A Systematic Review of the Gastrointestinal Microbiome: A Game Changer in Colorectal Cancer

Colorectal cancer (CRC) is a malignant condition of the colon and rectum. Generally, malignancies constitute a significant health threat to humans, and the result can be devastating. CRC is no exception. The gastrointestinal (GI) microbiome has long been suspected of impacting CRC. This review seeks to explore whether there is a connection between the two or not. For screening purposes, relevant articles were culled from various databases using key terms and phrases. Following a thorough search, the inclusion and exclusion criteria were applied, and a quality assessment was conducted. The articles retained were comprehensively studied, and revealed imbalances of the GI microbiome do indeed exhibit an association with CRC.


Methods
We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [10]. The Cochrane Risk Assessment bias tool, the Scale for the Assessment of Narrative Review Articles (SANRA) checklist, the Joanna Briggs Institute (JBI) check tool, and the Newcastle-Ottawa tool were utilized for quality assessment checks.
The PRISMA flow chart can be seen in Figure 1. PubMed, PubMed Central, and MEDLINE were searched for relevant literature about concepts one and two separate and, subsequently, concepts one and two combined. See Table 1 for how the concepts were used to collect articles.   Of note, an additional 20 articles were obtained from the reference section of several articles upon quality assessment check from the same database (PubMed The following inclusion and exclusion criteria were implemented for the search: free full text, meta-analysis, clinical trial/observational study, randomized controlled trial, systematic review, the timeline between the years 2018 and 2022, human and animal species, the English language, MEDLINE, and adult (19+ years). Duplicates were then removed.

Results
A total of 368,096 publications were retrieved from PubMed, PubMed Central, and MEDLINE searches. After implementing the inclusion and exclusion criteria, 1360 articles were left, and 940 duplicates were removed. Subsequently, 420 articles were screened by title. An additional 20 articles were obtained from reference sections of other studies, bringing the number to 440 studies for review by abstract. Of these, 80 articles were screened by review of free full text and quality assessment tool application and yielded 46 eligible articles. A total of 13 studies were included in our systematic review. The articles used for review incorporate one statistical journal, one case-control, one meta-analysis, two observational studies, and eight review studies. The review has sample sizes from eight of these studies with a total number of 3012 patients. The PRISMA flowchart can be seen in Figure 1.

Review Discussion
The disordered physiology of the GI tract should be highlighted and examined to fully understand the carcinogenesis of the colon and rectum.

Pathophysiology of CRC
The genesis of CRC commences with increased proliferation of the GI epithelium resulting in a disorganized structure forming adenomas that become incorporated into the submucosa and transform into carcinoma. This uncontrolled proliferation is influenced by specific pathways that are pro-inflammatory. Mainly, cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), interleukin 8 (IL-8), and interleukin 1 beta (IL-1β) are involved in this adenocarcinoma sequence of CRC by conduction of nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) [2,3] signal cascading pathways (see Figure 2).

FIGURE 2: The pathophysiology of colorectal cancer
The blue cells represent myeloid cells and the green cells represent lymphoid cells.
Adapted from the article entitled "Targeting IL-11 signaling in colon cancer." We used BioRender.com to create this diagram [11,12].
Like any other organ in the human body, the GI system has an environment of microorganisms. Its' composition, or in other words, microbiome, is pertinent to the special functions it conducts.

The Normal GI Microbiome
The normal GI microbiome consists of Firmicutes and Bacteroidetes, anaerobic phyla, Actinobacteria, and Verrucomicrobia to a lesser extent. It protects healthy persons through its metabolic and immunologic mechanisms [3]. The research proposes that the GI microbiome can act as an indicator of CRC [6] and possibly causes it [7,8]; for example, the fermentation of carbohydrates creates short-chain fatty acids (SCFAs) that are utilized as energy by the host; however, this fermentation can produce toxins such as phenols, ammonia, and sulfides, which may be carcinogenic [4]. Table 2 can be seen here, which describes the GI microbiome as an essential denominator in CRC disease development.

Study Author
Year  The alterations of the GI microbiome are postulated to have an outcome of CRC. Some studies have explored this idea and have provided statistics.

Dysbacteriosis and Its Correlation With CRC
CRC development is influenced by multiple factors, namely, genetic, environmental, and lifestyle. Disruption of the GI microbiome is another critical factor. Various studies have proven that specific microbes are correlated with an increased incidence of CRC.

Zhang et al. discovered that 14 of 24 species used in their study were increased in CRC patients, including
Parvimonas micra, Solobacterium moorei, and Clostridium symbiosum [2]. Yu et al. found similar findings specifically with these three organisms. Furthermore, Parvimonas micra had a 72.2% occurrence in patients with CRC compared to a 50% occurrence in controls [13]. In contrast, Solobacterium moorei demonstrated a 66.7% occurrence in patients with CRC compared to 27.7% occurrence in controls as per Osman et al. [14]. According to Lucas et al. [3], Bacteroides fragilis has a 38% occurrence in CRC and 12% in controls. Osman et al. showed a higher percentage of occurrence of B. fragilis in CRC at 77.8% [14]. Overall, changes within the GI microbiome, particularly a high prevalence of specific organisms, can be detrimental, leading to colorectal tumorigenesis.
Moreover, data show the GI microbiome has a role in CRC carcinogenesis at different stages. Coker et al. discovered that the altered GI microbiome demonstrates CRC (p = 0.0006) with greater statistical significance than control groups (p = 0.001) [15]. The fungi, Ascomycota and Basidiomycota being the most abundant among others, portrayed different clusters for control, early-stage (tumor, node, and metastasis (TNM) stage I and II) CRC, and late-stage (TNM stage III and IV) CRC, depicting a CRC-stage-specific disruption in microbiome homeostasis.
Zhang et al. determined that there is disruption of the symbiosis of the oral microbiome in the colorectal adenoma (CRA) and CRC, as evidenced by an imbalance in phyla composition and diversity as well as function [16]. Additionally, the probability of disease (POD) index for CRA and CRC was achieved with an area under the curve (AUC) value of 95.94% (95% CI: 90.83%-100%). See Table 3 below, which determines the possible culprits responsible for GI microbiome changes and describes how they expedite CRC progression.

Limitations
This systematic review divulges the correlation between the GI microbiome and CRC by expressing the quantity of alteration in the GI microbiome as seen by the high occurrence of various species but does not explicitly state how the change can be avoided to halt the progression of CRC. Additionally, the studies used were all reviews, therefore, pertinent research articles, some basic science and animal studies that look at the basic mechanism and link between the gut microbiome and cancer, as well as other clinical studies were omitted. Furthermore, the selection of only free articles may have led to the exclusion of relevant papers.

Conclusions
This systematic review targeted the GI microbiome and sought to determine if any changes within it cause CRC. The ways CRC evolves include inflammation and immunosuppression, as seen in the research. The review demonstrates that changes in the microbiome at different parts of the GI tract, including the oral cavity, are responsible for the progression of CRA and CRC, acting as predictors for morbidity. Additionally, fecal matter diversity is limited in CRC.
However, the study did not adequately delineate how adenoma and carcinoma formation can be circumvented. Further research needs to be implemented in GI microbiome homeostasis into CRC prevention and treatment. If proven to provide adequate management of CRC, it could lead to better outcomes, especially since it is less invasive, cost-effective, and easy for patients and healthcare providers.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.