Cancer, 64(7), 1103–1111. Palombo, J. D., Ganguly, A., Bistrian, B. R., & Menard, M. P. (2002). The antiproliferative effects of biologically active isomers of conjugated linoleic acid on human colorectal and prostatic cancer cells. Cancer Letters, 177(2), 163–172. Paolillo, R., Romano Carratelli, C., Sorrentino, S., Mazzola, N., & Rizzo, A. (2009). Immunomodulatory effects of Lactobacillus plantarum on human colon cancer cells. International Immunopharmacology, 9(11), 1265–1271. Pericleous, M., Mandair, D., & Caplin, M. E. (2013). Diet and supplements and their impact on colorectal cancer. Journal of Gastrointestinal Oncology, 4(4), 409–423. Perse, M. (2013). Oxidative stress in the pathogenesis of colorectal cancer: Cause or consequence? Biomedicine Research International, 2013, 725710. Rafter, J. (2004). The effects of probiotics on colon cancer development. Nutrition Research Reviews, 17(2), 277–284. Ramakrishna, B. S. (2009). Probiotic-induced changes in the intestinal epithelium: Implications in gastrointestinal disease. Tropical Gastroenterology, 30(2), 76–85. Ridlon, J. M., Kang, D. J., & Hylemon, P. B. (2006). Bile salt biotransformations by human intestinal bacteria. Journal of Lipid Research, 47(2), 241–259. Sachse, C., Smith, G., Wilkie, M. J., Barrett, J. H., Waxman, R., Sullivan, F., & Wolf, C. R. (2002). A pharmacogenetic study to investigate the role of dietary carcinogens in the etiology of colorectal cancer. Carcinogenesis, 23(11), 1839– 1849. Sakata, T., Kojima, T., Fujieda, M., Takahashi, M., & Michibata, T. (2003). Influences of probiotic bacteria on organic acid production by pig caecal bacteria in vitro. The Proceedings of the Nutrition Society, 62(1), 73–80. Sanders, M. E. (2011). Impact of probiotics on colonizing microbiota of the gut. Journal of Clinical Gastroenterology, 45(Suppl.), S115–S119. Saulnier, D. M., Ringel, Y., Heyman, M. B., Foster, J. A., Bercik, P., Shulman, R. J., & Guarner, F. (2013). The intestinal

472

Journal of Functional Foods 18 (2015) 463–472

microbiome, probiotics and prebiotics in neurogastroenterology. Gut Microbes, 4(1), 17–27. Savard, P., Lamarche, B., Paradis, M. E., Thiboutot, H., Laurin, E., & Roy, D. (2011). Impact of Bifidobacterium animalis subsp. lactis BB-12 and, Lactobacillus acidophilus LA-5-containing yoghurt, on fecal bacterial counts of healthy adults. International Journal of Food Microbiology, 149(1), 50–57. Sharma, R., Kapila, R., Dass, G., & Kapila, S. (2014). Improvement in Th1/Th2 immune homeostasis, antioxidative status and resistance to pathogenic E. coli on consumption of probiotic Lactobacillus rhamnosus fermented milk in aging mice. Age (Dordr), 36(4), 9686. Shen, L., Su, L., & Turner, J. R. (2009). Mechanisms and functional implications of intestinal barrier defects. Digestive Diseases (Basel, Switzerland), 27(4), 443–449. Siegel, R., Naishadham, D., & Jemal, A. (2012). Cancer statistics, 2012. CA: A Cancer Journal for Clinicians, 62(1), 10–29. Smolinska, K., & Paluszkiewicz, P. (2010). Risk of colorectal cancer in relation to frequency and total amount of red meat consumption. Systematic review and meta-analysis. Archives of Medical Science, 6(4), 605–610. Sobhani, I., Tap, J., Roudot-Thoraval, F., Roperch, J. P., Letulle, S., Langella, P., & Furet, J. P. (2011). Microbial dysbiosis in colorectal cancer (CRC) patients. PLoS ONE, 6(1), e16393. Sokol, H., Pigneur, B., Watterlot, L., Lakhdari, O., Bermudez-Humaran, L. G., Gratadoux, J. J., & Langella, P. (2008). Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proceedings of the National Academy of Sciences of the United States of America, 105(43), 16731– 16736. Soler, A. P., Miller, R. D., Laughlin, K. V., Carp, N. Z., Klurfeld, D. M., & Mullin, J. M. (1999). Increased tight junctional permeability is associated with the development of colon cancer. Carcinogenesis, 20(8), 1425–1431. Songisepp, E., Kals, J., Kullisaar, T., Mandar, R., Hutt, P., Zilmer, M., & Mikelsaar, M. (2005). Evaluation of the functional efficacy of an antioxidative probiotic in healthy volunteers. Nutrition Journal, 4, 22. Stone, W. L., Krishnan, K., Campbell, S. E., & Palau, V. E. (2014). The role of antioxidants and pro-oxidants in colon cancer. World Journal of Gastrointestinal Oncology, 6(3), 55–66. Tang, Y., Chen, Y., Jiang, H., & Nie, D. (2011). The role of short-chain fatty acids in orchestrating two types of programmed cell death in colon cancer. Autophagy, 7(2), 235– 237. Thirabunyanon, M., Boonprasom, P., & Niamsup, P. (2009). Probiotic potential of lactic acid bacteria isolated from fermented dairy milks on antiproliferation of colon cancer cells. Biotechnology Letters, 31(4), 571–576.

Thirabunyanon, M., & Hongwittayakorn, P. (2013). Potential probiotic lactic acid bacteria of human origin induce antiproliferation of colon cancer cells via synergic actions in adhesion to cancer cells and short-chain fatty acid bioproduction. Applied Biochemistry and Biotechnology, 169(2), 511–525. Turner, N. D., Ritchie, L. E., Bresalier, R. S., & Chapkin, R. S. (2013). The microbiome and colorectal neoplasia: Environmental modifiers of dysbiosis. Current Gastroenterology Reports, 15(9), 346. Uccello, M., Malaguarnera, G., Basile, F., D’Agata, V., Malaguarnera, M., Bertino, G., & Biondi, A. (2012). Potential role of probiotics on colorectal cancer prevention. BMC Surgery, 12(Suppl. 1), S35. Ulluwishewa, D., Anderson, R. C., McNabb, W. C., Moughan, P. J., Wells, J. M., & Roy, N. C. (2011). Regulation of tight junction permeability by intestinal bacteria and dietary components. The Journal of Nutrition, 141(5), 769–776. Verma, A., & Shukla, G. (2014). Synbiotic (Lactobacillus rhamnosus+Lactobacillus acidophilus+inulin) attenuates oxidative stress and colonic damage in 1,2 dimethylhydrazine dihydrochloride-induced colon carcinogenesis in Sprague-Dawley rats: A long-term study. European Journal of Cancer Prevention, 23(6), 550–559. Wan, Y., Xin, Y., Zhang, C., Wu, D., Ding, D., Tang, L., & Li, W. (2014). Fermentation supernatants of inhibit growth of human colon cancer cells and induce apoptosis through a caspase 3-dependent pathway. Oncology letter, 7(5), 1738–1742. Wang, L., Zhang, J., Guo, Z., Kwok, L., Ma, C., Zhang, W., & Zhang, H. (2014). Effect of oral consumption of probiotic Lactobacillus planatarum P-8 on fecal microbiota, SIgA, SCFAs, and TBAs of adults of different ages. Nutrition (Burbank, Los Angeles County, Calif.), 30(7–8), 776–783e1. Wu, N., Yang, X., Zhang, R., Li, J., Xiao, X., Hu, Y., & Zhu, B. (2013). Dysbiosis signature of fecal microbiota in colorectal cancer patients. Microbial Ecology, 66(2), 462–470. Zeng, H., Lazarova, D. L., & Bordonaro, M. (2014). Mechanisms linking dietary fiber, gut microbiota and colon cancer prevention. World J Gastrointest Oncol, 6(2), 41–51. Zhang, H., Sun, J., Liu, X., Hong, C., Zhu, Y., Liu, A., & Ren, F. (2013). Lactobacillus paracasei subsp. paracasei LC01 positively modulates intestinal microflora in healthy young adults. Journal of Microbiology (Seoul, Korea), 51(6), 777–782. Zhong, L., Zhang, X., & Covasa, M. (2014). Emerging roles of lactic acid bacteria in protection against colorectal cancer. World Journal of Gastroenterology, 20(24), 7878–7886. Zhu, Q., Gao, R., Wu, W., & Qin, H. (2013). The role of gut microbiota in the pathogenesis of colorectal cancer. Tumour Biology: The Journal of the International Society for Oncodevelopmental Biology and Medicine, 34(3), 1285–1300.