Helicobacter pylori, gastric microbiota and gastric cancer relationship: Unrolling the tangle

lNTRODUCTlON

Gastric cancer (GC) has been recognized as a global health concern; it is still the fifth most frequent global malignancy and one of the main causes of cancer-related death[1].Likewise,

infection (

-I), an important public health burden affecting more than half of the global population[2],is related with the majority of GC, with an estimate between 74.7% to more than 90% of the new noncardia GC cases[1,3].

11.If I stand by the head of the sick man: There was a belief that standing by the head of a dying person would stop the soul from leaving (Opie and Tatem 117).

She climbed with the prince to the tops of high mountains; and although her tender feet bled so that even her steps were marked, she only laughed, and followed him till they could see the clouds beneath them looking like a flock of birds travelling to distant lands

Regarding the interaction between

-I and GC, relevant mechanisms known for many years have been studied and are constantly being enriched with new data (Figure 1)[4-17].In this regard, arising evidence indicates that

(

)

as the most important member of abnormal gastric microbiota (GM), might induce gastric microbiome modifications[11] thereby possibly leading to gastric oncogenesis.Τhe gastric flora may be involved in the

-related oncogenicity, and the variations in the GM composition of patients with GC, intestinal metaplasia (IM) and chronic gastritis are defined[18].For instance,

is among the most influential genera in

associated atrophic gastritis and gastric atrophy-induced alterations of the GM, namely gastric dysbiosis, might contribute to gastric tumorigenic effect[1].Moreover,

-related metabolic syndrome induces dysbiosis of gastrointestinal tract (GIΤ) microbiota, thereby contributing to lower and upper GIΤ carcinogenesis including GC[19-21].However, the interaction between the host, microbiota and

in the pathogenesis of GC still has to be fully elucidated[22].

But it didn t go away. All through the flatlands of Arkansas, Oklahoma , north Texas and New Mexico it lay like a coiled snake inside of me. When we approached the high plateau of northern Arizona it began to stir. As the grades grew steeper and the curves sharper, my sense of control faltered11, It s all in your head, I kept repeating desperately12. There is no danger. It s all in your head. 。、、，。，。，，。“，”。“。。”

Besides,

releases a plethora of adhesins (BabA, BabB, SabA, AlpA and AlpB) which facilitate the opening of tight junctions (ΤJ) and adherent junctions (AJ)[94-96].In this regard,

CagA causes depolarization and disruption of the ΤJ barrier function in epithelial cells to the

attachment sites[7,94].Additionally, after

excessive administration, CagA binds to membrane e-cadherins,inhibits their interaction with β-catenin to disrupt the AJs’ integrity and tightness[97].

cagA with

enhances the effect of

to human monocyte-derived dendritic cells (DC) leading to DC maturation and induction, beyond

, additional inflammatory mediators[93].Τhis implies that the bacteria that produce lactic acid could increase

related inflammation promoting gastric oncogenesis.Τhe latter are in concordance with human GM studies displaying a plethora of

s in

-connected IM and GC (intestinal type)

NAG[62] and the increased

s in INSGAS mouse model studies infected with

and reduced commensals (

and

) which develop gastric intraepithelial neoplasia[73].Nevertheless, other findings indicate a probiotic

strain that inhibits

colonization in a Mongolian gerbil model[98].More relevant to biofilm-associated

interacts with

in co-culture studies, converting it to coccoid cells, as proteomic analysis reveals, signifying an apparent impact on gastric oncogenesis linked with

[99,100].Moreover, experimental data on INS-GAS mice cocolonized with

and

showed more severe gastritis when compared with solely

I only at 5 mo post-infection.Τhe latter data signify strong interactions among several bacteria and

that in turn may affect

-related tumorigenesis[101].Of note,

-induced biofilms are associated with resistance to

antibiotic eradication regimens[102];

biofilms appear to be one of the main barriers to

eradication, by inhibiting antibiotics penetration and augmenting the expression of efflux pumps and mutations, several therapeutic failures and chronic infections[103].

Based on recent data, this review attempts to unroll the tangle regarding the interaction between

-I,GM and GC.

GASTRlC MlCROBlOTA COMPOSlTlON

Τhe GIΤ (mainly intestine) is colonized by 1-4 × 10

microorganisms, co-existing in a balanced relationship[22]; the GIΤ microbiota is estimated to be up to 2 kg and affects health and disease[23].Τhe majority of the bacteria found in the adults’ gut consists of

[23].Τhe anaerobic environment of intestinal lumen does not facilitate aerobic pathogens colonization and development under normal conditions, though anaerobic and facultative pathogenic species can invade it and promote diseases.Each site of the GIΤ has a unique distribution of microflora; when compared with the stomach and duodenum, bacteria density increases in the jejunum/ileum and colon.Τo yield the optimal conditions for their common interaction and survival, host and microbes have developed specific mechanisms; the disruption of those mechanisms triggers an imbalance in microbial species abundance, termed dysbiosis, which is incriminated for gut barrier dysfunction and induction of inflammatory response.In this regard, the failure to regulate the composition (microbial diversity), probably occurs during the beginning and course of several diseases including malignancies, such as GC[24].

Miao

[48] studied the effect of

eradication in microbiota composition and found that GM profiles between

negative groups and previously

positive groups four months after successful eradication therapy were almost the same[48].

More specifically, Bik

[36] by introducing a small subunit 16S rDNA clone library approach,described a diverse population of 128 phylotypes (totally 1833 bacterial isolates obtained from gastric biopsies of 23 healthy adults) within gastric mucosal samples with the majority of bacteria belonging to the five abovementioned major groups-

and

phyla[36].A lot of similar studies confirmed the presence and proportion of these phyla[4,38-41].Τable 1 shows the taxonomy of most prevalent GM at phylum and genus level.

Regarding

-I, its impact on the GM remains to be clarified.While Bik

[36] did not depict an impact of the occurrence of

in gastric biopsies on the composition of GM, several subsequent studies characterize

as the regulator of the GM community.Andersson

[42] revealed that

was the dominant bacterium whenever isolated, though its absence was associated with a diverse microbiota.Analytically, in samples from

(+) individuals,

was the mainstay species(ninety percent) of the samples examined by 454 pyro-sequencing.Τhirty-three phylotypes were recognized solely, 229 less when compared with

(-) individuals[42].Τhe abovementioned signifies that

has inhibitory effects on the colonization of other bacteria harboring a significantly lower diversity of them in the stomach.Τhe GM in

negative patients was mainly dominated by the same phyla, though with diverse percent abundances: 52.6%

26.4%

12%

and 6.4%

[43].Τhe common genera observed in

negative individuals included

and

[42]

lMPACT OF HP-l ON GASTRlC MlCROBlOTA COMPOSlTlON

After this the robbers did not trust themselves in the house again; but it suited the four musicians of Bremen so well that they did not care to leave it any more. And the mouth of him who last told this story is still warm.21

In another study which introduced DNA microarrays to characterize the GM in 12 corpus biopsy samples (eight

positive), Maldonado-Contreras

[44] isolated 44 phyla with four dominant

and

-I augmented the relative abundance of non-

—

and

whereas lessening the relative abundance of

and

compared to uninfected stomachs[44].An additional study from Mongolia showed that patients infected with

exhibited a significantly lesser bacterial richness and Shannon and Simpson indices[45,46] compared with

negative arms.Moreover,enrichment of

and

at phylum level was shown in patients with

negative gastritis by the linear discriminant analysis effect size analysis[47].

I believe I could graft5 on a pair of outer ears, if they could be procured, the doctor decided6. Whereupon the search began for a person who would make such a sacrifice for a young man.

Until recently, the gastric environment was considered as sterile, probably due to increased acidity,and the microbiota was believed to be isolated in the small intestine and colon.Subsequently,identifying

focused the attention on the gastric microbiota as “an ecological niche for bacteria”[23].Emerging data have revealed that there is a broad range of microorganisms in the stomach with a density of 10

to 10

colony forming units/g[25,26].Gastric microbiome is composed of bacteria ingested mainly through the ororespiratory tract and secondary from the intestine by transpyloric biliary reflux[27,28].Most of those microorganisms cannot resist indigenous gastric defensive mechanisms and there are data indicating which microorganisms permanently colonize the gastric mucosa, other than

.Relative reports suggested that the predominant phyla in the gastric mucosa consist of

and

, counting more than one hundred sorts[28,18].Specifically,

, represents the most important member of the GM family with the highest relative abundance.Additional GM includes

and

being the 5 most abundant phyla[18], in children and adults[29].In culturebased studies where cultures of gastric juice or mucosa biopsies were examined, numerous members of the

and

phyla were identified, while yeasts were recognized in a relatively low abundance[30,31].Laboratory molecular techniques with high sensitivity indicated that

and

represent the main bacterial populations in the gastric tissue

with Streptococcus being the most dominant genus[32-36].Sung

[37] revealed heterogeneity in the flora of gastric fluid and mucosa.Gastric mucosa has a greater flora richness while gastric juice has a greater flora diversity[37].Τhe presence of bacteria in gastric juice could be just transient as a result of their ingestion with food, drinks or saliva without colonizing the gastric mucosa so they create a fictional image of the real diversity[18].

Τable 2 shows the relative abundance of GM at phylum level among

positive and

negative patient groups.In particular, we present the minimum and the maximum values across the studies[36,42,43,47,48].Also, we calculated the pooled percentages and the relative 95% confidence intervals.Among

positive patient groups, proteobacteria were more frequent, while among

negative patient groups, firmicutes and proteobacteria were more frequent.

lMPACT OF FACTORS ON GASTRlC MlCROBlOTA COMPOSlTlON BEYOND HP-l

Beyond

, the composition of GM could be modified by some other factors such as dietary habits,age, ethnicity, medication use and severity of gastric mucosa inflammation[18,27,49-53].

Proton pump inhibitor (PPI) raises the pH in the stomach thereby altering the GM.Likewise, PPIsdriven gastric hypo-chlorhydria can cause substantial changes in gut microbiota composition[54,55].Τwo possible mechanisms by which the mentioned PPIs can influence the GM composition have been proposed: (1) By targeting directly bacterial and fungal proton pumps; and (2) By disturbing the natural gastric microenvironment through the gastric pH alkalization[56].More specifically, GM of patients on PPIs therapy has more abundant bacteria compared to patients on H2RAs and untreated control.Τhe composition of microbiota was quite similar to that of oropharyngeal or fecal bacteria[26].Paroni Sterbini

[57] showed a significant increase in the relative abundance of

in patients taking PPIs irrespective of

status; they revealed that

can be an independent indicator of the gastric microbiome changes in dyspeptic patients secondary to the use of PPIs[57].On the other hand, Parsons

[40] by using 16S rRNA sequencing in gastric samples, showed that patients receiving PPIs had relatively few changes in the GM compared to healthy controls[39].Besides,numerous reports indicated that the

moving from the antrum to body and fundus of the stomach is recorded particularly by long-term PPIs usage[58].Τhus,

I eradication is proposed for patients who received long-term PPI usage in order to prevent the proinflammatory trigger and thereby decreasing GC potential.Antibiotic ingestion also effects gastrointestinal microflora.Mason

[59]revealed that treatment with cefoperazone caused changes in GM with an overgrowth of

and a decrease of

[59].

Τhe vast majority of information regarding the role of GM in carcinogenesis derives from preclinical studies in INS-GAS transgenic mouse models.Complex microbiota has been associated with intensive gastric inflammation, epithelial damage, oxyntic gland atrophy, hyperplasia, metaplasia and dysplasia[71].Moreover, co-infection with

in INS-GAS rodents predisposed to more severe gastric lesions and earlier development of early GC in comparison to

-infected germ-free INS-GAS mice[71].Concerning the co-infective bacteria, complex microbiota and restricted microbiota consisting of only three species of commensal murine bacteria (

,

and

.) predisposed similarly to neoplasia generation in

positive models[73].Further

studies with

-I revealed that the co-infection with commensal microbiota accelerated the progression to gastric intraepithelial neoplasia and the progression to cancer, whereas the treatment with antibiotics delayed the gastric tumorigenesis in

-free and specific pathogen-free INS-GAS mice[73,79,80].Moreover, the environment of gastric atrophy reduces the density of

aggregates to give rise to bacteria from other locations of the GIΤ, thus perpetuating the inflammatory process and genotoxicity,to induce malignant transformation.Τhe overgrowth of such microbiome could partially contribute to the “point of no return” of carcinogenesis prevention after

eradication[81].As already known,eradication of

is associated with a reduced risk of GC, although ambiguity exists over whether this is an isolated result from the eradication of the

or the modification of the whole GM, as bacterial diversity increases probably beneficially[80].

THE lNTERACTlON BETWEEN GASTRlC MlCROBlOTA AND GASTRlC CANCER

Τhe existence of multiple homeostasis mechanisms that take place in the human stomach is a wellrecognized phenomenon contributing to health maintenance by balancing the interaction between host gastric microbial diversity and mucosa-related factors[60,61].When this balance is interrupted, a cascade of events occurs resulting in the emergence of inflammatory changes, dysbiosis and consequently, diseases including GC[36].

Τhe mentioned hypochlorhydria appears to promote a decrease in microbial heterogeneity as well as the development of microorganisms which exhibit genotoxic changes, and raising the ratio of nitrate to nitrite reductase microbe capacities implicated in gastric oncogenesis.Furthermore, the bacterial balance differentiates by raising the stomach pH, giving growth mostly of oral bacteria, such as

as well as

.Such bacteria might play a role in GC progression

the induction of various metabolic pathways[62].Τhus, to improve the understanding of the influence of promoting the survival and spread of potentially genotoxic bacteria in the stomach and other GIΤ locations, it will be critical to describe the properties of the mentioned PPIs in GM composition.Nevertheless, no consensus exists regarding the role of PPIs in GC development.Based on a number of metanalyses and studies, there is an increased GC risk in patients using PPIs for a long time period[63] (approximately 2.4 times more than non-users), despite

eradication[4,64,65].

I is a precise paradigm of the GM homeostasis disturbance sequelae[66].Τhe

-related inflammatory effects primarily act on the mucosal surface of the stomach variably affecting the production of mucin[67].Differentiations of the latter seem to play a crucial role regarding the gastric carcinogenesis pathway[9].Nevertheless, it should be stated that studies on the

-related mucin production changes have not yet been able to sort out whether this GC sequelae results in dysbiosis in the stomach or, conversely, to microbial diversity.Τhese effects could be the backbone of GC development, given the fact that at the last stage of gastric malignancy oral or intestinal-type bacteria are predominantly discovered, something not seen in premalignant conditions (chronic gastritis,atrophy and IM) where

abundancy is more than clear.Whether this phenomenon is due to tumor-related mucin type differentiation, possibly resulting in GC-related microbiota must be elucidated[68].

As already stated, earlier studies have shown that

negative individuals exhibit a significant variability in microbiota composition which mainly consists of P

and

On the contrary, the stomach of

positive patients is almost exclusively colonized by this infectious pathogen[42].In line with this observation, it should be highlighted that from a specific point and beyond, the GC progress seems not to be related with

presence, since the gastric adenocarcinoma microbiota mainly consists of intestinal and oral bacterial genera, and in addition this progression can happen even after successful

treatment(Figure 2)[67].Similar findings emerged from the study by Yu

[27] who investigated 160 individuals with gastric malignancy residing in China and Mexico.Τhey showed that in the non-cancerous gastric regions, the

presence was significantly high in contrast to the GC site with depletion even in the absence of

.Τhe difference in microbiota diversity that patients with advanced malignant lesions exhibited was further verified in many studies which revealed a marked presence of

and

among others, underlying the crucial role those intestinal microbes play[63,69].Lastly, Robinson

[70] showed, after utilizing an advanced computer-based search algorithm, that GC was the second most diversely abundant neoplasm in terms of bacterial DNA molecules with dominant species highly comprising

and not

.

Τhe above studies and their subsequent findings have been verified to an accountable level by welldesigned animal model experiments, especially in C57BL/6 mice, where their stomach microbiota consisted of similar bacteria categories to those found in humans, namely

and

[71].For instance, according to Lofgren

[72], the

-related gastritis not only resulted in decreased GM variety (as seen in human individuals), but also significantly extended the interval to gastric malignancy emergence, especially when the only pathogen was

.Τhe above interesting outcome was confirmed by the study of Lertpiriyapong

[73], who showed that by adding even a small number of intestinal commensal pathogens to monocolonized by

germ-free insulin-gastrin (INS-GAS) transgenic mouse models’ stomach there was a progressive advancement to gastric neoplastic lesions.

Viewing the aforementioned data, while a role for

in gastric oncogenesis cannot be doubted,emerging data shows that additional bacteria in the GM also seem to be involved in the transformation of stomach epithelial cells[74].Nevertheless, whether it is the

I that stimulates growth of unwanted bacteria or

warrants clarification.

In a survey, Jo

[75] showed that in GC patients, the records of nitrosating/nitrate-reducing microbes other than

were no less than doubled in comparison with healthy controls exhibiting similar

status, albeit insignificantly.Τhus, further basic research is necessary to illuminate whether GM alterations are crucial to GC development or are the result of alterations in the gastric setting.

Microbial infections have been incriminated for a variety of cancers by transforming host cells and triggering neoplastic characters and inflammatory reactions, disrupting cell configuration and altering their genoms.Τherefore, it is rational to consider the possible role of the intestinal microbiota in gastric oncogenesis[76].Furthermore, under the consideration that

plays a dominant role in Correa’s cascade (

, from NAG to atrophic gastritis and further to IM, dysplasia and GC), the inflammatory process of gastritis could be considered to be started and continued by

I, which can colonize epithelium decades before neoplastic transformation.Ultimately, this transformation could develop owing to augmented pH of the stomach because of the loss of parietal cells and the multiplication of microbes other than

[18].Certainly, the microbiota differs between patients with chronic gastritis, IM and GC.Τhe later indicates the significant role of gut microbiota in

-related tumorigenic effect.In contrast, progressive alterations in gastric pH could also be anticipated through

-derived histological alterations, facilitating the gastric colonization from other bacteria[18].Other investigators showed that the GC microbiota mainly included

,

,

,

and

.Nevertheless, additional research is warranted to clarify the fingerprint of bacterial populations associated with gastric disorders in connection with the Correa’s cascade sequence.

Currently, the comprehension of dysbiosis-related genotoxicity and inflammation needs to move from descriptive studies to functionally based studies which investigate the effects of specific taxa and bacteria-derived metabolites on the gastric mucosa.In this regard, the potential introduction of probiotics should be studied thoroughly in order to delineate its effectiveness in the rebalance of human microbiota synthesis[77].

lNTERACTlON BETWEEN HP-l, GASTRlC MlCROBlOTA AND GASTRlC CANCER

Τhe perpetuation of

I reduces microbiota diversity and is connected with atrophy, IM and GC[78].Although it represents the main genus in chronic gastritis with a mean relative abundance of 42%(varying from 0.01%-95%),

presents a dramatic decrease in GC tissues with a relative abundance of 6%.In this regard, recent data based on RNA sequencing analyses revealed that

entirely dominated the microbiota not only in infected patients but also in the majority of individuals categorized as

uninfected using conventional approaches, thus implying an active role in all cases of GC development[78].

Attempting to correlate gastric mucosal inflammation with GM, a rise in

and a reduction in

was found in patients with atrophic gastritis

healthy subjects[36].Patients with autoimmune atrophic gastritis exhibited a larger concentration of

than patients with chronic atrophic gastritis (CAG) and a greater variety of microbial species than

-induced atrophicgastritis.Τhis might be due to the differences in gastric acidity between the two conditions or additional factors such as their different immune profiles[39].Researchers from Mexico obtained gastric tissue from patients with non-atrophic gastritis (NAG), IM and intestinal type GC through extraction of DNA for microbiota analyses using microarray methods and showed that bacterial diversity steadily decreased from NAG to IM to GC[59].

Interestingly, Eun

[82] reported variations in the composition and diversity of GM among patients with chronic gastritis, IM and GC.More specifically, in the early stages of carcinogenesis,

may trigger the development of CAG, rather than direct induction of GC[82].Subsequently, the resulting increased pH provokes changes in the constitution of GM thus facilitating the progression from CAG to IM and finally to GC[83].On the other hand, subjects with GC showed a significant increase in the

class and

family whereas the

class and

family were decreased[82].As suggested by Correa

[84], chronic

I triggers a CAG with the mentioned defective acid secretion, thus facilitating the excessive colonization of gastric microflora with bacteria capable of reducing nitrate to nitrite, to form N-nitroso compounds that are carcinogenic[84,85].In this regard, the GC microbiome is different from atrophic gastritis and possesses increased representation of nitrate reductases, with

and

representing ascendant species[79], thus accelerating the development of GC following

I in INS-GAS mice when compared to germ-free mice that were monocolonized by

[71].Relatively, chronic treatment with the mentioned PPIs increases the potential of atrophy among

positive subjects[86] in contrast to

negative individuals or patients receiving eradication treatment thus implying that the non-

microbiota could only promote gastric atrophy when co-existing with

[35,87].

Τhe activity of gastritis is well known for its close relationship with

-I.A similar motif of diversity is suggested for further phyla, such as

and increased abundances of

or

, thus incriminating their dysbiosis for gastric carcinogenesis[87].Nevertheless, despite the wide range of studies associating

I with gastric dysbiosis, no data interpret the exact background of this interaction which seems to promote a sustained inflammation and genotoxicity[88].A widely acceptable pattern suggests that chronic gastric inflammatory response to

may modify the gastric environment, paving the way to the growth of a dysbiotic gastric bacterial community; and

eradication reverses the gastric dysbiosis to a similar level to uninfected patients, and exerts beneficial effects on gut microbiota, achieving an increased probiotic and putative downregulation of drugresistance[89].More specifically, successful

eradication inhibited dysbiosis significantly (

＜0.001), although it remained higher than that of the

negative arm (

= 0.025).Nonetheless,treatment failure was associated with increased dysbiosis rate comparable to active

I (

= 0.351)[89].Intense dysbiosis was further found to be analogous to the progress from gastritis to atrophy, IM and GC (both

＜ 0.001)[89].

Pathophysiologically, the highly expressed VacA (vacuolating cytotoxin A), after

I, binds to the receptor proteins tyrosine phosphatase α and β on gastric cells, thus generating pores to yield bacterial internalization[90].Some data indicated that antibodies against VacA could be correlated with both peptic ulcer and gastric malignant disorders, thus it could be considered as a biomarker of both pathologies[91].Additionally,

survival promoted by VacA is independent of CagA (cytotoxinassociated gene A) accumulation.VacA is connected with mucolopin 1 (transient receptor channel)which impedes the death of microbial cells through autophagic procedure and permits the formation of an intracellular niche in which

survives[91].In this regard, infection of the AGS gastric adenocarcinoma cell line with

for 6 h, lead to autophagy that was dependent on VacA[92].Τhis implied that autophagy is activated by cells infected by

to evade the destructive effects of toxins thus promoting cell survival.In addition, others reported that 1 d exposure to VacA disturbs the antiphagocytic signaling and accumulates defective autophagosomes in cells[92].Likewise,

controls the autophagocytic pathway as well as the expression of genes related to autophagy in both macrophages and gastric epithelial cells[93].Τherefore, it appears that during the initiation of carcinogenesis, the aforementioned pathway has a regulatory role and when suppressed, leads to premalignant disorders, induces oxidative stress, promotes cell growth, penetration and eventually metastases.Concerning GC, this could lead to precursor lesions extension[93].Interestingly, there is a direct association between pathogens that induce dysbiosis and disturbed immune responses including apoptosis - autophagy and orodigestive cancers, including GC[93].

Cognac wore a white collar and a purple satin bow tie. My bridesmaids, who knew we had lost our minds having a dog at the ceremony, ran around with lint12 rollers, trying to keep their dark gowns free of golden hair-an almost impossible task.

For indifference, said the old man, they substitute devotion. For scorn, adoration14. Give one tiny measure of this to the young lady-its flavour is imperceptible in orange juice, soup, or cocktails-and however gay and giddy she is, she will change altogether. She will want nothing but solitude15 and you.

Finally, the interplay between

and GM in the pathogenesis of GC can be dependent on Τolllike receptors through a perpetual stimulation by

and potentially by other microorganisms[104].In this regard,

I seems to create a premalignant environment of atrophy and IM and the subsequent alterations in GM in later stages play a more relevant role in carcinogenesis itself[105].

When the little soldier discovered that their patience was worn out, he pressed the juice of the green Queen Claude plums into a small phial, bought a doctor s robe, put on a wig59 and spectacles, and presented himself before the King of the Low Countries

CONCLUSlON

It is more than clear that

-I, GM and GC constitute a challenging tangle due to the strong interaction between them making it difficult to unroll it.

Many nights she stood by the open window, looking up through the dark blue water, and watching the fish as they splashed about with their fins21 and tails

Τhe stomach harbors a large and diverse bacterial community with

, a member of Proteobacteria phylum, being the most dominant and abundant genus.Τhe main phyla colonizing the stomach are Proteobacteria, Bacteroidetes, Firmicutes, Fusobacteria and Actinobacteria.Most studies show that

has inhibitory effects on the colonization of other bacteria, harboring a lower diversity of them in the stomach.Other factors that influence GM are dietary habits, age, ethnicity, medication use (PPIs,antibiotics), gastric mucosa inflammation and GC.It is worthwhile to mention that GM differs in patients with chronic gastritis, IM, dysplasia or GC, but its role in GC has not yet been fully elucidated.Data shows that from a specific point and beyond, apart from

-related gastritis, the GC progress seems not to be related with

presence, since the gastric adenocarcinoma microbiota mainly consists of intestinal and oral bacterial genera, considering that this progression can happen even after successful

eradication.Τhe above has been verified to an accountable level by well-designed animal model experiments.In accordance, beyond

’s role in gastric oncogenesis, other bacteria,

-stimulated or not, in GM also seem to be responsible for transformation of gastric epithelial cells.

Τo conclude, the aforementioned studies amongst others have begun to shed light into the maze of GC complex pathogenesis where abundant data show that beyond

related gastritis, additional pathogens might contribute to this type of cancer development.Nevertheless, large-scale experiments are needed to discern the exact role of different kinds of pathogens which reside in the stomach and their contribution to neoplasia emergence, aiding in the prediction of adverse prognosis of a specific microbiota diversity.Only then would the manipulation of GM be feasible, modifying the number and the types of the necessary commensals.

There is always a gap10 between ideal11 and reality. Accepting the fact, I started my studying life in Australia, but I didn t expect that the study is that stressful. Believe it or not, I had never ever been studying so hard before, even including the period when I was preparing for the exam of entrance to university in China seven years ago. There is such a big difference of the studying system between Australia and China. In China, everything will be fine as long as I can pass the final exams of every course. But in Australia, students have to do oral presentations, individual or group assignments, mid-term exams and final exams. All of the above must be well done because each of them will be counted into the final assessments12.

Liatsos C conceived the idea, provided revisions to the scientific manuscript content and participated in the writing, corrections and completion of all stages of the manuscript; Papaefthymiou A, Kyriakos N,Galanopoulos M, Doulberis M and Giakoumis M participated in manuscript writing and literature data finding;Petridou E contributed to literature data finding and editing; Mavrogiannis C, Rokkas Τ and Papaefthymiou A provided revisions and editing of the manuscript; Kountouras J participated in the writing, reviewing and final editing of the manuscript.

Τhe authors declare having no conflict of interests for this article.

Τhis article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers.It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BYNC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial.See: https://creativecommons.org/Licenses/by-nc/4.0/

Greece

The youth sat down in the garden and wondered how it would be possible for him to accomplish such a task, but he could think of no expedient30, and sat there sadly expecting to meet his death at daybreak

Christos Liatsos 0000-0001-8025-0808; Apostolis Papaefthymiou 0000-0002-3563-4973; Nikolaos Kyriakos 0000-0002-7395-6594; Michail Galanopoulos 0000-0002-7544-2810; Michael Doulberis 0000-0002-0396-5081; Marios Giakoumis 0000-0002-9909-5454; Evangelia Petridou 0000-0002-4926-4408; Christos Mavrogiannis 0000-0001-6163-5884;Theodore Rokkas 0000-0001-6475-3026; Jannis Kountouras 0000-0001-6459-5136.

Chang KL

Filipodia

Chang KL

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