The interplay between the microbiome and the adaptive immune response in cancer development

Abstract

The data from different studies suggest a bacterial role in cancer genesis/progression, often modulating the local immune response. This is particularly so at the mucosal level where the bacterial presence is strong and the immune system is highly reactive. The epithelial surfaces of the body, such as the skin and mucosa, are colonized by a vast number of microorganisms, which represent the so-called normal microbiome. Normally the microbiome does not cause a proinflammatory response because the immune system has developed different strategies for the tolerance of commensal bacteria, but when these mechanisms are impaired or new pathogenic bacteria are introduced into this balanced system, the immune system reacts to the microbiome and can trigger tumor growth in the intestine. In this review, we discuss the potential role of the bacterial microbiome in carcinogenesis, focusing on the direct and indirect immune adaptive mechanisms, that the bacteria can modulate in different ways.

Keywords

adaptive immune response bacteria colorectal cancer microbiome Th17

Introduction

The involvement of infectious elements in the cancer etiology has recently polarized the attention of many researchers. In the past, in 1890, the Scottish pathologist William Russell [Russell, 1890] reported circumstantial evidence for the bacterial cause of cancer. Actually, the data from different studies have strengthened the theory proposed by Russell suggesting a bacteria role in carcinogenesis and cancer progression, often interfering with and modulating the local immune response [Shahanavaj et al. 2015]. This is especially true at the mucosal level, where the bacterial presence is strong and the immune system is highly reactive. Actually, the epithelial surfaces of the body, such as the skin and the mucosa, are colonized by a vast number of microorganisms, which represent the so-called normal microbiome (Figure 1).

Figure 1.

Different sorts of bacteria living in different places in and on the body.

The human microbiome is composed of organisms belonging to the domains of the Bacteria, Archaea, Eukarya and their viruses. Most of the commensal bacteria are symbiotic, however, after translocation through the mucosa or under specific conditions (e.g. immunodeficiency), commensal bacteria can cause pathology.

The intestinal mucosa is the largest surface of the body that is constantly exposed to dietary and bacterial antigens. The gastrointestinal tract of mammals harbors a bacterial community containing trillions of members, including thousands of different species. There are more than 50 bacterial phyla on Earth, but the human gut-associated microbiome is dominated by four main phyla: Firmicutes, Bacteroidetes, Actinobacteria and Proteobacteria [Eckburg et al. 2005; Mahowald et al. 2009] (Figure 1). A wide proportion, about 70%, of the human microbiome is composed of bacteria that cannot be cultivated by current microbiological methods. The traditional culture-based methods capture less than 30%, of our bacterial microbiome [Fraher et al. 2012]. However, today, genomic next-generation sequencing analysis has been essential in defining and understanding the bacterial microbiome and metagenome, and their key role in metabolism, inflammation and cancer progression [Kau et al. 2011; Human Microbiome Project Consortium, 2012].

The human microbiome is essential to body physiology, as it could produce an enormous quantity of molecules able to interact with the host. In particular, the bacteria of the gut microbiome represent a natural defense against colonization with pathogens and furthermore, they break down indigestible dietary components (e.g. vegetal polysaccharides) [Sonnenburg et al. 2004]. The bacteria communities are separated from the internal gut milieu by a single layer of epithelial cells, which not only is a physical and chemical barrier, but also balances the crosstalk between the external environment and immune host system. In addition, the epithelial surfaces have evolved protective mechanisms to counteract microorganism invasion. Effective innate and adaptive immune responses protect the mucosa and the internal environment of the human body. Almost 80% of the immunologically active cells belong to the mucosal-associated immune system. Most of these cells are present in the gastrointestinal tract, where immunogenic agents, such as food and components of the bacterial flora, are at the highest level with respect to other parts of the body.

Normally the microbiome does not cause a proinflammatory response because the immune system has developed various mechanisms to tolerate the commensal bacteria and preserve the homeostasis, but when these mechanisms are impaired or new pathogenic bacteria are introduced into this balanced system, the immune system reacts to the microbiome and can trigger tumor growth in the intestine [Schwabe and Jobin, 2013].

In this review we discuss the potential role of the bacterial microbiome in carcinogenesis, focusing on the direct and indirect immune adaptive mechanisms that the bacteria can modulate promoting, supporting or counteracting cancer development.

Microbiome’s role in tumor development

Recent evidence suggests that human disease is attributable not only to a single bacteria but also to global changes in the host microbiome [Turnbaugh et al. 2006; Smith et al. 2013]. Different studies in germfree animals associated with bacteria have revealed evidence for tumor-promoting effects of the microbiome in spontaneous and genetically induced cancers in several organs, including skin, colon, liver, breast and lungs [Dapito et al. 2012; Sacksteder, 1976; Dove et al. 1997].There are also data showing the contrary view that gut microbiota have a central role in limiting chemically induced injury and proliferative responses that lead to tumor development in germ-free animals [Zhan et al. 2013]. In 1975, Reddy and colleagues first linked the gut microbiome to intestinal cancer development, establishing that only 20% of genetically modified germ-free rodents develop chemically induced colon cancer. In contrast, the tumor incidence in conventional rats with a normal microbiome was about 90% with several neoplasms [Reddy et al. 1975]. Vannucci and colleagues confirmed these data showing that germ-free rats, compared with genotypically similar animals with a normal microbiome, develop smaller tumors, as spontaneously as after chemically induced carcinogenesis [Vannucci et al. 2008]. Moreover, in colitis-associated cancer and adenomatous polyposis coli (APC)-related colorectal cancer, germ-free mice display decreased tumor formation and less oncogenic mutations [Rakoff-Nahoum and Medzhitov, 2008]. In addition, antibiotics depletion of the gut microbiota in mice reduces cancer development in the colon and the liver [Dapito et al. 2012; Yoshimoto et al. 2013; Chen et al. 2008; Klimesova et al. 2013] as does the eradication of specific pathogens in humans and in mice [Lee et al. 2008; Wong et al. 2004].

All these studies provide compelling evidence for the microbiome’s role in tumor growth. Probably, the germ-free rats can develop a more active anticancer immune response in the absence of the physiological inflammation induced by the presence of a commensal microbiome. For this purpose, Sears and Pardoll [Sears and Pardoll, 2011] suggest that ‘alpha bugs’ (certain microbiome members possessing unique virulence traits), such as enterotoxigenic Bacteroides fragilis (ETBF), are directly pro-oncogenic and able to remold the mucosal immune response and colonic bacterial-removing species that protect against cancer thus promoting cancer growth.

The ‘bacterial driver–passenger’ model was first suggested by Tjalsma and colleagues [Tjalsma et al. 2012] to describe the microbial involvement in the development of colorectal cancer. According to this model, distinct indigenous intestinal bacteria, called ‘driver bacteria’ would create DNA damage and drive genome instability to initiate the first phases of cancer progression. As a consequence, the bacterial drivers (alpha bugs and their helpers) are gradually replaced by gut commensals with either tumor-promoting or tumor-suppressing properties (bacterial passengers). This model proposes that disease progression causes changes in the microenvironment as a result of the increasing tumor, resulting in a reformed selective pressure on the microbial community.

The importance of the human microbiome in host health and disease is also described by the ‘keystone pathogen’ hypothesis. The term ‘keystone’ has been introduced in the ecological literature to characterize species whose effects on their communities are disproportionately large relative to their abundance and which are thought to form the ‘keystone’ of the community’s structure. This hypothesis supposes that some low-abundance microbial pathogens can orchestrate inflammatory disease by remodeling a normally benign microbiome into a dysbiotic one [Hajishengallis et al 2012].

Finally, inflammatory responses elicited by bacteria were demonstrated to be able to enhance cancer progression [Fukata and Abreu, 2008]. Some bacteria are able to induce alterations of mucosal permeability, facilitating the translocation of bacteria and bacterial toxins (e.g. lipopolysaccharide). Inflammation contributes to the development, progression, and treatment of cancer, but it remains unclear whether commensal bacteria affect inflammation in the sterile tumor microenvironment. An increasing number of studies demonstrated the role of inflammation in establishing conditions that can deeply alter local immune responses and thus, tissue homeostasis. In particular, it is well documented that inflammatory mediators [such as interleukin (IL)-1, tumor necrosis factor-α (TNF-α), IL-8, nitric oxide or prostaglandin-2 derivatives] and molecules of the inflammatory pathways, are involved in a progressive interplay between the immune cells and tissue cells undergoing transformation [Mantovani et al. 2008].

The role of adaptive immune response in cancer progression

Vertebrates have evolved the machinery of adaptive immunity to counteract the pathogens that evade or overcome the innate immune defense. Normally the components of the adaptive immune system are silent; however, when activated, these components ‘adapt’ to the presence of infectious agents by activating, proliferating, and creating potent mechanisms to neutralize or eliminate the microbes. However, some of these responses can be protumorigenic.

There are two types of adaptive immune responses: humoral immunity, mediated by antibodies produced by B cells, and cell-mediated immunity, mediated by T cells, that are divided into two subsets: the CD8⁺ (CTL) and the CD4⁺ or T helper (Th). An effective antitumor immune response requires the involvement of both CD4⁺ and CD8⁺ T cells [Schreiber et al. 2011]. The role of CD4⁺ T cells in antitumor immunity has recently been extensively studied in preclinical animal models and in clinical cancer patients. CD4⁺ T cells are critical for priming tumor-specific CD8⁺ T cells and for the secondary expansion and memory of CD8⁺ T cells [Janssen et al. 2003]. However, the discovery of regulatory T cells (Treg) and Th17 cells not only updated the classical Th1/Th2 paradigm of Th cell differentiation, but also markedly revolutionized the concept regarding the role of CD4⁺ T cells in antitumor immunity [Wang et al. 2012]. It has been demonstrated that tumor-infiltrating Tregs induce an immunosuppressive microenvironment, preventing an effective antitumor immunity and becomes a major obstacle to the success of anticancer immunotherapy [Curiel, 2008]. Furthermore, the functional contribution of human Th17 cells to tumor immunity remains controversial since both protumor and antitumor effects have been observed varied among tumor types [Wilke et al. 2011].

In addition to protection against cancer cells and pathogens, acquired immunity is essential for the establishment of complex bacterial communities in the gut.

Mechanisms of microbiome-driven carcinogenesis substantially differ between organs and the microbiome can modulate tumor development through direct and indirect actions. The microbial products can directly promote tumor growth or indirectly, that is the bacteria per se are not able to promote tumor progression unless they interact with the immune system. Finally, it is also possible that deficiencies in specific mechanisms of the immune response allow the expansion of certain bacteria, which activate a protumorigenic immune response.

The following paragraphs describe how the microbiota influence the adaptive immune response and, in turn, promote or counteract tumor development.

Direct responsibility of bacterial factors in cancerogenesis

Gastric cancer represents the most studied example of carcinogenesis closely related to infection by a specific bacterial pathogen, Helicobacter pylori [Lofgren et al. 2011; Peek and Blaser, 2002; Fox and Wang, 2007]. H. pylori, identified as a carcinogenic pathogen [Parkin et al. 2002], colonizes the human stomach and duodenum, leading to the sequential development of gastritis, gastric ulcer, atrophy and finally gastric cancer [Fox and Wang, 2007; Amedei et al. 2014]. H. pylori infection contributes to global cancer mortality with gastric cancer occurring in 1–3% of infected individuals [Fox and Wang, 2007]. H. pylori producing gastric atrophy and hypochlorhydria, renders the stomach susceptible to bacterial overgrowth, and subsequently increased bacterial conversion of dietary nitrates into carcinogens [Lofgren et al. 2011].

In addition, H. pylori infection is associated with the lymphoid hyperplasia of gastric mucosa that represents a preneoplastic condition of the mucosa-associated lymphoid tissue (MALT), which may evolve to a B-cell lymphoma [Munari et al 2011], where the anti-H. pylori immune response, seems to have a key role, in particular the macrophages and the Th lymphocytes [Amedei et al. 2014]. Recently, Munari and colleagues showed how H. pylori infection induces a Th17 response [Munari et al 2014]. They studied the expression of cytokines in infected patients with chronic gastritis focusing on a role for B-cell activating factor (BAFF; CD257) in promoting Th17 differentiation. High levels of IL-17 and BAFF were present in gastric mucosa of H. pylori-positive patients with chronic gastritis and BAFF was especially abundant in macrophages and monocytes. Exposing monocytes to BAFF triggered reactive oxygen species (ROS) accumulation and also resulted in the production of IL-6, IL-1b, IL-23 and TGF-β. Monocytes exposed to H. pylori produced pro-Th17 cytokines and contribute directly to drive the gastric milieu in chronic gastritis. H. pylori affects the tumor microenvironment by increasing the IL-17A secretion and high levels of serum IL-23A in gastric cancer patients correlated with poor prognosis.

Recently, we have investigated the effector functions of gastric tumor-inﬁltrating lymphocytes speciﬁc for the H. pylori-secreted peptidyl prolyl cis, trans-isomerase (HP0175) [Amedei et al. 2014]. Tumor-inﬁltrating lymphocytes from patients with gastric adenocarcinoma, stimulated in vitro with HP0175, produced high levels of IL-17 and IL-21. T-cell clones derived from these populations were then tested for cytolytic ability and their ability to provide help to monocytes. While the cytolytic ability was poor, all of the Hp0175-speciﬁc Th17 clones were found to induce matrix metalloproteinase (MMP)-2 and MMP-9 production by monocytes. We hypothesized that HP0175-speciﬁc Th17 cells in the tumor drive the production of MMPs that promote angiogenesis and inﬂammation through IL-21 production.

Another example of tumors caused by specific bacterial pathogens is the gallbladder cancer associated with chronic Salmonella enterica subsp., Enterica serovar Typhi and Enterica serovar Paratyphi infections [Caygill et al. 1994; Welton et al. 1979].

Both Gallbladder cancer and gastric MALT are examples of tumors triggered by adaptive immune responses against specific pathogens [Caygill et al. 1994; Wotherspoon et al 1993]. In addition, some lymphomas are associated with bacterial infections, such as Campylobacter jejuni, Borrelia burgdorferi and Chlamydia psittaci, and after antibiotic treatment a regression has been observed [Lecuit and Lortholary, 2004; Ferreri et al. 2012].

Fusobacterium nucleatum has recently been shown to directly promote intestinal tumorigenesis when its adhensin, FadA, binds to E-cadherin on epithelial cells and activates b-catenin signaling to promote epithelial cell proliferation [Rubinstein et al. 2013; Kostic et al. 2013]. Additional bacterial pathogens such as Enterococcus faecalis, enterotoxigenic Bacteroides fragilis and Helicobacter hepaticus promote cancer in animal models, but there is no clear epidemiological link to human carcinogenesis.

Finally, the microbiome has the capacity to directly modulate tumorigenesis through the production of specific toxins, such as genotoxins, that induce DNA damage responses, or tumor-promoting metabolites. For example, different bacterial toxins such as cytolethal distending toxin (CDT), cytotoxic necrotizing factor 1,B. fragilis toxin and colibactin, affect crucial cellular processes, implicated in tumorigenesis, and especially the responses to DNA damage [Arthur et al. 2012; Wu et al. 2009]. Microorganisms relevant to colorectal, gastric and gallbladder cancer (e.g. E. coli, Helicobacter spp. and S. Typhi) are CDT producers [Smith et al. 2013].

Various bacterial-derived metabolites, for instance hydrogen sulphide and superoxide radicals, may cause genomic instability [Carbonero et al. 2012; Huycke and Gaskins, 2004]. Enterococcus faecalis can generate large amounts of extracellular superoxide, which causes double-strand DNA breaks and chromosome instability leading to the development of colorectal cancer in mice [Wang and Huycke, 2007; Wang et al. 2012]

Antibacteria-specific immune response and tumor starting

Host-derived immune and inflammatory responses are an important driving force that shape the microbial community composition and, when altered, may contribute to dysbiosis. Some members of the microbiota alter the adaptive immune response and, in turn, promote cancer growth. One of the main instruments by which the microbiome can indirectly promote tumor growth are the Th17 cells. Commensal microbiota actively shape intestinal T-cell responses to promote homeostasis. For example, Th17 cells control microbial invasion in the gut, but specific compensatory mechanisms are required to regulate in turn the Th17 cells.

In the mammalian intestine the commensal bacteria induce IL-1β production to maintain a basal level of Th17 cells in the lamina propria under physiological conditions [Shaw et al 2012]. However, in response to pathogenic extracellular bacterial or fungal infections, large numbers of naive Th cells differentiate into Th17 under the influence of IL-1β, IL-6, IL-23 or TGFβ in mucosal surfaces of the gut and respiratory tract [Ouyang et al. 2008]. If those mechanisms are impaired, Th17 cells become pathogenic and can induce autoimmune disease and chronic inflammation. When stimulated with IL-6 and TGF-β, the antigen-activated CD4⁺ T cells upregulate the transcription factor, retinoic acid receptor-related orphan receptor gamma t (RORγt) and secrete Th17-specific cytokines such as IL-17 and IL-22 [Korn et al. 2009]. Usually, the CD4⁺ T cells that express RORγt increase tight junction formation and stimulate the secretion of microbicidal protein, contributing to the barrier function of the intestinal epithelium but they can have also a protumorigenic role [Korn et al. 2009].

As stated previously, compelling evidence suggests that Th17 cells and their cytokines have a strong tumorigenic potential, but the functional role of Th17 in cancer is ambiguous, it appears to have protumorigenic and antitumorigenic activities and the responses seem to depend on the cancer type [Grivennikov et al. 2012; Muranski et al. 2008; Murugaiyan and Saha, 2009]. In addition to IL-17A production, Th17 cells can secrete IL-17F, IL-21, IL-22, interferon (IFN)-γ and granulocyte-macrophage colony-stimulating factor (GM-CSF) [Zheng et al. 2008; Mitsdoerffer et al. 2010].

Th17 responses and mainly the IL-17 action itself, were initially thought to be proangiogenic, proinvasive and cancer growth promoting [Numasaki et al. 2003]. In a mouse model, the Th17 cells are able to promote colorectal cancer development, induced by colon inflammation [Wu et al. 2009]. Experiments with genetically predisposed mice (APCmin/+) crossed with IL-17A-deficient mice point out drastic impairment in intestinal tumorigenesis [Chae et al. 2010]. In addition, it has been shown that APCmin/+ mice that cannot respond to IL-17 develop fewer tumors in the colon [Grivennikov et al. 2012].

In humans, the role of Th17 cells has been investigated in patients with different cancer types, including ovarian cancer, prostate cancer, and many others [Yang et al. 2009; Horlock et al. 2009; Zhang et al. 2008a, 2009; Wang et al. 2008; Dhodapkar et al. 2008; Charles et al. 2009; Derhovanessian et al. 2009; Inozume et al. 2009; Koyama et al. 2008]. Most of these studies have examined Th17 cells in peripheral blood, but Th17 cells may be induced in or recruited to the cancer microenvironment [Kryczek et al. 2007, 2009].

Above, we have affirmed that the intestinal microbiota promote colorectal cancer development. More direct proof for a role of bacterially stimulated tumor growth via Th17 cells comes from studies of enterotoxigenic Bacteroides fragilis. This human colonic bacterium secretes B. fragilis toxin (BFT) that causes human inflammatory diarrhea. Several mouse models, predisposed to develop gut tumors, indicate that between colonization of B. fragilis and nontoxigenic B. fragilis, only the first triggers colitis and induces colonic tumors [Wu et al. 2009]. In particular, B. fragilis induces selective colonic signal transducer and transcription-3 (STAT3) activation with colitis characterized by a selective Th17 response. Antibody-mediated blockade of IL-17, as well as the IL-23 receptor, inhibits B. fragilis-induced colitis, colonic hyperplasia and tumor formation. These results show a STAT3- and Th17-dependent pathway of inflammation-induced cancer by a common human commensal bacterium, providing a new mechanistic insight into human colon carcinogenesis. In other words, these data support the role of Th17 cells and their cytokines (IL-17 and IL-22) in intestinal carcinogenesis.

Further experimental conditions have confirmed the ability of the microbiome to modulate the Th17 response. The Th17 response upon contact with specific bacteria, stimulates the expansion of neutrophil cells, required for the clearance of invading bacteria [Aujla et al. 2007; Blaschitz and Raffatellu, 2010]. The Th17 response is important for protection against mucosal pathogens like Klebsiella pneumonia and Salmonella typhimurium. Mice deficient in Th17 cytokines show a serious pathology during infection with Salmonella or C. rodentium, with increased translocation of bacteria into lymph nodes. [Raffatellu et al. 2008].

Other bacteria species capable of activating Th17 are the segmented filamentous bacteria (SFB), belonging to nonculturable Clostridia-related species, and flagellin-positive bacteria. These bacteria interact with the epithelial cells in the host epithelial barrier promoting chronic inflammation, mediated by IL-17 and IL-22 release, which likely favors the development of intestinal cancer.

Recently, SFB has been shown to support the generation of Th17 cells [Suzuki et al. 2004] and only in the animals colonized with SFB, were found strong Th17 responses [Gaboriau-Routhiau et al. 2009; Korn et al. 2009; Reigstad and Backhed, 2010; Ivanov et al. 2009]. Moreover SFB-induced Th17 cells exacerbate autoimmunity, such as arthritis, that could be tempered by treating mice with certain antibiotics that reduced Th17 cells [Kosiewicz et al. 2011].

Based on such interesting data, some investigators became motivated to target the microbiome in order to enhance Th17 and CD8⁺ T-cell responses against cancer cells [Gajewski et al. 2013].

As reported previously, Th17 cells produce other cytokines such as IL-22, which has been linked to intestinal tumorigenesis in murine models [Kirchberger et al. 2013; Huber et al. 2012]. IL-22BP (IL-22 R) is regulated by the inflammasome and modulates tumorigenesis in the intestine and in human colon cancer [Jiang et al. 2013]. IL-22 is related to the development of human colorectal cancer by STAT3 activation. A procarcinogenic rule for IL-22 via the STAT3 pathway, was previously shown in several extracolonic cancers such as hepatocellular carcinoma and non-small cell lung cancer [Zhang et al. 2008b; Jiang et al. 2011]. Little is known about the IL-22 role in colorectal cancer, although polymorphisms in IL-22 were shown to be associated with an increased risk for cancer development [Thompson et al. 2010]. Furthermore, IL-22 in conjunction with IFN-γ can induce inducible nitric oxide synthase (iNOS) production and procarcinogenic nitric oxygen species in human colon carcinoma cell lines [Ziesché et al. 2007]

Finally, the cytokine IL-23 is produced by myeloid cells in response to different microbiome molecules, such as flagellin [Kinnebrew et al. 2012]. IL-23 has the ability to promote Th17-type responses characterized by the induction of the cytokines IL-17 and IL-22 [Liang et al. 2006]. IL-23 was found to be increased in human colon adenocarcinoma and, through induction of proinflammatory responses, promotes tumor growth [Langowski et al. 2006].

Antitumorigenic impact of microbiome

Although most of the studies show tumor-promoting activity of the bacterial commensal flora, antitumor effects have also been reported. In the past, antitumor effects were observed in patients with sarcomas, after the injection of heat killed bacteria or bacterial infections (termed Coley’s toxin) [Starnes, 1992]. Subsequent studies assign these antitumor effects to specific bacterial components as NOD-like receptor (NLR) agonists and Toll-like receptor (TLR) agonists. The activation of innate immunity can convert cancer tolerance into an anticancer immune response [Garaude et al. 2012].

In addition, murine studies described an effective immune role in tumor surveillance and in the inhibition of proliferation and metastasis, which results in the cancer regression [Muranski et al. 2008; Kryczek et al. 2009; Martin-Orozco et al. 2009].

An anticancer microbiome-mediated effect was noted in hematopoietic tumors, through the Th17 response. In mouse models, the alkylating agent, cyclophosphamide, alters the microbiome composition, inducing dysbiosis in the small intestine and inducing the translocation of selected species of Gram⁺ bacteria into secondary lymphoid organs. These bacteria stimulate the generation of a specific subset of ‘pathogenic’ Th17 cells and memory Th1 immune responses, which result in a potent cancer-suppressive Th17 response [Viaud et al. 2013].

In addition, in a recent study [Amedei et al. 2013], it was demonstrated that Th17 cells have a specific antitumor effector function in patients with pancreatic cancer, and that there are decreased levels of these cells in cancer tissue compared to healthy mucosa. These results suggest that the gut microbiome can help shape the anticancer immune response.

In other words, although some bacteria are able to induce Th17 cells, others could promote control of Th17 cells, limiting cancer development. Lactobacillus, Bifidobacteria, and Clostridium can induce Foxp3⁺ Treg cells, a specific subset of regulatory T cells in the intestine [Honda and Littman, 2012]. These Foxp3⁺ Treg cells, through IL-10 secretion, can control the production of IL-17A and the proliferation of Th17 cells [Huber et al. 2011]. These interactions can have an anti-tumorigenic activity in the intestine. It is still not clear if this is due to the suppression of Th17 pro-tumorigenic activity, but Foxp3⁺ Treg cells can actively block intestinal tumor growth through IL-10 secretion [Erdman et al. 2003; Erdman et al. 2005].

Also, the Bacteroides species have been shown to have immunomodulatory effects. In particular Bacteroides fragilis releases polysaccharide A (PSA), that seems to block intestinal inflammation. The colonization of mice with B. fragilis resulted in the suppression of a proinflammatory Th17 reaction and this modulation could be attributed to PSA because B. fragilis lacking PSA was unable to suppress Th17 response, and also failed to persistently colonize the intestine [Round et al. 2011].

Finally, a selected mixture of Clostridia strains, recently identified from the human microbiome, is found able to attenuate disease in preclinical models of colitis through the induction of Tregs [Atarashi et al. 2008], revealing a potential antitumorigenic role. These results suggest that therapeutic colonization with specific strains of human-associated bacteria may have the potential to reduce tumorigenesis.

In conclusion, it is plausible that the integration of such multiple signals through their cumulative effects on specific commensal microbial populations and the various immune arms will result in context-specific effects on cancer development, establishing the microbiome as a critical hub integrating host and environmental signals, that are implicated in tumor formation or suppression.

Conclusion

The growing awareness of the importance of the gut microbiome in health and diseases and recognition of the host–microbe mutualism at the immunological and metabolic levels become important for a better understanding of several pathologies, especially cancer, a plague of our century.

Multiple lines of evidence support the notion that the microbiome shapes the immune system and indirectly modulates the development of tumors through the immune system in different organs. A positive modulation of the composition and metabolic activity of the gut microbiota might represent an interesting approach to reduce the risk of carcinogenesis and cancer development.

Today, finding new methods to selectively manipulate the microbiome in order to stop tumor initiation and progression represents an exciting challenge. In the near future, high quality mechanistic experimental studies and interventional human studies might provide the scientific premise for the clinical use of probiotics for the therapy of cancer and other multifactorial human diseases. We need a better understanding of the mechanisms whereby altered immunity shapes microbiome composition and determines which microbes are present to embrace us with their metabolites.

Footnotes

Funding

This work was supported by grants from the regional contribution of “the Programma Attuativo Regionale (Toscana) funded by FAS (now FSC), the Italian Ministry of University and Research and the Foundation ‘Ente Cassa di Risparmio di Firenze’.

Conflict of interest statement

The authors declare no conflict of interest in preparing this article.

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