Impact of Bacterial Infection and Intestinal Microbiome on Colorectal Cancer Development
Colorectal cancer (CRC) is one of the most significant cancers affecting the global population, accounting for over 0.57 million deaths annually. It is the third most common cancer worldwide and the second most common in China. The progression of CRC is a stepwise process, beginning with the transformation of healthy tissue into precancerous polyps or adenomas in the colon. The colon, a natural habitat for a dynamic and highly competitive bacterial community, houses up to 100 trillion microorganisms. The intestinal microbiome, encompassing bacteria, viruses, archaea, fungi, their genomes, and environmental conditions, plays a crucial role in maintaining gut health. Dysfunction in the microbiome can lead to chronic inflammation and the production of carcinogenic metabolites, contributing to neoplasia. However, the direct links between microbial colonization and CRC risk are still being unraveled, with limited evidence supporting a direct connection between intestinal bacteria, their virulence factors, and human sporadic CRC.
Approximately 20% of human cancers are linked to infections by viruses, bacteria, or parasites. While much research has focused on viral infections and cancer, bacterial infections, particularly Helicobacter pylori and gastric cancer, have received less attention. Gram-negative Salmonella enterica, an intracellular pathogen affecting both humans and animals, poses a significant public health concern worldwide. Studies have shown higher antibody levels against Salmonella flagellin in CRC and precancer cases compared to controls in the US and the Netherlands, suggesting a potential link between Salmonella and CRC. Smoking and dietary factors, such as iron intake, may mediate this association. Research using mouse models has demonstrated that Salmonella infection, particularly strains expressing the bacterial protein AvrA, increases the incidence of colorectal tumors. Furthermore, AvrA is more frequently found in human tumor-adjacent mucosa than in non-cancer patients, indicating a potential role in CRC development.
The review highlights the progress in understanding the roles of bacterial infection and the microbiome in CRC pathophysiology, using Salmonella infection as a case study. It explores microbial contributions to the hallmarks of cancer and the mechanisms of host-microbial interactions in tumorigenesis. The hallmarks of cancer, as outlined by Hanahan and Weinberg, include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Emerging hallmarks include reprogramming energy metabolism and evading immune destruction. Microbes contribute to the multistep development of tumors by creating a tumor microenvironment conducive to growth. For instance, Bacteroides fragilis is found in higher abundance in the tumors of colon cancer patients and experimental animal models.
Colonic carcinogenesis involves the progressive accumulation of mutations in genetically susceptible hosts, leading to cellular autonomy. Chronic inflammation and infections are known to contribute to the development of many common cancers. Patients with inflammatory bowel disease (IBD) are at increased risk of developing CRC, and the presence of bacteria in the gut appears crucial in CRC pathogenesis. However, whether bacteria induce inflammation that results in tumorigenesis or directly cause CRC in humans remains unclear. The nature and regulation of host-bacterial interactions in the gut are areas of intense scientific and clinical interest. Pathogens manipulate host signaling pathways, such as p53, adenomatous polyposis coli (APC)/β-catenin, and nuclear factor kappa-B (NF-κB), using bacterial effectors and microbial metabolites.
Salmonella infection and its role in gastrointestinal cancer are particularly noteworthy. Salmonella infection affects over 1 million people annually in the US, primarily through foodborne illness. The widespread use of antibiotics has likely contributed to the high infection rate. Salmonella, belonging to the Enterobacteriaceae family, can cause a range of outcomes from mild gastroenteritis to severe systemic infections. Chronic carrier states, where bacteria are excreted without symptoms, represent another transmission mechanism. Recurrent Salmonella infection in animal models leads to a decline in protection against intestinal inflammation, accelerating molecular aging of protective host enzymes. Seroepidemiological studies indicate that the incidence of non-typhoid Salmonella infection is much higher than reported, with significant variations across countries. Chronic sequelae of Salmonella infection include irritable bowel syndrome and IBD. Studies from Scandinavian countries have found an increased risk of IBD following non-typhoid Salmonella infection. Additionally, Salmonella serotype Typhi carrier status is linked to an increased risk of gallbladder cancer. Antibody titers to Salmonella Typhimurium are higher in colorectal tumor cases than controls, suggesting a link to intestinal tumorigenesis. Population-based studies in the Netherlands and Denmark have shown an increased incidence of CRC following Salmonella infection, particularly with serotype Enteritidis and in the proximal colon. However, some studies have found no increased risk of CRC post-infection, indicating the need for further investigation.
Animal models have been instrumental in studying the chronic effects of Salmonella infection. Chronic infection with Salmonella Typhimurium in wild-type mice does not lead to CRC, but in genetically predisposed models, such as the azoxymethane (AOM)/dextran sodium sulfate (DSS) model or APC-deficient mice, colorectal tumor incidence significantly increases. The bacterial protein AvrA, detectable in human colorectal mucosa from CRC patients, plays a crucial role in tumorigenesis. These findings suggest that chronic infection may not induce tumorigenesis in hosts with a healthy immune system but poses a significant risk in genetically susceptible individuals.
Bacterial virulence factors, particularly the type 3 secretion system (T3SS), play a critical role in Salmonella infection. The T3SS injects effectors into the host cytoplasm, facilitating bacterial survival and manipulation of host cells. Salmonella pathogenicity islands (SPIs) encode virulence factors and secretion systems, with SPI1 and SPI2 being major determinants of infection. AvrA, an effector from SPI1, exerts anti-inflammatory activities by inhibiting NF-κB and c-Jun N-terminal kinase (JNK) pathways, reducing inflammatory mediators. AvrA is present in most non-typhoid Salmonella isolates but absent in typhoid strains. Its expression varies with clinical presentation, being detectable in isolates from enteritis but not systemic disease. The carbon storage regulator (Csr) system regulates AvrA expression post-transcriptionally. In animal models, AvrA+ Salmonella Typhimurium infection significantly increases colorectal tumor incidence compared to AvrA- strains. AvrA protein is more frequently detected in human CRC samples, indicating its role in tumorigenesis.
Microbial post-translational modifications (PTMs) also contribute to carcinogenesis. PTMs, such as phosphorylation, acetylation, and ubiquitination, regulate protein activity and are exploited by pathogens to modulate host proteins. Salmonella AvrA possesses deubiquitination and acetyltransferase properties, targeting host proteins like inhibitor of NF-κB (IκBα) and β-catenin. These modifications inhibit NF-κB pathways and activate the β-catenin pathway, contributing to colorectal carcinogenesis. Acetylation of p53 by AvrA increases its stability and transcriptional activities, influencing cancer progression. Bacterial infection induces early chromatin modifications in the gut microenvironment, affecting immune responses in epithelial and immune cells. These modifications involve histone methylation and acetylation, influencing gene activation and silencing.
The intestinal microbiome’s role in CRC is increasingly recognized. Changes in the microbiome composition, characterized by the overgrowth of oral pathogens and depletion of commensal species, are observed across stages of colorectal tumorigenesis. Functional studies have identified pivotal mutagenic or tumor-promoting bacteria, such as pks-positive Escherichia coli, Fusobacterium nucleatum, and Peptostreptococcus anaerobius. Salmonella infection alters the microbial community, with chronic infection potentially permanently changing the microbiome profile and function. Butyrate-producing microbes, known to downregulate Salmonella pathogenicity island 1 gene expression, decrease in adenoma and CRC. Factors affecting CRC risk, such as obesity, physical activity, and dietary intake, also influence the intestinal microbiome.
In summary, emerging evidence highlights the role of bacterial infection and the microbiome in CRC development. Salmonella infection, particularly through the expression of virulence factors like AvrA, manipulates host signaling pathways, contributing to tumorigenesis. The intestinal microbiome’s composition and function play a crucial role in CRC risk, with dysbiosis fostering chronic inflammation and carcinogenic metabolite production. Future research should focus on confirming the direct roles of infection in CRC development and identifying novel approaches to target specific pathways contributing to intestinal tumorigenesis. Integrated prospective studies and advanced methods, such as organoid cultures and “Omics,” will provide deeper insights into the molecular mechanisms and biomarkers for diagnosis and treatment.
doi.org/10.1097/CM9.0000000000001979
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