Role of Gut Microbiota in Predisposition to Colon Cancer: A Narrative Review

Abstract

Globally, colorectal cancer (CRC) is a leading cause of cancer-related mortality. Dietary habits, inflammation, hereditary characteristics, and gut microbiota are some of its causes. The gut microbiota, a diverse population of bacteria living in the digestive system, has an impact on a variety of parameters, including inflammation, DNA damage, and immune response. The gut microbiome has a significant role in colon cancer susceptibility. Many studies have highlighted dysbiosis, an imbalance in the gut microbiota’s makeup, as a major factor in colon cancer susceptibility. Dysbiosis has the potential to produce toxic metabolites and pro-inflammatory substances, which can hasten the growth of tumours. The ability of the gut microbiota to affect the host’s immune system can also influence whether cancer develops or not. By better comprehending these complex interactions between colon cancer predisposition and gut flora, new preventive and therapeutic techniques might be developed. Targeting the gut microbiome with dietary modifications, probiotics, or faecal microbiota transplantation may offer cutting-edge approaches to reducing the risk of colon cancer and improving patient outcomes. The complex connection between the makeup of the gut microbiota and the emergence of colorectal cancer is explored in this narrative review.

Introduction

Colorectal Cancer (CRC) is a major cause of cancer-related mortality globally, and its causes include dietary habits, inflammation, inherited traits, and gut microbiota [1, 2]. A variety of microorganisms including tumour cells, and non-neoplastic cells (stromal cells) all contribute to the complexity of colorectal cancer. It is interesting to note that over 95% of cases include people who do not have a genetic propensity for the illness [3]. Despite intensive research, the molecular causes of CRC are still unknown [4]. CRC accounted for about 10% incidence of all cancer cases worldwide. CRC was responsible for approximately 9% of all cancer-related deaths globally [2].

The vast majority of colorectal cancer cases (around 90%) occurred in individuals over 50, making it a disease predominantly affecting older populations. The 5-year survival rate for colorectal cancer varies depending on the stage at diagnosis [3]. On average, the global 5-year survival rate for all stages combined was around 65% [2]. Colorectal cancer incidence and mortality rates vary significantly across different regions and countries. Developed countries generally have higher rates compared to developing nations. Colorectal cancer imposes a considerable economic burden on healthcare systems and society due to the costs associated with diagnosis, treatment, and supportive care.

A better understanding of the relationship between the microbiome and cancer development may result in identifying novel prognostic markers and therapeutic targets [1]. In numerous tumour forms, increased levels of short-chain fatty acids (SCFA) and molecules involved in amino acid metabolism, such as polyamines, have been linked to the development and metastasis of cancer. Additionally, autoimmune diseases are recognized as contributing factors [5].

The microbiota in the gut produces a range of metabolites that can either be harmful or beneficial to the host. This study discusses the different microbiota in the gut and their mechanisms, the potential role of these gut microbiota in the causation of cancer, the influence of specific dietary factors on these microbiota and colorectal cancer risk, and the current strategies for treating colorectal malignancy.

Overview of Microbiota in the Gut

The gut is home to 100 trillion microorganisms, including bacteria, fungi, and viruses. Human cells are 10 times less numerous than microorganism cells. This amazing microbial family continuously interacts with the host to improve epithelial defence against infections, hastens immune system maturation, and absorbs nutrients from consumed meals [6, 7]. It develops largely during the first two years of life. Even though the microbiota fluctuates throughout adulthood in response to multiple factors- it stabilizes after the early stages and keeps a stable composition [8]. Although the microbiota composition gradually changes with age, identical physiological activities can still be maintained.

The gut microbiota prevents local hemostasis by triggering IgG antibodies which recognize the conserved antigen component of gram-negative bacteria, despite the mucus layer’s intercellular tight connection proteins, which secrete a significant number of antimicrobial compounds [9, 10]. The cells of the human body have become resistant to harmful infections through a variety of efficient methods. This demonstrates how microorganisms, particularly salmonella typhi, have evolved [11]. Numerous factors influence the gut community, some of which are probably highly influenced by lifestyle, nutrition, and host genotype [12, 13]. Various bacterial species are frequently found in the guts of humans: Primary phyla: are Firmicutes, Bacteroidetes and Actinobacteria, Firmicutes being the majority in number [14–18] (Fig. 1).

Fig. 1.

Simplified overview of gut microbiota and related factors

Microbiota and Gut Homeostasis

It is postulated that changes in the gut microbial composition can result in the production of metabolites that assist the disease’s progression [19–21]. Autoimmune diseases, obesity, and metabolic disorders are also contributing factors [22, 23]. The gut microbiota produces various metabolites that can either benefit or harm the host. Understanding its specific mechanisms and potential role in colorectal cancer development, the impact of diet on the microbiota and CRC risk, and current treatment strategies are important areas of research [24]. The microbiota and host cells have coevolved, leading to the development of mechanisms that make the host resistant to infections. Various factors, including lifestyle, nutrition, and host genetics, influence the gut microbiota [14, 24].

The gut microbiota performs protective, structural, and metabolic functions. Germ-free mice without a gut microbiota display increased susceptibility to infections and reduced immune responses. Restoring the gut microbiota in these mice restores immune function and affects gene expression related to nutrient absorption, metabolism, and barrier function. The gut microbiota is involved in anaerobic carbohydrate and proteolytic fermentation processes, resulting in the production of various metabolites that influence gene expression, intestinal cell function, energy utilization, and bacterial growth. Germ-free mice also exhibit structural changes in the intestine, such as longer villi and thinner mucosa and muscle walls, highlighting the structural role of the gut microbiota [25–27]. The presence of the microbiota provides “colonization resistance” and protects against gastrointestinal disorders by competing for nutrients, stabilizing the gut barrier, and producing antimicrobial substances [28, 29].

Gut Microbiota and Colon Cancer

The gut microbiota of healthy people is less varied than that of CRC patients, who exhibit a worldwide change in composition [30]. Several observational and mechanistic investigations have identified a correlation between particular bacteria and colorectal cancer [31]. A meta-analysis of 526 faecal samples from shotgun datasets for metagenomes has revealed seven bacteria that consistently exhibit increased presence in colorectal cancer, despite regional variations in gut microbiota [32].

Distinct regions of the body exhibit varying compositions of gut microbiota [33]. Moreover, mucosal bacterial biofilms have been found to impact tumour development not associated with distal CRC implying that the gut microbiota assumes distinct roles in different types of CRC according to anatomy [34]. One potential explanation is that when the local environment is altered, such as after surgery or illnesses, bacteria tend to gather in greater quantities at the furthest part of the colon [35]. Additionally, it was noted that persons with distal colorectal cancer (CRC) had higher concentrations of bacterial genes linked to cancer-promoting traits in their faeces than those with proximal CRC [36].

To develop advanced, accurate, and highly sensitive molecular techniques for early detection of colon-related diseases, it is essential to know the specific bacterial species associated with colorectal cancer (CRC). Similar to genetic tumor profiles, the detection of various microorganisms within tumors may eventually become a standard test to help with patient prognosis and therapy. A list of pertinent bacterial species is described below [37].

Fusobacterium nucleatum

Fusobacterium nucleatum may have a function in the emergence of colorectal cancer (CRC), according to genomic approaches like 16S rDNA and shotgun metagenomics studies. For the first time, Kostic et al. demonstrated that F. nucleatum increases the expression of genes linked to inflammation and encourages myeloid cells to infiltrate intestinal tumours in ApcMin/ + mice [38]. Additional investigations using Quantitative polymerase chain reaction provided further evidence to support the discovery that individuals with adenomas or adenocarcinomas exhibited elevated levels of Fusobacterium nucleatum in their tissues, faeces, and the mucous membrane of the colon compared to healthy individuals [39, 40]. Consistent findings have been observed across diverse ethnic populations and throughout different stages of colorectal cancers (CRCs) [39, 40].

Examination of human intestinal tissues has revealed multiple mechanisms through which Fusobacterium nucleatum promotes an environment that is conducive to tumor development. Yang et al. examined the patterns of microRNA (miRNA) expression in CRC cell lines after they had been treated with Fusobacterium nucleatum in mice [41]. Results showed that F. nucleatum controls microRNA21 and inflammatory factors via the toll-like receptors [41]. The toll-like receptors were found to influence two targets that miR21 acts upon [41]. The overexpression of miR21 in Fusobacterium nucleatum in the MAPK cascade’s activity is closely related to, and possibly contributing to the development of CRC [41].

Bacteroides fragilis

The mechanism by which Enterotoxigenic Bacteroides fragilis (ETBF) attaches to the cells lining the colon and the impact it has on the development of cancer remains unclear. Direct DNA damage can be brought on by ETBF, and it can also modify gene expression through a variety of signalling systems [37]. Wu et al. demonstrated that administering ETBF to mice with heterozygous APC gene mutations leads to the enhancement and spread of adenocarcinoma at an accelerated rate. This is because ETBF directly promotes carcinogenesis through the selective TH17 response [42]. Due to the presence of B. fragilis toxin (BFT) and ETBF colonization of colonic epithelial cells, E-cadherin has been cleaved as a result of signal transduction processes [43]. As a result, β-catenin is released, activating MAPKS, NF-B, and tyrosine kinases [44]. B. fragilis could be considered the primary and most influential risk factor for colorectal cancers (CRCs). Bacteroides fragilis toxin (BFT) exposure causes the promotion of proto-oncogenes like MYC and aids in the growth of CRCs in the colonic mucosa [44].

Escherichia coli

Escherichia coli usually lives symbiotically in the human gut. However, E. Coli is carcinogenic and can cause colon cancer. Colon cancer is thought to be connected with a high incidence of mucosal-associated E. coli. Certain E. coli produce a toxin called cyclomodulin (CM) that interferes with the host cell’s eukaryotic cell cycle, indicating a possible link between these bacteria and cancer [28]. Cyclomodulin is genotoxic and regulates cell differentiation, apoptosis and proliferation [29]. This has been previously demonstrated by Arthur et al. In I110-/- azoxymethane (AOM) given mice, single colonization of commensal E. coli NC101 mice led to the development of aggressive carcinoma. AOM/I110-/- mice, tumor multiplicity and invasion were reduced when genotoxic polypeptide synthase(pks)islands from E. coli NC101 were eliminated, but intestinal inflammation remained intact. In the case of IBD and CRC, a considerably greater number of mucosal-associated E. coli pks islands suggest that colitis might promote cancer [45]. E. coli leads to DNA instability and DNA damage and thus promotes carcinogenesis. It can lead to Double Standard Breaks (DSBs) in vitro as well as in vitro. Mistreated DSBs can lead to anaphase bridging and chromosomal aberrations [46]. In a state of dysbiosis, E. coli also produces a cytolethal distending toxin that can lead to DNA damage and make the bacteria procarcinogenic [47, 48]. Some strains primarily control the assembly of actin cytoskeleton and play a part in various cellular processes including control of transcription, cell motility, etc. CNF-1 can promote cell motility, activate the NFkB pathway, and protect cells from apoptosis by boosting anti-apoptotic proteins through Rho GTPase [49–53].

Streptococcus gallolyticus

Increased risk of CRC was demonstrated in patients suffering from S. bovis-associated endocarditis by various independent researchers [54–56] Quen Deng et al. demonstrated in mice that S. bovis-associated increased risk in cancer is TLR-4 CD11b cell-mediated [57]. Colonic epithelial tissue sampling in CRC patients showed that S. gallolyticus seropositive samples had the expression of NF-κB [58]. A subsequent study showed increased expression of IL-1 and COX-2 in CRC samples that were S. gallolyticus seropositive further supporting the NF-kB activation theory [59] Martin et al. showed that S. gallolyticus can easily and efficiently colonize the carcinogenic colonic mucosa with altered receptor. The Pil3 pilus of this bacterium binds to the mucin MUC2 which is predominant in normal colon and aids in colonization. At the same time, it can equally bind to MUC5AC seen only in colon cancer thus giving it an advantage over other microbiota [60].

Helicobacter pylori

There is no relation between H. pylori prevalence and colorectal cancer. However, CRC samples that were positive with any of the specific H. pylori proteins showed VacA has the strongest link [61, 62]. It is hypothesized that VacA, a known virulence factor, has various mechanisms like pro-inflammatory effects, effects of epithelial permeability and cell vacuolation, just to name a few [63]. Chronic gastritis is the proposed mechanism by which VacA increases the risk of cancer. H. pylori in chronic gastritis leads to increased production of gastrin that stimulates COX-2 expression [64]. Various studies have shown gastrin to be a risk factor for colorectal cancer [65, 66]. Gastric atrophy due to H. pylori leads to a rise in inflammatory mediators like PGE2 that might increase the risk of cancer [67, 68].

Enterococcus faecalis

E. faecalis extends its carcinogenic potential by inhibiting macrophage-induced bystander effects. 4-HNE made by E. Faecalis infected macrophages acts as a mitotic spindle inhibitor. Mice with interleukin-10 knockout developed inflammation and colorectal cancer when they were colonized with superoxide-producing E. faecalis [69]. Superoxide and hydrogen peroxide damage colon cell DNA leading to chromosomal instability, aneuploidy, and tetraploidy [70–72]. Netrin-1 production by colon epithelial cells in Enterococcus faecalis colonized mice resulted in the inhibition of apoptosis and accelerated cancer transformation [73]. Another postulated mechanism is that Enterococcus faecalis produces hydrogen peroxide that stimulates the Epidermal Growth Factor Receptor [74].

Parvimonas micra

P. micra, is frequently encountered in the human oral cavity [75]. In comparison to individuals who are in good health, the presence of P. micra was remarkably higher in both the body waste and patient tumour tissues diagnosed with colorectal cancer [76, 77]. The presence of other microorganisms in the gut does not affect the tumorigenic impact of P. micra [78].

Prevotella intermedia

The process of malignant transformation is marked by the invasion and migration of cells. P. intermedia notably enhanced cell colorectal cancer cells of all three kinds exhibit invasion [79].

Alistipes finegoldii

In patients with gastrointestinal pathologic diseases, A. finegoldii should be taken into consideration as a bacteremia agent [80].

Role of Fungi and Viruses in Triggering CRC

Studies have found some correlation between CRC and six enriched and depleted species of fungus. In CRC, as opposed to adenoma and healthy individuals, co-occurrent relationships among fungi that are abundant in CRC became more robust. Additionally, Lin et al. described the trans-kingdom connections between bacteria and enteric fungus in the development of colorectal cancer, discovering a substantial association between Fusobacterium nucleatum, a bacterium that is enriched in CRC, and Aspergillus rambellii. A. rambellii induced the growth of colorectal cancer cells in vitro and tumour formation in mice used as xenografts [81]. It is believed that inflammatory bowel disease (IBD) is made worse by fungal dysbiosis [82]. Through persistent inflammation and other pathways that encourage the malignant alteration of the colonic mucosa, IBD may contribute to CRC.

Due to its impairment of the intestinal barrier and promotion of opportunistic fungal translocation, fungal dysbiosis in the gut plays a role in the development and progression of colorectal cancer. Immune cells’ Pattern Recognition Receptors (PRRs) recognise components of the fungal cell wall, which sets off pro-inflammatory reactions that activate Th1 and Th17 cells and draw in phagocytes and neutrophils. Downstream of PRRs, a myeloid cell-specific protein called CARD9 induces innate lymphoid cells (ILCs) to generate IL-22, which promotes carcinogenesis by activating STAT3. Candida tropicalis is one of the fungi that can produce more myeloid-derived suppressor cells (MDSCs), which can stop cancer growth and the production of cytotoxic T lymphocytes (CTLs). Furthermore, oxidative stress and DNA damage are brought on by the toxic compounds of pathogenic fungi, and carcinogenesis is further promoted by the interactions and mechanisms that occur between the fungal and bacterial ecosystems [83].

Microorganisms may be extremely intriguing cofactors in the oncogenesis and development of colorectal cancer, according to mounting data. Yet, little is known about the related mechanisms, particularly as they relate to colonocytes and their interactions with the milieu. Only three of the officially recognised human carcinogens—the Epstein-Barr virus (EBV), the human papillomavirus (HPV), and the John Cunningham virus (JCV)—have been linked to colorectal cancer (CRC), albeit with differing degrees of evidence [84].

Hypothesised Model of Colon Cancers

Researchers and oncologists have long sought to develop human colon cancer models, essential for accurately replicating the course of the disease and understanding how it responds to treatment. Despite advancements in comprehending the biology of colorectal cancer and advancements in therapy, preclinical in vivo models remain pivotal in the advancement of innovative treatment strategies for CRC [1].

Genetically Engineered Mouse Models

Of the various in vivo models available, there is no doubt that Genetically Engineered Mouse Models (GEMMs) offer the most suitable means of reproducing the intricate complexity of the tumour ecosystem [2]. GEMMs can accurately simulate the pathogenesis of both sporadic and inherited CRC, by replicating the activation or inhibition of specific molecular pathways involved in the disease [1]. GEMMs have a crucial role in advancing our perception of the molecular mechanisms engaged in the initiation and succession of CRC, along with the interaction of commonly affected pathways. Though GEMMs have been highly beneficial for investigating CRC and devising effective therapeutic approaches; however, their effectiveness in replicating advanced stages of CRC is somewhat limited with most of the evidence concentrated in the early stages [3]. These models are not capable of accurately replicating the natural process of metastasis, which is a key component of advanced stages of CRC, exhibiting a reduced degree of dissemination and requiring a longer duration to develop metastases, which also exhibit high variability and reduced reproducibility [4]. In certain GEMM models of CRC that harbour Apc mutations, it is common for small bowel tumours to develop instead of colon tumours, and the overall tumour burden often shortens the lifespan of the animal, restricting the extent of malignant progression and resulting in a majority of cases not showing secondary disease [5, 6]. These models of CRC have additional limitations, such as increased heterogeneity in human tumours which may be attributed to varied diets, diverse microbiomes, and prolonged toxin exposure in humans compared to mice, lack of population genetic heterogeneity due to inbreeding in mice and limited genetic tumour pathways as tumours in GEMM arise from the same genetic mutation [6, 7] (Fig. 2).

Fig. 2.

Summary of Genetically Engineered Mouse Models (GEMMs)

Transplant Models for Colorectal Cancer

Syngeneic tumour transplantation refers to the engraftment of tumour tissue, into the same mouse strain, while xenogeneic grafts use cell lines or tumour tissue from an alternate human donor or mouse strain. Furthermore, tumour transplantation may be categorized as either heterotopic or orthotopic, depending on the precise site of engraftment [1].

The syngeneic model in therapeutic studies has advantages such as having tumour cells and surrounding tissue from the same species and an undamaged immune system, but also limitations such as the inability to study genetic modifiers in endogenic animals and low metastasis rates [8].

In recent decades, xenograft models have been increasingly utilized as an alternative to cell culture models in order to overcome their limitations [8]. These models have emerged as a successful approach and are now extensively employed by researchers worldwide to induce colorectal cancer in mice for studying carcinogenesis and therapeutic responses [9–11]. Similar to other models, the xenograft model also exhibits limitations, including its low metastatic capacity, which has prompted researchers to explore alternative approaches such as injection into the portal vein, spleen or liver to address this limitation [12, 13, 19]. Another drawback of subcutaneous xenografts is that they do not fully replicate the tumour/microenvironment interaction, which is a known factor in determining tumour behaviour such as indolent or aggressive growth and the potential for distant metastases [20, 21]. Despite its inherent limitations, its use is still prevalent in current times, particularly in the field of therapeutic studies [22].

Patient-derived xenografts (PDX) models are produced by implanting a piece of tumour obtained out of a surgical excision within the sides of immunodeficient mice, along with biopsy samples showing lesser rates of tumour engraftment [23]. In heterotopic mouse models, a common critique is the lack of tumour-stroma interaction or the “tumour microenvironment”, although, in the case of PDX models, the stromal component remains preserved while immune cells may be absent [14, 24]. Furthermore, PDX models are not only valuable for therapy development, but they also serve an essential purpose in maintaining a robust biobank by facilitating the setup of secondary cell lines and providing ample tumour specimens for exchange with other research organizations [15] (Fig. 3).

Fig. 3.

Summary of the Transplant Models for CRC

Orthotopic Model

To overcome the limitations of the aforementioned models, A novel approach involves directly infusing tumor cells into the target site, creating an orthotopic model, feasible in nude or immunocompromised mice [16]. Unlike subcutaneous models, orthotopic ones simulate distant metastasis better, providing a more realistic platform for studying metastasis dynamics [17]. A model for distal colon cancer was established in 2012, which could develop in vivo tumours in the distal colon that histologically resembled human colon cancer but did not observe the presence of disseminated illness [18]. In 2016, improvement of this model was done by utilizing various CRC cell lines from different colonic origins, resulting in the development of primary tumours in mice with morphophysiological characteristics, neural intrusion, and tumour stem cell recognition, making it a simple and duplicable model to study molecular and genetic routes of CRC, their relationship with the local environment, and the disseminated process [25].

Currently, orthotopic models are extensively utilized for in vivo confirmation of novel curative compounds and as a pilot study strategy [26, 27] (Fig. 4).

Fig. 4.

Summary of the Orthoptic Model for CRC

Role of Anal Intercourse in the Development of Colorectal Cancer

Numerous studies link anal cancer to anal sex due to Human Papilloma Virus (HPV) transmission. This risk primarily stems from the transmission of the HPV during anal intercourse. According to estimates from the National Cancer Institute, HPV infection is responsible for 90% of anal cancer cases, a concerning trend [85]. However, when it comes to the development of colorectal carcinoma and its relationship with anal intercourse, the existing research presents conflicting conclusions.

Early research on colorectal neoplastic tissue didn’t detect HPV DNA, likely due to limited sample numbers and detection techniques [86–88]. Despite advancements, recent findings remain unsettling. For example, according to research by Ramprasad et al., there is no statistically significant difference between women who had anal intercourse and those who did not in terms of the incidence of colorectal cancer [89].

On the other hand, Burnett-Hartman et al.’s assessment of nine case–control studies found a consistent positive correlation between HPV and colorectal neoplasia [90]. Chuang L et al. discovered that women with cervical HPV infections (excluding types 6 and 11) may face a higher risk of adenocarcinomas in the rectum and recto-sigmoid junction [91]. Additionally, a study on cancer risk among cervical cancer survivors suggested that colon cancer risk, in those with a history of cervical cancer, likely stems from radiation treatment rather than a shared cause like HPV for both cancers [92].

The prevailing theory linking anal intercourse to colorectal cancer involves HPV transmission. Burnett-Hartman and colleagues propose that HPV contributes to colorectal cancer by deactivating the p53 protein, mimicking the effects of a p53 mutation. This connection seems more significant in colorectal cancers lacking p53 mutations. Their findings align with research on oral carcinomas, suggesting that the subset without p53 mutations shows the strongest correlation with HPV [90].

Due to conflicting evidence on the link between colorectal cancer and HPV, further investigation is crucial. The current evidence is inconclusive, though some indicators suggest a possible connection. Large-scale, well-planned research is essential to thoroughly explore and understand the relationship between HPV and colon cancer.

Diet, Microbiota and Colorectal Cancers

Diet and Colorectal Cancer

The influence of diet on the likelihood of developing colorectal carcinoma has continuously been shown by epidemiological studies. Colorectal carcinoma risk has been associated with the consumption of diets that are rich in red and processed meats, saturated fats, and lacking in dietary fibre [93]. According to Chan et al.’s meta-analysis, there is a 12% increased probability of colorectal cancer for every additional 100 g/day in the diet of red and processed meat. On the other hand, diets high in fruits, vegetables, whole grains, and specific micronutrients like folate, calcium, and vitamin D have demonstrated a protective impact against colorectal cancer [94]. For instance, research by Song et al. observed that following a diet that prioritises consuming lots of fruits, vegetables, whole grains, and fish was linked to considerably decreased odds of colorectal carcinoma.

Diet-Microbiota Interactions

Healthy bacteria can multiply and diversify by using dietary substances including fibre, polyphenols, and prebiotics as substrates [95]. As an illustration, a study by Sonnenburg and Bäckhed found that dietary fibre can boost the number of Bifidobacterium and other helpful bacteria, which helps to support a healthy gut microbiota. Contrarily, diets that are rich in animal fats and lack fibre can change the makeup of the gut microbiota to become more inflammatory in nature [95]. These microbiome changes brought on by food may affect the risk of CRC.

Mechanisms Linking Diet, Microbiota, and Colorectal Cancer

A number of theories have been put out to clarify the complex relationship between nutrition, microbiome, and colorectal carcinoma. Studies show that short-chain fatty acids (SCFAs) are created when bacteria ferment dietary fibre. These SCFAs enhance the health of intestinal epithelial cells by having anti-inflammatory characteristics [96]. SCFAs give colonocytes a source of energy and ensure that the intestinal barrier is intact. Second, some bacteria have enzymes that can convert dietary procarcinogens such as heterocyclic amines into cancer-causing substances [97]. Chronic immunological activation and cancer promotion can result from the translocation of bacterial products caused by dysbiosis-induced inflammation and compromised gut barrier function [98].

Current Therapeutic Approaches and Future Directions

In light of the potential correlations elucidated between the gut microbiome and the advancement of CRC, there is a burgeoning curiosity in investigating microbiome-based approaches to bolster the prevention and management of this malignancy. Potential therapeutic methods for the treatment of CRC revolve around modulating the gut microbiome via Faecal Microbiota Transplantation (FMT), incorporating certain dietary modifications, prebiotic/probiotic supplementation, implementing antibiotic regimens, and exploring phage therapy. These interventions aspire to give promising results in the management of CRC [99].

Faecal Microbiota Transplantation (FMT) has exhibited immense ability to restore a favourable microbial composition in the gut in individuals with Clostridium difficile infection (CDI) [61]. Although favourable outcomes have been reported, establishing them on larger scales has proven a herculean task and conclusive data from human clinical trials employing FMT for the treatment of CRC are lacking. FMT holds promise as a strategy for treating CRC patients but still needs further investigation [100].

In the past, antibiotics have proven successful in modulating the microbiome as a more targeted approach specifically addressing bacteria associated with the progression of CRC. Nevertheless, it is crucial to acknowledge that the utilization of antibiotics results in dysbiosis and contributes to the emergence of drug resistance [101].

Furthermore, apart from its impact on CRC development, the gut microbiota influences the response to cancer immunotherapy, as well as governs the efficacy of chemotherapeutic compounds like oxiplatin. Butyrate-producing bacteria (Firmicutes), personalized dietary interventions and anti-tumorigenic probiotic supplements also have immense potential to improve the effectiveness of CRC treatments by activating apoptosis, and inactivating carcinogens [99, 102]. Probiotics are live microorganisms advocated in clinical practice for the treatment of necrotizing enterocolitis and inflammatory bowel disease as they possess a plethora of advantageous actions [103]. As a result, it contributes to the prevention of inflammatory disorders and colon malignancies by preserving the integrity of the mucosal barrier.

Dietary interventions such as higher intake of omega 3, fibre, low carbohydrate diet and vitamin D have also had extremely positive immunomodulatory effects and better survival chances in CRC-afflicted patients. Being cognizant of all these microbiota-modifying factors will stand us in good stead in the future by helping with attenuating risks and mitigating adverse effects commonly associated with immunotherapy and chemotherapeutic drugs thereby improving treatment outcomes and patient prognosis [104].

A vast majority of clinical studies implicating gut microbiota in the growth of CRC adopt a retrospective case–control study design which precedes backwards from effect to cause, therefore, alteration in microbiota cannot be unequivocally attributed to carcinogenicity of the colon. Additionally, most clinical trials have been assailed by small sample sizes, predominantly consisting of fewer than 100 participants [105]. These limited sample sizes are likely insufficient and woefully underpowered for effectively detecting predictive signals. Also, the short duration of most interventional and cross-sectional studies has made the attainment of incontrovertible evidence about host-microbiome interaction a formidable challenge. This warrants long-term, integrated prospective cohort studies, prior to the development of CRC to effectively characterise the influence of various factors on the progression of CRC.

Numerous epidemiological studies are corroborating the part intestinal microbiota plays in the growth of colonic adenomas which further solidifies their significance as a potential non-intrusive prognostic and diagnostic indicator for the disease as against the invasive colonoscopy screening currently employed in clinical practice [106]. However, the use of faecal microbiome as a screening test for CRC remains far-fetched as the heterogeneity of analytic models used in different research studies gives a very hazy picture of its ability to detect true differences and identify genuine discrepancies in the bacterial composition of stool samples. Other anticipated problems that warrant thorough investigation include acceptability by patients, cost-effectiveness and affordability compared with the conventional screening tests.

Furthermore, a deeper knowledge of the biological and essential roles of gut microorganisms can only be established by the synergistic confluence of sequence-based methods like metatranscriptomics and metabolomics complementary to metagenomics which elucidates the mechanism underlying dysbiosis in CRC [103]. This critical lacuna in existing knowledge using metatranscriptomic methods for gut microbiota warrants exhaustive research studies which can be parlayed into further cementing their importance as promising prognosticating and diagnostic markers while enhancing the knowledge about the aetiology of CRC.

Conclusion

The gut microbiome encompasses a diverse community of commensal and pathobiotic microorganisms colonising the intestine. Dysbiosis, an imbalance in this ecosystem, is frequently implicated in carcinogenic mutagenesis such as colorectal cancer. Among the postulated theories elucidating the induction of carcinogenesis by microorganisms, the frontrunner is the generation of genotoxicity, that is, the disruption of the surface cell epithelium of the intestine that in turn triggers the recruitment of inflammatory cell infiltrates accelerating oncogenic transformation. In summary, this review provides valuable insights into the multifaceted role of gut microbiota in the pathogenesis of CRC and highlights the importance of further research in elucidating its underlying mechanisms. By decoding the intricate interplay between gut microbiota and CRC, novel avenues for targeted interventions and personalised treatment approaches can be explored to improve patient outcomes.