Microbial carcinogenesis: lactic acid bacteria in gastric cancer

1
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Karla Vinasco1, Hazel M. Mitchell1, Nadeem O. Kaakoush2, Natalia Castaño-

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Rodríguez1*

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Australia

82School of Biotechnology and Biomolecular Sciences, UNSW Sydney, Sydney, NSW 2052,

School of Medical Sciences, UNSW Sydney, Sydney, NSW 2052, Australia

910Correspondence:

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Dr Natalia Castaño-Rodríguez

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School of Biotechnology and Biomolecular Sciences, Faculty of Science, UNSW Sydney

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Kensington, NSW 2052, Australia

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Phone: +61 2 93853514; Email: n.castanorodriguez@unsw.edu.au

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Keywords:

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microenvironment

gastric

adenocarcinoma,lactate,carcinogenesis,

microbiota,

tumor

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Abstract2

While Helicobacter pylori is a fundamental risk factor, gastric cancer (GC) aetiology involves

3

combined effects of microbial (both H. pylori and non-H. pylori), host and environmental

4factors. Significant differences exist between the gastric microbiome of those with gastritis,

5

intestinal metaplasia and GC, suggesting that dysbiosis in the stomach is dynamic and6correlates with progression to GC. Most notably, a consistent increase in abundance of lactic

7

acid bacteria (LAB) has been observed in GC patients including Streptococcus, Lactobacillus,

8

Bifidobacterium and Lactococcus. This review summarises how LAB can influence GC by a9number of mechanisms that include supply of exogenous lactate —a fuel source for cancer

10cells that promotes inflammation, angiogenesis, metastasis, epithelial-mesenchymal transition11

and immune evasion—, production of reactive oxygen species and N-nitroso compounds, as

12well as anti-H. pylori properties that enable colonization by other non-H. pylori carcinogenic

13

pathobionts.

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15

Abbreviations

16

A, antrum; AG, atrophic gastritis; ARG1, Arginase 1; B, body; C, cardia; CAF; cancer-

17

associated fibroblast; Cav-1, caveolin-1; CD147, chaperone protein cluster of differentiation

18

147; CFU; colony-forming units; CIN, chromosomal instability; DLD, dihydrolipoamide

19

dehydrogenase; EBV, Epstein-Barr virus; ECM, extracellular matrix; EMMPRIN,

20

extracellular matrix metalloproteinase inducer; ENO1, enolase 1; FD, functional dyspepsia;

21

GC, gastric cancer; GAC, gastric adenocarcinomas; GIT, gastrointestinal; GLO, glyoxalase;

22

GLUT, glucose transporter; GS, genomically stable; HP, Helicobacter pylori; HP+, HP-

23

positive; HP-, HP-negative; HCAR, hydrocarboxylic acid receptor; HIF-1, hypoxia-inducible

24

factor 1; HK2, hexokinase 2; INS-GAS, Insulin-Gastrin; IM, intestinal metaplasia; LAB, lactic

25

acid bacteria; LDH, lactate dehydrogenase; MAG, multifocal atrophic gastritis without2

1

intestinal metaplasia; MAG-IM, multifocal atrophic gastritis with intestinal metaplasia; MCT,

2monocarboxylate transporters; MDSC, myeloid-derived suppressor cell; MG, methylglyoxal;

3

MSI, microsatellite instability; NAG, non-atrophic gastritis; NK, natural killer; PDK1,

4

pyruvate dehydrogenase kinase 1; PKM2, pyruvate kinase; qPCR, quantitative PCR; ROS,

5

reactive oxygen species; SCFAs, short-chain fatty acids; SLC16A, solute carrier 16A family;

6

TAM, tumor-associated macrophages; TCGA, The Cancer Genome Atlas; TME, tumor

7

microenvironment; T-RFLP, terminal restriction fragment length polymorphism; VEGF,

8vascular endothelial growth factor.

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1. Microbes and carcinogenesis

2

Microbial carcinogenesis is most commonly explained through the simplistic model of3dysregulated inflammation. More recently, the role of microbes in cancer development has

4expanded to include the potential capacity to modulate several cancer hallmarks, including

5

tumor-promoting inflammation [1], altered immune response [2], tumor growth [3-5],

6angiogenesis [6], pro-carcinogenic metabolite production [7, 8], as well as DNA damage and7

induction of genomic instability [9] (Fig. 1).

8
9

A good example of this is the metabolite butyrate, which is produced by bacterial species

10through the anaerobic fermentation of carbohydrates and provides an important energy source

11

for host cells such as colonocytes. While butyrate has been shown in a range of studies to have12

beneficial anti-cancer effects [10], in the right genetic background, butyrate promotes

13

carcinogenesis through the increased proliferation of aberrant epithelial cells [10, 11]. Here,14

we summarise how lactate, a metabolite that is related to butyrate, and can be produced by both

15

host and microbial cells, has similar properties. We highlight the importance of lactate in

16

gastric carcinogenesis, and we present evidence towards a “lactate paradox” in the form of17

microbiome-produced lactate that acts as fuel for gastric tumor cells and shapes the tumor

18

microenvironment (TME).

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3
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Fig 1. Role of the gastrointestinal microbiome in cancer. The GIT microbiome is involved

2

in major steps of carcinogenesis including tumor-promoting inflammation, altered immune

3

response, tumor growth, angiogenesis, pro-carcinogenic metabolite production, DNA damage

4

and induction of genomic instability. In GAC, lactic acid bacteria are enriched. Four main5

mechanisms by which these bacteria may influence the outcome of gastric disease include: 1)

6increased N-nitroso compounds and reactive oxygen species (ROS). N-nitroso compounds

7

have been shown to promote mutagenesis, angiogenesis, protooncogene expression, and to8

inhibit apoptosis [12-14] while ROS have been shown to induce DNA damage [15]. 2)

9Increased EMT by induced multipotency [16], contributing to tumor progression [17]. 3)

10

Promote colonisation by non-H. pylori carcinogenic pathobionts by induced immune tolerance

11[18] and their anti-H. pylori microbial properties [19-21]. 4) Augmented production of

12

exogenous lactate. Lactate is involved in several hallmarks of cancer [22] and regulates the13

expression of important key players. Lactate can serve as a fuel source for oxidative cancer

14cells, upregulating MCT1 [23] and subsequently contributing to cell migration [24]. Cell

15

migration and metastasis are also correlated with high LDH [25] and VEGF expression [26,1627], the latter being an important angiogenic factor in cancer [28]. EMT can be induced by17

HIF-1 [29], which can be activated by lactate in an oxygen-independent manner [30-32].

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Lactate can also regulate the HCAR1/MCTs axis and enhance DNA repair capacity in tumor

19

cells contributing to chemoresistance [33]. Tumor growth can be potentiated by lactate-

20

mediated expression of HCAR1 [34] and MCT4 [35]. MCT4 is also indispensable for the21

activation of the inflammatory response of TAMs [36]. Lactate mediates M2-like polarization

22of TAMs, which is believed to be tumor supportive [37], and increases VEGF and ARG1

23

expression [30] in these cells, contributing to immune escape [38]. Lactate also inhibits T and24

NK cells function and survival [39], and increases the amount of MDSCs, which can further

25

supress NK cell cytotoxicity [40].

26

GIT, gastrointestinal; GAC, gastric adenocarcinoma; EMT, epithelial-mesenchymal transition;

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ROS, reactive oxygen species; TAM, tumor-associated macrophage; NK, natural killer;

28

MDSC, myeloid-derived suppressor cell; MCT1, monocarboxylate transporter 1; MCT4,29

monocarboxylate transporter 4; HCAR1, hydrocarboxylic acid receptor 1; HIF-1, hypoxia-

30

inducible factor-1; LDH, lactate dehydrogenase; VEGF, vascular endothelial growth factor;

31

ARG1, Arginase 1; CAFs, cancer-associated fibroblasts; Cav-1, caveolin-1.

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2. Gastric cancer

2

Gastric cancer (GC) is the 5th most common cancer worldwide [41, 42] and is considered a3leading cause of cancer death globally [43, 44] despite declining incidence and prevalence

4

rates. In fact, in 2013, GC was the third most common cause of cancer-related deaths in5developed countries, accounting for 984,000 new cases and 841,000 deaths worldwide [43].

6

Recent studies suggest that most GC cases are frequently diagnosed in the final stages of the7disease, resulting in generally poor survival rates. Almost two thirds of GC cases occur in East

8

Asia, Eastern Europe and Central and South America, these regions being classified as high9

GC risk populations [43].

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The majority of GCs are adenocarcinomas (GAC) which have been conventionally classified

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into a number of histological subtypes based on Lauren’s classification (i.e. intestinal, diffuse,

13

mixed and non-classifiable) [45]. More recently, the World Health Organization categorized

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GAC into four subtypes including papillary, mucinous, tubular, and signet ring cell [46].

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Importantly, recent advanced genome technologies have led to a novel GC classification

16

scheme. This classification, known as The Cancer Genome Atlas (TCGA) classification,

17

comprises four GC subtypes: (1) Epstein-Barr virus (EBV)-positive, (2) microsatellite

18

instability (MSI), (3) genomically stable (GS), and (4) chromosomal instability (CIN) [47].

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GAC is a multifactorial and multistep inflammatory disease. Correa’s cascade, a widely21

accepted model for GAC, illustrates the stages of gastric carcinogenesis from precancerous

22

lesions—superficial gastritis, chronic atrophic gastritis, intestinal metaplasia and dysplasia—

23

to adenocarcinoma [48]. A number of factors play a significant role in GAC, including host24

genetics [49-52], environmental factors (e.g. smoking, alcohol consumption, high salt and meat25

intake, and low vegetable/fruit intake), and microbial factors (i.e. Helicobacter pylori infection

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and the gastric microbiota) [53-55]. H. pylori, a Gram-negative curved rod has been associated2with 89% of new GAC cases around the world [56, 57]. H. pylori chronic infection plays an3

important role in the early stages of the disease including chronic gastritis, atrophic gastritis

4

and intestinal metaplasia [58-62], however, its colonization in atrophy and intestinal metaplasia

5

is scarce [63, 64], leading to the hypothesis that other bacteria within the gastric microbiome

6

are also involved in GAC development. Importantly, the latest clinical guidelines on the

7management of gastric epithelial precancerous conditions reiterated the need to identify

8patients with advanced stages of gastritis (i.e. atrophy and/or intestinal metaplasia affecting

9both antral and corpus mucosa) given that they are considered to be at higher risk for GAC

10

[65].

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3. Role of lactate in gastric carcinogenesis

13

Once a tissue has turned malignant, it exhibits limitless replicative potential, which requires

14changes and adaptations in energy metabolism to sustain the increased rate of cell division and15

anabolic tumor growth [66]. Malignant cells are mostly programmed to rely on aerobic

16

glycolysis instead of oxidative phosphorylation, which is less efficient in terms of adenosine

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triphosphate production but provides tumor cells with an appropriate fuel supply to support

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their accelerated growth rate. This provokes an increase in glucose uptake and high amounts

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of lactate in an oxygen-independent manner [67, 68], a well-established phenomenon known

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as the Warburg effect [69, 70]. Given that lactate is crucial for major processes during

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carcinogenesis including angiogenesis, immune evasion, cell migration, metastasis, and cell

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sufficiency, it has been recently proposed that upregulated lactagenesis is the ultimate purpose

23of the Warburg effect in cancer cells [22]. Indeed, basal lactate production in an average human24

is of the order of 0.8 mmol/kg body weight/h while lactate can be found at concentrations

25

ranging from 10-12.9 mmol/kg in glycolytic tumors [71-74]. This increased lactate8

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concentration will in turn impact on lactate transport and metabolism, oxygen levels, and the

2

TME.

3
4

3.1 Lactate transport

5Lactate transport is mainly carried out by four members of the solute carrier 16A family

6(SLC16A) known as the monocarboxylate transporters (MCT) 1, 2, 3 and 4, which are also

7

involved in the proton-linked transport of acetate, pyruvate, butyrate, and ketone bodies [75-877]. MCTs are involved in the regulation of important physiological and pathological processes

9in diverse tissues, however, they appear to be particularly important for the brain and malignant

10tumors (for a comprehensive review on this topic, please see [78]).

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12

The data on MCT regulation in GAC is somewhat conflicting. Pinheiro et al [79] reported that13

MCT1 expression was associated with advanced GAC while Lee et al [80] reported MCT4

14

overexpression to be mainly found in GAC cell lines derived from metastasis or ascites.

15

Furthermore, previous observations in patients with GAC have shown that high MCT416expression is found in stromal but not tumor cells and is correlated with a worse prognosis and17

increased tumor progression [81]. Importantly, inhibition of MCTs has been shown to result in18

reduced tumor cell proliferation and lactate uptake in GAC cell lines that overexpressed MCTs

19[80]. This is in line with several reports in diverse types of cancer where MCT inhibition

20

resulted in delayed tumor growth [32, 82-85]. However, significant decreased expression of21

MCT4 has also been reported in advanced GAC and metastasis as compared to normal gastric22

mucosa and early GC, suggesting a progressive loss of this isoform with disease progression

23

[79].

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The expression of the chaperone protein cluster of differentiation 147 (CD147) (aka basigin or2

extracellular matrix metalloproteinase inducer, EMMPRIN) is required for MCT1 and MCT4

3proper expression at the cell surface and functioning [86-89]. CD147 is considered a key

4

element in oncogenesis, being widely correlated with poor prognosis and progression of several

5

malignancies (for further information on this topic, please see the comprehensive review and6meta-analysis by [90]). CD147 interaction with MCT1 and MCT4 has been shown to be crucial

7

for their regulation in gastric tumor cells [79]. Moreover, upregulation of CD147 in GAC has

8been reported [79, 91] and has been associated with local invasion and poor prognosis via

9tumor growth and angiogenesis [92]. Importantly, a recent meta-analysis, comprising 199310

subjects, showed that CD147 expression is correlated with poor prognosis in GAC [93].

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3.2 Lactate metabolism in tumor cells

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There are two stereoisomeric forms of lactate, D- and L-lactate. D-lactate can be produced in

14

small amounts in cancer cells through the ubiquitous methylglyoxal (MG) pathway. MG is

15

produced from carbohydrate, fat and protein metabolism [94]. Interestingly, MG has been16

suggested to modify heat shock proteins, which can alter and/or enhance their chaperone

17functions and stress response activities in cancer cells [95]. Due to its reactive and toxic nature,18

MG is then converted to D-lactate via the intermediate S-D-lactoylglutathione by the enzymes

19

glyoxalase (GLO)-1 and GLO-2, the former being recently reported to be an important

20

metabolic oncogene in GAC that could be used as a prognostic factor [96, 97]. Thus, an

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interesting take would be that cancer cells, in an attempt to detoxify MG, increase their D-

22

lactate production, which in turn feeds the Warburg effect.

23
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L-lactate, on the other hand, is abundantly produced by tumour and stromal cells. The

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metabolic imbalance in glycolytic cells is promoted by the continuous conversion of pyruvate10

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to lactate through lactate dehydrogenase (LDH) [98], which is induced by oncogenes [99].

2

Increased levels of LDH has been correlated with poor prognosis in cancer and is a hallmark

3of highly glycolytic tumors [25, 100]. In the later stages of gastric carcinogenesis, lactate and4

LDH seem to play an important role. Using oxamate, an inhibitor of LDH-A, Liu et al [101]5demonstrated that lower levels of LDH-A decreased aerobic glycolysis, subsequently reducing

6

the production of lactic acid in GAC cells. Altered cell morphology, impaired migration and

7

proliferation, and increased apoptosis were also observed with the inhibition of LDH-A in GAC

8[101]. Additionally, the isoenzyme LDH-5 has been correlated with increased tumor and9stromal vascular endothelial growth factor (VEGF) and is also a marker for poor prognosis in

10

GAC [102]. Of note, the expression of one of the main LDH subunits, LDH-A, is also increased11

in cardia GC [103]. Further, increased expression of both LDH and dihydrolipoamide

12

dehydrogenase (DLD) has been suggested to influence the development and progression of

13

GAC [104].

14
15

3.3 Hypoxia

16

The rapid growth of cancer cells leads to the formation of new blood vessels; however, these17

new vessels are insufficient to sustain their accelerated growth. This leads to limited blood18

supply and hypoxia, which is a critical switch point for tumor cell metabolism. Consequently,

19

tumors are heterogeneous tissues containing both oxygenated and hypoxic/glycolytic cell

20

populations.

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Hypoxic conditions induce the expression of Hypoxia-inducible factor 1 (HIF-1) [105], a

23

critical transcription factor involved in the cellular responses to oxygen levels that increase

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tumor cell survival during hypoxia. HIF-1 promotes the expression of important glycolytic

25

enzymes and transporters including the M2 isoform of pyruvate kinase (PKM2), pyruvate11

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dehydrogenase kinase 1 (PDK1), glucose transporters (GLUTs), enolase 1 (ENO1), hexokinase2

2 (HK2), and LDH [106-110]. Importantly, HIF-1 can also be activated by lactate in an oxygen-3

independent manner [30-32].

4
5

HIF-1α is involved in angiogenesis, proliferation and metastasis [111]. HIF-1α expression is

6

frequently found in several human solid tumors and its over-expression has been associated7with poor prognosis in GAC [111, 112]. Further, a meta-analysis conducted by Lin et al [113]8

showed that HIF-1α positive expression was present in 50% of patients with GAC, and it was

9correlated with poor patient outcome. This appears to be mediated by HIF-1α contribution to10

chemoresistance and metastasis in GAC [114, 115].

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12

3.4 Tumor microenvironment

13

The TME not only consists of tumor cells but also cancer-associated fibroblasts (CAFs)

14

pericytes/endothelial cells, the extracellular matrix (ECM), and immune cells including tumor-

15

associated macrophages (TAMs), neutrophils, eosinophils, natural killer cells, and16lymphocytes. These heterogeneous cells have different metabolic profiles depending on

17oxygen, glucose and lactate availability. Epithelial cancer cells can induce a metabolic shift

18

towards aerobic glycolysis of neighbouring stromal cells, for example CAFs, which produce

19

and export lactate [116]. Lactate is later taken up by oxidative cancer cells through MCT120[117]. This metabolic setting provides a fuel-supportive microenvironment that feeds epithelial

21

tumor cells and supports tumor growth and angiogenesis. This model of lactate shuttling is22termed “the reverse Warburg effect” and plays an important role in tumor growth and23angiogenesis, increasing lactate production and secretion [118-120].

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TAMs are among the most frequent inflammatory tumor infiltrating immune cells of the TME

2and play an essential role in tumor progression by promoting cell migration, invasion, and3

metastasis [121, 122]. Once released by cancer cells, lactate can be taken up by TAMs via

4

MCT1 [30, 123]. Lactate has been shown to induce M2-like polarization of TAMs, which is5

mediated by HIF-α [30]. Interestingly, TAM infiltration has been associated with epithelial-

6

mesenchymal transition (EMT) in GAC [124], which has been demonstrated to occur through7

the activation of the Wnt/β-catenin pathway [125]. Indeed, increased levels of TAMs and M2

8

infiltration in patients with GAC is associated with poor prognosis [125, 126].

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4. Microbially-derived lactate in gastric carcinogenesis

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4.1. Lactic acid bacteria in gastric carcinogenesis

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The gastrointestinal microbiome plays an important role for the maintenance of energy

13

metabolism, absorption of nutrients, shaping of the immune system, and protection against

14

pathogenic microbes [127, 128]. It can influence health by the production of metabolites (e.g.

15butyrate) and pro-inflammatory compounds, dysregulation of cell proliferation and stem cells

16physiology, and alteration of the metabolism of chemotherapeutic agents [129-131].

17
18

The colonization density within the stomach ranges from 102 to 104 colony-forming units

19(CFU)/ml, being significantly lower than that in the healthy colon, which ranges from 10 10 to

201012 CFU/ml [132]. This is partly due to the low pH of the stomach and other mucosa-

21

associated mechanisms including peristaltic movement. H. pylori is currently considered the22most abundant microbial species of the stomach [133-135]. Despite this, other microorganisms

23

are also capable of colonizing the gastric mucosa.

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Table 1. Summarised main findings of recent gastric microbiota studies.
Author/year

Dicksved et al
2009

Ethnicity

Disease status (n)Total
Samplesize

Biological samples

Microbiome

Main findings

15

Gastric biopsies (A andB)

16S rRNA gene
amplification, T-RFLP
and 16S rRNA genesequencing (from six
GAC samples)No significant differences in microbiota composition between
GAC and control group. Enriched genera in GAC:
Streptococcus, Lactobacillus, Veillonella and Prevotella

15

Gastric biopsies (A andB)

16S rRNA microarray
G3 phylochip

Gradual change in the gastric microbiota profile from NAG to
IM to GAC. Increased trend of Lactobacillus colehominis andLachnospiraceae with carcinogenesis progression.

315

Gastric biopsies (A)qPCR (bacterial load in
315 patients) and 16S
rRNA gene sequencing(in 12 subjects)

Lactobacillus and Lachnospiraceae uncultured are enriched in
GAC. The gastric microbiota is altered in patients with GAC
and is correlated with bacterial overgrowth and diversification.
Enrichment of microbiota potentially associated with cancerpromoting activities.

40

Gastric biopsies (A, B,
incisura angularis)

16S rRNA genesequencing

Individuals from Tuquerres (town with 25-fold higher risk of
GAC compared to Tumaco), had increased abundance of
Leptotrichia wadei. Veillonella, Actinomyces, Prevotella andStreptococcus were correlated with the presence of MAG-IM.

GAC (10)
SwedishFD (5)NAG (5)Avilés-Jiménez
et al 2014

Mexican

IM (5)GAC (5)

Wang et al
2016

NAG (212)
ChineseGAC (103)

Tuquerres NAG (10)Tuquerres MAG (8)Yang et al 2016

Colombian(Tumaco andTuquerres)

Tuquerres MAG-IM(2)
Tumaco NAG (12)Tumaco MAG (7)Tumaco MAG-IM(1)

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Tseng et al
2016

Taiwanese

GAC (6, before andafter tumour
resection)

16S rRNA genesequencing

Changes in the gastric microbiota composition, diversity andgene functions were found before and after surgical removal of
GAC. Top genera before tumour resection: Ralstonia,
Helicobacter, Lactobacillus, Stenotrophomonas, Burkholderia,
Bacillus, Curvibacter, Bdellovibrio, Sulfuritalea, andLegionella.

Gastric biopsies (A, B)
and blood samples

16S rRNA gene 454pyrosequencing

The gastric microbiota composition was not significantly
different between cancer and control subgroups. Nitratereducing bacteria were increased in the cancer subgroup. Top
genera in GAC and HP- subjects: Stenotrophomonas,
Streptococcus, Propionibacterium, Ralstonia and Citrobacter.

33

Gastric biopsies (A, B)

16S rRNA genesequencing

HP reduces bacterial diversity in HP-infected patients and its
eradication restores microbial composition. GAC samples have
reduced bacterial diversity. Top genera in HP- individuals:
Haemophilus, Serratia, Neisseria, and Stenotrophomonas.

81

Gastric biopsies (A, B,
fundus)

16S rRNA genesequencing

Higher abundance and strong co-occurrence of oral bacteria in
GAC. Top genera enriched in GAC: Streptococcus,
Lactobacillus,
Peptostreptococcus,
Gemella,andFusobacterium.

160

Gastric biopsies(Mexican: A, B;
Chinese: C)

16S rRNA genesequencing

HP and oral microbiota dominate the stomach of most patientswith GAC. Top genera in non-malignant tissue: Helicobacter,Enterobacteriaceae (Chinese subgroup), and Streptococcus and
Lactobacillus (Mexican subgroup).

6

Healthy (16 HP+ and
13 HP-)Jo et al 2016

Korean63
GAC (15 HP+ and 19
HP-)

Gastric biopsies fromtumour and nontumour tissue

NAG (9, HP+)
IM (9)Li et al 2017

ChineseGAC (7, tumour andnon-tumour)HP- controls (8)Superficial gastritis(21)

Coker et al
2018

Chinese (Xi'an,81)*

AG (23)
IM (17)GAC (20, tumour andnon-tumour)
Chinese cardia GAC(80)

Yu et al 2017b

Chinese (80),Mexican (80)Mexican non-cardia
GAC (80, tumour andnon-tumour)15

CastañoRodriguez et al
2017

Sohn et al.
2017

Ferreira et al
2018

Ethnic Chinese(Malaysia andSingapore)

Korean32

Gastric biopsies (A)and blood samples

16S rRNA transcript
sequencing

HP infection status affects overall constitution of the gastricmicrobiota. Increased bacterial diversity in GAC. Enrichmentof proinflammatory oral bacterial species in GAC. Increased
abundance of LAB and upregulated SCFAs production
metabolism. Top genera in GAC: Lactococcus, Lactobacillus,
Veillonella, Fusobacterium, and Leptotrichia.

12

Gastric biopsies (B)and blood samples

16S rRNA gene 454pyrosequencing

Higher proportion of Streptococcus mitis group, including S.
pseudopneumoniae, S. mitis, S. infantis, S. oralis, and S.
tigurinus in HP- cancer subjects. Also, urease-producing andnitrate-reducing bacteria are enriched in this subgroup.

Gastric biopsies (A, B)

16S rRNA genesequencing and realtime qPCR

Higher dysbiosis and reduced bacterial diversity in GAC.
Increased nitrate reductase and nitrite reductase functions in
GAC. Lactobacillus, Clostridium and Rhodococcus are
significantly enriched in GAC.

16S rRNA genesequencing

Patients with GAC have an increased abundance ofClostridium, Fusobacterium and Lactobacillus. HP-infectedpatients exhibit a less diverse microbiota. Top species in GAC:
Clostridium
colicans,
Fusobacterium
canifelinum,
Fusobacterium
nucleatum,
Lactobacillus
gasseri,
Lactobacillus reuteri, Prevotella intermedia, and Prevotellaoris.

FD (20)GAC (12)FD (2 HP- and 3
HP+)
GAC (2 HP- and 5
HP+)

Chronic gastritis (81)Portuguese (135)**135
GAC (54)

Gastritis (9)Hsieh et al
2018

Taiwanese

IM (7)

27

Gastric biopsies (A, B,
C, fundus, and angle)

GAC (11)

Hu et al. 2018

ChineseSuperficial gastritis(5)
GAC (6)

11

Gastric mucosal
washes

Shotgun metagenomics

Composition and function of the gastric microbiota differs
between superficial gastritis and GAC individuals. HP
prevalence was not significantly different between these two
subgroups. Enrichment of 13 bacterial taxa and reduced species
richness in GAC. Increased relative abundance of oral
proinflammatory
bacteria
in
GAC:
strainPorphyromonas_endodontalis.t_GCF_000174815,
species

16

Streptococcus_mitis_oralis_pneumoniae
Alloprevotella.

Liu et al. 2019

1
2
3
4
5

ChineseGAC (276)

276

Gastric biopsies(normal, peritumour
and tumour)

16S rRNA genesequencing

and

genus

Gastric microbiota composition is altered in GAC and isdetermined by the stomach microenvironment but not by GAC
stage or subtype. HP is decreased in the tumoral microhabitatand has a negative co-occurrence with Prevotella, Bacteroides,
Faecalibacterium, Phascolarctobacterium and Roseburia.
Streptococcus, Selenomonas, Prevotella melaninogenica,
Streptococcus anginosus and Propionibacterium acnes wereenriched in the tumoral microhabitat.

HP, Helicobacter pylori; HP+, HP-positive; HP-, HP-negative; A, antrum; B, body; C, cardia; GAC, gastric adenocarcinoma; IM, intestinal metaplasia; AG, atrophic gastritis; FD, functional
dyspepsia; MAG, multifocal atrophic gastritis (without intestinal metaplasia); MAG-IM, multifocal atrophic gastritis with intestinal metaplasia; NAG, non-atrophic gastritis; qPCR, quantitative
PCR; T-RFLP, terminal restriction fragment length polymorphism; LAB, lactic acid bacteria; SCFAs, short-chain fatty acids. * These results were validated in 126 Inner Mongolians (56 superficial
gastritis, 51 AG and 19 GAC) **These results were validated in 38 Portuguese (15 chronic gastritis and 23 GAC), 53 Chinese (GAC) and 53 Mexican (GAC) subjects.

17

1

Using conventional culture methods, species belonging to the genera Lactobacillus,

2

Clostridium, and Veillonella, were reported to be the most representative microbes in the3healthy stomach [136]. Given that most of the microbes in the stomach are non-cultivable

4(approximately 80%), the development of new molecular methods, such as 16S rRNA gene5

sequencing, has led to a better characterization of the bacterial composition of the gastric6

environment. Several studies have reported consistent results in terms of the healthy gastric7

microbiota composition at the phyla level, although significant variability exists in relation to

8both abundance and dominance of lower taxonomic levels (Table 1). The most predominant9phyla in the stomach are Proteobacteria (which includes H. pylori), Firmicutes, Bacteroidetes,

10

Actinobacteria, and Fusobacteria [133, 134, 137-141].

11
12

A number of studies have shown that H. pylori infection is associated with significant changes

13in the gastric mucosa [133, 138, 141-143] (Table 1). In fact, it has been suggested that in

14

addition to being a direct promoter of GAC, H. pylori potentiates the transformation of the15

gastric mucosa into a hypochlorhidric environment [144-146], which would allow other16

microbes to colonize [135, 147, 148].

17
18

More recently, bacterial overgrowth that resulted in a significant alteration of the gastric19

microbiota, has been shown in patients with GAC [142]. To date, bacterial genera most20

consistently reported to be enriched in patients with GAC include Lactobacillus,

21

Streptococcus, Veillonella, Prevotella, Fusobacterium, Lachnospiraceae, Leptotrichia, and22

Clostridium (Table 1). Interestingly, some of these bacteria are known to have detrimental

23

effects in the stomach, despite being present in the normal intestinal flora [149, 150].

24

18

1

Most notably, recent reports show a consistent increase in abundance of lactic acid bacteria

2(LAB) in patients with GAC including Streptococcus [140, 143, 151, 152], Lactobacillus [140-3143, 153, 154], Bifidobacterium and Lactococcus [143] (Table 2). Importantly, this increase in

4abundance in LAB in GAC was found in the active gastric microbiota (RNA profiling) [143]5

and across different stages of the GAC cascade [141]. This suggests that this increase is not the6result of non-viable bacteria or contaminating DNA. In support, Lactobacillus,

7

Bifidobacterium, and Streptococcus have been found to be higher in GAC subjects using

8

culture-based methods [155, 156]. These findings would suggest that microbially-derived

9

lactate increases in the GAC cascade.

1011

Supporting this, early work by Armstrong et al [157] showed increased levels of L-lactate, D-

12lactate and LDH in GC patients compared to patients presenting with gastric ulcers and healthy

13

individuals, a highly relevant finding given that the D- stereoisomeric form is mostly produced

14

by bacteria. More recently, Parsons et al [158] reported D-LDH to be overexpressed in gastric

15

samples from H. pylori-induced atrophic gastritis patients as compared to samples from16

autoimmune atrophic gastritis patients. Given that D-LDH is required for the metabolism of D-

17

lactate, these findings suggest that H. pylori infection results in modulation of microbial lactate

18

metabolism in gastric precancerous lesions.

1920

4.2 Mechanisms involved in gastric carcinogenesis

21

There is overwhelming evidence supporting the recent notion that the microbiome can

22

influence cancer development and treatment [159]. In this context, it is plausible that microbial

23

lactate can shape the TEM in a similar manner to host lactate considering LAB can produce up

24

to 188 mM of D-lactate and 182 mM of L-lactate in just 48 hours [160]. There is limited

25

evidence on the direct effect of LAB and their lactate on eukaryotic cells, however, Ohta et al19

1Table 2. Studies reporting enrichment of gastric microbial taxa of interest during gastric carcinogenesis.
DiseasestatusLactobacillus

Streptococcus

Yang et al 2016

IM

Dicksved et al 2009

Dicksved et al

Avilés-Jiménez et al

2009

2014

Coker et al 2017

Tseng et al 2016
Wang et al 2016
Yu et al 2017b

CastañoRodriguez et al
2017
Hsieh et al 2018

Castaño-Rodriguez
et al 2017
Coker et al 2017

Hu et al. 2018
Liu et al. 2019

Prevotella

Clostridium

Yang et al 2016

Jo et al 2016

Yu et al 2017b

GAC

Lachnospiraceae

Fusobacterium

Leptotrichia

Li et al 2017

Li et al 2017

Dicksved et al2009
Avilés-Jiménez et al
2014
Wang et al 2016
Castaño-Rodriguez

Coker et al 2017

Castaño-Castaño-Rodriguez et al

Rodriguez et al
2017

et al 2017
Coker et al 2017

Hsieh et al 2018

2017
Ferreira et al 2018
Hsieh et al 2018

Castaño-Rodriguez
et al 2017
Coker et al 2017
Hsieh et al 2018

CastañoRodriguez et al2017

Liu et al. 2019

Liu et al. 2019

Ferreira et al 2018
Hsieh et al 2018

2

Sohn et al. 2017

IM, intestinal metaplasia; GAC, gastric adenocarcinoma.

20

1[16] have showed that LAB can turn human adult fibroblasts into multipotent cells resulting in2cell clusters that incorporate LAB into their cytoplasm and show increased expression of

3

NANOG, a known multipotency marker.

4
5

LAB have been widely shown to enhance gastrointestinal homeostasis, immunomodulation,

6

availability of essential micronutrients and protection against cancer [161]. However, it has

7also been established that LAB are especially potent inducers of reactive oxygen species (ROS)

8

generation in cultured cells and in vivo [162], which has been shown to induce DNA damage

9in colonic cells, suggesting contrasting impacts of LAB on the gastrointestinal tract [15].

10

Similarly, LAB have been shown to reduce nitrate to nitrite, which leads to the formation of

11large amounts of N-nitroso compounds [163, 164]. N-nitroso compounds promote

12

mutagenesis, angiogenesis, protooncogene expression, and inhibit apoptosis [12-14]. In line

13with these observations, Ferreira et al [153] demonstrated that there is an increased functional

14

activity of nitrate and nitrite reductases in the GAC microbiota as compared to the chronic

15

gastritis microbiota.

16
17

The strongest in vivo evidence for a role of LAB in gastric carcinogenesis is based on studies

18

using the Insulin-Gastrin (INS-GAS) transgenic mouse model, which overexpress human19

gastrin and spontaneously develop gastric atrophy [146, 165, 166]. Lertpiriyapong et al [146]20reported that colonization of male INS-GAS mice with restricted microbiota consisting of

21

Lactobacillus murinus ASF361, Clostridium ASF356, and Bacteroides ASF519, was sufficient22

to promote gastrointestinal intraepithelial neoplasias, which correlated with robust

23

upregulation of pro-inflammatory and cancer-associated genes. These findings suggest that the24

stomach of subjects presenting with gastric atrophy may be more susceptible to the detrimental

25

effects of colonization by opportunistic microbiota, including Lactobacillus spp. that are21

1

present in the human oral cavity and esophagus [167]. Once LAB colonize the gastric atrophic

2

mucosa, their capacity to induce immune tolerance [18] and their known anti-H. pylori

3

microbial properties [19-21, 168, 169] could favor the establishment of other important4

carcinogenic pathobionts including Veillonella, Prevotella, Fusobacterium, and Leptotrichia

5[170-174], all of which are shown to be enriched in patients with GAC [140, 143, 152, 154,

6

175, 176]. This would be in accordance with a less simplistic scenario, in which gastric7

carcinogenesis is the result of early colonization with H. pylori followed by atrophic gastritis

8

and subsequent colonization by pathobionts with synergistic effects, in a genetically9susceptible individual.

1011

5. Conclusions

12

Lactate not only acts as a fuel source for cancer cells but is also capable of promoting

13

inflammation, angiogenesis, metastasis, and altering immune responses and key glycolytic

14

enzymes, which could all result in poor disease outcome [22, 32, 177, 178]. The enrichment of

15

LAB members, particularly in the later stages of gastric carcinogenesis, could have detrimental

16

effects given that lactate is involved in all major steps of carcinogenesis (Fig. 1). LAB could

17

influence GAC by a number of mechanisms that include increased production of exogenous

18

lactate, ROS and N-nitroso compounds as well as increased EMT, immune tolerance and19colonisation by other carcinogenic pathobionts (Fig. 1). Although Lactobacillus strains have20

been used as probiotics to control colonization of pathogens like H. pylori [20, 21, 169], and21

are suggested to have anti-proliferative and pro-apoptotic effects in cell-lines derived from22

GAC [179], the findings from human microbiome studies as well as animal models would

23

caution against their use in patients with GAC. In fact, it may be worthwhile replacing LAB

24

from the gastric environment of these patients through microbiome manipulation therapies.

25

The mechanisms we highlight in this review may also be important in the context of other22

1

gastrointestinal (e.g. esophagus) and female reproductive cancers, where LAB constitute a2

large proportion of the resident microbiomes.

3
4

Acknowledgements

5

NCR is supported by a National Health and Medical Research Council, Australia Early Career

6

fellowship (APP1111461) and Cancer Australia Priority-driven Collaborative Cancer Research

7

grant (1129488). NOK is supported by a Cancer Institute NSW Career Development

8

Fellowship (15/CDF/1-11). HMM acknowledges funding from the Ministry of Higher

9

Education, Malaysia (UM.C/625/HIR/MOHE/CHAN/13/1) and from the University of New

10

South Wales.

11

23

1

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