Distribution and virulence of Escherichia coli harboring cyclomodulins and supplementary virulence genes isolates from clinical and environmental samples.

This study aimed to determine the prevalence of cyclomodulins (cdt, cnf, pks and cif) in Escherichia coli (E. coli) isolated from clinical and environmental samples, the presence of supplementary virulence genes (SVG), antibiotic resistance, and in vitro cytotoxicity. 413 E. coli were isolated from clinical (stool from obese subjects, normal weight subjects, children with diarrhea, and children without diarrhea; and urine from pregnant and non-pregnant women with urinary tract infections) and environmental (water and different foods) samples. PCR was performed to identify E. coli pathotypes, the four cyclomodulins, and 18 SVG; virulence score, cytotoxic assay, and antibiotic resistance assay were performed. Fifteen percent of E. coli were positive for cyclomodulins and were found in all isolation sources; however, in children with diarrhea, they were more frequent. The most frequent cyclomodulin was cdt. More DEC strains harbor cyclomodulins than non-DEC, and cyclomodulins were most frequent among aEPEC pathotype. SVG ehaC was associated with cyclomodulin-positive strains. Cyclomodulin-positive E. coli had a higher virulence score but no significant cytotoxic activity. They were slightly more resistant to antibiotics. In conclusion, cyclomodulins-positive E. coli was widely distributed in humans, food, and the environment, and they were associated with SVG ehaC, suggesting that these genes may play a role in the pathogenesis of the cyclomodulins. However, more research is needed.

Host-microbiota interactions and oncogenesis: Crosstalk and its implications in etiology.

A number of articles have discussed the potential of microbiota in oncogenesis. Several of these have evaluated the modulation of microbiota and its influence on cancer development. Even in recent past, a plethora of studies have gathered in order to understand the difference in microbiota population among different cancer and normal individuals. Although in majority of studies, microbiota mediated oncogenesis has been primarily attributed to the inflammatory mechanisms, there are several other ways through which microbiota can influence oncogenesis. These relatively less discussed aspects including the hormonal modulation through estrobolome and endobolome, production of cyclomodulins, and lateral gene transfer need more attention of scientific community. We prepared this article to discuss the role of microbiota in oncogenesis in order to provide concise information on these relatively less discussed microbiota mediated oncogenesis mechanisms.

The Role of Cyclomodulins and Some Microbial Metabolites in Bacterial Microecology and Macroorganism Carcinogenesis.

A number of bacteria that colonize the human body produce toxins and effectors that cause changes in the eukaryotic cell cycle-cyclomodulins and low-molecular-weight compounds such as butyrate, lactic acid, and secondary bile acids. Cyclomodulins and metabolites are necessary for bacteria as adaptation factors-which are influenced by direct selection-to the ecological niches of the host. In the process of establishing two-way communication with the macroorganism, these compounds cause limited damage to the host, despite their ability to disrupt key processes in eukaryotic cells, which can lead to pathological changes. Possible negative consequences of cyclomodulin and metabolite actions include their potential role in carcinogenesis, in particular, with the ability to cause DNA damage, increase genome instability, and interfere with cancer-associated regulatory pathways. In this review, we aim to examine cyclomodulins and bacterial metabolites as important factors in bacterial survival and interaction with the host organism to show their heterogeneous effect on oncogenesis depending on the surrounding microenvironment, pathological conditions, and host genetic background.

Phenotypicand Genotypic Characterization of Clinical Isolates of Intracellular Adherent-Invasive Escherichia coli Among Different Stages, Family History, and Treated Colorectal Cancer Patients in Iran.

There is increasing evidence showing that microbial dysbiosis impacts the health and cancer risk of the host. An association between adherent-invasive Escherichia coli (AIEC) and colorectal cancer (CRC) has been revealed. Cyclomodulins (CMs) have been receiving increasing attention for carcinogenic changes. In this study, the incidence and features of intracellular AIEC and cyclomodulin-encoding genes were investigated and the phylogenetic grouping and genetic relatedness were evaluated. E. coli strains were isolated from the colorectal biopsies. Adhesion and invasion assays and intramacrophage cell survival test were performed to separate the AIEC isolates. Virulence genotyping for the genes htrA, dsbA, chuA, and lpfA and the cyclomodulin toxins was also conducted. In addition, phylogenetic grouping of the isolates was determined. Subsequently, repetitive element sequence-based PCR (rep-PCR) fingerprinting was performed. A total of 24 AIEC pathovars were isolated from 150 patients. The prevalence rates of htr, dsbA, and lpfA were 70.83% and that of chuA was 91.66%. The frequencies of the cyclomodulin toxins were as follows: cnf1, 29.2%; cnf2, 25%; colibactin, 29.2%; and cdt, 4.2%; cif was not found. Among the AIEC isolates, 4.2%, 4.2%, 54.2%, 29.2%, and 8.3% with phylotypes A or C, B1, B2, D, and E were identified, respectively. Left-sided colon carcinoma and adenocarcinoma T≥1 stage (CRC2) were colonized by B2 phylogroup AIEC-producing CMs more often than the samples from the other groups. Close genetic relatedness was observed in AIEC isolates with rep-PCR.

Bacterial cyclomodulins: types and roles in carcinogenesis.

Various studies confirmed that bacterial infections contribute to carcinogenesis through the excessive accumulation of reactive oxygen species (ROS) and the expression of toxins that disrupt the cell cycle phases, cellular regulatory mechanisms and stimulate the production of tumorigenic inflammatory mediators. These toxins mimic carcinogens which act upon key cellular targets and result in mutations and genotoxicities. The cyclomodulins are bacterial toxins that incur cell cycle modulating effects rendering the expressing bacterial species of high carcinogenic potentiality. They are either cellular proliferating or cell cycle arrest cyclomodulins. Notably, cyclomodulins expressing bacterial species have been linked to different human carcinomas. For instance, Escherichia coli species producing the colibactin were highly prevalent among colorectal carcinoma patients, CagA+ Helicobacter pylori species were associated with MALT lymphomas and gastric carcinomas and Salmonella species producing CdtB were linked to hepatobiliary carcinomas. These species stimulated the overgrowth of pre-existing carcinomas and induced hyperplasia in in vivo animal models suggesting a role for the cyclomodulins in carcinogenesis. Wherefore, the prevalence and mode of action of these toxins were the focus of many researchers and studies. This review discusses different types of bacterial cyclomodulins highlighting their mode of action and possible role in carcinogenesis.

Prevalence of Cyclomodulin-Positive E. coli and Klebsiella spp. Strains in Mexican Patients with Colon Diseases and Antimicrobial Resistance.

Colon diseases, such as colorectal cancer (CRC), are multifactor diseases that affect more than one million people per year; recently, the microbiota has been associated with an etiologic factor, specifically bacterial cyclomodulin positivity (CM+). Unfortunately, there are no studies from Mexico that detail the presence of bacterial CM+ in patients with colon diseases. We therefore performed a comprehensive study to investigate the associations and prevalence of cyclomodulin-positive Diarrheagenic E. coli (DEC), non-DEC, and Klebsiella spp. strains isolated from Mexican subjects with colon diseases. In this work, we analyzed 43 biopsies, 87 different bacteria were isolated, and E. coli was the most frequently noted, followed by Klebsiella spp., and Enterococcus spp. E. coli, non-DEC, and EPEC belonging to phylogroup B2 were the most prevalent. More than 80% of E. coli and Klebsiella were CM+. pks, cdt, cnf, and cif were identified. cdt was associated with non-DEC, cif and its combinations with EPEC, as well as cdt and psk with Klebsiella. Lastly, all the CM+ bacteria were resistant to at least one antibiotic (34% were MDR, and 48% XDR). In conclusion, the high prevalence of bacterial CM+ in colon disease patients suggests that these bacteria play an important role in the genesis of these diseases.

E. coli and colorectal cancer: a complex relationship that deserves a critical mindset.

To the multiple factors that may eventually result in colorectal cancer (CRC), strains of E. coli have now been added, in particular strains producing colibactin from their polyketide synthesis (pks) locus. The evidence and mechanistic explanations for this unfortunate effect of what is in most cases a harmless commensal are discussed in the first part of this review. In the second part, observations are presented and discussed that do not fit with the hypothesis that colibactin-producing E. coli produce CRC. The last part of this review is reserved for an alternative explanation of the function of this enigmatic colibactin, a toxin that has not yet been isolated. It is hypothesized that E. coli preferentially colonizes cancerous lesions as an effect rather than a cause and that colibactin production provides a selective advantage to compete with other bacteria.

Corrigendum: Heterogeneous Family of Cyclomodulins: Smart Weapons That Allow Bacteria to Hijack the Eukaryotic Cell Cycle and Promote Infections.

[This corrects the article on p. 208 in vol. 7, PMID: 28589102.].

Heterogeneous Family of Cyclomodulins: Smart Weapons That Allow Bacteria to Hijack the Eukaryotic Cell Cycle and Promote Infections.

Some bacterial pathogens modulate signaling pathways of eukaryotic cells in order to subvert the host response for their own benefit, leading to successful colonization and invasion. Pathogenic bacteria produce multiple compounds that generate favorable conditions to their survival and growth during infection in eukaryotic hosts. Many bacterial toxins can alter the cell cycle progression of host cells, impairing essential cellular functions and impeding host cell division. This review summarizes current knowledge regarding cyclomodulins, a heterogeneous family of bacterial effectors that induce eukaryotic cell cycle alterations. We discuss the mechanisms of actions of cyclomodulins according to their biochemical properties, providing examples of various cyclomodulins such as cycle inhibiting factor, γ-glutamyltranspeptidase, cytolethal distending toxins, shiga toxin, subtilase toxin, anthrax toxin, cholera toxin, adenylate cyclase toxins, vacuolating cytotoxin, cytotoxic necrotizing factor, Panton-Valentine leukocidin, phenol soluble modulins, and mycolactone. Special attention is paid to the benefit provided by cyclomodulins to bacteria during colonization of the host.