## 4 Discussion
### Metabolic Pathways of Top Scoring Enzymes
Additionally, studies have found that mucosa-associated E. coli are more prevalent in CRC biopsies compared to those of healthy controls. These strains can survive within macrophages and induce a pro-inflammatory response, contributing to increased cell proliferation and cancer progression. The production of colibactin by these E. coli strains leads to DNA damage, cell cycle arrest, and chromosomal rearrangements in mammalian cells, further implicating them in CRC development [105]. A study found that the colonic mucosa of patients with colorectal carcinoma was colonized by intracellular E. coli, whereas normal colonic mucosa was not. This suggests a potential role of E. coli in colorectal carcinogenesis. Researchers observed an increased level of mucosa-associated and internalized E. coli in tumor tissues compared to normal tissues [106]. Pathogenic cyclomodulin-positive E. coli strains were more prevalent in patients with advanced-stage colon cancer. Infection with a colon-cancer-associated E. coli strain led to a significant increase in colonic polyps in mice, supporting the hypothesis that pathogenic E. coli could be a cofactor in CRC pathogenesis [106]. The evidence and mechanistic explanations for the role of colibactin-producing E. coli strains in CRC has been reported, and the authors also present observations that challenge this hypothesis, suggesting that E. coli may preferentially colonize cancerous lesions as an effect rather than a cause [107]. A study conducted in the Netherlands found that patients diagnosed with severe Salmonella infections had a significantly increased risk of developing cancer in the ascending and transverse parts of the colon. This risk was particularly associated with Salmonella Enteritidis infections, suggesting a potential role of this pathogen in colon cancer development. Research has indicated that repeated exposure to non-typhoidal Salmonella is significantly associated with an increased risk of colon cancer. In mouse models, repetitive low-dose NTS infections accelerated tumor growth, with the bacteria preferentially infecting the pre-transformed cells and exponentially increasing the rate of cellular transformation with each infection round [108]. It is also shown that infection with genotoxic-producing Salmonella enterica collaborates with the loss of the tumor suppressor APC gene to enhance genomic instability in colonic epithelial cells through the PI3K pathway [109]. Clostridioides difficile is a toxin-producing bacteria. The relationship between Clostrrioides difficile and CRC has been shown in the literature. In addition to that, a statistically significant correlation between obese patients with Clostrrioides difficile and an increased incidence of CRC has been shown [110]. In the literature, a study found that a variant of _Citrobacter freundii_ reduced the latent period of colon carcinogenesis in mice treated with 1,2-dimethylhydrazine, suggesting a potential role in promoting colorectal cancer development. These findings suggest that certain strains of _Citrobacter_, such as _Citrobacter freundii_, may influence colorectal carcinogenesis, potentially by reducing the latency period for tumor development [111]. Further research is needed to elucidate the mechanisms by which _Citrobacter_ species may contribute to CRC and to determine their potential as targets for therapeutic intervention. The review discusses various bacterial species implicated in CRC development, including Salmonella, E.coli, and _Citrobacter roedentium_. This study highlights that _Salmonella_ and _C. roedentium_ can induce epithelial-mesenchymal transition (EMT) in the intestinal cells, a process associated with cancer progression. Additionally, _C. rodentium_ has been shown to activate signaling pathways such as PI3K/AKT, WNT-\(\beta\)-catenin, and TLR-4-based NF-kB, which are involved in colorectal carcinogenesis. This study shows that E. coli produces a genotoxin that induces interstrand crosslinks in host cells, resulting in a mutational signature detected in CRC genomes [62].