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

Figures & data

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.

Table 1 GIT Cancers and Microbiota

Study	Source of Samples	Microbiota	Findings
OSCC
Nagy et al^Citation64	Tissues	Veillonella, Fusobacterium, Prevotella, Porphyromonas, Actinomyces, Clostridium, Haemophilus, Enterobacteriaceae, Streptococcus spp.	Higher in OSCC vs adjacent healthy mucosa
Katz et al^Citation65	Tissues	P. gingivalis	Higher in gingival SCC vs normal gingiva
Tateda et al^Citation66	Gingival smears	S. anginosus	High in HNSCC
Sasaki et al^Citation67	Tissues/plaque	S. anginosus	High in OSCC tissues and dental plaque
Mager et al^Citation68	Saliva	C. gingivalis, P^ҙ. melaninogenica, S. mitis	Higher in OSCC patients vs healthy controls
Pushalkar et al^Citation69	Saliva	Streptococcus, Rothia, Gemella, Peptostreptococcus, Porphyromonas, Micromonas, Lactobacillus	Higher in OSCC vs healthy controls
		P^ҙ. Neisseria, Leptotrichia, Capnocytophaga, Actinobacillus, Oribacterium	Lower in OSCC vs healthy controls
Schmidt et al^Citation70	Tissues	Streptococcus and Rothia Fusobacterium	Lower in OSCC vs contra-lateral normal High in OSCC vs contra-lateral normal
Chang et al^Citation72	Tissues/plaque	P. gingivalis, F. nucleatum, S. sanguinis	High in OSCC, paracancerous and subgingival plaque vs normal tissues
Esophageal Cancer
Narikiyo et al^Citation97	Tissues/saliva	T. denticola, S. mitis, and S. anginosus	High in esophageal cancer and normal tissues from patients vs saliva from healthy controls
Zaidi et al^Citation100	Tissues	E. coli	High in Barrett’s esophagus and EAC vs adjacent normal, dysplasia, and GERD within patients
Nasrollahzadeh et al^Citation103	Tissues	Clostridiales, Erysipelotrichales	High in gastric corpus of esophageal cancer vs normal esophagus
Chen et al^Citation105	Saliva	Lautropia, Bulleidia, Catonella, Corynebacterium, Moryella, Peptococcus, Cardiobacterium	Lower in ESCC vs healthy controls
Gao et al^Citation106	Tissues	P. gingivalis	High in ESSC, adjacent mucosal vs healthy controls
Peters et al^Citation107	Mouthwash samples	T^ҙ. forsythia P. gingivalis	High in EAC High in ESCC
Meng et al^Citation104	Saliva	P. gingivalis	High in ESCC vs healthy controls
Yamamura et al^Citation109	Tissues	F. nucleatum	Higher in ESCC vs normal controls and significantly linked to shorter survival time
Gastric Cancer
Nomura et al^Citation407	Serum IgG Ab	H. Pylori	Higher in GC vs normal controls
Kikuchi et al^Citation133	Serum CagA Ab	H. Pylori	H. Pylori are related to risks of intestinal-type, diffuse-type, early, advanced, and distal GC
Bartchewsky et al^Citation129	Tissues	H. Pylori	CagA, VacA virulence factors are higher in GC vs chronic gastritis, H. Pylori-positive, and uninfected individuals
Correa et al^Citation143	HPE	H. Pylori	HPE (patients with multifocal nonmetaplastic atrophy and/or intestinal metaplasia, precancerous lesions) interferes with the precancerous process and increases the rate of regression of precursor lesions
Chen et al^Citation148 Rokkas et al^Citation149	HPE	H. Pylori	HPE was linked to reduced risk, when the lesions were non-atrophic or atrophic gastritis but not in intestinal metaplastic or dysplastic lesions
Gastric MALT Lymphoma
Wotherspoon et al^Citation157	Tissues	H. Pylori	Expression in most investigated samples Gastric MALT lymphoma
Parsonnet et al^Citation160	Serum	H. Pylori	Higher H. Pylori in gastric lymphoma vs non-gastric lymphoma
Stolte et al^Citation161	HPE	H. Pylori	Complete remission in 80% of low grade stage E1 lymphomas patients
Gastric DLBCL
Morgner et al^Citation191	HPE	H. Pylori	HPE led to complete remission in 7/8 patients with DLBCL.
Kuo et al^Citation186	HPE	H. Pylori	HPE led to complete pathological response in most of DLBCL cases
Kuo et al^Citation187	CagA	H. Pylori	CagA detected in gastric DLBCL and is associated with H. Pylori dependence
Chen et al^Citation192	HPE/long-term follow-up	H. Pylori	No tumor recurrence was observed in DLBCL (MALT) after more than 5 years in complete responders
CRC
Klein et al^Citation209	Fecal sample	S. bovis/S. gallolytucis	Higher in colon cancer vs controls
Abdulamir et al^Citation210,Citation408	Feces, mucosa of colorectum, and colorectal tissues	S. bovis/S. gallolytucis	High in CRC tissues vs healthy controls 25–80% of patients with S. gallolytucis bacteremia had CRC
Sobhani et al^Citation214	Fecal sample	Bacteroides/Prevotella	Higher in CRC patients vs controls
Wang et al^Citation215	Fecal sample	B. fragilis, Enterococcus, Escherichia/Shigella, Klebsiella, Streptococcus, Peptostreptococcus,	Higher in CRC patients vs controls
		Roseburia, Lachnospiraceae	Lower level
Purcell et al^Citation216	Mucosal tissue	ETBF	Higher in early-stage lesions
Boleij et al^Citation222	Mucosal tissues	ETBF	Higher in CRC patients vs controls
Maddocks et al^Citation224	Tissues	E. coli	Higher in CRC vs normal colonic mucosa of CRC patients
Buc et al^Citation226	Tissues	E. coli	Cnf and Cdt higher in CRC vs diverticulosis
Bundgaard-Nielsen et al^Citation232	Tissues	F. nucleatum and B. fragilis	Higher in CRC and diverticular vs adenoma
Amitay et al^Citation233	Fecal samples	F. nucleatum	Higher in CRC vs advanced adenomas, non-advanced adenomas and normal controls
Balamurugan et al^Citation240	Fecal samples	E^ҙ. faecalis	Higher in CRC vs normal controls
Rokkas et al^Citation149 Wu et al^Citation244 Chen et al^Citation245	CRC/adenomas vs healthy controls	H. Pylori	Positive association between H. Pylori and the risk of CRC
Teimoorian et al^Citation246	Serum	H. Pylori	H. Pylori higher in colon cancer and adenomatous polyps vs healthy controls
Marchesi et al^Citation250	Tissues	Coriobacteridae, Roseburia, Fusobacterium and Faecalibacterium	Higher in cancer, vs healthy tissues within CRC patients
		Enterobacteriaceae, Citrobacter, Shigella, Cronobacter, and Salmonella	Lower in CRC tissues
Shah et al^Citation251	CRC vs adjacent tissues/fecal samples	Fusobacterium, Parvimonas, Streptococcus	Higher in CRC
		Faecalibacterium, Ruminococcaceae	Lower in CRC vs tumor-adjacent tissues/fecal samples from same cases
HCC
Zhang et al^Citation302	Fecal/cecal samples	Lactobacillus, Bifidobacterium, Enterococcus	Lower in rat model of (DEN) induced HCC
		E. coli and Atopobium cluster	Higher level
Yoshimoto et al^Citation304	Fecal sample	Clostridium genus producing DCA	High in genetically or (HFD)-induced obesity in mice model. Higher incidence of HCC upon the administration of the chemical carcinogen (DMBA)
Xie et al^Citation305	Fecal sample	Atopobium, Bacteroides, Clostridium, Desulfovibrio	High in mice model mimics the development of steatosis and subsequent progression to NASH and HCC. Correlated with LPS levels and the pathophysiological features
Fox et al^Citation307	Liver tumors	H. hepaticus	Intestinal colonization was sufficient to promote aflatoxin- and HCV transgene-induced HCC in exposed mice
Huang et al^Citation308	Tissues	Helicobacter spp.	Higher in HCC vs controls
Dore et al^Citation309	Tissues	H. Pylori	VacA and CagA higher level in HCC
Lu et al^Citation312	Tongue coat	Oribacterium and Fusobacterium	Higher in HCC vs healthy controls
Grat et al^Citation313	Fecal samples	E. coli	Higher in HCC in cirrhosis/HCC vs cirrhosis only
Ponziani et al^Citation314	Fecal samples	Bacteroides and Ruminococcaceae Bifidobacterium	Higher in NAFLD-cirrhosis/HCC vs NAFLD-cirrhosis Lower level
Pancreatic Cancer
Raderer et al^Citation337	Blood samples	H. Pylori	Twofold increase in risk in infected patients with pancreatic carcinoma vs controls
Stolzenberg-Solomon et al^Citation338	Serum level of Abs of H. Pylori and CagA+	H. Pylori	Smoker men, seropositive males for antibodies or CagA+ strains had increased risk for pancreatic cancer compared with seronegative.
Michaud et al^Citation359	Blood samples/Abs	P. gingivalis	Twofold increase in risk of pancreatic cancer in patients with high P. gingivalis
Mitsuhashi et al^Citation364	Tissues	Fusobacterium spp.	Found in 8.8% of PDAC tissues
Gaida et al^Citation365	Tissues/cell lines	P^ж. aeruginosa	Enhanced the expression of ABCB1 in PDAC and promoted cell invasion and metastasis
Gallbladder Cancer
Nagaraja et al^Citation377	S^ҙ.Typhi Ab/GBC vs control	S^ҙ. Typhi	Chronic S^ҙ. Typhi carrier state is important risk factor among GBC patients
Caygill et all^Citation385	Long-term typhoid carriage	S^ҙ. Typhi	Chronic typhoid carriers have an almost 167-fold higher risk of GBC
Shukla et al^Citation386	Culture/S^ҙ.Typhi Vi Ab	S^ҙ.Typhi	Eightfold more risk of GBC in culture-positive typhoid carriers than non-carriers
Yakoob et al^Citation380	Bile/GB tissues	H. Pylori	Higher in chronic cholecystitis and GBC
Parajuli et al^Citation399	GB tissues	H. hepaticus	Higher in GBC vs chronic cholecystitis
Murata et al^Citation400	GB tissues	H. bilis	Higher in GBC, bile duct cancer vs cholecystolithiasis
Fallone et al^Citation401	Bile	Helicobacter spp.	Not detected in patients diagnosed with gallstones or hepato-biliary malignancies
Csendes et al^Citation404	Bile	E. coli, E^ҙ. faecalis, Klebsiella and Enterobacter	Higher in GBC, gallstones vs controls
Roa et al^Citation405	Bile	E. coli, Streptococci-Enterococci, Enterobacter, Klebsiella, Proteus	Higher in GBC vs controls, S^ҙ. Typhi not detected
Tsuchiya et al^Citation381	Bile	F. nucleatum, E. coli, Enterobacter	High in GBC, S^ҙ. Typhi not detected

Note: Plain rows represent clinical studies, rows highlighted with pink represent meta-analysis/systematic reviews and rows highlighted with blue represent in vivo studies.

Abbreviations: Ab, antibody; ABCB1, ATP-binding cassette sub-family B member 1; B, Bifidobacterium; C, Capnocytophaga; CagA, cytotoxin-associated gene A; Cdt; cytolethal distending toxin; Cnf, cytotoxic necrotizing factor; CRC, colorectal cancer; CYP450, Cytochrome P450 enzymes; DCA, deoxycholic acid; DEN, diethylnitrosamine; DLBCL, diffuse large B cell lymphoma; DMBA, dimethylbenz(a)anthracene; DMH, 1;2-dimethylhydrazine; E, Escherichia; E^ҙ, Enterococcus; EAC, esophageal adenocarcinoma; ETBF, Enterotoxigenic Bacteroides fragilis; ESCC, esophageal squamous cell carcinoma; F, Fusobacterium; FAP, familial adenomatous polyposis; GB, gallbladder; GBC, gallbladder cancer; GC, gastric cancer; GERD, gastroesophageal reflux disorder; GIT, gastrointestinal tract; H, Helicobacter; HCC, Hepatocellular carcinoma, HCV, hepatitis C virus; HFD, high-fat diet; HNSCC, head and neck squamous cell carcinoma; HPE, H. Pylori eradication therapy; IgG, immunoglobulin G; L, Lactobacillus; LPS, Lipopolysaccharide; MALT, mucosa-associated lymphoid tissue; NAFLD, non-alcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; OSCC, oral squamous cell carcinoma; PDAC, pancreatic ductal adenocarcinoma; P, Porphyromonas; P^ҙ, Prevotella; P^ж, Pseudomonas; S, Streptococcus; S^ҙ, Salmonella; SCC, squamous cell carcinoma; spp, species; T, Treponema; T^ҙ, Tannerella; VacA, vacuolating cytotoxin A; vs, versus.

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

Probiotic Strains	Model of Investigation	Findings
Gastric Cancer
B. bifidum, L. acidophilus, L. rhamnosus, L. salivarius	Animal models	Inhibition of H. Pylori infection as a major risk factor of gastric cancer.^Citation152
L. acidophilus LB	Clinical trial	Increase H. Pylori eradication rate.^Citation409
L. acidophilus La5 B. lactis Bb12	Clinical trial	Increase H. Pylori eradication rate. Reduction of adverse effects caused by H. Pylori eradication therapy.^Citation410,Citation411
L. casei	Clinical trial	Increase H. Pylori eradication rate.^Citation412
L. reuteri	Clinical trial	Increase H. Pylori eradication rate.^Citation413
L. reuteri	Clinical trial	Reduction of adverse effects caused by H. Pylori eradication therapy.^Citation414
CRC
VSL#3 (S. thermophiles, B. breve, B. longum, B. infantis, L. paracasei, L. Bulgaricus, L. acidophilus, L. plantarum)	Mice model	Reduction of adenoma and adenocarcinoma formation.^Citation260
VSL#3	Rat model	Reduction of adverse effects caused by irinotecan (Weight loss, moderate and severe diarrhea).^Citation262
KFRI342 L. acidophilus	Rat model	Reduction of the development of colorectal preneoplastic lesions. Reduction of E. coli and aerobic bacteria.^Citation263
B. longum and L. gasseri	Mice model	Inhibition of tumor induction by DMH. Reduction of colon tumor size and number. Inhibition of colonic mucosa cellular proliferation.^Citation264
L. casei	Rat models	Downregulation of CYP450 expression and activity.^Citation266
L. salivarius REN	Rat model	Inhibition of tumor induction by DMH. Rehabilitation of gut microbiota.^Citation265
VSL#3/inulin	Clinical trial	Inhibition of cell proliferation. Potentiation of detoxification capacity of pouch mucosal cells in FAP patients.^Citation272
L. rhamnosus LC705 (LC705) and P. freudenreichii ssp. Shermani JS (PJS)	Clinical trial	Reduction of the bacterial enzymes β-glucosidase, and urease.^Citation273
L. gasseri (LG21)	Clinical trial	A deterioration of the intestinal environment in CRC patients. Improvement in intestinal environment.^Citation415
L. rhamnosus GG	Clinical trial	Reduction of adverse effects caused by 5-FU (diarrhea).^Citation274
HCC
VSL#3	Rat model	Inhibition of DEN-induced hepato-carcinogenesis. Reduction of LPS serum levels, number and size of HCC.^Citation302
Prohep (L. rhamnosus GG, viable E. coliNissle 1917 and heat-inactivated VSL#3 (1:1:1)).	Mice model	Reduction of tumor growth and size. Rehabilitation of fecal microbiota. Induction of the anti-inflammatory cytokine IL-10 and suppression of the secretion of the inflammatory cytokines IL-17, IL-6, and interferon (IFN)- γ. Reduction of the tumor populations of migratory Th17 cells. Differentiation of type 1 regulatory T cells in the gut and enhancement of T regulatory cell immune-response by bacteria-derived metabolites. Downregulation of proangiogenic genes.^Citation317
L. rhamnosus LC705 and P. freudenreichii ssp. Shermani	Clinical trial	Reduction of the biologically effective dose of aflatoxin exposure and aflatoxin-DNA toxic adduct.^Citation319

Abbreviations: B, Bifidobacterium; CRC, colorectal cancer; CYP450, Cytochrome P450 enzymes; DEN, diethylnitrosamine; DMH, 1,2-dimethylhydrazine; E, Escherichia; FAP, familial adenomatous polyposis; 5-FU, 5-Fluorouracil; H, Helicobacter; HCC, Hepatocellular carcinoma; IL, interleukin; L, Lactobacillus; LPS, Lipopolysaccharide; P, Propionibacterium; S, Streptococcus.

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