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ABSTRACTThe etiology of colorectal cancer (CRC) is influenced by bacterial communities that colonize the gastrointestinal tract. These microorganisms derive essential nutrients from indigestible dietary or host-derived compounds and activate molecular signaling pathways necessary for normal tissue and immune function. Associative and mechanistic studies have identified bacterial species whose presence may increase CRC risk, including notable examples such as Fusobacterium nucleatum, Enterotoxigenic Bacteroides fragilis, and pks+ E. coli. In recent years this work has expanded in scope to include aspects of host mutational status, intra-tumoral microbial heterogeneity, transient infection, and the cumulative influence of multiple carcinogenic bacteria after sequential or co-colonization. In this review, we will provide an updated overview of how host-bacteria interactions influence CRC development, how this knowledge may be utilized to diagnose or prevent CRC, and how the gut microbiome influences CRC treatment efficacy.

Introduction: Pathogenic strains of Escherichia coli have been clearly identified as the causative agents of extraintestinal and diarrheal infections; however, the etiopathogenic role of E. coli in other conditions, including colorectal cancer, remains unclear. Methods: This study aimed to characterize mucosal E. coli isolates (n = 246) from 61 neoplasia patients and 20 healthy controls for the presence of 35 genetic determinants encoding known virulence factors. Results: Virulence determinants encoding invasin (ibeA), siderophore receptor (iroN), S-fimbriae (sfa), and genotoxin (usp) were more prevalent among E. coli isolated from patients with neoplasia compared to the control group (p < 0.05). In addition, the prevalence of these virulence determinants was increased in more advanced neoplasia stages (padj < 0.0125). Compared to patients with advanced colorectal adenoma and carcinoma, the ibeA gene was rarely found in the control group and among patients with non-advanced adenoma (p < 0.05), indicating its potential as the advanced-neoplasia biomarker. Patients with neoplasia frequently had E. coli strains with at least one of the abovementioned virulence factors, whereby specific combinations of these virulence factors were found. Discussion: These findings suggest that E. coli strains isolated from patients with colorectal neoplasia possess several virulence factors, which could contribute to the development of neoplastic processes in the large intestine. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, and its incidence is steadily rising in developing areas. Bacterial pathogens from the gut microbiota have been recognized as important risk factors for CRC. This review updates the current knowledge of Escherichia coli-produced genotoxins related to CRC. Emerging evidence indicates bacterial infections contribute to the formation of cancers. Bacterial genotoxins are effectors that cause DNA damage by introducing single- and double-strand DNA breaks in the host cells. The first bacterial genotoxin cytolethal distending toxin (CDT) was a protein identified in 1987 in a pathogenic strain in Escherichia coli (E. coli) isolated from a young patient. The peptide-polyketide genotoxin colibactin is produced by the phylogenetic group B2 of E. coli. Recently, a protein produced by attaching/effacing (A/E) pathogens, including enteropathogenic and enterohemorrhagic E. coli (EPEC and EHEC) and their murine equivalent Citrobacter rodentium (CR), has been reported as a novel protein genotoxin, being injected via the type III secretion system (T3SS) into host cells and harboring direct DNA digestion activity with a catalytic histidine-aspartic acid dyad. These E. coli-produced genotoxins impair host DNA, which results in senescence or apoptosis of the target cells if the damage is beyond repair. Conversely, host cells can survive and proliferate if the genotoxin-induced DNA damage is not severe enough to kill them. The surviving cells may accumulate genomic instability and acquire malignant traits. This review presents the cellular responses of infection with the genotoxins-producing E. coli and discusses the current knowledge of the tumorigenic potential of these toxins. [ABSTRACT FROM AUTHOR]

Abstract Background Colibactin is a genotoxin that induces DNA double-strand breaks that may lead to carcinogenesis and is produced by Escherichia coli strains harboring the pks island. Human and animal studies have shown that colibactin-producing gut bacteria promote carcinogenesis and enhance the progression of colorectal cancer through cellular senescence and chromosomal abnormalities. In this study, we investigated the impact of prebiotics on the genotoxicity of colibactin-producing E. coli strains Nissle 1917 and NC101. Methods Bacteria were grown in medium supplemented with 20, 30 and 40 mg/mL of prebiotics inulin or galacto-oligosaccharide, and with or without 5 μM, 25 μM and 125 μM of ferrous sulfate. Colibactin expression was assessed by luciferase reporter assay for the clbA gene, essential for colibactin production, in E. coli Nissle 1917 and by RT-PCR in E. coli NC101. The human epithelial colorectal adenocarcinoma cell line, Caco-2, was used to assess colibactin-induced megalocytosis by methylene blue binding assay and genotoxicity by γ-H2AX immunofluorescence analysis. Results Inulin and galacto-oligosaccharide enhanced the expression of clbA in pks+ E. coli. However, the addition of 125 μM of ferrous sulfate inhibited the expression of clbA triggered by oligosaccharides. In the presence of either oligosaccharide, E. coli NC101 increased dysplasia and DNA double-strand breaks in Caco-2 cells compared to untreated cells. Conclusion Our results suggest that, in vitro, prebiotic oligosaccharides exacerbate DNA damage induced by colibactin-producing bacteria. Further studies are necessary to establish whether oligosaccharide supplementation may lead to increased colorectal tumorigenesis in animal models colonized with pks+ E. coli.

Epidemiological studies have found an increased incidence of colorectal cancer (CRC) in people who undergo cholecystectomy compared to healthy individuals. After cholecystectomy, bile enters the duodenum directly, unregulated by the timing of meals. Disruption of the balance of bile acid metabolism and increased production of primary bile acids, which in turn affects the composition and abundance of intestinal microorganisms. The link among cholecystectomy, the gut microbiota, and the occurrence and development of CRC is becoming clearer. However, due to the complexity of the microbial community, the mechanistic connections are less well understood. In this review, we summarize the changes of gut microbiota after cholecystectomy and illuminate the potential mechanisms on CRC, such as inflammation and immune regulation, production of genotoxins, metabolism of dietary ingredients, activation of signaling pathways, and so on. By reviewing these, we aimed to unravel the interactions between the gut microbiota and its host and be better positioned to develop treatments for CRC after cholecystectomy.

Epidemiological studies have found an increased incidence of colorectal cancer (CRC) in people who undergo cholecystectomy compared to healthy individuals. After cholecystectomy, bile enters the duodenum directly, unregulated by the timing of meals. Disruption of the balance of bile acid metabolism and increased production of primary bile acids, which in turn affects the composition and abundance of intestinal microorganisms. The link among cholecystectomy, the gut microbiota, and the occurrence and development of CRC is becoming clearer. However, due to the complexity of the microbial community, the mechanistic connections are less well understood. In this review, we summarize the changes of gut microbiota after cholecystectomy and illuminate the potential mechanisms on CRC, such as inflammation and immune regulation, production of genotoxins, metabolism of dietary ingredients, activation of signaling pathways, and so on. By reviewing these, we aimed to unravel the interactions between the gut microbiota and its host and be better positioned to develop treatments for CRC after cholecystectomy. [ABSTRACT FROM AUTHOR]

Background: Colibactin is a genotoxin that induces DNA double-strand breaks that may lead to carcinogenesis and is produced by Escherichia coli strains harboring the pks island. Human and animal studies have shown that colibactin-producing gut bacteria promote carcinogenesis and enhance the progression of colorectal cancer through cellular senescence and chromosomal abnormalities. In this study, we investigated the impact of prebiotics on the genotoxicity of colibactin-producing E. coli strains Nissle 1917 and NC101.Methods: Bacteria were grown in medium supplemented with 20, 30 and 40 mg/mL of prebiotics inulin or galacto-oligosaccharide, and with or without 5 μM, 25 μM and 125 μM of ferrous sulfate. Colibactin expression was assessed by luciferase reporter assay for the clbA gene, essential for colibactin production, in E. coli Nissle 1917 and by RT-PCR in E. coli NC101. The human epithelial colorectal adenocarcinoma cell line, Caco-2, was used to assess colibactin-induced megalocytosis by methylene blue binding assay and genotoxicity by γ-H2AX immunofluorescence analysis.Results: Inulin and galacto-oligosaccharide enhanced the expression of clbA in pks+ E. coli. However, the addition of 125 μM of ferrous sulfate inhibited the expression of clbA triggered by oligosaccharides. In the presence of either oligosaccharide, E. coli NC101 increased dysplasia and DNA double-strand breaks in Caco-2 cells compared to untreated cells.Conclusion: Our results suggest that, in vitro, prebiotic oligosaccharides exacerbate DNA damage induced by colibactin-producing bacteria. Further studies are necessary to establish whether oligosaccharide supplementation may lead to increased colorectal tumorigenesis in animal models colonized with pks+ E. coli. [ABSTRACT FROM AUTHOR]

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The frequent occurrence of E. coli positive for cyclomodulins such as colibactin (CLB), the cytotoxic necrotizing factor (CNF), and the cytolethal distending factor (CDT) in colorectal cancer (CRC) patients published so far provides the opportunity to use them as CRC screening markers. We examined the practicability and performance of a low-cost detection approach that relied on culture followed by simplified DNA extraction and PCR in E. coli isolates recovered from 130 CRC patients and 111 controls. Our results showed a statistically significant association between CRC and the presence of colibactin genes clbB and clbN, the cnf gene, and newly, the hemolytic phenotype of E. coli isolates. We also observed a significant increase in the mean number of morphologically distinct E. coli isolates per patient in the CRC cohort compared to controls, indicating that the cyclomodulin-producing E. coli strains may represent potentially preventable harmful newcomers in CRC patients. A colibactin gene assay showed the highest detection rate (45.4%), and males would benefit from the screening more than females. However, because of the high number of false positives, practical use of this marker must be explored. In our opinion, it may serve as an auxiliary marker to increase the specificity and/or sensitivity of the well-established fecal immunochemical test (FIT) in CRC screening.

Colibactin is a secondary metabolite encoded by the pks gene island identified in several Enterobacteriaceae, including some pathogenic Escherichia coli (E. coli) commonly enriched in mucosal tissue collected from patients with inflammatory bowel disease and colorectal cancer. E. coli harboring this biosynthetic gene cluster cause DNA damage and tumorigenesis in cell lines and pre-clinical models, yet fundamental knowledge regarding colibactin function is lacking. To accurately assess the role of pks+ E. coli in cancer etiology, the biological mechanisms governing production and delivery of colibactin by these bacteria must be elucidated. In this review, we will focus on recent advances in our understanding of colibactin’s structural mode-of-action and mutagenic potential with consideration for how this activity may be regulated by physiologic conditions within the intestine.

The frequent occurrence of E. coli positive for cyclomodulins such as colibactin (CLB), the cytotoxic necrotizing factor (CNF), and the cytolethal distending factor (CDT) in colorectal cancer (CRC) patients published so far provides the opportunity to use them as CRC screening markers. We examined the practicability and performance of a low-cost detection approach that relied on culture followed by simplified DNA extraction and PCR in E. coli isolates recovered from 130 CRC patients and 111 controls. Our results showed a statistically significant association between CRC and the presence of colibactin genes clbB and clbN, the cnf gene, and newly, the hemolytic phenotype of E. coli isolates. We also observed a significant increase in the mean number of morphologically distinct E. coli isolates per patient in the CRC cohort compared to controls, indicating that the cyclomodulin-producing E. coli strains may represent potentially preventable harmful newcomers in CRC patients. A colibactin gene assay showed the highest detection rate (45.4%), and males would benefit from the screening more than females. However, because of the high number of false positives, practical use of this marker must be explored. In our opinion, it may serve as an auxiliary marker to increase the specificity and/or sensitivity of the well-established fecal immunochemical test (FIT) in CRC screening. [ABSTRACT FROM AUTHOR]

Patients with multiple recurrent Clostridioides difficile infection (rCDI) have a disturbed gut microbiota that can be restored by fecal microbiota transplantation (FMT). Despite extensive screening, healthy feces donors may carry bacteria in their intestinal tract that could have long-term health effects, such as potentially procarcinogenic polyketide synthase-positive (pks +) Escherichia coli. Here, we aim to determine whether the pks abundance and persistence of pks + E coli is influenced by pks status of the donor feces. In a cohort of 49 patients with rCDI treated with FMT and matching donor samples—the largest cohort of its kind, to our knowledge—we retrospectively screened fecal metagenomes for pks + E coli and compared the presence of pks in patients before and after treatment and to their respective donors. The pks island was more prevalent (P =.026) and abundant (P <.001) in patients with rCDI (pre-FMT, 27 of 49 [55%]; median, 0.46 reads per kilobase per million [RPKM] pks) than in healthy donors (3 of 8 donors [37.5%], 11 of 38 samples [29%]; median, 0.01 RPKM pks). The pks status of patients post-FMT depended on the pks status of the donor suspension with which the patient was treated (P =.046). Particularly, persistence (8 of 9 cases) or clearance (13 of 18) of pks + E coli in pks + patients was correlated to pks in the donor (P =.004). We conclude that FMT contributes to pks + E coli persistence or eradication in patients with rCDI but that donor-to-patient transmission of pks + E coli is unlikely. [Display omitted] Transplantation of fecal microbiota can affect the amount of potentially cancer-causing bacteria in recipient patients. Thus, donor selection may contribute to minimizing the risk of colorectal cancer development. [ABSTRACT FROM AUTHOR]

Colibactin is a secondary metabolite encoded by the pks gene island identified in several Enterobacteriaceae, including some pathogenic Escherichia coli (E. coli) commonly enriched in mucosal tissue collected from patients with inflammatory bowel disease and colorectal cancer. E. coli harboring this biosynthetic gene cluster cause DNA damage and tumorigenesis in cell lines and pre-clinical models, yet fundamental knowledge regarding colibactin function is lacking. To accurately assess the role of pks+ E. coli in cancer etiology, the biological mechanisms governing production and delivery of colibactin by these bacteria must be elucidated. In this review, we will focus on recent advances in our understanding of colibactin's structural mode-of-action and mutagenic potential with consideration for how this activity may be regulated by physiologic conditions within the intestine. [ABSTRACT FROM AUTHOR]