INTRODUCTION

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the third leading cause of cancer death[1] with higher incidence and mortality rates for African Americans (AA) among general population[2]. The incidence rates are 24% higher in Non-Hispanic (NH) black males and 19% higher in NH black females, while the death rates are 47% higher in NH black men and 34% higher in NH black women compared to NH white men and women[3]. This significant impact underscores the importance of further understanding the mechanisms and factors that influence the progression of CRC so as to alter the disease process before it has progressed to cancer or improve outcomes in those with a CRC diagnosis. The microbiome and its potential role in colorectal carcinogenesis is a newly emerging yet important field of study.

Current evidence indicates a complex interplay between the gut microbiome,genetic alterations and environmental factors. The gut microbiome is highly diverse and compared to the human genome it contains approximately 100 times the number of genes[4]. There are vast differences found in the microbiota of apparently healthy individuals. Variables such as differences in host genetics, antibiotics usage, environmental and lifestyle factors, including ethnicity, geographic location, and urbanization may modify the gut microbiome[5]. The epithelial surface and mucus layer are enriched with

,

s and

and the intestinal lumen is enriched with

,

and

[6]. Certain microorganisms could protect against pathogens that promote carcinogenesis by competing for attachment sites and thus preventing the development of CRC[7]. Probiotic strains of

and

are thought to play a protective role by competing for adhesion sites, secreting antibacterial peptides and displacing the enteropathogens,

and

(

)

as demonstrated in an enterocyte-like Caco-2 cell layer[8]. In CRC patients, a significantly reduced level of

has been found[7]. In contrast, several studies have reported increased levels of

enterotoxigenic

(

),

(

)

(

)

(

) and

in CRC subjects[9-15]. Additional human studies also have confirmed that

is associated with other Gram-negative bacteria, such as

,

and

, and synergistically promotes CRC[14].

Recent epidemiological studies have examined the association between periodontal diseases and CRC risk. Periodontitis is one of the most common bacterial infections in humans. In periodontitis, pathogenic opportunistic microorganisms in the oral cavity damage the integrity of the tooth-supporting tissues causing increased systemic inflammation, immune dysregulation, gut microbiota dysbiosis and thereby possibly influencing colorectal carcinogenesis[16,17].

is one of the most prevalent species found in extra-oral sites. This bacterium regulates biofilm organization and interacts with the host cells by producing various adhesins and associates with other bacteria through cross-feeding and metabolic interactions[18]. As such,

has been suggested to be a "driver bacterium" with pro-carcinogenic characteristics that contribute to tumor development by facilitating "passenger bacteria" to continue the progression of CRC[19]. Periodontal-associated bacteria such as

,

, and

have been found in CRC tissues[9] and

and

in feces of CRC patients[19,20]. Half of Americans age 30 or older have periodontitis and this increases to 70% for adults aged 65 years and older[7].Moreover, the prevalence in NH blacks is 59.1% as compared to 40.8% in NH whites[7].

Race/ethnicity also has been associated with variations in microbial abundance.Analysis of the gut microbiota by 16S in 1673 participants in the United States reported 12 microbial genera and families that vary by race/ethnicity. This suggests that the gut microbiota could be inherited and associated with human genetic variation[21].Farhana

[22] analyzed microbial communities in colonic effluents using 16SRNA profiling from AA and Caucasian American (CA) patients scheduled for an outpatient screening colonoscopy. The results showed higher levels of

in AAs compared to CAs. Pro-inflammatory bacteria such as

and

species were significantly higher in AAs. Also, AA patients had decreased microbial diversity compared to CA patients[22]. A study conducted in Malaysia reported that

,

,

and

Some bacterial communities could protect intestinal cells from inflammation and tumorigenesis. SCFAs function as signaling molecules between gut epithelia and immune cells modulating changes in the gene expression and providing nutrition to colonocytes. The three major SCFAs produced by bacterial fermentation of carbohydrates are acetate, propionate, and butyrate[70]. Published evidence supports the idea that butyrate is tumor-suppressive by inhibiting the proliferation of CRC cell lines while stimulating their apoptosis and/or differentiation (Figure 3)[40,54,55]. A Western diet slows mucus growth rate and increases penetrability of the colonic mucus barrier, and this effect co-occurs with the shifts in microbial community characterized by gradual decrease of SCFA-producing bacteria, such as

and

family and increases in

[71].

The “Hallmarks of Cancer,” proposed by Hanahan and Weinburg[25] organize the fundamental processes involved in the complex progression from normal cell to a tumorigenic state within a neoplastic environment. During carcinogenesis, various changes affect the host environment processes such as cellular metabolism and immunological function. Several intestinal microbes may influence the initiation and progression of tumorigenesis by modulating host factors that comprise the hallmarks of cancer[26]. This influence may occur locally and distantly through infection and microbial products, by changing the metabolism of the products produced by host and microbes or by modulating tumor immunosurveillance, which in turn alters the balance between the rate of cell proliferation and apoptosis, triggering chronic inflammation and immunosuppression[27].

She desired to have everything brought up to her, but he said: There is such a quantity of things that it would take many days to bring them up, and they would take up so many rooms that you would have no space for them in your house

Here, we summarize the current knowledge on how specific members of the microbiota and their bacterial machinery influence the hallmarks of cancer in the initiation and progression of CRC (Table 1). Each listed bacterial species is systematically presented according to the following scheme:(1) Tumor-promoting inflammation; (2) Avoiding immune destruction; (3) Deregulating cellular energetics; (4)Sustaining proliferative signaling; (5) Inducing angiogenesis; (6) Resisting cell death;and (7) Genome instability and mutations.

TUMOR-PROMOTING INFLAMMATION

A progressive interplay between tissue cells, microbiota and immune cells has been described. T and B cells present in the intestinal mucosa have location-specific phenotypes and functions that can be modified by the microbiota[28]. Commensal microbiota can modulate innate immune cells to release pro-inflammatory cytokines such as interleukin 6 (IL-6), IL-23 and IL-1β, which stimulate the expansion of Thelper-17 (Th17) cells. Th17 cells are a unique CD4

T-helper subset that secrete the cytokine IL-17. IL-17 increases Paneth cell production of anti-microbial peptides and promotes inflammation by the recruitment of polymorphonuclear neutrophils from the bloodstream[29]. Th17 have pro-tumorigenic effects and it has been associated with worse prognosis in CRC, as shown in Figure 1[30]. While Th17 immuneresponses promote tumor development, other cytotoxic immune cells, such as natural killer (NK) and CD8+ T cells, are essential for recognizing and eliminating cancer cells[31].

One commonality across many diseases in which microbiota contribute to progression is the disruption of the mucosal/epithelial layers of organs, allowing bacteria and their metabolites to enter compartments that are not normally in close proximity to microbes[32]. This can trigger a local chronic inflammatory response, due to perpetually injured tissues and thus a constant stream of infiltrating microbes/microbial products. Resident commensal bacteria may trigger exaggerated immune responses (colitis) when key components of immune tolerance are broken and/or modify the general immune response upon entering systemic circulation[33-35]. Such disruption may allow some non-native bacterial species to colonize the gut and adapt to the new environment, including oral bacterium. For example,

,

and

access and adhere to the basement membrane of the gut in setting of CRA and CRC[9].

is an obligate anaerobic gram-negative bacteria commonly present in the mouth and typically a poor colonizer of healthy and intact intestinal mucosa[9].Elevated

colonization in the normal tissues may predispose to the development of colorectal adenoma (CRA). Its virulence factor FadA adhesion gene (

) has been found in the colon tissue from patients with CRA and CRC in > 10-100 times higher compared to healthy individuals[36]. Other studies using metagenomic and transcriptomic analyses also have shown an enrichment of

species in CRA compared with adjacent normal tissue[7,37-39]. Infections of

(

) have been associated with CRC and CRA.

,formerly known as

(

), bacteremia has been associated with colon cancer in 25% to 80% of cases and

endocarditis has been associated with colon cancer in 18% to 62% of cases[11,40-45].

has shown a specific association with CRC and CRA when compared with the more dominant intestinal bacteria,

[46].

Enterotoxigenic

(

) is an anaerobic gram-negative rod that is known to have an affinity for colonizing the colonic mucosa[47]. Asymptomatic carriage can be seen in up to 40% of healthy children and adult fecal samples[48]. The pathogenicity of

is a result of the

toxin (BFT), which has 3 isotypes(BFT-1, BFT-2, BFT-3). BFT-1 is believed to more commonly colonize stool and BFT-2 more commonly colonizes the mucosa[49]. An association between

and CRC is emerging.

enhances Th17-driven inflammation and colonic tumor development.

preferentially colonize the epithelial crypts of the colonic mucosa and thus evade the host immune response leading to a more stable colonization in CRC[10,50].In general,

in CRC patients has been more commonly found on the colonic mucosa as opposed to stool samples[51]. It has been hypothesized that the human colon’s exposure to BFT may lead to a chronic, possibly focal, inflammation of colonic mucosa thus creating sites susceptible to carcinogenesis. BFT induces both acute and chronic colitis and carcinogenesis mediated by IL-17[52]. In multiple intestinal neoplasia (Min) mice, Wu

[53] described a signal transducer and activator of transcription 3 that led to a pro-carcinogenic Th17-dependent pathway for inflammation-induced cancer by

Everything in the right place was the mottoaccording to which they also acted here, and therefore all thepaintings which had once been the honour and glory of the oldmansion were now hung up in the passage which led to the servants rooms

Some bacterial species, such as

and

,have evolved to survive amidst harsh conditions of immune activation[54,55].

,which is benign under homeostatic conditions, possesses a significant growth advantage as it utilizes inflammatory nitric oxides as an energy source[54]. In the absence of IgA, the commensal bacterium

expresses high levels of gene products that are involved in the metabolism of nitric oxide and generates pro-inflammatory signals in the gut[55].

is capable of affecting both innate and adaptive immune responses[7].

enhances inflammation through engagement of its adhesin FadA. The host endothelial receptor for FadA is the vascular endothelial cadherin (CDH5), which is a member of the cadherin family[15]. FadA adheres to and invades epithelial and endothelial cells and activates inflammatory cytokines (IL-6, IL-8, IL-10, IL-18, TNF-α and NF-κB levels) that create a pro-inflammatory environment which accelerates the progression of CRC (Table 1)[15,56,57].

She lightly touches the tiny gold bracelet10 that she wears. It was a present from her mother and father, and she refuses to remove it from her wrist. It is engraved11 with her name on the side that is visible to others, but as in everything there are two sides, and only she knows the other is there. It is a single word engraved on the side of the bracelet that touches her skin and touches her heart: “Hope.” One small word that says so much about her life and what is now missing from it. She vaguely12 remembers hope -- what it felt like to hope for a college basketball scholarship or maybe a chance to dance professionally. Only now, she’s not sure she remembers hope as it was then -- a driving force, a fundamental part of her life. Now, hope is something that haunts her.

(

) is a small, spiral, gram-negative bacillus that has a wellestablished association with the development of gastric cancer and is considered a carcinogen by the World Health Organization[60]. There are conflicting data on the correlation of

as an etiological factor of CRC. The production of oxidative stress involves alteration of the intragastric environment through bacterial and neutrophilic production of ROS, pro-inflammatory cytokines, and upregulation of cyclooxygenase-2 (COX-2)[61]. This includes excessive production of ROS by neutrophils in an effort to eradicate the bacteria. The bacterial infection causes inflammation, leading to increased production and activity of COX-2 and prostaglandin E2, a biomarker associated with inflammation and CRC risk. Some evidence has been reported to support a potential association between

and CRC. Shmuely

[62] described that cag-positive

strains were associated with a 10.6-fold increased risk of CRC compared to cagA negative strains. A systematic review with a meta-analysis found a moderate correlation between

infection and the risk of CRC[63].Further investigations should be conducted to determine the role of cagA, and the mechanism by which

induces gastric carcinogenesis and potentially CRC.

produce a similar effect as

.

experiments have shown that the binding of

to intestinal cells leads to production of cytokines[36,46,64]. It has been described that treatment with

or wall-extracted antigens in adult rats promoted the progression of preneoplastic lesions through the increased formation of hyperproliferative aberrant colonic crypts, and increased the production of IL-8 in the colonic mucosa[64].

AVOIDING IMMUNE DESTRUCTION

Several etiological mechanisms of

in CRC pathology have been hypothesized. One alternative is that chronic

infection can lead to hypergastrinemia, which is considered to be a nutrient factor in the colorectal mucosa and may lead to the promotion of mutagenesis. In addition, this bacterial infection and bacterial CagA protein lead to chronic gastritis with an increase in gastrin production (Figure 6)[62]. Ammonia produced by

might also act as an endogenous carcinogen.More studies are needed to investigate the potential role of gastrin in the mechanisms of metastasis of the tumor cells[63].

Furthermore, various microRNAs are induced during the macrophage inflammatory response and modulate host-cell responses to pathogens. MicroRNA-21 increases the levels of IL-10 and prostaglandin E2, which suppress antitumor T-cellmediated adaptive immunity through the inhibition of the antigen-presenting capacities of dendritic cells and T-cell proliferation in CRC cells (Figure 2).

can expand myeloid-derived immune cells, which inhibits T cell proliferation and activation resulting in tumor cell growth by blocking the middle (G1) phase of the cell cycle and attracting myeloid-derived suppressor cells to the tumor site.

also induces T-cell apoptosis in CRC (Table 1)[66].

DEREGULATING CELLULAR ENERGETICS

Fermentation of dietary fibers leads to the production of short-chain fatty acids(SCFAs), such as butyrate, which serve as the primary energy source for intestinal cells(Figure 3). The presence of butyrate has an anticancer effect by starving cancer cells.Additionally, it produces epigenetic modifications by inhibiting cell proliferation and promoting apoptosis by inhibiting histone deacetylase[67]. Non-cancerous colonocytes utilize butyrate as their primary energy source in contrast with CRC cells which primarily use glucose and undergo increased glycolysis, a phenomenon known as the Warburg effect or aerobic glycolysis, decreasing mitochondrial oxidative metabolism[55,68].

species also participate in the metabolism of amino acids ingested in the diet, generating formyl-methionyl-leucyl-phenylalanine and SCFAs that chemoattract myeloid cells. This explains the intratumoral expansion of myeloid cells that interconnect tumor, bacterial and immune cells metabolism (Table 1)[39]. In addition,

is an asaccharolytic bacterium, a competitive advantage in the tumor milieu; therefore, it will not compete for glucose, a preferred substrate for tumor metabolism[69].

were enriched in colon tissue of CRC patients[23]. Another study described four periodontal pathogens,

,

,

, and

, to be more prevalent among AAs than among CAs[24].Significant differences in oral and gut microbial diversity and abundance between AA and CA may play a role in the CRC disparity observed between the populations.

A higher prevalence of

and

in feces of CRC patients has been reported[19,20]. An increase in glutamate levels by 76% in fecal samples from colon cancer patient samples was reported but there was no increase in glutamine levels. The authors hypothesized that tumor cells may exhibit an increase of glutaminase activity, which results in the conversion of glutamine to glutamate. This supports the theory of the role of certain bacteria as "driver bacteria" with procarcinogenic characteristics that contribute to tumor development and then a transition to "passenger bacteria" that contribute to an environment conducive to cancer[19].

They even suggested that she should carry weights in her pockets, or have them tied to her ankles; but this idea was given up, as the princess found it so uncomfortable

Hester

[72] compared bacteria and SCFA in stool samples of AA and CA in a small pilot study. They found lower acetate, butyrate, total SCFA content and a higher pH in AA compared to the other racial groups. Similar results reported in another study where AA had increased levels of SCFAs in stool than other racial/ethnic groups and significantly lower intake of non-starchy vegetables[73]. Wnt/B-catenin signaling plays a fundamental role in several biological processes such as development and cell proliferation related to tumorigenesis. Butyrate has beneficial effects in reducing colon cancer risk with anti-inflammatory, immunomodulatory effects and down regulating Wnt signaling, which inhibits cell proliferation and migration. In addition, AA had higher levels of

bacteria compared to CA and Hispanics.Moreover, the ratio of

compared to

, which has been associated with obesity, was higher in AA. These results continue to suggest that AA have higher risk of developing colon cancer[72].

SUSTAINING PROLIFERATIVE SIGNALING

The mucosa associated/internalized

have been shown to occur more frequently in patients with CRC than healthy controls[76-78]. Pathogenic

produces virulence factors called cyclomodulins (CM). These CMs can modulate cell cycle progression, apoptosis, cell differentiation, and proliferation (Table 1)[79,80].

E-cadherin is a type of cell adhesion molecule and usually is targeted by various intestinal bacteria promoting epithelial proliferation by activating the Wnt/β-catenin pathway.

, an enterotoxin-producing bacterium, is involved in the initiation and progression of CRC by not only modulating the mucosal immune response, but also inducing epithelial cell changes. BFT promotes cleavage of E-cadherin (Table 1). This produces nuclear translocation of β-catenin and subsequent transcription of the c-Myc proto-oncogene causing hyperplasia due to proliferation of colonocytes[74]. After treatment of HT29/C1 human colon cancer cells with BFT, cleavage of membraneassociated E-cadherin and loss of intercellular adhesion occurs. This in turn leads to subsequent expression of β-catenin nuclear signaling and induction of c-Myc translation resulting in persistent cell proliferation[75]. The presence of

may contribute to chronic colon diseases, including oncogenic transformation, intestinal inflammation, chronic colonic dysfunctions, and colorectal precancerous and cancerous lesions[75].

In the summer, at the pool, I got stung by a bee. She held my hand and told me that she was there and that it was okay to cry -- so I did. In the fall, we raked the leaves into piles and took turns jumping, never afraid because we knew that the multicolored bed would break our fall.

Senescent cells secrete growth factors that increases cell proliferation resulting in tumor growth. Colibactin-producing (pks+)

promote CRC cancer in a murine AOM/IL-10?/?(azoxymethane/IL) mouse model by expression of SENP1,microRNA-20a-5p, hepatocyte growth factor (HGF) and phosphorylation of HGF receptor. In addition, senescence-associated secretory phenotype induces epithelial cell proliferation

the production of growth factors by senescent cells. SENP1 downregulation and p53 SUMOylation are key features of pks+

-induced senescence as result of modifying p53 function[81].

has shown a propensity to adhere to mucosa enabling it to invade human epithelial and endothelial cells[7]. The percentage of

-enriched CRC gradually increases from rectum to cecum, suggesting that the rate of bacteria proliferation differs among the intestinal sites[82].

enhances epithelial proliferation through engagement of its adhesin FadA. FadA modulates E-cadherin, a tumor suppressor gene, and activates β-catenin signaling, leading to increased expression of oncogenes, Wnt genes, and inflammatory genes as well as growth stimulation of CRC cells (Figure 4 and Table 1)[56]. The FadA binding site on Ecadherin has been mapped to an 11-amino-acid region. The experimental use of an 11-amino-acid inhibitory synthetic peptide has been shown to inhibit

from binding and invading the epithelial cells and abolishing all subsequent host responses,including tumor growth and inflammatory responses (Table 1)[56].

She would certainly have betrayed that this was not the kind of narcissus she wanted, but for the Fairy Melinette, who had been anxiously watching the inter25, and now thought it quite time to interfere26

-induced mucosal inflammation may lead to enhanced mucosal permeability and increased entry for

into colonic cells.

also has shown strong adherence to the proteins of the extracellular matrix,collagen I, collagen II and collagen IV, enabling it to have easy entry into cells and successfully colonize both colonic and vascular tissues[46,83].

is able to grow in bile and can easily bypass the hepatic reticulo-endothelial system and access the systemic circulation[84].

endocarditis infections also have been associated with increased hepatic dysfunction[85]. It is hypothesized that underlying colonic disease or

’s effects on the liver’s production of immunoglobulins and bile acids may promote

overgrowth and thus altering the colonic microbiome[85]. Although the mechanism is unclear,

whole bacteria and wall extracted antigens have shown greater propensity towards colonizing colonic tumor cells compared to normal mucosa (Table 1)[36].

also may induce uncontrolled cell proliferation by triggering proteins known as mitogen activated protein kinases that promote cellular transformation and genetic mutations[36].

Within the host cytoplasm,

may release its RNA, leading to detection by cytosolic retinoic acid-inducible gene I (RIG-I), a cytosolic pattern recognition receptor (PRR) responsible for the type-1 interferon (IFN1) response, thereby stimulating cytosolic NF-kB and promoting inflammation. It generates a pro-inflammatory microenvironment outside the tumor cell through recruitment of tumor-infiltrating immune cells as the primary mechanism[15]. The ability of

to invade HEK293T cells, human embryonic kidney cells, which lack endogenous Tolllike receptors, allows the bacteria to activate a pro-inflammatory response through cytosolic pattern recognition receptors, NOD-1, NOD-2 and NF-?B signaling. This proinflammatory response is mediated by the p38 MAPK signaling pathway[58]. In a mouse model of intestinal cancer, introduction of

to Apc

mice resulted in accelerated small intestinal and colonic tumorigenesis, infiltration of specific myeloid cell subsets into tumors, and an NF-κB proinflammatory signature. This proinflammatory signature is shared with human CRC tissues with a high

abundance[39]. Additionally, a positive correlation has been found between the bacterial concentration in human tissues, for adenoma and non-adenoma controls, and TNF-α and IL-10 abundance[59]. Unlike other bacteria associated with CRC, however,

does not exacerbate colitis, enteritis, or inflammation-associated intestinal carcinogenesis. This suggests that

may drive non-colitis-associated intestinal tumorigenesis (Table 1).

INDUCING ANGIOGENESIS

is believed to promote the advancement of preneoplastic lesions to neoplastic lesions through the increased formation of aberrant colonic crypts that show increased expression of cytokines such as IL-8 (Table 1)[64]. IL-8 is a cytokine that stimulates angiogenesis which in turn also may promote carcinogenesis[86]. The pattern of IL-8 mRNA expression in the tumor microenvironment may function as a significant regulatory factor rather than a promoter for the adenoma progression and the adenoma–carcinoma transition. This might be attributed to the angiogenic role of IL-8 by which new blood vessels are formed to meet the increasing demands of cancer growth[46]. Moreover,

-induced overexpression of COX-2

prostaglandins acts as a promoter of carcinogenesis by inducing angiogenesis[36].

RESISTING CELL DEATH

In this review, we highlight the various gut and oral microbiota associated with CRC and CRA, and their proposed molecular mechanisms in relation to the processes of“the hallmarks of cancer.” Common oncogenic mechanisms include disruption of mucosal/epithelial layer of organs, promotion of inflammation and neoangiogenesis,use of genotoxins by bacteria, altering of genetic expression, and modification or weakening of the existing immune system.

GENOME INSTABILITY AND MUTATIONS

A study comparing microbiota from more than 1000 fecal samples including 416 pairs of twins identified numerous microbial taxa whose abundance was influenced by host genetics. In the case of monozygotic twins, a more similar microbiota was observed than in dizygotic twins. However, it is unclear whether the host's genetic variation shapes and interacts with the gut microbiome to affect the host's phenotype[89]. The analysis of gut microbiota in stool of 2084 participants in the Healthy Living in an Urban Environment Study described that people who live in the same city tend to show similar gut microbiota with other people of their ethnic origin[90]. Ethnic differences in alpha diversity and inter-individual differences were independent of metabolic health and were only partially explained by ethnic characteristics, including sociodemographic, lifestyle, or dietary factors. Therefore, the ethnicity of individuals may be an important factor to consider in the research of microbiome and cancer CRC[90].

Sulfidogenic bacteria, such as

,

and

,have been implicated in CRC development through the production of hydrogen sulfide (Figure 6)[91]. Hydrogen sulfide is a genotoxic compound that has been shown to damage DNA leading to genomic or chromosomal instability (CIN), effecting DNA repair in a multistep carcinogenic process. One hypothesis is that hydrogen sulfide diffuses into intestinal epithelial cells and interferes with mitochondrial function,ultimately leading to hyperproliferation

the Ras/MAPK pathway[92]. The hyperactivation of the Ras/MAPK pathway is a known mechanism of carcinogenesis in CRC. A study described the concentration of specific bacterial DNA in colonic tissue biopsies, and showed that AA with CRC had higher concentrations of sulfidogenic bacteria compared to NH whites. At the same time, AA with CRC had increased levels of sulfidogenic bacteria compared to AA without CRC[93].

Some bacterial products, such as colibactin or BFT, may damage the genetic information inside the nucleus, and actively induce DNA damage in organs that are in direct contact with the microbiome (Figure 6 and Table 1)[94]. These genotoxins may directly promote the release from macrophages and other inflammatory cells of reactive oxygen species (ROS), reactive nitrogen species (RNS) and hydrogen sulfide(H

S) from the bacterial microbiota products[95]. ROS and RNS inhibit the activity of T cells, including antitumor cytolytic CD8+ T cells. An abundance of myeloid-derived suppressor cells also leads to increased production of ROS and RNS and subsequent tumor-supporting inflammation and neoangiogenesis[70]. Hydrogen sulfide has been shown to damage DNA leading to genomic or CIN, affecting DNA repair in a multistep carcinogenic process. One hypothesis is that hydrogen sulfide diffuses into intestinal epithelial cells and interferes with mitochondrial function, ultimately leading to hyperproliferation

the Ras/MAPK pathway[92]. Furthermore, metabolic actions of the microbiome may promote the development of CRC by activation of other genotoxins such as acetaldehyde, dietary nitrosamine and other carcinogens[95].

We had a family. A name and address from the church, we knew the situation, dad s been out of work, the baby s been sick, mom didn t want to put up a Christmas tree because she didn t want the children to be disappointed when Santa didn t come. The Power Company had shut the gas off once, but the church had paid the bill.

I like to oblige, said the old man. Then customers come back, later in life, when they are better off, and want more expensive things. Here you are. You will find it very effective.

As shown in Figure 6, various gut microbes and their bacterial products can cause DNA mutations.

contribute to the accumulation of mutations resulting from DNA damage induced by genotoxins, or by downregulating host DNA mismatch repair proteins (Table 1)[96]. One cyclomodulin is a hybrid polyketidenonribosomal peptide called colibactin, encoded by the polyketide synthase (pks) genomic island.Colibactin possesses genotoxic properties that result in CIN and double-strand breaks in the DNA of human eukaryotic cells.

strains harboring the pks genotoxic island, which are found in a significantly high percentage of inflammatory bowel disease and CRC patients[79].

studies using different mammalian cells,including normal intestinal cells, showed that pks+

produce DNA double-strand breaks affecting the normal cellular division with the consequent cell cycle arrest and aneuploidy[97]. Conversely, different commensal bacteria could harm DNA strands by stimulating host inflammation and producing a pro-oxidant microenvironment.

causes DNA damage by peroxide that comes from the colonocyte expression of enzyme spermine oxidase[98].

may have a microbiome driven bystander effect that leads to increased COX-2 expression in macrophages leading to ROS formation, which in turn promotes CIN in intestinal epithelial cells. Primary colonic epithelial cells can have induction of CIN or malignant tumor aneuploidy

macrophages that have been polarized by

[99]. These results validate a novel mechanism for CRC that involves endogenous CIN and cellular transformation arising through a microbiome-driven bystander effect (Figure 6)[100].

have increasingly been shown to cause infections in the elderly. They are gram positive, facultative anaerobe, diplococci that grow as short chains.

has been found to aggregate at higher levels in stool samples in CRC patients than in healthier controls[101,102]. It also has been shown to be in greater abundance in the adjacent tissues of CRC when compared to healthy mucosa in controls[103]. It has been postulated that

can damage colonic DNA and cause genomic instability

its ability to generate ROS that predisposes to mutations leading to CIN and subsequent carcinogenesis (Figure 6)[12].

And then what a number of subscriptions8 to charities, and what innocent verses! Persons seeking interviews and engagements, all so plainly and naturally stated

A large abundance of

has been shown to induce a series of tumorspecific molecular events, including the CpG island methylating phenotype (CIMP),microsatellite instability (MSI), and genetic mutations in BRAF, CHD7, CHD8 and TP53. A higher abundance of

DNA in CRC tissues has been associated with an increased CRC-specific mortality, evidence that suggests

may potentially serve as a prognostic biomarker (Figure 6)[82].

directly interacts with the host immune system. Fap2, an autotransporter domain found in the bacterial outer membrane protein, facilitates

to adapt to different body habitats. In the oral cavity, Fap2 attaches to neighboring bacteria by co-adhering to different microorganisms, increasing the diversity and the stability of the developing dental biofilm[65]. Fap2 protein adhesion directly interacts with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains(TIGIT) expressed in tumor-infiltrating lymphocytes, leading to the inhibition of NK cell cytotoxicity (Figure 2)[31]. TIGIT is an inhibitory receptor present on human NK cells and on various T cells. The interaction between

, Fap2 and TIGIT induces lymphocytes apoptosis and generates an immuno-suppressive microenvironment that promotes the progression of colorectal tumors[15]. Fap2 protein is believed to directly interact with TIGIT, leading to the inhibition of NK cell cytotoxicity[31]. These results identify a bacterium-dependent, tumor-immune evasion mechanism in which tumors exploit the Fap2 protein of

to inhibit immune cell activity

TIGIT[31]. Several clinical and animal studies have correlated the abundance of

with suppression of antitumor T cell response by affecting the enhancement of myeloid-derived suppressor cells and tumor-associated macrophages (Table 1).

CONCLUSION

plays an essential role in the oncogenic progression through different factors that cause an anti-apoptotic effect in colorectal mucosa as shown in Figure 5. In Abdulamir

[46],

appeared to induce mRNA expression of proinflammatory cytokines, IL-1 and COX-2 which induce transformation of normal or premalignant colorectal tissues into malignant status. After analysis of mRNA expression of the oncogene c-Myc and antiapoptotic Bcl-2 were not linked to colonization by these bacteria, but were associated with CRC transformation. These results may suggest that

does not induce oncogenic changes or suppress cellular apoptosis, and might instead have a role as a propagator for premalignant or oncogene-positive tissues to enter the transformation cycle through inflammatory and angiogenic microclimates (Table 1)[87]. The release of PGE2-mediated by

is correlated with the overexpression of COX-2, which is seen in about 85%of colon cancers, and through its association with enhanced angiogenesis and inhibition of apoptosis, is favorable to the development and progression of CRC[36]. In addition, this group also found

-seropositive CRC patients were significantly associated with higher mRNA expression of both NF-kB and IL-8 that play an integrated role in a series of steps to escape cell death signals[88].

To understand whether host genetics play a role in the associations between race/ethnicity, and oral and gut microbiota, it is essential to perform genome-wide association studies with microbial data among diverse populations. In 2016, 81% of existing genome-wide association study data was generated from individuals of European descent where the proportion of samples from individuals of African descent only increased by 2.5% and that of ancestry Hispanic or Latin American by about 0.5%[104]. There are huge gaps in knowledge related to understanding the underlying causes of racial/ethnic differences in the gastrointestinal microbiota and their possible role in colon cancer. Therefore, it is essential to be able to generate new knowledge by generating large and representative cross-sectional studies with gut,oral and fecal samples in populations that include individuals with various social determinants of health (for example, NHANES). Variables that could cause these racial/ethnic differences, such as diet, habits, socioeconomic status and oral health status should also be further studied. Genetic factors may contribute to biological reasons for CRC disparity. Diverse studies described somatic alterations in wellknown CRC genes (APC, BRAF, KRAS, and PIK3CA) and lower frequency of MSI, a good prognostic biomarker, among AA patients[105,106].

levels have been found to be significantly higher in AAs[22] and has been shown to induce a series of tumor-specific molecular events, including CIMP, MSI, and genetic mutations in oncogenes and tumor suppressors[82].

Differences in the immunological profiles of colon tumors from AA compared to CA suggested a deficiency of appropriate immune defense mechanisms in terms of gene expression, recruitment of immune cells and systemic secretion of cytokines. As such,these immune differences could be mitigated through population-specific therapeutic approaches[106]. Studies of associations between specific taxa in microbiome and race/ethnicity could provide an insight for examining specific bacterial members as mediators of health disparities. Defining the composition of a “healthy microbiota” is one of the challenges in the field of microbiome research. Our review reveals that unique opportunities exist in targeting racial/ethnic differences in oral and gut microbiome for a greater understanding of the complexity of CRC and CRA etiology and carcinogenesis.

Now it chanced that the way to the capital led right past the village where Helena was, and often when she was leading her cattle forth18 to the meadows Prince Fickle rode past her, without ever noticing the poor herd-girl, so engrossed19 was he in thoughts of his new bride

When the apple was ready she painted her face, and dressed herself up as a country-woman, and so she went over the seven mountains to the seven dwarfs. She knocked at the door. Snow-white put her head out of the window and said, I cannot let any one in; the seven dwarfs have forbidden me. It is all the same to me, answered the woman, I shall soon get rid of my apples. There, I will give you one.

As knowledge is gained regarding the microbiome as it pertains to CRC, the clinical implications will continue to grow and hopefully come to the forefront in the prevention, detection, and treatment of CRC in clinical practice. Current non-invasive screening methods for CRC include FIT and Cologuard. However, their ability to detect precancerous lesions is not entirely reliable, thus creating a void for superior noninvasive screening methods that microbiome studies could likely one day fill[107].When combining testing for oral bacteria

with FIT, the combination showed superior sensitivity than FIT alone in detecting CRC, and additionally increased the performance of adenoma detection, suggesting the potential of bacterial biomarkers as more useful diagnostic tools over current diagnostic strategies[108]. In addition, the ratio

showed superior sensitivity of 84.6%and specificity of 92.3% for diagnosing CRC in comparison with the use of a single fecal bacterial biomarker candidate[109].

The deficit in the number of butyrate-producing bacteria can have detrimental consequences in the progression of the disease, hence the screening of SCFA and microbial-derived metabolites have potential as biomarkers and diagnostic tools for CRC. Some studies already have shown that using microbiome profiles in conjunction with certain risk factors such as age, race and body mass index can help predict healthy colon

one with adenomas or carcinomas[110]. While detection of CRC and precancerous lesions is our current goal in preventing CRC mortality, the microbiome also provides promise into potentially preventing CRC by inhibiting colorectal tumorigenesis. A recent study by Li

[111] aimed to look at the role of depleted bacteria,specifically

(

), in CRC to see if when used as a probiotic that it could prevent CRC. They showed in a mouse model that tumor formation could be reduced using

by oral gavage, and it was specifically the β-Galactosidase secreted by

that was critical to retarding the growth of CRC cells.

also was able to increase other known probiotics, including Bifidobacterium and Lactobacillus,

β-Galactosidase. Albeit,just in a mouse model, it highlights the potential for possible prevention and reversal of CRC by use of the microbiome.

Additional prospective human studies must be undertaken to determine the role of the microbiome in CRC therapy and in the reliability of certain profiles for screening and prevention. Furthermore, when certain microbiome signatures that predispose risk for CRC do arise, the age at which one is to start looking for these predispositions also needs to be established to enable clinical use. The heterogeneity of CRC could be related to different microbiota communities that either predispose or provide resistance to the disease, and the profile analysis of the oral microbiome may offer an alternative screen as a biomarker for detecting CRC[112]. Only single studies detected associations with

or

and CRC[110,113]. Further studies with a larger sample size are needed to confirm the identified associations and estimate the potential utilization of the oral microbiota and periodontal diagnosis and treatment for use in CRC early detection or prevention.

The gut microbiome and its metabolites have therapeutic implications for CRC and other cancers. It has been postulated that therapeutic response to immune checkpoint inhibitors (ICI) may be influenced by presence of the gut microbiome. In 100 patients diagnosed with non- small cell lung cancer and on ICI therapy, the stool of patients responding to ICI therapy was rich in

compared to nonresponders[114]. The baseline microbiome or its modulation using antibiotics,probiotics or FMT have influenced treatment efficacy in numerous cancers[115]. For example, patients with non-small cell lung cancer, renal cell carcinoma or urothelial cancer treated with antibiotics for routine indications shortly before, during, or shortly after treatment with anti-PD1/PD-L1 mAB had significantly lower progression-free survival and overall survival rates compared to patients who had not received antibiotics. This suggests that disrupting the gut microbiota (

antibiotic use) could potentially impair anti-tumor immune responses as well as response to immune checkpoint blockade[114,115].

The gut microbiome is a dynamic meditator of immune and cellular response to cancer and influences the efficacy of cancer therapies. Manipulating the gut microbiome will likely emerge as a viable option of modulating the responsiveness of cancers to immune mediated and other therapies. In addition, other decisions regarding the use of antibiotics with cancer and other therapies should be weighed carefully considering their impact on the gut microbiome. Large prospective studies on the impact of dietary interventions (prebiotics), antibiotic use and the influence of environmental pollutants are needed to clarify many unanswered questions on the factors that impact the gut microbiome and the durability of that effect. Lastly, the price and availability of microbiome analysis will have to come to a point where it is widely available and accessible to make it mainstay in the clinical realm.

Above all things she loves any assembly for settling the affairs of her kingdom, for on those occasions she can talk and talk without fear of interruption; but, even then, the moment it is over she is ready to begin again about anything or nothing, as the case may be

The flood which had overtaken them could not destroy them, but it separated them and carried them far away. When the water receded27 and they both reached dry land again, their human forms returned again, but neither knew where the other one was. They found themselves among strange people who did not know their native land. High mountains and deep valleys lay between them. In order to earn a living, they both had to herd28 sheep. For long years they drove their flocks through fields and woods, and were filled with sorrow and longing22.

Dr. Lim S for reviewing our manuscript and offering good feedback.

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