Genotoxicity of Escherichia coli Nissle 1917 strain cannot be dissociated from its probiotic activity

Olier, Maı̈wenn; Marcq, Ingrid; Salvador–Cartier, Christel; Sécher, Thomas; Dobrindt, Ulrich; Boury, Michèle; Bacquié, Valerie; Pénary, Marie; Gaultier, Eric; Nougayrède, Jean-Philippe; Fioramonti, Jean; Oswald, Éric

doi:10.4161/gmic.21737

Cited by 133 publications

(146 citation statements)

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“…The clb GI of E. coli is present not only in pathogenic strains (28). E. coli Nissle 1917 is a probiotic bacterium used for the treatment of ulcerative colitis (56), and its beneficial effect on the host was shown to be dependent on the presence of the clb GI (26). Understanding the role of the clb biosynthetic pathway in the bee microbiota could also point toward the ecological functions of this GI in more complex communities, such as those present in the human gut or inhabiting corals.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, natural products of animal-dwelling symbionts often reveal chemical and structural properties distinct from those of free-living microbes and thus hold promise for novel drug discovery (24,25). In Escherichia coli strains and related coliform Enterobacteriaceae, a hybrid NRPS-PKS biosynthetic gene cluster was found to be involved in symbiotic interactions in the human gut (26)(27)(28)(29). This hybrid NRPS-PKS pathway produces a family of largely uncharacterized small molecules termed "colibactin."…”

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confidence: 99%

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Gut Symbionts from Distinct Hosts Exhibit Genotoxic Activity via Divergent Colibactin Biosynthesis Pathways

Engel

Vizcaino

Crawford

2015

Appl Environ Microbiol

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e Secondary metabolites produced by nonribosomal peptide synthetase (NRPS) or polyketide synthase (PKS) pathways are chemical mediators of microbial interactions in diverse environments. However, little is known about their distribution, evolution, and functional roles in bacterial symbionts associated with animals. A prominent example is colibactin, a largely unknown family of secondary metabolites produced by Escherichia coli via a hybrid NRPS-PKS biosynthetic pathway that inflicts DNA damage upon eukaryotic cells and contributes to colorectal cancer and tumor formation in the mammalian gut. Thus far, homologs of this pathway have only been found in closely related Enterobacteriaceae, while a divergent variant of this gene cluster was recently discovered in a marine alphaproteobacterial Pseudovibrio strain. Herein, we sequenced the genome of Frischella perrara PEB0191, a bacterial gut symbiont of honey bees and identified a homologous colibactin biosynthetic pathway related to those found in Enterobacteriaceae. We show that the colibactin genomic island (GI) has conserved gene synteny and biosynthetic module architecture across F. perrara, Enterobacteriaceae, and the Pseudovibrio strain. Comparative metabolomics analyses of F. perrara and E. coli further reveal that these two bacteria produce related colibactin pathway-dependent metabolites. Finally, we demonstrate that F. perrara, like E. coli, causes DNA damage in eukaryotic cells in vitro in a colibactin pathway-dependent manner. Together, these results support that divergent variants of the colibactin biosynthetic pathway are widely distributed among bacterial symbionts, producing related secondary metabolites and likely endowing its producer with functional capabilities important for diverse symbiotic associations. C haracteristic bacterial communities colonize the digestive tracts of almost all animals and influence the health and disease of their hosts (1-4). These communities are typically dominated by specialist bacteria, which are adapted to live in the gut of their host and have evolved specific functions for symbiotic interactions. The honey bee, Apis mellifera, harbors such a characteristic gut microbiota (5). Its simple composition of only eight bacterial species makes the honey bee gut microbiota an ideal model to study the ecology and evolution of gut bacteria and to understand mutualistic, commensal, and parasitic relationships (6). Furthermore, honey bees are important pollinators for agriculture and almost all terrestrial ecosystems. Thus, it is essential to characterize the genomic capabilities of these symbiotic bacteria so as to better understand their impact on the health of their host.In the anterior part of the honey bee hindgut, two gammaproteobacteria, Gilliamella apicola and Frischella perrara, and one betaproteobacterium, Snodgrassella alvi, are the dominant members of this gut community (7-9). Comparative genomics and functional analyses have recently revealed that S. alvi and G. apicola harbor complementary metabolic pathways, co...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Gut Symbionts from Distinct Hosts Exhibit Genotoxic Activity via Divergent Colibactin Biosynthesis Pathways

Engel

Vizcaino

Crawford

2015

Appl Environ Microbiol

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“…The capacity of colibactin to engender ds DNA breaks was determined in HeLa cells by ␥-H2AX immunofluorescence analysis (5,29); this assay monitors the phosphorylation of histone H2AX, a sensitive marker of ds DNA breaks. HeLa cells (1.5 ϫ 10 4 cells in 200 l Dulbecco's modified Eagle's medium supplemented with 10% fetal calf serum, 80 g/ml gentamicin, and 0.1 unit/ml bovine insulin) were dispensed into 96-well cell culture plates.…”

Section: Methodsmentioning

confidence: 99%

The Genotoxin Colibactin Is a Determinant of Virulence in Escherichia coli K1 Experimental Neonatal Systemic Infection

et al. 2015

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Escherichia coli strains expressing the K1 capsule are a major cause of sepsis and meningitis in human neonates. The development of these diseases is dependent on the expression of a range of virulence factors, many of which remain uncharacterized. Here, we show that all but 1 of 34 E. coli K1 neonatal isolates carried clbA and clbP, genes contained within the pks pathogenicity island and required for the synthesis of colibactin, a polyketide-peptide genotoxin that causes genomic instability in eukaryotic cells by induction of double-strand breaks in DNA. Inactivation of clbA and clbP in E. coli A192PP, a virulent strain of serotype O18:K1 that colonizes the gastrointestinal tract and translocates to the blood compartment with very high frequency in experimental infection of the neonatal rat, significantly reduced the capacity of A192PP to colonize the gut, engender double-strand breaks in DNA, and cause invasive, lethal disease. Mutation of clbA, which encodes a pleiotropic enzyme also involved in siderophore synthesis, impacted virulence to a greater extent than mutation of clbP, encoding an enzyme specific to colibactin synthesis. Restoration of colibactin gene function by complementation reestablished the fully virulent phenotype. We conclude that colibactin contributes to the capacity of E. coli K1 to colonize the neonatal gastrointestinal tract and to cause invasive disease in the susceptible neonate.E scherichia coli strains belonging to phylogenetic group B2 are found with increasing frequency in the feces of healthy individuals from high-income countries (1) and are responsible for a range of extraintestinal diseases that include urinary tract infections, sepsis, pneumonia, and neonatal meningitis (2). These extraintestinal pathogenic E. coli (ExPEC) strains carry genes encoding a diverse range of virulence determinants that promote colonization, invasion, survival in the blood compartment, and the capacity to evade host defenses and damage the host (3). These virulence-enhancing genes tend to cluster on pathogenicity islands, genomic elements that facilitate dissemination by horizontal gene transfer (4). The pks genomic island is found in 30% to 40% of E. coli B2 strains and codes for the production of colibactin, a polyketide-peptide genotoxin of as-yet-unknown chemical structure that causes doublestrand (ds) breaks in DNA, leading to cell cycle arrest, chromosome instability, and increased lymphopenia in septic rodents (5-8). Carriage of the pks island is linked to long-term persistence in the gastrointestinal (GI) tract (9), and pks-bearing strains represent a high-virulence subset within the B2 group (6). The 54-kb pks island encodes nonribosomal peptide synthases, polyketide synthases, and hybrid synthases, in addition to accessory, tailoring, and editing enzymes; the clbA gene encodes a phosphopantetheinyl transferase required for colibactin synthesis, and clbP specifies a D-amino peptidase involved in colibactin maturation (10, 11). The pks island also contributes to the synthesis of siderophore...

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“…Indeed, E. coli Nissle 1917 harbors a functional pks island that induces DSBs in the host cell genome [30]. The deletion of colibactin genes to improve the biosafety of this strain resulted in the loss of antiinflammatory activities [30].…”

Section: E Coli At the Gut Microbiota Scalementioning

confidence: 99%

When our genome is targeted by pathogenic bacteria

Lemercier

2015

Cell. Mol. Life Sci.

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Eukaryotic cells repair thousands of lesions arising in the genome at each cell cycle. The most hazardous damage is likely DNA doublestrand breaks (DSB) that cleave the double helix backbone. DSBs occur naturally during T-cell receptor and immunoglobulin gene recombination in lymphocytes. DSBs can also arise as a consequence of exogenous stresses (e.g. ionizing irradiation, chemotherapeutic drugs, viruses) or oxidative processes. An increasing number of studies have reported that infection with pathogenic bacteria also alters the host genome, producing DSB and other modifications on DNA. This review focuses on recent data on bacteria-induced DNA damage and the known strategies used by these pathogens to maintain a physiological niche in the host. Even after DNA repair in infected cells, "scars" often remain on chromosomes and might generate genomic instability at the next cell division. Chronic inflammation in tissue, combined with infection and DNA damage, can give rise to genomic instability and eventually cancer. A functional link between the DNA damage response and the innate immune response has been recently established. Pathogenic bacteria also highjack the host cell cycle, often acting on the stability of the master regulator p53, or dampen the DNA damage response to support bacterial replication in an appropriate reservoir. Except in a few cases, the molecular mechanisms responsible for DNA lesions are poorly understood, although ROS release during infection is a serious candidate for generating DNA breaks. Thus, chronic or repetitive infections with genotoxic bacteria represent a common source of DNA lesions that compromise host genome integrity.

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Genotoxicity of Escherichia coli Nissle 1917 strain cannot be dissociated from its probiotic activity

Cited by 133 publications

References 39 publications

Gut Symbionts from Distinct Hosts Exhibit Genotoxic Activity via Divergent Colibactin Biosynthesis Pathways

Gut Symbionts from Distinct Hosts Exhibit Genotoxic Activity via Divergent Colibactin Biosynthesis Pathways

The Genotoxin Colibactin Is a Determinant of Virulence in Escherichia coli K1 Experimental Neonatal Systemic Infection

When our genome is targeted by pathogenic bacteria

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