Open Access

The microbiome, its molecular mechanisms and its potential as a therapeutic strategy against colorectal carcinogenesis (Review)

  • Authors:
    • Stella Baliou
    • Maria Adamaki
    • Demetrios A. Spandidos
    • Anthony M. Kyriakopoulos
    • Ioannis Christodoulou
    • Vassilis Zoumpourlis
  • View Affiliations

  • Published online on: December 20, 2018     https://doi.org/10.3892/wasj.2018.6
  • Pages: 3-19
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Abstract

Microbiota is receiving significant attention in the research field, given that it is essential in homeostasis and an indirect modulator of diseases, such as cancer. Humans harbor a multitude of microorganisms that affect both human health and disease. Colorectal cancer is a genetic disease that is composed of distinct subtypes. In all cases, the intestinal microbiota has recently emerged as a crucial factor that promotes tumor growth at all stages through various mechanisms, such as the modulation of inflammation, the stimulation of DNA damage and toxic metabolite synthesis. In this review, we assess the contribution of the gut microbiome to homeostasis, its role as a potentiator or blocker of tumor progression and the underlying molecular mechanisms; we harness human data from both meta‑omics analyses and studies using animal models. Furthermore, we evaluate the ways through which microbes can be manipulated for diagnostic and prognostic purposes, and how they respond to chemotherapy or immunotherapy. Mounting evidence suggests that the microbiota may be used for the development of novel therapeutic strategies against colon cancer.

1. Role of microbiota in homeostasis

The analysis of microbiota composition has become routine in our time, mostly due to the explosion and availability of new technologies [metagenomic sequencing technologies that incorporate next-generation DNA sequencing methods with the computational approach of targeted (16S rRNA hypervariable regions) or whole-genome shotgun sequence reads], that allow for the identification and classification of a great variety of microbial species (1,2). The genome of the microbiota is 100-fold more extensive than the human genome (3). The distribution of microbial cells surpasses the number of all human cells, including somatic and germ cells throughout the human body (4-8). Microbiota is a term that has been established as the sum of bacteria, fungi, parasites and viruses occupying the host (7). The microbiota genome is known as the ‘microbiome’, which acts as 'an indirect genome' with significant functions that are several fold more numerous than those of the human genome (6,7,9,10). The microbiota and host form a complex ‘super-organism’ in which their symbiotic association confers benefits to the host regarding key aspects of life. However, defects in the host regulatory circuits that control bacterial sensing and homeostasis, or alterations in the microbiome, through environmental changes (infection, diet or lifestyle), may disrupt the symbiotic relationship and promote disease. Increasing evidence indicates a key role for bacterial microbiota in carcinogenesis (6,7,9-11). The International Agency for Research on Cancer (IARC) has classified only 10 microorganisms from the total number of 3.7x1030 microorganisms as pathogenic (12).

The microbiota colonizes any surface in the human body, with significant functional roles in homeostasis. Each surface in different organs (such as the lungs, skin, vagina and oral cavity) is exposed to the external environment and has its distinct microbiome. The highest percentage of microbial mass is located in the gastrointestinal tract (99%), which is the reason why the intestinal microbiota is the most extensively investigated type of microbiota thus far (13,14). In particular, 100 trillion micro-organisms of distinct structures (bacteria, parasites, fungi and viruses) are colonized in the human intestine, thus termed the intestinal microbiome (15,16). The absolute number of micro-organisms fluctuates between the mouth and rectum (17).

In order to establish the composition of the microbiota, it is only reasonable to consider a human being from the early stages of life, i.e. birth. The microbial composition is acquired during the first three years of childhood; following the initial stages, microbiota development continues with environmental exposure (17-19,29). As a general note, the gut microbiota displays a consistent composition and differs among individuals. During late stages of life, in the elderly, the composition of the microbiota changes again, but retains a stable function (21-24).

With regards to the microbiota of the human gastrointestinal tract, 50 distinct phyla and five hundred bacterial species have been reported as dominant (25). High throughput sequencing techniques have provided deep insight into the composition of the microbiota (26). A high proportion of gut microbiota is divided into three categories: The Firmicutes (30-50%), the Bacteroidetes (20-40%) and Actinobacteria (1-10%) (27). The majority of the microbiota is strictly anaerobic, such as Bacteroides, Eubacterium, Bifidobacterium, Fusobacterium, Peptostreptococcus and Atopobium, whereas the minority is facultative anaerobic and comprises Lactobacilli, Enterococci, Streptococci and Enterobacteriaceae (28). The gut microbiota varies in mass and composition along the gut, that is, from the luminal to the mucosal regions (17,25). For example, microbial composition is denser in the large intestine as compared to the small intestine, potentially explaining the higher susceptibility of the large intestine to cancer (30,31). The close association between the gut microbiota and colon cancer was initially revealed in 1975, when researchers observed that the potential of developing colon cancer in a chemically-dependent manner was reduced in germ-free rats (32). Furthermore, the colon is dominated by Bacteroidetes and Actinobacteria (90%), whereas the small intestine is colonized by Bacteroidetes and Actinobacteria (50%). The composition of the microbiota in the small intestine also includes other bacterial phyla, such as Firmicutes species (40%) (33). Despite the fluctuations of microbiota in composition and mass along the gut, the main population of micro-organisms is most certainly composed of bacteria, residing within the gastrointestinal lumen (34), either competing or cooperating with other micro-organisms (35).

The symbiotic association of micro-organisms with the human gut (host) is accomplished after several years of co-evolution and co-adaptation, contributing to a balanced homeostasis in the gut (4,36-38). The microbiota plays a key role in homeostasis, as confirmed by its participation in a wide range of processes, such as wound healing, the maintenance of barrier function, and the modulation of cellular growth and immune system regulation (39). Apart from participating in these processes, the microbiota also expands to the digestion of complex carbohydrates and the establishment of ecological niches that might otherwise be occupied by non-innocuous microorganisms (11). The gut microbiota is characterized by a high self-restitution capacity following perturbation (40).

Other beneficial functions of the microbiota include a significant contribution to the maturation of the immune system and to the protection against infectious agents (41-45). It is important to highlight that the murine gut microbiota displays high homology to the human gut microbiota, paving the way for translational research based on experimental mouse models (46,47). For example, the microbiota has been reported to actively participate in the developmental stages of a healthy immune system, as illustrated by severe immune defects in mice bred under germ-free conditions (18,48). As a general note, the immune system of the gut is responsible for eradicating pathogenic microbes, whereas at the same time it has developed immuno-tolerance mechanisms against classical gut microbes. The mucosal immune system is under the control of the adaptive immune system and it functions in a cell-autonomous manner (39). The disruption of the microbiota has been shown to confer a significant impact on the immune system in many aspects. Importantly, the microbiota has been demonstrated to affect immune structures, in addition to immune cell populations. This was initially illustrated in experimental mice bred under germ-free conditions, which displayed hallmark changes in immunoglobulin A (IgA) secretion and functionality defects in Peyer's patches and draining mesenteric lymph nodes (mLNs) (49,50). Notably, in a previous study, gut-associated lymphoid tissues (GALTs) were efficiently matured with the concomitant activation of T cells and IgA-secreting plasma cells in the presence of the microbiota, which mediated the necessary signals for both epithelial and dendritic cell (DC) activation (51). Furthermore, the gut microbiota appears to be essential for the function of basic immune populations, such as the secretion of interleukin (IL)-22 by type 3 innate lymphoid cells (ILC3 cells). ILC3 cells have been shown to be essential for the growth of T cells in a microbiota status-dependent manner, independently of IL-22, IL-23 or IL-17 synthesis (52). Subsequent scientific evidence has suggested that some bacterial strains are particularly associated with the functions of the immune system. For example, certain microbiota components seem to initiate inflammation and to regulate immune cells within the lamina propria of the intestine. The absence of segmented filamentous bacteria (SFB) causes low enrichments of IgA titers, the reduction of T helper 1 (Th1) and T helper 17 (Th17) cells, and the alleviation of immune responses to classical intestinal pathogens (Citrobacter rodentium and Salmonella spp.) (48,53,54). Yang et al highlighted the significance of SFB in the function of T helper 17 (Th17) cells, through the expression of a T cell receptor (TCR) directed to a specific SFB antigen (55). Despite the beneficial effects mediated by SFB, it was noted that SFB also increases susceptibility to autoimmune disorders (56). Specifically, it has been demonstrated that the induction of SFB to germ-free mice renders them susceptible to the development of collagen-induced arthritis (57). In addition, the expression of the innate-like cytokine IL-17C seems to be under the control of microbiota during intestinal tumorigenesis, as the latter was shown to mediate Toll-like receptor (TLR)/MyD88 signaling, which in turn lead a to IL-17C upregulation during colon cancer progression and ultimately to the uncontrolled proliferation of intestinal epithelial cells (IECs) (58).

On the other hand, the gut microbiota also has the capacity to induce an anti-inflammatory environment, by producing certain metabolic by-products that maintain barrier integrity. For example, the differentiation of IL-10-secreting Tregs has been shown to be absolutely dependent on the signal transduction pathway triggered by Bacteroides fragilis (51). Specifically, polysaccharide A secreted by Bacteroides fragilis induces Treg cell expansion via the TLR2 signaling pathway (51). Similarly, it has been reported that Helicobacter hepaticus (Hh) stimulates T cells to differentiate into T regulatory cells (59). The induction of Tregs was also observed following the incubation of clostridial strains, conferring significant benefits to experimentally-induced colitis (35,60). For example, Faecalibacterium prausnitzii is a clostridial organism that has been shown to protect patients from the onset of inflammatory bowel disease (IBD) (61). The gut microbiota therefore appears to be indispensable for the immune system as a whole (62).

Apart from the gut, the skin also harbors a significant number of microbial niches that sustain the recruitment of Th1/Th17 cells and provide protection against pathogens, such as Leishmania major (63). Indicatively, the functionality and persistent response of CD8+ T cells has been attributed to the skin microbe, Staphylococcus epidermidis (64). The oral cavity also contains microbial communities with key roles in modulating persistent immune responses to various infections (65,66). For example, it has been demonstrated that in the absence of microbiota in the oral cavity, immune cells cannot combat mucosal influenza virus (67). Even though the microbiota exerts its effect on the immune system locally on each surface barrier, the gut microbiome appears to be the most efficient in controlling systemic immune homeostasis (67-69). The insuperable effect of the gut microbiome on the immune system has been attributed to its great variability, the high number of associated micro-organisms and the relatively large surface area that is available to expand on (13). In line with this, it has been demonstrated that the incubation of certain bacterial strains in the skin of germ-free mice does not seem to display systemic effects and to reconstitute Th cell populations in the intestine (63). The significance of the presence of the microbiota in various anatomical sites was established when experimental animal models lacking microbial communities exhibited signs of autoimmune disorders (multiple sclerosis or arthritis) (57,70,71).

However, as described above, the microbiota does not only include populations of bacteria, but also consists of other micro-organisms, such as archaea, fungi, viruses, etc. For example, fungi such as Candida appear to be overexpressed in animal models following treatment with antibiotics (72). Nonetheless, the role of microbiota subtypes other than bacteria is still in its infancy and additional studies are required in order to assess their impact on the immune system (72,73).

2. Healthy gut conditions

The protection of the gut against exogenous pathogens is provided by the presence of the epithelial barrier. The integrity of the epithelial barrier is mediated through tight junctions between epithelial cells, the mucous layer, soluble antibacterial factors and distinct cells of innate and adaptive immunity (74-76). Under normal gut conditions, one hundred trillion organisms (particularly microbiota) thrive in the intestine, creating a protected, warm and nutrient-rich microenvironment, which in turn helps the microbiota to be in equilibrium with the host organism (eubiosis). When eubiosis is disrupted, the composition of the microbiota is altered and as a consequence, it is mostly represented by facultative anaerobic bacteria instead of aerobic bacteria (present in healthy conditions) (11). The interaction of the microbiota with epithelial cells is indirect, through the mucous layer, which separates the compartment of commensal bacteria from that of the host (49). If one considers that the gut microbiota is in close proximity to the IECs that line the mucous layer, it is only to be expected that dysbiosis can rupture the mucous layer, thereby leading to inflammatory conditions or even cancer (7,11,62). The mucous layer can be ruptured by microbial translocation, due to specific molecular alterations or abnormal regulatory signals (77).

3. Role of microbiota in colorectal carcinogenesis

One of the hallmarks of cancer is the uncontrolled growth of malignant cells, which ultimately constitutes one of the main causes of mortality. Colorectal cancer is the most predominant type of cancer in the USA and the third most common cause of mortality, therefore presenting a considerable tumor burden (78). Colorectal cancer, as the name implies, is characterized by carcinogenic alterations that occur in the colon and rectal epithelial cells. Different forms of colon cancer arise due to variations in genetic profiles, histological patterns and sensitivity to potential therapeutic drugs (79,80). Indeed, colorectal cancer can be divided into three subtypes, the first of which (35%) is ultimately linked to genetic alterations, the second (65%) is associated with exogenous factors and the third, which accounts for 1% of all colorectal cancer subtypes, is accompanied by chronic IBD (81). Consequently, the majority of patients with colorectal cancer (95%) are not directly genetically vulnerable to cancer, thereby supporting the notion that the gut microbiota is actively implicated in cancer development (82).

The uncontrolled growth of intestinal malignant cells begins with the conversion of normal epithelial cells into hyperplastic cells. In this manner, epithelial cells lose their morphological characteristics and become dysplastic. This is followed by the invasion of hyperproliferative epithelial cells into the gut lumen, where they form adenomas, and the subsequent protrusion of epithelial cells into the gut, which ultimately leads to cancer. From a genetic aspect, IECs are transformed into hyperplastic intestinal cells after the following sequence of genetic events: First the loss of tumor suppressor genes, such as adenomatous polyposis coli (Apc) and subsequently mutations in genes that encode the machinery for DNA repair, such as hMSH2.

Even though significant efforts have been made in order to elucidate the driver mechanisms that cause colorectal carcinogenesis, the landscape remains obscure. The effect of the gut microbiota on carcinogenesis has become a burgeoning issue of research in recent times, considering that the gut microbiota is vital in sustaining the homeostasis and regulation of the immune system. Since colorectal carcinogenesis is a multifactorial cancer type with a genetic basis, it has been proposed that inflammatory processes or perturbations of the intestinal microbiota can lead to the cancer development through genetic alterations. The impact of the gut microbiota appears to be more prominent in colon cancer, independent of the type and cause, where it seems to systemically influence cancer progression either as individual species or as a microbial community (12).

If one considers that microbes create a dynamic symbiotic interplay with the host, it is logical to assume that the gut microbiota can function either as a blocker or as a potentiator of colon cancer (Fig. 1). The first efforts made in the treatment of cancer through the natural effects of the gut microbiota were made in the late nineteenth century, when it was realized that bacterial infections or injections of heat-killed bacteria, such as Coley's toxin prevented the development of sarcoma in patients (83,84). Nowadays, Coley's toxin, which includes a mixture of killed bacteria (e.g., Streptococcus pyogenes and Serratia marcescens) is regarded a precursor of current immunotherapeutic agents. For example, the injection of Mycobacterium bovis Bacillus Calmette-Guérin (BCG) is currently used as the classical therapeutic approach in non-muscle invasive bladder cancer (85). Consistent with the above, experiments have demonstrated that animals bred under germ-free conditions exhibit a stronger likelihood for developing colon cancer than those bred under microbiota-rich environments (86).

Additional in vivo experiments have indicated that the microbiota has the capacity to induce cancer in a wider range of organs than previously considered, including the skin, colon, liver, breast and lungs (86-93). In a similar manner, it was shown that the elimination of intestinal microbiota (through antibiotics) ameliorates colorectal cancer or hepatic carcinogenesis (88,94-97).

Consequently, the majority of studies have concentrated on investigating the role of the gut microbiota in colitis-associated colorectal cancers, using either germ-free conditions or antibiotics (90,98). Using genetically engineered experimental models specifically predisposed to cancer, such as TCR-deficient (TCRb-/-) and double p53 KO (X p53-/-) mice, it was previously demonstrated that the gut microbiota can indeed induce colon cancer. The animals did not develop adenocarcinomas under germ-free conditions (99); however, TGFb1-/- mice gut-colonized with Helicobacter hepaticus demonstrated a greater potential for colon cancer development (100). Similarly, the gut colonization of Rag2-/- mice with Helicobacter hepaticus, and that of Tbet-/- Rag2-/- mice with microbiota, has been shown to induce colon carcinogenesis (101,102). The resulting phenotype of these experimental animal models (TGFb1-/- and Tbet-/- Rag2-/-) under germ-free conditions was very similar to the phenotype following antibiotic treatment (98,103). Additional studies reported that IL10-/- mice developed tumors following treatment with the chemical carcinogen azoxymethane (AOM) and incubation with Enterococcus faecalis, as compared to mice bred under germ-free conditions, which remained healthy (90,104).

However, since AOM, in combination with dextran sulfate sodium (DSS), has been shown to induce colon cancer formation, the role of the gut microbiota in colorectal carcinogenesis in experimental mouse models may be obscured by the effects of chemically induced carcinogenesis (92,105-110). In other words, it is difficult to assess which animal models of colorectal cancer are the most suitable for elucidating the role of the microbiome in cancer development. Despite the seemingly unsurpassed selective pressures displayed by malignant cells, the concept of microbe-driven cancer formation does not cease to exist. A significant number of research studies have explored whether micro-organisms are directly involved in tumor progression or whether they participate indirectly through their metabolites. Recent metagenomic analyses have revealed essential differences between healthy and cancer states and assessed the tumor-promoting effects of microbiota in certain types of cancer. The mechanisms through which specific microbes target certain cancers, contributing to the acceleration of tumor progression remain elusive. For example, human papillomavirus (HPV), hepatitis B virus, hepatitis C virus, human herpesvirus 8 and human T-lymphotropic virus 1 have been shown to trigger carcinogenesis via well-defined processes (5,11). Specifically, HPV can cause anogenital or oropharyngeal carcinomas, hepatic B or C virus can induce hepatocellular carcinoma and human immunodeficiency virus (HIV) or Epstein-Barr virus (EBV) or human T-cell lymphotropic virus type 1 (HTLV-1) can lead to lymphoma (7). As regards individual bacterial species, it has been revealed that specific bacterial strains drive carcinogenesis (111). As highlighted by epidemiological data, the most highly-associated microbe to cancer development, especially gastric cancer, is Helicobacter pylori (H. pylori) (112). Helicobacter pylori releases toxins (CagA or VacA) that cause cytoskeletal rearrangements which cannot be surpassed by the host repair mechanisms (113,114). Notably, the close association of Helicobacter pylori with gastric cancer has been regarded a landmark discovery and was awarded a Nobel Prize (115). Furthermore, Streptococcus bovis, Helicobacter pylori, Bacteroides fragilis, Enterococcus faecalis, Clostridium septicum, Fusobacterium spp. and Escherichia coli have also been identified as bacterial species that can lead to the development of intestinal neoplasms. Other bacterial strains, including Bacteroides fragilis, Escherichia coli, Enterococcus faecalis and Fusobacterium nucleatum, have been identified in experimental animal models chemically predisposed to colon cancer as microbes with an ability to modulate normal immune responses (Table I) (116-121).

Table I.

Microbes modulate immune responses in murine models of colon cancer.

Table I.

Microbes modulate immune responses in murine models of colon cancer.

Bacterial strainsSecreted factorMolecular mechanismMurine experimental model predisposed to colon cancerRefs.
Bacteroides fragilis (B. fragilis)Enterotoxin (ETBF)Changing host immune system Apcmin/+(116,117,132)
Escherichia coli (E. coli)UnknownImmune stimulation IL10-/-(118)
Enterococcus faecalis (E. faecalis)SuperoxidePolarization to M1 macrophages IL10-/-(118,119)
Fusobacterium nucleatum (F. nucleatum)UnknownMDSCs, TAMs, TANs, CD103+ DC infiltration ApcMin/+(120)
Fusobacterium nucleatum (F. nucleatum)Fap2Suppression of immune responsesAllograft of wild-type mice with CT26 cancer cells(121)
Fusobacterium nucleatum (F. nucleatum)Fap2Fap2 engagement to TIGIT, avoiding NK cell toxicity ApcMin/+(127)

[i] MDSCs, myeloid-derived suppressor cells; TAMs, tumor-associated macrophages; TANs, tumor-associated neutrophils; DC, dendritic cells; NK, natural killer.

An important breakthrough was achieved in the case of Fusobacterium nucleatum. In general, Fusobacterium nucleatum is localized in the oral cavity. As a resident member of the oral microbiota, Fusobacterium nucleatum has been extensively studied and has been found highly associated with periodontitis and appendicitis (122). Fusobacterium nucleatum is an anaerobic Gram-negative rod bacterium and one of the leading micro-organisms in intrauterine infections causing premature death. Compared to the gut microbiota of healthy individuals, Fusobacteria are often found in patients with colon adenocarcinoma and IBD, thus suggesting an association between Fusobacteria and the colon inflammatory environment (120,123-126). In the human body, Fusobacterium nucleatum can be introduced through the oral cavity and transferred into the gastrointestinal tract, thereby affecting human colon adenocarcinoma. From an immune point of view, Fusobacterium nucleatum triggers inflammatory signaling pathways and functions as a shield to tumor cells against an immune attack (12,127). It has been proposed that certain bacterial strains possess many adhesins, mediating their binding to TLR4 and RIG-I, as well as their direct interaction with natural killer (NK) cells via binding to the NKp46 receptor (128-130). In this context, the Fap2 protein of Fusobacterium nucleatum has been shown to bind to the human (not mouse) TIGIT [T cell immunoreceptor with Ig and ITIM (immunoreceptor tyrosine-based inhibitory motif)] receptor present on NK cells and T cells in a hemagglutination-dependent manner (Table I) (127). The hemagglutination potency of Fap2 has been tightly linked to TIGIT suppression. In this manner, Fusobacterium nucleatum manages to abolish NK cell-mediated destruction of human cancer cells. Notably, Fusobacterium nucleatum has been shown to bind to many tumor cells through interactions of its Fap2 protein with the Gal-GalNac protein of cancer cells. Consistent with the above, the exposure of experimental ApcMin/+ animal models to Fusobacterium nucleatum has been shown to cause enriched myeloid cell infiltration (predominantly DCs, macrophages) and the activation of the nuclear factor (NF)-κB signal transduction pathway. In addition, Fusobacterium nucleatum has been shown to augment the numbers of two types of myeloid-derived suppressor cells (MDSCs), thus inhibiting activated T cell responses and exacerbating small intestinal adenocarcinoma development (Table I) (120). Substantial experimental data have highlighted that Fusobacterium nucleatum-fed mice are enriched for tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), CD103+ regulatory DCs, thus exhibiting a promotion of neoplastic progression (Table I) (120).

Fusobacterium nucleatum seems to recapitulate tumor progression through its effects on the tumor microenvironment. For example, Fusobacterium nucleatum has been shown to synthesize hydrogen sulfide following red meat consumption, thus promoting DNA damage responses and genomic instability in colon epithelial cells, which can in turn lead to tumor development (131,132). The onset of colorectal carcinoma and the extent of tumor progression appear to be more prominent in individuals with mutations or perturbations in the DNA-damage response (e.g., ATR and ATM). In support of this notion, both in vitro and in vivo xenograft experiments have highlighted the potential of Fusobacterium nucleatum to trigger the Wnt/β-catenin pathway, via FadA binding, which is highly associated with the proliferation of neoplastic cells (126).

Furthermore, it has been illustrated that enterotoxigenic Bacteroides fragilis (ETBF) can potentiate tumor formation by activating the signal transducer and activator of transcription 3 (STAT3) signaling transduction pathway and recruiting T helper 17 cells (Th17) in ApcMin/+ mice (Table I) (132). The oncogenicity of Bacteroides fragilis became evident from its capacity to trigger the Wnt/β-catenin pathway, thus aiding in distant site colonization by tumor cells. Overall, Bacteroides, Escherichia coli and Enterococcus faecalis are the bacterial strains found to be DNA damage inducers in animal models (Table II) (119,133-136). Enterococcus faecalis has been shown to stimulate the DNA damage response in epithelial cells by secreting high levels of reactive oxygen species (ROS) (119,137), Bacteroides fragilis has been shown to trigger the Wnt signaling pathway and Escherichia coli is able to initiate double-stranded DNA breaks, thus resulting in increased genomic instability (133-135). Escherichia coli, in particular, has been found to contain polyketide synthase pathogenicity islands (pks), which contain the gene responsible for the toxin (colibactin) that triggers DNA damage response in IECs (Table II) (134,138,139). The significant oncogenicity of Escherichia coli was highlighted when IL10-/- mice developed intestinal tumorigenesis following treatment with AOM and Escherichia coli strains, without any indication of inflammatory sites (134). Therefore, these microbes (Enterococcus faecalis, Bacteroides fragilis, Escherichia coli) are considered to be key mediators of the DNA damage response and tumor progression, without the need for a pro-inflammatory environment (Table II). Last but not least, other bacterial strains have been shown to use other, multifaceted mechanisms in order to induce carcinogenesis in animal models (Table III) (140-143).

Table II.

Microbes modulate DNA damage responses in murine models of colon cancer.

Table II.

Microbes modulate DNA damage responses in murine models of colon cancer.

Bacterial strainsSecreted factorMolecular mechanismMurine experimental model predisposed to colon cancerRefs.
Bacteroides fragilis (B. fragilis)EnterotoxinDNA damage through spermine oxidase action ApcMin(133)
Enterococcus faecalis (E. faecalis) Epithelial DNA damage through ROS induction (119,137)
Escherichia coli (E. coli)ColibactinDNA damage and senescence activation IL-10-/-, AOM(134,135)
Helicobacter hepaticus (H. hepaticus)CDTDNA damage Rag2-/-(136)

[i] AOM, azoxymethane; CDT, cytolethal distending toxin.

Table III.

Microbes use various mechanisms in murine models of colon cancer.

Table III.

Microbes use various mechanisms in murine models of colon cancer.

Bacterial strainsSecreted factorMolecular mechanismMurine experimental model predisposed to colon cancerRefs.
Bilophila wadsworthia (B. wadsworthia)SulfideUncontrolled growth due to augmented bile acid production IL-10-/-(140)
Helicobacter spp.UnknownROS generationGpx1-/-, Gpx2-/-(142)
Helicobacter spp.UnknownROS generation Smad3-/-(141)
Streptococcus gallolyticus (S. gallolyticus)CDTInduction of angiogenesisAOM(143)

[i] ROS, reactive oxygen species; AOM, azoxymethane; CDT, cytolethal distending toxin.

4. Role of dysbiotic microbiota in inflammation and colorectal cancer

Even though recent data have suggested that individual micro-organisms specifically influence the formation of cancer, carcinogenesis may also be the result of altered microbiota composition (dysbiosis) (144). The defects in the symbiotic interplay between the host and intestinal microbiota can result in alterations in the composition of the microbiota or in defects in the regulatory signals that orchestrate the normal association of microbiota with the host. In this manner, the balance in the commensal community changes (termed dysbiosis) and colon cancer can become the following event (6,8). Possible causes of dysbiosis can be either pathogenic microorganisms or environmental cues, such as antibiotics, xenobiotics or obesity (11). Other causes may be genetic defects in epithelial, myeloid, or lymphoid cells of the gut, which can stimulate dysbiosis and consequently lead to inflammatory states, such as Crohn's disease, which may in turn confer some predisposition to carcinogenesis (35).

Dysbiotic bacteria appear to be indispensable to the creation of an inflammatory environment in the gut. Nevertheless, additional genetic changes are required for the initiation of colorectal carcinogenesis (11,145,146).

A significant number of studies have investigated the precise mechanisms through which the microbiota can be implicated in tumor development. In general, experimental mouse models chemically predisposed to colon cancer exhibit a lower incidence of tumor formation when treated with antibiotics or when bred under germ-free conditions, as compared to animals bred under conventional conditions (86,92,93,95-97,147,148). It remains to be clarified whether inflammation precedes or follows dysbiosis, before ultimately leading to cancer. On one hand, it has been suggested that a dysbiotic microbial community can lead to carcinogenesis by inducing chronic inflammation (149). For example, IL-18-, IL-18R- and MyD88-deficient mice are unable to mount adequate immune responses due to intestinal dysbiosis that occurs through the expansion of bacterial phyla Bacteroidetes (Prevotellaceae) and TM7, which ultimately leads to colon cancer (108,150,151). Other immune-deficient mice [Nod2-/-, Asc-/- (also known as Pycard-/-) and Nlrp6-/-] also display dysbiotic microbiota and exhibit carcinogenesis (152,153). The functional significance of dysbiotic microbiota has been highlighted by the fact that the transfer of dysbiotic intestinal microbiota in healthy mice renders them susceptible to colon cancer (151). Similarly, genetically-edited mice (Tlr5 or IL1- or Tbx1 or Rag2 immunologically ablated) display prominent signs of colon cancer due to dysbiotic microbiota, as compared to immunologically wild-type mice (111). Last but not least, mice deficient for mucin (total Mucin 2 KO) present a defective intestinal barrier and for this they have been classified as models of intestinal neoplasia (154).

On the other hand, it has been proposed that inflammation causes barrier deterioration (dysbiosis), thus facilitating bacterial translocation, which in turn facilitates the creation of amplification feedback loops between intestinal barrier loss and carcinogenesis (145). For example, if mice display defects in pattern recognition receptors which specifically bind to microbial-associated molecular patterns (MAMPs), then these mice are characterized by bacterial translocation, dysbiosis and ultimately exhibit carcinogenesis (134,152,153).

In addition to the local gut microbiota effect on cancer described above, other changes can cause long-distance effects, determining the outcome of neoplasms other than colorectal cancer (e.g., pancreatic, liver and breast cancer) (88,94,155-157). A characteristic example of cancer caused by the distant effect of dysbiotic microbiota is represented by hepatocellular carcinoma. The long-distance effects to host organs are exerted by dysbiotic intestinal microbiota either via the activation of pro-inflammatory MAMPs or via the secretion of bacterial metabolites. For example, the gut microbiota is capable of stimulating hepatocellular carcinoma following entry into the liver through the portal vein (88,94,158,159). Similarly, it has been demonstrated that antibiotics ameliorate the progression of hepatocellular carcinoma (88,159,160). Notably, dysbiotic microbiota have been shown to influence estrogen metabolism, thereby affecting tumors in distant sites (7). In the lungs, Candida overgrowth has been observed following antibiotic-mediated gut dysbiosis, with subsequent increases in plasma prostaglandin E2 levels and macrophage differentiation towards the M2 lineage (72). These findings are in agreement with the results of epidemiological studies supporting a strong link between dysbiosis and the development of extracolonic neoplasms, including breast carcinoma (161,162). It was concluded that bacteria and their products are systemically distributed throughout the body, compromising the integrity of the intestinal barrier (94).

5. Role of microbiota in genotoxic stress

If one considers that cancer is tightly associated with genetic diseases, it makes sense to assume that the microbiota exerts a tumor-promoting role via genotoxic stress. The gut microbiota is highly implicated in colorectal carcinogenesis through the secretion of toxic metabolites as by-products of fermentation. Toxic metabolites bind to specific surface receptors on intestinal cells, thereby affecting key signaling pathways. As a general note, microbiota-secreted toxins trigger DNA damage response, causing cell cycle arrest, which is often followed by apoptosis (116,134,139,163-167).

A particular toxin, termed CagA, secreted by Helicobacter pylori, has been shown to induce both inflammation and cancer (168,169). ETBF, another well-described toxin, is secreted by Bacteroides fragilis and is also implicated in colorectal carcinogenesis. Specifically, ETBF binds to the epithelial receptor, stimulating the Wnt and NF-κB signal transduction pathways, thus leading to enhanced cell proliferation and DNA damage response (133,171-172). ETBF stimulates IL-17 synthesis in the ApcMin/+ mouse model, thereby predisposing it to intestinal neoplasia (116,172,173). The underlying molecular mechanisms of ETBF have been shown to include the epithelial damage through E-cadherin cleavage, which in turn activates the β-catenin/Wnt pathway and the STAT3 signaling pathway (critical for the growth of malignant cells) (116,174).

Since DNA damage is tightly associated with genomic instability, proteins that are responsible for all the changes caused by double-strand DNA breaks, such as cytolethal distending toxin (CDT) and colibactin, can be regarded as true genotoxins (139,165). Colibactin, however, stands out among other toxins, as it is capable of inducing oxidative burst, in addition to causing genome instability (134,139).

Bacteria-secreted toxins may also have a profound impact on the oxidation status of cancer cells (175). Enterococcus faecalis seems to be the main bacterial strain producing reactive oxygen intermediates (superoxide and hydrogen peroxide) and inducing harmful changes in epithelial cells and malignant transformation. Notably, these effects are exacerbated in IL-10-deficient mice, suggesting that the microbiota leads to colorectal carcinogenesis via reactive toxins in an established inflammatory environment (104,176). It has also been indicated that IECs are toxically hampered by sulfate-reducing bacteria through production of hydrogen sulfide (H2S) (177,178). Finally, it has been argued that bacteria can obtain virulence factors and convert them to pathogens. The capacity of bacteria to bind to IECs seems to be facilitated via the acquisition of virulence factors (11,179-181). For example, FadA has been identified as the virulence factor secreted by Fusobacterium nucleatum in order to activate colorectal cancer (126,182). Similarly, the afa and eae adhesins have been identified as the virulence factors released by Escherichia coli strains in order to drive intestinal malignant transformation (107,183).

6. Role of gut microbiota in metabolism

Recent experimental data have confirmed that the gut microbiota can synthesize an enormous quantity of metabolic by-products that affect tumor progression either positively or negatively, upon interaction with the host. In general, the microbiota is responsible for metabolizing dietary factors into bioactive food components. Commencal bacteria are known to exert their fermentation capacity in the gut, metabolizing non-digestible carbohydrates such as polysaccharides (e.g., resistant starch, cellulose, hemicellulose, pectins and gums), oligosaccharides, and lignins into short-chain fatty acids (SCFAs). The SCFAs are composed of acetate, propionate and butyrate, which are regarded as tumor suppressors with great anti-inflammatory and chemo-preventive properties (184,185). SCFAs are final fermentation products of dietary fiber in gut bacteria and provide the appropriate energy to sustain the health of gut epithelial cells. The type of diet directly influences bacterial abundance and composition, as indicated by technologies, such as metagenomics (effect of diet on microbiota), metaproteomics (microbial gene expression) and metabolomics (microbial metabolites). On the other hand, the microbiota can exert beneficial effects on the host organism, as it is responsible for vitamin synthesis, such as vitamin K and most B vitamins (186). In addition, carbohydrates, branched chain amino acids, ammonia, amines, phenols, indoles and phenylacetic acid are also generated through the actions of gut microbiota (187,188). Several Bacteroides spp. and some Firmicutes have been classified as the bacteria responsible for the synthesis of phenylacetic acid, phenols, indoles and p-cresol. These metabolites are known to be quite toxic as they cause the nitrogen alkylation of DNA (189,190). For example, N-nitroso compounds (NOCs) are exogenously supplied or endogenously synthesized through the nitrosation of amines by gut microbiota. The abundance of NOCs has been positively linked to an increased incidence of colorectal cancer in European populations (94). Some products, such as ammonium are carcinogenic despite being produced at low concentrations (191).

SCFAs, such as acetate, propionate and butyrate are efficiently absorbed by the gut lumen, despite differences in their distribution and their effects on host cell metabolism. Each SCFA has specific characteristics that distinguish it from the other SFCAs. Despite low concentration levels of butyrate in the systemic circulation, IECs predominantly use butyrate to fuel their energy stores (60-70%). Normal colonocytes exploit butyrate as their primary energy source, as butyrate follows the procedure of mitochondrial β-oxidation every 7 days (192-194). With respect to the distribution of other SCFAs, the liver has the greatest metabolizing capacity of propionate, while most of the peripheral blood is occupied by high concentrations of acetate (0.10-0.15 mM) (195).

SCFAs also exert growth-inhibitory effects against pathogens (196). The anti-inflammatory and anti-carcinogenic effects of butyrate attenuate inflammation in IBDs such as colitis and Crohn's disease in both rodent models and humans. More than five microbiome studies have confirmed that butyrate-producing bacteria are diminished in patients with colon cancer, as compared to healthy individuals (197). Particularly, the anti-inflammatory properties of butyrate and propionate (but not acetate) have emerged through their capacity to reduce the activity of histone deacetylases (HDACs) in colonocytes and immune cells. This results in histone hyperacetylation, the recruitment of the transcriptional machinery to specific genes and the downregulation of IL-6/12 signal transduction pathways (198-200). In this context, butyrate and propionate are regarded as powerful stimuli to the differentiation and function of Tregs (201-203). Furthermore, tumor cells use glycose aerobically through the Warburg effect (204) and the majority of butyrate translocate to the nucleus, where it exerts its action (205,206). Consistent with this, colon tumor-bearing mice colonized with wild-type butyrate-producing bacteria do not show any signs of cancer following a high-fiber diet. By contrast, in the absence of butyrate-producing bacteria, the same mice exhibit obvious tumor signs (205,207). Butyrate seems to exert its effects at specific genomic regions, such as the Fas and p21 genes, which are actively involved in apoptosis and the inhibition of cell cycle progression, respectively (197,208), thereby reinforcing the hypothesis that butyrate is a well-established HDAC inhibitor (197,208). Another example of the beneficial effects of butyrate was demonstrated in experimental ApcMin/+ MSH2-/- mice. Polyp formation is abrogated in ApcMin/+ MSH2-/- mice following a low carbohydrate diet due to the production of butyrate (185). Apart from functioning as an HDAC inhibitor, butyrate has been found to mediate its signals through certain G protein coupled receptors (209,210).

Butyrate and niacin also constitute main representative metabolites of microbiota-secreted SCFAs that have been shown to influence the immune system through two opposing mechanisms. From one perspective, microbial metabolites may mediate their action through binding to the GPR109A receptor, thereby triggering IL-18 synthesis in IECs and affecting DCs, macrophages and T cells (211). Form another perspective, gut microbial metabolites may exert anti-inflammatory properties, supporting Treg differentiation and expansion, thus establishing an immunosuppressive micro-environment (201).

Importantly, the gut microbiota is significantly implicated in metabolizing certain food supplements and nutrients. For example, berries and nuts involve ellagic acid, which is converted to urolithins by gut microbiota. Urolithins diminish Cox2 levels, thus exhibiting a certain anti-cancer effect (212,213). Daidzen is another nutrient metabolized by gut sulfate-reducing microbiota into equols (214,215). Epidemiological data from Asian populations have reported an association between high urinary or plasma equol concentrations and a decreased breast and prostate cancer risk (216). Another characteristic example is the elimination by certain gut microbiota (Lactobacilli and Bifidobacteria) of linoleic acid levels, which are regarded very toxic as they convert omega-6 to omega-3 and produce prostaglandins (217). Finally, resveratrol constitutes another example of the metabolizing effect mediated by gut microbiota (218).

In contrast to the above, the gut microbiota may promote carcinogenesis through the synthesis of secondary bile acids. Characteristically, a minor portion of primary bile acids (5%) escapes the classical enterohepatic circulation and reaches the colon. The following procedure deconjugates and transforms primary bile acids into secondary bile acids (such as DCA and LCA) though the action of specific bacteria (219). The presence of mutations that are insensitive to apoptosis enables secondary bile salts to act as promoters of tumorigenesis (220). DCA is such a toxic metabolite, provoking epithelial DNA damage and apoptosis in a p53-independent but PKC-ERK1/2-dependent manner, with direct associations to the formation of colon cancer or hepatocellular carcinoma or esophageal cancer (94,221-225). Recent data illustrate that bacteria in Clostridium cluster IX are responsible for enrichment of DCA levels in obese mice, rendering them highly susceptible to cancer formation (144). Similarly, certain types of microbiota that convert ethanol into acetaldehyde have been regarded as major stimulators of carcinogenesis (191).

Last but not least, the cumulative exposure of humans to xenobiotics or pharmaceuticals has helped in the understanding that gut microbiota may have direct or indirect implications in the breakdown of such substances (226).

7. Association of cancer therapy with microbiota

Significant efforts are being made in order to manipulate gut microbiota for preventive, diagnostic and therapeutic purposes. For the diagnostic purposes, identification of specific bacterial strains can offer enormous benefit in the context of new, reliable, non-invasive biomarkers for cancer. For cancer prevention purposes, Fusobacterium nucleatum has been proven to be a valuable prognostic biomarker, if one considers the abundance of Fusobacterium nucleatum in patients with high-grade colon cancer and adenomas (227,228). This has been supported by elevated fecal levels of Fusobacterium nucleatum in patients with colorectal cancer (120,227,229,230). Notably, recent evidence has suggested that the percentage of Fusobacterium nucleatum present in fecal samples is inversely associated with the survival of patients with colon cancer (231).

A subset of microbes have also been shown to reduce chronic inflammation or to mitigate malignant transformation (132,232,233). Below, we discuss some potential avenues through which microbiota can be therapeutically exploited.

First of all, the gut microbiota appears to be essential to the effectiveness of classical chemotherapeutic drugs such as oxiplatin, cisplatin, and cyclophosphamide (CTX). In general, chemotherapeutic compounds elicit toxic effects on tumor cells, including ROS activation by myeloid cells, intrinsic mitochondrial apoptosis, and the stimulation of inflammatory genes (132,234,235). The beneficial contribution of the microbiota to chemotherapy has been determined by the composition of the microbiota on myeloid cells (24,236). Similarly, microbiota located on myeloid cells has been found to exert a positive effect on cancer immunotherapy or total body irradiation (TBI). Therefore, the importance of the gut microbiota in cancer therapy emerges from its interaction with anti-neoplastic agents in a bidirectional manner.

On the one hand, many current anti-cancer therapeutic strategies (chemotherapy and radiation therapy) negatively affect microbial composition, by fostering dysbiosis (24,236). Radiation therapy, allogeneic stem cell transplantation and several chemotherapeutic agents, including irinotecan and 5-fluorouracil, appear to negatively affect the composition of the gut microbiota (237-239). On the other hand, a considerable body of evidence has demonstrated that the gut microbiota is of the utmost importance to the efficacy of therapeutic drugs, by eliminating side-effects and by interfering in a pharmacodynamic or immunological manner (132,234,240,241).

Currently, therapeutic interventions based on the gut microbiota are categorized as follows: i) Antibiotics; ii) probiotics; ii) prebiotics; and iv) postbiotics. Each therapeutic perspective of the gut microbiota is distinct. Antibiotics are usually used for the eradication of specific bacterial strains. Probiotics are living bacteria and prebiotics are non-digestible compounds, both of which provide strong support to the host. Postbiotics are non-viable products of microbiota, recapitulating a wide range of functions in the human body. All of these therapeutic categories have been shown to confer significant benefits to the host.

Probiotics and prebiotics are known for their capacity to sustain a balanced microbial community, obviating pro-inflammatory or signaling pathways that lead to carcinogenesis (5-8,11,242,243). Probiotics are usually administered as a curative strategy for antibiotic-mediated dysbiosis and side-effects in studies with mice and humans (244). Probiotics are innocuous microbes, critical for homeostasis, preventing entry of pathogens by stimulating AMPS, IgA and contributing to intestinal barrier integrity (243,245,246). A number of studies have proposed probiotics as a preventive intervention for inflammatory bowel disease or ulcerative colitis (247-251).

Notably, the chemo-preventive efficacy of probiotics and prebiotics seems to be higher than that elicited by antibiotics, through alleviation of inflammation. Antibiotics are not only insufficient as chemopreventive agents, but they can also eliminate commensal homeostatic bacteria and make certain bacterial strains resistant (252). However, human microbiome reconstitution following antibiotic treatment is defective due to impairment of commensal microbial community (253-255), and a time-consuming process (256). For this reason, efforts have focused on devising therapeutic strategies which sustain the microbial composition and population, thereby conferring benefit to the host. Based on data derived from 20 studies, 36% of patients with IBD who were transplanted fecal-derived microbiota from healthy donors exhibited an alleviation of symptoms (257). In another case, fecal microbiota transplantation has been shown to alleviate diarrhea symptoms in individuals with severe Clostridium difficile infections, following the use of antibiotics (258). The most impressive results were derived from the study by Suez et al, who demonstrated that autologous fecal microbiome transplantation was able to reconstitute the microbial community in its initial configuration in both murine and human samples following treatment with antibiotics. The rapid and complete recovery of the microbiome niche in aFMT-samples following the use of antibiotics, as compared to incomplete niche following treatment with probiotics, was compelling (259).

Mounting evidence suggests that the microbiota can be a determinant factor in modulating the host immune response. Several studies have demonstrated the crucial role of the microbiota in the response of distinct cancer types to classical immunotherapy (immune checkpoint inhibitors) (260-264). For example, the gut microbiota can positively influence the effectiveness of recently developed immunotherapeutic molecules [cytotoxic T lymphocyte associated protein 4 (CTLA4) or programmed death protein 1 (PD-1) antibodies]. The effects of germ-free state or the effects of colonization with specific bacterial strains on therapies using immune checkpoint inhibitors have been investigated. Bacteroides spp. appears to be necessary in the anti-CTLA treatment against sarcomas (265) and Bifidobacterium seems to be essential in anti-PDL1 therapy against melanoma (266). Furthermore, the microbiota seem to elicit an efficient response to immunotherapy [CpG-oligodeoxynucleotides (ODN) with neutralization antibody against IL-10], as indicated by experiments using mice (132). Similarly, mice grown under conventional conditions have exhibited stronger responses to CpG-ODN than TLR4-deficient mice (132).

Additional research efforts are required in order to elucidate the mechanisms through which the gut microbiota modulates the clinical effectiveness of various drugs, thus facilitating the design of appropriate personalized therapies based on the microbiota profile of an individual patient. The binding of the Fap2 protein of Fusobacterium nucleatum to the Ig and ITIM domains (TIGIT) of the human inhibitory receptor that is present on NK cells protects tumors from an immune attack by NK cells (127). Therefore, the presence of Fusobacterium nucleatum in patients may be a direct determinant and/or predictor of resistance to immunotherapy, and special considerations will have to be taken into account when designing personalized therapies for this particular patient group.

Certain issues will also have to be addressed before we move forward in the design of more personalized therapies. For example, the gut microbiota can be directed towards a specific immune population so as to serve as a tool for enriching the specific immune population against cancer. A better understanding of the microbiome effect on anti-PD1 therapy, currently applied to various types of cancer, may help to address the question (262-264). Another issue may be whether host T cells can be equipped with a TCR that is specific for a bacterial epitope and thereby to orchestrate an appropriate immune response. The ultimate goal will be to use microbiota or microbiota-derived molecules as novel immunotherapeutic approaches that will spare patients from the side-effects associated with systemic immunotherapies. For example, an organized and enriched CD8+ T cell response already looks promising in effectively enhancing the therapeutic action of immune checkpoint inhibitors in melanoma without adverse effects (262).

8. Conclusion

A considerable body of evidence exists nowadays that supports how essential the microbiota is in deciding the fate of neoplastic formations, their progression and their sensitivity to classical therapeutic drugs. The effect of the microbiota on cancer is usually elicited locally but it can also be developed systemically, through alterations in the whole immunological milieu. The knowledge pertaining to the microbiome expands rapidly, however therapeutic interventions of intestinal carcinogenesis are still limited. Further experiments will be critical in understanding the underlying molecular mechanisms of microbiota, using animal models or epidemiological data derived from clinical trials towards inventing new treatments. Nevertheless, the available methodologies need to incorporate new technologies in order to facilitate the growth of microbes in conditions that are a direct replica to those within the gastrointestinal tract of the human body. The combination of metagenomics (effect of diet on microbiota), metaproteomics (microbial gene expression), and metabolomics (microbial metabolites) seems to play an important role in developing strategies for disease prevention.

Acknowledgements

Not applicable.

Funding

No funding was received.

Availability of data and materials

Not applicable.

Authors' contributions

All authors (SB, MA, DAS, AMK, IC and VZ) were involved in the design and conception of the study and have revised and approved the final manuscript. SB performed the literature search, has written the manuscript, has critically analyzed the existing knowledge and has designed the picture and the tables. MA contributed to editing the manuscript concerning the role of microbiota in metabolism and role of dysbiotic microbiota in inflammation and colorectal cancer, AMK contributed to editing of manuscript concerning the role of microbiota in genotoxic stress, IC contributed to editing the manuscript concerning the role of microbiota in homeostasis, DA contributed to editing of manuscript concerning association of cancer therapy with microbiota. SB, MA, DAS, AMK, IC and VZ were significantly involved in the drafting of the manuscript. All authors have taken the responsibility for publishing this review paper and all authors have read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

DAS is the Editor-in-Chief for the journal, but had no personal involvement in the reviewing process, or any influence in terms of adjudicating on the final decision, for this article. All the other authors do not have any competing interests to declare.

References

1 

Iida N, Dzutsev A, Stewart CA, Smith L, Bouladoux N, Weingarten RA, Molina DA, Salcedo R, Back T, Cramer S, et al: Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science. 342:967–970. 2013.PubMed/NCBI View Article : Google Scholar

2 

Boleij A, Hechenbleikner EM, Goodwin AC, Badani R, Stein EM, Lazarev MG, Ellis B, Carroll KC, Albesiano E, Wick EC, et al: The Bacteroides fragilis toxin gene is prevalent in the colon mucosa of colorectal cancer patients. Clin Infect Dis. 60:208–215. 2015.PubMed/NCBI View Article : Google Scholar

3 

Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, Nielsen T, Pons N, Levenez F, Yamada T, et al: MetaHIT Consortium: A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 464:59–65. 2010.PubMed/NCBI View Article : Google Scholar

4 

Blaser MJ: Who are we? Indigenous microbes and the ecology of human diseases. EMBO Rep. 7:956–960. 2006.PubMed/NCBI View Article : Google Scholar

5 

Bultman SJ: Emerging roles of the microbiome in cancer. Carcinogenesis. 35:249–255. 2014.PubMed/NCBI View Article : Google Scholar

6 

Clemente JC, Ursell LK and Parfrey LW and Knight R: The impact of the gut microbiota on human health: An integrative view. Cell. 148:1258–1270. 2012.PubMed/NCBI View Article : Google Scholar

7 

Plottel CS and Blaser MJ: Microbiome and malignancy. Cell Host Microbe. 10:324–335. 2011.PubMed/NCBI View Article : Google Scholar

8 

Petersen C and Round JL: Defining dysbiosis and its influence on host immunity and disease. Cell Microbiol. 16:1024–1033. 2014.PubMed/NCBI View Article : Google Scholar

9 

Dietert RR and Dietert JM: The microbiome and sustainable healthcare. Healthcare (Basel). 3:100–129. 2015.PubMed/NCBI View Article : Google Scholar

10 

Arslan N: Obesity, fatty liver disease and intestinal microbiota. World J Gastroenterol. 20:16452–16463. 2014.PubMed/NCBI View Article : Google Scholar

11 

Schwabe RF and Jobin C: The microbiome and cancer. Nat Rev Cancer. 13:800–812. 2013.PubMed/NCBI View Article : Google Scholar

12 

Garrett WS: Cancer and the microbiota. Science. 348:80–86. 2015.PubMed/NCBI View Article : Google Scholar

13 

Human Microbiome Project Consortium: Structure, function and diversity of the healthy human microbiome. Nature. 486:207–214. 2012.PubMed/NCBI View Article : Google Scholar

14 

Grice EA and Segre JA: The skin microbiome. Nat Rev Microbiol. 9:244–253. 2011.PubMed/NCBI View Article : Google Scholar

15 

Suau A, Bonnet R, Sutren M, Godon JJ, Gibson GR, Collins MD and Doré J: Direct analysis of genes encoding 16S rRNA from complex communities reveals many novel molecular species within the human gut. Appl Environ Microbiol. 65:4799–4807. 1999.PubMed/NCBI

16 

Savage DC: Microbial ecology of the gastrointestinal tract. Annu Rev Microbiol. 31:107–133. 1977.PubMed/NCBI View Article : Google Scholar

17 

Neish AS: Microbes in gastrointestinal health and disease. Gastroenterology. 136:65–80. 2009.PubMed/NCBI View Article : Google Scholar

18 

Goncharova GI, Dorofeĭchuk VG, Smolianskaia AZ and Sokolova KIa: Microbial ecology of the intestines in health and in pathology. Antibiot Khimioter. 34:462–466. 1989.(In Russian). PubMed/NCBI

19 

Dominguez-Bello MG, Blaser MJ, Ley RE and Knight R: Development of the human gastrointestinal microbiota and insights from high-throughput sequencing. Gastroenterology. 140:1713–1719. 2011.PubMed/NCBI View Article : Google Scholar

20 

Mulder IE, Schmidt B, Lewis M, Delday M, Stokes CR, Bailey M, Aminov RI, Gill BP, Pluske JR, Mayer CD, et al: Restricting microbial exposure in early life negates the immune benefits associated with gut colonization in environments of high microbial diversity. PLoS One. 6(e28279)2011.PubMed/NCBI View Article : Google Scholar

21 

Claesson MJ, Cusack S, O'Sullivan O, Greene-Diniz R, de Weerd H, Flannery E, Marchesi JR, Falush D, Dinan T, Fitzgerald G, et al: Composition, variability, and temporal stability of the intestinal microbiota of the elderly. Proc Natl Acad Sci USA. 108((Suppl 1)): 4586–4591. 2011.PubMed/NCBI View Article : Google Scholar

22 

Rajilić-Stojanović M, Heilig HGHJ, Molenaar D, Kajander K, Surakka A, Smidt H and de Vos WM: Development and application of the human intestinal tract chip, a phylogenetic microarray: Analysis of universally conserved phylotypes in the abundant microbiota of young and elderly adults. Environ Microbiol. 11:1736–1751. 2009.PubMed/NCBI View Article : Google Scholar

23 

Turnbaugh PJ, Bäckhed F, Fulton L and Gordon JI: Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe. 3:213–223. 2008.PubMed/NCBI View Article : Google Scholar

24 

Zwielehner J, Liszt K, Handschur M, Lassl C, Lapin A and Haslberger AG: Combined PCR-DGGE fingerprinting and quantitative-PCR indicates shifts in fecal population sizes and diversity of Bacteroides, bifidobacteria and Clostridium cluster IV in institutionalized elderly. Exp Gerontol. 44:440–446. 2009.PubMed/NCBI View Article : Google Scholar

25 

Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson KE and Relman DA: Diversity of the human intestinal microbial flora. Science. 308:1635–1638. 2005.PubMed/NCBI View Article : Google Scholar

26 

Sommer F and Bäckhed F: The gut microbiota - masters of host development and physiology. Nat Rev Microbiol. 11:227–238. 2013.PubMed/NCBI View Article : Google Scholar

27 

Bäckhed F, Ley RE, Sonnenburg JL, Peterson DA and Gordon JI: Host-bacterial mutualism in the human intestine. Science. 307:1915–1920. 2005.PubMed/NCBI View Article : Google Scholar

28 

Tlaskalová-Hogenová H, Stepánková R, Hudcovic T, Tucková L, Cukrowska B, Lodinová-Zádníková R, Kozáková H, Rossmann P, Bártová J, Sokol D, et al: Commensal bacteria (normal microflora), mucosal immunity and chronic inflammatory and autoimmune diseases. Immunol Lett. 93:97–108. 2004.PubMed/NCBI View Article : Google Scholar

29 

Wang L, Zhao N, Zhang F, Yue W and Liang M: Effect of taurine on leucocyte function. Eur J Pharmacol. 616:275–280. 2009.PubMed/NCBI View Article : Google Scholar

30 

O'Hara AM and Shanahan F: The gut flora as a forgotten organ. EMBO Rep. 7:688–693. 2006.PubMed/NCBI View Article : Google Scholar

31 

Proctor LM: The human microbiome project in 2011 and beyond. Cell Host Microbe. 10:287–291. 2011.PubMed/NCBI View Article : Google Scholar

32 

Weisburger JH, Reddy BS, Narisawa T and Wynder EL: Germ-free status and colon tumor induction by N-methyl-N'-nitro-N-nitrosoguanidine. Proc Soc Exp Biol Med. 148:1119–1121. 1975.PubMed/NCBI

33 

Peterson DA, Frank DN, Pace NR and Gordon JI: Metagenomic approaches for defining the pathogenesis of inflammatory bowel diseases. Cell Host Microbe. 3:417–427. 2008.PubMed/NCBI View Article : Google Scholar

34 

Walsh CJ, Guinane CM, O'Toole PW and Cotter PD: Beneficial modulation of the gut microbiota. FEBS Lett. 588:4120–4130. 2014.PubMed/NCBI View Article : Google Scholar

35 

Kamada N and Núñez G: Role of the gut microbiota in the development and function of lymphoid cells. J Immunol. 190:1389–1395. 2013.PubMed/NCBI View Article : Google Scholar

36 

Blaser MJ and Falkow S: What are the consequences of the disappearing human microbiota? Nat Rev Microbiol. 7:887–894. 2009.PubMed/NCBI View Article : Google Scholar

37 

Hooper LV and Macpherson AJ: Immune adaptations that maintain homeostasis with the intestinal microbiota. Nat Rev Immunol. 10:159–169. 2010.PubMed/NCBI View Article : Google Scholar

38 

Palmer C, Bik EM, DiGiulio DB, Relman DA and Brown PO: Development of the human infant intestinal microbiota. PLoS Biol. 5(e177)2007.PubMed/NCBI View Article : Google Scholar

39 

Neish AS: Mucosal immunity the microbiome. Ann Am Thorac Soc. 11((Suppl 1)): S28–S32. 2014.PubMed/NCBI View Article : Google Scholar

40 

Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK and Knight R: Diversity, stability and resilience of the human gut microbiota. Nature. 489:220–230. 2012.PubMed/NCBI View Article : Google Scholar

41 

Morgan XC and Huttenhower C: Chapter 12: Human microbiome analysis. PLOS Comput Biol. 8(e1002808)2012.PubMed/NCBI View Article : Google Scholar

42 

Hooper LV, Littman DR and Macpherson AJ: Interactions between the microbiota and the immune system. Science. 336:1268–1273. 2012.PubMed/NCBI View Article : Google Scholar

43 

Khoruts A, Dicksved J, Jansson JK and Sadowsky MJ: Changes in the composition of the human fecal microbiome after bacteriotherapy for recurrent Clostridium difficile-associated diarrhea. J Clin Gastroenterol. 44:354–360. 2010.PubMed/NCBI View Article : Google Scholar

44 

Reid G, Younes JA, Van der Mei HC, Gloor GB, Knight R and Busscher HJ: Microbiota restoration: Natural and supplemented recovery of human microbial communities. Nat Rev Microbiol. 9:27–38. 2011.PubMed/NCBI View Article : Google Scholar

45 

Swiatczak B, Rescigno M and Cohen IR: Systemic features of immune recognition in the gut. Microbes Infect. 13:983–991. 2011.PubMed/NCBI View Article : Google Scholar

46 

Arthur JC and Jobin C: The struggle within Microbial influences on colorectal cancer. Inflamm Bowel Dis. 17:396–409. 2011.PubMed/NCBI View Article : Google Scholar

47 

Ley RE, Bäckhed F, Turnbaugh P, Lozupone CA, Knight RD and Gordon JI: Obesity alters gut microbial ecology. Proc Natl Acad Sci USA. 102:11070–11075. 2005.PubMed/NCBI View Article : Google Scholar

48 

Ivanov II, Frutos R de L, Manel N, Yoshinaga K, Rifkin DB, Sartor RB, Finlay BB and Littman DR: Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe. 4:337–349. 2008.PubMed/NCBI View Article : Google Scholar

49 

Johansson MEV, Jakobsson HE, Holmén-Larsson J, Schütte A, Ermund A, Rodríguez-Piñeiro AM, Arike L, Wising C, Svensson F, Bäckhed F, et al: Normalization of host intestinal mucus layers requires long-term microbial colonization. Cell Host Microbe. 18:582–592. 2015.PubMed/NCBI View Article : Google Scholar

50 

Spiljar M, Merkler D and Trajkovski M: The immune system bridges the gut microbiota with systemic energy homeostasis: focus on TLRs, mucosal barrier, and SCFAs. Front Immunol. 8(1353)2017.PubMed/NCBI View Article : Google Scholar

51 

Round JL and Mazmanian SK: Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc Natl Acad Sci USA. 107:12204–12209. 2010.PubMed/NCBI View Article : Google Scholar

52 

Hepworth MR, Monticelli LA, Fung TC, Ziegler CG, Grunberg S, Sinha R, Mantegazza AR, Ma HL, Crawford A, Angelosanto JM, et al: Innate lymphoid cells regulate CD4+ T-cell responses to intestinal commensal bacteria. Nature. 498:113–117. 2013.PubMed/NCBI View Article : Google Scholar

53 

Gaboriau-Routhiau V, Rakotobe S, Lécuyer E, Mulder I, Lan A, Bridonneau C, Rochet V, Pisi A, De Paepe M, Brandi G, et al: The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity. 31:677–689. 2009.PubMed/NCBI View Article : Google Scholar

54 

Garland CD, Lee A and Dickson MR: Segmented filamentous bacteria in the rodent small intestine: Their colonization of growing animals and possible role in host resistance to Salmonella. Microb Ecol. 8:181–190. 1982.PubMed/NCBI View Article : Google Scholar

55 

Yang Y, Torchinsky MB, Gobert M, Xiong H, Xu M, Linehan JL, Alonzo F, Ng C, Chen A, Lin X, et al: Focused specificity of intestinal TH17 cells towards commensal bacterial antigens. Nature. 510:152–156. 2014.PubMed/NCBI View Article : Google Scholar

56 

Schnupf P, Gaboriau-Routhiau V and Cerf-Bensussan N: Host interactions with segmented filamentous bacteria: An unusual trade-off that drives the post-natal maturation of the gut immune system. Semin Immunol. 25:342–351. 2013.PubMed/NCBI View Article : Google Scholar

57 

Wu HJ, Ivanov II, Darce J, Hattori K, Shima T, Umesaki Y, Littman DR, Benoist C and Mathis D: Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity. 32:815–827. 2010.PubMed/NCBI View Article : Google Scholar

58 

Song X, Gao H, Lin Y, Yao Y, Zhu S, Wang J, Liu Y, Yao X, Meng G, Shen N, et al: Alterations in the microbiota drive interleukin-17C production from intestinal epithelial cells to promote tumorigenesis. Immunity. 40:140–152. 2014.PubMed/NCBI View Article : Google Scholar

59 

Xu M, Pokrovskii M, Ding Y, Yi R, Au C, Harrison OJ, Galan C, Belkaid Y, Bonneau R and Littman DR: c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont. Nature. 554:373–377. 2018.PubMed/NCBI View Article : Google Scholar

60 

Kamada N and Núñez G: Regulation of the immune system by the resident intestinal bacteria. Gastroenterology. 146:1477–1488. 2014.PubMed/NCBI View Article : Google Scholar

61 

Martín R, Miquel S, Chain F, Natividad JM, Jury J, Lu J, Sokol H, Theodorou V, Bercik P, Verdu EF, et al: Faecalibacterium prausnitzii prevents physiological damages in a chronic low-grade inflammation murine model. BMC Microbiol. 15(67)2015.PubMed/NCBI View Article : Google Scholar

62 

Honda K and Littman DR: The microbiota in adaptive immune homeostasis and disease. Nature. 535:75–84. 2016.PubMed/NCBI View Article : Google Scholar

63 

Naik S, Bouladoux N, Wilhelm C, Molloy MJ, Salcedo R, Kastenmuller W, Deming C, Quinones M, Koo L, Conlan S, et al: Compartmentalized control of skin immunity by resident commensals. Science. 337:1115–1119. 2012.PubMed/NCBI View Article : Google Scholar

64 

Naik S, Bouladoux N, Linehan JL, Han SJ, Harrison OJ, Wilhelm C, Conlan S, Himmelfarb S, Byrd AL, Deming C, et al: Commensal-dendritic-cell interaction specifies a unique protective skin immune signature. Nature. 520:104–108. 2015.PubMed/NCBI View Article : Google Scholar

65 

Hajishengallis G, Liang S, Payne MA, Hashim A, Jotwani R, Eskan MA, McIntosh ML, Alsam A, Kirkwood KL, Lambris JD, et al: Low-abundance biofilm species orchestrates inflammatory periodontal disease through the commensal microbiota and complement. Cell Host Microbe. 10:497–506. 2011.PubMed/NCBI View Article : Google Scholar

66 

Hajishengallis G and Lamont RJ: Breaking bad: Manipulation of the host response by Porphyromonas gingivalis. Eur J Immunol. 44:328–338. 2014.PubMed/NCBI View Article : Google Scholar

67 

Abt MC, Osborne LC, Monticelli LA, Doering TA, Alenghat T, Sonnenberg GF, Paley MA, Antenus M, Williams KL, Erikson J, et al: Commensal bacteria calibrate the activation threshold of innate antiviral immunity. Immunity. 37:158–170. 2012.PubMed/NCBI View Article : Google Scholar

68 

Belkaid Y and Naik S: Compartmentalized and systemic control of tissue immunity by commensals. Nat Immunol. 14:646–653. 2013.PubMed/NCBI View Article : Google Scholar

69 

Ichinohe T, Pang IK, Kumamoto Y, Peaper DR, Ho JH, Murray TS and Iwasaki A: Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proc Natl Acad Sci USA. 108:5354–5359. 2011.PubMed/NCBI View Article : Google Scholar

70 

Chervonsky AV: Microbiota autoimmunity. Cold Spring Harb Perspect Biol. 5(a007294)2013.PubMed/NCBI View Article : Google Scholar

71 

Lee YK, Menezes JS, Umesaki Y and Mazmanian SK: Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA. 108((Suppl 1)): 4615–4622. 2011.PubMed/NCBI View Article : Google Scholar

72 

Kim YG, Udayanga KGS, Totsuka N, Weinberg JB, Núñez G and Shibuya A: Gut dysbiosis promotes M2 macrophage polarization and allergic airway inflammation via fungi-induced PGE2. Cell Host Microbe. 15:95–102. 2014.PubMed/NCBI View Article : Google Scholar

73 

Mangeney M, Pothlichet J, Renard M, Ducos B and Heidmann T: Endogenous retrovirus expression is required for murine melanoma tumor growth in vivo. Cancer Res. 65:2588–2591. 2005.PubMed/NCBI View Article : Google Scholar

74 

Vaishnava S, Behrendt CL, Ismail AS, Eckmann L and Hooper LV: Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface. Proc Natl Acad Sci USA. 105:20858–20863. 2008.PubMed/NCBI View Article : Google Scholar

75 

Ménard S, Cerf-Bensussan N and Heyman M: Multiple facets of intestinal permeability and epithelial handling of dietary antigens. Mucosal Immunol. 3:247–259. 2010.PubMed/NCBI View Article : Google Scholar

76 

Mortha A, Chudnovskiy A, Hashimoto D, Bogunovic M, Spencer SP, Belkaid Y and Merad M: Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis. Science. 343(1249288)2014.PubMed/NCBI View Article : Google Scholar

77 

Rescigno M: Intestinal microbiota and its effects on the immune system. Cell Microbiol. 16:1004–1013. 2014.PubMed/NCBI View Article : Google Scholar

78 

Siegel R, Desantis C and Jemal A: Colorectal cancer statistics 2014. CA Cancer J Clin. 64:104–117. 2014.PubMed/NCBI View Article : Google Scholar

79 

Shen H, Yang J, Huang Q, Jiang MJ, Tan YN, Fu JF, Zhu LZ, Fang XF and Yuan Y: Different treatment strategies and molecular features between right-sided and left-sided colon cancers. World J Gastroenterol. 21:6470–6478. 2015.PubMed/NCBI View Article : Google Scholar

80 

Tamas K, Walenkamp AM, de Vries EG, van Vugt MA, Beets-Tan RG, van Etten B, de Groot DJ and Hospers GA: Rectal and colon cancer: Not just a different anatomic site. Cancer Treat Rev. 41:671–679. 2015.PubMed/NCBI View Article : Google Scholar

81 

Carethers JM and Jung BH: Genetics and genetic biomarkers in sporadic colorectal Cancer. Gastroenterology. 149:1177–1190.e3. 2015.PubMed/NCBI View Article : Google Scholar

82 

Watson AJ and Collins PD: Colon cancer A civilization disorder. Dig Dis. 29:222–228. 2011.PubMed/NCBI View Article : Google Scholar

83 

Starnes CO: Coley's toxins in perspective. Nature. 357:11–12. 1992.PubMed/NCBI View Article : Google Scholar

84 

Hoption Cann SA, van Netten JP and van Netten C: Dr William Coley and tumour regression: A place in history or in the future. Postgrad Med J. 79:672–680. 2003.PubMed/NCBI

85 

Grange JM, Bottasso O, Stanford CA and Stanford JL: The use of mycobacterial adjuvant-based agents for immunotherapy of cancer. Vaccine. 26:4984–4990. 2008.PubMed/NCBI View Article : Google Scholar

86 

Reddy BS, Mastromarino A and Wynder EL: Further leads on metabolic epidemiology of large bowel cancer. Cancer Res. 35:3403–3406. 1975.PubMed/NCBI

87 

Schreiber H, Nettesheim P, Lijinsky W, Richter CB and Walburg HE Jr: Induction of lung cancer in germfree, specific-pathogen-free, and infected rats by N-nitrosoheptamethyleneimine: Enhancement by respiratory infection. J Natl Cancer Inst. 49:1107–1114. 1972.PubMed/NCBI

88 

Dapito DH, Mencin A, Gwak GY, Pradere JP, Jang MK, Mederacke I, Caviglia JM, Khiabanian H, Adeyemi A, Bataller R, et al: Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell. 21:504–516. 2012.PubMed/NCBI View Article : Google Scholar

89 

Reddy BS and Watanabe K: Effect of intestinal microflora on 2,2'-dimethyl-4-aminobiphenyl-induced carcinogenesis in F344 rats. J Natl Cancer Inst. 61:1269–1271. 1978.PubMed/NCBI

90 

Uronis JM, Mühlbauer M, Herfarth HH, Rubinas TC, Jones GS and Jobin C: Modulation of the intestinal microbiota alters colitis-associated colorectal cancer susceptibility. PLoS One. 4(e6026)2009.PubMed/NCBI View Article : Google Scholar

91 

Lofgren JL, Whary MT, Ge Z, Muthupalani S, Taylor NS, Mobley M, Potter A, Varro A, Eibach D, Suerbaum S, et al: Lack of commensal flora in Helicobacter pylori-infected INS-GAS mice reduces gastritis and delays intraepithelial neoplasia. Gastroenterology. 140:210–220. 2011.PubMed/NCBI View Article : Google Scholar

92 

Vannucci L, Stepankova R, Kozakova H, Fiserova A, Rossmann P and Tlaskalova-Hogenova H: Colorectal carcinogenesis in germ-free and conventionally reared rats: Different intestinal environments affect the systemic immunity. Int J Oncol. 32:609–617. 2008.PubMed/NCBI View Article : Google Scholar

93 

Dove WF, Clipson L, Gould KA, Luongo C, Marshall DJ, Moser AR, Newton MA and Jacoby RF: Intestinal neoplasia in the ApcMin mouse: Independence from the microbial and natural killer (beige locus) status. Cancer Res. 57:812–814. 1997.PubMed/NCBI

94 

Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S, Iwakura Y, Oshima K, Morita H, Hattori M, et al: Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature. 499:97–101. 2013.PubMed/NCBI View Article : Google Scholar

95 

Chen GY, Shaw MH, Redondo G and Núñez G: The innate immune receptor Nod1 protects the intestine from inflammation-induced tumorigenesis. Cancer Res. 68:10060–10067. 2008.PubMed/NCBI View Article : Google Scholar

96 

Grivennikov SI, Wang K, Mucida D, Stewart CA, Schnabl B, Jauch D, Taniguchi K, Yu GY, Osterreicher CH, Hung KE, et al: Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature. 491:254–258. 2012.PubMed/NCBI View Article : Google Scholar

97 

Klimesova K, Kverka M, Zakostelska Z, Hudcovic T, Hrncir T, Stepankova R, Rossmann P, Ridl J, Kostovcik M, Mrazek J, et al: Altered gut microbiota promotes colitis-associated cancer in IL-1 receptor-associated kinase M-deficient mice. Inflamm Bowel Dis. 19:1266–1277. 2013.PubMed/NCBI View Article : Google Scholar

98 

Garrett WS, Punit S, Gallini CA, Michaud M, Zhang D, Sigrist KS, Lord GM, Glickman JN and Glimcher LH: Colitis-associated colorectal cancer driven by T-bet deficiency in dendritic cells. Cancer Cell. 16:208–219. 2009.PubMed/NCBI View Article : Google Scholar

99 

Kado S, Uchida K, Funabashi H, Iwata S, Nagata Y, Ando M, Onoue M, Matsuoka Y, Ohwaki M and Morotomi M: Intestinal microflora are necessary for development of spontaneous adenocarcinoma of the large intestine in T-cell receptor beta chain and p53 double-knockout mice. Cancer Res. 61:2395–2398. 2001.PubMed/NCBI

100 

Engle SJ, Ormsby I, Pawlowski S, Boivin GP, Croft J, Balish E and Doetschman T: Elimination of colon cancer in germ-free transforming growth factor beta 1-deficient mice. Cancer Res. 62:6362–6366. 2002.PubMed/NCBI

101 

Erdman SE, Poutahidis T, Tomczak M, Rogers AB, Cormier K, Plank B, Horwitz BH and Fox JG: CD4+ CD25+ regulatory T lymphocytes inhibit microbially induced colon cancer in Rag2-deficient mice. Am J Pathol. 162:691–702. 2003.PubMed/NCBI View Article : Google Scholar

102 

Garrett WS, Lord GM, Punit S, Lugo-Villarino G, Mazmanian SK, Ito S, Glickman JN and Glimcher LH: Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell. 131:33–45. 2007.PubMed/NCBI View Article : Google Scholar

103 

Garrett WS, Gallini CA, Yatsunenko T, Michaud M, DuBois A, Delaney ML, Punit S, Karlsson M, Bry L, Glickman JN, et al: Enterobacteriaceae act in concert with the gut microbiota to induce spontaneous and maternally transmitted colitis. Cell Host Microbe. 8:292–300. 2010.PubMed/NCBI View Article : Google Scholar

104 

Balish E and Warner T: Enterococcus faecalis induces inflammatory bowel disease in interleukin-10 knockout mice. Am J Pathol. 160:2253–2257. 2002.PubMed/NCBI View Article : Google Scholar

105 

Zhan Y, Chen PJ, Sadler WD, Wang F, Poe S, Núñez G, Eaton KA and Chen GY: Gut microbiota protects against gastrointestinal tumorigenesis caused by epithelial injury. Cancer Res. 73:7199–7210. 2013.PubMed/NCBI View Article : Google Scholar

106 

Hussain SP, Hofseth LJ and Harris CC: Radical causes of cancer. Nat Rev Cancer. 3:276–285. 2003.PubMed/NCBI View Article : Google Scholar

107 

Maddocks ODK, Short AJ, Donnenberg MS, Bader S and Harrison DJ: Attaching and effacing Escherichia coli downregulate DNA mismatch repair protein in vitro and are associated with colorectal adenocarcinomas in humans. PLoS One. 4(e5517)2009.PubMed/NCBI View Article : Google Scholar

108 

Salcedo R, Worschech A, Cardone M, Jones Y, Gyulai Z, Dai RM, Wang E, Ma W, Haines D, O'hUigin C, et al: MyD88-mediated signaling prevents development of adenocarcinomas of the colon: Role of interleukin 18. J Exp Med. 207:1625–1636. 2010.PubMed/NCBI View Article : Google Scholar

109 

Saleh M and Trinchieri G: Innate immune mechanisms of colitis and colitis-associated colorectal cancer. Nat Rev Immunol. 11:9–20. 2011.PubMed/NCBI View Article : Google Scholar

110 

Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S and Medzhitov R: Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell. 118:229–241. 2004.PubMed/NCBI View Article : Google Scholar

111 

Sears CL and Garrett WS: Microbes, microbiota, and colon cancer. Cell Host Microbe. 15:317–328. 2014.PubMed/NCBI View Article : Google Scholar

112 

Eslick GD: Helicobacter pylori infection causes gastric cancer? A review of the epidemiological, meta-analytic, and experimental evidence. World J Gastroenterol. 12:2991–2999. 2006.PubMed/NCBI View Article : Google Scholar

113 

Buti L, Spooner E, van der Veen AG, Rappuoli R, Covacci A and Ploegh HL: Helicobacter pylori cytotoxin-associated gene A (CagA) subverts the apoptosis-stimulating protein of p53 (ASPP2) tumor suppressor pathway of the host. Proc Natl Acad Sci USA. 108:9238–9243. 2011.PubMed/NCBI View Article : Google Scholar

114 

Wroblewski LE, Peek RM Jr and Wilson KT: Helicobacter pylori and gastric cancer: Factors that modulate disease risk. Clin Microbiol Rev. 23:713–739. 2010.PubMed/NCBI View Article : Google Scholar

115 

Marshall BJ and Warren JR: Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet. 1:1311–1315. 1984.PubMed/NCBI View Article : Google Scholar

116 

Wu S, Rhee KJ, Albesiano E, Rabizadeh S, Wu X, Yen HR, Huso DL, Brancati FL, Wick E, McAllister F, et al: A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med. 15:1016–1022. 2009.PubMed/NCBI View Article : Google Scholar

117 

Geis AL, Fan H, Wu X, Wu S, Huso DL, Wolfe JL, Sears CL, Pardoll DM and Housseau F: Regulatory T-cell response to enterotoxigenic Bacteroides fragilis colonization triggers IL17-dependent colon carcinogenesis. Cancer Discov. 5:1098–1109. 2015.PubMed/NCBI View Article : Google Scholar

118 

Kim SC, Tonkonogy SL, Albright CA, Tsang J, Balish EJ, Braun J, Huycke MM and Sartor RB: Variable phenotypes of enterocolitis in interleukin 10-deficient mice monoassociated with two different commensal bacteria. Gastroenterology. 128:891–906. 2005.PubMed/NCBI View Article : Google Scholar

119 

Wang X, Yang Y, Moore DR, Nimmo SL, Lightfoot SA and Huycke MM: 4-Hydroxy-2-nonenal mediates genotoxicity and bystander effects caused by Enterococcus faecalis-infected macrophages. Gastroenterology. 142:543–551, e7. 2012.PubMed/NCBI View Article : Google Scholar

120 

Kostic AD, Chun E, Robertson L, Glickman JN, Gallini CA, Michaud M, Clancy TE, Chung DC, Lochhead P, Hold GL, et al: Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe. 14:207–215. 2013.PubMed/NCBI View Article : Google Scholar

121 

Abed J, Emgård JEM, Zamir G, Faroja M, Almogy G, Grenov A, Sol A, Naor R, Pikarsky E, Atlan KA, et al: Fap2 mediates fusobacterium nucleatum colorectal adenocarcinoma enrichment by binding to tumor-expressed Gal-GalNAc. Cell Host Microbe. 20:215–225. 2016.PubMed/NCBI View Article : Google Scholar

122 

Signat B, Roques C, Poulet P and Duffaut D: Fusobacterium nucleatum in periodontal health and disease. Curr Issues Mol Biol. 13:25–36. 2011.PubMed/NCBI

123 

Strauss J, Kaplan GG, Beck PL, Rioux K, Panaccione R, Devinney R, Lynch T and Allen-Vercoe E: Invasive potential of gut mucosa-derived Fusobacterium nucleatum positively correlates with IBD status of the host. Inflamm Bowel Dis. 17:1971–1978. 2011.PubMed/NCBI View Article : Google Scholar

124 

Sobhani I, Tap J, Roudot-Thoraval F, Roperch JP, Letulle S, Langella P, Corthier G, Tran Van Nhieu J and Furet JP: Microbial dysbiosis in colorectal cancer (CRC) patients. PLoS One. 6(e16393)2011.PubMed/NCBI View Article : Google Scholar

125 

Castellarin M, Warren RL, Freeman JD, Dreolini L, Krzywinski M, Strauss J, Barnes R, Watson P, Allen-Vercoe E, Moore RA, et al: Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Res. 22:299–306. 2012.PubMed/NCBI View Article : Google Scholar

126 

Rubinstein MR, Wang X, Liu W, Hao Y, Cai G and Han YW: Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/β-catenin signaling via its FadA adhesin. Cell Host Microbe. 14:195–206. 2013.PubMed/NCBI View Article : Google Scholar

127 

Gur C, Ibrahim Y, Isaacson B, Yamin R, Abed J, Gamliel M, Enk J, Bar-On Y, Stanietsky-Kaynan N, Coppenhagen-Glazer S, et al: Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack. Immunity. 42:344–355. 2015.PubMed/NCBI View Article : Google Scholar

128 

Liu H, Redline RW and Han YW: Fusobacterium nucleatum induces fetal death in mice via stimulation of TLR4-mediated placental inflammatory response. J Immunol. 179:2501–2508. 2007.PubMed/NCBI View Article : Google Scholar

129 

Lee P and Tan KS: Fusobacterium nucleatum activates the immune response through retinoic acid-inducible gene I. J Dent Res. 93:162–168. 2014.PubMed/NCBI View Article : Google Scholar

130 

Chaushu S, Wilensky A, Gur C, Shapira L, Elboim M, Halftek G, Polak D, Achdout H, Bachrach G and Mandelboim O: Direct recognition of Fusobacterium nucleatum by the NK cell natural cytotoxicity receptor NKp46 aggravates periodontal disease. PLoS Pathog. 8(e1002601)2012.PubMed/NCBI View Article : Google Scholar

131 

Huycke MM and Gaskins HR: Commensal bacteria, redox stress, and colorectal cancer Mechanisms and models. Exp Biol Med (Maywood). 229:586–597. 2004.PubMed/NCBI

132 

Rooks MG and Garrett WS: Bacteria, food, and cancer. F1000 Biol Rep 3. 12:2011.PubMed/NCBI View Article : Google Scholar

133 

Goodwin AC, Destefano Shields CE, Wu S, Huso DL, Wu X, Murray-Stewart TR, Hacker-Prietz A, Rabizadeh S, Woster PM, Sears CL, et al: Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis-induced colon tumorigenesis. Proc Natl Acad Sci USA. 108:15354–15359. 2011.PubMed/NCBI View Article : Google Scholar

134 

Arthur JC, Perez-Chanona E, Mühlbauer M, Tomkovich S, Uronis JM, Fan TJ, Campbell BJ, Abujamel T, Dogan B, Rogers AB, et al: Intestinal inflammation targets cancer-inducing activity of the microbiota. Science. 338:120–123. 2012.PubMed/NCBI View Article : Google Scholar

135 

Cougnoux A, Dalmasso G, Martinez R, Buc E, Delmas J, Gibold L, Sauvanet P, Darcha C, Déchelotte P, Bonnet M, et al: Bacterial genotoxin colibactin promotes colon tumour growth by inducing a senescence-associated secretory phenotype. Gut. 63:1932–1942. 2014.PubMed/NCBI View Article : Google Scholar

136 

Mangerich A, Knutson CG, Parry NM, Muthupalani S, Ye W, Prestwich E, Cui L, McFaline JL, Mobley M, Ge Z, et al: Infection-induced colitis in mice causes dynamic and tissue-specific changes in stress response and DNA damage leading to colon cancer. Proc Natl Acad Sci USA. 109:E1820–E1829. 2012.PubMed/NCBI View Article : Google Scholar

137 

Wang X, Allen TD, May RJ, Lightfoot S, Houchen CW and Huycke MM: Enterococcus faecalis induces aneuploidy and tetraploidy in colonic epithelial cells through a bystander effect. Cancer Res. 68:9909–9917. 2008.PubMed/NCBI View Article : Google Scholar

138 

Buc E, Dubois D, Sauvanet P, Raisch J, Delmas J, Darfeuille-Michaud A, Pezet D and Bonnet R: High prevalence of mucosa-associated Ecoli producing cyclomodulin and genotoxin in colon cancer. PLoS One. 8(e56964)2013.PubMed/NCBI View Article : Google Scholar

139 

Cuevas-Ramos G, Petit CR, Marcq I, Boury M, Oswald E and Nougayrède JP: Escherichia coli induces DNA damage in vivo and triggers genomic instability in mammalian cells. Proc Natl Acad Sci USA. 107:11537–11542. 2010.PubMed/NCBI View Article : Google Scholar

140 

Devkota S, Wang Y, Musch MW, Leone V, Fehlner-Peach H, Nadimpalli A, Antonopoulos DA, Jabri B and Chang EB: Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in IL10-/- mice. Nature. 487:104–108. 2012.PubMed/NCBI View Article : Google Scholar

141 

Maggio-Price L, Treuting P, Zeng W, Tsang M, Bielefeldt-Ohmann H and Iritani BM: Helicobacter infection is required for inflammation and colon cancer in SMAD3-deficient mice. Cancer Res. 66:828–838. 2006.PubMed/NCBI View Article : Google Scholar

142 

Chu F-F, Esworthy RS, Chu PG, Longmate JA, Huycke MM, Wilczynski S and Doroshow JH: Bacteria-induced intestinal cancer in mice with disrupted Gpx1 and Gpx2 genes. Cancer Res. 64:962–968. 2004.PubMed/NCBI View Article : Google Scholar

143 

Ellmerich S, Schöller M, Duranton B, Gossé F, Galluser M, Klein JP and Raul F: Promotion of intestinal carcinogenesis by Streptococcus bovis. Carcinogenesis. 21:753–756. 2000.PubMed/NCBI

144 

Sheflin AM, Whitney AK and Weir TL: Cancer-promoting effects of microbial dysbiosis. Curr Oncol Rep. 16(406)2014.PubMed/NCBI View Article : Google Scholar

145 

Jobin C: Colorectal cancer: CRC - all about microbial products and barrier function? Nat Rev Gastroenterol Hepatol. 9:694–696. 2012.PubMed/NCBI View Article : Google Scholar

146 

Rao VP, Poutahidis T, Ge Z, Nambiar PR, Boussahmain C, Wang YY, Horwitz BH, Fox JG and Erdman SE: Innate immune inflammatory response against enteric bacteria Helicobacter hepaticus induces mammary adenocarcinoma in mice. Cancer Res. 66:7395–7400. 2006.PubMed/NCBI View Article : Google Scholar

147 

Reddy BS, Weisburger JH, Narisawa T and Wynder EL: Colon carcinogenesis in germ-free rats with 1,2-dimethylhydrazine and N-methyl-n'-nitro-N-nitrosoguanidine. Cancer Res. 34:2368–2372. 1974.PubMed/NCBI

148 

Reddy BS, Narisawa T, Wright P, Vukusich D, Weisburger JH and Wynder EL: Colon carcinogenesis with azoxymethane and dimethylhydrazine in germ-free rats. Cancer Res. 35:287–290. 1975.PubMed/NCBI

149 

Winter SE, Lopez CA and Bäumler AJ: The dynamics of gut-associated microbial communities during inflammation. EMBO Rep. 14:319–327. 2013.PubMed/NCBI View Article : Google Scholar

150 

Allen IC, TeKippe EM, Woodford RM, Uronis JM, Holl EK, Rogers AB, Herfarth HH, Jobin C and Ting JP: The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. J Exp Med. 207:1045–1056. 2010.PubMed/NCBI View Article : Google Scholar

151 

Elinav E, Strowig T, Kau AL, Henao-Mejia J, Thaiss CA, Booth CJ, Peaper DR, Bertin J, Eisenbarth SC, Gordon JI, et al: NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell. 145:745–757. 2011.PubMed/NCBI View Article : Google Scholar

152 

Couturier-Maillard A, Secher T, Rehman A, Normand S, De Arcangelis A, Haesler R, Huot L, Grandjean T, Bressenot A, Delanoye-Crespin A, et al: NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer. J Clin Invest. 123:700–711. 2013.PubMed/NCBI View Article : Google Scholar

153 

Hu B, Elinav E, Huber S, Strowig T, Hao L, Hafemann A, Jin C, Wunderlich C, Wunderlich T, Eisenbarth SC, et al: Microbiota-induced activation of epithelial IL-6 signaling links inflammasome-driven inflammation with transmissible cancer. Proc Natl Acad Sci USA. 110:9862–9867. 2013.PubMed/NCBI View Article : Google Scholar

154 

Velcich A, Yang W, Heyer J, Fragale A, Nicholas C, Viani S, Kucherlapati R, Lipkin M, Yang K and Augenlicht L: Colorectal cancer in mice genetically deficient in the mucin Muc2. Science. 295:1726–1729. 2002.PubMed/NCBI View Article : Google Scholar

155 

Ochi A, Nguyen AH, Bedrosian AS, Mushlin HM, Zarbakhsh S, Barilla R, Zambirinis CP, Fallon NC, Rehman A, Pylayeva-Gupta Y, et al: MyD88 inhibition amplifies dendritic cell capacity to promote pancreatic carcinogenesis via Th2 cells. J Exp Med. 209:1671–1687. 2012.PubMed/NCBI View Article : Google Scholar

156 

Michaud DS, Joshipura K, Giovannucci E and Fuchs CS: A prospective study of periodontal disease and pancreatic cancer in US male health professionals. J Natl Cancer Inst. 99:171–175. 2007.PubMed/NCBI View Article : Google Scholar

157 

Farrell JJ, Zhang L, Zhou H, Chia D, Elashoff D, Akin D, Paster BJ, Joshipura K and Wong DT: Variations of oral microbiota are associated with pancreatic diseases including pancreatic cancer. Gut. 61:582–588. 2012.PubMed/NCBI View Article : Google Scholar

158 

Wiest R and Garcia-Tsao G: Bacterial translocation (BT) in cirrhosis. Hepatology. 41:422–433. 2005.PubMed/NCBI View Article : Google Scholar

159 

Seki E, De Minicis S, Osterreicher CH, Kluwe J, Osawa Y, Brenner DA and Schwabe RF: TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med. 13:1324–1332. 2007.PubMed/NCBI View Article : Google Scholar

160 

Yu LX, Yan HX, Liu Q, Yang W, Wu HP, Dong W, Tang L, Lin Y, He YQ, Zou SS, et al: Endotoxin accumulation prevents carcinogen-induced apoptosis and promotes liver tumorigenesis in rodents. Hepatology. 52:1322–1333. 2010.PubMed/NCBI View Article : Google Scholar

161 

Xuan C, Shamonki JM, Chung A, Dinome ML, Chung M, Sieling PA and Lee DJ: Microbial dysbiosis is associated with human breast cancer. PLoS One. 9(e83744)2014.PubMed/NCBI View Article : Google Scholar

162 

Velicer CM, Heckbert SR, Lampe JW, Potter JD, Robertson CA and Taplin SH: Antibiotic use in relation to the risk of breast cancer. JAMA. 291:827–835. 2004.PubMed/NCBI View Article : Google Scholar

163 

Wu S, Powell J, Mathioudakis N, Kane S, Fernandez E and Sears CL: Bacteroides fragilis enterotoxin induces intestinal epithelial cell secretion of interleukin-8 through mitogen-activated protein kinases and a tyrosine kinase-regulated nuclear factor-kappaB pathway. Infect Immun. 72:5832–5839. 2004.PubMed/NCBI View Article : Google Scholar

164 

Nougayrède JP, Taieb F, De Rycke J and Oswald E: Cyclomodulins: Bacterial effectors that modulate the eukaryotic cell cycle. Trends Microbiol. 13:103–110. 2005.PubMed/NCBI View Article : Google Scholar

165 

Nesić D, Hsu Y and Stebbins CE: Assembly and function of a bacterial genotoxin. Nature. 429:429–433. 2004.PubMed/NCBI View Article : Google Scholar

166 

Oswald E, Nougayrède JP, Taieb F and Sugai M: Bacterial toxins that modulate host cell-cycle progression. Curr Opin Microbiol. 8:83–91. 2005.PubMed/NCBI View Article : Google Scholar

167 

Travaglione S, Fabbri A and Fiorentini C: The Rho-activating CNF1 toxin from pathogenic E. coli: A risk factor for human cancer development? Infect Agent Cancer. 3(4)2008.PubMed/NCBI View Article : Google Scholar

168 

Fox JG and Wang TC: Inflammation, atrophy, and gastric cancer. J Clin Invest. 117:60–69. 2007.PubMed/NCBI View Article : Google Scholar

169 

Ohnishi N, Yuasa H, Tanaka S, Sawa H, Miura M, Matsui A, Higashi H, Musashi M, Iwabuchi K, Suzuki M, et al: Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse. Proc Natl Acad Sci USA. 105:1003–1008. 2008.PubMed/NCBI View Article : Google Scholar

170 

Sears CL: Enterotoxigenic Bacteroides fragilis: A rogue among symbiotes. Clin Microbiol Rev. 22:349–369. 2009.PubMed/NCBI View Article : Google Scholar

171 

Wu S, Lim KC, Huang J, Saidi RF and Sears CL: Bacteroides fragilis enterotoxin cleaves the zonula adherens protein, E-cadherin. Proc Natl Acad Sci USA. 95:14979–14984. 1998.PubMed/NCBI

172 

Wu S, Shin J, Zhang G, Cohen M, Franco A and Sears CL: The Bacteroides fragilis toxin binds to a specific intestinal epithelial cell receptor. Infect Immun. 74:5382–5390. 2006.PubMed/NCBI View Article : Google Scholar

173 

Toprak NU, Yagci A, Gulluoglu BM, Akin ML, Demirkalem P, Celenk T and Soyletir G: A possible role of Bacteroides fragilis enterotoxin in the aetiology of colorectal cancer. Clin Microbiol Infect. 12:782–786. 2006.PubMed/NCBI View Article : Google Scholar

174 

Wu S, Morin PJ, Maouyo D and Sears CL: Bacteroides fragilis enterotoxin induces c-Myc expression and cellular proliferation. Gastroenterology. 124:392–400. 2003.PubMed/NCBI View Article : Google Scholar

175 

Owen RW, Spiegelhalder B and Bartsch H: Generation of reactive oxygen species by the faecal matrix. Gut. 46:225–232. 2000.PubMed/NCBI View Article : Google Scholar

176 

Huycke MM, Abrams V and Moore DR: Enterococcus faecalis produces extracellular superoxide and hydrogen peroxide that damages colonic epithelial cell DNA. Carcinogenesis. 23:529–536. 2002.PubMed/NCBI

177 

Wallace JL: Hydrogen sulfide-releasing anti-inflammatory drugs. Trends Pharmacol Sci. 28:501–505. 2007.PubMed/NCBI View Article : Google Scholar

178 

Attene-Ramos MS, Wagner ED, Gaskins HR and Plewa MJ: Hydrogen sulfide induces direct radical-associated DNA damage. Mol Cancer Res. 5:455–459. 2007.PubMed/NCBI View Article : Google Scholar

179 

Le Gall T, Clermont O, Gouriou S, Picard B, Nassif X, Denamur E and Tenaillon O: Extraintestinal virulence is a coincidental by-product of commensalism in B2 phylogenetic group Escherichia coli strains. Mol Biol Evol. 24:2373–2384. 2007.PubMed/NCBI View Article : Google Scholar

180 

Escobar-Páramo P, Grenet K, Le Menac'h A, Rode L, Salgado E, Amorin C, Gouriou S, Picard B, Rahimy MC, Andremont A, et al: Large-scale population structure of human commensal Escherichia coli isolates. Appl Environ Microbiol. 70:5698–5700. 2004.PubMed/NCBI View Article : Google Scholar

181 

Darfeuille-Michaud A, Boudeau J, Bulois P, Neut C, Glasser AL, Barnich N, Bringer MA, Swidsinski A, Beaugerie L and Colombel JF: High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn's disease. Gastroenterology. 127:412–421. 2004.PubMed/NCBI View Article : Google Scholar

182 

Han YW, Ikegami A, Rajanna C, Kawsar HI, Zhou Y, Li M, Sojar HT, Genco RJ, Kuramitsu HK and Deng CX: Identification and characterization of a novel adhesin unique to oral fusobacteria. J Bacteriol. 187:5330–5340. 2005.PubMed/NCBI View Article : Google Scholar

183 

Prorok-Hamon M, Friswell MK, Alswied A, Roberts CL, Song F, Flanagan PK, Knight P, Codling C, Marchesi JR, Winstanley C, et al: Colonic mucosa-associated diffusely adherent afaC+ Escherichia coli expressing lpfA and pks are increased in inflammatory bowel disease and colon cancer. Gut. 63:761–770. 2014.PubMed/NCBI View Article : Google Scholar

184 

Morrison DJ and Preston T: Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism. Gut Microbes. 7:189–200. 2016.PubMed/NCBI View Article : Google Scholar

185 

Belcheva A, Irrazabal T, Robertson SJ, Streutker C, Maughan H, Rubino S, Moriyama EH, Copeland JK, Surendra A, Kumar S, et al: Gut microbial metabolism drives transformation of MSH2-deficient colon epithelial cells. Cell. 158:288–299. 2014.PubMed/NCBI View Article : Google Scholar

186 

LeBlanc JG, Milani C, de Giori GS, Sesma F, van Sinderen D and Ventura M: Bacteria as vitamin suppliers to their host: A gut microbiota perspective. Curr Opin Biotechnol. 24:160–168. 2013.PubMed/NCBI View Article : Google Scholar

187 

Russell WR, Gratz SW, Duncan SH, Holtrop G, Ince J, Scobbie L, Duncan G, Johnstone AM, Lobley GE, Wallace RJ, et al: High-protein, reduced-carbohydrate weight-loss diets promote metabolite profiles likely to be detrimental to colonic health. Am J Clin Nutr. 93:1062–1072. 2011.PubMed/NCBI View Article : Google Scholar

188 

Windey K, De Preter V and Verbeke K: Relevance of protein fermentation to gut health. Mol Nutr Food Res. 56:184–196. 2012.PubMed/NCBI View Article : Google Scholar

189 

Neis EP, Dejong CH and Rensen SS: The role of microbial amino acid metabolism in host metabolism. Nutrients. 7:2930–2946. 2015.PubMed/NCBI View Article : Google Scholar

190 

Verbeke KA, Boobis AR, Chiodini A, Edwards CA, Franck A, Kleerebezem M, Nauta A, Raes J, van Tol EA and Tuohy KM: Towards microbial fermentation metabolites as markers for health benefits of prebiotics. Nutr Res Rev. 28:42–66. 2015.PubMed/NCBI View Article : Google Scholar

191 

Louis P, Hold GL and Flint HJ: The gut microbiota, bacterial metabolites and colorectal cancer. Nat Rev Microbiol. 12:661–672. 2014.PubMed/NCBI View Article : Google Scholar

192 

Donohoe DR, Garge N, Zhang X, Sun W, O'Connell TM, Bunger MK and Bultman SJ: The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab. 13:517–526. 2011.PubMed/NCBI View Article : Google Scholar

193 

Roediger WE: Role of anaerobic bacteria in the metabolic welfare of the colonic mucosa in man. Gut. 21:793–798. 1980.PubMed/NCBI View Article : Google Scholar

194 

Roediger WE: Utilization of nutrients by isolated epithelial cells of the rat colon. Gastroenterology. 83:424–429. 1982.PubMed/NCBI

195 

Sleeth ML, Thompson EL, Ford HE, Zac-Varghese SE and Frost G: Free fatty acid receptor 2 and nutrient sensing: A proposed role for fibre, fermentable carbohydrates and short-chain fatty acids in appetite regulation. Nutr Res Rev. 23:135–145. 2010.PubMed/NCBI View Article : Google Scholar

196 

Pessione E: Lactic acid bacteria contribution to gut microbiota complexity: Lights shadows. Front Cell Infect Microbiol. 2(86)2012.PubMed/NCBI View Article : Google Scholar

197 

Hamer HM, Jonkers D, Venema K, Vanhoutvin S, Troost FJ and Brummer RJ: Review article: The role of butyrate on colonic function. Aliment Pharmacol Ther. 27:104–119. 2008.PubMed/NCBI View Article : Google Scholar

198 

Fung KYC, Cosgrove L, Lockett T, Head R and Topping DL: A review of the potential mechanisms for the lowering of colorectal oncogenesis by butyrate. Br J Nutr. 108:820–831. 2012.PubMed/NCBI View Article : Google Scholar

199 

Wilson AJ, Chueh AC, Tögel L, Corner GA, Ahmed N, Goel S, Byun DS, Nasser S, Houston MA, Jhawer M, et al: Apoptotic sensitivity of colon cancer cells to histone deacetylase inhibitors is mediated by an Sp1/Sp3-activated transcriptional program involving immediate-early gene induction. Cancer Res. 70:609–620. 2010.PubMed/NCBI View Article : Google Scholar

200 

Chang PV, Hao L, Offermanns S and Medzhitov R: The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc Natl Acad Sci USA. 111:2247–2252. 2014.PubMed/NCBI View Article : Google Scholar

201 

Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly YM, Glickman JN and Garrett WS: The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science. 341:569–573. 2013.PubMed/NCBI View Article : Google Scholar

202 

Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, Nakanishi Y, Uetake C, Kato K, Kato T, et al: Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature. 504:446–450. 2013.PubMed/NCBI View Article : Google Scholar

203 

Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P, Liu H, Cross JR, Pfeffer K, Coffer PJ, et al: Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature. 504:451–455. 2013.PubMed/NCBI View Article : Google Scholar

204 

Vander Heiden MG, Cantley LC and Thompson CB: Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science. 324:1029–1033. 2009.PubMed/NCBI View Article : Google Scholar

205 

Donohoe DR, Holley D, Collins LB, Montgomery SA, Whitmore AC, Hillhouse A, Curry KP, Renner SW, Greenwalt A, Ryan EP, et al: A gnotobiotic mouse model demonstrates that dietary fiber protects against colorectal tumorigenesis in a microbiota- and butyrate-dependent manner. Cancer Discov. 4:1387–1397. 2014.PubMed/NCBI View Article : Google Scholar

206 

Donohoe DR, Collins LB, Wali A, Bigler R, Sun W and Bultman SJ: The Warburg effect dictates the mechanism of butyrate-mediated histone acetylation and cell proliferation. Mol Cell. 48:612–626. 2012.PubMed/NCBI View Article : Google Scholar

207 

Sebastián C and Mostoslavsky R: Untangling the fiber yarn: Butyrate feeds Warburg to suppress colorectal cancer. Cancer Discov. 4:1368–1370. 2014.PubMed/NCBI View Article : Google Scholar

208 

Davie JR: Inhibition of histone deacetylase activity by butyrate. J Nutr. 133((Suppl 7)): 2485S–2493S. 2003.PubMed/NCBI View Article : Google Scholar

209 

Gonçalves P and Martel F: Butyrate and colorectal cancer: The role of butyrate transport. Curr Drug Metab. 14:994–1008. 2013.PubMed/NCBI View Article : Google Scholar

210 

Thangaraju M, Cresci GA, Liu K, Ananth S, Gnanaprakasam JP, Browning DD, Mellinger JD, Smith SB, Digby GJ, Lambert NA, et al: GPR109A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon. Cancer Res. 69:2826–2832. 2009.PubMed/NCBI View Article : Google Scholar

211 

Singh N, Gurav A, Sivaprakasam S, Brady E, Padia R, Shi H, Thangaraju M, Prasad PD, Manicassamy S, Munn DH, et al: Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity. 40:128–139. 2014.PubMed/NCBI View Article : Google Scholar

212 

Larrosa M, González-Sarrías A, García-Conesa MT, Tomás-Barberán FA and Espín JC: Urolithins, ellagic acid-derived metabolites produced by human colonic microflora, exhibit estrogenic and antiestrogenic activities. J Agric Food Chem. 54:1611–1620. 2006.PubMed/NCBI View Article : Google Scholar

213 

González-Sarrías A, Larrosa M, Tomás-Barberán FA, Dolara P and Espín JC: NF-kappaB-dependent anti-inflammatory activity of urolithins, gut microbiota ellagic acid-derived metabolites, in human colonic fibroblasts. Br J Nutr. 104:503–512. 2010.PubMed/NCBI View Article : Google Scholar

214 

Atkinson C, Frankenfeld CL and Lampe JW: Gut bacterial metabolism of the soy isoflavone daidzein: Exploring the relevance to human health. Exp Biol Med (Maywood). 230:155–170. 2005.PubMed/NCBI

215 

Bolca S, Possemiers S, Herregat A, Huybrechts I, Heyerick A, De Vriese S, Verbruggen M, Depypere H, De Keukeleire D, Bracke M, et al: Microbial and dietary factors are associated with the equol producer phenotype in healthy postmenopausal women. J Nutr. 137:2242–2246. 2007.PubMed/NCBI View Article : Google Scholar

216 

Lampe JW: Emerging research on equol cancer. J Nutr. 140:1369S–1372S. 2010.PubMed/NCBI View Article : Google Scholar

217 

Davis CD and Milner JA: Gastrointestinal microflora, food components and colon cancer prevention. J Nutr Biochem. 20:743–752. 2009.PubMed/NCBI View Article : Google Scholar

218 

Bode LM, Bunzel D, Huch M, Cho GS, Ruhland D, Bunzel M, Bub A, Franz CM and Kulling SE: In vivo and in vitro metabolism of trans-resveratrol by human gut microbiota. Am J Clin Nutr. 97:295–309. 2013.PubMed/NCBI View Article : Google Scholar

219 

Greer JB and O'Keefe SJ: Microbial induction of immunity, inflammation, and cancer. Front Physiol. 1(168)2011.PubMed/NCBI View Article : Google Scholar

220 

Ridlon JM, Kang DJ and Hylemon PB: Bile salt biotransformations by human intestinal bacteria. J Lipid Res. 47:241–259. 2006.PubMed/NCBI View Article : Google Scholar

221 

Wells JE, Williams KB, Whitehead TR, Heuman DM and Hylemon PB: Development and application of a polymerase chain reaction assay for the detection and enumeration of bile acid 7alpha-dehydroxylating bacteria in human feces. Clin Chim Acta. 331:127–134. 2003.PubMed/NCBI View Article : Google Scholar

222 

Rubin DC, Shaker A and Levin MS: Chronic intestinal inflammation: Inflammatory bowel disease and colitis-associated colon cancer. Front Immunol. 3(107)2012.PubMed/NCBI View Article : Google Scholar

223 

Powolny A, Xu J and Loo G: Deoxycholate induces DNA damage and apoptosis in human colon epithelial cells expressing either mutant or wild-type p53. Int J Biochem Cell Biol. 33:193–203. 2001.PubMed/NCBI View Article : Google Scholar

224 

Imray CH, Radley S, Davis A, Barker G, Hendrickse CW, Donovan IA, Lawson AM, Baker PR and Neoptolemos JP: Faecal unconjugated bile acids in patients with colorectal cancer or polyps. Gut. 33:1239–1245. 1992.PubMed/NCBI View Article : Google Scholar

225 

Nagengast FM, Grubben MJ and van Munster IP: Role of bile acids in colorectal carcinogenesis. Eur J Cancer. 31A:1067–1070. 1995.PubMed/NCBI View Article : Google Scholar

226 

Carmody RN and Turnbaugh PJ: Host-microbial interactions in the metabolism of therapeutic and diet-derived xenobiotics. J Clin Invest. 124:4173–4181. 2014.PubMed/NCBI View Article : Google Scholar

227 

Flanagan L, Schmid J, Ebert M, Soucek P, Kunicka T, Liska V, Bruha J, Neary P, Dezeeuw N, Tommasino M, et al: Fusobacterium nucleatum associates with stages of colorectal neoplasia development, colorectal cancer and disease outcome. Eur J Clin Microbiol Infect Dis. 33:1381–1390. 2014.PubMed/NCBI View Article : Google Scholar

228 

McCoy AN, Araújo-Pérez F, Azcárate-Peril A, Yeh JJ, Sandler RS and Keku TO: Fusobacterium is associated with colorectal adenomas. PLoS One. 8(e53653)2013.PubMed/NCBI View Article : Google Scholar

229 

Fukugaiti MH, Ignacio A, Fernandes MR, Ribeiro Júnior U, Nakano V and Avila-Campos MJ: High occurrence of Fusobacterium nucleatum and Clostridium difficile in the intestinal microbiota of colorectal carcinoma patients. Braz J Microbiol. 46:1135–1140. 2015.PubMed/NCBI View Article : Google Scholar

230 

Zackular JP, Rogers MAM, Ruffin MT IV and Schloss PD: The human gut microbiome as a screening tool for colorectal cancer. Cancer Prev Res (Phila). 7:1112–1121. 2014.PubMed/NCBI View Article : Google Scholar

231 

Mima K, Nishihara R, Qian ZR, Cao Y, Sukawa Y, Nowak JA, Yang J, Dou R, Masugi Y, Song M, et al: Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis. Gut. 65:1973–1980. 2016.PubMed/NCBI View Article : Google Scholar

232 

Ballal SA, Veiga P, Fenn K, Michaud M, Kim JH, Gallini CA, Glickman JN, Quéré G, Garault P, Béal C, et al: Host lysozyme-mediated lysis of Lactococcus lactis facilitates delivery of colitis-attenuating superoxide dismutase to inflamed colons. Proc Natl Acad Sci USA. 112:7803–7808. 2015.PubMed/NCBI View Article : Google Scholar

233 

Veiga P, Gallini CA, Beal C, Michaud M, Delaney ML, DuBois A, Khlebnikov A, van Hylckama Vlieg JE, Punit S, Glickman JN, et al: Bifidobacterium animalis subsplactis fermented milk product reduces inflammation by altering a niche for colitogenic microbes. Proc Natl Acad Sci USA. 107:18132–18137. 2010.PubMed/NCBI View Article : Google Scholar

234 

Viaud S, Saccheri F, Mignot G, Yamazaki T, Daillère R, Hannani D, Enot DP, Pfirschke C, Engblom C, Pittet MJ, et al: The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science. 342:971–976. 2013.PubMed/NCBI View Article : Google Scholar

235 

Siddik ZH: Cisplatin: Mode of cytotoxic action and molecular basis of resistance. Oncogene. 22:7265–7279. 2003.PubMed/NCBI View Article : Google Scholar

236 

Yang J, Liu KX, Qu JM and Wang XD: The changes induced by cyclophosphamide in intestinal barrier and microflora in mice. Eur J Pharmacol. 714:120–124. 2013.PubMed/NCBI View Article : Google Scholar

237 

Nam YD, Kim HJ, Seo JG, Kang SW and Bae JW: Impact of pelvic radiotherapy on gut microbiota of gynecological cancer patients revealed by massive pyrosequencing. PLoS One. 8(e82659)2013.PubMed/NCBI View Article : Google Scholar

238 

Jenq RR, Ubeda C, Taur Y, Menezes CC, Khanin R, Dudakov JA, Liu C, West ML, Singer NV, Equinda MJ, et al: Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation. J Exp Med. 209:903–911. 2012.PubMed/NCBI View Article : Google Scholar

239 

Von Bültzingslöwen I, Adlerberth I, Wold AE, Dahlén G and Jontell M: Oral and intestinal microflora in 5-fluorouracil treated rats, translocation to cervical and mesenteric lymph nodes and effects of probiotic bacteria. Oral Microbiol Immunol. 18:278–284. 2003.PubMed/NCBI View Article : Google Scholar

240 

Wallace BD, Wang H, Lane KT, Scott JE, Orans J, Koo JS, Venkatesh M, Jobin C, Yeh LA, Mani S, et al: Alleviating cancer drug toxicity by inhibiting a bacterial enzyme. Science. 330:831–835. 2010.PubMed/NCBI View Article : Google Scholar

241 

Lam W, Bussom S, Guan F, Jiang Z, Zhang W, Gullen EA, Liu SH and Cheng YC: The four-herb Chinese medicine PHY906 reduces chemotherapy-induced gastrointestinal toxicity. Sci Transl Med. 2(45ra59)2010.PubMed/NCBI View Article : Google Scholar

242 

Cesaro C, Tiso A, Del Prete A, Cariello R, Tuccillo C, Cotticelli G, Del Vecchio Blanco C and Loguercio C: Gut microbiota and probiotics in chronic liver diseases. Dig Liver Dis. 43:431–438. 2011.PubMed/NCBI View Article : Google Scholar

243 

Hemarajata P and Versalovic J: Effects of probiotics on gut microbiota: Mechanisms of intestinal immunomodulation and neuromodulation. Therap Adv Gastroenterol. 6:39–51. 2013.PubMed/NCBI View Article : Google Scholar

244 

Ekmekciu I, von Klitzing E, Fiebiger U, Neumann C, Bacher P, Scheffold A, Bereswill S and Heimesaat MM: The probiotic compound VSL#3 modulates mucosal, peripheral, and systemic immunity following murine broad-spectrum antibiotic treatment. Front Cell Infect Microbiol. 7(167)2017.PubMed/NCBI View Article : Google Scholar

245 

Rao RK and Samak G: Protection and restitution of gut barrier by probiotics Nutritional and clinical implications. Curr Nutr Food Sci. 9:99–107. 2013.PubMed/NCBI

246 

Kamada N, Chen GY, Inohara N and Núñez G: Control of pathogens and pathobionts by the gut microbiota. Nat Immunol. 14:685–690. 2013.PubMed/NCBI View Article : Google Scholar

247 

Jonkers D and Stockbrügger R: Probiotics and inflammatory bowel disease. J R Soc Med. 96:167–171. 2003.PubMed/NCBI

248 

Celiberto LS, Bedani R, Rossi EA and Cavallini DC: Probiotics: The scientific evidence in the context of inflammatory bowel disease. Crit Rev Food Sci Nutr. 57:1759–1768. 2017.PubMed/NCBI View Article : Google Scholar

249 

Sheil B, Shanahan F and O'Mahony L: Probiotic effects on inflammatory bowel disease. J Nutr. 137:(Suppl 2):819S–824S. 2007.PubMed/NCBI View Article : Google Scholar

250 

Tamboli CP, Caucheteux C, Cortot A, Colombel JF and Desreumaux P: Probiotics in inflammatory bowel disease: A critical review. Best Pract Res Clin Gastroenterol. 17:805–820. 2003.PubMed/NCBI View Article : Google Scholar

251 

Bibiloni R, Fedorak RN, Tannock GW, Madsen KL, Gionchetti P, Campieri M, De Simone C and Sartor RB: VSL#3 probiotic-mixture induces remission in patients with active ulcerative colitis. Am J Gastroenterol. 100:1539–1546. 2005.PubMed/NCBI View Article : Google Scholar

252 

Kim S, Covington A and Pamer EG: The intestinal microbiota: Antibiotics, colonization resistance, and enteric pathogens. Immunol Rev. 279:90–105. 2017.PubMed/NCBI View Article : Google Scholar

253 

Dethlefsen L, Huse S, Sogin ML and Relman DA: The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol. 6(e280)2008.PubMed/NCBI View Article : Google Scholar

254 

Dethlefsen L and Relman DA: Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc Natl Acad Sci USA. 108((Suppl 1)): 4554–4561. 2011.PubMed/NCBI View Article : Google Scholar

255 

Jernberg C, Löfmark S, Edlund C and Jansson JK: Long-term ecological impacts of antibiotic administration on the human intestinal microbiota. ISME J. 1:56–66. 2007.PubMed/NCBI View Article : Google Scholar

256 

Lankelma JM, Cranendonk DR, Belzer C, de Vos AF, de Vos WM, van der Poll T and Wiersinga WJ: Antibiotic-induced gut microbiota disruption during human endotoxemia: A randomised controlled study. Gut. 66:1623–1630. 2017.PubMed/NCBI View Article : Google Scholar

257 

Lopez J and Grinspan A: Fecal microbiota transplantation for inflammatory bowel disease. Gastroenterol Hepatol (NY). 12:374–379. 2016.PubMed/NCBI

258 

McFarland LV: Epidemiology, risk factors and treatments for antibiotic-associated diarrhea. Dig Dis. 16:292–307. 1998.PubMed/NCBI View Article : Google Scholar

259 

Suez J, Zmora N, Zilberman-Schapira G, Mor U, Dori-Bachash M, Bashiardes S, Zur M, Regev-Lehavi D, Ben-Zeev Brik R, Federici S, et al: Post-antibiotic gut mucosal microbiome reconstitution is impaired by probiotics and improved by autologous FMT. Cell. 174:1406–1423, e16. 2018.PubMed/NCBI View Article : Google Scholar

260 

Chaput N, Lepage P, Coutzac C, Soularue E, Le Roux K, Monot C, Boselli L, Routier E, Cassard L, Collins M, et al: Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol. 28:1368–1379. 2017.PubMed/NCBI View Article : Google Scholar

261 

Frankel AE, Coughlin LA, Kim J, Froehlich TW, Xie Y, Frenkel EP and Koh AY: Metagenomic shotgun sequencing and unbiased metabolomic profiling identify specific human gut microbiota and metabolites associated with immune checkpoint therapy efficacy in melanoma patients. Neoplasia. 19:848–855. 2017.PubMed/NCBI View Article : Google Scholar

262 

Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, Hoffman K, Wei SC, et al: Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 359:97–103. 2018.PubMed/NCBI View Article : Google Scholar

263 

Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre ML, Luke JJ and Gajewski TF: The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science. 359:104–108. 2018.PubMed/NCBI View Article : Google Scholar

264 

Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, Fluckiger A, Messaoudene M, Rauber C, Roberti MP, et al: Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 359:91–97. 2018.PubMed/NCBI View Article : Google Scholar

265 

Vétizou M, Pitt JM, Daillère R, Lepage P, Waldschmitt N, Flament C, Rusakiewicz S, Routy B, Roberti MP, Duong CP, et al: Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 350:1079–1084. 2015.PubMed/NCBI View Article : Google Scholar

266 

Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, Benyamin FW, Lei YM, Jabri B, Alegre ML, et al: Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science. 350:1084–1089. 2015.PubMed/NCBI View Article : Google Scholar

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APA
Baliou, S., Adamaki, M., Spandidos, D.A., Kyriakopoulos, A.M., Christodoulou, I., & Zoumpourlis, V. (2019). The microbiome, its molecular mechanisms and its potential as a therapeutic strategy against colorectal carcinogenesis (Review). World Academy of Sciences Journal, 1, 3-19. https://doi.org/10.3892/wasj.2018.6
MLA
Baliou, S., Adamaki, M., Spandidos, D. A., Kyriakopoulos, A. M., Christodoulou, I., Zoumpourlis, V."The microbiome, its molecular mechanisms and its potential as a therapeutic strategy against colorectal carcinogenesis (Review)". World Academy of Sciences Journal 1.1 (2019): 3-19.
Chicago
Baliou, S., Adamaki, M., Spandidos, D. A., Kyriakopoulos, A. M., Christodoulou, I., Zoumpourlis, V."The microbiome, its molecular mechanisms and its potential as a therapeutic strategy against colorectal carcinogenesis (Review)". World Academy of Sciences Journal 1, no. 1 (2019): 3-19. https://doi.org/10.3892/wasj.2018.6