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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 2  |  Issue : 1  |  Page : 2-9

An overview of systematic evidence on oral microbial composition for orodigestive tract cancer risk


1 Research Fellow, Centre for Chronic Disease Control, C-1/52, 2ND FL, Safdarjung Development Area, New Delhi, India
2 Senior Research Assistant, Public Health Foundation of India, Plot 47, Sector 44, Institutional Area, Gurgaon, Haryana, India
3 Senior Research Scientist & Associate Professor (adjunct), Epidemiologist, Public Health Foundation of India (PHFI), Plot 47, Sector 44, Institutional Area, Gurgaon, Haryana 122002; Research Scientist, Centre for Chronic Disease Control (CCDC), C-1/52, 2ND FL, Safdarjung Development Area, New Delhi, India

Date of Submission01-May-2022
Date of Decision16-May-2022
Date of Acceptance17-May-2022
Date of Web Publication15-Jun-2022

Correspondence Address:
Dr. Krithiga Shridhar
MDS, MSc, Centre for Chronic Conditions and Injuries, Public Health Foundation of India, No. 47, Sector 44, Gurgaon - 122 002, Haryana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aort.aort_11_22

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  Abstract 

We summarized published systematic reviews of studies evaluating oral microbial composition for orodigestive cancer risk. A PubMed literature search was conducted for the most recent time period between January 1, 2019 and April 25, 2022, for systematic reviews in English language using keywords and MeSH terms in combination. Seven systematic reviews included all published observational studies until June 2021 with 8–34 individual studies evaluated in each of those reviews. The individual studies were primarily hospital-based case–control studies with only six population-based evaluations (five prospective; one case control). The oral cavity, oro-and hypopharynx, esophagus, stomach, colorectum, liver, and pancreas were the cancer sites investigated. Saliva, oral rinse, subgingival and dental plaque, surface tissue swabs, biopsy tissue specimens, and tongue-coating samples were analyzed for oral microbial composition using next-generation sequencing techniques primarily 16S rRNA sequencing. The total sample size in different reviews ranged between 578 and 2769 cases and 261 and 3519 controls with small individual studies (3–250 cases and 2–465 controls). To date, there were four hospital-based case–control studies from India. The overall findings were restricted to bacterial communities. Compared to controls, the alpha-and beta-diversity for these cancer sites either showed no difference or inconsistent patterns. A few noteworthy differential abundances at the genus level for selected cancer sites included oral cavity – increased Fusobacterium, Parvimonas, and Peptostreptococcus and decreased Streptococcus, colorectum – increased Fusobacterium, Gemella, Peptostreptococcus, Prevotella, and Lautropia, pancreas – increased Porphyromonas and Alloprevotella, and esophagus – increased Tannerella. For clinical and public health translation, the identified leads might require validations in prospective population-based studies with rigorous methods, species-level characterizations, and functional analysis to prove causal associations.

Keywords: Cancer, microbiota, next-generation sequencing, oral microbiome, review


How to cite this article:
Kuriakose S, Vinutha R S, Shridhar K. An overview of systematic evidence on oral microbial composition for orodigestive tract cancer risk. Ann Oncol Res Ther 2022;2:2-9

How to cite this URL:
Kuriakose S, Vinutha R S, Shridhar K. An overview of systematic evidence on oral microbial composition for orodigestive tract cancer risk. Ann Oncol Res Ther [serial online] 2022 [cited 2022 Jun 25];2:2-9. Available from: http://www.aort.com/text.asp?2022/2/1/2/347553


  Introduction Top


The oral cavity comprises diverse microorganisms including aerobic and anaerobic bacteria, archaea, lower and higher eukaryotes (e.g., fungi), and viruses in saliva, dental plaque, and gingival and mucosal surfaces.[1] Terminologically, a community of microscopic organisms is referred to as “microbiota” and the genes associated with the microbiota as “microbiome.”[2] A healthy equilibrium[3] in “stable dynamics” (i.e., more beneficial and less pathogenic) is maintained between these microorganisms, regulated by multiple factors including oral hygiene and health, lifestyle factors, host immune-inflammatory response, as well as the genetic landscape of the individuals. With disruptions in equilibrium, the composition of the oral microbiome becomes “dysbiotic” with less beneficial and more pathogenic features.

Systematic evidence for the role of dysbiotic oral microbial composition in cancer initiation and promotion is rapidly mounting through mechanistic and epidemiological studies, particularly for orodigestive tract cancers.[4],[5],[6],[7] Orodigestive cancers are the cancers of the oral cavity, oro-and hypopharynx, esophagus, liver and biliary tract, pancreas, gallbladder, stomach, small intestine, colon, rectum, and anus. Several plausible cancer-initiating and-promoting mechanisms exist based on animal models and epidemiological studies focusing on specific oral pathogens.[6],[7] These mechanisms include cancer initiation through endotoxin-mediated DNA damage, activation of cell-cycle signaling through pathogen-associated toll-like receptors, as well as the promotion of local and systemic inflammation. The influence of these oral pathogens is suggested to be independent and/or synergistic with other known lifestyle risk factors (e.g., tobacco or alcohol as well as diet).[8] The ability of oral microbiota to disseminate systemically through the bloodstream or through the enteral route while swallowing successfully evading host immune mechanisms enables them to survive in systemic circulation and reach the digestive tract[9] as well as other distant organs.[10]

Next-generation sequencing (NGS) technology has widened the scope to characterize the complexity of the oral microbiome. 16S rRNA sequencing and metagenomic whole-genome shotgun sequencing (mWGS) are the most recent NGS techniques.[11] While 16S rRNA sequencing helps to identify specific taxonomic groups, largely the bacterial communities, present in a sample by targeting selected conserved and variable gene regions of the microorganisms (termed as oral microbiota), and mWGS sequences the entire taxonomic groups present in the oral cavity more deeply (termed as oral microbiome). It allows for a detailed classification of all organisms in a community with the potential for functional pathway analysis.[11]

The present overview aims to provide an update of the published systematic evidence for the association between the oral microbiota or microbiome and different types of orodigestive cancers. We summarize systematic reviews of studies evaluating oral microbial composition for orodigestive cancer risk using NGS techniques.


  Methods Top


A PubMed literature search was conducted for the most recent time period between January 1, 2019 and April 25, 2022, for all published systematic reviews in the English language evaluating the association of oral microbiome or microbiota with orodigestive tract cancer risk. Keywords and MeSH terms used in combination included “cancer,” “tumor,” “malignancy,” “carcinoma,” “neoplasm,” “oral microbiome,” “oral microbiota,” “oral,” “oropharynx,” “hypopharynx.” “digestive tract,” “gastrointestinal tract,” “colon,” “esophageal,” “gallbladder,” “gastric,” “liver,” “pancreas,” “colorectum,” “small intestine,” “stomach,” “anal,” and “biliary duct.” Boolean operators “AND” as well as “OR” were used with filters confined to the English language and humans. Records identified through database search included 250 articles and a total of nine systematic reviews were screened and assessed for eligibility based on title and abstract. Full-text publications of seven systematic reviews were finally included for the synthesis of findings after excluding one systematic review on in vitro studies[5] and another on specific target pathogens.[6] Manual searches for references of the included articles were conducted to avoid the omission of relevant publications. Two investigators (SK and VRS) independently reviewed titles and abstracts and the data were extracted by three researchers independently (SK, VRS, and KS). Information on author, year, time of included studies, number and type of included studies, microbial analytic method, type of samples, exposure assessment, and cancer sites included, total sample size, significant differences in microbial composition in terms of taxa abundance at genus level and/or alpha-and beta-diversity, and richness measures associated with risk for specific cancer sites were extracted from the published systematic reviews.


  Results Top


[Table 1] summarizes the basic characteristics of the included systematic reviews. The seven systematic reviews included all published observational studies until June, 2021 with 8–34 individual studies evaluated in each of those reviews. The individual studies were primarily hospital-based case–control or cross-sectional studies. There were six population-based studies in total (two cohorts; three nested case control, and one case control). One review comprehensively included all cancer sites and human microbiomes,[1] two included digestive tract cancers and oral microbiota or microbiome[8],[12] and the rest focused on oral and oropharyngeal cancers and oral microbiota or microbiome.[13],[14],[15],[16] The oral cavity, oro-and hypopharynx, esophagus, stomach, colorectum, liver, and pancreas were the cancer sites investigated. Saliva, oral rinse, subgingival and dental plaque, surface tissue swabs, biopsy tissue specimens, and tongue-coating samples were analyzed for oral microbial composition. These reviews included studies involving NGS techniques. 16S rRNA was the common microbial analytic method utilized in individual studies, followed by Sanger sequencing, PathoChip NGS, pyrosequencing and gas chromatography, and less frequently whole-metagenome shotgun (mWGS) and transcriptomics. A few reviews[9],[12],[15] included selected studies based on indirect immunofluorescence microscopy (n = 2 studies), immunohistochemistry (n = 1 study), and DNA–DNA hybridization (n = 1 study). The total sample size in different reviews ranged between 578 and 2769 cases and 261 and 3519 controls with small sample sizes in individual studies generally ranging between 3 and 250 for cases and 2 and 465 for controls. To date, there were four published hospital-based case–control studies using 16S rRNA sequencing from India.[17],[18],[19],[20] Alpha-and beta-diversity, richness, and relative and absolute abundance of taxa were the exposure measures reported and the differences in composition were analyzed between cases and controls. The control selection for individual studies ranged from adjacent normal tissues to unrelated healthy cancer-free participants. The overall findings reported in the reviews were restricted to bacterial communities except for one study which analyzed yeast colonization using agar plates.[1] Associations in the framework of risk factors such as tobacco, betel nut products, and alcohol presence of human papillomavirus infection and sociodemographics as well as family history, and oral health and hygiene were reported in selected reviews.[1],[8],[13],[14],[16] Further, although less frequently, systemic antibiotic use[12] and findings related to microbial functional analyses were also reviewed.[14] One review summarized studies assessing prognostic value of oral microbiota in oral cavity cancers.[15]
Table 1: Basic characteristics of included systematic reviews

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[Table 2] summarizes the findings of the included reviews in terms of diversities, richness, and abundance of taxa.
Table 2: Summary of results in the included systematic reviews

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Diversities and richness

The summary measure of microbiome included alpha-diversity and beta-diversity. Alpha-diversity summarizes the differences in microbial composition within samples and calculated using indices such as Shannon, Chao, and Simpson. Beta-diversity summarizes differences in microbial composition between individuals, and is based on distance metrics (e.g., bray–curtis and uniFrac). Richness measures the total number of microbial communities in the samples. These were less systematically summarized and no clear pattern was evident for any of the orodigestive cancer sites, although Huybrechts, et al. concluded that these cancer sites showed significantly lower bacterial diversity than the healthy controls.[1] Overall, the bacterial diversities and richness in cases either showed no difference or inconsistent pattern (i.e., both decreased and increased) compared to controls. The one study which evaluated fungi reported increased diversity of fungi with Candida as the predominant genus in oral cavity cancers compared to healthy controls.[21]

Differential abundance of taxa

Abundance of taxa is measured as “actual abundance of a taxon in a unit volume of an ecosystem” known as absolute abundance and as “the fraction of the taxon observed in the feature table relative to the sum of all taxa in the sample” known as relative abundance between 0 and 1.[10] Although nearly all reviews summarized differences in abundance between cases and controls for specific cancer sites at multiple levels such as phylum, class, order, family, and genus, the detailed systematic evaluations did not reveal any individual bacteria or a consortium or signatures to be consistently increased or decreased in cases across the studies. Species-level characterizations were limited.[1],[14] Few noteworthy differences in composition at genus level, the lowest level consistently reported, for selected cancer sites included increased Fusobacterium, Parvimonas, and Peptostreptococcus and decreased Streptococcus in oral cavity cancers, increased Fusobacterium, Gemella, Peptostreptococcus, Prevotella, and Lautropia in colorectal cancers, increased Porphyromonas and Alloprevotella in pancreatic cancers, and increased Tanerella in esophageal adenocarcinoma. While decreased Streptococcus, Haemophilus, and Actinomyces as well as Rothia were noted in few cancer sites including the oral cavity and pancreas and was reported to be strong associations, particularly for Streptococcus,[1] these findings were not consistent.


  Discussion and Conclusion Top


In the present overview, we summarized seven previously published systematic reviews on oral microbial composition and orodigestive tract cancers. The reviews included all observational studies published until June 2021 utilizing NGS techniques for oral microbial analysis. To our knowledge, this is the first overview evaluating the systematic evidence to date for oral microbial composition and orodigestive tract cancer risk.

Overall, although NGS methods have increased the scope of understanding the role of oral microbiome in orodigestive cancer risk, the evidence was inconsistent with less standardized methodology of reporting accounting for confounders, modifiers, and mediators. The evidence so far from the hospital-based case–control studies with very limited data from population-based prospective settings restricts the scope for confirming causal associations. The “human microbiome project” at the National Institute of Health, USA,[11] is involved in generating systematic prospective evidence for oral microbiome pathways of cancer risk at the population level. Evidence from the Indian population will contribute vital information with regional and global significance. If proven systematically, evidence-based cancer preventive and treatment strategies can be employed intervening through “oral microbiome” pathways.

As reported by Huybrechts et al., to date, the highest number of evaluations for the associations of the human microbiome for cancer risk have been published in relation to gut microbiome,[1] An interesting new dimension to research is “oral–gut” axis. The interactions between oral and gut bacterial microbiota have been documented with preliminary hypothesis-driven evidence for obesity and inflammatory bowel disease, wherein modulating effects of oral microbiome on the gut microbiome in the disease pathway have been reported.[22],[23] This is an emerging field of research with promising leads.

The major limitation of the summarized systematic reviews is the lack of clear inclusion and exclusion criteria for eligible studies. For example, studies with sample sizes <10 per group are also included in these reviews. Certain reviews included both culture-based and NGS studies as well as selected studies on specific microbiota explorations using quantitative polymerase chain reaction analysis. However, in an emerging field of research with evolving analytic techniques and methods, strict criteria are difficult to exercise that may lead to exclusion of a majority of published studies.

Nevertheless, the findings were suggestive of altered oral microbial composition in orodigestive cancers compared to the controls. The identified leads might require validations in prospective population-based epidemiological studies to prove causal associations. The inconsistent findings need to be explored with detailed species-level characterizations. Further, mWGS sequencing, in addition to 16S rRNA sequencing, will provide deep insights into the functions and pathways of oral microbiome up to the lowest taxonomic level. In fact, a review summarized at least six different potential pathways related to microbial function that could be associated with cancer risk, including xenobiotic metabolism, bacterial virulence, and proinflammatory components. These pathways may require further explorations in large representative samples.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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