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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]

IntroductionPathogenic 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.MethodsThis 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.ResultsVirulence 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.DiscussionThese 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.

The identity and role of environmental factors in the etiology of sporadic amyotrophic lateral sclerosis (sALS) is poorly understood outside of three former high-incidence foci of Western Pacific ALS and a hotspot of sALS in the French Alps. In both instances, there is a strong association with exposure to DNA-damaging (genotoxic) chemicals years or decades prior to clinical onset of motor neuron disease. In light of this recent understanding, we discuss published geographic clusters of ALS, conjugal cases, single-affected twins, and young-onset cases in relation to their demographic, geographic and environmental associations but also whether, in theory, there was the possibility of exposure to genotoxic chemicals of natural or synthetic origin. Special opportunities to test for such exposures in sALS exist in southeast France, northwest Italy, Finland, the U.S. East North Central States, and in the U.S. Air Force and Space Force. Given the degree and timing of exposure to an environmental trigger of ALS may be related to the age at which the disease is expressed, research should focus on the lifetime exposome (from conception to clinical onset) of young sALS cases. Multidisciplinary research of this type may lead to the identification of ALS causation, mechanism, and primary prevention, as well as to early detection of impending ALS and pre-clinical treatment to slow development of this fatal neurological disease.

Leptospirosis is a globally important neglected zoonotic disease. Previous data suggest that a family of virulence-modifying (VM) proteins (PF07598) is a distinctive feature of group I pathogenic Leptospira that evolved as important virulence determinants. Here, we show that one such VM protein, LA3490 (also known as Q8F0K3), is expressed by Leptospira interrogans serovar Lai, as a secreted genotoxin that is potently cytotoxic to human cells. Structural homology searches using Phyre2 suggested that VM proteins are novel R-type lectins containing tandem N-terminal ricin B-chain-like β-trefoil domains. Recombinant LA3490 (rLA3490) and an N-terminal fragment, t3490, containing only the predicted ricin B domain, bound to the terminal galactose and N-acetyl-galactosamine residues, asialofetuin, and directly competed for asialofetuin-binding sites with recombinant ricin B chain. t3490 alone was sufficient for binding, both to immobilized asialofetuin and to the HeLa cell surface but was neither internalized nor cytotoxic. Treatment of HeLa cells with rLA3490 led to cytoskeleton disassembly, caspase-3 activation, and nuclear fragmentation, and was rapidly cytolethal. rLA3490 had DNase activity on mammalian and bacterial plasmid DNA. The combination of cell surface binding, internalization, nuclear translocation, and DNase functions indicate that LA3490 and other VM proteins evolved as novel forms of the bacterial AB domain-containing toxin paradigm.

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.

Leptospirosis is a globally important neglected zoonotic disease. Previous data suggest that a family of virulence-modifying (VM) proteins (PF07598) is a distinctive feature of group I pathogenic Leptospira that evolved as important virulence determinants. Here, we show that one such VM protein, LA3490 (also known as Q8F0K3), is expressed by Leptospira interrogans serovar Lai, as a secreted genotoxin that is potently cytotoxic to human cells. Structural homology searches using Phyre2 suggested that VM proteins are novel R-type lectins containing tandem N-terminal ricin B-chain-like β-trefoil domains. Recombinant LA3490 (rLA3490) and an N-terminal fragment, t3490, containing only the predicted ricin B domain, bound to the terminal galactose and N-acetyl-galactosamine residues, asialofetuin, and directly competed for asialofetuin-binding sites with recombinant ricin B chain. t3490 alone was sufficient for binding, both to immobilized asialofetuin and to the HeLa cell surface but was neither internalized nor cytotoxic. Treatment of HeLa cells with rLA3490 led to cytoskeleton disassembly, caspase-3 activation, and nuclear fragmentation, and was rapidly cytolethal. rLA3490 had DNase activity on mammalian and bacterial plasmid DNA. The combination of cell surface binding, internalization, nuclear translocation, and DNase functions indicate that LA3490 and other VM proteins evolved as novel forms of the bacterial AB domain-containing toxin paradigm. [ABSTRACT FROM AUTHOR]

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]

The cytolethal distending toxins (CDTs) comprise a family of intracellular-acting bacterial protein toxins whose actions upon eukaryotic cells result in several consequences, the most characteristic of which is the induction of G2/M cell cycle arrest. Most CDTs are hetero-tripartite assemblies of CdtA, CdtB, and CdtC, with CdtB required for CDT-mediated cell cycle arrest. Several lines of evidence indicate that CdtA and CdtC are required for the optimal intracellular activity of CdtB, although the exact functional roles of CdtA and CdtC remain poorly understood. The genes encoding the CDTs have been identified in a diverse array of Gram-negative pathogenic bacteria. More recently, the genes encoding several CdtB subunits have been associated with alternatively linked subunits resembling the B-subunits of pertussis toxin. Although the CDTs are generally considered to all function as bacterial genotoxins, the extent to which individual members of the CDTs employ similar mechanisms of cell surface binding, uptake, and trafficking within sensitive cells is poorly understood. Recently, data have begun to emerge suggesting differences in the molecular basis by which individual CDTs interact with and enter host cells, suggesting the possibility that CDTs possess properties reflecting the specific niches idiosyncratic to those CDT bacterial pathogens that produce them. The extent to which functional differences between individual CDTs reflect the specific requirements for intoxicating cells and tissues within the diverse range of host microenvironments colonized by CDT-producing pathogenic bacteria remains to be experimentally explored.

The cytolethal distending toxins (CDTs) comprise a family of intracellular-acting bacterial protein toxins whose actions upon eukaryotic cells result in several consequences, the most characteristic of which is the induction of G2/M cell cycle arrest. Most CDTs are hetero-tripartite assemblies of CdtA, CdtB, and CdtC, with CdtB required for CDT-mediated cell cycle arrest. Several lines of evidence indicate that CdtA and CdtC are required for the optimal intracellular activity of CdtB, although the exact functional roles of CdtA and CdtC remain poorly understood. The genes encoding the CDTs have been identified in a diverse array of Gram-negative pathogenic bacteria. More recently, the genes encoding several CdtB subunits have been associated with alternatively linked subunits resembling the B-subunits of pertussis toxin. Although the CDTs are generally considered to all function as bacterial genotoxins, the extent to which individual members of the CDTs employ similar mechanisms of cell surface binding, uptake, and trafficking within sensitive cells is poorly understood. Recently, data have begun to emerge suggesting differences in the molecular basis by which individual CDTs interact with and enter host cells, suggesting the possibility that CDTs possess properties reflecting the specific niches idiosyncratic to those CDT bacterial pathogens that produce them. The extent to which functional differences between individual CDTs reflect the specific requirements for intoxicating cells and tissues within the diverse range of host microenvironments colonized by CDT-producing pathogenic bacteria remains to be experimentally explored. [ABSTRACT FROM AUTHOR]