Diversification and deleterious role of microbiome in gastric cancer

Abstract Gut microbiota dictates the fate of several diseases, including cancer. Most gastric cancers (GC) belong to gastric adenocarcinomas (GAC). Helicobacter pylori colonizes the gastric epithelium and is the causative agent of 75% of all stomach malignancies globally. This bacterium has several virulence factors, including cytotoxin‐associated gene A (CagA), vacuolating cytotoxin (VacA), and outer membrane proteins (OMPs), all of which have been linked to the development of gastric cancer. In addition, bacteria such as Escherichia coli, Streptococcus, Clostridium, Haemophilus, Veillonella, Staphylococcus, and Lactobacillus play an important role in the development of gastric cancer. Besides, lactic acid bacteria (LAB) such as Bifidobacterium, Lactobacillus, Lactococcus, and Streptococcus were found in greater abundance in GAC patients. To identify potential diagnostic and therapeutic interventions for GC, it is essential to understand the mechanistic role of H. pylori and other bacteria that contribute to gastric carcinogenesis. Furthermore, understanding bacteria‐host interactions and bacteria‐induced inflammatory pathways in the host is critical for developing treatment targets for gastric cancer.

contribute significantly to the early stages of GAC.However, other gastric microbiotas are also involved in the development of GAC. 8 Helicobacter pylori, which colonizes the gastric epithelium, is responsible for 75% of all gastric cancers worldwide. 10Other than H. pylori, the stomach harbors to nearly 10 3 -10 4 bacteria. 10Wang Z. et al., 2020 reported that the diversity of bacteria was gradually reduced in normal healthy individuals, non-atrophic chronic gastritis, intestinal metaplasia, and gastric cancer. 11H. pylori induce the progression of the gastric mucosa to develop gastric cancer through sequential alterations of the gastric mucosa such as atrophic gastritis (AG), intestinal metaplasia (IM), and dysplasia. 12The oncoprotein CagA and vacuolating cytotoxin A (VacA) of H. pylori are responsible for infection. 13gA induces tumorigenesis through activation of cell proliferation, inflammation, loss of contact inhibition, and suppression of apoptosis.
VacA is involved in immunosuppression through the prevention of regulatory T cells activity, activation of mast cells to secrete proinflammatory cytokines, and cell differentiation through activation of Wnt/beta-catenin and the MAP kinase pathway. 14H. pylori induce up-regulation of TLR9, which enhances the risk of GC development. 15cherichia coli, Streptococcus, Clostridium, Haemophilus, Veillonella, Staphylococcus, Neisseria, Nitrospirae, and Lactobacillus showed a significant contribution to the development of gastric cancer through the production of carcinogenic N-nitroso compounds. 16Lactic acid bacteria (LAB) are responsible for the production of reactive oxygen species (ROS), which induce DNA damage and reduce nitrate to nitrite which drive activation of the oncogenes, enhance angiogenesis, and inhibit apoptosis. 8Clostridium sporogenes, Ruminococcus gnavus, and Lactobacillus sp. are involved in the progression of the tumor through the inhibition of antitumor immune responses. 9Metabolites from the gut microbiota influence the development of tumorigenesis as well as improve anticancer therapy in GC patients. 17Interactions between H. pylori and other bacteria could possibly play a role in the development of gastric cancer.
Gut microbiota must play an important target for next-generation cancer therapy.This study also indicates the potential application of pharmacomicrobiomics in the treatment of gastric cancer.The present narrative review provides a bird's eye view of the role of alterations in gut microbiota and their metabolites in gastric cancer.

| BACTERIAL DIVERSITY IN STOMACH OF HEALTHY INDIVIDUALS AND GASTRIC CANCER PATIENTS
The microbial load varies in the different parts of the gastrointestinal tract, such as 10 12 CFU/mL (oral cavity), 10 7 CFU/mL (stomach), and 10 14 CFU/mL (colon).Due to the lower oxygen concentration in the upper gastrointestinal tract, Gram-positive cocci such as Gemella and Streptococcus are predominant, whereas Clostridium and Faecalibacterium are predominant in the intestines and colon.Akkermansia muciniphila, Bacteroides thetaiotaomicron, Bacteroides fragilis, Bifidobacterium bifidium, and Ruminoccous gnavus are involved in the utilization of glycans of the mucus layer of the gastric region through the action of enzymes such as glycosidase, sulphatase, and sialidase. 18Age, diet, ethnicity, sex, lifestyle, use of antibiotics and proton pump inhibitors (PPI), and infection with H. pylori may modulate alterations in the gut microbiome. 19Bacteria and fungus are unable to survive in the stomach due to its low pH.Metagenomic analysis of mucosal biopsies of healthy subjects revealed that phylum Proteobacteria is the most predominant, followed by Firmicutes, Bacteroidetes, Actinobacteria, and Fusobacteria.1][22][23] Haemophilus, Lactobacillus, Prevotella, Streptococci, Veillonella, and Neisseria showed higher abundance in the gastric mucosa of gastric cancer patients. 23Firmicutes are mainly represented by Clostridium, Dorea, Eubacterium, Ruminococcus, Peptostreptococcus, and Lactobacillus. 24Cladosporium, Candida, and Saccharomyces are common fungal genera found in the human gut. 25ti-tumor immune responses are activated by gut bacteria via T-cell activation against bacterial virulence factors. 26ctobacillus coleohominis and Lachnospiracea showed higher abundance, but Porphyromonas and Neisseria showed lower abundance in gastric cancer patients.Pseudomonas showed a significantly higher abundance in gastric cancer. 27Clostridium and Prevotella showed higher abundance in the mucosa of gastric cancer patients. 21The relative abundance of Clostridium, Fusobacterium, Lactobacillus, Lachnospiraceae, Leptotrichia, Streptococcus, Veillonella, and Prevotella was increased in gastric cancer patients. 23Fusobacterium, Streptococcus, Prevotella, and Leptotrichia showed higher abundance in intestinal metaplasia. 28etary patterns, lifestyle, age, gender, and geographical variation might influence gut microbiota alterations. 29Achromobacter, Clostridium, Citrobacter, and Rhodococcus showed higher abundance in gastric cancer patients from Portuguese populations. 30Lactobacillus showed higher abundance during the progression of gastric cancer patients in the Mexican, Swedish, and Taiwanese populations. 14,23In gastric tumors, Prevotella copri and Bacteroides uniformis were found in lower abundance, while Propionibacterium acnes, Prevotella melaninogenica, and Streptococcus anginosus were found in higher abundance as compared to healthy individuals. 31P. acnes induce the progression of lymphocytic gastritis to develop GC thorough the secretion of IL-15.
P. copri induce secretion of redox protein, which is responsible for the development of inflammation in GC. 32 Anoxybacillus, Novosphingobium, Ochrobactrum, Pseudoxanthomonas and Ralstonia showed higher abundance in the early stage of gastric cancer patients, whereas Burkholderia, Salinivibrio, Tsukamurella, and Uruburuella enriched in the advanced stage of gastric cancer patients. 11Oral bacteria such as Dialister pneumosintes, Fusobacterium, Peptostreptococcus stomatis, Parvimonas micra, S. anginosus, and Slackia exigua showed higher abundance in gastric cancer patients.Changes in stomach pH may cause oral bacteria to aggregate together in the gastric area. 33cterial genera such as Clostridium, Fusobacterium, Lactobacillus, Lachnospiraceae, Leptotrichia, Prevotella, Streptococcus, and Veillonella showed higher abundance in GAC patients. 34The presence of Fusobacterium nucleatum showed an association with a worse prognosis in Lauren's diffuse-type GC and the expression of p53 in tumor tissue. 35,36actic acid bacteria (LAB) such as Bifidobacterium, Lactobacillus, Lactococcus, and Streptococcus showed significantly higher abundance in patients with gastric adenocarcinoma (GAC). 8Colonization of LAB in gastric atrophic mucosa induces the over growth of oncobacteria such as Veillonella, Prevotella, Fusobacterium, and Leptotrichia in patients with GAC.LAB is responsible for the production of reactive oxygen species (ROS), which induce DNA damage.LAB is involved in the reduction of nitrate to nitrite, which drives mutagenesis, over expression of the proto-oncogene, enhancement of angiogenesis, and inhibition of programmed cell death 8 (Figure 1).LAB is also involved in epithelial mesenchymal transition. 37The levels of L-lactate, D-lactate, and D-LDH showed higher abundance in GAC patients. 38 pylori induce overexpression of DLDH in atrophic gastritis patients.39 LAB induces colonization of non-H.pylori carcinogenic bacteria.84 LAB enhances the secretion of exogenous lactate which induces cell migration through the activation of monocarboxylate transporter 1 (MCT1) and epithelial mesenchymal transition through the activation of hypoxia-inducible factor-1 (HIF-1). Latate develops the chemoresistance property of tumors through the expression of hydrocarboxylic acid receptor 1 (HCAR1) and MCT1 (Figure 1).
Lactate induces the expression of VEGF and also drives overexpression of myeloid derived suppressor cells, which prevent the cytotoxic activity of natural killer cells. 28Bifidobacteria induces over expression of type I interferon (IFN) in antigen-presenting cells of secondary lymphoid organs. 40LAB may have an effect on GAC by inducing secretions of lactate, ROS, and N-nitroso compounds, as well as EMT.

| ROLE OF HELICOBACTER PYLORI IN GASTRIC CANCER
The pH of the gastric region varies from pH 1-2 in the gastric lumen region and pH 6-7 on the mucosal surface. 41Microorganisms prefer growing on the mucosal surface. 42Bacteria enter the stomach from the upper digestive tract and respiratory tract. 43Helicobacter pylori, which colonizes in the acidic environment of the stomach, are responsible for the development of noncardiac adenocarcinomas.It is a Gram-negative, spiral-shaped, flagellated bacterium that belongs to the phylum Proteobacteria. 16It possesses urease, catalase, and oxidase activities. 19This bacterium is responsible for the development of atrophic gastritis, chronic gastritis, gastric adenocarcinoma, and mucosa associated lymphoid tissue lymphoma (MALT). 44ood group antigen-binding adhesion (BabA), sialic acid binding adhesion protein (SabA), AlpA/B, HopZ, and OipA are outer membrane proteins of H. pylori that bind to the gastric epithelium.H. pylori induce gastric epithelial cells to express sialyl-dimeric-Lewis glycosphingolipid, which acts as a receptor for SabA. 45Adhesin BabA of H. pylori binds with ABO/Leb blood-group antigens on gastric epithelial cells. 46This bacterium has several virulence factors, including cytotoxin-associated gene A (CagA), vacuolating cytotoxin (VacA), and outer membrane proteins (OMPs), all of which have been linked to the development of gastric cancer 47 (Figure 1).This bacterium induces the development of gastric cancer through the damage of hydrochloric acid-secreting gastric glands. 48gA protein has a molecular weight of 120 to 140 kD and is secreted in the cytosol of the bacteria.The genes that encode CagA and Cag type IV secretion system (T4SS) are located in cag Pathogenicity Island (cag PAI).The CagA protein of H. pylori enters the host cell through the cag pathogenicity island (cagPAI)-encoded type IV secretion system (T4SS).CagA induces cell proliferation by activating PI3 kinase-AKT, MEK-ERK, and β-catenin-WNT pathways.CagA prevents apoptosis of gastric epithelial cells through the inhibition of p53 and RUNX.CagA and T4SS induce gastric carcinoma by activating NF-κB pathways that drive inflammation and reactive oxygen species mediated DNA damage. 49CagA is involved in chronic gastritis; mucosa associated lymphoid tissue lymphoma, and gastric cancer in humans. 5,50CagA of H. pylori is involved in the epigenetic silencing of miRNA let-7 which drives overexpression of Ras in gastric carcinogenesis. 51CagA is phosphorylated by Src kinases at the Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs in gastric epithelial cells.This event triggers the activation of pathways such as JAK/STAT3, NF-κB, PI3K/ Akt, Wnt/β-catenin, and Ras/Erk pathways that drive carcinogenesis. 52gA also induces activation of tyrosine phosphatase SHP2 through binding with SRC homology 2 domains (SH2), which drives the malignant transformation of gastric epithelial cells. 53CagA disrupts adherens junctions (AJs) in gastric epithelial cells. 54CagA triggers epithelialmesenchymal transition (EMT) in gastric cells. 55 Pylori has urease activities, which are responsible for the enhancement of pH in the gastric region through the transformation of urea into ammonia and bicarbonate.The flagellum of H. pylori is responsible for the invasion of the gastric mucosa.The adhesions (HopQ, HopP, and HopS) of H. Pylori are responsible for H. pylori adhesion to gastric epithelial cells.The virulence factors CagA and VacA of H. pylori are responsible for the cytotoxic effect.56 Genetic alterations in Cag A and VacA of H. pylori are responsible for the enhancement of inflammation through the secretion of IL-22 and IL-8, the infiltration of neutrophils, and the colonization of bacteria through their outer membrane proteins such as BabA, and HopH.57 VacA is also involved in the over-expression of VEGF, MAP kinase, and ERK1/2, and the activation of the Wnt/β-catenin signaling pathway, and PI3K/Akt signaling pathway which drive proliferation and differentiation of gastric epithelial cells.58 VacA inhibits the dephosphorylation of the transcription factor nuclear factor of activated T cells (NFAT), which blocks the transcriptional activation of IL-2 and antigen-dependent cell proliferation.59 VacA exhibits immunosuppression through the activation of secretion of anti-inflammatory cytokines such as IL-10 and IL-18 from dendritic cells that drive differentiation of Treg cells.59 Due to the immunosuppressive property of VacA, H. pylori may bypass the host immune system, which drives the survival of gastric tumors.60 The outer inflammatory protein (OipA) of H. pylori induces ulcers in the duodenum.CagL induces hypergastrinemia, which drives the development of gastric adenocarcinoma.CagL interacts with α5β1 integrin, which causes the host cell to secrete IL-8.61 H. pylori induces inflammation in gastric epithelial cells through activation of NF-κB which drives the secretion of inflammatory cytokines such as interleukin-1β (IL-1b), IL-2, IL-6, IL-7, IL-8, IL-10, IL-18, interferon-γ, and TNF-α.62 H. pylori also induce inflammation by activating Cyclooxygenase-2 (COX-2) and prostaglandin PGE2.62 Pathogen-associated molecular patterns (PAMPs) of H. pylori bind with pattern recognition receptors (PRR) on host cells, which induce innate immune responses.TLRs of PRR also bind with flagellin, LPS, lipoteichoic acid, and lipoproteins of H. pylori.These events induce the secretion of inflammatory cytokines such as IL-1, IL-2, IL-6, IL-8, IL-12, TNF-α, and IFN-γ.24 H. pylori are also involved in the epigenetic regulation of gastric epithelial cells.This bacterium is involved in the DNA methylation of CpG islands of E-cadherin and tumor-suppressor genes such as trefoil factor 2 (TFF2) and a forkhead box transcriptional regulator (FOXD3), which drives the development of gastric cancer.63,64 H. Pylori induces hypermethylation of the promoter region of the RUNX3 tumor suppressor gene in gastric epithelial cells.65 This bacterium is involved in the methylation of the promoter region of miR-210, which induces the proliferation of gastric cells through over expression of STMN1 and DIMT1.66 H. pylori-positive gastric cancer patients showed a higher degree of promoter hypermethylation of tumor suppressor genes such as CDKN2A, APC, and p41ARC. H.pylori infection induces the hypermethylation of Connexin 32 (Cx32) and Connexin 43 (Cx43) in gastric cancer patients.It also induces the hypermethylation of O6-methylguanine DNA methyltransferase (MGMT) in the gastric cancer patients.67 H. pylori prompt the expression of cytidine deaminase, which induces double-strand breaks in gastric epithelial cells.68 H. pylori activate epidermal growth factor receptor (EGFR) through PI3K/AKT pathway.69 H. pylori aid in the production of reactive oxygen and nitrogen species (ROS/NOS) from neutrophils, macrophages, and vascular endothelial cells, which induce DNA damage and activate apoptosis or autophagy in gastric epithelial cells.ROS activates tyrosine phosphorylation at the C terminus of SHP2.70,71 Bacterial peptidoglycans also activate the nucleotide-binding oligomerization domain (NOD).Outer membrane vesicles of gram-negative bacteria bind with NOD-2, whereas the virulent factor of H. pylori binds with NOD-1.16 H. pyori infection reduces the level of vitamin B12 in the serum, which enhances the risk of developing non-cardia gastric adenocarcinoma.9 H. pylori inhibit the expression of miR-22 and NLR family pyrin domain containing 3 (NLRP3), which drives the progression of GC through over expression of cyclin D1. 72 TLR1 rs4833095 and TLR10 rs10004195 polymorphisms contribute significantly to the infection of H. pylori to gastric epithelial cells.73 H. pylori induced the expression of PD-L1 in gastric epithelial cells and prevented the proliferation of CD4+ T cells in the blood.26 CD4+ T cells showed higher expression in gastric cancer, whereas CD8+ T cells showed lower expression.74 MALT lymphoma of the stomach is a slow growing B-cell neoplasia.H. pylori infection is primarily responsible for the development of gastric MALT lymphomas.75 Chronic inflammation induces the development of mucosal associated lymphoid tissues (MALT) in the gastric mucosa.76 The CagA protein of H. pylori contributes significantly to the development of gastric MALT lymphoma through inhibition of B cell apoptosis and proliferation of B cells. 76Streptococcus bovis, Achromobacter xylosoxidans, and Haemophilus influenzae are also responsible for the development of gastric MALT lymphomas.77 Prolonged H. pylori infection causes an inflammatory response, which leads to atrophic gastritis and an increased risk of developing GC.The CagA protein induces cell proliferation, blocks apoptosis, and interrupts cell-cell adhesions, which drive the development of gastric tumors.

| DIVERSITY MICROBIOTA IN GASTRIC REGION OF PATIENTS WITH GASTRIC CANCER IN THE PRESENCE AND ABSENCE OF H. PYLORI
Inflammation elevates the pH of the stomach, reducing the abundance of H. pylori while increasing the abundance of non-H.pylori bacteria in the stomach. 78H. pylori induce inflammation in the gastric region, whereas other bacteria are responsible for the enhancement of inflammation, development of dysplasia, and the progression of gastric adenocarcinoma. 79Helicobacter pylori are responsible for the modification of the mucous layer of the gastric region which drives dysbiosis of gastric microbiota.In H. pylori positive individuals, Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria showed higher abundance at the phylum level and Streptococcus showed higher abundance at the genus level. 56Pseudomonas and Staphylococcus are common bacterial genera in H. pylori free children's stomach. 41higher abundance of Acidobacteria, Proteobacteria, and Spirochetes have been reported in H. pylori positive gastric cancer patients compared to H. pylori negative gastric cancer patients.80 γ-Proteobacteria, β-Proteobacteria, Bacteroidia, Flavobacteria, Fusobacteria or Negativicutes and Clostridia showed higher abundance in H. pylori-negative gastric cancer patients.41 A higher abundance of Firmicutes and Bacteroidetes and lower abundance of Proteobacteria and Actinobacteria were reported in gastric cancer patients after gastrectomy.81 Distal gastrectomy induced the abundance of Escherichia/Shigella, Veillonella, and Clostridium XVIII and reduced the abundance of Bacteroides.82 Prevotella copri showed significantly higher abundance in H. pylori-positive patients.83 Patients with atrophic gastritis showed higher abundance of Lactobacillus and H. Pylori.84 Fusobacteriaceae, Helicobacteraceae, Prevotellaceae, and Streptococcaceae are the predominant taxa in patients having chronic atrophic gastritis. Meabolic enzymes such as alanine dehydrogenase, glycolate oxidase, fumarate reductase, and ketol-acid reductor isomerase are significantly elevated whereas succinate dehydrogenase is significantly reduced in H. pylori-induced atrophic gastritis.85 The abundance of Tannerella, Treponema, and Prevotella spp. was significantly reduced in atrophic gastritis patients.86 Higher abundance of Coriobacteriaceae, Enterococcaceae, Succinivibrio, and Rikenellaceae was reported in individuals having H. pylori infection.87 H. pylori infected individuals showed an elevation of metabolic pathways related to fatty acid metabolism, xenobiotics metabolism by cytochrome P450, glycosphingolipid biosynthesis, N-glycan biosynthesis, glycosaminoglycan degradation, and LPS biosynthesis.Peptidoglycan biosynthesis was reduced in individuals with H. pylori infection.88 H. pylori may provide a favorable environment for the development of opportunistic pathogens that enhance the progression of GC.

| ROLE OF BACTERIAL METABOLITES IN GASTRIC CANCER
Bile acids (BAs), branched-chain amino acids (BCAAs), short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), tryptophan, and indole derivatives are derived from gut microbiota. 89Free BAs, such as cholic acid, deoxycholic acid, and chenodeoxycholic acid induce apoptosis and inhibit the secretion of interleukin 6 (IL-6) whereas conjugated BAs such as glycolic acid, glycodeoxycholic acid, and glycochenodeoxycholic acid induce cell proliferation and inflammation through secretion of IL-6. 90SCFAs produced by gut bacteria are implicated in T cells modulation through the expression of G-proteincoupled receptors GPR41 or GPR43. 91The gut microbiome regulates host metabolism and immune response through the synthesis of spermidine and Vitamin B6. 92 Gut bacteria-released metabolites promote the progression and development of gastric cancer.SCFAs, polyamines, and metabolites derived from tryptophan catabolism contribute significantly to the development and progression of the tumor through alterations of epigenetic regulations, immunomodulation, and cell cycle regulations.SCAFs play a role in regulating apoptosis, cell cycle, and immunomodulation by inhibiting of NF-kB and HDACs activity, DNA methylation, and regulating Akt/mTOR and MEK/ ERK signaling pathways. 9SCFAs such as acetate, butyrate, and propionate are synthesized by gut microbiota from fermentable non-digestible carbohydrates.Phylum Bacteroidetes are responsible for the synthesis of acetate and propionate whereas Firmicutes are responsible for the synthesis of butyrate. 93tyrate inhibits the synthesis of TNF-α, IL-6, MCP-1, iNOS, and IFN-γ by inhibiting transcriptional activation of NF-κB. 94Butyrate may prevent tumorigenesis by inhibiting the NF-kB signaling pathway; as well as the activity of differentiated T cells that secrete IL10, and regulatory T cell.It also inhibits the proliferation of tumors through the activation of programmed cell death 95 (Figure 2).Faecalibacterium prausnitzii is responsible for butyrate synthesis, which boosts the gastrointestinal immunity, and maintains the integrity of the gastrointestinal barrier.Butyrate induces the proliferation of gastric epithelial cells. 9opionate inhibits the secretion of pro-inflammatory cytokines such as IL-4, IL-5, and IL-17A as well as induces the secretion of antiinflammatory cytokine IL-10 from Treg cells.H. Pylori induce the gut microbiome to secrete BCAAs such as isoleucine, leucine, and valine which block autophagy of gut epithelial cells and activate chronic inflammation through the activation of the mTORC1 complex.TAMO induces the secretion of pro-inflammatory cytokines such as IL-8 and TNF-α through over-expression of NF-κB 18 (Figure 2).Polyamines (PAs) such as cadaverine, spermidine, spermine, and putrescine which are synthesized by Firmicutes in the gut are responsible for cell wall stability, siderophores formation, and antioxidant activity.Clostridium sporogenes, Ruminococcus gnavus, and Lactobacillus sp. are all involved in the tryptophan metabolism, which triggers tumor progression by inhibiting antitumor immune responses. 9higher abundance of bacteria in the gastric fluid is responsible for the production of nitroso compounds that drive the development of gastric cancer through DNA damage.Bacteria such as Escherichia coli, Streptococcus, Clostridium, Haemophilus, Veillonella, Staphylococcus, Neisseria, Nitrospirae, and Lactobacillus are accountable for the development of gastric cancer.These bacteria are involved in the production of carcinogenic N-nitroso compounds which induce over expression of proto-oncogenes, angiogenesis, and inhibition of apoptosis.19 A higher abundance of nitrite has been reported in the gastric juice of gastric cancer patients.96 Bacterial genera Hemophilia and Veillonella are involved in the reduction of nitrate more efficiently than nitrite in the stomach.97 N-nitroso compounds from tobacco smoke and diet enhance the risk of gastric cancer.98 Endogenous N-nitroso compounds which are derived nitrites contribute significantly to the development of gastric cancer.99  γproteobacteria reduces the toxic effect of gemcitabine through its conversion into 2 0 , 2 0 -difluorodeoxyuridine.103 More research related to the role of the microbiome in improving therapeutic outcomes and reducing toxicity is required.

| ROLE OF PROBIOTICS IN GASTRIC CANCER
Probiotics are living organisms that provide benefits to the host after adequate ingestion.Bacterial genera such as Aerococcus, Enterococcus, and Lactobacillus belong to phylum Firmicutes, and Bifidobacterium belongs to phylum Actinobacteria commonly use as probiotics. 104timicrobial metabolites of L. reuteri showed inhibitory activity against H. pylori. 105Bifidobacterium, and Lactobacillus showed antitumor activity through activation of apoptosis, and suppression of proinflammatory cytokine secretion. 9Lactobacillus acidophilus and Lactobacillus bulgaricus can reduce the adherence of H. pylori to gastric mucosal cells.L. Bulgaricus reduces the secretion of IL-8 from mucosal cells through alterations of TLR4/NF-kB pathways. 106Bacillus cereus, Bifidobacterium infantis, Enterococcus faecalis, and L. acidophilus synergistically suppressed inflammation in GC patients. 107Lactobacillus casei, and Bifidobacterium suppressed radiotherapy-associated diarrhea in a mouse model by blocking mRNA expression of IL1b, IL6 and TNF.Bifidobacterium pseudolongum, Lactobacillus johnsonii, and Olsenella improved the efficacy of anti-CTLA4 and anti-PD-L1 immunotherapy.Higher abundance of Bifidobacterium in tumor microenvironment also enhanced the efficacy of anti-CD47 immunotherapy. 108ctobacillus johnsonii, Lactobacillus murinus, and Enterococcus hirae enhance cyclophosphamide mediated immune responses in the tumor microenvironment.103 Bifidobacterium derived hippurate blocks PD-1 expression that drives natural killer (NK) cells to kill tumors through perforin and IFN-γ.109 Bifidobacterium pseudolongum and Akkermansia muciniphila secretes inosine which reduces the tumor volume through activation of Th1 response via adenosine 2A receptors.Lactobacillus rhamnosus GG stimulates activity of CD8+ T cell to tumor cells through activation of dendritic cells. 110Probiotic strains may inhibit

F I G U R E 1
Role of virulent factors of H. pylori and other bacteria in the development of gastric cancer through alteration of hallmarks of tumorigenesis.The figure illustrates the mechanistic role of H. pylori and Lactobacillus in progression of gastric cancers.H. pylori activate several pro-inflammatory pathways and cytokines which in turn trigger pre-carcinogenic switches.Likewise, Lactobacillus is responsible for triggering of ROS, DNA damage agents and other drivers responsible for initiating gastric cancer.
Haemophilus parainfluenzae and Veillonella parvula reduced nitrate more efficiently than nitrite F I G U R E 2 Role of gut bacterial metabolites in the development and progression of gastric cancer.reduction, which escalates the concentration of nitrite in the gastric juice. 100Microbial metabolites may be considered as diagnostic biomarkers for GC.A low level of gastric acid is considered to be one of the risk factors for the development of gastric cancer.Proton pump inhibitors (PPI) are responsible for reducing acid production in the gastric region.Interleukin-1β induces gastric acid secretion, and reduced expression of IL-1β enhances the risk of gastric development. 101Elevation of pH induces the growth of Lactobacillus in the stomach which favors the growth of gastric cancer.The use of PPI treatments enhances the abundance of Lactobacillus and Streptococcus, which are responsible for the development of gastric cancer. 102E coli blocks activity of blapachone, cladribine, doxorubicin, daunorubicin, etoposide phosphate, and idarubicin.Simultaneously, it induces antitumor activity of 5-fluorouracil (FU), 5-fluorocytosine, mercaptopurine, and fludarabine phosphate.Cytidine deaminase of

H
. pylori infection by stimulating the activity of natural killer (NK) cells, and secretion of anti-inflammatory cytokines.7 | CONCLUSIONSThe gut microbiome contributes to the development of tumor by altering treatment response.Age, ethnicity, diet, and gender may all have an effect on bacterial populations in the stomach and their association to cancer development.H. pylori are well known pathogenic bacteria that contribute to the development of GC.It is necessary to assess the functional relevance of additional microorganisms linked to progressive gastritis and stomach cancer.Exogenous lactate of LAB contributes to carcinogenesis by producing ROS, N-nitroso compounds, and enhancing EMT.Chemotherapeutic and immunotherapeutic agents are also modulated by gut microbiota.Understanding the function of H. Pylori and other bacteria-induced gastric carcinogenesis is crucial for identifying viable diagnostic and therapeutic treatments for GC.Understanding how bacteria interact with their hosts and how bacteria cause inflammatory pathways in the host is also critical for developing therapeutic targets for stomach cancer.Probiotics can be used to treat GC by preventing the growth of oncobacteria.The gut microbiota is an important determinant for making chemotherapy or immunotherapy safer and enhancing survival rates of cancer patients.Synergistic approaches such as clinical trials by using microbiota along with chemotherapy or immunotherapy are highly anticipated in the treatment of GC.Additional in vitro and in vivo experimental approaches are required to develop a better treatment plan for GC inhibition.Further research is also required to have a better knowledge of understanding microbiome-drug interactions to improve treatment outcomes.