Commensals and Foodborne Pathogens Can Arbitrate Epithelial-Carcinogenesis

British Microbiology Research Journal 15(3): 1-11, 2016, Article no.BMRJ.26690 ISSN: 2231-0886, NLM ID: 101608140

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Commensals and Foodborne Pathogens can Arbitrate Epithelial-carcinogenesis

Yvon Woappi 1 and Om V. Singh 1*

1Division of Biological and Health Sciences, University of Pittsburgh, Bradford, PA-16701, USA.

Authors’ contributions

This work was carried out in collaboration between both authors. Author YW designed the study, and wrote the first draft of the manuscript and managed literature searches. Author OVS evaluated, advised, and finalized the manuscript for publication. Both authors read and approved the final manuscript.

Article Information

DOI: 10.9734/BMRJ/2016/26690 Editor(s): (1) Eggehard Holler, Cedars-Sinai Medical Center, Department of Neurosurgery, Los Angeles, USA and University of Regensburg, Germany. Reviewers: (1) Dipak Kumar Sahoo, Iowa State University, USA. (2) Anonymous, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, USA. Complete Peer review History: http://sciencedomain.org/review-history/14978

Received 28 th April 2016 th Mini-review Article Accepted 4 June 2016 Published 10 th June 2016

ABSTRACT

Major shifts in intestinal commensal bacteria often result in changes in CD4 + T lymphocyte populations, leading to an influx of Th17 cells, chronic inflammation, and eventually cancer. Consequently, the inappropriate propagation of certain commensal species in the gut has been associated with mucosal inflammatory diseases and cancer development. Recent experiments investigating the relationships between food-borne pathogens, enteric bacteria, and cancer have exposed the ability of certain bacterial species to significantly reduce tumor size and tumor progression in mice. In similar studies, pro-inflammatory Th17 and Th1 cells were at times found present along with anti-inflammatory Treg populations in the intestinal mucosa. This antitumor response was mediated by a balanced production of pro- and anti-inflammatory cytokines, resulting in a controlled threshold of mucosal immunity largely moderated by CD4 + T lymphocyte populations, through a dendritic cell-dependent pathway. These findings provide new evidence that certain species of bacteria can help manage subcutaneous tumor development by calibrating mucosal and, in some instances, systemic thresholds of innate and adaptive immunity.

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*Corresponding author: E-mail: [email protected], [email protected];

Woappi and Singh; BMRJ, 15(3): 1-11, 2016; Article no.BMRJ.26690

Keywords: Foodborne pathogens; carcinogenesis; inflammatory disease; commensal bacteria; toxins; immunity.

1. INTRODUCTION stimulates colonic inflammation and enhances colonic tumor formation, can at times improve The role of commensal bacteria and food-borne host antitumor response by contributing to pathogens is now being recognized as a major immune homeostasis through the balancing of + driving factor in the development of many types CD4 Treg, Th1, and Th2 cell populations of human cancers. In recent years, food-borne [18-20]. More recently, Viaud et al. [4] pathogens such as Salmonella spp. and demonstrated that commensals L. johnsonii and Escherichia coli have been demonstrated to E. hirae were able to polarize T cells into Th1 induce genomic mutations through the secretion and Th17 cell phenotypes and elicited a strong of carcinogenic endotoxins and cytolethal antitumor response in mice treated with distending toxins (CDT) harmful to mammalian chemotherapy compared to germ-free control cells [1-3]. And further study demonstrated that mice [4,21]. These findings provide new such strains, independent of immune cells, could evidence that certain species of enteric successfully transform mammalian cells in vitro, commensals can help manage subcutaneous thus highlighting microbials’ highly tumor- tumor development by calibrating mucosal and, promoting characteristics [1,2]. Still, despite their in some instances, systemic thresholds of innate transformed status, the cells required further and adaptive immunity [19]. genomic aberrations before becoming malignant. In vitro this is achieved by genetically Numerous key advancements in microbiological engineering cells to lack functional P53 and studies now allow us to molecularly characterize overexpress c-MYC [2]. The need for these and discern pathogenic microbes from beneficial aberrations to be present before a bacterial- gut microbial species such as commensals. induced transformed cell becomes malignant These molecular distinctions are now being indicates that additional factors besides the mere investigated for their contributing role in bacterial toxins are needed to drive pathogenesis, particularly cancer of the mucosal carcinogenesis and to maintain cells in a tissue [1,2]. More recently, however, the malignant state. influence that bacterial infections have on the development of certain cancers, such as gastric Microbial dysbiosis resulting in major shifts in cancer and gall bladder cancer, has gained intestinal commensal bacteria often result in increasing attention [1,2,15-18]. Unlike viruses, changes in CD4 + T lymphocyte populations in bacteria do not integrate their DNA into the host vivo , leading to an influx of Th17 cells, chronic genome [1,2]. Consequently, the role of bacteria inflammation, and eventually cancer [4-6]. in carcinogenesis involves many factors that are Consequently, the inappropriate propagation of not host-cell specific, some of which include the certain commensal species in the gut has been chronic stimulation of inflammatory immune associated with mucosal inflammatory diseases responses through a dramatic modulation of the and cancer development [3,7-10]. However, host mucosal immune landscape in vivo [15]. In recent experiments investigating the this article, we chose to explore the potential role relationships between enteric bacteria and of food-borne pathogens and enteric bacteria as cancer have exposed the ability of certain immune regulatory agents with the potential to species of intestinal commensals to significantly hinder primary cutaneous squamous cell influence tumor size and progression in mice carcinomas and adenocarcinomas of mammalian [4,11]. In similar studies, pro-inflammatory Th17 origin. and Th1 cells were at times found present along with anti-inflammatory Treg populations in the 2. COMMENSALS REGULATE MUCOSAL intestinal mucosa. This antitumor response was IMMUNITY AND HOMEOSTASIS mediated by a balanced production of pro- and anti-inflammatory cytokines, resulting in a Within mucosal tissue, a group of immune controlled threshold of mucosal immunity largely regulatory cells (Treg) and pro-inflammatory moderated by CD4 + T lymphocyte populations, immune cells, T helper type 1 (Th1) and Th2, through a dendritic cell-dependent pathway play symbiotic supervisory roles for each other, [12-17]. Certain species of commensals, such as enabling the maintenance of a healthy Bacteroides fragilis , a gram-negative obligate microbiome and regulating the growth of gut anaerobe, whose enterotoxigenic strain microbial populations. This natural biological

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check and balance system is now being revealed inflammation are responsible for over 15-20% of as a potential key factor in the hindrance, but all cancers worldwide, with foodborne pathogens also sometimes the development, of several lines making a large contribution of these cancer- of epithelial cancers. In this article, we discuss causing infections [16,17,32]. Among the best the therapeutic potential of enteric commensal documented of these is the causal relationship bacteria as a cancer management tool in vivo . In between Helicobacter pylori and stomach cancer. consideration of these studies, we believe that Studies describing H. pylori -associated health certain combinations of human intestinal benefits and disease-causing effects have commensal bacteria can be cultivated to impede consistently demonstrated that its colonization tumor growth at local and distant tumor sites by involves strong Th1 and Treg responses [18,33]. modulating CD4+ T lymphocyte cell activation The implication of these findings is that (Table 1). exogenously driven Th1 responses may discourage further upregulation of local Th1 3. FOODBORNE PATHOGENS INFLU- responses by the host, thereby inadvertently ENCE INFLAMMATION preventing excessive gastric inflammation and gastroduodenal disease. Thus balancing these Infections by food-borne pathogens remain a H. pylori -mediated Th1 responses may be a major cause of illness in people with promising approach to better calibrate these immunodeficiency [30]. Food-borne pathogens pathogen’s health benefits [18]. such as Salmonella can dramatically influence the host’s immune landscape, leaving it in a state On the other hand, the immune-protective effect of chronic inflammation [1]. Therefore, when of many strains of food-based bacteria is also coupled with immune deficiencies, infections by well known. And certain groups of bacteria found foodborne pathogens may be fertile ground for in food have been demonstrated to boost or cell transformation and cancer. Today, foodborne positively influence immune response [32]. Given pathogens represent approximately 15% of all these observations, it is likely that such strains pathogenic ailments [31]. can also have a preventative or perhaps even inhibitory effect against cancer of the digestive It is currently estimated that nearly 50 million system, notably the gut. This is likely achieved by food-borne infections occur each year, and attenuating the presence of other groups of pathogenic infections that lead to chronic inflammatory bacteria in the gut (Fig. 1).

Table 1. Immune cells influenced by commensals and foodborne pathogens

Cell type Food -borne pathogens Regulatory role Effect on immunity Source T and B Salmonella spp, Recognition of Depletion leads to 15 lymphocytes Campylobacter pathogenic invaders. increased susceptibility to food-borne bacteria infection CD4 + T Enterococcus faecalis Orchestration of Presence controls 12 - 14 lymphocytes adaptive immune threshold of mucosal response in the gut immunity Th17 cells Salmonella spp., Orchestration of the Characterized by their 4 - 6 Escherichia coli, mucosal defense expression of the pro- L. johnsonii and E. hirae against pathogens. inflammatory cytokine interleukin-17. Treg B. intestinalis Prevention of colonic Characterized by their 22, 23 inflammation expression of the anti- inflammatory cytokine Th1 Bacteroides fragilis, Regulation of Involved in pro- 4, 24-27 L. johnsonii and E. hirae Th1/Th2 equilibrium inflammatory response Th2 Bacteroides fragilis Induces secretion of Leads to higher 26 - 28 Th2 type cytokines production of IgE Macrophage Salmonella spp. Recognition of Surveillance of gut 29 pathogen-associated mucosa molecular patterns

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negating the combinatorial effects of enteric microbial species. Furthermore, the use of murine intestinal bacteria also undervalues the biological and genetic differen ces between the murine microbiome and that of humans [1 5,22]. To address this disparity, Faith et al. [ 22] developed procedures for generating germ -free mice through embryo transfer that also permit transplantation of human fecal microbiota intergenera tionally, enabling researchers to study mice containing a “humanized” gut microbiome, and thus making it possible to conduct complex investigations heretofore impractical. Such humanized models have considerably expanded our abilities to conduct stage-spec ific studies involving metabolic and signaling pathways in vivo . More recently, these tools have enabled investigators to thoroughly characterize effector strains found in host microbiota, and permitted them to better define their influences on host

Fig. 1. Schematic depicting the combinatorial immune regulation [36]. role of foodborne pathogens and commensals on mucosal immunity The shaping of human mucosal immunity homeostasis depends highly on the presence of unique (1) The balanced presence of 3 bacterial species groups of enteric bacteria species known as influences dendritic cell production, leading to the “keystone species,” specific microbial species moderate presence of Th1 and Treg cells through the which have strong inhibitory or stimulatory effects induction of INF-y and Foxp3 respectively. on neighboring bacteria. Consequently these (2) Reduction of one or more species can lead to species can strongly influence and regulate imbalance and promote tumorigenesis. (3) Signals mucosal immune response [19]. Similar species, induced during tumorigenesis can reshape the gut such as Enterococcus faecalis and Bacteroides microbiome and stimulate the presence of pre - fragilis , have been described as putative implanted anti-inflammatory Treg cells contributors to immune homeostasis, yet their 3.1 Bystander Effect roles in immune homeostasis fluctuate depending on the enteric environment. Typically, Studies such as that of Hansen et al. [ 33] have commensal transition to a pathogen is favored to contributed significantly to the understanding of occur during chronic stimulation of pro - the bystander effect and the communal influence inflammatory cytokines (small cell signaling that microbial species exhibit on neighboring proteins that induce inf lammation) and microbial species. This has led to the discovery proliferation of the Th1 and Th17 T cell that low levels of gastric Tregs are linked to an populations. Remarkably, further studies have increa sed risk of peptic ulceration [ 15,18,33]. demonstrated that certain species of gut Despite the several links between gut bacteria commensals, such as Lactobacillus johnsonii and and inflammatory diseases, the relationship Enterococcus hirae , can polarize T cells into between intestinal bacteria and human disease is protective Th1 and Th17 cell phenotypes. These highly contextual. Enteric bacteria can exist at phenotypes elicit a strong antitumor response in different points b etween mutualism and chemotherapy-treated mice as compared with pathogenicity depending on the immune and germ-free controls. microbiological landscape of the host [ 34,35]. Analogous experiments also demonstrated that The majority of studies exploring relationships protective Th1 and Th17 responses were between bacteria and cancer emphasize immune compromised severely in the absence of similar changes taking place after bacteria inoculation in groups of commensal species [ 4, 11,22]. These the host, but the microbiological context is often findings reveal that, depending on the microbial overlooked. Such studies are typically performed context, pro-inflammatory T-cell phenotypes using a sing le murine intestinal bacteria species could b e beneficial against tumor growth, (i.e., a species that originates from mice), thus highlighting the pressing need for combinatorial

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microbial studies to determine consortia of unchanged regardless of the presence of enteric commensals that are beneficial against intestinal bacterial flora in the mice [22,38,39]. cancer development and tumor growth. Several These findings articulate the significance of CD4 + of these studies were conducted by transplanting T lymphocyte populations in enteric-mediated intact uncultured microbiota from human donors immune response and are supportive evidence into germ-free mice. The culture collection was that intestinal bacteria modulate mucosal and then randomly divided into groups and the systemic immunity primarily through a CD4 + T modulatory effects on T cell regulation were lymphocyte-dependent pathway. monitored. This approach provided a more direct way to assess the modulatory effects of T cells 3.3 Intestinal Commensals Drive on human microbiota by making use of human Antitumor Response fecal content that harbored enteric microbiota from human subjects [4,11,22]. This Certain enteric commensal species, such as the experimental design is an amelioration of commensal bacterium Lactobacillus plantarum , previous studies that have limited themselves to have been found to reduce intestinal the murine microbiome. Yet studies using inflammation through the induction of protective humanized-microbiome mice still have a interlukin-10 (IL-10), and are able to protect the prevailing drawback, since they continue to host against inflammation-based mucosal perform the immune assessment in non- diseases, such as inflammatory bowel disease humanized mice strains that possess a (IBD) and perhaps cancer [3,40]. In addition, significantly different immune profile than that of other species, such as E. hirae , have been humans. One approach or solution to this could demonstrated to be able to direct pro- be transplantation of intact uncultured human inflammatory T cells to elicit strong antitumor microbiota into a humanized mouse model with responses [4,11,41]. Further investigation of mucosal immune regulatory functions mimicking these dynamics has revealed an increased those of humans. survival rate in cancer-bearing mice that had been inoculated with a bacteria-derived product 3.2 CD4+ T Lymphocytes Regulate such as lipopolysaccharide (LPS) [7,11,42]. In these mice, LPS was able to improve host Mucosal Immunity antigenic memory, eradicate tumors, and increase survival when compared to the control Studies by Faith and colleagues, using a group [11,42]. collection of bacteria in gnotobiotic mice, found that strains of the Bacteroides species and the The antitumorigenic abilities of microbial broad Bacteroidales phylum were able to products, such as LPS, were equally explored in + stimulate colonic Foxp3+ Treg cells among CD4 Pseudomonas aeruginosa by testing its signal T cells [22]. In their experiments, commensals B. molecule (O-DDHSL) on pancreatic carcinoma intestinalis and E. coli were able to induce a cells, where it significantly reduced pancreatic significant increase in colonic Tregs, while the carcinoma cell mobility and viability. In their normal intestinal microbiota negative control, experiments, different concentrations of O- Collinsella aerofaciens, could not. These DDHSL were used on ductal epithelial cell lines responses seemed to be greatly influenced by (HPDE) and prostate cancer cells (Panc-1). Cell host diet, mostly composed of casein and starch, viability was then determined in both lines indicating that microbial metabolic byproducts between 24 and 48 hr after treatment. The could play an immune stimulatory role in the gut findings revealed that, compared to the control, mucosa. These groups of commensals have treatment of cells with O-DDHSL concentrations been found to alter immunity not only in local between 25-300 µM resulted in a significant tissue, but also in tissue sites distant from the gut decrease in cell viability [43]. Table 2 [20,22,37]. These researchers identify enteric summarizes the food borne and commensals microbiota as key players in the shaping of with potential roles in chronic mucosal immune signaling at the mucosal and systemic inflammation. level. Analysis of splenocytes (a branch of immune cells that originates from the spleen) 3.4 Commensals Play Functionally demonstrated that populations of CD4 + T cells Contextual Roles in Cancer were lower in germ-free mice compared to Development conventionally colonized mice, while the proportions of other lymphocyte populations, Although many groups of intestinal microbiota such as CD8 + T cells and B cells, were have a mutualistic (i.e., coexisting without

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becoming pathogenic) relationship with their antitumor environment that considerably impedes host, certain species can exist at different points cancer development and tumor growth [22]. between mutualism and pathogenicity [35]. Various chemokins revealed their influential Consequently, how commensal bacteria behave effects on foodborne pathogenic bacteria as in the gut is highly contextual, with the same summarized in Table 3. microbe becoming commensal or parasitic depending on the immune and microbiological 4. BENEFITS AND LIMITATIONS landscape of the host [19]. Commensals that cause a deficiency in T-bet and Tregs (i.e., The experiments described in this article aim to immunosuppressive T regulatory cells) usually illustrate the combined effects of enteric bacteria induce pro-inflammatory Th17 cells, chronic on systemic and local inflammatory response. inflammation, and eventually cancer. However, at Given the bacterial properties described by many low doses, endotoxins and commensal- laboratories, we expect that the combination of associated molecular patterns (CAMPS) could Enterococcus hirae, Bacteroides fragilis, and potentially mediate moderate levels of Escherichia coli will elicit the strongest response inflammatory response that impede cancer cell against tumor progression, as species within this growth and retard tumor progression in mice group robustly stimulate Treg cell proliferation [7,58-60]. and induce high levels of protective anti-tumoral Th1 and Th17 cells. This can also be expected Helicobacter pylori , the etiological agent of from less studied commensal species such as stomach cancer, for instance, has been Alistipes shahii, and Faecalibacterium prausnitzii associated with protective properties against which have been demonstrated to be present in other types of cancers, such as esophageal high numbers during mammalian tumor adenocarcinoma, by preventing pan-gastric regression [4,11]. Although bacteria species inflammation and reflux esophagitis in human could likely form stable communities in rodents , it hosts [18,33]. Such findings have redefined is possible that some of these species will not scientists’ understanding of microbial survive when introduced to a humanized mouse commensalism, and are consistent with the model or when combined with human ATTC gut premise that combining bacterial species that strains, highlighting the limitations of this induce anti-inflammatory response with those approach. One of the ways to overcome this that regulate levels of protective pro- would be to maintain mice on a specific diet inflammatory signals can mediate a favorable containing desired species of colonizing bacteria.

Table 2. Foodborne and commensal bacteria with potential roles in chronic mucosal inflammation

Species Regulatory role Source Salmonella spp. Induction of pro-inflammatory cytokines through 1, 2, 44 secretion of carcinogenic endotoxins and cytolethal distending toxins (CDT) Escherichia coli Induction of pro-inflammatory cytokines through 1, 44, 45 secretion of carcinogenic endotoxins and CDT Bacteroides fragilis Stimulation of colonic inflammation and 13, 18 - 20 enhancement of colonic tumor formation Lactobacillus johnsonii Polarization of T cells into Th1 and Th17 cell 4, 19 phenotypes Enterococcus hirae Polarization of T cells into Th1 and Th17 cell 4, 11, 41 phenotypes Bacteroides intestinalis Increase in colonic Tregs 4, 11, 41, 46 Lactobacillus plantarum Influential role on intestinal and systemic 3, 40 immunity Pseudomonas aeruginosa Reduction of pancreatic carcinoma cell mobility 43 and viability Helicobacter pylori Protective anti-tumorigenic properties 18, 33

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Table 3. Chemokines with influential effects on foodborne cancer-modifying bacteria

Cytokine Cancer-modifying Regulatory role Immune influence Source bacteria IL-10 Lactobacillus Protection against Reduction of mucosal 3, 40 plantarum inflammation-based inflammation mucosal diseases and cancer IL-4 Escherichia coli Reduction of mucosal Reduction of Th2 cells 47 inflammation IL-6 Lactobacillus Balance of mucosal Regulation of inflammatory 48 spp homeostasis and non-inflammatory signals in the small and large intestine IL-10 Campylobacter jejuni Anti-inflammatory Contextual macrophage 29, 49 regulation activation TGF-β Escherichia coli and Immune homeostasis Promoting regulatory T cell 50 Helicobacter pylori differentiation IFNy Clostridium difficile Anti-inflammatory Essential mediator of anti- 51 and Cryptosporidum regulation inflammatory immune parvum response IL-5 Escherichia coli Pro- inflammatory Associated with a shift of the 28 response Th1/Th2 balance IL-13 Helicobacter pylori Pro- inflammatory Released by signals from an 52 response injured or inflamed epithelium IL-17 Salmonella spp. and Pro- inflammatory Essential for inflammation 5 Escherichia coli response mucosal immune response IL-17A, Helicobacter pylori Pro- inflammatory Permeability and maintenance 53 and Bacteroides response of mucosal barrier integrity intestinalis IL-17F Salmonella spp. and Pro- inflammatory Mediate pro-inflammatory 54 Escherichia coli response responses IL-21 Salmonella spp. and Pro- inflammatory Regulation of effector T cells in 55 Escherichia coli response the gut Campylobacter spp. IL-23 Helicobacter pylori Pro- inflammatory Master regulation of gut 56 and Bacteroides response mucosal immunity intestinalis IL-27 Helicobacter pylori Pro- inflammatory Control of intestinal T cell pool 57 response homeostasis and moderation of intestinal inflammatory response

We expect that inoculation of mice, prior to tumor tumor cells, while Tregs and Th2 cells will keep growth, with commensals able to maintain this pro-inflammatory response acute and Foxp3+ Treg cell proliferation and induce manageable. Certain groups of cytokines in the moderate levels of inflammatory signals will serum or intestinal lavage may not be detected at mediate an antitumorigenic mucosal environment the serum or peritoneal levels. For this purpose, that considerably impedes tumor growth. We the use of reconfigurable microfluidics combined anticipate that once tumor growth is detected, with antibody microarrays for enhanced detection moderate levels of inflammatory signals will likely of T-cell-secreted cytokines may prove very be stimulated to create a toxic environment for beneficial.

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5. CONCLUSION REFERENCES

Many studies have demonstrated that commensal-mediated antitumor response can be 1. Scanu T, Spaapen RM, Bakker JM, Pratap influenced by unique groups of food-borne CB, Wu LE, Hofland I, et al. Salmonella pathogens and intestinal murine bacteria. The manipulation of host signaling pathways combined effects of enteric bacteria may have provokes cellular transformation systemic and local inflammatory responses, in associated with gallbladder carcinoma. addition to cancer development and tumor Cell Host Microbe. 2015;17:763–774. growth . The proposed concepts exceed the mere 2. Boccellato F, Meyer TF. Bacteria moving investigation of mono-associations between into focus of human cancer. Cell Host bacteria and tumor regression, however Microbe. 2015;17:728–730. emphasize the “bystander effect,” i.e. combined 3. Gevers D, Kugathasan S, Denson LA, role of unique groups of gut commensal bacteria Vázquez-Baeza Y, Van Treuren W, Ren B in host antitumor response [11,19]. Moreover, et al. The treatment-naive microbiome in unlike previous studies, this article centers on the new-onset crohn’s disease. Cell Host use of mice engrafted with a humanized mucosal Microbe. 2014;15:382–392. immune profile as a reliable molecular tool for the 4. Viaud S, Saccheri F, Mignot G, Yamazaki investigation of microbial studies in a model T, Daillère R, Hannani D, et al. The system that mimics the human immune profile. intestinal microbiota modulates the With the pioneering advances in gnotobiotic anticancer immune effects of biology, such as that of Faith et al. [22], it is fitting cyclophosphamide. Science. 2013;342: to speculate that inoculation of mice (prior to 971–976. tumor growth) with commensals that are known to induce proliferation of anti-inflammatory cells, 5. Blaschitz C, Raffatellu M. Th17 Cytokines such as Foxp3 + Treg, and commensals able to and the Gut Mucosal Barrier. J Clin moderate levels of inflammatory signals will Immunol. 2010;30:196–203. create an antitumorigenic mucosal environment, 6. Round JL, Mazmanian SK. The gut which will considerably impede tumor growth. It microbiota shapes intestinal immune could be anticipated that once tumor growth is responses during health and disease. Nat. detected, moderate levels of inflammatory Rev. Immunol. 2009;9:313–323. signals are likely to be stimulated to create a 7. Lundin JI, Checkoway H. Endotoxin and toxic environment for tumor cells, while Treg cells cancer. Environ Health Perspect. 2009; and Th2 cells will be able to keep this pro- 117:1344–1350. inflammatory response acute and manageable. These major shifts in intestinal commensal 8. Xuan C, Shamonki JM, Chung A, DiNome bacteria often result in systemic changes that LM, Chung M, Sieling AP. Microbial can have whole-tissue antitumorigenic dysbiosis is associated with human breast responses. Coupled with immunotherapy, these cancer. PlosOne. 2014;9:e83744. approaches may prove efficiency in presenting 9. Gao Z, Bomin G, Renyuan G, Qingchao Z, and eliminating dysplastic cells. Future research Huanlong Q. Microbiota disbiosis is challenges would include identifying specific associated with colorectal cancer. Front microbial candidates that could be maintained in Microbiol; 2015. vivo at sub-potent levels and administered to DOI: 10.3389/fmicb.2015.00020 patients to cure or manage cancers. The challenges of this novel treatment and cancer 10. Gagniere J, Raisch J, Veziant J, Barnich management methodology are likely to require N, Bonnet R, Buc E. Gut microbiota further thorough experimentation to help clearly imbalance and colorectal cancer. World J define beneficial microbial combinations and their Gastroenterol. 2016;22:501-518. respective curative modes of action. Indeed, the 11. Iida N, Dzutsev A, Stewart CA, Smith L, modulation of commensal microbiota for the Bouladoux N, Weingarten RA, et al. stimulation of immune response against cancer Commensal bacteria control cancer appears to be exceptionally promising. response to therapy by modulating the tumor microenvironment. Science. 2013; COMPETING INTERESTS 342:967–970.

Authors have declared that no competing 12. Erdman SE. CD4+CD25+ regulatory interests exist. lymphocytes induce regression of intestinal

Woappi and Singh; BMRJ, 15(3): 1-11, 2016; Article no.BMRJ.26690

tumors in ApcMin/+ mice. Cancer Res. 26. Mazmanian SK, Liu CH, Tzianabos AO, 2005;65:3998–4004. Kasper DL. An immunomodulatory 13. Lee YK, Mazmanian SK. Microbial learning molecule of symbiotic bacteria directs lessons: SFB educate the immune system. maturation of the host immune system. Immunity. 2014;40:457–459. Cell. 2005;1:107–118. 14. Mazmanian SK, Kasper DL. The love–hate 27. Wang Q, McLoughlin RM, Cobb BA, relationship between bacterial Charrel-Dennis M, Zaleski KJ, Golenbock polysaccharides and the host immune D, Tzianabos, et al. A bacterial system. Nat Rev Immunol. 2006;6:849– carbohydrate links innate and adaptive 858. responses through Toll-like receptor 2. J 15. Dethlefsen L, McFall-Ngai M, Relman DA. Exp Med. 2006;13:2853-2863. An ecological and evolutionary perspective 28. Hwang J-S, Im C-R, Im S-H. Immune on human–microbe mutualism and disorders and its correlation with gut disease. Nature. 2007;449:811–818. Microbiome. Immune Network. 2012;12: 16. Condeelis J, Pollard JW. Macrophages: 129. obligate partners for tumor cell migration, 29. Mantovani A, Marchesi F. IL-10 and invasion, and metastasis. Cell. 2006.124: macrophages orchestrate gut 263–266. homeostasis. Immunity. 2014;40:637–639. 17. Coussens LM, Werb Z. Inflammation and 30. Lund BM, O’Brien SJ. The occurrence and cancer. Nature. 2002;420:860–867. prevention of foodborne disease in 18. Atherton JC, Blaser MJ. Coadaptation of vulnerable people. Foodborne Path. Dis. Helicobacter pylori and humans: Ancient 2011;8:961–973. history, modern implications. J. Clin. 31. Scallan E, Hoekstra RM, Angulo FJ, Tauxe Invest. 2009;119:2475–2487. RV, Widdowson MA, Roy SL, et al. 19. Belkaid Y, Hand TW. Role of the Foodborne illness acquired in the united Microbiota in Immunity and Inflammation. states—major pathogens. Emerging Infect. Cell. 2014;157:121–141. Dis. 2011;17:7–15. 20. Belkaid Y, Naik S. Compartmentalized and 32. Lollo PCB, de Moura CS, Morato PN, Cruz systemic control of tissue immunity by AG, Castro W deF, Betim CB, et al. commensals. Nature Immunol. 2013;14: Probiotic yogurt offers higher immune- 646–653. protection than probiotic whey beverage. 21. Bordon Y. Tumor immunology: Anticancer Food Res. Int. 2013;54:118–124. drugs need bugs. Nat. Rev. Immunol. 33. Hansen S, Melby KK, Aase S, Jellum E, 2013;14. Vollset SE. Helicobacter pylori infection 22. Faith JJ, Ahern PP, Ridaura VK, Cheng J, and risk of cardia cancer and non-cardia Gordon JI. Identifying gut microbe-host gastric cancer. A nested case-control phenotype relationships using study. Scand. J. Gastroenterol. 1999;34: combinatorial communities in gnotobiotic 353–360. mice. Sci Trans Med. 2014;6:220ra11– 34. Belkain Y, Hand TW. Role of the 220ra11. microbiota in immunity and inflammation. 23. Gray DHD, Liston A. Uhrf to Treg cells: Cell. 2014;157:121-141. reinforcing the mucosal peacekeepers. 35. Hooper LV, Macpherson AJ. Immune Nature Immunol. 2014;15:533–534. adaptations that maintain homeostasis 24. Gritz EC, Bhandari V. The human neonatal with the intestinal microbiota. Nature Rev. gut microbiome: A brief review. Frontiers Immunol. 2010;10:159–169. Pediatrics. 2015;3. 36. Ahern PP, Faith JJ, Gordon JI. Mining the Available:http://doi.org/10.3389/fped.2015. human gut microbiota for effector strains 00017 that shapte the immune system. Immunity. 25. Macatonia SE, Hosken NA, Litton M, Vieira 2014;40:815-823. P, Hsieh CS, Culpepper JA, et al. Dendritic 37. Ganal SC, Sanos SL, Kallfass C, Oberle K, cells produce IL-12 and direct the Johner C, Kirschning C, et al. Priming of development of Th1 cells from naive CD4+ natural killer cells by nonmucosal T cells. J Immunol. 1995;10:5071–5079. mononuclear phagocytes requires

Woappi and Singh; BMRJ, 15(3): 1-11, 2016; Article no.BMRJ.26690

instructive signals from commensal inflammation. J Clin Pathol. 1994;47: microbiota. Immunity. 2012;37:171–186. 1015–1018. 38. Dixon DM, Misfeldt ML. Proliferation of 48. Rosser EC, Oleinika K, Tonon S, Doyle R, immature T cells within the splenocytes of Bosma A, Carter NA, et al. Regulatory B athymic mice by Pseudomonas exotoxin A. cells are induced by gut microbiota–driven Cell Immunol. 1994;158:71-82 . interleukin-1β and interleukin-6 production. 39. Tzianabos AO, Finberg RW, Wang Y, Nature Med. 2014;20:1334–1339. Chan M, Onderdonk AB, Jennings HJ, et 49. Couper KN, Blount DC, Riley EM. IL-10: al. T cells activated by zwitterionic The master regulator of immunity to molecules prevent abscesses induced by infection. J. Immunol. 2008;180:5771– pathogenic bacteria. J. Biol. Chem. 2000; 5777. 275:6733–6740. 50. Biancheri P, Giuffrida P, Docena GH, 40. Xia Y, Chen H-Q, Zhang M, Jiang YQ, MacDonald TT, Corazza GR, Di Sabatino Hang XM, Qin HL . Effect of Lactobacillus A. The role of transforming growth factor plantarum LP-Onlly on gut flora and colitis (TGF)-β in modulating the immune in interleukin-10 knockout mice: Probiotic response and fibrogenesis in the gut. Cyto therapy in colitis. J. Gastroenterol Hepatol. Growth Factor Rev. 2014;25:45–55. 2011;26:405–411. 51. Ito R, Shin-Ya M, Kishida T, Urano A, 41. Marshall BJ, Warren JR. Unidentified Takada R, Sakagami J, et al. Interferon- curved bacilli on gastric epithelium in gamma is causatively involved in active chronic gastritis. Lancet. 1983;1: experimental inflammatory bowel disease 1273–1275. in mice. Clin Exp Immunol. 2006;146:330– 42. Won EK, Zahner MC, Grant EA, Gore P, 338. Chicoine MR. Analysis of the antitumoral 52. Mannon P, Reinisch W. Interleukin 13 and mechanisms of lipopolysaccharide against its role in gut defense and inflammation. glioblastoma multiforme. Anti-Cancer Gut. 2012;61:1765–1773. Drugs. 2003;14:457–466. 53. Lee JS, Tato CM, Joyce-Shaikh B, Gulen 43. Kumar AS, Bryan JN, Kumar SR. Bacterial MF, Cayatte C, Chen Y, et al. Interleukin- quorum sensing molecule N-3-Oxo- 23-Independent IL-17 production regulates Dodecanoyl-L-Homoserine lactone causes intestinal epithelial permeability. Immunity. direct cytotoxicity and reduced cell motility 2015;43:727–738. in human pancreatic carcinoma cells. PLoS ONE. 2014;9:e106480. 54. Jin W, Dong C. IL-17 cytokines in immunity and inflammation. Emerging Microbes Inf. 44. DeWaal C, Grooters S. Antibiotic 2013;2:e60. resistance in foodborne pathogens. Center for Science in The Public Interest. Available:http://doi.org/10.1038/emi.2013.5 2013; Accessed April 20, 2016. 8 Available:http://cspinet.org/new/pdf/outbre 55. Fantini MC, Monteleone G, MacDonald TT. aks_antibiotic_resistance_in_foodborne_p IL-21 comes of age as a regulator of athogens_2013.pdf effector T cells in the gut. Mucosal 45. Crane JK, Broome JE, Lis A. Biological Immunol. 2008;1:110–115. activities of uric acid in infection due to 56. Ciccia F, Bombardieri M, Principato A, enteropathogenic and shiga-toxigenic Giardina A, Tripodo C, Porcasi R, et al. Escherichia coli . Infect. Immunity; 2016. Overexpression of interleukin-23, but not DOI: pii: IAI.01389-15 interleukin-17, as an immunologic 46. Ciccone EJ, Greenwald JH, Lee PI, signature of subclinical intestinal Biancotto A, Read SW, Yao MA, et al. inflammation in ankylosing spondylitis. CD4+ T cells, including Th17 and cycling Arthritis Rheum. 2009;60:955–965. subsets, are intact in the gut mucosa of 57. Troy AE, Zaph C, Du Y, Taylor BC, Guild HIV-1-infected long-term nonprogressors. KJ, Hunter CA, et al. IL-27 regulates J. Virol. 2011;85:5880–5888. homeostasis of the intestinal CD4+ effector 47. Karttunnen R, Breese EJ, Walker-Smith T cell pool and limits intestinal JA, MacDonald TT. Decreased mucosal inflammation in a murine model of colitis. interleukin-4 (IL-4) production in gut J. Immunol. 2009;183:2037–2044.

Woappi and Singh; BMRJ, 15(3): 1-11, 2016; Article no.BMRJ.26690

58. Lange JH. Will sewage workers with Receptor-Trafficking from apical endotoxin related symptoms have the membrane to cytoplasmic compartments in benefit of reduced lung cancer? polarized intestinal epithelium. Am J Occupational Environ. Med. 2003;60:144– Pathol. 2002;1:165-173. 145. 60. Louis P, Georgina LH, Harry JF. The gut 59. Cario E, Brown D, McKee M, Lynch- microbiota, bacterial metabolites and Devaney K, Guido G, Podolsky KD. colorectal cancer. Nat Rev Micro. 2014;12: Commensal-Associated Molecular 661-612. Patterns Induce Selective Toll-Like ______© 2016 Woappi and Singh; This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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