Back to Journals » Clinical and Experimental Gastroenterology » Volume 13

The Bacterial Microbiota of Gastrointestinal Cancers: Role in Cancer Pathogenesis and Therapeutic Perspectives

Authors Elsalem L , Jum'ah AA , Alfaqih MA , Aloudat O

Received 22 December 2019

Accepted for publication 13 April 2020

Published 6 May 2020 Volume 2020:13 Pages 151—185

DOI https://doi.org/10.2147/CEG.S243337

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Professor Andreas M. Kaiser



Lina Elsalem,1 Ahmad A Jum’ah,2 Mahmoud A Alfaqih,3 Osama Aloudat4

1Department of Pharmacology, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan; 2Department of Conservative Dentistry, Faculty of Dentistry, Jordan University of Science and Technology, Irbid, Jordan; 3Department of Physiology and Biochemistry, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan; 4Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan

Correspondence: Lina Elsalem
Department of Pharmacology, Faculty of Medicine, Jordan University of Science and Technology, Irbid 22110, Jordan
Tel +962 27201000 Ext 23800
Fax +962 27201064
Email [email protected]

Abstract: The microbiota has an essential role in the pathogenesis of many gastrointestinal diseases including cancer. This effect is mediated through different mechanisms such as damaging DNA, activation of oncogenic pathways, production of carcinogenic metabolites, stimulation of chronic inflammation, and inhibition of antitumor immunity. Recently, the concept of “pharmacomicrobiomics” has emerged as a new field concerned with exploring the interplay between drugs and microbes. Mounting evidence indicates that the microbiota and their metabolites have a major impact on the pharmacodynamics and therapeutic responses toward anticancer drugs including conventional chemotherapy and molecular-targeted therapeutics. In addition, microbiota appears as an attractive target for cancer prevention and treatment. In this review, we discuss the role of bacterial microbiota in the pathogenesis of different cancer types affecting the gastrointestinal tract system. We also scrutinize the evidence regarding the role of microbiota in anticancer drug responses. Further, we discuss the use of probiotics, fecal microbiota transplantation, and antibiotics, either alone or in combination with anticancer drugs for prevention and treatment of gastrointestinal tract cancers.

Keywords: microbiome, dysbiosis, antibiotics, probiotics, cancer treatment, prevention

Introduction

Cancer is considered as a main leading cause of death worldwide.1 The International Agency for Research on Cancer reported an estimated 18.1 million new cancer cases and 9.6 million cancer deaths in 2018.2 The hallmarks of cancer were early described to include six biological capabilities which have essential roles in contributing to tumor complexity.3 They include sustaining proliferative capacity, evading growth suppressors, resisting cell apoptosis, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis.3 In 2011, Hanahan and Weinberg4 described two enabling characteristics underlying these hallmarks including genome instability and inflammation. In addition, advances in cancer research revealed another two emerging hallmarks including reprogramming of energy metabolism and evading immune destruction.4 Mounting evidence indicates that tumors exhibit another dimension of complexity relating to the presence of unique tumor microenvironments, which are less easily assayed but have profound effects on cancer progression.5 Substantial findings from in vitro, in vivo, and human studies point to the role of microbiota in cancer pathogenesis through modulating tumor microenvironment.6,8

In the late 19th century, Rudolf Virchow, a German pathologist, described that cancer may be considered as a consequence of chronic inflammation elicited by hostile toxic triggers, including infections.9 During the same period, the role of bacterial infections as a possible cause of cancer was suggested following the innovative work of Robert Koch and Louis Pasteur, upon the discovery of bacteria in tumor tissues.9 However, only recent data from experimental and clinical work have conclusively demonstrated the bacterial role in oncogenesis and raised the possibility of its impact as a cause of malignancy.10 The “human microbiome” is a term used to describe all microorganisms harboring the human body and their collective genomes.11,12 Currently, around 20% of neoplasms worldwide can be attributed to infections,13 with approximately 1.2 million cases every year.14 The research in the microbiome field and mainly the role of bacteria in cancer pathogenesis is rapidly evolving, with more than 100 trillion bacteria already identified in the human body.15,16 In this regard, there is convincing evidence linking bacterial dysbiosis to cancer, Helicobacter Pylori (H. Pylori) with gastric cancer17 and mucosa-associated lymphoid tissue (MALT) lymphoma18 as primary examples. This was further supported by the role of Salmonella Typhi (S. Typhi) in gallbladder cancer (GBC),19 Chlamydia pneumonia in lung cancer,20 and Streptococcus bovis/gallolytucis (S. bovis/S. gallolytucis) in colorectal cancer (CRC).21

The role of microbiome in tumor development and progression has been described to be driven through different mechanisms,8,22 including: damaging DNA, activating oncogenic pathways and epithelial cell proliferation,23 production of carcinogenic metabolites,24 stimulation of chronic inflammation,25,26 and inhibition of antitumor immunity.22,24 These findings have highlighted the possible interactions between the tumor microenvironment and systemic microbial-immune networks to broader extents than previously thought.7,23 Of note, microbial dysbiosis also has a major impact on therapeutic responses toward anticancer treatment.27,28 This was mainly attributed to the microbial ability to metabolize drugs and to influence inflammation as well as immune responses within the tumor microenvironment, which in turn has a major role in treatment outcomes and drugs toxicities.29 Indeed, the association between microbiota and responses to anticancer therapies has been described as a bidirectional way, where both factors can have a significant effect on each other.27,30 Recently, the concept of “pharmacomicrobiomics” has emerged as a new field investigating the interplay between drugs and microbes.27 In this regard, the role of probiotics and antibiotics either alone or in combination with anticancer drugs has been explored in order to manipulate the microbiota, which in turn might have positive outcomes in terms of cancer prevention and treatment.27,31

The human gastrointestinal tract (GIT) is a complex environment in the body which is inhabited by trillions of microorganisms, including bacteria, archaea, fungi, parasites, and viruses.12,32 Bacteria are considered as the major microbiota colonizing the GIT.33 Currently, cancers affecting the GIT system are well known as a major health problem.2 According to the Global Cancer Statistics 2018,2 GIT cancers have high incidence and mortality rates. Accumulating evidence points to the impact of bacterial infection on the pathogenesis and progression of many GIT diseases including cancers.34,37 In addition, substantial data indicate the role of GIT microbiota in modulating tumor response to anticancer drugs including conventional chemotherapy and molecular-targeted therapeutics.27,38 Therefore, bacterial microbiota can be an attractive target for prevention or treatment of GIT cancers.

Manipulating the microbiota is considered as a hot topic in cancer research. The concept of fecal microbiota transplantation (FMT) has recently been investigated as a novel method for treatment of diseases affecting the GIT.39,40 FMT is defined as the transplantation of gut microbiota from healthy individuals to diseased individuals in an attempt to revert the intestinal microbiota to its healthy status.41 Although FMT is still in its naive, promising results have been obtained regarding its clinical efficacy against Clostridium difficile infection.42 Lately, there has been substantial interest regarding the therapeutic potential of FMT for treatment of other diseases affecting the GIT, including irritable bowel syndrome,43 Crohn’s disease,44 and cancers.39,45

The present review discusses current knowledge on the relationship between the bacterial microbiota and pathogenesis of cancers affecting the GIT system. It will emphasize on its role as a potential target for therapeutic intervention including cancer treatment and prevention, in addition to its impact on tumor response to anticancer treatment. Figure 1 summarizes the most common bacterial species associated with cancers affecting GIT. Cancer types that will be discussed in this review include: oral carcinoma, esophageal cancer, gastric cancer, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, gastric diffuse large B cell lymphoma (DLBCL), colorectal cancer, pancreatic cancer, liver cancer, and gallbladder cancer.

Figure 1 Most common bacterial microbiota associated with GIT cancers. Microbiota detected in cancer tissues (A), fecal samples (B), or bile secretions (C) from patients with GIT cancers. Abbreviations: CRC, colorectal carcinoma; DLBCL, diffuse large B cell lymphoma; E. coli, Escherichia coli; E. faecalis, Enterococcus faecalis; ETBF, enterotoxigenic Bacteroides fragilis; F. nucleatum, Fusobacterium nucleatum; GBC, gallbladder carcinoma; GIT, gastrointestinal; HCC, hepatocellular carcinoma; H. Pylori, Helicobacter Pylori; MALT, mucosa-associated lymphoid tissue; OSCC, oral squamous cell carcinoma; PDAC, pancreatic ductal adenocarcinoma; P. gingivalis, Porphyromonas gingivalis; S. anginosus, Streptococcus anginosus; S. gallolytucis, Streptococcus gallolytucis; S. sanguinis, Streptococcus sanguinis; S. Typhi, Salmonella Typhi; SCC, squamous cell carcinoma; spp., species.

Oral Carcinoma

Oral cancer, particularly oral squamous cell carcinoma (OSCC), remains a major health issue as it is usually detected at advanced stages.46,47 The 5-year survival rate is less than 50% with high recurrence rates.48,49 Many risk factors are involved in the pathogenesis of oral cancer,50 with smoking and alcohol consumptions being the major risk factors.51 Human papillomavirus (HPV) infection is also a well-known risk factor of OSCC, particularly among young patients and non-smoking females.52 Genetic factors including genetic polymorphism of drug metabolizing enzymes and DNA repair mechanisms were also reported to increase the patient susceptibility to OSCC.53,54 Nutritional deficiencies are also among the OSCC risk factors.55 Chronic inflammation was also suggested to increase the risk for OSCC, particularly in patients with periodontal diseases.56 Since the discovery of the role of bacterial infection in the initiation and progression of certain cancer types, as described earlier in this review, research has been directed to explore the role of bacterial infection in OSCC carcinogenesis.56,58

The oral cavity is enriched by different types of bacterial microbiota which play an important role in maintaining a “microbial homeostasis” and have commensal as well as mutualistic relation with the host.59,60 However, the loss of the homeostatic state can cause an “ecological shift” or “dysbiosis” which in turn can contribute to the development of diseases including OSCC.56,61,63 Nagy et al64 reported significantly higher levels of Porphyromonas, Fusobacterium, and other bacterial species (spp.) in OSCC tissue compared with adjacent healthy mucosa, using culture-based analysis of surface swabs. In addition, higher colonization of Porphyromonas gingivalis (P. gingivalis) was shown in gingival squamous cell carcinoma lesions compared to healthy gingival tissues.65 Tateda et al66 also showed that Streptococcus anginosus (S. anginosus) was observed in all studied samples of head and neck squamous cell carcinoma including OSCC, which was also supported by results from Sasaki et al,67 where it was reported in 45% of OSCC samples. The comparison between bacterial species expression in saliva of patients with OSCC and cancer free controls showed that Capnocytophaga gingivalis (C. gingivalis), Prevotella melaninogenica (P. melaninogenica), and Streptococcus mitis (S. mitis) were significantly higher in the cases group.68 In a subsequent study, Pushalkar et al69 found the genera Streptococcus, Rothia, Gemella, Peptostreptococcus, Porphyromonas, Micromonas, and Lactobacillus to be highly abundant in the salivary secretion of individuals with OSCC. In comparison, Prevotella Neisseria (P. Neisseria), Leptotrichia, Capnocytophaga, Actinobacillus, and Oribacterium were higher in the saliva samples of healthy controls.69 However, conflicting results were reported in a larger-scale study upon analysis of swabs from lesion and contra-lateral normal tissues from 18 OSCC patients, eight pre-cancer cases, and nine healthy individuals.70 Schmidt et al70 reported significantly lower genera of Streptococcus and Rothia in tumor samples compared with contra-lateral normal and pre-cancer samples. In contrast, the tumors were enriched with the genus Fusobacterium, while the phylum Bacteroidetes was remarkably higher in both cancer and normal tissues of OSCC patients compared with pre-cancer and healthy individuals.70 However, due to limitations in previous detection techniques where classification was not possible beyond the genus level, accurate conclusion of the possible relation between bacteria and oral cancer cannot be achieved.70 Recently, applying a novel bioinformatics techniques with 16S rRNA reference sequences enabled the classification to the species level.71 Al-Hebshi et al71 detected 228 bacterial species in three samples of OSCC DNA, of which 35 species were present in all samples. More recently, P. gingivalis, Fusobacterium nucleatum (F. nucleatum) and Streptococcus sanguinis (S. sanguinis) have been shown to be highly abundant in OSCC tissues, paracancerous tissues, and subgingival plaque samples in comparison to normal tissues, pointing to the role of periodontal pathogens in OSCC.72 P. gingivalis infection was positively correlated with advanced clinical staging, low differentiation, and lymph node involvement in OSCC patients,72 which was also associated with more severe periodontal diseases in these patients.72 Table 1 summarizes findings from studies concerned with microbiota and GIT cancers.

Table 1 GIT Cancers and Microbiota

Based on the aforementioned findings, it is obvious that there is limited agreement on which bacterial species are associated with OSCC and whether any microbial dysbiosis identified has a role in the etiology, progression of oral cancer, or it is just a consequence.56,58 However, most in vitro and in vivo studies support the hypothesis that P. gingivalis can mediate OSCC pathogenesis through different mechanisms.62,73,74 These include inhibition of apoptosis,75,79 activation of cell proliferation,80,82 promotion of cellular invasion,83,86 acquisition of stem cell characteristics,87 and induction of chronic inflammation.84,88 Nakhjiri et al75 found that P. gingivalis inhibited chemically-induced apoptosis in gingival epithelial cells (GECs). It has been suggested that P. gingivalis activated Janus kinase 1 (JAK1)/Signal transducer and activator of transcription 3 (STAT3) (JAK1/STAT3) and Phosphoinositide 3-kinase (PI3K)/Protein kinase B (PKB, Akt) (PI3K/Akt) signaling, which in turn affected the intrinsic mitochondrial apoptosis pathways.76,77 In addition, P. gingivalis has been shown to increase microRNA-203 (miR-203) in GECs that can activate STAT3 upon the downregulation of suppressor of cytokine signaling 3 (SOCS3), resulting in apoptosis suppression.89 P. gingivalis was also found to secrete a nucleoside diphosphate kinase (NDK), which can inhibit the adenosine triphosphate (ATP)-dependent apoptosis driven by purinergic receptor (P2X7) on GECs.78 Recently, Gallimidi et al79 have shown that chronic coinfection with P. gingivalis and F. nucleatum enhanced the progression of chemically-induced OSCC in an animal model through the activation of the interleukin-6 (IL-6)/STAT3 pathway. P. gingivalis was also reported to enhance GECs proliferation by increasing the progression of GECs through the S and G2 phases of the cell cycle.80,81 These mechanisms were suggested to be mediated by fimbrillin (FimA) fimbriae as well as the bacterial lipopolysaccharide (LPS) through dysregulation of tumor protein p53 (p53).90 Zhou et al82 also suggested that P. gingivalis may increase GECs proliferation via β-catenin and gingipain-dependent proteolytic process. In addition to its roles in apoptosis and proliferation, P. gingivalis was reported to affect the other hallmarks of cancer, including migration and invasion.83,91 P. gingivalis infection was found to increase the expression level of pro-matrix metalloproteinase-9 (MMP-9) in OSCC cells.83,91 In addition, it was demonstrated to enhance epithelial to mesenchymal transition (EMT) and increase the production of MMP-1 and MMP-10, with both mechanisms contributing to increased cellular invasion.84,85 Chronic inflammation was also among the suggested mechanisms by which bacteria mediate oral carcinogenesis.84,88 This might provide a possible explanation to the link between periodontitis and increased risk of development of OSCC.72,88 In this regard, Groeger et al92 reported increased expression of B7 homolog 1 (B7-H1) and B7 co-stimulatory family member on dendritic cells (B7-DC) receptors, which are known to be involved in chronic inflammation, in both GECs and OSCC cell lines upon infection by P. gingivalis. In addition, Andrian et al93 demonstrated upregulation of the inflammatory mediators (IL-1, IL-6, IL-8, and tumor necrosis factor (TNF-α)) following infection in engineered human oral mucosa. These findings were further validated by recent bioinformatical analyses of OSCC clinical samples.88

Therapeutic Perspectives

In vitro investigations have evaluated targeting OSCC cell lines infected with P. gingivalis using acetylshikonin.74 Acetylshikonin is a flavonoid with anti‑inflammatory activity and was found to suppress OSCC cell proliferation and induce apoptosis. Cho et al74 revealed that acetylshikonin significantly reduced the invasion of P. gingivalis infected OSCC cell lines via downregulation of IL‑8 release and IL‑8‑dependent MMP release. However, evidence from clinical studies is needed to support the role of P. gingivalis eradication in OSCC prevention and treatment.

Infection with P. gingivalis has recently been shown to have a negative impact on OSCC cells response to chemotherapy.86 Woo et al86 showed that the tumor xenografts of P. gingivalis infected OSCC cells were more resistant to Taxane treatment in comparison with uninfected cells, which was attributed to Notch1 activation.

Esophageal Cancer

Esophageal cancer is considered to be the eighth most commonly diagnosed cancer worldwide and the sixth leading cause of cancer death.2 Despite advances in the current treatment modalities including surgery, chemotherapy, and radiotherapy, the prognosis is poor, even in patients with total excision.94,95 Therefore, more studies should be directed toward understanding the pathogenesis of esophageal cancer and the role of microbiomes which might have diagnostic and therapeutic implications.15 Table 1 summarizes findings from studies concerned with microbiota and GIT cancers.

Adenocarcinoma and squamous cell carcinoma (SSC) are the most common histopathological subtypes of esophageal cancer.96 Narikiyo et al97 described the enrichment of normal and neoplastic esophageal tissues excised from patients with esophageal cancer with the oral periodontopathic spirochete Treponema denticola (T. denticola), S. mitis, and S. anginosus. However, the pathological subtypes, whether SSC or adenocarcinoma, have not been determined.97 In addition, Blackett et al98 revealed that Campylobacter were significantly more dominant in Gastroesophageal reflux disease (GERD) and Barrett’s esophagus than in esophageal adenocarcinoma.

Many in vivo studies have explored the relationship between the microbiome and esophageal adenocarcinoma development.99,100 The effect of using antibiotics (penicillin G and streptomycin) on the development of esophageal adenocarcinoma was evaluated using a rat animal model and showed that the proportions of Lactobacillales were reduced in the antibiotic treated group, while Clostridium were elevated in comparison with control.99 However, the incidence of esophageal adenocarcinoma was not affected by such microbiota alteration.99 Zaidi et al100 reported a high level of Escherichia coli (E. coli) in Barrett’s esophagus and esophageal adenocarcinoma compared with normal epithelium among the studied patients. In addition, increased expression of toll-like receptor (TLR) 1–3, 6, 7, and 9 signaling pathways were significantly observed in esophageal adenocarcinoma, pointing to a potential mechanism by which E. coli might drive the carcinogenesis of esophageal adenocarcinoma.100 Changes in the microbiota composition were suggested to mediate the progression of GERD and Barrett’s esophagus toward adenocarcinoma.101 However, currently, limited evidence is available about the exact role of microbiome in esophageal adenocarcinoma initiation and progression.15,101

The role of microbiome in SSC of the esophagus is not well defined.15 Inverse correlation between esophageal microbial complexity and esophageal squamous dysplasia was described.102 Yu et al102 suggested that esophageal squamous cell dysplasia might be more common among people with lower esophageal microbiota. On the other hand, Nasrollahzadeh et al103 reported a predominance of Clostridiales and Erysipelotrichales in the gastric corpus microbiota of patients with esophageal squamous cell dysplasia and SSC, when compared to control cases. This suggests a possible involvement of gastric microbial imbalances in the transformation of esophageal squamous dysplasia to SSC.103 Changes in bacterial microbiota in the saliva of patients with esophageal SCC were also reported.104 Less enrichment of genera Lautropia, Bulleidia, Catonella, Corynebacterium, Moryella, Peptococcus, and Cardiobacterium was observed in comparison with controls.105 In addition, P. gingivalis, which was detected in esophageal SSC and adjacent mucosal tissues,106,107 has recently been shown to be significantly dominant in the saliva of patients with esophageal SCC, compared with healthy individuals.104 Meng et al104 described that P. gingivalis enhanced the proliferation and motility of SCC cell lines via the nuclear factor kappa B (NF-κB) signaling pathway. These findings suggest a role of oral pathogens in inducing esophageal SCC tumorgenesis, metastasis, severity, as well as poor prognosis.104,106,107 Findings from previous studies and others indicate that poor oral health might contribute to higher risk of esophageal SSC.104,106,108

Recently, possible correlation between the presence of F. nucleatum and the prognosis of esophageal SSC has been demonstrated.109 F. nucleatum was found in esophageal cancer tissues of nearly 23% of patients with esophageal cancer (74/325) and was significantly linked to shorter survival time.109 Increased gene expression of the specific chemokine CCL20 has been observed, suggesting that F. nucleatum promotes an aggressive tumor phenotype by activating the cytokine–cytokine receptor interactions.109

Therapeutic Perspectives

Currently, limited evidence is available regarding the role of microbiomes in esophageal cancer treatment or prevention, which might be considered as an attractive topic to be investigated.110 Iida et al111 showed that disruption of the microbiota using antibiotics reduced the sensitivity of xenograft tumors in animal models to subsequent CpG-oligonucleotide immunotherapy and platinum chemotherapy (oxaliplatin). These findings were also observed in germ-free mice models.111,112 It has been suggested that intact commensal microbiota is needed to obtain optimal cancer treatment, since microbiota promotes the effect of cancer therapy through myeloid-derived cell functions in the tumor microenvironment.111,112 However, future studies are required to clarify the clinical implications of microbiome in esophageal cancer.

Gastric Cancer

The cause of gastric cancer (GC) is multifactorial including; environmental, dietary, and host-related factors.113,114 In addition, genetic and epigenetic alterations were described to interplay in the etiology of gastric cancer.114,116 According to the World Health Organization (WHO), H. Pylori was described as a class I carcinogen since it has a crucial role in the initiation of GC.117 H. Pylori was found in the gastric mucosa of 50% of the human population.118 Currently, two main mechanisms in which H. Pylori infection may result in intestinal-type GC have been suggested; the indirect processes through inflammation mediation and direct pathological role through bacterial virulence factors.119 Chronic inflammation caused by H. Pylori infection accelerates gastric cell turnover, which may lead to mitotic errors. This, in turn, enhances epithelial transformation and eventually can cause gastric adenocarcinomas.120,121 The sequential processes of H. Pylori chronic inflammation was described by Correa model.122 H. Pylori can initiate early pre-neoplastic lesions such as atrophic gastritis and enhance the progression to advanced lesions, including metaplasia, dysplasia, and ultimately development of gastric adenocarcinomas.120,123,124 The inflammatory process is complex and indirect, involving the interplay between H. Pylori, acidic environment, immune cells, reactive oxygen, and nitrogen species, collectively, leading to increased oxidative stress, DNA damage, and the expression of pro-inflammatory mediators.125,127 Increased levels of cytokines (IL1B, IL-6, IL-8, and TNF-α) and cyclooxygenase-2 (COX-2) in the nucleus of gastric mucosal cells was described to enhance the progression of atrophic changes and induce intracellular signaling transformation.128,129 In addition to H. Pylori-associated inflammatory response, aberrant DNA methylation and gene silencing were observed in gastric epithelial cells and were described to be involved in the development of H. Pylori-related gastric carcinomas.130,131 These include genes involved in cell adhesion, cell cycle regulation, DNA mismatch repair, inflammation, transcription, autophagy, and tumor suppression.130,131

The direct effects of H. Pylori infection are mainly mediated by the virulence factors.132 Cytotoxin-associated gene A (CagA) and vacuolating cytotoxin A (VacA) are among the most frequently investigated virulence factors.117,132 Both factors were found to mediate the transition of precancerous gastric lesions toward malignant ones.133,134 CagA has been suggested to potentiate the inflammatory reactions, which in turn facilitate the progression of gastritis to GC.135,136 In addition, together with the cag pathogenicity island (cag PAI), CagA was found to affect multiple cellular signaling pathways, such as the mitogen-activated protein kinase (MAPK) cascade, NF-κB expression, PI3K/Akt signaling pathways, and EMT through the oncogenic yes-associated protein (YAP) pathway.134,137 Moreover, cag PAI was shown to have an impact on GC through induction of gene mutation of p53.138,140 On the other hand, VacA was found to affect the epithelial cell barrier and inhibit the T-cell mediated immune response, which results in a favorable environment for H. Pylori.141,142 Table 1 summarizes findings from studies concerned with microbiota and GIT cancers.

Therapeutic Perspectives

The role of H. Pylori eradication for prevention of gastric carcinoma was investigated by many researchers.143,144 Despite the fact that H. Pylori is considered amajor risk factor of GC, studies showed that eradication therapy was not enough for absolute effective prevention of GC development, indicating that H. Pylori is not the sole cause for gastric cancer.145 Findings from one clinical trial among Colombian people with high risk for GC showed no significant difference in cancer incidence among groups treated with anti-H. Pylori triple therapy and untreated groups after a 6-year follow-up.143 However, a significant increase in the regression rate of cancer precursor lesions was reported among the treated group.143 Results from meta-analysis of six randomized controlled trials revealed that eradication of H. Pylori can contribute to a 44% reduction in GC incidence among healthy, asymptomatic, infected patients in comparison to untreated individuals.144 In addition, Ma et al146 reported a 39% reduction in incidence of precancerous lesions upon H. Pylori eradication in a placebo-controlled clinical trial with a 15-year follow-up. Vannella et al147 also showed that, after 8 years of eradication, reversal of atrophic body gastritis was observed in 50% of treated patients.Findings from a meta-analysis of 10 studies involving 7,955 participants showed that H. Pylori eradication significantly reduced the risk of GC among treated patients.148 This was further supported by results from a recent systematic review and meta-analysis of 26 studies (10 randomized controlled trials and 16 cohort studies) in which 52,363 subjects were included.149 The risk of GC was shown to significantly lower in patients in whom successful eradication of H. Pylori was achieved in comparison to untreated controls.149 However, regarding H. Pylori eradication in patients with precancerous lesions, subgroup analyses revealed that reducing the risk of GC was mainly when the lesions were non-atrophic or atrophic gastritis, but not in intestinal metaplastic or dysplastic lesions.148,149 Based on the aforementioned findings, it is obvious that H. Pylori eradication has an essential role in reducing the risk of GC, which can have a major impact and application for gastric cancer prevention. However, H. Pylori eradication therapy is recognized to be highly valuable if initiated at early stages of the infection, before the development of intestinal metaplasia, which is currently considered as a “point of no return” in the precancerous cascade of gastric cancer pathogenesis.148,149

Results from animal studies showed that the use of DNA demethylating agent, 5-aza-2′-deoxycytidine (5-aza-dC), resulted in suppression of aberrant DNA methylation and reduced the incidence of gastric cancer development.150 However, limited evidence is available regarding the use of demethylating agents as chemoprevention for gastric cancer in humans, due to their high toxicity profile.130 Novel DNA demethylating agents with minimal side-effects should be designed to be used for chemoprevention, particularly in patients who are at high-risk for gastric adenocarcinoma.130

According to the United Nations and WHO, Probiotics are defined as “live microorganisms which when administered in adequate amounts confer a health benefit for the host”.151 Investigations on probiotics use in gastric cancer are mainly directed toward eradication of H. Pylori infection since it is a major risk factor.31 The use of probiotics showed inhibitory effects on H. Pylori infection using animal models.152 In addition, findings from recent meta-analysis on clinical trials investigating the use of probiotics as a supplementation with antibiotic therapy reported positive effects.153,154 These include a reduction in side-effects, better patient compliance, and enhanced eradication.153,154 Table 2 summarizes findings from studies concerned with probiotics interventions in GIT cancers.

Table 2 In vivo Studies and Clinical Trials of Probiotics Interventions in GIT Cancers: Gastric Cancer, CRC, and HCC

Gastric MALT Lymphoma

Normal gastric mucosa contains no lymphoid tissues, however, the GIT is considered as the most common site for the extranodal lymphomas, with 30–45% of the cases reported in the stomach.155,156 Primary lymphomas affecting the stomach were described to have the properties of mucosa-associated lymphoid tissue (MALT),157 which accounts to 2–8% of gastric tumors.156 Gastric MALT lymphoma is a low-grade tumor with expression of dense lymphoid infiltrate of small-size lymphocytes that have the ability to invade and destroy gastric glands.158 The development of gastric MALT lymphoma was reported to be associated with local infections such as H. Pylori infections.158,159 This was first reported by Wotherspoon et al157 in 1991. Among 450 patients with H. Pylori-associated gastritis, 125 showed mucosal lymphoid follicles and, in eight patients, B lymphocytes were found to infiltrate the epithelium, which is a main feature of MALT lymphoma.157 In addition, 92% of tissues diagnosed with gastric MALT lymphoma were found to be enriched by H. Pylori.157 Since then, H. Pylori infections were also reported by other studies, supporting its association with development of gastric MALT lymphomas.160,161

In contrast to gastric carcinoma, the virulence factors of H. Pylori appear to not have a significant role in the pathogenesis of gastric lymphoma.162 CagA positive strains did not have a crucial role in low-grade MALT lymphoma in comparison to high grade lymphomas or what is currently known as diffuse large B cell lymphoma (DLBCL).163 H. Pylori has been shown to drive the pathogenesis of MALT lymphoma through different mechanisms.156 It was described to induce the production of a proliferation inducing ligand (APRIL) by macrophages in the tumor microenvironment,164 which is a novel cytokine that plays an important role in sustained B-cell proliferation and hence is highly associated with H. Pylori MALT lymphoma.165 In addition, H. Pylori infections were shown to cause genetic alterations leading to B cells transformation into a malignant clone.156 Three chromosomal translocations were described to be involved in the activation of NF-κB, and thus affect the immunity, inflammation, and apoptosis.166,167 Of note, the t(11;18)(q21;q21) was found in approximately one third of MALT cases and is often the only cytogenic alteration reported.168 The resulting translocation interferes with B cells apoptosis which contributes to monoclonal expansion.169 H. Pylori infection was also reported to mediate epigenetic alterations in gastric MALT lymphoma.170 Aberrant DNA methylation linked to inactivation of tumor suppressor genes was observed in 61.9% of MALT lymphomas, but none of the control group specimens.170 However, the underlying mechanism by which H. Pylori infection leads to CpG island hypermethylation is yet to be elucidated.170 Table 1 summarizes findings from studies concerned with microbiota and GIT cancers.

Therapeutic Perspectives

Currently, H. Pylori eradication therapy is highly recommended for early stage, low-grade, MALT lymphoma; that is when the neoplasia is confined in the stomach or in perigastric lymph nodes.159,171 The first evidence regarding complete histological remission of gastric MALT lymphoma upon H. Pylori eradication was shown in the early 1990s,172 in 83% of gastric MALT patients (N=6 cases).172 Findings from a systematic review on 32 studies, including 1,408 patients, described that. H. Pylori eradication is effective in treating approximately 75% of patients with early stage gastric lymphoma.173 Since probiotics use as an adjuvant to H. Pylori eradication therapy showed promising results in GC, as described previously, future studies are needed to explore the outcome of probiotics administration in gastric MALT lymphoma, as limited evidence is available in this regard.

Different predictive factors for gastric MALT lymphoma cure by H. Pylori eradication were recognized. These include the stage, the level of gastric wall penetration, and localization in the stomach.174 However, the reinfection with the same strain of H. Pylori can cause relapse and regrowth of the lymphoma.18 In addition, at advanced stages, adjunctive anti-tumor therapy might also be prescribed as the tumor might be H. Pylori independent evolved from low-grade lymphomas.175 The patient ethnicity was also found to play a role in the patient response to H. Pylori eradication, with a higher response rate reported in an Asian population in comparison to western populations.175 The presence of t(11;18)(q21:q21) chromosomal translocation with increasing chromosomal damage was also suggested to make gastric MALT lymphomas less responsive to H. Pylori eradication therapy.176,178 Recent findings have also shown that this translocation is associated with disseminated disease involving the stomach, small intestine, colon, and lung.179 The ratio of Forkhead Box P3/cluster of differentiation 4 (FOXP3+/CD4+) regulatory T cells (Treg) and the absolute number of FOXP3+ cells were also shown to be significantly higher in gastric MALT lymphomas sensitive to H. Pylori eradication as compared with resistance ones.179,180 This suggests a possible role of microbiome-immunity interactions within the tumor microenvironment in the therapeutic response of low grade MALT lymphoma.180 In contrast, increased expression of either miR-142-5p (ie, hematopoietic specific microRNA) or miR-155 (ie, potential oncogenic microRNA) in MALT-lymphoma tissues were linked to treatment resistance.181 In this regard, future studies are needed to identify other biomarkers for therapeutic response of MALT lymphoma and understand the underlying causes for treatment failure.182

Gastric DLBCL

Diffuse large B cell lymphoma (DLBCL) is another form of extranodal non-Hodgkin’s lymphoma that affects the stomach.182 It is a clinically heterogeneous aggressive disease with a histopathological appearance of a large number of transformed cells.183 Tumors without histological evidence of MALT lymphoma, dense infiltration of centrocyte like cells in the lamina propria, and typical lymphoepithelial lesions are classified as pure or de novo DLBCL.183,184 In contrast, those with evidence of MALT are classified as DLBCL (MALT).184 DLBCL (MALT) was previously known as “high-grade” MALT lymphoma and was suggested to be developed from gastric MALT lymphoma that has undergone high-grade transformation.177,184

The involvement of H. Pylori in the pathogenesis of DLBCL remains controversial.185 Studies have shown that H. Pylori has an important role in DBLCL (MALT) with the expression of H. Pylori virulence factor CagA being more frequent in H. Pylori-dependent cases.186,187 DLBCL was also described to gain H. Pylori-independent growth through indirect activation of NF-κB.188 Overexpression of B-cell activating factor of the TNF family (BAFF), with subsequent B-cell lymphoma/leukemia 10 (BCL10) upregulation and indirect NF-κB activation was reported.188 More recently, H. Pylori involvement has also been observed in de novo gastric DLBCL.186 As with gastric MALT lymphoma, hypermethylation and epigenetic silencing were highly prevalent in DLBCLs (93.3%).170,189 However, the chromosomal translocation t(11;18)(q21:q21) is uncommon in gastric DLBCL with or without MALT properties.182 Table 1 summarizes findings from studies concerned with microbiota and GIT cancers.

Therapeutic Perspectives

H. Pylori eradication therapy was found to play an essential role in the treatment of DLBCL cases.184 It was shown as potential curative therapy for the DLBCL (MALT) cases.186,190 The expression of CagA was associated with rapid response to H. Pylori eradication and suggested as predictive marker for the candidate patients with gastric DLBCL for eradication therapy without chemotherapy.187 Morgner et al191 reported that a complete pathological response had been achieved in seven of eight cases with DLBCL (MALT) upon eradication of H. Pylori. In addition, Chen et al192 have shown long-term results of H. Pylori eradication in early-stage gastric DLBCL (MALT) lymphomas confined to mucosa and submucosa, with complete pathological response reported in 64% of cases. However, with more penetration, the success of eradication therapy is limited.193 Another study from Japan showed that a complete pathological response was found in four of six cases with DLBCL (MALT) confined to the mucosa/submucosa, but in only one of four cases with invasion beyond the muscularis propria.193 In such cases, chemotherapy is considered the standard treatment modality.184 Of note, BAFF overexpression was reported in 70% of DLBCLs that were resistant to eradication therapy in comparison with 18.8% of those that were sensitive.188

Currently, there are sufficient data about the application of H. Pylori eradication in de novo DLBCL.186 In a retrospective study conducted by Kuo et al,186 it has been shown that complete pathological response was achieved in more than two thirds of the cases with de novo DLBCL upon eradication therapy. Therefore, the recommendations are to treat these cases with antibiotics, thus saving the patients from the harmful effects of conventional chemotherapy.182,184

Colorectal Cancer

Colorectal cancer (CRC) is considered as the third most commonly diagnosed cancer in males and the second in females. According to the Global Cancer Statistics, 1.8 million new CRC cases were diagnosed in 2018 and 881,000 deaths were reported in the same year.2 Adenocarcinoma is the most common histopathological subtype of CRC.194 Although the etiology of this highly lethal disease remains unclear, many environmental factors such as smoking, diet, and lifestyle were shown to determine individual’s risk for CRC.195 CRC incidence is well known to be increased with age.196 Individuals with certain genetic disorders such as Adenomatous Polyposis Coli (APC) and with family history of CRC are highly susceptible for CRC development.196 In addition, ulcerative colitis and Crohn’s disease are risk factors for CRC.197 However, 80% of CRC cases are sporadic.198

The role of infectious implications and alterations of the gut microbiome in CRC pathogenesis and therapy has also been suggested.199,200 Human intestine is a perfect habitat for more than 500 different species of bacteria, with the highest concentration found in the colon.201 The majority of gut microbiota are strict anaerobes such as Bacteroides, Eubacterium, Bifidobacterium, Fusobacterium, Peptostreptococcus, and Atopobium.33,202 Facultative anaerobes contribute to the minor percentage of gut inhabitants including Enterococci, Lactobacilli, Enterobacteriaceae, and Streptococci.33,203 Dysbiosis has been implicated in the pathogenesis of many diseases affecting the colon including inflammatory bowel disease, colitis, and CRC.202,203 Findings from in vitro and in vivo studies support the microbiome hypothesis of CRC.202,203 CRC was identified in 20% of germ-free rats using chemically induced CRC models in comparison to 93% of conventional rats.204 In addition, the tumor size was smaller in the germ-free group.205 However, the specific mechanism of the intestinal flora in causing CRC is unclear.206

Results from human studies have also supported the role of the gut microbiome in CRC.207,210 McCoy and Mason207 first reported a case of enterococcal endocarditis associated with a carcinoma of the cecum. It has been suggested to be caused by S. gallolytucis (previously known as S. bovis).207 The correlation between S. gallolytucis septicemia and CRC has been observed by many studies.208,210 Between 25% and 80% of patients with S. gallolytucis bacteremia had CRC.209,210 In addition, patients with CRC showed higher fecal carriage of S. gallolytucis in comparison with control subjects.209 The prevalence of S. gallolytucis in CRC patients was reported to be from 33% to 100%, while it was found in only 2.5–15% of the normal population.210 However, the exact underlying mechanism by which S. gallolytucis promotes CRC is yet to be elucidated.202,208,211 Animal studies showed that S. gallolytucis increased the expression of proliferation markers and polyamines.21 Colonic adenoma was observed in 50% of affected rats and a higher number of aberrant colonic crypts were reported.21 In addition, increased production of IL-8 in the colonic mucosa was suggested to be caused by S. gallolytucis.211 It was shown that IL-8 enhanced the generation of free radicals which promoted the neoplastic process.211 S. gallolytucis was also described to colonize and grow in colorectal tissues via collagen-binding proteins and histone-like protein A that allow adherence to collagen I, IV, fibronectin, fibrinogen, and proteoglycans in colon tissues.210 Accordingly, it is highly recommended that all patients with S. gallolytucis bacteremia should undergo a complete endoscopic screening of the colon.212

Bacteroides fragilis (B. fragilis) strains account for 0.1% of colon normal flora with 80% of children and adults carriers of B. fragilis in their colonic flora.213 However, the “enterotoxigenic B. fragilis” (ETBF), producing metalloprotease fragilisyn, has been shown to be increased in fecal samples as well as colonic mucosal tissues of CRC patients.214,216 Fragilisyn interferes with cell-to-cell adhesion as it causes cleavage of the extracellular domain of the E-cadherin, which is an invasion suppressor.217,218 In vitro studies showed that treatment of HT29/C1 cells with B. fragilis toxin promoted cell proliferation through the β-catenin pathway, with subsequent c-myelocytomatosis oncogene product (c-MYC) and cyclin D1 transcription and translation.219 The activation of β-catenin signaling via mutations in one or more of the APC complex proteins was found to be associated with inherited and sporadic forms of CRC.220 Results from clinical studies showed that the enterotoxin gene is highly expressed in mucosal samples from CRC patients compared to control groups.221,222 ETBF resulted in CRC development in multiple intestinal neoplasia (Min) in mice.219 This was mediated through the activation of STAT3 and a selective T helper 17 (TH17) cells response.223 In contrast, ETBF-induced tumor development was inhibited upon antibody-blockade of IL-17 and IL-23 receptor involved in TH17 responses.223

E. coli is part of the normal colonic flora.9 The colonic mucosa of patients with adenomas and carcinomas exhibited increased carriage of E. coli.224 This bacteria harbors cytotoxic necrotizing factor (Cnf) and cytolethal distending toxin (Cdt), which are significantly associated with CRC biopsies.225 In addition, Colibactin, a polyketide-peptide genotoxin, was most frequently associated with E. coli colonizing CRC.226,227 E. coli strains of the phylogenetic group B2 have a genomic island called “pks” which codes for the production of colibactin.228 Animal studies showed that infection with E. coli harboring the pks Island caused the formation of sporadic CRC in infected mice.228,229 Colibactin was described to interfere with the cell cycle and promote proliferation of epithelial cells via DNA damage, mutation, and genomic instability.230

F. nucleatum was described in colorectal adenomas.231 In addition, it was reported to be significantat higher levels in CRC tissues and fecal samples of CRC patients compared to healthy controls.232,233 It was linked to high CRC mortality, low overall survival, and increased CRC metastasis.234 F. nucleatum was suggested to stimulate CRC expansion via its Fap2 protein that interferes with the antitumor immune cell activity.235,236 FadA is another virulence factor of F. nucleatum that was described to mediate adhesion to E-cadherin, activate β-catenin signaling, and enhance subsequent inflammatory and oncogenic responses.237 Yang et al238 showed that F. nucleatum enhanced CRC cell lines proliferation and invasion, as well as in vivo tumors formation. This was mediated through TLR4 signaling, NF−κB stimulation, and enhanced miR-21 expression.238

Enterococcus faecalis (E. faecalis) has been recognized as a human pathogen,239 and a significantly high level was observed in fecal specimens of CRC patients compared to healthy controls.240 The role of E. faecalis in the generation of reactive oxygen and nitrogen species (RONS) with subsequent DNA break, point mutation, and chromosomal instability has been suggested as the main driving mechanism of its oncogenic activity in CRC.239,241

The association between H. Pylori and CRC is much less clear in comparison with its role in gastric carcinoma.242 Several meta-analyses demonstrated statistically significant association between H. Pylori and the risk of CRC.243,245 A recent study has revealed a significant increase in H. Pylori infection among patients with colon cancer and adenomatous polyps compared with the healthy controls.246 The role of H. Pylori in mediating microenvironment hypergastrinemia has been suggested as the underlying mechanism behind its association with CRC.247,248 In addition, the seropositivity of CagA toxin was linked to increased risk for CRC.249

Results from clinical studies also described the alteration of other bacterial species in samples derived from CRC patients.214,250 Bacteroides/Prevotella species were found to be abundant in fecal samples of CRC patients compared with controls.214 Coriobacteridae, Roseburia, Fusobacterium, and Faecalibacterium were shown to be highly expressed in tumor tissues, compared to healthy tissues within CRC patients.250 In contrast, the Enterobacteriaceae, such as Citrobacter, Shigella, Cronobacter, and Salmonella, were significantly lower in CRC tissues.250

Findings from aforementioned studies support the microbiota hypothesis in CRC pathogenesis, however, limited evidence is available regarding how bacterial species expressed in CRC tissues differ from the microbiota of adjacent non-tumorous tissues or fecal samples within the same investigated cases.251 In this regard, recent findings from Shah et al's251 pooled analysis using 16S rRNA gene sequence data from CRC patients revealed that Fusobacterium, Parvimonas, and Streptococcus were consistently abundant within tumor biopsies. In addition, Faecalibacterium and Ruminococcaceae levels were decreased in tumor tissues compared to tumor-adjacent tissues and fecal samples from the same cases.251

Most of the previous investigations were concerned with the differential expression level of gut microbiota, however, little is known regarding how specific bacteria species are selected and whether the host might have an effect on microbial gene expression. Liu et al252 identified fecal miRNAs and showed that miRNAs can affect specific bacterial gene expression as well as gut microbial growth. Recent investigations by Yuan et al253 have revealed differential expression of 76 miRNAs from CRC tumors and normal tissues that were linked to the relative enrichment of several bacterial taxa, including Firmicutes, Bacteroidetes, and Proteobacteria. The detected miRNAs were suggested to have an impact on targets involved in host-microbiome interactions as well as glycan production, which may enhance the recruitment of pathogenic microbiota.253,254

The association between gut microbiota dysbiosis and different early precursor lesions of CRC has also been suggested.255,257 Shen et al256 found higher Proteobacteria and lower Bacteroidetes numbers in tumor cases compared with controls upon assessing adherent bacteria in 21 adenoma and 23 non-adenoma subjects. A case-control study among an Iranian population of different ethnicities has shown increased levelsof F. nucleatum, E. faecalis, S. bovis, ETBF, and Porphyromonas species in fecal samples of tubular adenoma and villous/tubulovillous polyps’ patients than in healthy controls and patients with hyperplastic or sessile-serrated polyps (SSPs). In contrast, lower levels of Lactobacillus, Roseburia, and Bifidobacterium species were found.255 A very recent prospective study among individuals undergoing screening or surveillance colonoscopy has shown that both the gut microbiome analysis combined with advanced machine learning and colonoscopy had comparable results for polyps detection.257 This suggests that gut microbiome analysis might be considered as a promising non-invasive approach for polyps detection.257 Table 1 summarizes findings from studies concerned with microbiota and GIT cancers.

Therapeutic Perspectives

Based on the aforementioned studies, the gut microbiome might be considered as an attractive target for personalized treatment of CRC.225 However, limited clinical evidence is available regarding the role of bacterial eradication in the treatment of CRC. In this regard, E. coli was one of the targeted bacteria for CRC treatment.225 In vitro investigations using small molecule inhibitors against colibactin-activating peptidase (ClbP), a key enzyme involved in colibactin synthesis, showed blockage of the subsequent pathways activated by this toxin in a dose-dependent manner. In addition, using a murine colon loop model, these compounds suppressed the genotoxic activity of colibactin and significantly inhibited tumor growth and numbers.225 Fusobacterium was also investigated as a potential target for CRC treatment.258 The use of metronidazole in mice with colon cancer xenograft reduced the Fusobacterium load, cancer cell proliferation, and overall tumor growth.258

Manipulation of gut microbiota using probiotics might be considered as novel therapeutic modality for prevention of CRC development or reduction of chemotherapy induced adverse effects.27,202,259 Probiotics were shown to affect the gut microbiota through different mechanisms described previously in Compare and Nardone’s9 review. In vitro and animal studies reported positive outcomes and protective anticancer effects of probiotics in CRC.260,261 Bassaganya-Riera et al260 evaluated the role of VSL#3 in modulating mucosal immune responses using mouse models of inflammation driven CRC. It was found that both adenoma and adenocarcinoma formation was diminished upon treatment.260 In addition, VLS#3 administration resulted in reduction of irinotecan’s adverse effects, including weight loss and diarrhea.262 Many investigations also showed that administration of Lactobacillus acidophilus (L. acidophilus) KFRI342,263 Bifidobacterium longum (B. longum), Lactobacillus gasseri (L. gasseri),264 and Lactobacillus salivarius (L. salivarius) REN265 reduced the development of 2-Dimethylhydrazine (DMH) induced colorectal preneoplastic lesions. The microbiota populations of both E. coli and aerobic bacteria were also significantly reduced.263 The probiotic Lactobacillus casei (L. casei) was also described to reduce the expression and activity of the drug metabolizing enzymes, cytochromes P450, which are known to be associated with CRC carcinogenesis.266

In comparison to preclinical studies, controversial results have been reported upon reviewing clinical studies. It is well known that yogurt and dairy products are a good source and rich in probiotics.267 In this regard, high consumption in Finland has been linked to lower CRC incidence in comparison with other countries.267 This was also supported in two population-based case-control studies, where an inverse association was observed between yoghurt/cultured milk consumption and CRC development.268,269 In contrast, two American prospective studies did not show any evidence of the role of dairy products intake in reducing CRC risk.270 Results from a cohort study in the Netherlands revealed a weak non-significant inverse association of fermented dairy products intake with CRC in an elderly population.271 Recently, an intervention study using probiotics was conducted in 17 patients with familial adenomatous polyposis (FAP).272 Patients were treated with (I) sulindac; (II) inulin/VSL#3; and (III) sulindac/inulin/VSL#3. It has been shown that cell proliferation was reduced upon treatment with sulindac or VSL#3/inulin.272 Since FAP is a rare disorder, the small sample size of this single-center study was considered as the main drawback of its findings. The use of Lactobacillus rhamnosus (L. rhamnosus), however, resulted in downregulation of the bacterial enzymes β-glucosidase and urease, which might be involved in development of colon cancer by generating carcinogens.273 In addition, L. rhamnosus reduced diarrhea incidence in cancer patients treated with 5-fluorouracil (5-FU).274 Results from a prematurely terminated pilot study have also revealed that probiotics can reduce in the incidence and severity of gastrointestinal toxicity associated with irinotecan.275 It is well known that many factors might negatively affect human studies. Therefore, evidence from in vitro, in vivo, and human studies is highly needed to clarify the role of probiotics in CRC prevention and treatment.9,31 Table 2 summarizes findings from studies concerned with probiotics interventions in GIT cancers.

Manipulation of tumor microbiota using FMT has also been investigated as a potential therapeutic modality for CRC treatment and prevention.276 Rosshart et al276 described better resistance to CRC development and improvement of inflammation in mice treated with FMT from wild mice in comparison to control mice. However, limited evidence is available in this regard.45 Therefore, further studies from animal and clinical investigations are needed to validate the concept of FMT in CRC.

The presence of microbiota in a CRC tumor microenvironment was described to modulate anticancer drug efficacy.277 F. nucleatum was reported to be abundant in CRC tissues in patients with recurrence following chemotherapy.277 It was associated with CRC resistance to oxaliplatin and 5-FU through a molecular network of the Toll-like receptor, microRNAs, and autophagy.277 In vivo studies reported gemcitabine resistance in Mycoplasma hyorhinis (M. hyorhinis)-infected colon cancer cells.278 This was due to deamination of gemcitabine to inactive metabolite mediated by M. hyorhinis nucleoside analog-catabolizing enzymes.278 Gemcitabine resistance in a colon cancer mouse model was also caused by Gammaproteobacteria and attributed to the enzyme cytidine deaminase. Administration of the antibiotic ciprofloxacin resensitized the tumour response to gemcitabine, pointing to the role of these bacteria in treatment failure.278 On the other hand, Idia et al111 have shown that cisplatin resistance can be developed upon treatment of a colon cancer mouse model with antibiotics, which was linked to a decreased microbiota-dependent ROS production that plays an important role in platinum compounds mediated cytotoxicity. In addition, the cytotoxicity of the drug CB 1954 was found to be increased in the E. coli infected CT26 colon cancer cell line due to the ability of E. coli’ nitroreductase enzyme to activate the prodrug CB 1954.279

Changes in the microbiota composition can also affect the efficacy of immunotherapeutic agents used for treatment of cancers, since microbiota can have a strong impact on inflammation and immunity.38 Administration of intratumor CpG oligodeoxynucleotides in combination with an antibody against the IL-10 receptor to mice bearing MC38 colon carcinoma resulted in delayed tumor growth and prolonged survival.111 In comparison, the efficacy was reduced in germ-free mice and in antibiotics treated mice.111 The efficacy of Ipilimumab, which is a monoclonal antibody against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), was also significantly reduced upon treatment of a MC38 colon carcinoma mice model with broad-spectrum antibiotics or using a germ-free model.280

Microbiota was also described to affect the drug toxicity profile. SN-38G, the inactive metabolite of irinotecan, was reported to be reactivated to SN-38 inside the intestine by the bacterial β-glucuronidases, which was associated with severe intestinal toxicity.281,282 However, animal studies showed that co-administration of irinotecan with a selective inhibitor of bacterial β-glucuronidase reduced the incidence of irinotecan adverse effects including colonic damage or diarrhea.281 Lin et al283 also reported enrichment of a colon cancer bearing rat model with Clostridium cluster XI and Enterobacteriaceae upon irinotecan treatment, which was highly associated with the development of diarrhea. On the other hand, results from metastatic CRC patients treated with irinotecan reported a reduction of diarrhea in patients receiving the antibiotic levofloxacin.284 In addition, findings revealed a significant decrease in the microbial diversity of rats treated with irinotecan with an increase in Fusobacteria and Proteobacteria in fecal microbiota, which were linked to intestinal inflammation.285 Gut microbiota was also linked to oxaliplatin-induced peripheral neuropathy. Shen et al286 have shown that administration of antibiotics resulted in reduced oxaliplatin-induced pain in treated mice.

Liver Cancer

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the third most common cause of cancer-related death.287,288 The majority of HCC cases are related to liver cirrhosis or fibrosis, with chronic infections caused by hepatitis B and C viruses, alcoholic cirrhosis, as well as hemochromatosis are well recognized for their role in the etiology of HCC.289,290 Obesity and non-alcoholic fatty liver disease (NAFLD) are suggested as risk factors of HCC in developed countries, although the exact mechanisms are yet to be identified.291 The role of bacterial infections in HCC in comparison to other risk factors is less well defined.292 It is well known that the liver is generally considered sterile, however, it interacts directly with the gut through the hepatic portal and bile secretion systems.293 Intestinal dysbiosis leads to disruption of the intestinal wall, increases the permeability, and enhances bacterial translocation with their active metabolites.294,295 Therefore, the intestinal microbiome is considered as the main source of portal-vein endotoxins, such as LPS, and hence can mediate the progression of hepatic diseases.296 As a consequence, gut microbiota can cause many harmful effects and hepatic diseases including NAFLD/nonalcoholic steatohepatitis (NASH), alcoholic liver disease (ALD), and liver cirrhosis.297,301 However, only a few studies have reported any evidence of this association in HCC.292,296 In this regard, most of the data about gut microbe’s role in hepatocarcinogenesis comes from animal studies.292,302,303 Dapito et al303 reported a significant reduction in the total volume and number of HCC tumors in germ-free mice or in antibiotics-treated animals in comparison to controls, using the chemically induced HCC animal model. Analysis of the fecal and cecal microbiota in a rat model of a diethylnitrosamine (DEN) hepatocarcinogenesis showed an imbalance in gut microbiota composition.302 This includes significant suppression of Lactobacillus, Bifidobacterium, and Enterococcus species and a significant growth of E. coli and Atopobium cluster as well as upregulation of serum LPS levels.302 In addition, disruption of intestinal homeostasis by penicillin or dextran sulfate sodium (DSS) resulted in significant tumor formation.302

The potential role of obesity associated intestinal bacteria in HCC pathogenesis has also been explored.304 It is well known that an increased level of the secondary bile acid deoxycholic acid (DCA) contributes to hepatocarcinogenesis.304 It was found that genetically or high-fat diet (HFD)-induced obesity in a mice model increased the levels of DCA, which was correlated with higher incidence of HCC upon the administration of the chemical carcinogen dimethylbenz(a)anthracene (DMBA).304 The fecal microbiota of this group showed an increase in the relative abundance of Clostridium genus producing DCA. On the other hand, control mice fed a normal diet failed to develop HCC.304 Vancomycin use or reducing the levels of DCA also inhibited HCC development.304 Results of Xie et al's305 study also revealed significant changes in the gut microbiota during the progression of liver diseases and HCC using mice model mimics the development of steatosis and subsequent progression to NASH and HCC. The bacterial species, Atopobium, Bacteroides, Clostridium, and Desulfovibrio were significantly enriched in the fecal samples of a mice model and correlated with LPS levels as well as the pathophysiological features.305 Recent findings by Yamada et al306 showed that mice fed a steatohepatitis-inducing high-fat diet (HFD), namely STHD-01, developed HCC. In contrast, treatment with antibiotics significantly reduced tumor development and accumulation of secondary bile acids. In this study, secondary bile acids such as DCA were found to activate the mammalian target of rapamycin (mTOR) pathway in hepatocytes of mice fed STHD-01, which was suppressed upon treatment with antibiotics.306

In addition to the aforementioned bacterial species, the role of Helicobacter species in HCC was also explored. In vivo studies with intestinal inoculation of Helicobacter hepaticus (H. hepaticus) revealed disruption of enterohepatic homeostasis and development of HCC.307 This was suggested to be mediated through NF-ҝB and wingless-related integration site (Wnt) signaling pathways, hepatocyte turnover, and oxidative stress.307

Results from clinical studies showed the presence of Helicobacter species 16S rDNA in the liver of HCC patients, but not in controls.308 In addition, H. Pylori virulence factors including VacA and CagA were detected in HCC tissues.309,310 LPS from H. Pylori was found to enhance the growth and migration of liver cancer cell lines through the upregulation of IL-8 and the transforming growth factor (TGF-β1).311 Recently, an altered microbiome profile was reported in the tongue coat of patients with HCC compared to healthy controls, using a metagenomics approach with abundance of both Oribacterium and Fusobacterium in the HCC group.312 A recent study among patients with cirrhosis showed an increased fecal count of E. coli in patients with HCC in comparison to those without HCC, suggesting that the intestinal enrichment may mediate hepatocarcinogenesis of liver cirrhosis.313 More recently, Ponziani et al314 have shown that fecal microbiota of NAFLD-related cirrhosis and HCC has a higher level of Bacteroides and Ruminococcaceae in comparison to NAFLD-related cirrhosis without HCC and healthy controls, while Bifidobacterium was reduced. These findings suggest that gut microbiota is involved in the hepatocarcinogenesis process in patients with cirrhosis and NAFLD.314 Table 1 summarizes findings from studies concerned with microbiota and GIT cancers.

Therapeutic Perspectives

Since dysbiosis of the gut microbiota has been shown to be associated with HCC pathogenesis, studies have been directed toward the investigation on modulation of gut microbiota using probiotics,315 which can be considered as a novel therapeutic modality for prevention or treatment of HCC.315 Findings from Kumar et al's316 study using a rat model showed that the use of probiotic-fermented milk and chlorophyllin on Aflatoxin B1 (AFB1) induced HCC reduced the tumor incidence. In addition, the levels of c-MYC, BCL-2, cyclin D1, and RAS p21 were diminished.316 Zhang et al302 also reported that the administration of VSL#3 to rats inhibited DEN-induced hepatocarcinogenesis. LPS serum levels as well as the number and size of HCC were also reduced.302 Recently, it has been shown that the administration of a novel probiotic mixture (Prohep) reduced the tumor growth and volume by 40% in treated mice in comparison to controls.317 In addition, it increased the level of beneficial bacteria that resulted in induction of anti-inflammatory effects, stimulation of T-cell immune-responses, reduction of the tumor populations of migratory TH17 cells, and downregulation of pro-angiogenic factors, all of which might contribute to HCC prevention, treatment, and improved prognosis.317

In comparison to animal studies, there is little evidence from clinical studies regarding the beneficial outcome of using probiotics in HCC.318 Accordingly, future studies should be conducted using extensive human clinical trials to confirm observations obtained from animal experimental studies.318 El-Nezami et al319 reported that using probiotics reduces the biologically effective dose of aflatoxin exposure and aflatoxin-DNA toxic adduct which is associated with an increased risk of liver cancer. Therefore, probiotics might be considered as an effective dietary approach to lower the risk of HCC.319 Table 2 summarizes findings from studies concerned with probiotics interventions in GIT cancers.

Mounting evidence indicates the potential of using FMT as a therapy to control liver diseases.320,322 This includes findings from animal models regarding protective effects of FMT against high-fat diet-induced and alcohol-induced liver injuries.320,321 Results from clinical studies also supported the beneficial effects of FMT in patients with severe alcoholic hepatitis,322 chronic hepatitis B,323 advanced liver cirrhosis,324 and hepatic encephalopathy.325 However, future studies are needed to confirm whether FMT is also applicable in liver cancers.

Pancreatic Cancer

Pancreatic cancer is considered a rapidly progressive and fatal disease, with only a quarter of patients surviving 1-year after diagnosis.326 The majority of the patients are diagnosed at late stages and, therefore, the main goal of cancer treatment is palliative, including radiotherapy or chemotherapy modalities, rather than surgery.326 Pancreatic ductal adenocarcinoma (PDAC), which is the most common type of pancreatic cancer, is recognized as one of the leading causes of cancer death.327

The risk factors for pancreatic cancer have been studied extensively,328 and chronic pancreatitis is currently known as an established risk factor.329 Incidence rates were found to be 160% higher in patients with chronic pancreatitis compared with healthy populations.330 In addition, a 13-fold higher risk of PDAC development was reported among patients with chronic pancreatitis.331 Mounting data suggest an association between bacterial infections and pancreatic carcinogenesis.332,334 However, the role of microbiota might be better correlated with tumor progression, modulation of tumor microenvironment, activation of immune responses, and interplay with the inflammation processes rather than being causative of pancreatic cancer.335,336 Nevertheless, understanding the role of the microbiome in pancreatic cancer pathogenesis is essential.334 This will aid in the discovery of biomarkers and/or novel targets that can be utilized for early detection or for therapeutic intervention in terms of cancer prevention or treatment.335

Positive correlation between H. Pylori infections and pancreatic cancer has been described.337,344 This was first reported by a case–control study where a 2-fold increase in risk was found in infected patients compared with controls.337 Results from a prospective cohort study showed that, among male smokers, seropositive males for H. Pylori antibodies or CagA strains had increased risk compared with seronegative.338 These findings were also supported by subsequent epidemiological and meta-analysis studies.339,344 A positive correlation has also been observed between gastric peptic ulcer, which is known to be caused by H. Pylori, and pancreatic cancer in two large cohort studies.345,346 Studies have shown that H. Pylori can promote pancreatic diseases including pancreatic cancer through production of ammonia, LPS, and inflammatory mediators.347 In vitro investigations showed that the level of IL-8 and vascular endothelial growth factor (VEGF) as well as the activities of proliferation factors were increased in human pancreatic cancer cell lines when co-cultured with H. Pylori.348 This resulted in dysregulation of cellular processes and promoting inflammation, both of which play an important role in pancreatic carcinogenesis.348 In vitro and in vivo studies also reported that the LPS from H. Pylori can enhance KRAS genes mutation and initiation of pancreatic carcinogenesis.349,350 In fact, KRAS gene mutations were described in more than 90% of pancreatic adenocarcinoma.351 H. Pylori infection was also found to enhance STAT3 activation, which in turn has been suggested to mediate pancreatic cancer progression via increasing the level of anti-apoptotic and pro-proliferative proteins such as B-cell lymphoma-extra-large (Bcl-xL), myeloid cell leukemia-1 (MCL-1), survivin, c-MYC, and cyclin D1.352,354 However, whether H. Pylori infection is a causative factor of pancreatic cancer, future work should include clinical interventional studies using eradication therapy to clarify the H. Pylori role in pancreatic cancer initiation.336

Many studies also reported a positive correlation between pathogenic bacteria involved in periodontal diseases and risk of pancreatic cancer.355,357 In this regard, the association of P. gingivalis has been widely explored.358,359 Findings from the European Prospective Investigation into the Cancer cohort revealed more than a 2-fold increase in risk of pancreatic cancer in patients with high levels of P. gingivalis antibodies.359 Although the exact underlying mechanism is yet to be elucidated, P. gingivalis’ LPS stimulation of the TLR4 pathway has been suggested.360,361 In vitro and in vivo studies showed that TLR4 was highly expressed and has a key role in human PDAC, including suppression of apoptosis and promoting tumor growth, angiogenesis, as well as invasion.360,362 Fusobacterium species, another oral bacterial group, were found in 8.8% of pancreatic cancer tissues.363 The enrichment of pancreatic cancer tissues was linked to poor prognosis and suggested as negative independent biomarker for pancreatic cancer prognosis.364 A recent study has shown Pseudomonas aeruginosa (P. aeruginosa) to be involved in pancreatic cancer. Gaida et al365 described that P. aeruginosa enhanced the expression of the ATP-binding cassette sub-family B member 1 (ABCB1) and promoted cell invasion and metastasis. Table 1 summarizes findings from studies concerned with microbiota and GIT cancers.

Therapeutic Perspectives

Bacterial microbiota as a target for pancreatic cancer treatment was recently evaluated.366 Pushalkar et al366 have shown that treatment of mice bearing an invasive orthotopic PDAC model with an ablative oral antibiotic regimen resulted in ~50% reduction of tumor burdens. This was suggested to be driven by immunogenic reprogramming of the PDAC tumor microenvironment such as reduction in myeloid-derived suppressor cells and an increase in M1 macrophage differentiation.366 In addition, antibiotics treatment enhanced the efficacy of checkpoint-targeted immunotherapy against programmed death receptor-1 (PD-1), synergistically reduced tumor size, and enhanced T-cell activation.366 Accordingly, clinical trial of combination treatment using antibiotics with pembrolizumab, a checkpoint-based immunotherapy, is beginning prior to resection among patients with locally advanced PDAC.334

Limited evidence is available regarding the use of probiotics for prevention of PDAC. In fact, most available data are mainly based on the correlation of probiotics effects on pancreatic cancer risk factors such as pancreatitis, diet, obesity, and diabetes.367 Olah et al368 have shown that administration of Lactobacillus plantarum 299 to patients with acute pancreatitis reduced the development of pancreatic sepsis and the need for surgical interventions compared with control patients. The route of administration as enteral nutrition resulted in positive outcomes in comparison to the parenteral route.369 These include less fibrosis, acinar cell loss, parenchymal necrosis, inflammation, ductal damage, atypical reactive regeneration, and vacuolization that might prevent pancreatic cancer.369

The microbiota was also found to affect the response of PDAC toward treatment with gemcitabine.278 Drug resistance was linked to the enrichment of PDAC tissues with Gammaproteobacteria, with 76% of investigated tissues positive for bacteria.278

Gallbladder Cancer

Biliary tract cancer includes tumors of the bile duct, gallbladder, and ampulla of Vater.370 Gallbladder cancer (GBC) is the most prevalent cancer of the biliary tract.371 Although it is rare among the western world population, high incidence rates are reported in Chile, central Europe, Thailand, Japan, Northeastern, India, and Pakistan.372,374 The main risk factors include chronic gallbladder inflammation (cholelithiasis), the presence of gallstones, obesity, hormonal factors, environmental exposure to specific mutagens, genetic predisposition factors, as well as gallbladder abnormalities.375 In addition, bacterial infection has been suggested to be involved in the malignant transformation of the gallbladder epithelium.376 S. Typhi was found to be prominently associated with GBC.372,377 In addition, Helicobacter bilis (H. bilis), H. hepaticus, and E. coli have been suggested to be involved.378,381

Salmonella enterica serovar Typhi, the causative pathogen of typhoid fever, has the ability to cause asymptomatic chronic infection in a small percentage (2–3%) of patients after acute infections.382 Chronic typhoid carrier state was described to be correlated with an increased incidence of hepatobiliary diseases including GBC.383,384 Results from a large cohort study on the 1964 Aberdeen outbreak revealed that chronic typhoid carriers have an almost 167-fold higher risk of GBC.385 Many subsequent cohort and case control studies supported the increased risk for GBC among chronic typhoid carriers.372,377,386 In contrast, findings from a recent case-control study regarding the metagenomics of microbial communities in gallbladder bile from Bolivia and Chile patients with GBC or cholelithiasis revealed F. nucleatum, E. coli, and Enterobacter species as the predominant species in investigated patients, but not Salmonella species.381 The conflicting findings were suggested to be related to the small sample size of the Bolivian GBC patients and the reduction of infection rate of S. Typhi in the Chilean patients.381 Currently, limited evidence is available regarding the causal mechanism(s) underlying the suggested correlation of chronic S. Typhi infection and development of GBC. Therefore, the hypothesis of this association is not generally accepted.377 Results from preclinical and clinical studies described that gallstones have a fundamental role in enabling gallbladder colonization.387,389 Hence, gallbladder excision (cholecystectomy) is the best treatment that is usually considered in chronic typhoid carriers.390 Investigations showed that S. Typhi irreversibly transforms mice gallbladder organoids and mouse embryonic fibroblasts (MEFs) with mutated p53 and amplified c-MYC through Akt/MAPK pathways during infection.391 This was also reported in GBC patients from India where GBC is marked by S. Typhi DNA.391 In addition, the bacterial glucuronidase was found to produce a high-energy metabolite upon acting on bile which is potentially carcinogenic and has the ability to bind to DNA.392 Increased concentrations of secondary bile acids that are known as tumor promoters and initiators have also been described in the gallbladder secretions of patients with GBC and are suggested to be caused by the bacterial enzymes.393

Helicobacter infection is another example of microbiota associated with GBC.378,381 Studies have reported 2–3-fold higher risk for GBC among infected patients in comparison to controls based on the detection of Helicobacter species in bile or gallbladder tissue from GBC patients.378,381 Helicobacter species are bile-resistant organisms that were described to cause persistent infection, chronic inflammation, and gallstone formation due to urease production.394,395 Gallstones and chronic inflammation, in turn, can induce transformation that might be aggravated by many Helicobacter carcinogenic toxins and metabolites.394,395 H. hepaticus was detected in the gallbladder, liver, and bile.396,398 In addition, it was found in GBC.399 H. bilis was reported in the biliary tract and GBC of Japanese, Thai, and Mexican populations.400,401 Recently, Wang et al402 found that H. Pylori was rapidly induced into H. Pylori L-form in human bile, and hence both forms should be considered for detection in bile. However, larger epidemiological studies are required to clarify the role of Helicobacter species infections in GBC.

Mixed bacterial infections with E. coli, E. faecalis, Klebsiella, and Enterobacter species were also described at a significantly higher level in GBC.403 E. coli and Enterobacter sp. B10 (2014) were detected in the bile of GBC patients from Chile.381,404,405 Since E. coli and Enterobacter species infections were described to promote colon cancer,406 it has been suggested that both might be implicated in GBC by the same mechanisms.381 However, further studies are required to clarify the exact role in GBC. Table 1 summarizes findings from studies concerned with microbiota and GIT cancers.

Therapeutic Perspectives

Limited evidence is available from experimental or clinical investigations on bacterial eradication using antibiotics or bacterial manipulation using probiotics as treatment or preventive measures of GBC. Findings from Scano et al391 revealed that Salmonella- infected mouse embryonic fibroblasts were able to produce tumors upon transplantation into immunodeficient mice, even if these cells were pre-treated with ciprofloxacin to eradicate bacterial infection. It has been shown that Salmonella infection causes cell transformation with upregulation of Akt/MAPK activity, which were suggested to remain upregulated and mediate the carcinogenesis process, even after bacterial eradication.391 Therefore, cholecystectomy remains the ideal treatment for chronic typhoid carriers in order to prevent GBC.384 Future studies are needed to determine the therapeutic implications of GBC microbiota in terms of cancer prevention and treatment.

Conclusion

Gastrointestinal cancers have high incidence, mortality, and morbidity rates according to the latest estimates of the Global Cancer Statistics 2018. Many risk factors are well known and documented to be associated with the carcinogenesis process of GIT cancers. Currently, there is substantial evidence pointing to the role of bacterial microbiota in cancer pathogenesis. In this regard, H. Pylori was highly correlated with the development of gastric adenocarcinoma and MALT lymphoma. S. Typhi was also reported to have a major impact in gallbladder cancer, especially in patients with gallbladder stones and S. gallolytucis was linked to colorectal cancer. Therefore, currently bacterial eradication is highly recommended for cancer treatment and prevention, mainly in gastric cancer and MALT lymphoma, while cholecystectomy remains the ideal prevention modality of gallbladder cancer. In addition, complete endoscopic screening of the colon is required for patients with a previous history of S. gallolytucis bacteremia. Due to advances in diagnostic tools for bacterial isolation and identification in cancer tissues, mounting data indicate the contribution of many bacterial species in the pathogenesis process of GIT cancers. The underlying mechanisms were attributed to the microbiota impact on damaging DNA, activation of oncogenic pathways, production of carcinogenic metabolites, stimulation of chronic inflammation, and inhibition of antitumor immunity. Therefore, microbiota might act as an attractive target for cancer treatment and prevention. In this regard, promising results were obtained upon the use of antibiotics for eradication of bacterial infection for cancer treatment purposes. In addition, many studies revealed the positive effects of probiotics use, including enhancement of bacterial eradication, prevention of cancer development, and/or reduction of chemotherapy associated toxicities. These were mainly observed in gastric, colorectal, and hepatocellular carcinomas. However, most of the current evidence is based on findings from in vivo experimental models. Therefore, future clinical trials are needed to clarify the usefulness of antibiotics and probiotics for GIT cancer treatment and prevention.

Recently, the concept of “pharmacomicrobiomics” has emerged as a new field exploring the interplay between drugs and microbiota. The presence of certain types of bacteria was associated with reduced efficacy of anticancer drugs including conventional chemotherapy and molecular-targeted therapeutics. Microbiota was also described to affect the toxicity profile and adverse effects of anticancer drugs. Therefore, studies on GIT microbiota appear as wide filed with many potential pharmacological applications. These include investigations on the use of antibiotics and probiotics either alone or in combination with chemotherapy and immunotherapy. Very recently, manipulation of microbiota with fecal microbiota transplantation appears as a hot topic in cancer research. Promising results were observed against Clostridium difficile infection, and currently there is substantial interest regarding its therapeutic potential for treatment of other diseases including GIT cancers. In this regard, future studies are also needed to explore the potential application for personalized medicine.

Disclosure

All authors report no conflicts of interest in this work.

References

1. Torre LA, Siegel RL, Ward EM, Jemal A. Global cancer incidence and mortality rates and Trends—an update. Cancer Epidemiol Biomarkers Prev. 2016;25(1):16–27. doi:10.1158/1055-9965.EPI-15-0578

2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. doi:10.3322/caac.21492

3. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70. doi:10.1016/S0092-8674(00)81683-9

4. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674. doi:101016/jcell201102013

5. Semenza GL. The hypoxic tumor microenvironment: a driving force for breast cancer progression. Biochim Biophys Acta. 2016;1863(3):382–391. doi:101016/jbbamcr201505036

6. Rea D, Coppola G, Palma G, et al. Microbiota effects on cancer: from risks to therapies. Oncotarget. 2018;9(25):17915–17927. doi:1018632/oncotarget24681

7. Poutahidis T, Erdman SE. Commensal bacteria modulate the tumor microenvironment. Cancer Lett. 2016;380(1):356–358. doi:101016/jcanlet201512028

8. Helmink BA, Khan MAW, Hermann A, Gopalakrishnan V, Wargo JA. The microbiome, cancer, and cancer therapy. Nat Med. 2019;25(3):377–388. doi:10.1038/s41591-019-0377-7

9. Compare D, Nardone G. The bacteria-hypothesis of colorectal cancer: pathogenetic and therapeutic implications. Transl Gastrointest Cancer. 2014;3(1):44–53.

10. Francescone R, Hou V, Grivennikov SI. Microbiome, inflammation, and cancer. Cancer J. 2014;20(3):181–189. doi:101097/PPO0000000000000048

11. Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI. The human microbiome project. Nature. 2007;449(7164):5. doi:101038/nature06244

12. Lloyd-Price J, Abu-Ali G, Huttenhower C. The healthy human microbiome. Genome Med. 2016;8(1):51. doi:10.1186/s13073-016-0307-y

13. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Biological agents. Volume 100 B. A review of human carcinogens. IARC Monogr Eval Carcinog Risks Hum. 2012;100(PtB):1–441.

14. de Martel C, Franceschi S. Infections and cancer: established associations and new hypotheses. Crit Rev Oncol Hematol. 2009;70(3):183–194. doi:101016/jcritrevonc200807021

15. Baba Y, Iwatsuki M, Yoshida N, Watanabe M, Baba H. Review of the gut microbiome and esophageal cancer: pathogenesis and potential clinical implications. Ann Gastroenterol Surg. 2017;1(2):99–104. doi:101002/ags312014

16. Bhatt AP, Redinbo MR, Bultman SJ. The role of the microbiome in cancer development and therapy. CA Cancer J Clin. 2017;67(4):326–344. 103322/caac21398

17. DÃaz P, Valenzuela Valderrama M, Bravo J, Quest AFG. Helicobacter pylori and gastric cancer: adaptive cellular mechanisms involved in disease progression. Front Microbiol. 2018;9:5.

18. Floch P, Mégraud F, Lehours P. Helicobacter pylori strains and gastric MALT lymphoma. Toxins (Basel). 2017;9(4):132. doi:103390/toxins9040132

19. Welton JC, Marr JS, Friedman SM. Association between hepatobiliary cancer and typhoid carrier state. Lancet (London, England). 1979;1(8120):791–794. doi:10.1016/S0140-6736(79)91315-1

20. Littman AJ, Jackson LA, Vaughan TL. Chlamydia pneumoniae and lung cancer: epidemiologic evidence. Cancer Epidemiol Biomarkers Prev. 2005;14(4):773–778. doi:10.1158/1055-9965.EPI-04-0599

21. Ellmerich S, Scholler M, Duranton B, et al. Promotion of intestinal carcinogenesis by Streptococcus bovis. Carcinogenesis. 2000;21(4):753–756. doi:10.1093/carcin/21.4.753

22. Schwabe RF, Jobin C. The microbiome and cancer. Nat Rev Cancer. 2013;13(11):800–812. doi:10.1038/nrc3610

23. Fulbright LE, Ellermann M, Arthur JC. The microbiome and the hallmarks of cancer. PLoS Pathog. 2017;13(9):e1006480. doi:10.1371/journal.ppat.1006480

24. Johnson CH, Spilker ME, Goetz L, Peterson SN, Siuzdak G. Metabolite and microbiome interplay in cancer immunotherapy. Cancer Res. 2016;76(21):6146–6152. doi:10.1158/0008-5472.CAN-16-0309

25. Elinav E, Nowarski R, Thaiss CA, Hu B, Jin C, Flavell RA. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer. 2013;13(11):759–771. doi:10.1038/nrc3611

26. Dzutsev A, Goldszmid RS, Viaud S, Zitvogel L, Trinchieri G. The role of the microbiota in inflammation, carcinogenesis, and cancer therapy. Eur J Immunol. 2015;45(1):17–31. doi:10.1002/eji.201444972

27. Panebianco C, Andriulli A, Pazienza V. Pharmacomicrobiomics: exploiting the drug-microbiota interactions in anticancer therapies. Microbiome. 2018;6(1):92. doi:10.1186/s40168-018-0483-7

28. Li W, Deng Y, Chu Q, Zhang P. Gut microbiome and cancer immunotherapy. Cancer Lett. 2019;447:41–47. doi:10.1016/j.canlet.2019.01.015

29. Gopalakrishnan V, Helmink BA, Spencer CN, Reuben A, Wargo JA. The Influence of the gut microbiome on cancer, immunity, and cancer immunotherapy. Cancer Cell. 2018;33(4):570–580. doi:10.1016/j.ccell.2018.03.015

30. Fessler J, Matson V, Gajewski TF. Exploring the emerging role of the microbiome in cancer immunotherapy. J ImmunoTher Cancer. 2019;7(1):108. doi:10.1186/s40425-019-0574-4

31. Javanmard A, Ashtari S, Sabet B, et al. Probiotics and their role in gastrointestinal cancers prevention and treatment; an overview. Gastroenterol Hepatol Bed Bench. 2018;11(4):284–295.

32. Rodrigues Hoffmann A, Proctor LM, Surette MG, Suchodolski JS. The microbiome: the trillions of microorganisms that maintain health and cause disease in humans and companion animals. Vet Pathol. 2016;53(1):10–21. doi:10.1177/0300985815595517

33. de Vos WM, Rajilić-Stojanović M. The first 1000 cultured species of the human gastrointestinal microbiota. FEMS Microbiol Rev. 2014;38(5):996–1047. doi:10.1111/1574-6976.12075

34. Meng C, Bai C, Brown TD, Hood LE, Tian Q. Human gut microbiota and gastrointestinal cancer. Genomics Proteomics Bioinformatics. 2018;16(1):33–49. doi:10.1016/j.gpb.2017.06.002

35. Weng M-T, Chiu Y-T, Wei P-Y, Chiang C-W, Fang H-L, Wei S-C. Microbiota and gastrointestinal cancer. J Formos Med Assoc. 2019;118:S32–S41. doi:10.1016/j.jfma.2019.01.002

36. Vivarelli S, Salemi R, Candido S, et al. Gut microbiota and cancer: from pathogenesis to therapy. Cancers (Basel). 2019;11(1):38. doi:10.3390/cancers11010038

37. Wong SH, Kwong TNY, Wu C-Y, Yu J. Clinical applications of gut microbiota in cancer biology. Semin Cancer Biol. 2019;55:28–36. doi:10.1016/j.semcancer.2018.05.003

38. Ma W, Mao Q, Xia W, Dong G, Yu C, Jiang F. Gut microbiota shapes the efficiency of cancer therapy. Front Microbiol. 2019;10:1050. doi:10.3389/fmicb.2019.01050

39. Chen D, Wu J, Jin D, Wang B, Cao H. Fecal microbiota transplantation in cancer management: current status and perspectives. Int J Cancer. 2019;145(8):2021–2031. doi:10.1002/ijc.32003

40. Wortelboer K, Nieuwdorp M, Herrema H. Fecal microbiota transplantation beyond Clostridioides difficile infections. EBioMedicine. 2019;44:716–729. doi:10.1016/j.ebiom.2019.05.066

41. Kelly CP. Fecal microbiota transplantation — an old therapy comes of age. N Engl J Med. 2013;368(5):474–475. doi:10.1056/NEJMe1214816

42. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal Infusion of donor feces for recurrent clostridium difficile. N Engl J Med. 2013;368(5):407–415. doi:10.1056/NEJMoa1205037

43. Mizuno S, Masaoka T, Naganuma M, et al. Bifidobacterium-rich fecal donor may be a positive predictor for successful fecal microbiota transplantation in patients with irritable bowel syndrome. Digestion. 2017;96(1):29–38. doi:10.1159/000471919

44. Sokol H, Landman C, Seksik P, et al. Fecal microbiota transplantation to maintain remission in Crohn’s disease: a pilot randomized controlled study. Microbiome. 2020;8(1):12. doi:10.1186/s40168-020-0792-5

45. Filip M, Tzaneva V, Dumitrascu DL. Fecal transplantation: digestive and extradigestive clinical applications. Clujul Med. 2018;91(3):259–265. doi:10.15386/cjmed-946

46. Markopoulos AK. Current aspects on oral squamous cell carcinoma. Open Dent J. 2012;6:126–130. doi:10.2174/1874210601206010126

47. Jadhav KB, Gupta N. Clinicopathological prognostic implicators of oral squamous cell carcinoma: need to understand and revise. N Am J Med Sci. 2013;5(12):671–679. doi:10.4103/1947-2714.123239

48. Camisasca DR, Silami MA, Honorato J, Dias FL, de Faria PA, Lourenco Sde Q. Oral squamous cell carcinoma: clinicopathological features in patients with and without recurrence. ORL J Otorhinolaryngol Relat Spec. 2011;73(3):170–176. doi:10.1159/000328340

49. Wang B, Zhang S, Yue K, Wang XD. The recurrence and survival of oral squamous cell carcinoma: a report of 275 cases. Chin J Cancer. 2013;32(11):614–618. doi:10.5732/cjc.012.10219

50. Rivera C. Essentials of oral cancer. Int J Clin Exp Pathol. 2015;8(9):11884–11894.

51. Radoi L, Paget-Bailly S, Cyr D, et al. Tobacco smoking, alcohol drinking and risk of oral cavity cancer by subsite: results of a French population-based case-control study, the ICARE study. Eur J Cancer Prev. 2013;22(3):268–276. doi:10.1097/CEJ.0b013e3283592cce

52. Syrjänen S, Syrjänen K. HPV in head and neck carcinomas: different HPV profiles in oropharyngeal carcinomas – why? Acta Cytol. 2019;63(2):124–142. doi:10.1159/000495727

53. Kietthubthew S, Sriplung H, Au WW, Ishida T. Polymorphism in DNA repair genes and oral squamous cell carcinoma in Thailand. Int J Hyg Environ Health. 2006;209(1):21–29. doi:10.1016/j.ijheh.2005.06.002

54. Hatagima A, Costa EC, Marques CF, Koifman RJ, Boffetta P, Koifman S. Glutathione S-transferase polymorphisms and oral cancer: a case-control study in Rio de Janeiro, Brazil. Oral Oncol. 2008;44(2):200–207. doi:10.1016/j.oraloncology.2007.02.001

55. Llewellyn CD, Johnson NW, Warnakulasuriya KA. Risk factors for oral cancer in newly diagnosed patients aged 45 years and younger: a case-control study in Southern England. J Oral Pathol Med. 2004;33(9):525–532. doi:10.1111/j.1600-0714.2004.00222.x

56. Perera M, Al-Hebshi NN, Speicher DJ, Perera I, Johnson NW. Emerging role of bacteria in oral carcinogenesis: a review with special reference to perio-pathogenic bacteria. J Oral Microbiol. 2016;8:32762. doi:10.3402/jom.v8.32762

57. Yang CY, Yeh YM, Yu HY, et al. Oral microbiota community dynamics associated with oral squamous cell carcinoma staging. Front Microbiol. 2018;9:862. doi:10.3389/fmicb.2018.00862

58. Healy CM, Moran GP. The microbiome and oral cancer: more questions than answers. Oral Oncol. 2019;89:30–33. doi:10.1016/j.oraloncology.2018.12.003

59. Chen T, Yu WH, Izard J, Baranova OV, Lakshmanan A, Dewhirst FE. The human oral microbiome database: a web accessible resource for investigating oral microbe taxonomic and genomic information. Database. 2010;2010:baq013. doi:10.1093/database/baq013

60. Do T, Devine D, Marsh PD. Oral biofilms: molecular analysis, challenges, and future prospects in dental diagnostics. Clin Cosmet Investig Dent. 2013;5:11–19. doi:10.2147/CCIDE.S31005

61. Zarco MF, Vess TJ, Ginsburg GS. The oral microbiome in health and disease and the potential impact on personalized dental medicine. Oral Dis. 2012;18(2):109–120. doi:10.1111/j.1601-0825.2011.01851.x

62. Karpinski TM. Role of oral microbiota in cancer development. Microorganisms. 2019;7(1):20. doi:10.3390/microorganisms7010020

63. Gholizadeh P, Eslami H, Yousefi M, Asgharzadeh M, Aghazadeh M, Kafil HS. Role of oral microbiome on oral cancers, a review. Biomed Pharmacother. 2016;84:552–558. doi:10.1016/j.biopha.2016.09.082

64. Nagy KN, Sonkodi I, Szoke I, Nagy E, Newman HN. The microflora associated with human oral carcinomas. Oral Oncol. 1998;34(4):304–308. doi:10.1016/S1368-8375(98)80012-2

65. Katz J, Onate MD, Pauley KM, Bhattacharyya I, Cha S. Presence of porphyromonas gingivalis in gingival squamous cell carcinoma. Int J Oral Sci. 2011;3(4):209–215. doi:10.4248/IJOS11075

66. Tateda M, Shiga K, Saijo S, et al. Streptococcus anginosus in head and neck squamous cell carcinoma: implication in carcinogenesis. Int J Mol Med. 2000;6(6):699–703. doi:10.3892/ijmm.6.6.699

67. Sasaki M, Yamaura C, Ohara-Nemoto Y, et al. Streptococcus anginosus infection in oral cancer and its infection route. Oral Dis. 2005;11(3):151–156. doi:10.1111/j.1601-0825.2005.01051.x

68. Mager DL, Haffajee AD, Devlin PM, Norris CM, Posner MR, Goodson JM. The salivary microbiota as a diagnostic indicator of oral cancer: a descriptive, non-randomized study of cancer-free and oral squamous cell carcinoma subjects. J Transl Med. 2005;3:27. doi:10.1186/1479-5876-3-27

69. Pushalkar S, Mane SP, Ji X, et al. Microbial diversity in saliva of oral squamous cell carcinoma. FEMS Immunol Med Microbiol. 2011;61(3):269–277. doi:10.1111/j.1574-695X.2010.00773.x

70. Schmidt BL, Kuczynski J, Bhattacharya A, et al. Changes in abundance of oral microbiota associated with oral cancer. PLoS One. 2014;9(6):e98741. doi:10.1371/journal.pone.0098741

71. Al-Hebshi NN, Nasher AT, Idris AM, Chen T. Robust species taxonomy assignment algorithm for 16S rRNA NGS reads: application to oral carcinoma samples. J Oral Microbiol. 2015;7:28934. doi:10.3402/jom.v7.28934

72. Chang C, Geng F, Shi X, et al. The prevalence rate of periodontal pathogens and its association with oral squamous cell carcinoma. Appl Microbiol Biotechnol. 2019;103(3):1393–1404. doi:10.1007/s00253-018-9475-6

73. Olsen I, Yilmaz O. Possible role of Porphyromonas gingivalis in orodigestive cancers. J Oral Microbiol. 2019;11(1):1563410. doi:10.1080/20002297.2018.1563410

74. Cho BH, Jung YH, Kim DJ, et al. Acetylshikonin suppresses invasion of Porphyromonas gingivalisinfected YD10B oral cancer cells by modulating the interleukin-8/matrix metalloproteinase axis. Mol Med Rep. 2018;17(2):2327–2334. doi:10.3892/mmr.2017.8151

75. Nakhjiri SF, Park Y, Yilmaz O, et al. Inhibition of epithelial cell apoptosis by Porphyromonas gingivalis. FEMS Microbiol Lett. 2001;200(2):145–149. doi:10.1111/j.1574-6968.2001.tb10706.x

76. Yilmaz O, Jungas T, Verbeke P, Ojcius DM. Activation of the phosphatidylinositol 3-kinase/Akt pathway contributes to survival of primary epithelial cells infected with the periodontal pathogen Porphyromonas gingivalis. Infect Immun. 2004;72(7):3743–3751. doi:10.1128/IAI.72.7.3743-3751.2004

77. Mao S, Park Y, Hasegawa Y, et al. Intrinsic apoptotic pathways of gingival epithelial cells modulated by Porphyromonas gingivalis. Cell Microbiol. 2007;9(8):1997–2007. doi:10.1111/j.1462-5822.2007.00931.x

78. Yilmaz O, Yao L, Maeda K, et al. ATP scavenging by the intracellular pathogen Porphyromonas gingivalis inhibits P2X7-mediated host-cell apoptosis. Cell Microbiol. 2008;10(4):863–875.

79. Binder Gallimidi A, Fischman S, Revach B, et al. Periodontal pathogens Porphyromonas gingivalis and Fusobacterium nucleatum promote tumor progression in an oral-specific chemical carcinogenesis model. Oncotarget. 2015;6(26):22613–22623. doi:10.18632/oncotarget.4209

80. Kuboniwa M, Hasegawa Y, Mao S, et al. P. gingivalis accelerates gingival epithelial cell progression through the cell cycle. Microbes Infect. 2008;10(2):122–128. doi:10.1016/j.micinf.2007.10.011

81. Pan C, Xu X, Tan L, Lin L, Pan Y. The effects of Porphyromonas gingivalis on the cell cycle progression of human gingival epithelial cells. Oral Dis. 2014;20(1):100–108. doi:10.1111/odi.12081

82. Zhou Y, Sztukowska M, Wang Q, et al. Noncanonical activation of beta-catenin by Porphyromonas gingivalis. Infect Immun. 2015;83(8):3195–3203. doi:10.1128/IAI.00302-15

83. Inaba H, Sugita H, Kuboniwa M, et al. Porphyromonas gingivalis promotes invasion of oral squamous cell carcinoma through induction of proMMP9 and its activation. Cell Microbiol. 2014;16(1):131–145.

84. Ha NH, Park DG, Woo BH, et al. Porphyromonas gingivalis increases the invasiveness of oral cancer cells by upregulating IL-8 and MMPs. Cytokine. 2016;86:64–72. doi:10.1016/j.cyto.2016.07.013

85. Lee J, Roberts JS, Atanasova KR, Chowdhury N, Han K, Yilmaz O. Human primary epithelial cells acquire an epithelial-mesenchymal-transition phenotype during long-term infection by the oral opportunistic pathogen, porphyromonas gingivalis. Front Cell Infect Microbiol. 2017;7:493. doi:10.3389/fcimb.2017.00493

86. Woo BH, Kim DJ, Choi JI, et al. Oral cancer cells sustainedly infected with Porphyromonas gingivalis exhibit resistance to Taxol and have higher metastatic potential. Oncotarget. 2017;8(29):46981–46992. doi:10.18632/oncotarget.16550

87. Ha NH, Woo BH, Kim DJ, et al. Prolonged and repetitive exposure to Porphyromonas gingivalis increases aggressiveness of oral cancer cells by promoting acquisition of cancer stem cell properties. Tumour Biol. 2015;36(12):9947–9960. doi:10.1007/s13277-015-3764-9

88. Geng F, Wang Q, Li C, et al. Identification of potential candidate genes of oral cancer in response to chronic infection with porphyromonas gingivalis using bioinformatical analyses. Front Oncol. 2019;9:91.

89. Moffatt CE, Lamont RJ. Porphyromonas gingivalis induction of microRNA-203 expression controls suppressor of cytokine signaling 3 in gingival epithelial cells. Infect Immun. 2011;79(7):2632–2637. doi:10.1128/IAI.00082-11

90. Whitmore SE, Lamont RJ. Oral bacteria and cancer. PLoS Pathog. 2014;10(3):e1003933. doi:10.1371/journal.ppat.1003933

91. Inaba H, Amano A, Lamont RJ, Murakami Y. Involvement of protease-activated receptor 4 in over-expression of matrix metalloproteinase 9 induced by Porphyromonas gingivalis. Med Microbiol Immunol. 2015;204(5):605–612. doi:10.1007/s00430-015-0389-y

92. Groeger S, Domann E, Gonzales JR, Chakraborty T, Meyle J. B7-H1 and B7-DC receptors of oral squamous carcinoma cells are upregulated by Porphyromonas gingivalis. Immunobiology. 2011;216(12):1302–1310. doi:10.1016/j.imbio.2011.05.005

93. Andrian E, Grenier D, Rouabhia M. In vitro models of tissue penetration and destruction by Porphyromonas gingivalis. Infect Immun. 2004;72(8):4689–4698. doi:10.1128/IAI.72.8.4689-4698.2004

94. D’Journo XB, Thomas PA. Current management of esophageal cancer. J Thorac Dis. 2014;6 Suppl 2(Suppl2):S253–S264. doi:10.3978/j.issn.2072-1439.2014.04.16

95. Sohda M, Kuwano H. Current status and future prospects for esophageal cancer treatment. Ann Thorac Cardiovasc Surg. 2017;23(1):1–11. doi:10.5761/atcs.ra.16-00162

96. Arnold M, Soerjomataram I, Ferlay J, Forman D. Global incidence of oesophageal cancer by histological subtype in 2012. Gut. 2015;64(3):381. doi:10.1136/gutjnl-2014-308124

97. Narikiyo M, Tanabe C, Yamada Y, et al. Frequent and preferential infection of Treponema denticola, Streptococcus mitis, and Streptococcus anginosus in esophageal cancers. Cancer Sci. 2004;95(7):569–574. doi:10.1111/j.1349-7006.2004.tb02488.x

98. Blackett KL, Siddhi SS, Cleary S, et al. Oesophageal bacterial biofilm changes in gastro-oesophageal reflux disease, Barrett’s and oesophageal carcinoma: association or causality? Aliment Pharmacol Ther. 2013;37(11):1084–1092. doi:10.1111/apt.12317

99. Sawada A, Fujiwara Y, Nagami Y, et al. Alteration of esophageal microbiome by antibiotic treatment does not affect incidence of rat esophageal adenocarcinoma. Dig Dis Sci. 2016;61(11):3161–3168. doi:10.1007/s10620-016-4263-6

100. Zaidi AH, Kelly LA, Kreft RE, et al. Associations of microbiota and toll-like receptor signaling pathway in esophageal adenocarcinoma. BMC Cancer. 2016;16:52. doi:10.1186/s12885-016-2093-8

101. Snider EJ, Freedberg DE, Abrams JA. Potential role of the microbiome in barrett’s esophagus and esophageal adenocarcinoma. Dig Dis Sci. 2016;61(8):2217–2225. doi:10.1007/s10620-016-4155-9

102. Yu G, Gail MH, Shi J, et al. Association between upper digestive tract microbiota and cancer-predisposing states in the esophagus and stomach. Cancer Epidemiol Biomarkers Prev. 2014;23(5):735–741. doi:10.1158/1055-9965.EPI-13-0855

103. Nasrollahzadeh D, Malekzadeh R, Ploner A, et al. Variations of gastric corpus microbiota are associated with early esophageal squamous cell carcinoma and squamous dysplasia. Sci Rep. 2015;5:8820. doi:10.1038/srep08820

104. Meng F, Li R, Ma L, et al. Porphyromonas gingivalis promotes the motility of esophageal squamous cell carcinoma by activating NF-kappaB signaling pathway. Microbes Infect. 2019;21(7):296–304. doi:10.1016/j.micinf.2019.01.005

105. Chen X, Winckler B, Lu M, et al. Oral microbiota and risk for esophageal squamous cell carcinoma in a high-risk area of China. PLoS One. 2015;10(12):e0143603. doi:10.1371/journal.pone.0143603

106. Gao S, Li S, Ma Z, et al. Presence of Porphyromonas gingivalis in esophagus and its association with the clinicopathological characteristics and survival in patients with esophageal cancer. Infect Agent Cancer. 2016;11:3. doi:10.1186/s13027-016-0049-x

107. Peters BA, Wu J, Pei Z, et al. Oral microbiome composition reflects prospective risk for esophageal cancers. Cancer Res. 2017;77(23):6777–6787. doi:10.1158/0008-5472.CAN-17-1296

108. Chen X, Yuan Z, Lu M, Zhang Y, Jin L, Ye W. Poor oral health is associated with an increased risk of esophageal squamous cell carcinoma - a population-based case-control study in China. Int J Cancer. 2017;140(3):626–635. doi:10.1002/ijc.30484

109. Yamamura K, Baba Y, Nakagawa S, et al. Human microbiome fusobacterium nucleatum in esophageal cancer tissue is associated with prognosis. Clin Cancer Res. 2016;22(22):5574–5581. doi:10.1158/1078-0432.CCR-16-1786

110. Carmody RN, Turnbaugh PJ. Host-microbial interactions in the metabolism of therapeutic and diet-derived xenobiotics. J Clin Invest. 2014;124(10):4173–4181. doi:10.1172/JCI72335

111. Iida N, Dzutsev A, Stewart CA, et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science. 2013;342(6161):967–970. doi:10.1126/science.1240527

112. Goldszmid RS, Dzutsev A, Viaud S, Zitvogel L, Restifo NP, Trinchieri G. Microbiota modulation of myeloid cells in cancer therapy. Cancer Immunol Res. 2015;3(2):103–109. doi:10.1158/2326-6066.CIR-14-0225

113. Zabaleta J. Multifactorial etiology of gastric cancer. Methods Mol Biol. 2012;863:411–435.

114. Ishaq S, Nunn L. Helicobacter pylori and gastric cancer: a state of the art review. Gastroenterol Hepatol Bed Bench. 2015;8(Suppl 1):S6–S14.

115. Patel TN, Roy S, Ravi R. Gastric cancer and related epigenetic alterations. Ecancermedicalscience. 2017;11:714. doi:10.3332/ecancer.2017.714

116. Rivas-Ortiz CI, Lopez-Vidal Y, LJR A-H, Castillo-Rojas G. Genetic alterations in gastric cancer associated with helicobacter pylori infection. Front Med. 2017;4:47. doi:10.3389/fmed.2017.00047

117. Pucułek M, Machlowska J, Wierzbicki R, Baj J, Maciejewski R, Sitarz R. Helicobacter pylori associated factors in the development of gastric cancer with special reference to the early-onset subtype. Oncotarget. 2018;9(57):31146–31162. doi:10.18632/oncotarget.25757

118. Bittencourt PF, Rocha GA, Penna FJ, Queiroz DM. Gastroduodenal peptic ulcer and Helicobacter pylori infection in children and adolescents. J Pediatr (Rio J). 2006;82(5):325–334. doi:10.1590/S0021-75572006000600004

119. Zhang R-G, Duan G-C, Fan Q-T, Chen S-Y. Role of Helicobacter pylori infection in pathogenesis of gastric carcinoma. World J Gastrointest Pathophysiol. 2016;7(1):97–107. doi:10.4291/wjgp.v7.i1.97

120. Watari J, Chen N, Amenta PS, et al. Helicobacter pylori associated chronic gastritis, clinical syndromes, precancerous lesions, and pathogenesis of gastric cancer development. World J Gastroenterol. 2014;20(18):5461–5473. doi:10.3748/wjg.v20.i18.5461

121. Moss SF. The clinical evidence linking helicobacter pylori to gastric cancer. Cell Mol Gastroenterol Hepatol. 2016;3(2):183–191. doi:10.1016/j.jcmgh.2016.12.001

122. Correa P, Haenszel W, Cuello C, Tannenbaum S, Archer M. A model for gastric cancer epidemiology. Lancet (London, England). 1975;2(7924):58–60. doi:10.1016/S0140-6736(75)90498-5

123. Liu KS, Wong IO, Leung WK. Helicobacter pylori associated gastric intestinal metaplasia: treatment and surveillance. World J Gastroenterol. 2016;22(3):1311–1320. doi:10.3748/wjg.v22.i3.1311

124. Song H, Ekheden IG, Zheng Z, Ericsson J, Nyren O, Ye W. Incidence of gastric cancer among patients with gastric precancerous lesions: observational cohort study in a low risk Western population. BMJ (Clinical Research Ed). 2015;351:h3867. doi:10.1136/bmj.h6432

125. Bhattacharyya A, Chattopadhyay R, Mitra S, Crowe SE. Oxidative stress: an essential factor in the pathogenesis of gastrointestinal mucosal diseases. Physiol Rev. 2014;94(2):329–354. doi:10.1152/physrev.00040.2012

126. Butcher LD, den Hartog G, Ernst PB, Crowe SE. Oxidative stress resulting from helicobacter pylori infection contributes to gastric carcinogenesis. Cell Mol Gastroenterol Hepatol. 2017;3(3):316–322. doi:10.1016/j.jcmgh.2017.02.002

127. Tsai H-F, Hsu P-N. Interplay between Helicobacter pylori and immune cells in immune pathogenesis of gastric inflammation and mucosal pathology. Cell Mol Immunol. 2010;7(4):255–259. doi:10.1038/cmi.2010.2

128. Lindholm C, Quiding-Jarbrink M, Lonroth H, Hamlet A, Svennerholm AM. Local cytokine response in Helicobacter pylori-infected subjects. Infect Immun. 1998;66(12):5964–5971. doi:10.1128/IAI.66.12.5964-5971

129. Bartchewsky W Jr., Martini MR, Masiero M, et al. Effect of Helicobacter pylori infection on IL-8, IL-1beta and COX-2 expression in patients with chronic gastritis and gastric cancer. Scand J Gastroenterol. 2009;44(2):153–161. doi:10.1080/00365520802530853

130. Maeda M, Moro H, Ushijima T. Mechanisms for the induction of gastric cancer by Helicobacter pylori infection: aberrant DNA methylation pathway. Gastric Cancer. 2017;20(Suppl 1):8–15. doi:10.1007/s10120-016-0650-0

131. Muhammad JS, Eladl MA, Khoder G. Helicobacter pylori-induced DNA methylation as an epigenetic modulator of gastric cancer: recent outcomes and future direction. Pathogens. 2019;8(1). doi:10.3390/pathogens8020071

132. Chang W-L, Yeh Y-C, Sheu B-S. The impacts of H. pylori virulence factors on the development of gastroduodenal diseases. J Biomed Sci. 2018;25(1):68. doi:10.1186/s12929-018-0466-9

133. Kikuchi S, Crabtree JE, Forman D, Kurosawa M. Association between infections with CagA-positive or -negative strains of Helicobacter pylori and risk for gastric cancer in young adults. Research Group on Prevention of Gastric Carcinoma Among Young Adults. Am J Gastroenterol. 1999;94(12):3455–3459. doi:10.1111/j.1572-0241.1999.01607.x

134. Yong X, Tang B, Li B-S, et al. Helicobacter pylori virulence factor CagA promotes tumorigenesis of gastric cancer via multiple signaling pathways. Cell Commun Signal. 2015;13:30. doi:10.1186/s12964-015-0111-0

135. Hatakeyama M. Oncogenic mechanisms of the Helicobacter pylori CagA protein. Nat Rev Cancer. 2004;4(9):688–694. doi:10.1038/nrc1433

136. Hatakeyama M, Higashi H. Helicobacter pylori CagA: a new paradigm for bacterial carcinogenesis. Cancer Sci. 2005;96(12):835–843. doi:10.1111/j.1349-7006.2005.00130.x

137. Li N, Feng Y, Hu Y, et al. Helicobacter pylori CagA promotes epithelial mesenchymal transition in gastric carcinogenesis via triggering oncogenic YAP pathway. J Exp Clin Cancer Res. 2018;37(1):280. doi:10.1186/s13046-018-0962-5

138. Wei J, Noto J, Zaika E, et al. Pathogenic bacterium Helicobacter pylori alters the expression profile of p53 protein isoforms and p53 response to cellular stresses. Proc Natl Acad Sci U S A. 2012;109(38):E2543–E2550. doi:10.1073/pnas.1205664109

139. Li N, Xie C, Lu N-H. p53, a potential predictor of Helicobacter pylori infection-associated gastric carcinogenesis? Oncotarget. 2016;7(40):66276–66286. doi:10.18632/oncotarget.11414

140. Shibata A, Puligandla B, Vogelman JH, et al. CagA status of Helicobacter pylori infection and p53 gene mutations in gastric adenocarcinoma. Carcinogenesis. 2002;23(3):419–424. doi:10.1093/carcin/23.3.419

141. Torres VJ, VanCompernolle SE, Sundrud MS, Unutmaz D, Cover TL. Helicobacter pylori vacuolating cytotoxin inhibits activation-induced proliferation of human T and B lymphocyte subsets. J Immunol. 2007;179(8):5433–5440. doi:10.4049/jimmunol.179.8.5433

142. Palframan SL, Kwok T, Gabriel K. Vacuolating cytotoxin A (VacA), a key toxin for Helicobacter pylori pathogenesis. Front Cell Infect Microbiol. 2012;2:92. doi:10.3389/fcimb.2012.00092

143. Correa P, Fontham ET, Bravo JC, et al. Chemoprevention of gastric dysplasia: randomized trial of antioxidant supplements and anti-helicobacter pylori therapy. J Natl Cancer Inst. 2000;92(23):1881–1888. doi:10.1093/jnci/92.23.1881

144. Ford AC, Forman D, Hunt RH, Yuan Y, Moayyedi P. Helicobacter pylori eradication therapy to prevent gastric cancer in healthy asymptomatic infected individuals: systematic review and meta-analysis of randomised controlled trials. BMJ (Clinical Research Ed). 2014;348:g3174.

145. Cheung KS, Leung WK. Risk of gastric cancer development after eradication of Helicobacter pylori. World J Gastrointest Oncol. 2018;10(5):115–123. doi:10.4251/wjgo.v10.i5.115

146. Ma JL, Zhang L, Brown LM, et al. Fifteen-year effects of Helicobacter pylori, garlic, and vitamin treatments on gastric cancer incidence and mortality. J Natl Cancer Inst. 2012;104(6):488–492. doi:10.1093/jnci/djs003

147. Vannella L, Lahner E, Bordi C, et al. Reversal of atrophic body gastritis after H. pylori eradication at long-term follow-up. Dig Liver Dis. 2011;43(4):295–299. doi:10.1016/j.dld.2010.10.012

148. Chen H-N, Wang Z, Li X, Zhou Z-G. Helicobacter pylori eradication cannot reduce the risk of gastric cancer in patients with intestinal metaplasia and dysplasia: evidence from a meta-analysis. Gastric Cancer. 2016;19(1):166–175. doi:10.1007/s10120-015-0462-7

149. Rokkas T, Rokka A, Portincasa P. A systematic review and meta-analysis of the role of Helicobacter pylori eradication in preventing gastric cancer. Ann Gastroenterol. 2017;30(4):414–423. doi:10.20524/aog.2017.0144

150. Niwa T, Toyoda T, Tsukamoto T, Mori A, Tatematsu M, Ushijima T. Prevention of Helicobacter pylori-induced gastric cancers in gerbils by a DNA demethylating agent. Cancer Prev Res. 2013;6(4):263–270. doi:10.1158/1940-6207.CAPR-12-0369

151. Araya M, Morelli L, Reid G, et al. Guidelines for the evaluation of probiotics in food; Report of a Joint FAO/WHO Working Group Report on Drafting Guidelines for the Evaluation of Probiotics in Food. Food and Agriculture Organization of the United Nations; World Health Organization; 2002. Available from: https://www.who.int/foodsafety/fs_management/en/probiotic_guidelines.pdf.

152. Zhu XY, Liu F. Probiotics as an adjuvant treatment in Helicobacter pylori eradication therapy. J Dig Dis. 2017;18(4):195–202. doi:10.1111/1751-2980.12466

153. Losurdo G, Cubisino R, Barone M, et al. Probiotic monotherapy and Helicobacter pylori eradication: A systematic review with pooled-data analysis. World J Gastroenterol. 2018;24(1):139–149. doi:10.3748/wjg.v24.i1.139

154. Zhu R, Chen K, Zheng -Y-Y, et al. Meta-analysis of the efficacy of probiotics in Helicobacter pylori eradication therapy. World J Gastroenterol. 2014;20(47):18013–18021. doi:10.3748/wjg.v20.i47.18013

155. Zucca E, Roggero E, Bertoni F, Cavalli F. Primary extranodal non-Hodgkin’s lymphomas. Part 1: gastrointestinal, cutaneous and genitourinary lymphomas. Ann Oncol. 1997;8(8):727–737. doi:10.1023/A:1008282818705

156. Zullo A, Hassan C, Ridola L, Repici A, Manta R, Andriani A. Gastric MALT lymphoma: old and new insights. Ann Gastroenterol. 2014;27(1):27–33.

157. Wotherspoon AC, Ortiz-Hidalgo C, Falzon MR, Isaacson PG. Helicobacter pylori-associated gastritis and primary B-cell gastric lymphoma. Lancet (London, England). 1991;338(8776):1175–1176. doi:10.1016/0140-6736(91)92035-Z

158. Isaacson PG. Update on MALT lymphomas. Best Pract Res Clin Haematol. 2005;18(1):57–68. doi:10.1016/j.beha.2004.08.003

159. Violeta Filip P, Cuciureanu D, Sorina Diaconu L, Maria Vladareanu A, Silvia Pop C. MALT lymphoma: epidemiology, clinical diagnosis and treatment. J Med Life. 2018;11(3):187–193. doi:10.25122/jml-2018-0035

160. Parsonnet J, Hansen S, Rodriguez L, et al. Helicobacter pylori Infection and Gastric Lymphoma. N Engl J Med. 1994;330(18):1267–1271. doi:10.1056/NEJM199405053301803

161. Stolte M, Bayerdörffer E, Morgner A, et al. Helicobacter and gastric MALT lymphoma. Gut. 2002;50(suppl3):iii19. doi:10.1136/gut.50.suppl_3.iii19

162. Miehlke S, Meining A, Morgner A, et al. Frequency of vacA genotypes and cytotoxin activity in Helicobacter pylori associated with low-grade gastric mucosa-associated lymphoid tissue lymphoma. J Clin Microbiol. 1998;36(8):2369–2370. doi:10.1128/JCM.36.8.2369-2370.1998

163. Peng H, Ranaldi R, Diss TC, Isaacson PG, Bearzi I, Pan L. High frequency of CagA+ Helicobacter pylori infection in high-grade gastric MALT B-cell lymphomas. J Pathol. 1998;185(4):409–412. doi:10.1002/(SICI)1096-9896(199808)185:4<409::AID-PATH121>3.0.CO;2-T

164. Munari F, Lonardi S, Cassatella MA, et al. Tumor-associated macrophages as major source of APRIL in gastric MALT lymphoma. Blood. 2011;117(24):6612–6616. doi:10.1182/blood-2010-06-293266

165. Planelles L, Medema JP, Hahne M, Hardenberg G. The expanding role of APRIL in cancer and immunity. Curr Mol Med. 2008;8(8):829–844. doi:10.2174/156652408786733711

166. Farinha P, Gascoyne RD. Molecular pathogenesis of mucosa-associated lymphoid tissue lymphoma. J clin oncol. 2005;23(26):6370–6378. doi:10.1200/JCO.2005.05.011

167. Bertoni F, Zucca E. Delving deeper into MALT lymphoma biology. J Clin Invest. 2006;116(1):22–26. doi:10.1172/JCI27476

168. Cavalli F, Isaacson PG, Gascoyne RD, Zucca E. MALT lymphomas. Hematol Am Soc Hematol Educ Program. 2001;2001:241–258. doi:10.1182/asheducation-2001.1.241

169. Suzuki H, Saito Y, Hibi T. Helicobacter pylori and gastric mucosa-associated lymphoid tissue (MALT) lymphoma: updated review of clinical outcomes and the molecular pathogenesis. Gut Liver. 2009;3(2):81–87. doi:10.5009/gnl.2009.3.2.81

170. Kondo T, Oka T, Sato H, et al. Accumulation of aberrant CpG hypermethylation by Helicobacter pylori infection promotes development and progression of gastric MALT lymphoma. Int J Oncol. 2009;35(3):547–557. doi:10.3892/ijo_00000366

171. Zucca E, Dreyling M. Gastric marginal zone lymphoma of MALT type: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21(Suppl 5):v175–v176. doi:10.1093/annonc/mdq182

172. Wotherspoon AC, Doglioni C, Diss TC, et al. Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet (London, England). 1993;342(8871):575–577. doi:10.1016/0140-6736(93)91409-F

173. Zullo A, Hassan C, Cristofari F, et al. Effects of Helicobacter pylori eradication on early stage gastric mucosa-associated lymphoid tissue lymphoma. Clin Gastroenterol Hepatol. 2010;8(2):105–110. doi:10.1016/j.cgh.2009.07.017

174. Nakamura S, Matsumoto T. Helicobacter pylori and gastric mucosa-associated lymphoid tissue lymphoma: recent progress in pathogenesis and management. World J Gastroenterol. 2013;19(45):8181–8187. doi:10.3748/wjg.v19.i45.8181

175. Testerman TL, Morris J. Beyond the stomach: an updated view of Helicobacter pylori pathogenesis, diagnosis, and treatment. World J Gastroenterol. 2014;20(36):12781–12808. doi:10.3748/wjg.v20.i36.12781

176. Kim JS, Kang SH, Moon HS, Sung JK, Jeong HY. Clinical outcome of eradication therapy for gastric mucosa-associated lymphoid tissue lymphoma according to H. pylori infection status. Gastroenterol Res Pract. 2016;2016:6794848. doi:10.1155/2016/6794848

177. Zucca E, Bertoni F. The spectrum of MALT lymphoma at different sites: biological and therapeutic relevance. Blood. 2016;127(17):2082. doi:10.1182/blood-2015-12-624304

178. Kuo S-H, Yeh K-H, Wu M-S, et al. First-line antibiotic therapy in Helicobacter pylori-negative low-grade gastric mucosa-associated lymphoid tissue lymphoma. Sci Rep. 2017;7(1):14333. doi:10.1038/s41598-017-14102-8

179. Micaella K, Multani M, Nimal P, et al. A rare case of helicobacter pylori-negative gastric-MALT lymphoma, disseminated to the small bowel, colon, and lung. Gastro Med Res. 2018;2(3):GMR.000537.002018.

180. Iwaya Y, Kobayashi M, Momose M, et al. High levels of FOXP3(+) regulatory T cells in gastric MALT lymphoma predict responsiveness to Helicobacter pylori eradication. Helicobacter. 2013;18(5):356–362. doi:10.1111/hel.12051

181. Saito Y, Suzuki H, Tsugawa H, et al. Overexpression of miR-142-5p and miR-155 in gastric mucosa-associated lymphoid tissue (MALT) lymphoma resistant to Helicobacter pylori eradication. PLoS One. 2012;7(11):e47396–e47396. doi:10.1371/journal.pone.0047396

182. Juárez-Salcedo LM, Sokol L, Chavez JC, Dalia S. Primary gastric lymphoma, epidemiology, clinical diagnosis, and treatment. Cancer Control. 2018;25(1):1073274818778256. doi:10.1177/1073274818778256

183. Xie Y, Pittaluga S, Jaffe ES. The histological classification of diffuse large B-cell lymphomas. Semin Hematol. 2015;52(2):57–66. doi:10.1053/j.seminhematol.2015.01.006

184. Paydas S. Helicobacter pylori eradication in gastric diffuse large B cell lymphoma. World J Gastroenterol. 2015;21(13):3773–3776. doi:10.3748/wjg.v21.i13.3773

185. Ferreri AJ, Govi S, Ponzoni M. The role of Helicobacter pylori eradication in the treatment of diffuse large B-cell and marginal zone lymphomas of the stomach. Curr Opin Oncol. 2013;25(5):470–479. doi:10.1097/01.cco.0000432523.24358.15

186. Kuo S-H, Yeh K-H, Wu M-S, et al. Helicobacter pylori eradication therapy is effective in the treatement of early-stage H pylori–positive gastric diffuse large B-cell lymphomas. Blood. 2012;119(21):4838. doi:10.1182/blood-2012-01-404194

187. Kuo S-H, Chen L-T, Lin C-W, et al. Expressions of the CagA protein and CagA-signaling molecules predict Helicobacter pylori dependence of early-stage gastric DLBCL. Blood. 2017;129(2):188. doi:10.1182/blood-2016-04-713719

188. Kuo S-H, Yeh P-Y, Chen L-T, et al. Overexpression of B cell–activating factor of TNF family (BAFF) is associated with Helicobacter pylori–independent growth of gastric diffuse large B-cell lymphoma with histologic evidence of MALT lymphoma. Blood. 2008;112(7):2927. doi:10.1182/blood-2008-03-140830

189. Oka T, Sato H, Ouchida M, Utsunomiya A, Yoshino T. Cumulative epigenetic abnormalities in host genes with viral and microbial infection during initiation and progression of malignant lymphoma/leukemia. Cancers (Basel). 2011;3(1):568–581. doi:10.3390/cancers3010568

190. Cheung DY. Helicobacter pylori eradication therapy, the reasonable first line therapy for gastric mucosa-associated lymphoid tissue lymphoma irrespective of infection status and disease stages. Gut Liver. 2016;10(5):659–660. doi:10.5009/gnl16359

191. Morgner A, Miehlke S, Fischbach W, et al. Complete remission of primary high-grade B-cell gastric lymphoma after cure of Helicobacter pylori infection. J clin oncol. 2001;19(7):2041–2048. doi:10.1200/JCO.2001.19.7.2041

192. Chen LT, Lin JT, Tai JJ, et al. Long-term results of anti-Helicobacter pylori therapy in early-stage gastric high-grade transformed MALT lymphoma. J Natl Cancer Inst. 2005;97(18):1345–1353. doi:10.1093/jnci/dji277

193. Nakamura S, Matsumoto T, Suekane H, et al. Predictive value of endoscopic ultrasonography for regression of gastric low grade and high grade MALT lymphomas after eradication of Helicobacter pylori. Gut. 2001;48(4):454–460. doi:10.1136/gut.48.4.454

194. Fleming M, Ravula S, Tatishchev SF, Wang HL. Colorectal carcinoma: pathologic aspects. J Gastrointest Oncol. 2012;3(3):153–173. doi:10.3978/j.issn.2078-6891.2012.030

195. Tuan J, Chen Y-X. Dietary and lifestyle factors associated with colorectal cancer risk and interactions with microbiota: fiber, red or processed meat and alcoholic drinks. Gastrointest Tumors. 2016;3(1):17–24. doi:10.1159/000442831

196. Kuipers EJ, Grady WM, Lieberman D, et al. Colorectal cancer. Nat Rev Dis Primers. 2015;1:15065. doi:10.1038/nrdp.2015.65

197. Axelrad JE, Lichtiger S, Yajnik V. Inflammatory bowel disease and cancer: the role of inflammation, immunosuppression, and cancer treatment. World J Gastroenterol. 2016;22(20):4794–4801. doi:10.3748/wjg.v22.i20.4794

198. Vacante M, Borzì AM, Basile F, Biondi A. Biomarkers in colorectal cancer: current clinical utility and future perspectives. World J Clin Cases. 2018;6(15):869–881. doi:10.12998/wjcc.v6.i15.869

199. Montalban-Arques A, Scharl M. Intestinal microbiota and colorectal carcinoma: implications for pathogenesis, diagnosis, and therapy. EBioMedicine. 2019;48:648–655. doi:10.1016/j.ebiom.2019.09.050

200. Garrett WS. The gut microbiota and colon cancer. Science. 2019;364(6446):1133–1135. doi:10.1126/science.aaw2367

201. Canny GO, McCormick BA. Bacteria in the intestine, helpful residents or enemies from within? Infect Immun. 2008;76(8):3360–3373. doi:10.1128/IAI.00187-08

202. Jahani-Sherafat S, Alebouyeh M, Moghim S, Ahmadi Amoli H, Ghasemian-Safaei H. Role of gut microbiota in the pathogenesis of colorectal cancer; a review article. Gastroenterol Hepatol Bed Bench. 2018;11(2):101–109.

203. Baliou S, Adamaki M, Spandidos DA, Kyriakopoulos AM, Christodoulou I, Zoumpourlis V. The microbiome, its molecular mechanisms and its potential as a therapeutic strategy against colorectal carcinogenesis (Review). World Acad Sci J. 2019;1:3–19.

204. Weisburger JH, Reddy BS, Narisawa T, Wynder EL. Germ-free status and colon tumor induction by N-methyl-N’-nitro-N-nitrosoguanidine. Proc Soc Exp Biol Med. 1975;148(4):1119–1121. doi:10.3181/00379727-148-38700

205. Vannucci L, Stepankova R, Kozakova H, Fiserova A, Rossmann P, Tlaskalova-Hogenova H. Colorectal carcinogenesis in germ-free and conventionally reared rats: different intestinal environments affect the systemic immunity. Int J Oncol. 2008;32(3):609–617.

206. Han S, Gao J, Zhou Q, Liu S, Wen C, Yang X. Role of intestinal flora in colorectal cancer from the metabolite perspective: a systematic review. Cancer Manag Res. 2018;10:199–206. doi:10.2147/CMAR.S153482

207. Mc CW, Mason JM 3rd. Enterococcal endocarditis associated with carcinoma of the sigmoid; report of a case. J Med Assoc State Ala. 1951;21(6):162–166.

208. Pasquereau-Kotula E, Martins M, Aymeric L, Dramsi S. Significance of Streptococcus gallolyticus subsp. gallolyticus Association with Colorectal cancer. Front Microbiol. 2018;9:614. doi:10.3389/fmicb.2018.00614

209. Klein RS, Recco RA, Catalano MT, Edberg SC, Casey JI, Steigbigel NH. Association of Streptococcus bovis with Carcinoma of the Colon. N Engl J Med. 1977;297(15):800–802. doi:10.1056/NEJM197710132971503

210. Abdulamir AS, Hafidh RR, Abu Bakar F. The association of Streptococcus bovis/gallolyticus with colorectal tumors: the nature and the underlying mechanisms of its etiological role. J Exp Clin Cancer Res. 2011;30(1):11. doi:10.1186/1756-9966-30-11

211. Boleij A, van Gelder MM, Swinkels DW, Tjalsma H. Clinical Importance of Streptococcus gallolyticus infection among colorectal cancer patients: systematic review and meta-analysis. Clin Infect Dis. 2011;53(9):870–878. doi:10.1093/cid/cir609

212. Ferrari A, Botrugno I, Bombelli E, Dominioni T, Cavazzi E, Dionigi P. Colonoscopy is mandatory after Streptococcus bovis endocarditis: a lesson still not learned. Case report. World J Surg Oncol. 2008;6:49. doi:10.1186/1477-7819-6-49

213. Sansonetti PJ. To be or not to be a pathogen: that is the mucosally relevant question. Mucosal Immunol. 2011;4(1):8–14. doi:10.1038/mi.2010.77

214. Sobhani I, Tap J, Roudot-Thoraval F, et al. Microbial dysbiosis in colorectal cancer (CRC) patients. PLoS One. 2011;6(1):e16393. doi:10.1371/journal.pone.0016393

215. Wang T, Cai G, Qiu Y, et al. Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers. ISME J. 2012;6(2):320–329. doi:10.1038/ismej.2011.109

216. Purcell RV, Pearson J, Aitchison A, Dixon L, Frizelle FA, Keenan JI. Colonization with enterotoxigenic Bacteroides fragilis is associated with early-stage colorectal neoplasia. PLoS One. 2017;12(2):e0171602–e0171602. doi:10.1371/journal.pone.0171602

217. Wu S, Rhee KJ, Zhang M, Franco A, Sears CL. Bacteroides fragilis toxin stimulates intestinal epithelial cell shedding and gamma-secretase-dependent E-cadherin cleavage. J Cell Sci. 2007;120(Pt 11):1944–1952. doi:10.1242/jcs.03455

218. Kharlampieva D, Manuvera V, Podgorny O, et al. Recombinant fragilysin isoforms cause E-cadherin cleavage of intact cells and do not cleave isolated E-cadherin. Microb Pathog. 2015;83–84:47–56. doi:10.1016/j.micpath.2015.05.003

219. Wu S, Morin PJ, Maouyo D, Sears CL. Bacteroides fragilis enterotoxin induces c-Myc expression and cellular proliferation. Gastroenterology. 2003;124(2):392–400. doi:10.1053/gast.2003.50047

220. Zhang L, Shay JW. Multiple roles of APC and its therapeutic implications in colorectal cancer. J Natl Cancer Inst. 2017;109(8):djw332. doi:10.1093/jnci/djw332

221. Toprak NU, Yagci A, Gulluoglu BM, et al. A possible role of Bacteroides fragilis enterotoxin in the aetiology of colorectal cancer. Clin Microbiol Infect. 2006;12(8):782–786. doi:10.1111/j.1469-0691.2006.01494.x

222. Boleij A, Hechenbleikner EM, Goodwin AC, et al. The Bacteroides fragilis toxin gene is prevalent in the colon mucosa of colorectal cancer patients. Clin Infect Dis. 2015;60(2):208–215. doi:10.1093/cid/ciu787

223. Wu S, Rhee KJ, Albesiano E, et al. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med. 2009;15(9):1016–1022. doi:10.1038/nm.2015

224. Maddocks OD, Short AJ, Donnenberg MS, Bader S, Harrison DJ. Attaching and effacing Escherichia coli downregulate DNA mismatch repair protein in vitro and are associated with colorectal adenocarcinomas in humans. PLoS One. 2009;4(5):e5517. doi:10.1371/journal.pone.0005517

225. Faïs T, Delmas J, Cougnoux A, Dalmasso G, Bonnet R. Targeting colorectal cancer-associated bacteria: A new area of research for personalized treatments. Gut Microbes. 2016;7(4):329–333. doi:10.1080/19490976.2016.1155020

226. Buc E, Dubois D, Sauvanet P, et al. High prevalence of mucosa-associated E. coli producing cyclomodulin and genotoxin in colon cancer. PLoS One. 2013;8(2):e56964. doi:10.1371/journal.pone.0056964

227. Arthur JC, Perez-Chanona E, Muhlbauer M, et al. Intestinal inflammation targets cancer-inducing activity of the microbiota. Science. 2012;338(6103):120–123. doi:10.1126/science.1224820

228. Cuevas-Ramos G, Petit CR, Marcq I, Boury M, Oswald E, Nougayrede JP. Escherichia coli induces DNA damage in vivo and triggers genomic instability in mammalian cells. Proc Natl Acad Sci U S A. 2010;107(25):11537–11542. doi:10.1073/pnas.1001261107

229. Cougnoux A, Dalmasso G, Martinez R, et al. Bacterial genotoxin colibactin promotes colon tumour growth by inducing a senescence-associated secretory phenotype. Gut. 2014;63(12):1932–1942. doi:10.1136/gutjnl-2013-305257

230. Faïs T, Delmas J, Barnich N, Bonnet R, Dalmasso G. Colibactin: more than a new bacterial toxin. Toxins (Basel). 2018;10(4):151. doi:10.3390/toxins10040151

231. McCoy AN, Araújo-Pérez F, Azcárate-Peril A, Yeh JJ, Sandler RS, Keku TO. Fusobacterium is associated with colorectal adenomas. PLoS One. 2013;8(1):e53653–e53653. doi:10.1371/journal.pone.0053653

232. Bundgaard-Nielsen C, Baandrup UT, Nielsen LP, Sørensen S. The presence of bacteria varies between colorectal adenocarcinomas, precursor lesions and non-malignant tissue. BMC Cancer. 2019;19(1):399. doi:10.1186/s12885-019-5571-y

233. Amitay EL, Werner S, Vital M, et al. Fusobacterium and colorectal cancer: causal factor or passenger? Results from a large colorectal cancer screening study. Carcinogenesis. 2017;38(8):781–788. doi:10.1093/carcin/bgx053

234. Kelly D, Yang L, Pei Z. Gut microbiota, fusobacteria, and colorectal cancer. Diseases. 2018;6(4):109. doi:10.3390/diseases6040109

235. Gur C, Ibrahim Y, Isaacson B, et al. Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack. Immunity. 2015;42(2):344–355. doi:10.1016/j.immuni.2015.01.010

236. Wu J, Li Q, Fu X. Fusobacterium nucleatum contributes to the carcinogenesis of colorectal cancer by inducing inflammation and suppressing host immunity. Transl Oncol. 2019;12(6):846–851. doi:10.1016/j.tranon.2019.03.003

237. Rubinstein MR, Wang X, Liu W, Hao Y, Cai G, Han YW. Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/β-catenin signaling via its FadA adhesin. Cell Host Microbe. 2013;14(2):195–206. doi:10.1016/j.chom.2013.07.012

238. Yang Y, Weng W, Peng J, et al. Fusobacterium nucleatum increases proliferation of colorectal cancer cells and tumor development in mice by activating toll-like receptor 4 signaling to nuclear factor−κB, and up-regulating expression of microRNA-21. Gastroenterology. 2017;152(4):851–866.e824. doi:10.1053/j.gastro.2016.11.018

239. Pillar CM, Gilmore MS. Enterococcal virulence–pathogenicity island of E. Faecalis. Front Biosci. 2004;9:2335–2346. doi:10.2741/1400

240. Balamurugan R, Rajendiran E, George S, Samuel GV, Ramakrishna BS. Real-time polymerase chain reaction quantification of specific butyrate-producing bacteria, Desulfovibrio and Enterococcus faecalis in the feces of patients with colorectal cancer. J Gastroenterol Hepatol. 2008;23(8 Pt 1):1298–1303. doi:10.1111/j.1440-1746.2008.05490.x

241. Fearon ER. Molecular genetics of colorectal cancer. Annu Rev Pathol. 2011;6:479–507. doi:10.1146/annurev-pathol-011110-130235

242. Papastergiou V, Karatapanis S, Georgopoulos SD. Helicobacter pylori and colorectal neoplasia: is there a causal link? World J Gastroenterol. 2016;22(2):649–658. doi:10.3748/wjg.v22.i2.649

243. Rokkas T, Sechopoulos P, Pistiolas D, Kothonas F, Margantinis G, Koukoulis G. The relationship of Helicobacter pylori infection and colon neoplasia, on the basis of meta-analysis. Eur J Gastroenterol Hepatol. 2013;25(11):1286–1294. doi:10.1097/MEG.0b013e328363d3cd

244. Wu Q, Yang ZP, Xu P, Gao LC, Fan DM. Association between Helicobacter pylori infection and the risk of colorectal neoplasia: a systematic review and meta-analysis. Colorectal Dis. 2013;15(7):e352–e364. doi:10.1111/codi.12284

245. Chen YS, Xu SX, Ding YB, Huang XE, Deng B. Helicobacter pylori Infection and the risk of colorectal adenoma and adenocarcinoma: an updated meta-analysis of different testing methods. Asian Pac J Cancer Prev. 2013;14(12):7613–7619. doi:10.7314/APJCP.2013.14.12.7613

246. Teimoorian F, Ranaei M, Hajian Tilaki K, Shokri Shirvani J, Vosough Z. Association of Helicobacter pylori infection with colon cancer and adenomatous polyps. Iran J Pathol. 2018;13(3):325–332.

247. Smith JP, Wood JG, Solomon TE. Elevated gastrin levels in patients with colon cancer or adenomatous polyps. Dig Dis Sci. 1989;34(2):171–174. doi:10.1007/BF01536047

248. Tatishchev SF, Vanbeek C, Wang HL. Helicobacter pylori infection and colorectal carcinoma: is there a causal association? J Gastrointest Oncol. 2012;3(4):380–385. doi:10.3978/j.issn.2078-6891.2012.058

249. Shmuely H, Passaro D, Figer A, et al. Relationship between Helicobacter pylori CagA status and colorectal cancer. Am J Gastroenterol. 2001;96(12):3406–3410. doi:10.1111/j.1572-0241.2001.05342.x

250. Marchesi JR, Dutilh BE, Hall N, et al. Towards the human colorectal cancer microbiome. PLoS One. 2011;6(5):e20447. doi:10.1371/journal.pone.0020447

251. Shah MS, DeSantis T, Yamal JM, et al. Re-purposing 16S rRNA gene sequence data from within case paired tumor biopsy and tumor-adjacent biopsy or fecal samples to identify microbial markers for colorectal cancer. PLoS One. 2018;13(11):e0207002. doi:10.1371/journal.pone.0207002

252. Liu S, da Cunha AP, Rezende RM, et al. The host shapes the gut microbiota via Fecal MicroRNA. Cell Host Microbe. 2016;19(1):32–43. doi:10.1016/j.chom.2015.12.005

253. Yuan C, Burns MB, Subramanian S, Blekhman R. Interaction between host MicroRNAs and the gut microbiota in colorectal cancer. mSystems. 2018;3(3). doi:10.1128/mSystems.00205-17

254. Yuan C, Steer CJ, Subramanian S. Host⁻MicroRNA⁻microbiota interactions in colorectal cancer. Genes (Basel). 2019;10(4):270. doi:10.3390/genes10040270

255. Rezasoltani S, Asadzadeh Aghdaei H, Dabiri H, Akhavan Sepahi A, Modarressi MH, Nazemalhosseini Mojarad E. The association between fecal microbiota and different types of colorectal polyp as precursors of colorectal cancer. Microb Pathog. 2018;124:244–249. doi:10.1016/j.micpath.2018.08.035

256. Shen XJ, Rawls JF, Randall T, et al. Molecular characterization of mucosal adherent bacteria and associations with colorectal adenomas. Gut Microbes. 2010;1(3):138–147. doi:10.4161/gmic.1.3.12360

257. Dadkhah E, Sikaroodi M, Korman L, et al. Gut microbiome identifies risk for colorectal polyps. BMJ Open Gastroenterol. 2019;6(1):e000297. doi:10.1136/bmjgast-2019-000297

258. Bullman S, Pedamallu CS, Sicinska E, et al. Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer. Science. 2017;358(6369):1443–1448. doi:10.1126/science.aal5240

259. Drago L. Probiotics and colon cancer. Microorganisms. 2019;7(3):66. doi:10.3390/microorganisms7030066

260. Bassaganya-Riera J, Viladomiu M, Pedragosa M, De Simone C, Hontecillas R. Immunoregulatory mechanisms underlying prevention of colitis-associated colorectal cancer by probiotic bacteria. PLoS One. 2012;7(4):e34676. doi:10.1371/journal.pone.0034676

261. Molska M, Reguła J. Potential mechanisms of probiotics action in the prevention and treatment of colorectal cancer. Nutrients. 2019;11(10):2453. doi:10.3390/nu11102453

262. Bowen JM, Stringer AM, Gibson RJ, Yeoh AS, Hannam S, Keefe DM. VSL#3 probiotic treatment reduces chemotherapy-induced diarrhea and weight loss. Cancer Biol Ther. 2007;6(9):1449–1454. doi:10.4161/cbt.6.9.4622

263. Chang JH, Shim YY, Cha SK, Reaney MJ, Chee KM. Effect of Lactobacillus acidophilus KFRI342 on the development of chemically induced precancerous growths in the rat colon. J Med Microbiol. 2012;61(Pt 3):361–368. doi:10.1099/jmm.0.035154-0

264. Foo NP, Ou Yang H, Chiu HH, et al. Probiotics prevent the development of 1,2-dimethylhydrazine (DMH)-induced colonic tumorigenesis through suppressed colonic mucosa cellular proliferation and increased stimulation of macrophages. J Agric Food Chem. 2011;59(24):13337–13345. doi:10.1021/jf203444d

265. Zhang M, Fan X, Fang B, Zhu C, Zhu J, Ren F. Effects of Lactobacillus salivarius Ren on cancer prevention and intestinal microbiota in 1, 2-dimethylhydrazine-induced rat model. J Microbiol. 2015;53(6):398–405. doi:10.1007/s12275-015-5046-z

266. Matuskova Z, Siller M, Tunkova A, et al. Effects of Lactobacillus casei on the expression and the activity of cytochromes P450 and on the CYP mRNA level in the intestine and the liver of male rats. Neuro Endocrinol Lett. 2011;32(Suppl 1):8–14.

267. Malhotra SL. Dietary factors in a study of cancer colon from Cancer Registry, with special reference to the role of saliva, milk and fermented milk products and vegetable fibre. Med Hypotheses. 1977;3(3):122–126. doi:10.1016/0306-9877(77)90024-X

268. Peters RK, Pike MC, Garabrant D, Mack TM. Diet and colon cancer in Los Angeles County, California. Cancer Causes Control. 1992;3(5):457–473. doi:10.1007/BF00051359

269. Young TB, Wolf DA. Case-control study of proximal and distal colon cancer and diet in Wisconsin. Int J Cancer. 1988;42(2):167–175. doi:10.1002/ijc.2910420205

270. Kampman E, Giovannucci E, van ‘T Veer P, et al. Calcium, vitamin D, dairy foods, and the occurrence of colorectal adenomas among men and women in two prospective studies. Am J Epidemiol. 1994;139(1):16–29. doi:10.1093/oxfordjournals.aje.a116931

271. Kampman E, Goldbohm RA, van den Brandt PA, van ‘T Veer P. Fermented dairy products, calcium, and colorectal cancer in The Netherlands Cohort Study. Cancer Res. 1994;54(12):3186–3190.

272. Friederich P, Verschuur J, van Heumen BWH, et al. Effects of intervention with sulindac and inulin/VSL#3 on mucosal and luminal factors in the pouch of patients with familial adenomatous polyposis. Int J Colorectal Dis. 2011;26(5):575–582. doi:10.1007/s00384-010-1127-y

273. Hatakka K, Holma R, El-Nezami H, et al. The influence of Lactobacillus rhamnosus LC705 together with Propionibacterium freudenreichii ssp. shermanii JS on potentially carcinogenic bacterial activity in human colon. Int J Food Microbiol. 2008;128(2):406–410. doi:10.1016/j.ijfoodmicro.2008.09.010

274. Osterlund P, Ruotsalainen T, Korpela R, et al. Lactobacillus supplementation for diarrhoea related to chemotherapy of colorectal cancer: a randomised study. Br J Cancer. 2007;97(8):1028–1034. doi:10.1038/sj.bjc.6603990

275. Mego M, Chovanec J, Vochyanova-Andrezalova I, et al. Prevention of irinotecan induced diarrhea by probiotics: A randomized double blind, placebo controlled pilot study. Complement Ther Med. 2015;23(3):356–362. doi:10.1016/j.ctim.2015.03.008

276. Rosshart SP, Vassallo BG, Angeletti D, et al. Wild mouse gut microbiota promotes host fitness and improves disease resistance. Cell. 2017;171(5):1015–1028.e1013. doi:10.1016/j.cell.2017.09.016

277. Yu T, Guo F, Yu Y, et al. Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy. Cell. 2017;170(3):548–563.e516. doi:10.1016/j.cell.2017.07.008

278. Geller LT, Barzily-Rokni M, Danino T, et al. Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science. 2017;357(6356):1156–1160. doi:10.1126/science.aah5043

279. Lehouritis P, Cummins J, Stanton M, et al. Local bacteria affect the efficacy of chemotherapeutic drugs. Sci Rep. 2015;5(1):14554. doi:10.1038/srep14554

280. Vétizou M, Pitt JM, Daillère R, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350(6264):1079–1084. doi:10.1126/science.aad1329

281. Wallace BD, Wang H, Lane KT, et al. Alleviating cancer drug toxicity by inhibiting a bacterial enzyme. Science. 2010;330(6005):831–835. doi:10.1126/science.1191175

282. Xu Y, Villalona-Calero MA. Irinotecan: mechanisms of tumor resistance and novel strategies for modulating its activity. Ann Oncol. 2002;13(12):1841–1851. doi:10.1093/annonc/mdf337

283. Lin XB, Dieleman LA, Ketabi A, et al. Irinotecan (CPT-11) chemotherapy alters intestinal microbiota in tumour bearing rats. PLoS One. 2012;7(7):e39764. doi:10.1371/journal.pone.0039764

284. Flieger D, Klassert C, Hainke S, Keller R, Kleinschmidt R, Fischbach W. Phase II clinical trial for prevention of delayed diarrhea with cholestyramine/levofloxacin in the second-line treatment with irinotecan biweekly in patients with metastatic colorectal carcinoma. Oncology. 2007;72(1–2):10–16. doi:10.1159/000111083

285. Forsgard RA, Marrachelli VG, Korpela K, et al. Chemotherapy-induced gastrointestinal toxicity is associated with changes in serum and urine metabolome and fecal microbiota in male Sprague-Dawley rats. Cancer Chemother Pharmacol. 2017;80(2):317–332. doi:10.1007/s00280-017-3364-z

286. Shen S, Lim G, You Z, et al. Gut microbiota is critical for the induction of chemotherapy-induced pain. Nat Neurosci. 2017;20(9):1213–1216. doi:10.1038/nn.4606

287. White DL, Kanwal F, Jiao L, et al. Epidemiology of hepatocellular carcinoma. In: Carr BI, editor. Hepatocellular Carcinoma: Diagnosis and Treatment. Cham: Springer International Publishing; 2016:3–24.

288. Wu C-H, Chiu N-C, Yeh Y-C, et al. Uncommon liver tumors: case report and literature review. Medicine (Baltimore). 2016;95(39):e4952–e4952. doi:10.1097/MD.0000000000004952

289. Blonski W, Kotlyar DS, Forde KA. Non-viral causes of hepatocellular carcinoma. World J Gastroenterol. 2010;16(29):3603–3615. doi:10.3748/wjg.v16.i29.3603

290. Balogh J, Victor D 3rd, Asham EH, et al. Hepatocellular carcinoma: a review. J Hepatocell Carcinoma. 2016;3:41–53. doi:10.2147/JHC.S61146

291. Mittal S, El-Serag HB. Epidemiology of hepatocellular carcinoma: consider the population. J Clin Gastroenterol. 2013;47(Suppl):S2–S6. doi:10.1097/MCG.0b013e3182872f29

292. Sanduzzi Zamparelli M, Rocco A, Compare D, Nardone G. The gut microbiota: A new potential driving force in liver cirrhosis and hepatocellular carcinoma. United Eur Gastroenterol J. 2017;5(7):944–953. doi:10.1177/2050640617705576

293. Ohtani N. Microbiome and cancer. Semin Immunopathol. 2015;37(1):65–72. doi:10.1007/s00281-014-0457-1

294. Schnabl B, Brenner DA. Interactions between the intestinal microbiome and liver diseases. Gastroenterology. 2014;146(6):1513–1524. doi:10.1053/j.gastro.2014.01.020

295. Yu LX, Schwabe RF. The gut microbiome and liver cancer: mechanisms and clinical translation. Nat Rev Gastroenterol Hepatol. 2017;14(9):527–539. doi:10.1038/nrgastro.2017.72

296. Gupta H, Youn GS, Shin MJ, Suk KT. Role of gut microbiota in hepatocarcinogenesis. Microorganisms. 2019;7(5):121. doi:10.3390/microorganisms7050121

297. Boursier J, Diehl AM. Implication of gut microbiota in nonalcoholic fatty liver disease. PLoS Pathog. 2015;11(1):e1004559–e1004559. doi:10.1371/journal.ppat.1004559

298. Minemura M, Shimizu Y. Gut microbiota and liver diseases. World J Gastroenterol. 2015;21(6):1691–1702. doi:10.3748/wjg.v21.i6.1691

299. Brenner DA, Paik YH, Schnabl B. Role of gut microbiota in liver disease. J Clin Gastroenterol. 2015;49(Suppl 1):S25–27. doi:10.1097/MCG.0000000000000391

300. Bajaj JS, Heuman DM, Hylemon PB, et al. Altered profile of human gut microbiome is associated with cirrhosis and its complications. J Hepatol. 2014;60(5):940–947. doi:10.1016/j.jhep.2013.12.019

301. Qin N, Yang F, Li A, et al. Alterations of the human gut microbiome in liver cirrhosis. Nature. 2014;513(7516):59–64. doi:10.1038/nature13568

302. Zhang HL, Yu LX, Yang W, et al. Profound impact of gut homeostasis on chemically-induced pro-tumorigenic inflammation and hepatocarcinogenesis in rats. J Hepatol. 2012;57(4):803–812. doi:10.1016/j.jhep.2012.06.011

303. Dapito DH, Mencin A, Gwak GY, et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell. 2012;21(4):504–516. doi:10.1016/j.ccr.2012.02.007

304. Yoshimoto S, Loo TM, Atarashi K, et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature. 2013;499(7456):97–101. doi:10.1038/nature12347

305. Xie G, Wang X, Liu P, et al. Distinctly altered gut microbiota in the progression of liver disease. Oncotarget. 2016;7(15):19355–19366. doi:10.18632/oncotarget.8466

306. Yamada S, Takashina Y, Watanabe M, et al. Bile acid metabolism regulated by the gut microbiota promotes non-alcoholic steatohepatitis-associated hepatocellular carcinoma in mice. Oncotarget. 2018;9(11):9925–9939. doi:10.18632/oncotarget.24066

307. Fox JG, Feng Y, Theve EJ, et al. Gut microbes define liver cancer risk in mice exposed to chemical and viral transgenic hepatocarcinogens. Gut. 2010;59(1):88–97. doi:10.1136/gut.2009.183749

308. Huang Y, Fan XG, Wang ZM, Zhou JH, Tian XF, Li N. Identification of helicobacter species in human liver samples from patients with primary hepatocellular carcinoma. J Clin Pathol. 2004;57(12):1273–1277. doi:10.1136/jcp.2004.018556

309. Dore MP, Realdi G, Mura D, Graham DY, Sepulveda AR. Helicobacter infection in patients with HCV-related chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Dig Dis Sci. 2002;47(7):1638–1643. doi:10.1023/A:1015848009444

310. Queiroz DM, Rocha AM, Rocha GA, et al. Association between Helicobacter pylori infection and cirrhosis in patients with chronic hepatitis C virus. Dig Dis Sci. 2006;51(2):370–373. doi:10.1007/s10620-006-3150-y

311. Liu X, Liang J, Li G. Lipopolysaccharide promotes adhesion and invasion of hepatoma cell lines HepG2 and HepG2.2.15. Mol Biol Rep. 2010;37(5):2235–2239. doi:10.1007/s11033-009-9710-4

312. Lu H, Ren Z, Li A, et al. Deep sequencing reveals microbiota dysbiosis of tongue coat in patients with liver carcinoma. Sci Rep. 2016;6:33142. doi:10.1038/srep33142

313. Grat M, Wronka KM, Krasnodebski M, et al. Profile of gut microbiota associated with the presence of hepatocellular cancer in patients with liver cirrhosis. Transplant Proc. 2016;48(5):1687–1691. doi:10.1016/j.transproceed.2016.01.077

314. Ponziani FR, Bhoori S, Castelli C, et al. Hepatocellular carcinoma is associated with gut microbiota profile and inflammation in nonalcoholic fatty liver disease. Hepatology (Baltimore, Md). 2019;69(1):107–120. doi:10.1002/hep.30036

315. Wan MLY, El-Nezami H. Targeting gut microbiota in hepatocellular carcinoma: probiotics as a novel therapy. Hepatobiliary Surg Nutr. 2018;7(1):11–20. doi:10.21037/hbsn.2017.12.07

316. Kumar M, Verma V, Nagpal R, et al. Effect of probiotic fermented milk and chlorophyllin on gene expressions and genotoxicity during AFB(1)-induced hepatocellular carcinoma. Gene. 2011;490(1–2):54–59. doi:10.1016/j.gene.2011.09.003

317. Li J, Sung CY, Lee N, et al. Probiotics modulated gut microbiota suppresses hepatocellular carcinoma growth in mice. Proc Natl Acad Sci U S A. 2016;113(9):E1306–E1315. doi:10.1073/pnas.1518189113

318. Tajiri K, Shimizu Y. Gut bacteria may control development of hepatocellular carcinoma. Hepatobiliary Surg Nutr. 2017;6(6):417–419. doi:10.21037/hbsn.2017.07.05

319. El-Nezami HS, Polychronaki NN, Ma J, et al. Probiotic supplementation reduces a biomarker for increased risk of liver cancer in young men from Southern China. Am J Clin Nutr. 2006;83(5):1199–1203. doi:10.1093/ajcn/83.5.1199

320. Zhou D, Pan Q, Shen F, et al. Total fecal microbiota transplantation alleviates high-fat diet-induced steatohepatitis in mice via beneficial regulation of gut microbiota. Sci Rep. 2017;7(1):1529. doi:10.1038/s41598-017-01751-y

321. Ferrere G, Wrzosek L, Cailleux F, et al. Fecal microbiota manipulation prevents dysbiosis and alcohol-induced liver injury in mice. J Hepatol. 2017;66(4):806–815. doi:10.1016/j.jhep.2016.11.008

322. Philips CA, Pande A, Shasthry SM, et al. Healthy donor fecal microbiota transplantation in steroid-ineligible severe alcoholic hepatitis: a pilot study. Clin Gastroenterol Hepatol. 2017;15(4):600–602. doi:10.1016/j.cgh.2016.10.029

323. Ren YD, Ye ZS, Yang LZ, et al. Fecal microbiota transplantation induces hepatitis B virus e-antigen (HBeAg) clearance in patients with positive HBeAg after long-term antiviral therapy. Hepatology (Baltimore, Md). 2017;65(5):1765–1768. doi:10.1002/hep.29008

324. Bajaj JS, Kakiyama G, Savidge T, et al. Antibiotic-associated disruption of microbiota composition and function in cirrhosis is restored by fecal transplant. Hepatology (Baltimore, Md). 2018;68(4):1549–1558. doi:10.1002/hep.30037

325. Bajaj JS, Kassam Z, Fagan A, et al. Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: A randomized clinical trial. Hepatology (Baltimore, Md). 2017;66(6):1727–1738. doi:10.1002/hep.29306

326. Weledji EP, Enoworock G, Mokake M, Sinju M. How grim is pancreatic cancer? Oncol Rev. 2016;10(1):294. doi:10.4081/oncol.2016.294

327. Adamska A, Domenichini A, Falasca M. Pancreatic ductal adenocarcinoma: current and evolving therapies. Int J Mol Sci. 2017;18(7):1338. doi:10.3390/ijms18071338

328. McGuigan A, Kelly P, Turkington RC, Jones C, Coleman HG, McCain RS. Pancreatic cancer: a review of clinical diagnosis, epidemiology, treatment and outcomes. World J Gastroenterol. 2018;24(43):4846–4861. doi:10.3748/wjg.v24.i43.4846

329. Malka D, Hammel P, Maire F, et al. Risk of pancreatic adenocarcinoma in chronic pancreatitis. Gut. 2002;51(6):849–852. doi:10.1136/gut.51.6.849

330. Lowenfels AB, Maisonneuve P, Cavallini G, et al. Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N Engl J Med. 1993;328(20):1433–1437. doi:10.1056/NEJM199305203282001

331. Yadav D, Lowenfels AB. The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology. 2013;144(6):1252–1261. doi:10.1053/j.gastro.2013.01.068

332. Wang C, Li J. Pathogenic microorganisms and pancreatic cancer. Gastrointest Tumors. 2015;2(1):41–47. doi:10.1159/000380896

333. Michaud DS, Izard J. Microbiota, oral microbiome, and pancreatic cancer. Cancer J. 2014;20(3):203–206. doi:10.1097/PPO.0000000000000046

334. Wei M-Y, Shi S, Liang C, et al. The microbiota and microbiome in pancreatic cancer: more influential than expected. Mol Cancer. 2019;18(1):97. doi:10.1186/s12943-019-1008-0

335. Zambirinis CP, Pushalkar S, Saxena D, Miller G. Pancreatic cancer, inflammation, and microbiome. Cancer J. 2014;20(3):195–202. doi:10.1097/PPO.0000000000000045

336. Michaud DS. Role of bacterial infections in pancreatic cancer. Carcinogenesis. 2013;34(10):2193–2197. doi:10.1093/carcin/bgt249

337. Raderer M, Wrba F, Kornek G, et al. Association between Helicobacter pylori infection and pancreatic cancer. Oncology. 1998;55(1):16–19. doi:10.1159/000011830

338. Stolzenberg-Solomon RZ, Blaser MJ, Limburg PJ, et al. Helicobacter pylori seropositivity as a risk factor for pancreatic cancer. J Natl Cancer Inst. 2001;93(12):937–941. doi:10.1093/jnci/93.12.937

339. de Martel C, Llosa AE, Friedman GD, et al. Helicobacter pylori infection and development of pancreatic cancer. Cancer Epidemiol Biomarkers Prev. 2008;17(5):1188–1194. doi:10.1158/1055-9965.EPI-08-0185

340. Lindkvist B, Johansen D, Borgstrom A, Manjer J. A prospective study of Helicobacter pylori in relation to the risk for pancreatic cancer. BMC Cancer. 2008;8:321. doi:10.1186/1471-2407-8-321

341. Risch HA, Yu H, Lu L, Kidd MS. ABO blood group, Helicobacter pylori seropositivity, and risk of pancreatic cancer: a case-control study. J Natl Cancer Inst. 2010;102(7):502–505. doi:10.1093/jnci/djq007

342. Trikudanathan G, Philip A, Dasanu CA, Baker WL. Association between Helicobacter pylori infection and pancreatic cancer. A cumulative meta-analysis. JOP. 2011;12(1):26–31.

343. Rabelo-Gonçalves EM, Roesler BM, Zeitune JM. Extragastric manifestations of Helicobacter pylori infection: possible role of bacterium in liver and pancreas diseases. World J Hepatol. 2015;7(30):2968–2979. doi:10.4254/wjh.v7.i30.2968

344. Gravina AG, Zagari RM, De Musis C, Romano L, Loguercio C, Romano M. Helicobacter pylori and extragastric diseases: A review. World J Gastroenterol. 2018;24(29):3204–3221. doi:10.3748/wjg.v24.i29.3204

345. Bao Y, Spiegelman D, Li R, Giovannucci E, Fuchs CS, Michaud DS. History of peptic ulcer disease and pancreatic cancer risk in men. Gastroenterology. 2010;138(2):541–549. doi:10.1053/j.gastro.2009.09.059

346. Luo J, Nordenvall C, Nyren O, Adami HO, Permert J, Ye W. The risk of pancreatic cancer in patients with gastric or duodenal ulcer disease. Int J Cancer. 2007;120(2):368–372. doi:10.1002/ijc.22123

347. Manes G, Balzano A, Vaira D. Helicobacter pylori and pancreatic disease. JOP. 2003;4(3):111–116.

348. Takayama S, Takahashi H, Matsuo Y, Okada Y, Manabe T. Effects of Helicobacter pylori infection on human pancreatic cancer cell line. Hepato-Gastroenterology. 2007;54(80):2387–2391.

349. Huang H, Daniluk J, Liu Y, et al. Oncogenic K-Ras requires activation for enhanced activity. Oncogene. 2014;33(4):532–535. doi:10.1038/onc.2012.619

350. Daniluk J, Liu Y, Deng D, et al. An NF-kappaB pathway-mediated positive feedback loop amplifies Ras activity to pathological levels in mice. J Clin Invest. 2012;122(4):1519–1528. doi:10.1172/JCI59743

351. Di Magliano MP, Logsdon CD. Roles for KRAS in pancreatic tumor development and progression. Gastroenterology. 2013;144(6):1220–1229. doi:10.1053/j.gastro.2013.01.071

352. Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer. 2009;9(11):798–809. doi:10.1038/nrc2734

353. Fukuda A, Wang SC, Morris J, et al. Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression. Cancer Cell. 2011;19(4):441–455. doi:10.1016/j.ccr.2011.03.002

354. Lesina M, Kurkowski MU, Ludes K, et al. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell. 2011;19(4):456–469. doi:10.1016/j.ccr.2011.03.009

355. Hujoel PP, Drangsholt M, Spiekerman C, Weiss NS. An exploration of the periodontitis-cancer association. Ann Epidemiol. 2003;13(5):312–316. doi:10.1016/S1047-2797(02)00425-8

356. Michaud DS, Joshipura K, Giovannucci E, Fuchs CS. A prospective study of periodontal disease and pancreatic cancer in US male health professionals. J Natl Cancer Inst. 2007;99(2):171–175. doi:10.1093/jnci/djk021

357. Ahn J, Segers S, Hayes RB. Periodontal disease, Porphyromonas gingivalis serum antibody levels and orodigestive cancer mortality. Carcinogenesis. 2012;33(5):1055–1058. doi:10.1093/carcin/bgs112

358. Tribble GD, Kerr JE, Wang BY. Genetic diversity in the oral pathogen Porphyromonas gingivalis: molecular mechanisms and biological consequences. Future Microbiol. 2013;8(5):607–620. doi:10.2217/fmb.13.30

359. Michaud DS, Izard J, Wilhelm-Benartzi CS, et al. Plasma antibodies to oral bacteria and risk of pancreatic cancer in a large European prospective cohort study. Gut. 2013;62(12):1764. doi:10.1136/gutjnl-2012-303006

360. Zhang JJ, Wu HS, Wang L, Tian Y, Zhang JH, Wu HL. Expression and significance of TLR4 and HIF-1alpha in pancreatic ductal adenocarcinoma. World J Gastroenterol. 2010;16(23):2881–2888. doi:10.3748/wjg.v16.i23.2881

361. Ikebe M, Kitaura Y, Nakamura M, et al. Lipopolysaccharide (LPS) increases the invasive ability of pancreatic cancer cells through the TLR4/MyD88 signaling pathway. J Surg Oncol. 2009;100(8):725–731. doi:10.1002/jso.21392

362. Ochi A, Nguyen AH, Bedrosian AS, et al. MyD88 inhibition amplifies dendritic cell capacity to promote pancreatic carcinogenesis via Th2 cells. J Exp Med. 2012;209(9):1671–1687. doi:10.1084/jem.20111706

363. Zhang H, Sun L. When human cells meet bacteria: precision medicine for cancers using the microbiota. Am J Cancer Res. 2018;8(7):1157–1175.

364. Mitsuhashi K, Nosho K, Sukawa Y, et al. Association of Fusobacterium species in pancreatic cancer tissues with molecular features and prognosis. Oncotarget. 2015;6(9):7209–7220. doi:10.18632/oncotarget.3109

365. Gaida MM, Mayer C, Dapunt U, et al. Expression of the bitter receptor T2R38 in pancreatic cancer: localization in lipid droplets and activation by a bacteria-derived quorum-sensing molecule. Oncotarget. 2016;7(11):12623–12632. doi:10.18632/oncotarget.7206

366. Pushalkar S, Hundeyin M, Daley D, et al. The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression. Cancer Discov. 2018;8(4):403–416. doi:10.1158/2159-8290.CD-17-1134

367. Singhal B, Mukherjee A, Srivastav S. Role of probiotics in pancreatic cancer prevention: the prospects and challenges. Adv Biosci Biotechnol. 2016;07(11):33. doi:10.4236/abb.2016.711045

368. Olah A, Belagyi T, Poto L, Romics L Jr., Bengmark S. Synbiotic control of inflammation and infection in severe acute pancreatitis: a prospective, randomized, double blind study. Hepato-gastroenterology. 2007;54(74):590–594.

369. Olah A, Romics L Jr. Early enteral nutrition in acute pancreatitis–benefits and limitations. Langenbecks Arch Surg. 2008;393(3):261–269. doi:10.1007/s00423-008-0291-9

370. Marsh Rde W, Alonzo M, Bajaj S, et al. Comprehensive review of the diagnosis and treatment of biliary tract cancer 2012. Part I: diagnosis-clinical staging and pathology. J Surg Oncol. 2012;106(3):332–338. doi:10.1002/jso.23028

371. Rakic M, Patrlj L, Kopljar M, et al. Gallbladder cancer. Hepatobiliary Surg Nutr. 2014;3(5):221–226. doi:10.3978/j.issn.2304-3881.2014.09.03

372. Andia ME, Hsing AW, Andreotti G, Ferreccio C. Geographic variation of gallbladder cancer mortality and risk factors in Chile: a population-based ecologic study. Int J Cancer. 2008;123(6):1411–1416. doi:10.1002/ijc.23662

373. Zhou D, Wang J-D, Weng M-Z, et al. Infections of Helicobacter spp. in the biliary system are associated with biliary tract cancer: a meta-analysis. Eur J Gastroenterol Hepatol. 2013;25(4):447–454. doi:10.1097/MEG.0b013e32835c0362

374. Hundal R, Shaffer EA. Gallbladder cancer: epidemiology and outcome. Clin Epidemiol. 2014;6:99–109. doi:10.2147/CLEP.S37357

375. Rustagi T, Dasanu CA. Risk factors for gallbladder cancer and cholangiocarcinoma: similarities, differences and updates. J Gastrointest Cancer. 2012;43(2):137–147. doi:10.1007/s12029-011-9284-y

376. Walawalkar YD, Gaind R, Nayak V. Study on Salmonella Typhi occurrence in gallbladder of patients suffering from chronic cholelithiasis-a predisposing factor for carcinoma of gallbladder. Diagn Microbiol Infect Dis. 2013;77(1):69–73. doi:10.1016/j.diagmicrobio.2013.05.014

377. Nagaraja V, Eslick GD. Systematic review with meta-analysis: the relationship between chronic Salmonella typhi carrier status and gall-bladder cancer. Aliment Pharmacol Ther. 2014;39(8):745–750. doi:10.1111/apt.12655

378. de Martel C, Plummer M, Parsonnet J, van Doorn LJ, Franceschi S. Helicobacter species in cancers of the gallbladder and extrahepatic biliary tract. Br J Cancer. 2009;100(1):194–199. doi:10.1038/sj.bjc.6604780

379. Pandey M, Mishra RR, Dixit R, Jaiswal R, Shukla M, Nath G. Helicobacter bilis in human gallbladder cancer: results of a case-control study and a meta-analysis. Asian Pac J Cancer Prev. 2010;11(2):343–347.

380. Yakoob J, Khan MR, Abbas Z, et al. Helicobacter pylori: association with gall bladder disorders in Pakistan. Br J Biomed Sci. 2011;68(2):59–64. doi:10.1080/09674845.2011.11730324

381. Tsuchiya Y, Loza E, Villa-Gomez G, et al. Metagenomics of microbial communities in gallbladder bile from patients with gallbladder cancer or cholelithiasis. Asian Pac J Cancer Prev. 2018;19(4):961–967. doi:10.22034/APJCP.2018.19.4.961

382. Ruby T, McLaughlin L, Gopinath S, Monack D. Salmonella’s long-term relationship with its host. FEMS Microbiol Rev. 2012;36(3):600–615. doi:10.1111/j.1574-6976.2012.00332.x

383. Koshiol J, Wozniak A, Cook P, et al. Salmonella enterica serovar Typhi and gallbladder cancer: a case-control study and meta-analysis. Cancer Med. 2016;5(11):3235–3310. doi:10.1002/cam4.915

384. Gunn JS, Marshall JM, Baker S, Dongol S, Charles RC, Ryan ET. Salmonella chronic carriage: epidemiology, diagnosis, and gallbladder persistence. Trends Microbiol. 2014;22(11):648–655. doi:10.1016/j.tim.2014.06.007

385. Caygill CP, Hill MJ, Braddick M, Sharp JC. Cancer mortality in chronic typhoid and paratyphoid carriers. Lancet (London, England). 1994;343(8889):83–84. doi:10.1016/S0140-6736(94)90816-8

386. Shukla VK, Singh H, Pandey M, Upadhyay SK, Nath G. Carcinoma of the gallbladder–is it a sequel of typhoid? Dig Dis Sci. 2000;45(5):900–903. doi:10.1023/A:1005564822630

387. Crawford RW, Rosales-Reyes R, Ramirez-Aguilar Mde L, Chapa-Azuela O, Alpuche-Aranda C, Gunn JS. Gallstones play a significant role in Salmonella spp. gallbladder colonization and carriage. Proc Natl Acad Sci U S A. 2010;107(9):4353–4358. doi:10.1073/pnas.1000862107

388. Prouty AM, Schwesinger WH, Gunn JS. Biofilm formation and interaction with the surfaces of gallstones by Salmonella spp. Infect Immun. 2002;70(5):2640–2649. doi:10.1128/IAI.70.5.2640-2649.2002

389. Crawford RW, Gibson DL, Kay WW, Gunn JS. Identification of a bile-induced exopolysaccharide required for Salmonella biofilm formation on gallstone surfaces. Infect Immun. 2008;76(11):5341–5349. doi:10.1128/IAI.00786-08

390. Gonzalez-Escobedo G, Gunn JS. Gallbladder epithelium as a niche for chronic salmonella carriage. Infect Immun. 2013;81(8):2920.

391. Scanu T, Spaapen RM, Bakker JM, et al. Salmonella manipulation of host signaling pathways provokes cellular transformation associated with gallbladder carcinoma. Cell Host Microbe. 2015;17(6):763–774. doi:10.1016/j.chom.2015.05.002

392. Kinoshita H, Nagata E, Hirohashi K, Sakai K, Kobayashi Y. Carcinoma of the gallbladder with an anomalous connection between the choledochus and the pancreatic duct. Report of 10 cases and review of the literature in Japan. Cancer. 1984;54(4):762–769. doi:10.1002/1097-0142(1984)54:4<762::AID-CNCR2820540429>3.0.CO;2-K

393. Sharma V, Chauhan VS, Nath G, Kumar A, Shukla VK. Role of bile bacteria in gallbladder carcinoma. Hepato-Gastroenterology. 2007;54(78):1622–1625.

394. Belzer C, Kusters JG, Kuipers EJ, van Vliet AH. Urease induced calcium precipitation by Helicobacter species may initiate gallstone formation. Gut. 2006;55(11):1678–1679. doi:10.1136/gut.2006.098319

395. Jergens AE, Wilson-Welder JH, Dorn A, et al. Helicobacter bilis triggers persistent immune reactivity to antigens derived from the commensal bacteria in gnotobiotic C3H/HeN mice. Gut. 2007;56(7):934–940. doi:10.1136/gut.2006.099242

396. Apostolov E, Al-soud WA, Nilsson I, et al. Helicobacter pylori and other Helicobacter species in gallbladder and liver of patients with chronic cholecystitis detected by immunological and molecular methods. Scand J Gastroenterol. 2005;40(1):96–102. doi:10.1080/00365520410009546

397. Kobayashi T, Harada K, Miwa K, Nakanuma Y. Helicobacter genus DNA fragments are commonly detectable in bile from patients with extrahepatic biliary diseases and associated with their pathogenesis. Dig Dis Sci. 2005;50(5):862–867. doi:10.1007/s10620-005-2654-1

398. Kosaka T, Tajima Y, Kuroki T, et al. Helicobacter bilis colonization of the biliary system in patients with pancreaticobiliary maljunction. BJS. 2010;97(4):544–549. doi:10.1002/bjs.6907

399. Parajuli S, Koirala U. Incidence of Helicobacter hepaticus and its relation to gallbladder carcinoma. J Pathol Nepal. 2011;1(2):122–125. doi:10.3126/jpn.v1i2.5406

400. Murata H, Tsuji S, Tsujii M, et al. Helicobacter bilis infection in biliary tract cancer. Aliment Pharmacol Ther. 2004;20(s1):90–94. doi:10.1111/j.1365-2036.2004.01972.x

401. Fallone CA, Tran S, Semret M, Discepola F, Behr M, Barkun AN. Helicobacter DNA in bile: correlation with hepato-biliary diseases. Aliment Pharmacol Ther. 2003;17(3):453–458. doi:10.1046/j.1365-2036.2003.01424.x

402. Wang DN, Ding WJ, Pan YZ, et al. The Helicobacter pylori L-form: formation and isolation in the human bile cultures in vitro and in the gallbladders of patients with biliary diseases. Helicobacter. 2015;20(2):98–105. doi:10.1111/hel.12181

403. Kumar S, Kumar S, Kumar S. Infection as a risk factor for gallbladder cancer. J Surg Oncol. 2006;93(8):633–639. doi:10.1002/jso.20530

404. Csendes A, Becerra M, Burdiles P, Demian I, Bancalari K, Csendes P. Bacteriological studies of bile from the gallbladder in patients with carcinoma of the gallbladder, cholelithiasis, common bile duct stones and no gallstones disease. Eur J Surg. 1994;160(6–7):363–367.

405. Roa I, Ibacache G, Carvallo J, et al. Estudio bacteriológico de la bilisvesicular en un área de alto riesgode cáncer vesicular [Microbiological study of gallbladder bile in a high risk zone for gallbladder cancer]. Rev Med Chil. 1999;127(9):1049–1055. Spanish.

406. Gagnaire A, Nadel B, Raoult D, Neefjes J, Gorvel JP. Collateral damage: insights into bacterial mechanisms that predispose host cells to cancer. Nat Rev Microbiol. 2017;15(2):109–128. doi:10.1038/nrmicro.2016.171

407. Nomura A, Stemmermann GN, Chyou PH, Kato I, Perez-Perez GI, Blaser MJ. Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. N Engl J Med. 1991;325(16):1132–1136. doi:10.1056/NEJM199110173251604

408. Abdulamir AS, Hafidh RR, Bakar FA. Molecular detection, quantification, and isolation of Streptococcus gallolyticus bacteria colonizing colorectal tumors: inflammation-driven potential of carcinogenesis via IL-1, COX-2, and IL-8. Mol Cancer. 2010;9:249. doi:10.1186/1476-4598-9-249

409. Canducci F, Armuzzi A, Cremonini F, et al. A lyophilized and inactivated culture of Lactobacillus acidophilus increases Helicobacter pylori eradication rates. Aliment Pharmacol Ther. 2000;14(12):1625–1629. doi:10.1046/j.1365-2036.2000.00885.x

410. Sheu BS, Wu JJ, Lo CY, et al. Impact of supplement with Lactobacillus- and Bifidobacterium-containing yogurt on triple therapy for Helicobacter pylori eradication. Aliment Pharmacol Ther. 2002;16(9):1669–1675. doi:10.1046/j.1365-2036.2002.01335.x

411. Sheu BS, Cheng HC, Kao AW, et al. Pretreatment with Lactobacillus- and Bifidobacterium-containing yogurt can improve the efficacy of quadruple therapy in eradicating residual Helicobacter pylori infection after failed triple therapy. Am J Clin Nutr. 2006;83(4):864–869. doi:10.1093/ajcn/83.4.864

412. Sykora J, Valeckova K, Amlerova J, et al. Effects of a specially designed fermented milk product containing probiotic Lactobacillus casei DN-114 001 and the eradication of H. pylori in children: a prospective randomized double-blind study. J Clin Gastroenterol. 2005;39(8):692–698. doi:10.1097/01.mcg.0000173855.77191.44

413. Ojetti V, Bruno G, Ainora ME, et al. Impact of lactobacillus reuteri supplementation on anti-helicobacter pylori levofloxacin-based second-line therapy. Gastroenterol Res Pract. 2012;2012:740381. doi:10.1155/2012/740381

414. Lionetti E, Miniello VL, Castellaneta SP, et al. Lactobacillus reuteri therapy to reduce side-effects during anti-Helicobacter pylori treatment in children: a randomized placebo controlled trial. Aliment Pharmacol Ther. 2006;24(10):1461–1468. doi:10.1111/j.1365-2036.2006.03145.x

415. Ohara T, Yoshino K, Kitajima M. Possibility of preventing colorectal carcinogenesis with probiotics. Hepato-Gastroenterology. 2010;57(104):1411–1415.

Creative Commons License © 2020 The Author(s). This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.