Introduction

Cancer has remained a serious concern in human society worldwide.Carcinogenesis is a well-known multi-factorial process,involving genetic and environmental perturbations.15.4%–17.8%of cancers since 1990 were estimated to be related to infections,which accounted for 21.0%–26.3%and 5.0–9.0%of the cases in developing and developed countries, respectively [1–4]. Nonetheless, among the 3.7×1030 microorganisms on the earth,only a few have been defined as carcinogenic agents by the International Agency for Research on Cancer(IARC).These include Helicobacter pylori,hepatitis B virus,hepatitis C virus,HIV type 1,human papillomavirus,Epstein-Barr virus,human herpesvirus type 8,human T-cell lymphotropic virus type 1,Opisthorchis viverrini,Clonorchis sinensis,and Schistosoma haematobium [4]. Although humans are colonized by trillions of microbes in general,only some individuals suffer from cancers.Therefore, the host,microbiota,and many other risk-driving factors are believed to be collectively responsible for the process of carcinogenesis[5].

The human gut is perhaps one of the most complex networks in the body and is colonized by trillions of microorganisms including bacteria,archaea,fungi,protists,and viruses,among which bacteria are the major inhabitants[6].For decades,researchers have been trying to understand the complex relationships between the human microbiota and diseases.Mounting evidence has suggested that the gut microbiota are related to a variety of cancers,which may enlighten potential development of cancer therapies targeted at the gut microbiome [5,7].This review provides a comprehensive survey of the studies on the human gut microbiota and GI cancers,specifically esophageal, gastric, colorectal, liver, and pancreatic cancers.

During the last 30 years,gene-based and cultureindependent methods for microbial profiling,e.g.,16S rRNA sequencing,have made remarkable progress[8,9]and have been used to differentiate and quantitatively evaluate various bacterial species as the method of choice[10].High-throughput sequencing technologies,such as next-generation sequencing and random shotgun sequencing,as well as omics-based approaches,have enabled a more comprehensive examination of microbial communities without cultivation [11].Specially,TruSeq,a synthetic long-read sequencing technology,allows researchers to assemble whole microbial genomes more completely[12].Big data generated with these new sequencing technologies have been accurately analyzed using advanced computational strategies,such as genome assembly and genefinding software,statistical modeling and simulations,and gene annotation tools.The flourishing advancements in computation and sequencing technologies have signi ficantly promoted the development of the entire field of human microbiology.

It is now known that Actinobacteria,Firmicutes,Bacteroidetes,and Proteobacteria phyla are predominant in the human stomach,whereas Proteobacteria,Firmicutes,and Bacteroidetes phyla are frequently found in the colon tract[13].Symbiotic gut microbiota have been characterized by high diversity,stability,resistance,and resilience,whereas dysbiotic gut microbiota exhibit low relative abundance as well as loss of commensalism and diversity.

Various studies have demonstrated that the carcinogenicity is mainly attributed to microbial dysbiosis(Table 1).(1)Chronic inflammation:Chronic inflammation has been verified as a driving cause of cancer.Inflammation promotes tumor progression and accelerates the invasion and metastasis.Inflammatory cytokines directly lead to DNA damage in the epithelium.Aberrant DNA methylation triggers inflammation-associated cancers[14].Increased interleukin-1,6,10,and tumor necrosis factorα (TNF-α)levels will initiate the process of cancer development,followed by three steps.These include(I)the activation of nuclear factor kappa-light-chain-enhancer of activated B cells(NF-κB),Wnt signaling and mitogenactivated protein kinases(MAPK)pathway,(II)the inhibition of apoptosis,and(III)a boost in oxidative stress[15].IL-6 and IL-11 can sensitize signal transducer and activator of transcription 3(STAT3),which exerts a significant impact on transforming epithelial cells[16].βcatenin,forming complexes with adenomatous polyposis coli(APC),glycogen synthase kinase(GSK)3β,and axin,can cause aberrations in the Wnt pathway in epithelial cells,thus activating proto-oncogenes encoding c-myc and cyclin D1[17,18].The generation of inflammationassociated factors can also inactivate tumor-suppressor genes(e.g.,P53 mutation),and activate oncogenes(e.g.,KRAS mutation)[19,20].(2)Immune regulation:Dysbiosis of the gut microbiota triggers a number of innate and adaptive immune responses involved in the tumor formation process[21–23].The innate immune system can recognize the structural components of bacteria,such as flagellin, lipopolysaccharide (LPS), and peptidoglycan[23,24].Toll-like receptors(TLRs)play a critical role in the innate immune system given their ability in distinguishing microbial molecules from host molecules.Nodlike receptors(NLRs)also regulate the innate immune response,correspondingly modulating microbial composition and activating in flammasome-mediated dysbiosis.Additionally,T helper(Th)cells,T regulatory(Treg)cells,and B cells,which collectively secrete immunoglobulin A(IgA),participate in tumorigenesis through the adaptive immune system [22].(3)Microbial metabolites:Lipoteichoic acid(LTA),secondary bile acids,and short chain fatty acids(SCFAs)have dual roles in carcinogenesis[25].LTA speci fically binds to cluster of differentiation 14(CD14)or TLR2,causing excessive secretion of proinflammatory factors[26,27].Secondary bile acids activate G protein-coupled bile acid receptor 1(GPBAR1),which increases intestinal cell proliferation[28],promotes DNA damage[29],and induces cellular senescence,leading to a senescence-associated secretory phenotype [30].These aforementioned microbial metabolites advance malignant transformation.On the contrary,SCFAs are able to mediate immunoregulation through Tregs, therefore exhibiting anti-inflammatory and anti-carcinogenic effects[31–33].

Chronic inflammation produces considerable inflammatory mediators,such as TNFα,IL6,IL1b,and other cytokines,which activate NF-κB,leading to colon carcinogenesis[91].Inflammatory bowel diseases(IBDs)link to a higher risk of CRC.For instance,patients with pancolitis have a more serious risk to develop cancer compared to patients with limited colitis[92].Gut microbiota of IBD patients have less diversity and dysbiosis,characterized with lower abundance of Firmicutes and Bacteroidetes,compared with healthy subjects[93].Enterotoxigenic Bacteroides fragilis(ETBF)exhibits a signif icant correlation with the presence of active IBD[94,95].Both IBD and CRC share a common process with an increase in the levels of transforming growth factor-beta(TGF-β),TNFα,NF-κB,ROS,and other signaling molecules,leading to microbial dysbiosis in the intestinal tract[96].It has been demonstrated that patients with CRC accompanied by IBD have a worse prognosis than those without IBD only[97].

Gut microbiota and gastric cancer

H.pylori

Gastric cancer is considered as an inflammation-associated cancer.Known as a Class I risk factor,infection by H.pylori can stimulate immune responses and inflammation,regulate many signaling pathways,and induce achlorhydria,epithelial atrophy,and dysplasia.Therefore,effective eradication of H.pylori could prevent gastric cancer[34].

Oncoproteins cytotoxin-associated gene A(CagA)and vacuolating toxin A(VacA)are critical virulence factors of H.pylori[35].Cag+strain infections present a highly increased risk of gastric cancers[36,37].Elevated accumulation of inflammatory cytokines is found in the stomach of H.pylori-infected individuals,which include interferon-γ,TNF-α,IL-1,IL1β,IL-6,IL-7,IL-8,IL-10,and IL-18.Consequently,diverse types of immune cells are stimulated,encompassing lymphocytes, peripheral mononuclear cells,eosinophils,macrophages,neutrophils,mast cells,and dendritic cells.The activity of oncogenic pathways containing ERK/MAPK,PI3K/Akt,NF-κB,Wnt/β-catenin,Ras,sonic hedgehog,as well as STAT3 is upregulated with the infection of Cag+H.pylori strains.Conversely,tumor suppressor pathways are inactivated with induced P53 mutations[38–40].

VacA can cause cell vacuolation[41–43]and induce autophagy within human-derived gastric epithelial cells[44,45],by acting directly on mitochondria[46–48],upregulating MAP kinase and ERK1/2 expression [49],activating vascular endothelial growth factor[50,51],upregulating Wnt/β-catenin signaling pathway which is essential for cell growth and differentiation[52],and inhibiting GSK3 via the PI3K/Akt signaling pathway[53].

Furthermore,H.pylori infection can cause methylations on CpG islands of E-cadherin[54]and tumor-suppressor genes,including those encoding the trefoil factor 2(TFF2)and a forkhead box transcriptional regulator(FOXD3),resulting in the significantly increased risk of adenocarcinoma in the stomach[55].

Non-H.pylori microbiota

Current sequencing technologies allow researchers to dive deeply into the complexity of gut microbiota,which may be influenced by multiple factors[56].Microbial community in H.pylori-positive individuals is characterized by an increase in the counts of Proteobacteria,Spirochaetes,and Acidobacteria,as well as a decrease in the counts of Actinobacteria,Bacteroidetes,and Firmicutes [57].Conversely,H.pylorinegative individuals carry more abundant phyla of Firmicutes,Bacteroidetes,and Actinobacteria[58].Microbial dysbiosis is also associated with gastric carcinogenesis[59].Using quantitative PCR,it has been shown that gastric cancer patients bear a much diversified composition of microbiota,exemplified by the reduction of Porphyromonas,Neisseria,the TM7 group,Prevotella pallens,Streptococcus sinensis,and simultaneous enrichment of Lactobacillus coleohominis,Klebsiella pneumoniae,Acinetobacter baumannii,and Lachnospiraceae[60–62].Pathogenic components derived from Helicobacter species other than H.pylori,such as the outer membrane proteins phospholipase C-gamma 2,BAK protein,and nickel-binding proteins,assist microbes with colonization in the mucosal layer of the gastric tract and then promote the process of gastritis,ultimately enhancing the possibility of tumorigenesis in the stomach[56].To precisely elucidate the correlations between the microbial dynamics and pathogenesis of gastric cancer,further functional and mechanistic studies are needed.

Gut microbiota and esophageal cancer

Esophageal cancer(EC)is subdivided histologically into two major groups:esophageal squamous cell carcinoma(ESCC)and esophageal adenocarcinoma(EAC).It has been reported that the upper aerodigestive tract carcinomas are closely associated with common potential risk factors,such as infections from the human papilloma[61,63,64]and Epstein-Barr viruses,although the pathogenic mechanism(s)remain controversial[65].In addition to viruses,bacterial infections also contribute to the formation of esophageal malignant neoplasms.

高校学历继续教育的对象是在职人员，他们的学习需求与学习特征基本一致，高校必须明确学历继续教育人才培养的方向，正确树立学历继续教育观，积极建立人才培养新模式，并改进教学与学习评价方法，注意提高学员的实践能力，培养更多优秀的应用型人才，全面提升学历继续教育人才培养的质量，从而满足市场与社会对人才的需求，为继续教育和经济社会的可持续发展提供可靠支撑。

H.pylori constitutes a decreased risk of EC

In the last 20 years,the incidence rate of EAC has shown a tendency of reduction in the general population infected with H.pylori,especially in Eastern populations.In the meantime,the incidence of ESCC has also diminished[66].Gastroesophageal reflux disease(GERD)is a leading cause of Barrett’s esophagus,a premalignant condition of EAC[67].By inhibiting parietal cell function and/or inducing the development of atrophic gastritis,chronic H.pylori infections can restrain parietal cells from secreting hydrochloric acid,thus increasing the pH in the gastric tract and eventually leading to a reduction of EAC.There is a higher relative abundance of Enterobacteriaceae in the stomach of patients with oesophagitis and Barrett’s esophagus compared to normal populations.It has been suggested that antibiotics may alter the microbiome in the esophagus of patients with GERD[68].Gut microbiota colonized in the esophagus and stomach are notably altered by treatment with proton pump inhibitors(PPIs).However,it is not conclusive whether the changes caused by PPIs are beneficial or not[69].The latest systematic review and meta-analysis show that PPIs do not decrease the development of dysplasia and Barrett’s esophagus-related EAC[70].

限制性喷嘴在压力增加过程到某一临界范围后，气体速度随着气体压力的变化显得不明显。由此相关研究人员通过对限制型喷嘴的结构改进，这就是目前使用最为广泛的紧耦合雾化法。原理是缩短喷嘴出气口和液流间的距离，合理利用气体动能达到高效破碎目的。依据是增加气体动能的传输效率。紧耦合雾化法由于气体动能传输效率高，可以将熔体直接雾化成熔滴，其熔体冷却速度≥105K/s，粉末平均粒度≤50μm。[13]该技术最早实际生产应用在英国PSI公司。

Other gut microbiota and EC

The esophagus is traditionally considered as a microbe-free site,with limited microbial passengers coming from swallowing and gastroesophageal reflux.By applying 16S rRNA sequencing technology,some specific microbes were found to populate the esophageal mucosa,including Firmicutes,Bacteroidetes,Proteobacteria,Actinobacteria,and Fusobacteria phyla.Moreover,distinct microbial communities were found in esophagus of individuals with ESCC(stage I–II)and esophageal squamous dysplasia(ESD),compared to normal esophagus[71].Consistent with the normal gastric mucosa microbiota,the most common phyla in the samples of early ESCC and ESD are Proteobacteria,Firmicutes,and Bacteroidetes[71],which are involved in the tumorigenic process in the esophagus when esophageal microbiota are dysbiotic[65,72].It has been found that the human distal esophagus has its own characteristic microbiota.Gram-positive bacteria,including Firmicutes and Streptococcus were dominant in the normal esophagus,while gram-negative anaerobes/microaerophiles,such as Bacteroidetes,Proteobacteria,Fusobacteria,and Spirochaetes,were mainly associated with esophagitis and Barrett’s esophagus[73].LPS,an important component of gram-negative bacterial cell wall,participates in the oncogenic process through multiple mechanisms.These include activating innate immune responses that lead to NF-κB activation[74],promoting the release of inflammation-associated mediators including IL1β,IL6,IL8,and TNFα [75],raising the levels of inducible nitric oxide synthase(iNOS)and nitric oxide(NO),increasing the risk of reflux through relaxing lower esophageal sphincter,and delaying gastric emptying[76].

Gut microbiota and colorectal cancer

The gut microbiome in the large intestinal tract is the most complicated community in the human body.The bacterial population primarily comprises gram-positive Firmicutes,and gram-negative Bacteroidetes and Proteobacteria.

Diet,microbial metabolites,and colorectal cancer

Various factors contribute to colorectal cancer(CRC)and diet is a well-known and important environmental factor associated with CRC.Many different gut microbiota metabolites have either tumorigenic or anti-tumorigenic characteristics.

Celecoxib is a selective COX2 inhibitor that alters the gastrointestinal microbial community as well as downregulates the polyp load in the gut.A recent study has found that celecoxib treatment significantly reduces the burden of polyps in a mouse model.In addition,the gut microbial community is characterized by decreased populations of Lactobacillaceae and Bifidobacteriaceae species,and an increased population of Coriobacteriaceae species.A metabolomics analysis shows that celecoxib treatment reduces the formation of pathogenic microbial products and thus inhibits cell proliferation[228].

Chronic inflammation and CRC

张弓《现代汉语修辞学》也将借代(书中叫“代替”,还说也叫“换名”)分为两大类:对代和随代。对代包括八类:实代虚,虚代实,果代因,因代果,局部代全体,全体代局部,泛称代特称,特称代泛称。随代,就是借从属物以代替本体,分为四类:以特征代本体,以特征的喻体代本体(可以看成比喻兼借代),以标识代本体,以所在地代事物本体。[注] 张弓:《现代汉语修辞学》,石家庄:河北教育出版社,1993年,第97-101页。

Toxins secreted by B.fragilis can result in tumorigenesis in the large intestine by stimulating E-cadherin,β-catenin,NF-κB,and STAT3[98,99].For instance,fragilysin,an enterotoxin secreted by B.fragilis,stimulates expression of IL-8,TGFβ,C5a,leukotriene 4(LTB4),and growth related oncogene-α (GRO-α),resulting in an inflammatory environment[100].Moreover,fragilysin induces proliferation of colonic epithelial cells and the expression of the oncogene c-myc[101].Adenomatous polyps or adenomas are considered premalignant for CRC.The diversity,relative abundance,and distribution of the gut microbiota in adenoma populations are significantly different from those in healthy populations[102].Patients with colorectal adenomas harbor significantly more Proteobacteria as well as less Bacteroidetes compared with healthy controls.The bacteria adherent to the colorectal mucus layer form a particular biofilm and intervene in the formation of adenomatous polyps in the colon[103].Dysbiosis of the gut microbiota can thus promote the process of tumor formation in the large intestine tract[104–106].

Fusobacterium adhesin A(FadA),a cell surface virulence factor expressed by Fusobacterium,is frequently detected in patients with adenomatous polyp or CRC.FadA interacts with E-cadherin on the endothelium and modulates the E-cadherin/β-catenin pathway,resulting in an increased expression of transcription factors,oncogenes,and inflammatory genes.It also promotes Fusobacterium to adhere to and invade E-cadherin-expressing cells,thereby,directly influencing epithelial cell proliferation and growth[107–109].A recent report has indicated that the overall abundance of Fusobacterium in CRC tissues is over 400 times higher than that in the adjacent normal tissues[110].Therefore,FadA may be a potential biomarker for the diagnosis and therapy of CRC.

Immune regulation and CRC

Upon interacting with microorganisms and their gene products,dendritic cells become activated,switching on the gut immune response[111].The host innate immune system can recognize microbial molecules,including LPS,flagellin,peptidoglycans,and other microbe-associated molecular patterns(MAMPs).The activation of pattern recognition receptors,for instance,NLRs and TLRs,regulates inflammatory pathways and the proliferation of multiple cell types[112–114].NLR-mediated inflammasome activation and enhanced TLR2 expression play a protective role in maintaining the complete structure and function of colonic epithelium by suppressing the inflammatory environment[115–117].

TLRs are confirmed to recognize diverse molecules from microbes and promote tumorigenesis[118].Protein levels of TLR2,4,7,8,and 9 are increased in CRC tumor tissues compared to those in the healthy surrounding tissues[119].Overexpression of TLR4 results in the activation of β-catenin and increased colitis-associated cancer development,whereas the inhibition of TLR4 expression is shown to protect against CRC[118].

In a meta-analysis of microarray studies,a significant difference in the NLR signaling pathways between tumor tissue and non-tumor tissue of patients with CRC has been observed[114,120].The nucleotide-binding oligomerization domaincontaining protein 1(Nod1),an innate immune receptor and a NLR,recognizes microbial molecules,then initiates immune responses,and inhibits the tumorigenic process.In contrast,Nod1 deficiency increases intestinal permeability,leading to colitis-associated cancers[121].

采用SPSS 16.0软件对数据进行分析处理，计量资料以（均数±标准差）表示，采用t检验；计数资料以（n，%）表示，采用χ2检验，以P＜0.05表示差异具有统计学意义。

Gut microbiota dysbiosis and genetic instability

The diversity and abundance of beneficial commensals could be minimized,if gut microbiota remain at the dysbiotic state.Once the disturbed microbes overgrow,they give rise to accumulating exotoxins and endotoxins,such as cytolethal distending toxin and colibactin from Escherichia coli,cytolethal distending toxin from Shigella dysenteriae,B.fragilis toxin from B.fragilis,extracellular superoxide,and hydrogen peroxide from Enterococcus faecalis,etc.These bacterial toxins are able to directly or indirectly induce DNA damage,genomic instability,tumorigenesis,and the invasion of adenocarcinomas[122–130].Additionally,dysbiosis results in increased the exposure of colonic epithelial cells to carcinogens[131].The accumulation of unrepaired DNA and base excision repair(BER)intermediates leads to genomic instability and ultimately carcinogenesis[132,133].Furthermore,microbial dysbiosis can dysregulate the immune response and increase inflammation,resulting in PIK3CA mutations,which may accelerate the initiation and/or growth of rectal cancers[134].

一是强化在评标阶段对虚假材料的甄别。二是坚持增加竞标活动的透明度，同时防范恶意质疑和投诉。三是统一供应商违规行为处罚政策，加大处罚力度。对虚假应标的处罚，监管部门应严格按《中华人民共和国政府采购法》第十三条、第七十七条(一)规定，处以罚款，并列入不良行为记录名单，一至三年内禁止参加政府采购活动。四是推出供应商违规行为的赔偿政策，打击供应商侥幸心理，调动政府采购各参与方追究违规供应商行为的积极性。

Gut microbe and epithelial-to-mesenchymal transition

Microbes induce epithelial-to-mesenchymal transitions(EMT)through various signaling pathways,such as TGFβ,Wnt,and Notch,which work together with the transcription factors(TFs)Slug,SNAIL,Twist,ZEB1,and ZEB2 to suppress E-cadherin,leading to tumor invasion,metastasis,and acquired drug resistance[135–137].It is worth noting that the cells undergoing EMT are claimed to obtain stem cell-like properties and thus constitute a cancer stem cell(CSC)population[138,139].

全国家用电器工业信息中心（NAIC）隶属于中国轻工业信息中心，是面向全国家用电器行业服务的专业信息机构，其前身为全国家用电器工业科技情报站。

Gut microbiota and liver cancer

Although liver is generally considered sterile,the hepatic environment is greatly influenced by the pathogens or metabolites produced by the microbiota in the GI tract through the hepatic portal venous system[140].Liver exerts an essential effect on the host microbial community by filtering the blood stream as well as metabolizing and neutralizing toxins derived from intestinal microbes.Gut microbial dysbiosis contributes to hepatocarcinogenesis because the microbiota and microbial metabolites are detected by liver resident immune cells and are able to modify hepatic metabolism[140].

Hepatocellular carcinoma(HCC)and cholangiocarcinoma(CCA)are the most common histological types of liver cancer.Alcoholic liver disease(ALD),non-alcoholic fatty liver disease(NAFLD),as well as infections with foodborne contaminant aflatoxin B1(AFB1),hepatitis B or C virus[141]are considered as the major risk factors for HCC[142,143].Of note,dysbiosis of the gut microbiota is one of the key inducers for nonalcoholic fatty liver disease[144,145].The abundance of E.coli in feces from patients with HCC is much higher than that in feces from healthy controls[146],while Dietziaceae,Pseudomonadaceae,and Oxalobacteraceae are more abundant in the bile duct samples from patients with CCA than samples from non-CCA individuals.It has been hypothesized that excessive microbial growth in the gut may promote liver cancer development[147],which needs to be further explored.

H.pylori and liver cancer

H.pylori generally inhabits the human stomach[148,149].However,H.pylori from the gut can reach the liver tissue[150]through the blood stream of the portal vein[151,152]after surviving phagocytic elimination,or by reverse migration via the duodenum.VacA and CagA produced by H.pylori have been found in liver tissues with HCC[153,154].It has been shown that LPS from H.pylori directly promotes the growth and migration of liver cancer by increasing the levels of IL-8 and TGF-β1[155].

As a member of the Helicobacteraceae family,H.hepaticus causes the development of HCC by activating the NF-κB and Wnt signaling pathways,hepatocyte turnover,and oxidative stress[156].Additionally,some Helicobacter species,such as H.pylori,H.bilis,H.hepaticus,and H.ganmani,are specif ically related to CCA,but not non-tumor diseases in the bile duct[157].

Gut microbial metabolites and liver cancer

Microbial metabolites disturb the metabolic pathways and immune response in the liver.TLR4 recognizes LPS coming from bacteria and activates Kupffer cells through LPS-induced TNF-β and IL-6[158].It can also stimulate stellate cells through growth factors such as epiregulin[159],and initiate various inflammatory and oncogenic pathways[160].The LPS-TLR4 pathway promotes HCC,whereas removal of LPS or genetic inactivation of TLR4 could decrease HCC development[159].However,whether the intestinal microbiota and TLR4 contribute to HCC initiation remains controversial[159,161].

Cholic acid and chenodeoxycholic acid are the major primary bile acids produced by the liver.They cause DNA damage by increasing the production of reactive oxygen species(ROS),thus inducing the development of liver cancers[162].In addition,bile acids are also confirmed to regulate the gut microbiome.Decreased quantities of bile acid result in the overgrowth of gut microbiota and accelerate inflammation[163].The enterohepatic circulation of deoxycholic acid(DCA)produced by Clostridium causes DNA damage and provokes a senescence-associated secretory phenotype(SASP)in hepatic stellate cells.This process involves numerous inflammatory cytokines and growth factors,thereby contributing to inflammatory and obesity-associated HCC transitions[164–166].DCA and lithocholic acid are shown to directly promote cancer through DNA damage[29].

Gut microbiota,obesity,and liver cancer

Obesity increases the likelihood of various cancers,such as liver cancer[167,168],and causes microbial dysbiosis.Under the obesity condition,tight junctions of gut epithelium get degraded due to chronic inflammation.As a result,there is an increase in intestinal permeability,as well as bacterial counts and the levels of metabolites translocated from the gut epithelium into circulation because of the chronic inflammation[166].IL-6 and plasminogen activator inhibitor-1 induced in obesity also lead to inflammatory responses and tumorigenesis[169].In addition,the number of grampositive bacteria as well as the serum level of DCA are increased in mice put on a high-fat diet,indicating that the DCA-SASP axis plays a critical role in the progression of obesity-associated liver cancer[164].

Gut microbiota and pancreatic cancer

Pancreas is an extragastric digestive organ.Pancreatic ductal adenocarcinoma(PDAC),one of the most deadly cancers globally,is the most common type of pancreatic cancer.Accumulating studies have demonstrated that gut microbiota might influence pancreatic carcinogenesis[170,171]by promoting inflammation,activating the immune response,and perpetuating cancer-associated inflammation[172].

H.pylori and pancreatic cancer

Risk factors for pancreatic adenocarcinoma include age,cigarette smoking,obesity,chronic pancreatitis,and diabetes.A review of hundreds of meta-analyses on pancreatic cancer revealed that H.pylori infection is another considerable risk factor for PDAC[173].Besides PDAC[174–176],H.pylori is also involved in the acute and chronic pancreatitis[177–179],as well as autoimmune pancreatitis[180].

Many pathogenic components derived from H.pylori,including ammonia and LPS,as well as large quantities of resulting inflammatory cytokines,damage the pancreas[181].H.pylori infections activate both NF-κB and AP-1,leading to dysregulation of cellular processes.Increased IL-8 levels accelerate inflammation,eventually resulting in pancreatic carcinogenesis[182].KRAS performs an essential function in normal tissue signaling,while KRAS gene mutations are present in over 90%of the cases of pancreatic adenocarcinoma[183].LPS from H.pylori is confirmed to hyperstimulate mutations of KRAS genes and initiate the process of pancreatic carcinogenesis[184,185].In addition,persistent STAT3 activation by H.pylori infections can promote pancreatic cancer progression by upregulating the expression of anti-apoptotic and pro-proliferative proteins,including Bcl-xL,MCL-1,survivin,c-myc,and cyclin D1[173,186,187].

Inflammation and immune response in pancreatic cancer

As mentioned earlier,ETBF promotes the development of IBD as well as IL-17A-dependent CRC[225].An ETBF-clearance mouse model was established by cefoxitin administration.It is found that expression of the mucosal IL-17A was inhibited with cefoxitin treatment.The ETBF clearance prohibits colon adenoma formation and IL-17A-dependent tumorigenesis.However,the effects of antibiotics are twosided.Antibiotic exposure may induce cancers as well.A nested case-control investigation has demonstrated is a link between the exposure of penicillin and high risks of esophageal,gastric,and pancreatic cancers[226].Another recent nested case-control study on liver cancer has also shown a trend of increased risk of liver cancer in cases having antibiotic therapy,compared to the cases without antibiotic therapy.However,it is uncertain whether the dose of antibiotics is correlated to the risk of liver cancer[227].

NLRs are cytoplasmic pattern recognition receptors(PRRs)that are involved in the activation of NF-κB and the formation of inflammasomes.P38 mitogen-activated protein kinases(P38 MAPKs)are responsive to cytokines,and are involved in cell differentiation,apoptosis,and autophagy,thereby accelerating the process of PDCA.Thus,P38 inhibitors are possible therapeutic agents for pancreatic cancer[193].

5-Fluorouracil

Future directions

Anticancer immunotherapy

Prebiotics

The World Health Organization(WHO)defines ‘‘prebiotics”as ‘‘a non-viable food component that confers health benefit(s)on the host associated with modulation of the microbiota”[196].A healthy diet,with increased consumption of plant foods and limited intake of meat,will be helpful to set up a healthy gut microbiota[197].

Dietary flaxseeds benefit the colonic microenvironment and reduce the susceptibility to gut-related diseases[198].Inulin diets significantly decrease the pH of the cecal content,the concentration of phenol,p-cresol,and indole in the colon tract,inhibit the activity of microbial enzymes,including βglucuronidase,azoreductase,and nitroreductase,and decrease the possibility of colonic precancerous lesions [199].Avenanthramide-C (2c),an avenanthramide particularly found in oats,is extensively metabolized by gut bacteria and exerts an anti-inflammatory effect[200].Urolithins are gut microflora metabolites of ellagitannins and ellagic acid.Intake of pomegranate extract significantly increases the quantities of ellagic acid and urolithins in the CRC tissues[201].The hops plant,Humulus lupulus L.,is a primary agent in beer containing prenyl flavonoids with weak estrogenic effect.Prenyl flavonoids are augmented by the gut microbiota,exerting anticancer effects on CRC models [202]. Agarooligosaccharides from seaweed show a positive effect on high-fat diet-induced gut dysbiosis and CRC development by altering the amount of SCFAs,bile acid,and phospholipids[203].Nutmeg exhibits antimicrobial activity by decreasing IL-6 levels and normalizing dysregulated lipid metabolism[204].Fermentation of nuts results in higher concentrations of SCFA,and the formation of vaccenic acid,a conjugated linoleic acid,which could be a potential chemopreventive metabolite[205].Polyphenols subjected to microbial metabolism have both anti-carcinogenic and anti-mutagenic effect to prevent colon cancer[206].Eicosapentaenoic acid-free fatty acid,an omega-3 fatty acid,effectively inhibits the process of inflammation as well as the formation of polyps and colitisassociated cancers[207].Both the COLON study[208]and a RCT study[209]revealed the beneficial effects of polydextrose on gut microbiota and in the prevention of CRC.Another recent study has shown that although the intake of palm dates did not significantly change the relative abundance of gut microbiota or SCFAs,it can significantly increase bowel movements and stool frequency,while significantly reducing the stool ammonia concentration and the genotoxicity in human fecal water[210].

Probiotics

Probiotics are defined by the Food and Drug Administration(FDA)and WHO as ‘‘live microorganisms,which when administered in adequate amounts,confer a health benefit on the host.”A number of studies have claimed the benefits of probiotics on the suppression of CRC,notably through participating in the innate immune system and apoptosis,decreasing oxidative stress,and improving the community of gut microbiota[211–213].

采用统计软件SPSS17.0进行统计分析,计数资料(n,%)x2检验,计量资料(均数±标准差)t检验,P<0.05差异具有统计学意义。

Lactobacillus species are the most commonly used probiotics in clinical trials because of a reduction in the abundance of Enterobacter and the regulation of immune response in gut of patients with CRC,whereas Bifidobacterium longum administration has no such effect[214].Lactobacillus salivarius REN administration can effectively suppress the development of CRC in 1,2-dimethylhydrazine-induced experimental animals.It has been shown that the injection with this potent carcinogen remarkably altered the microbial community by increasing the number of Ruminococcus species(sp.)and Clostridiales bacteria,while decreasing the number of Prevotella sp.Furthermore,Ren intake promotes the rehabilitation of gut microbiota,suggesting that Ren may potentially be beneficial for the prevention of colon cancer[215].A probiotic cocktail,comprising Lactobacillus acidophilus,Bifidobacteria bifidum,and Bifidobacteria infantum(LBB),enriched with oligofructose and maltodextrin,decreases the counts of the species of Pseudomonas,Congregibacter,Clostridium,Escherichia,Helicobacter,while increasing the counts of Lactobacillus in CRC[216].Probiotic Prohep(a mixture of Lactobacillus rhamnosus GG[LGG],E.coli Nissle 1917[EcN],and heat inactivated VSL#3(probiotic medical food[1:1:1])decreases the growth of HCC significantly by inhibiting angiogenesis and inflammation.It has been shown that the population of gut microbiota shifts to specific bacteria,such as Prevotella and Oscillibacter,creating favorable anti-inflammatory products.Th17 cells are pro-inflammatory Th cells,which are able to produce interleukin 17(IL-17)as an angiogenic factor.Prohep administration helps downregulate the Th17 frequency and the production of IL-1,inhibits the angiogenesis,and promotes the differentiation of anti-inflammatory Treg cells in the GI tract[217].

2012年，父亲已到了快退休的年纪，家里的承包地在农场节水灌溉项目的扶持下架设了滴灌设施。闲暇时和父亲站在地头聊天，父亲感叹地说，滴灌浇庄稼轻松又均匀，以前大水漫灌的浇水技巧用不到了，这高腰雨靴是彻底退休喽。现在是浇水不拿锹，背着管件包，田间脚不湿，开阀水灌苗，肥料随水走，省心又高效。种庄稼灌水都不是啥苦活了，加上还有咱农机合作社的那些先进机械，我还想种到65岁，多闻闻这庄稼的香甜味呢！

Furthermore,the conventional treatment of H.pylori infection with amoxicillin,clarithromycin,and PPIs can alter the indigenous gut microbiota to cause a long-term impact[218].In a randomized controlled trial comparing the conventional treatment group to the combination treatment group with probiotics,the gut microbial community in the conventional treatment group is changed more significantly,with a greater proportion of drug-resistant bacteria.It has been pointed out that probiotic administration would help the gut microbiota fight back the perturbation induced by the treatment of H.pylori infection[219].

Synbiotics

Synbiotics are combinations of prebiotics and probiotics[196].A previous study has demonstrated that synbiotic supplementation during neoadjuvant chemotherapy for EC improves the gut microbial community and reduces the side effects caused by chemotherapeutic agents[220].Since alterations in the gastric microbiome contribute to the increased incidence of esophageal adenocarcinomas,particularly those that arise within the gastroesophageal junction,the esophageal microbiome may be manipulated with antibiotics,probiotics,or inhibitors of specific host cell pathways to prevent disorders at this site[221].

虽然“智”与“勇”是内政与外交的需要，是贵有天下的君主所必需的品质，但在孟子那里，二者已经与“仁”不直接联结，而降低为一般性的德目。

Antibiotics

The incidence and severity of colitis-associated cancer are reduced by administering antibiotics[222,223].Antibiotic administration during the primary inflammation stage can inhibit the initiation of carcinogenesis in an animal colonic cancer model[224].

Microbes incur mild and sustained immune responses and inflammatory reactions,resulting in the formation of pancreatic cancer[188].Many studies have been performed to explore the possible mechanisms.TLRs expressed on various immune cells enable the immune cells to recognize both numerous microbe-associated molecular patterns(MAMPs)and noninfectious inflammatory damage-associated molecular patterns(DAMPs),then activate the NF-κB and MAPK signaling pathways[185,189].Consequently,these processes initiate and perpetuate pancreatitis,and finally promote the progression of pancreatic cancer[190–192].

COX2-inhibitor

The subunits of the LPS receptor expressed on colonocytes inhibit cell death,activate cellular immune response via TLR2,and then stimulate downstream proinflammatory cytokine signaling,leading to tumorigenesis[26,77,78].LTA,an element arising from the cell wall of gram-positive bacteria,is regarded as the counterpart of LPS,the component of gram-negative bacterial cell wall[79].High-fat diets boost the relative abundance of sulfate-reducing bacteria,such as Desulfovibrio vulgaris,which transforms primary bile acids to secondary bile acids such as lithocholic acid and deoxycholic acid,is potentially tumorigenic[80].Conversely,butyric acid(BA),an important short-chain fatty acid(SCFA)that is generated from fermentable fibers in diets by colonic bacteria,has been shown to be anti-tumorigenic[81].The most important butyrate-producing microbial groups that are involved in the process of fermentation are Faecalibacterium prausnitzii and Eubacterium rectale[82].BA is utilized by the mitochondria in colonocytes,which helps to maintain a healthy energy balance and benefit colonic epithelial cell proliferation[83].GPR109a,a receptor of SCFAs expressed on immune cells,primarily activates the ligands of BA,then inhibits inflammatory cytokines,thus suppressing the process of inflammation[84].The host immune response fights back DNA methylation-mediated GPR109a silencing through IFNγ,therefore encouraging anti-carcinogenic effects accordingly[85,86].In addition,BA exerts various chemopreventive effects by inducing P21 gene expression,inhibiting the activator protein-1(AP-1)signaling pathway,and increasing the phosphorylation of c-Fos and ERK1/2[87,88].Additionally,urolithins such as urolithin A are intestinal microflora metabolites of fruits and nuts with plenty of ellagic acid.They have been reported to inhibit Wnt signaling and show benefits against cancer[89,90].

Pharmacodynamics of anticancer agents

Irinotecan

Irinotecan is one of the main chemotherapeutic agents for CRC patients.Gut microbiota mediate the toxicity of irinotecan(CPT-11)chemotherapy that can induce the loss of intestinal barrier function[229].The counts of cecal Clostridium cluster XI,Enterobacteriaceae,pathogenic E.coli,and Clostridium difficile increased after CPT-11 administration.Glutamine treatment can induce temporary alternations of the gut microbiota and reduce the intestinal toxicity of CPT-11[230].

Taste receptor 2 member 38(T2R38)is a bitter taste receptor.Interestingly,T2R38 is expressed not only in oral cells but also in pancreatic cancer cells.Pseudomonas aeruginosa is a unique ligand for T2R38 that is stated to activate T2R38,induce multi-drug resistance protein 1(ABCB1),and get involved in cancer invasion and metastasis[194].Additionally,Fusobacterium species exist in 8.8%of pancreatic cancer tissues.It is of note that the status of Fusobacterium species is an independent negative prognostic biomarker of pancreatic cancer[195].

任务实施是学生或小组按照计划逐步完成任务的环节。在这个环节中引入MOOC的知识点讲解，将学生任务中需要掌握的知识点，以线上MOOC的资源方式引导学生自主完成学习。再充分应用自己已经掌握的知识，并就解决问题、完成任务的实施步骤形成详细的计划。学生在这个环节要完成的工作主要是进一步收集信息，完成任务或解决问题，汇报PPT、图纸或其他形式的学习成果。

5-fluorouracil(5-FU)is an important chemotherapeutic agent for CRC treatment.However,usage of 5-FU is limited by chemoresistance.In 5-FU-resistant CRC cells,Lactobacillus plantarum supernatant(LPSN)inhibits the expression of particular biomarkers of cancer stem cells,promotes cell death and apoptosis,and selectively inactivates the Wnt/β-catenin signaling pathway,thus enhancing 5-FU efficacy,and reversing the development of resistance to anticancer drugs.This implies that probiotic substances could be useful therapeutic alternatives as biotherapeutics for chemoresistant CRCs[117].Urolithin A,a gut microbial metabolite from diets containing ellagic acid,targets the colonic mucosa of patients with CRC,showing the capacity to counteract inflammation and prevent cancers.When co-treated with supplementary urolithin A,the IC50 values of 5-FU and 5′DFUR also decreased,indicating lower drug doses would be needed,thus reducing the side effects of hemotherapy[231].

Gut microbiota are closely related to GI cancers.Prebiotics,probiotics,synbiotics,and some specific antibiotics are often applied to build up a healthy gut.Quite a few recent studies have shown that gut microbiota affect the efficacy of antitumor treatments,including chemotherapy and immunotherapy.

Microbes can enhance the therapeutic effect of cancer immunotherapy[232].A previous study has shown that the anti-cancer efficacy and immunostimulatory effect of cytotoxic T-lymphocyte-associated protein 4(CTLA-4)blockade,an immune checkpoint blockade,rely upon different Bacteroides species,such as the Bacteroides thetaiotaomicron and B.fragilis[233].The efficacy of programmed cell death protein 1 ligand 1(PD-L1)inhibitors,another important immune-oncology therapy,is significantly augmented by Bifidobacterium administration.Moreover,tumor progression is almost prohibited after the treatment[234].

Traditional Chinese Medicine

Baicalin and baicalein

单次照射3 d后，所有大鼠iv FITC荧光标记的葡聚糖（2 mg/kg），完成肠黏膜血流量检测后，处死大鼠，取1 cm小肠组织，反复灌洗去除血液，组织充分匀浆后，3 000×g离心20 min，取上清，荧光酶标仪540 nm处检测上清的吸光度（A）值，再根据标准曲线，计算出组织间隙中FITC荧光标记葡聚糖的浓度。

Baicalin,a flavone glycoside isolated from the root of Scutellaria baicalensis,which is one of the commonly used herbs in the Traditional Chinese Medicine,slightly inhibits cell proliferation and induces apoptosis.Baicalein,a flavonoid isolated from S.baicalensis,has anti-inflammatory effects and strongly inhibits cell proliferation in vitro,particularly on CRC cells lines.It functions by arresting the cell cycle at the S phase,activating caspase 3 and caspase 9,thereby inducing apoptosis[235].

Curcumin

Curcumin,which is produced by the roots of the Curcuma longa plant,has potential anti-carcinogenesis properties by maintaining the diversity of gut microbiota.It has also been demonstrated to be an anti-inflammatory,anti-oxidative,and anti-proliferative agent[236].However,numerous clinical studies assessing the efficacy of curcumin in cancer treatment has been inconclusive[237].

侧吹浸没燃烧熔炼属于强化熔池熔炼工艺，通过喷枪浸没于液态渣层中，对渣层进行搅拌。通过调整还原煤加入量，可方便的调整炉渣中铁的还原度，镍铁品位可根据需求灵活调整。同时由于侧吹炉可灵活调节金属层和渣层的厚度，对渣和镍铁金属量比有宽泛的适应性。

PHY906

PHY906(a Chinese herbal medicine)can restore the gut epithelium through stimulating the regeneration of intestinal stem or progenitor cells upon transformation by bacterial βglucuronidase,which is highly expressed by the gut microbiota.It was reported that PHY906 administration in advanced CRC patients reduces the GI toxicity of irinotecan and exerts an anti-tumor effect[238–243].

Prognostic biomarkers

Fusobacterium nucleatum may accelerate cancer progression and inhibit T cell-mediated immune responses in CRC.In a cohort consisting of 1069 CRC cases,the abundance of F.nucleatum was found to be related to high microsatellite instability and thus was independent of the BRAF mutation status.The higher quantity of F.nucleatum DNA in the tumor tissue was proportional to worse prognosis.Therefore,this may serve as a potential prognostic biomarker for colorectal cancers[244].

Concluding remarks

Mechanistic studies trying to understand how gut microbes regulate body health and cancers are still at the early stage,revealing primarily a correlation rather than a causal relationship.However,people have realized that gut microbiota are closely and functionally related to the humans and play an important and unique role in human health and disease.People have begun to take bold efforts,trying to regulate gut microbes.The aims are multifaceted,ranging from regulating human metabolism,immune and inflammatory response,to preventing carcinogenesis,inhibiting the progression of cancers,and improving the efficacy of personal cancer treatment.Gut microbiota are able to play a synergistic effect with chemotherapeutic and immunotherapeutic agents.Based on the studies of gut microbiota,people are also exploring new therapeutic targets,as well as diagnostic,predictive,and prognostic cancer biomarkers using human gut microbiota.The challenging tasks are awaiting.These may include exploring a deeper mechanistic understanding of microbiome in the basic research,accelerating the translation of gut microbiota studies in precision medicine,and finding the way out to human gut microbial biological Engineering.Clinical trials using microbiota in combination with chemotherapy or immunotherapy are eagerly expected.

Competing interests

The authors declare no competing interests.

This work was supported by the National Institutes of Health(NIH;Grant No.CA190122)and Department of Defense(DoD;Award No.W81XWH-16-1-0151)of the United States awarded to QT.Opinions,interpretations,conclusions and recommendations are those of the authors and are not necessarily endorsed by the NIH or DoD.This work was also supported by Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(CIFMS;Grant No.2016-12M-1-001)awarded to CB.Opinions,interpretations,conclusions and recommendations are those of the authors and are not necessarily endorsed by the CIFMS.

国内外研究报告指出，甲醛是许多水产品的一种代谢中间产物，分布广泛。但大多天然食物中甲醛含量较低，不会对人体健康造成威胁。水产品中内源性甲醛的主要前体物质是氧化三甲胺，是鱼鲜美味道的主要来源。目前认为水产品中内源性甲醛主要通过2种途径产生：一为生物途径，氧化三甲胺可在内源性氧化三甲胺酶和微生物作用下，脱甲基生成二甲胺和甲醛；另一条为非酶途径，主要是高温过程的热分解。这2种分解途径都使得鱼肉组织发生变化，影响水产品的品质和风味。此外，体内脂质的氧化或过氧化、氨基酸的代谢，以及脱甲基反应也可产生甲醛；甲醛亦是嘌呤、胸腺嘧啶生物合成的中间产物。

References

[1]Pisani P,Parkin DM,Munoz N,Ferlay J.Cancer and infection:estimates of the attributable fraction in 1990.Cancer Epidemiol Biomarkers Prev 1997;6:387–400.

[2]de Martel C,Ferlay J,Franceschi S,Vignat J,Bray F,Forman D,et al.Global burden of cancers attributable to infections in 2008:a review and synthetic analysis.Lancet Oncol 2012;13:607–15.

[3]Parkin DM.The global health burden of infection-associated cancers in the year 2002.Int J Cancer 2006;118:3030–44.

[4]Plummer M,de Martel C,Vignat J,Ferlay J,Bray F,Franceschi S.Global burden of cancers attributable to infections in 2012:a synthetic analysis.Lancet Glob Health 2016;4:e609–16.

[5]Garrett WS.Cancer and the microbiota.Science 2015;348:80–6.

[6]Gill SR,Pop M,Deboy RT,Eckburg PB,Turnbaugh PJ,Samuel BS,et al.Metagenomic analysis of the human distal gut microbiome.Science 2006;312:1355–9.

[7]Hamm AK,Weir TL.Editorial on ‘‘cancer and the microbiota”published in science.Ann Transl Med 2015;3:175.

[8]Ericsson AC,Akter S,Hanson MM,Busi SB,Parker TW,Schehr RJ,et al.Differential susceptibility to colorectal cancer due to naturally occurring gut microbiota.Oncotarget 2015;6:33689–704.

[9]Hiergeist A,Gläsner J,Reischl U,Gessner A.Analyses of intestinal microbiota:culture versus sequencing.ILAR J 2015;56:228–40.

[10]Olsen GJ,Lane DJ,Giovannoni SJ,Pace NR,Stahl DA.Microbial ecology and evolution:a ribosomal RNA approach.Annu Rev Microbiol 1986;40:337–65.

[11]Tebani A,Afonso C,Marret S,Bekri S.Omics-based strategies in precision medicine:toward a paradigm shift in inborn errors of metabolism investigations.Int J Mol Sci 2016;17:E1555.

[12]Kuleshov V,Jiang C,Zhou W,Jahanbani F,Batzoglou S,Snyder M.Synthetic long-read sequencing reveals intraspecies diversity in the human microbiome. Nat Biotechnol 2016;34:64–9.

[13]Eckburg PB,Bik EM,Bernstein CN,Purdom E,Dethlefsen L,Sargent M,et al.Diversity of the human intestinal microbial flora.Science 2005;308:1635–8.

[14]Hattori N,Ushijima T.Epigenetic impact of infection on carcinogenesis:mechanisms and applications.Genome Med 2016;8:10.

[15]Klampfer L.Cytokines,in flammation and colon cancer.Curr Cancer Drug Targets 2011;11:451–64.

[16]Putoczki TL,Thiem S,Loving A,Busuttil RA,Wilson NJ,Ziegler PK,et al.Interleukin-11 is the dominant IL-6 family cytokine during gastrointestinal tumorigenesis and can be targeted therapeutically.Cancer Cell 2013;24:257–71.

[17]Shitashige M,Satow R,Honda K,Ono M,Hirohashi S,Yamada T.Regulation of Wnt signaling by the nuclear pore complex.Gastroenterology 2008;134:1961–71,1971.e1-4.

[18]Shitashige M,Hirohashi S,Yamada T.Wnt signaling inside the nucleus.Cancer Sci 2008;99:631–7.

[19]Hussain SP,Amstad P,Raja K,Ambs S,Nagashima M,Bennett WP,et al.Increased p53 mutation load in noncancerous colon tissue from ulcerative colitis:a cancer-prone chronic inflammatory disease.Cancer Res 2000;60:3333–7.

[20]Raponi M,Winkler H,Dracopoli NC.KRAS mutations predict response to EGFR inhibitors. Curr Opin Pharmacol 2008;8:413–8.

[21]Gensollen T,Iyer SS,Kasper DL,Blumberg RS.How colonization by microbiota in early life shapes the immune system.Science 2016;352:539–44.

[22]Palm NW,de Zoete MR,Flavell RA.Immune-microbiota interactions in health and disease.Clin Immunol 2015;159:122–7.

[23]Vijay-Kumar M,Gewirtz AT.Flagellin:key target of mucosal innate immunity.Mucosal Immunol 2009;2:197–205.

[24]Hayashi F,Smith KD,Ozinsky A,Hawn TR,Yi EC,Goodlett DR,et al.The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5.Nature 2001;410:1099–103.

[25]Brown DG,Rao S,Weir TL,O’Malia J,Bazan M,Brown RJ,et al.Metabolomics and metabolic pathway networks from human colorectal cancers,adjacent mucosa,and stool.Cancer Metab 2016;4:11.

[26]Ginsburg I.Role of lipoteichoic acid in infection and inflammation.Lancet Infect Dis 2002;2:171–9.

[27]Hermann C,Spreitzer I,Schroder NW,Morath S,Lehner MD,Fischer W,et al.Cytokine induction by purified lipoteichoic acids from various bacterial species–role of LBP,sCD14,CD14 and failure to induce IL-12 and subsequent IFN-gamma release.Eur J Immunol 2002;32:541–51.

[28]Carino A,Graziosi L,D’Amore C,Cipriani S,Marchiano`S,Marino E,et al.The bile acid receptor GPBAR1(TGR5)is expressed in human gastric cancers and promotes epithelialmesenchymal transition in gastric cancer cell lines.Oncotarget 2016;7:61021–35.

[29]Louis P,Hold GL,Flint HJ.The gut microbiota,bacterial metabolites and colorectal cancer.Nat Rev Microbiol 2014;12:661–72.

[30]Saretzki G.Cellular senescence in the development and treatment of cancer.Curr Pharm Des 2010;16:79–100.

[31]Smith PM,Howitt MR,Panikov N,Michaud M,Gallini CA,Bohlooly-Y M,et al.The microbial metabolites,short-chain fatty acids,regulate colonic Treg cell homeostasis.Science 2013;341:569–73.

[32]Furusawa Y,Obata Y,Fukuda S,Endo TA,Nakato G,Takahashi D,et al.Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells.Nature 2013;504:446–50.

[33]Arpaia N,Campbell C,Fan X,Dikiy S,van der Veeken J,deRoos P,et al.Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation.Nature 2013;504:451–5.

[34]Doorakkers E,Lagergren J,Engstrand L,Brusselaers N.Eradication of Helicobacter pylori and gastric cancer:a systematic review and meta-analysis of cohort studies.J Natl Cancer Inst 2016;108:djw132.

[35]Khatoon J,Rai RP,Prasad KN.Role of Helicobacter pylori in gastric cancer: updates. World J Gastrointest Oncol 2016;8:147–58.

[36]Odenbreit S,Puls J,Sedlmaier B,Gerland E,Fischer W,Haas R.Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion.Science 2000;287:1497–500.

[37]Kwok T,Zabler D,Urman S,Rohde M,Hartig R,Wessler S,et al.Helicobacter exploits integrin for type IV secretion and kinase activation.Nature 2007;449:862–6.

[38]Moyat M,Velin D.Immune responses to Helicobacter pylori infection.World J Gastroenterol 2014;20:5583–93.

[39]Udhayakumar G,Jayanthi V,Devaraj N,Devaraj H.Interaction of MUC1 with beta-catenin modulates the Wnt target gene cyclinD1 in H.pylori-induced gastric cancer.Mol Carcinog 2007;46:807–17.

[40]Yong X,Tang B,Li BS,Xie R,Hu CJ,Luo G,et al.Helicobacter pylori virulence factor CagA promotes tumorigenesis of gastric cancer via multiple signaling pathways.Cell Commun Signal 2015;13:30.

[41]Hotchin NA,Cover TL,Akhtar N.Cell vacuolation induced by the VacA cytotoxin of Helicobacter pylori is regulated by the Rac1 GTPase.J Biol Chem 2000;275:14009–12.

[42]Suzuki J,Ohnsihi H,Shibata H,Wada A,Hirayama T,Iiri T,et al.Dynamin is involved in human epithelial cell vacuolation caused by the Helicobacter pylori-produced cytotoxin VacA.J Clin Invest 2001;107:363–70.

[43]Mashima H,Suzuki J,Hirayama T,Yoshikumi Y,Ohno H,Ohnishi H,et al.Involvement of vesicle-associated membrane protein 7 in human gastric epithelial cell vacuolation induced by Helicobacter pylori-produced VacA. Infect Immun 2008;76:2296–303.

[44]Yahiro K,Akazawa Y,Nakano M,Suzuki H,Hisatune J,Isomoto H,et al.Helicobacter pylori VacA induces apoptosis by accumulation of connexin 43 in autophagic vesicles via a Rac1/ERK-dependent pathway.Cell Death Discov 2015;1:15035.

[45]Ricci V.Relationship between VacA toxin and host cell autophagy in Helicobacter pylori infection of the human stomach:a few answers,many questions.Toxins(Basel)2016;8:E203.

[46]Galmiche A,Rassow J.Targeting of Helicobacter pylori VacA to mitochondria.Gut Microbes 2010;1:392–5.

[47]Willhite DC,Blanke SR.Helicobacter pylori vacuolating cytotoxin enters cells,localizes to the mitochondria,and induces mitochondrial membrane permeability changes correlated to toxin channel activity.Cell Microbiol 2004;6:143–54.

[48]Jain P,Luo ZQ,Blanke SR.Helicobacter pylori vacuolating cytotoxin A(VacA)engages the mitochondrial fission machinery to induce host cell death.Proc Natl Acad Sci U S A 2011;108:16032–7.

[49]Ki MR,Lee HR,Goo MJ,Hong IH,Do SH,Jeong DH,et al.Differential regulation of ERK1/2 and p38 MAP kinases in VacA-induced apoptosis of gastric epithelial cells.Am J Physiol Gastrointest Liver Physiol 2008;294:G635–47.

[50]Caputo R,Tuccillo C,Manzo BA,Zarrilli R,Tortora G,CeV Blanco,et al.Helicobacter pylori VacA toxin up-regulates vascular endothelial growth factor expression in MKN 28 gastric cells through an epidermal growth factor receptor-,cyclooxygenase-2-dependent mechanism.Clin Cancer Res 2003;9:2015–21.

[51]Liu N,Zhou N,Chai N,Liu X,Jiang H,Wu Q,et al.Helicobacter pylori promotes angiogenesis depending on Wnt/beta-catenin-mediated vascular endothelial growth factor via the cyclooxygenase-2 pathway in gastric cancer.BMC Cancer 2016;16:321.

[52]Song X,Xin N,Wang W,Zhao C.Wnt/β-catenin,an oncogenic pathway targeted by H.pylori in gastric carcinogenesis.Oncotarget 2015;6:35579–88.

[53]Nakayama M,Hisatsune J,Yamasaki E,Isomoto H,Kurazono H,Hatakeyama M,et al.Helicobacter pylori VacA-induced inhibition of GSK3 through the PI3K/Akt signaling pathway.J Biol Chem 2009;284:1612–9.

[54]Sato F,Meltzer SJ.CpG island hypermethylation in progression of esophageal and gastric cancer.Cancer 2006;106:483–93.

[55]Sitaraman R.Helicobacter pylori DNA methyltransferases and the epigenetic field effect in cancerization.Front Microbiol 2014;5:115.

[56]De Witte C,Schulz C,Smet A,Malfertheiner P,Haesebrouck F.Other Helicobacters and gastric microbiota.Helicobacter 2016;21:62–8.

[57]Maldonado-Contreras A,Goldfarb KC,Godoy-Vitorino F,Karaoz U,Contreras M,Blaser MJ,et al.Structure of the human gastric bacterial community in relation to Helicobacter pylori status.ISME J 2011;5:574–9.

[58]Bik EM,Eckburg PB,Gill SR,Nelson KE,Purdom EA,Francois F,et al.Molecular analysis of the bacterial microbiota in the human stomach.Proc Natl Acad Sci U S A 2006;103:732–7.

[59]Iizasa H,Ishihara S,Richardo T,Kanehiro Y,Yoshiyama H.Dysbiotic infection in the stomach.World J Gastroenterol 2015;21:11450–7.

[60]Aviles-Jimenez F,Vazquez-Jimenez F,Medrano-Guzman R,Mantilla A,Torres J.Stomach microbiota composition varies between patients with non-atrophic gastritis and patients with intestinal type of gastric cancer.Sci Rep 2014;4:4202.

[61]Wang J,Zhao L,Yan H,Che J,Huihui L,Jun W,et al.A metaanalysis and systematic review on the association between human papillomavirus(types 16 and 18)infection and esophageal cancer worldwide.PLoS One 2016;11:e0159140.

[62]Dias-Jacome E,Libaˆnio D,Borges-Canha M,Galaghar A,Pimentel-Nunes P.Gastric microbiota and carcinogenesis:the role of non-Helicobacter pylori bacteria–a systematic review.Rev Esp Enferm Dig 2016;108:530–40.

[63]Mohiuddin MK,Chava S,Upendrum P,Latha M,Zubeda S,Kumar A,et al.Role of human papilloma virus infection and altered methylation of specific genes in esophageal cancer.Asian Pac J Cancer Prev 2013;14:4187–93.

[64]Ludmir EB,Stephens SJ,Palta M,Willett CG,Czito BG.Human papillomavirus tumor infection in esophageal squamous cell carcinoma.J Gastrointest Oncol 2015;6:287–95.

[65]Xu W,Liu Z,Bao Q,Qian Z.Viruses,other pathogenic microorganisms and esophageal cancer.Gastrointest Tumors 2015;2:2–13.

[66]Xie FJ,Zhang YP,Zheng QQ,Jin HC,Wang FL,Chen M,et al.Helicobacter pylori infection and esophageal cancer risk:an updated meta-analysis. World J Gastroenterol 2013;19:6098–107.

[67]Runge TM,Abrams JA,Shaheen NJ.Epidemiology of Barrett’s esophagus and esophageal adenocarcinoma.Gastroenterol Clin North Am 2015;44:203–31.

[68]Neto AG,Whitaker A,Pei Z.Microbiome and potential targets for chemoprevention of esophageal adenocarcinoma.Semin Oncol 2016;43:86–96.

[69]Amir I,Konikoff FM,Oppenheim M,Gophna U,Half EE.Gastric microbiota is altered in oesophagitis and Barrett’s oesophagus and further modified by proton pump inhibitors.Environ Microbiol 2014;16:2905–14.

[70]Hu Q,Sun TT,Hong J,Fang JY,Xiong H,Meltzer SJ.Proton pump inhibitors do not reduce the risk of esophageal adenocarcinoma in patients with Barrett’s esophagus:a systematic review and meta-analysis.PLoS One 2017;12:e0169691.

[71]Nasrollahzadeh D,Malekzadeh R,Ploner A,Shakeri R,Sotoudeh M,Fahimi S,et al.Variations of gastric corpus microbiota are associated with early esophageal squamous cell carcinoma and squamous dysplasia.Sci Rep 2015;5:8820.

[72]Patel T,Bhattacharya P,Das S.Gut microbiota:an indicator to gastrointestinal tract diseases.J Gastrointest Cancer 2016;47:232–8.

[73]Yang L,Lu X,Nossa CW,Francois F,Peek RM,Pei Z.Inflammation and intestinal metaplasia of the distal esophagus are associated with alterations in the microbiome.Gastroenterology 2009;137:588–97.

[74]Cani PD,Amar J,Iglesias MA,Poggi M,Knauf C,Bastelica D,et al.Metabolic endotoxemia initiates obesity and insulin resistance.Diabetes 2007;56:1761–72.

[75]Yang L,Francois F,Pei Z.Molecular pathways:pathogenesis and clinical implications of microbiome alteration in esophagitis and Barrett esophagus.Clin Cancer Res 2012;18:2138–44.

[76]Lee SJ,Park H,Chang JH,Conklin JL.Generation of nitric oxide in the opossum lower esophageal sphincter during physiological experimentation.Yonsei Med J 2006;47:223–9.

[77]Chiu WT,Lin YL,Chou CW,Chen RM.Propofol inhibits lipoteichoic acid-induced iNOS gene expression in macrophages possibly through downregulation of toll-like receptor 2-mediated activation of Raf-MEK1/2-ERK1/2-IKK-NFkappaB.Chem Biol Interact 2009;181:430–9.

[78]Kuo WT,Lee TC,Yang HY,Chen CY,Au YC,Lu YZ,et al.LPS receptor subunits have antagonistic roles in epithelial apoptosis and colonic carcinogenesis.Cell Death Differ 2015;22:1590–604.

[79]Su SC,Hua KF,Lee H,Chao LK,Tan SK,Yang SF,et al.LTA and LPS mediated activation of protein kinases in the regulation of inflammatory cytokines expression in macrophages.Clin Chim Acta 2006;374:106–15.

[80]Wells JE,Hylemon PB.Identification and characterization of a bile acid 7alpha-dehydroxylation operon in Clostridium sp.strain TO-931,a highly active 7alpha-dehydroxylating strain isolated from human feces.Appl Environ Microbiol 2000;66:1107–13.

[81]Canani RB,Costanzo MD,Leone L,Pedata M,Meli R,Calignano A.Potential beneficial effects of butyrate in intestinal and extraintestinal diseases.World J Gastroenterol 2011;17:1519–28.

[82]Louis P,Flint HJ.Diversity,metabolism and microbial ecology of butyrate-producing bacteria from the human large intestine.FEMS Microbiol Lett 2009;294:1–8.

[83]Richards JL,Yap YA,McLeod KH,Mackay CR,Marino E.Dietary metabolites and the gut microbiota:an alternative approach to control inflammatory and autoimmune diseases.Clin Transl Immunol 2016;5:e82.

[84]Elangovan S,Pathania R,Ramachandran S,Ananth S,Padia RN,Lan L,et al.The niacin/butyrate receptor GPR109A suppresses mammary tumorigenesis by inhibiting cell survival.Cancer Res 2014;74:1166–78.

[85]Singh N,Gurav A,Sivaprakasam S,Brady E,Padia R,Shi H,et al.Activation of Gpr109a,receptor for niacin and the commensal metabolite butyrate,suppresses colonic inflammation and carcinogenesis.Immunity 2014;40:128–39.

[86]Bardhan K,Paschall AV,Yang D,Chen MR,Simon PS,Bhutia YD,et al.IFNγ induces DNA methylation-silenced GPR109A expression via pSTAT1/p300 and H3K18 acetylation in colon cancer.Cancer Immunol Res 2015;3:795–805.

[87]Pudlo NA,Urs K,Kumar SS,German JB,Mills DA,Martens EC.Symbiotic human gut bacteria with variable metabolic priorities for host mucosal glycans.MBio 2015;6,e01282–15.

[88]Nepelska M,Cultrone A,Be´guet-Crespel F,Le Roux K,Dore´J,Arulampalam V,et al.Butyrate produced by commensal bacteria potentiates phorbol esters induced AP-1 response in human intestinal epithelial cells.PLoS One 2012;7:e52869.

[89]Gonzalez-Sarrıas A,Gimenez-Bastida JA,Nunez-Sanchez M,Larrosa M,Garcıa-Conesa MT,Tomas-Barberan FA,et al.Phase-II metabolism limits the antiproliferative activity of urolithins in human colon cancer cells.Eur J Nutr 2014;53:853–64.

[90]Sharma M,Li L,Celver J,Killian C,Kovoor A,Seeram NP.Effects of fruit ellagitannin extracts,ellagic acid,and their colonic metabolite,urolithin A,on Wnt signaling.J Agric Food Chem 2010;58:3965–9.

[91]Saleh M,Trinchieri G.Innate immune mechanisms of colitis and colitis-associated colorectal cancer. Nat Rev Immunol 2011;11:9–20.

[92]Tomasello G,Tralongo P,Damiani P,Sinagra E,Di Trapani B,Zeenny MN,et al.Dismicrobism in inflammatory bowel disease and colorectal cancer:changes in response of colocytes.World J Gastroenterol 2014;20:18121–30.

[93]Sokol H,Leducq V,Aschard H,Pham HP,Jegou S,Landman C,et al.Fungal microbiota dysbiosis in IBD.Gut 2017;66:1039–48.

[94]Prindiville TP,Sheikh RA,Cohen SH,Tang YJ,Cantrell MC,Silva J.Bacteroides fragilis enterotoxin gene sequences in patients with inflammatory bowel disease.Emerg Infect Dis 2000;6:171–4.

[95]Basset C,Holton J,Bazeos A,Vaira D,Bloom S.Are Helicobacter species and enterotoxigenic Bacteroides fragilis involved in inflammatory bowel disease? Dig Dis Sci 2004;49:1425–32.

[96]Jurjus A,Eid A,Al Kattar S,Zeenny MN,Gerges-Geagea A,Haydar H,et al.Inflammatory bowel disease,colorectal cancer and type 2 diabetes mellitus:the links.BBA Clin 2016;5:16–24.

[97]Ou B,Zhao J,Guan S,Lu A.Survival of colorectal cancer in patients with or without inflammatory bowel disease:a metaanalysis.Dig Dis Sci 2016;61:881–9.

[98]Wu S,Powell J,Mathioudakis N,Kane S,Fernandez E,Sears CL.Bacteroides fragilis enterotoxin induces intestinal epithelial cell secretion of interleukin-8 through mitogen-activated protein kinases and a tyrosine kinase-regulated nuclear factor-kappaB pathway.Infect Immun 2004;72:5832–9.

[99]Wu S,Rhee KJ,Albesiano E,Rabizadeh S,Wu X,Yen HR,et al.A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses.Nat Med 2009;15:1016–22.

[100]Kim JM,Lee JY,Yoon YM,Oh YK,Kang JS,Kim YJ,et al.Bacteroides fragilis enterotoxin induces cyclooxygenase-2 and fluid secretion in intestinal epithelial cells through NF-kappaB activation.Eur J Immunol 2006;36:2446–56.

[101]Wu S,Morin PJ,Maouyo D,Sears CL.Bacteroides fragilis enterotoxin induces c-Myc expression and cellular proliferation.Gastroenterology 2003;124:392–400.

[102]Peters BA,Dominianni C,Shapiro JA,Church TR,Wu J,Miller G,et al.The gut microbiota in conventional and serrated precursors of colorectal cancer.Microbiome 2016;4:69.

[103]Dejea CM,Sears CL.Do biofilms confer a pro-carcinogenic state?Gut Microbes 2016;7:54–7.

[104]Coleman OI,Nunes T.Role of the microbiota in colorectal cancer:updates on microbial associations and therapeutic implications.Biores Open Access 2016;5:279–88.

[105]Gagniere J,Raisch J,Veziant J,Barnich N,Bonnet R,Buc E,et al.Gut microbiota imbalance and colorectal cancer.World J Gastroenterol 2016;22:501–18.

[106]Shen XJ,Rawls JF,Randall T,Burcal L,Mpande CN,Jenkins N,et al.Molecular characterization of mucosal adherent bacteria and associations with colorectal adenomas.Gut Microbes 2010;1:138–47.

[107]Castellarin M,Warren RL,Freeman JD,Dreolini L,Krzywinski M,Strauss J,et al.Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma.Genome Res 2012;22:299–306.

[108]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;14:195–206.

[109]Kostic AD,Chun E,Robertson L,Glickman JN,Gallini CA,Michaud M,et al.Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment.Cell Host Microbe 2013;14:207–15.

[110]Repass J,Maherali N,Owen K,Biology RPC,Biology RPC.Registered report:Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma.Elife 2016;5:e10012.

[111]Lightfoot YL,Mohamadzadeh M.Tailoring gut immune responses with lipoteichoic acid-deficient Lactobacillus acidophilus.Front Immunol 2013;4:25.

[112]Fukata M,Abreu MT.TLR4 signalling in the intestine in health and disease.Biochem Soc Trans 2007;35:1473–8.

[113]Rakoff-Nahoum S,Medzhitov R.Innate immune recognition of the indigenous microbial flora.Mucosal Immunol 2008;1:S10–4.

[114]Parlato M,Yeretssian G.NOD-like receptors in intestinal homeostasis and epithelial tissue repair.Int J Mol Sci 2014;15:9594–627.

[115]Asquith M,Powrie F.An innately dangerous balancing act:intestinal homeostasis,inflammation,and colitis-associated cancer.J Exp Med 2010;207:1573–7.

[116]Fukata M,Abreu MT.Microflora in colorectal cancer:a friend to fear.Nat Med 2010;16:639–41.

[117]An J,Ha EM.Combination therapy of Lactobacillus plantarum supernatant and 5-fluouracil increases chemosensitivity in colorectal cancer cells.J Microbiol Biotechnol 2016;26:1490–503.

[118]Beutler B.Inferences,questions and possibilities in Toll-like receptor signalling.Nature 2004;430:257–63.

[119]Moossavi S,Rezaei N.Toll-like receptor signalling and their therapeutic targeting in colorectal cancer.Int Immunopharmacol 2013;16:199–209.

[120]Lascorz J,Hemminki K,Forsti A.Systematic enrichment analysis of gene expression profiling studies identifies consensus pathways implicated in colorectal cancer development.J Carcinog 2011;10:7.

[121]Chen GY,Shaw MH,Redondo G,Nunez G.The innate immune receptor Nod1 protects the intestine from inflammation-induced tumorigenesis.Cancer Res 2008;68:10060–7.

[122]Arthur JC,Perez-Chanona E,Muhlbauer M,Tomkovich S,Uronis JM,Fan TJ,et al.Intestinal inflammation targets cancerinducing activity of the microbiota.Science 2012;338:120–3.

[123]NesicD,Hsu Y,Stebbins CE.Assembly and function of a bacterial genotoxin.Nature 2004;429:429–33.

[124]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;107:11537–42.

[125]De Rycke J,Oswald E.Cytolethal distending toxin(CDT):a bacterial weapon to control host cell proliferation?FEMS Microbiol Lett 2001;203:141–8.

[126]Lara-Tejero M,Galan JE.Cytolethal distending toxin:limited damage as a strategy to modulate cellular functions.Trends Microbiol 2002;10:147–52.

[127]Smith JL,Bayles DO.The contribution of cytolethal distending toxin to bacterial pathogenesis. Crit Rev Microbiol 2006;32:227–48.

[128]Yamtich J,Nemec AA,Keh A,Sweasy JB.A germline polymorphism of DNA polymerase beta induces genomic instability and cellular transformation.PLoS Genet 2012;8:e1003052.

[129]Huycke MM,Abrams V,Moore DR.Enterococcus faecalis produces extracellular superoxide and hydrogen peroxide that damages colonic epithelial cell DNA. Carcinogenesis 2002;23:529–36.

[130]Wang X,Huycke MM.Extracellular superoxide production by Enterococcus faecalis promotes chromosomal instability in mammalian cells.Gastroenterology 2007;132:551–61.

[131]Klimesova K,Kverka M,Zakostelska Z,Hudcovic T,Hrncir T,Stepankova R,et al.Altered gut microbiota promotes colitisassociated cancer in IL-1 receptor-associated kinase M-deficient mice.Inflamm Bowel Dis 2013;19:1266–77.

[132]Ray D,Kidane D.Gut microbiota imbalance and base excision repair dynamics in colon cancer.J Cancer 2016;7:1421–30.

[133]Brevik A,Joshi AD,Corral R,Onland-Moret NC,Siegmund KD,Le Marchand L,et al.Polymorphisms in base excision repair genes as colorectal cancer risk factors and modifiers of the effect of diets high in red meat.Cancer Epidemiol Biomarkers Prev 2010;19:3167–73.

[134]Ogino S,Lochhead P,Giovannucci E,Meyerhardt JA,Fuchs CS,Chan AT.Discovery of colorectal cancer PIK3CA mutation as potential predictive biomarker:power and promise of molecular pathological epidemiology.Oncogene 2014;33:2949–55.

[135]Umar S.Enteric pathogens and cellular transformation:bridging the gaps.Oncotarget 2014;5:6573–5.

[136]Thiery JP,Acloque H,Huang RY,Nieto MA.Epithelialmesenchymal transitions in development and disease.Cell 2009;139:871–90.

[137]Chandrakesan P,Roy B,Jakkula LU,Ahmed I,Ramamoorthy P,Tawfik O,et al.Utility of a bacterial infection model to study epithelial-mesenchymal transition,mesenchymal-epithelial transition or tumorigenesis.Oncogene 2014;33:2639–54.

[138]Li CW,Xia W,Huo L,Lim SO,Wu Y,Hsu JL,et al.Epithelialmesenchymal transition induced by TNF-α requires NF-κB-mediated transcriptional upregulation of Twist1.Cancer Res 2012;72:1290–300.

[139]Mladinich M,Ruan D,Chan CH.Tackling cancer stem cells via inhibition of EMT transcription factors.Stem Cells Int 2016;2016:5285892.

[140]Ohtani N.Microbiome and cancer.Semin Immunopathol 2015;37:65–72.

[141]Schinzari V,Barnaba V,Piconese S.Chronic hepatitis B virus and hepatitis C virus infections and cancer:synergy between viral and host factors.Clin Microbiol Infect 2015;21:969–74.

[142]Wong CR,Nguyen MH,Lim JK.Hepatocellular carcinoma in patients with non-alcoholic fatty liver disease.World J Gastroenterol 2016;22:8294–303.

[143]French SW.Epigenetic events in liver cancer resulting from alcoholic liver disease.Alcohol Res 2013;35:57–67.

[144]Yu J,Marsh S,Hu J,Feng W,Wu C.The pathogenesis of nonalcoholic fatty liver disease:interplay between diet,gut microbiota,and genetic background.Gastroenterol Res Pract 2016;2016:2862173.

[145]Aqel B,DiBaise JK.Role of the gut microbiome in nonalcoholic fatty liver disease.Nutr Clin Pract 2015;30:780–6.

[146]Grat M,Wronka KM,Krasnodebski M,Masior Ł,Lewandowski Z,Kosin´ska I,et al.Profile of gut microbiota associated with the presence of hepatocellular cancer in patients with liver cirrhosis.Transplant Proc 2016;48:1687–91.

[147]Chng KR,Chan SH,Ng AH,Li C,Jusakul A,Bertrand D,et al.Tissue microbiome profiling identifies an enrichment of specific enteric bacteria in Opisthorchis viverrini associated cholangiocarcinoma.EBioMedicine 2016;8:195–202.

[148]Roubaud Baudron C,Franceschi F,Salles N,Gasbarrini A.Extragastric diseases and Helicobacter pylori.Helicobacter 2013;18:44–51.

[149]Pellicano R,Me´nard A,Rizzetto M,Me´graud F.Helicobacter species and liver diseases:association or causation?Lancet Infect Dis 2008;8:254–60.

[150]de Magalha˜es Queiroz DM,Santos A.Isolation of a Helicobacter strain from the human liver. Gastroenterology 2001;121:1023–4.

[151]Tu QV,Okoli AS,Kovach Z,Mendz GL.Hepatocellular carcinoma:prevalence and molecular pathogenesis of Helicobacter spp..Future Microbiol 2009;4:1283–301.

[152]Tsuneyama K,Harada K,Kono N,Hiramatsu K,Zen Y,Sudo Y,et al.Scavenger cells with gram-positive bacterial lipoteichoic acid infiltrate around the damaged interlobular bile ducts of primary biliary cirrhosis.J Hepatol 2001;35:156–63.

[153]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;47:1638–43.

[154]Queiroz DM,Rocha AM,Rocha GA,Cinque SM,Oliveira AG,Godoy A,et al.Association between Helicobacter pylori infection and cirrhosis in patients with chronic hepatitis C virus.Dig Dis Sci 2006;51:370–3.

[155]Liu X,Liang J,Li G.Lipopolysaccharide promotes adhesion and invasion of hepatoma cell lines HepG2 and HepG2.2.15.Mol Biol Rep 2010;37:2235–9.

[156]Fox JG,Feng Y,Theve EJ,Raczynski AR,Fiala JL,Doernte AL,et al.Gut microbes define liver cancer risk in mice exposed to chemical and viral transgenic hepatocarcinogens.Gut 2010;59:88–97.

[157]Zhou D,Wang JD,Weng MZ,Zhang Y,Wang XF,Gong W,et al.Infections of Helicobacter spp.in the biliary system are associated with biliary tract cancer:a meta-analysis.Eur J Gastroenterol Hepatol 2013;25:447–54.

[158]Maeda S,Kamata H,Luo JL,Leffert H,Karin M.IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis.Cell 2005;121:977–90.

[159]Dapito DH,Mencin A,Gwak GY,Pradere JP,Jang MK,Mederacke I,et al.Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4.Cancer Cell 2012;21:504–16.

[160]Szabo G,Dolganiuc A,Mandrekar P.Pattern recognition receptors:a contemporary view on liver diseases.Hepatology 2006;44:287–98.

[161]Yu LX,Yan HX,Liu Q,Yang W,Wu HP,Dong W,et al.Endotoxin accumulation prevents carcinogen-induced apoptosis and promotes liver tumorigenesis in rodents.Hepatology 2010;52:1322–33.

[162]Payne CM,Weber C,Crowley-Skillicorn C,Dvorak K,Bernstein H,Bernstein C,et al.Deoxycholate induces mitochondrial oxidative stress and activates NF-kappaB through multiple mechanisms in HCT-116 colon epithelial cells.Carcinogenesis 2007;28:215–22.

[163]Ridlon JM,Kang DJ,Hylemon PB,Bajaj JS.Bile acids and the gut microbiome.Curr Opin Gastroenterol 2014;30:332–8.

[164]Yoshimoto S,Loo TM,Atarashi K,Kanda H,Sato S,Oyadomari S,et al.Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome.Nature 2013;499:97–101.

[165]Hara E.Relationship between obesity,gut microbiome and hepatocellular carcinoma development.Dig Dis 2015;33:346–50.

[166]Carvalho BM,Saad MJ.Influence of gut microbiota on subclinical inflammation and insulin resistance.Mediators Inflamm 2013;2013:986734.

[167]Turati F,Talamini R,Pelucchi C,Polesel J,Franceschi S,Crispo A,et al.Metabolic syndrome and hepatocellular carcinoma risk.Br J Cancer 2013;108:222–8.

[168]Borena W,Strohmaier S,Lukanova A,Bjørge T,Lindkvist B,Hallmans G,et al.Metabolic risk factors and primary liver cancer in a prospective study of 578,700 adults.Int J Cancer 2012;131:193–200.

[169]Park EJ,Lee JH,Yu GY,He G,Ali SR,Holzer RG,et al.Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression.Cell 2010;140:197–208.

[170]Wang C,Li J.Pathogenic microorganisms and pancreatic cancer.Gastrointest Tumors 2015;2:41–7.

[171]Michaud DS,Izard J.Microbiota,oral microbiome,and pancreatic cancer.Cancer J 2014;20:203–6.

[172]Zambirinis CP,Pushalkar S,Saxena D,Miller G.Pancreatic cancer, inflammation, and microbiome. Cancer J 2014;20:195–202.

[173]Yu H,Pardoll D,Jove R.STATs in cancer inflammation and immunity:a leading role for STAT3.Nat Rev Cancer 2009;9:798–809.

[174]Rabelo-Gonc¸alves EM,Roesler BM,Zeitune JM.Extragastric manifestations of Helicobacter pylori infection:possible role of bacterium in liver and pancreas diseases.World J Hepatol 2015;7:2968–79.

[175]Bulajic M,Panic N,Lohr JM.Helicobacter pylori and pancreatic diseases.World J Gastrointest Pathophysiol 2014;5:380–3.

[176]Goni E,Franceschi F.Helicobacter pylori and extragastric diseases.Helicobacter 2016;21:45–8.

[177]Warzecha Z,Dembin´ski A,Ceranowicz P,Dembin´ski M,Sendur R,Pawlik WW,et al.Deleterious effect of Helicobacter pylori infection on the course of acute pancreatitis in rats.Pancreatology 2002;2:386–95.

[178]Niemann T,Larsen S,Mouritsen EA,Thorsgaard N.Helicobacter pylori infection in patients with chronic pancreatitis and duodenal ulcer.Scand J Gastroenterol 1997;32:1201–3.

[179]Manes G,Dominguez-Munoz JE,Hackelsberger A,Leodolter A,Rossner A,Malfertheiner P.Prevalence of Helicobacter pylori infection and gastric mucosal abnormalities in chronic pancreatitis.Am J Gastroenterol 1998;93:1097–100.

[180]Kountouras J,Zavos C,Chatzopoulos D.A concept on the role of Helicobacter pylori infection in autoimmune pancreatitis.J Cell Mol Med 2005;9:196–207.

[181]Manes G,Balzano A,Vaira D.Helicobacter pylori and pancreatic disease.JOP 2003;4:111–6.

[182]Takayama S,Takahashi H,Matsuo Y,Okada Y,Manabe T.Effects of Helicobacter pylori infection on human pancreatic cancer cell line.Hepatogastroenterology 2007;54:2387–91.

[183]di Magliano MP,Logsdon CD.Roles for KRAS in pancreatic tumor development and progression. Gastroenterology 2013;144:1220–9.

[184]Huang H,Daniluk J,Liu Y,Chu J,Li Z,Ji B,et al.Oncogenic K-Ras requires activation for enhanced activity.Oncogene 2014;33:532–5.

[185]Daniluk J,Liu Y,Deng D,Chu J,Huang H,Gaiser S,et al.An NF-κB pathway-mediated positive feedback loop amplifies Ras activity to pathological levels in mice. J Clin Invest 2012;122:1519–28.

[186]Fukuda A,Wang SC,Morris JP,Folias AE,Liou A,Kim GE,et al.Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression. Cancer Cell 2011;19:441–55.

[187]Lesina M,Kurkowski MU,Ludes K,Rose-John S,Treiber M,Kloppel G,et al.Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer.Cancer Cell 2011;19:456–69.

[188]Wormann SM,Diakopoulos KN,Lesina M,Algul H.The immune network in pancreatic cancer development and progression.Oncogene 2014;33:2956–67.

[189]Sharif R,Dawra R,Wasiluk K,Phillips P,Dudeja V,Kurt-Jones E,et al.Impact of toll-like receptor 4 on the severity of acute pancreatitis and pancreatitis-associated lung injury in mice.Gut 2009;58:813–9.

[190]Ochi A,Graffeo CS,Zambirinis CP,Rehman A,Hackman M,Fallon N,et al.Toll-like receptor 7 regulates pancreatic carcinogenesis in mice and humans. J Clin Invest 2012;122:4118–29.

[191]Ochi A,Nguyen AH,Bedrosian AS,Mushlin HM,Zarbakhsh S,Barilla R,et al.MyD88 inhibition amplifies dendritic cell capacity to promote pancreatic carcinogenesis via Th2 cells.J Exp Med 2012;209:1671–87.

[192]Ding SP,Li JC,Jin C.A mouse model of severe acute pancreatitis induced with caerulein and lipopolysaccharide.World J Gastroenterol 2003;9:584–9.

[193]Alam MS,Gaida MM,Bergmann F,Lasitschka F,Giese T,Giese NA,et al.Selective inhibition of the p38 alternative activation pathway in infiltrating T cells inhibits pancreatic cancer progression.Nat Med 2015;21:1337–43.

[194]Gaida MM,Mayer C,Dapunt U,Stegmaier S,Schirmacher P,Wabnitz GH,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;7:12623–32.

[195]Mitsuhashi K,Nosho K,Sukawa Y,Matsunaga Y,Ito M,Kurihara H,et al.Association of Fusobacterium species in pancreatic cancer tissues with molecular features and prognosis.Oncotarget 2015;6:7209–20.

[196]Pandey KR,Naik SR,Vakil BV.Probiotics,prebiotics and synbiotics-a review.J Food Sci Technol 2015;52:7577–87.

[197]Greiner AK,Papineni RV,Umar S.Chemoprevention in gastrointestinal physiology and disease.Natural products and microbiome.Am J Physiol Gastrointest Liver Physiol 2014;307:G1–G15.

[198]Power KA,Lepp D,Zarepoor L,Monk JM,Wu W,Tsao R,et al.Dietary flaxseed modulates the colonic microenvironment in healthy C57Bl/6 male mice which may alter susceptibility to gut-associated diseases.J Nutr Biochem 2016;28:61–9.

[199]Pattananandecha T,Sirilun S,Duangjitcharoen Y,Sivamaruthi BS,Suwannalert P,Peerajan S,et al.Hydrolysed inulin alleviates the azoxymethane-induced preneoplastic aberrant crypt foci by altering selected intestinal microbiota in Sprague-Dawley rats.Pharm Biol 2016;54:1596–605.

[200]Wang P,Chen H,Zhu Y,McBride J,Fu J,Sang S.Oat avenanthramide-C(2c)is biotransformed by mice and the human microbiota into bioactive metabolites.J Nutr 2015;145:239–45.

[201]Nunez-Sanchez MA,Garcia-Villalba R,Monedero-Saiz T,Garcia-Talavera NV,Gomez-Sanchez MB,Sanchez-alvarez C,et al.Targeted metabolic profiling of pomegranate polyphenols and urolithins in plasma,urine and colon tissues from colorectal cancer patients.Mol Nutr Food Res 2014;58:1199–211.

[202]Allsopp P,Possemiers S,Campbell D,Gill C,Rowland I.A comparison of the anticancer properties of isoxanthohumol and 8-prenylnaringenin using in vitro models of colon cancer.Biofactors 2013;39:441–7.

[203]Higashimura Y,Naito Y,Takagi T,Uchiyama K,Mizushima K,Ushiroda C,et al.Protective effect of agaro-oligosaccharides on gut dysbiosis and colon tumorigenesis in high-fat diet-fed mice.Am J Physiol Gastrointest Liver Physiol 2016;310:G367–75.

[204]Li F,Yang XW,Krausz KW,Nichols RG,Xu W,Patterson AD,et al.Modulation of colon cancer by nutmeg.J Proteome Res 2015;14:1937–46.

[205]Schlormann W,Birringer M,Lochner A,Lorkowski S,Richter I,Rohrer C,et al.In vitro fermentation of nuts results in the formation of butyrate and c9,t11 conjugated linoleic acid as chemopreventive metabolites.Eur J Nutr 2016;55:2063–73.

[206]Miene C,Weise A,Glei M.Impact of polyphenol metabolites produced by colonic microbiota on expression of COX-2 and GSTT2 in human colon cells (LT97).Nutr Cancer 2011;63:653–62.

[207]Piazzi G,D’Argenio G,Prossomariti A,Lembo V,Mazzone G,Candela M,et al.Eicosapentaenoic acid free fatty acid prevents and suppresses colonic neoplasia in colitis-associated colorectal cancer acting on Notch signaling and gut microbiota.Int J Cancer 2014;135:2004–13.

[208]Winkels RM,Heine-Broring RC,van Zutphen M,van Harten-Gerritsen S,Kok DE,van Duijnhoven FJ,et al.The COLON study:colorectal cancer:longitudinal,observational study on nutritional and lifestyle factors that may influence colorectal tumour recurrence,survival and quality of life.BMC Cancer 2014;14:374.

[209]Costabile A,Fava F,RoytioH,Forssten SD,Olli K,Klievink J,et al.Impact of polydextrose on the faecal microbiota:a doubleblind,crossover,placebo-controlled feeding study in healthy human subjects.Br J Nutr 2012;108:471–81.

[210]Eid N,Osmanova H,Natchez C,Walton G,Costabile A,Gibson G,et al.Impact of palm date consumption on microbiota growth and large intestinal health:a randomised,controlled,cross-over,human intervention study.Br J Nutr 2015;114:1226–36.

[211]Zhu Y,Michelle Luo T,Jobin C,Young HA.Gut microbiota and probiotics in colon tumorigenesis. Cancer Lett 2011;309:119–27.

[212]Tojo R,Suarez A,Clemente MG,de los Reyes-Gavilan CG,Margolles A,Gueimonde M,et al.Intestinal microbiota in health and disease:role of bifidobacteria in gut homeostasis.World J Gastroenterol 2014;20:15163–76.

[213]Ambalam P,Raman M,Purama RK,Doble M.Probiotics,prebiotics and colorectal cancer prevention.Best Pract Res Clin Gastroenterol 2016;30:119–31.

[214]Gianotti L,Morelli L,Galbiati F,Rocchetti S,Coppola S,Beneduce A,et al.A randomized double-blind trial on perioperative administration of probiotics in colorectal cancer patients.World J Gastroenterol 2010;16:167–75.

[215]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;53:398–405.

[216]Kuugbee ED,Shang X,Gamallat Y,Bamba D,Awadasseid A,Suliman MA,et al.Structural change in microbiota by a probiotic cocktail enhances the gut barrier and reduces cancer via TLR2 signaling in a rat model of colon cancer.Dig Dis Sci 2016;61:2908–20.

[217]Li J,Sung CY,Lee N,Ni Y,Pihlajamäki J,Panagiotou G,et al.Probiotics modulated gut microbiota suppresses hepatocellular carcinoma growth in mice.Proc Natl Acad Sci U S A 2016;113:E1306–15.

[218]Jakobsson HE,Jernberg C,Andersson AF,Sjolund-Karlsson M,Jansson JK,Engstrand L.Short-term antibiotic treatment has differing long-term impacts on the human throat and gut microbiome.PLoS One 2010;5:e9836.

[219]Oh B,Kim BS,Kim JW,Kim JS,Koh SJ,Kim BG,et al.The effect of probiotics on gut microbiota during the Helicobacter pylori eradication:randomized controlled trial.Helicobacter 2016;21:165–74.

[220]Motoori M,Yano M,Miyata H,Sugimura K,Saito T,Omori T,et al.Randomized study of the effect of synbiotics during neoadjuvant chemotherapy on adverse events in esophageal cancer patients.Clin Nutr 2017;36:93–9.

[221]Abreu MT,Peek RM.Gastrointestinal malignancy and the microbiome.Gastroenterology 2014;146:1534–46.

[222]Couturier-Maillard A,Secher T,Rehman A,Normand S,De Arcangelis A,Haesler R,et al.NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer.J Clin Invest 2013;123:700–11.

[223]Pestell RG,Rizvanov AA.Antibiotics for cancer therapy.Oncotarget 2015;6:2587–8.

[224]Zackular JP,Baxter NT,Chen GY,Schloss PD.Manipulation of the gut microbiota reveals role in colon tumorigenesis.mSphere 2015;1:e00001–15.

[225]DeStefano Shields CE,Van Meerbeke SW,Housseau F,Wang H,Huso DL,Casero RA,et al.Reduction of murine colon tumorigenesis driven by enterotoxigenic Bacteroides fragilis using Cefoxitin Treatment.J Infect Dis 2016;214:122–9.

[226]Boursi B,Mamtani R,Haynes K,Yang YX.Recurrent antibiotic exposure may promote cancer formation–another step in understanding the role of the human microbiota?Eur J Cancer 2015;51:2655–64.

[227]Yang B,Hagberg KW,Chen J,Sahasrabuddhe VV,Graubard BI,Jick S,et al.Associations of antibiotic use with risk of primary liver cancer in the clinical practice research datalink.Br J Cancer 2016;115:85–9.

[228]Montrose DC,Zhou XK,McNally EM,Sue E,Yantiss RK,Gross SS,et al.Celecoxib alters the intestinal microbiota and metabolome in association with reducing polyp burden.Cancer Prev Res(Phila)2016;9:721–31.

[229]Wallace BD,Wang H,Lane KT,Scott JE,Orans J,Koo JS,et al.Alleviating cancer drug toxicity by inhibiting a bacterial enzyme.Science 2010;330:831–5.

[230]Lin XB,Dieleman LA,Ketabi A,Bibova I,Sawyer MB,Xue H,et al.Irinotecan (CPT-11)chemotherapy alters intestinal microbiota in tumour bearing rats.PLoS One 2012;7:e39764.

[231]Gonzalez-Sarrias A,Tome´-Carneiro J,Bellesia A,Tomas-Barberan FA,Espin JC.The ellagic acid-derived gut microbiota metabolite,urolithin A,potentiates the anticancer effects of 5-fluorouracil chemotherapy on human colon cancer cells.Food Funct 2015;6:1460–9.

[232]Leslie M.MICROBIOME.Microbes aid cancer drugs.Science 2015;350:614–5.

[233]Ve´tizou M,Pitt JM,Daillere R,Lepage P,Waldschmitt N,Flament C,et al.Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota.Science 2015;350:1079–84.

[234]Sivan A,Corrales L,Hubert N,Williams JB,Aquino-Michaels K,Earley ZM,et al.Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy.Science 2015;350:1084–9.

[235]Wang CZ,Zhang CF,Chen L,Anderson S,Lu F,Yuan CS.Colon cancer chemopreventive effects of baicalein,an active enteric microbiome metabolite from baicalin.Int J Oncol 2015;47:1749–58.

[236]McFadden RM,Larmonier CB,Shehab KW,Midura-Kiela M,Ramalingam R,Harrison CA,et al.The role of curcumin in modulating colonic microbiota during colitis and colon cancer prevention.Inflamm Bowel Dis 2015;21:2483–94.

[237]Nelson KM,Dahlin JL,Bisson J,Graham J,Pauli GF,Walters MA.The essential medicinal chemistry of curcumin.J Med Chem 2017;60:1620–37.

[238]Lam W,Bussom S,Guan F,Jiang Z,Zhang W,Gullen EA,et al.The four-herb Chinese medicine PHY906 reduces chemotherapyinduced gastrointestinal toxicity.Sci Transl Med 2010;2:45ra59.

[239]Lam W,Jiang Z,Guan F,Hu R,Liu SH,Chu E,et al.The number of intestinal bacteria is not critical for the enhancement of antitumor activity and reduction of intestinal toxicity of irinotecan by the Chinese herbal medicine PHY906(KD018).BMC Complement Altern Med 2014;14:490.

[240]Kummar S,Copur MS,Rose M,Wadler S,Stephenson J,O’Rourke M,et al.A phase I study of the Chinese herbal medicine PHY906 as a modulator of irinotecan-based chemotherapy in patients with advanced colorectal cancer.Clin Colorectal Cancer 2011;10:85–96.

[241]Wang E,Bussom S,Chen J,Quinn C,Bedognetti D,Lam W,et al.Interaction of a traditional Chinese medicine(PHY906)and CPT-11 on the inflammatory process in the tumor microenvironment.BMC Med Genomics 2011;4:38.

[242]Zhang W,Saif MW,Dutschman GE,Li X,Lam W,Bussom S,et al.Identification of chemicals and their metabolites from PHY906,a Chinese medicine formulation,in the plasma of a patient treated with irinotecan and PHY906 using liquid chromatography/tandem mass spectrometry(LC/MS/MS).J Chromatogr A 2010;1217:5785–93.

[243]Farrell MP,Kummar S.Phase I/IIA randomized study of PHY906,a novel herbal agent,as a modulator of chemotherapy in patients with advanced colorectal cancer.Clin Colorectal Cancer 2003;2:253–6.

[244]Mima K,Nishihara R,Qian ZR,Cao Y,Sukawa Y,Nowak JA,et al.Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis.Gut 2016;65:1974–80.