Interactions between microsatellite instability and human gut colonization by Escherichia coli in colorectal cancer

2017 ◽  
Vol 131 (6) ◽  
pp. 471-485 ◽  
Author(s):  
Johan Gagnière ◽  
Virginie Bonnin ◽  
Anne-Sophie Jarrousse ◽  
Emilie Cardamone ◽  
Allison Agus ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Escherichia Coli ◽  
Microsatellite Instability ◽  
Colorectal Carcinogenesis ◽  
E Coli ◽  
Dna Mismatch ◽  
Gut Colonization ◽  
Pathogenic Escherichia Coli ◽  
Mmr Proteins

Recent studies suggest that colonization of colonic mucosa by pathogenic Escherichia coli could be involved in the development of colorectal cancer (CRC), especially through the production of genotoxins such as colibactin and/or by interfering with the DNA mismatch repair (MMR) pathway that leads to microsatellite instability (MSI). The present study, performed on 88 CRC patients, revealed a significant increase in E. coli colonization in the MSI CRC phenotype. In the same way, E. coli persistence and internalization were increased in vitro in MMR-deficient cells. Moreover, we demonstrated that colibactin-producing E. coli induce inhibition of the mutL homologue 1 (MLH1) MMR proteins, which could lead to genomic instability. However, colibactin-producing E. coli were more frequently identified in microsatellite stable (MSS) CRC. The present study suggests differences in the involvement of colibactin-producing E. coli in colorectal carcinogenesis according to the CRC phenotype. Further host–pathogen interactions studies should take into account CRC phenotypes.

scholarly journals An Escherichia coli Effector Protein Promotes Host Mutation via Depletion of DNA Mismatch Repair Proteins

mBio ◽  
2013 ◽  
Vol 4 (3) ◽  
Author(s):  
Oliver David Kenneth Maddocks ◽  
Karen Mary Scanlon ◽  
Michael S. Donnenberg
Keyword(s):  
Escherichia Coli ◽  
Host Cell ◽  
Mismatch Repair ◽  
Colorectal Carcinogenesis ◽  
Effector Protein ◽  
Repair System ◽  
Content Type ◽  
E Coli ◽  
Dna Mismatch ◽  
Mmr Proteins

ABSTRACT Enteropathogenic Escherichia coli (EPEC) is an attaching and effacing (A/E) human pathogen that causes diarrhea during acute infection, and it can also sustain asymptomatic colonization. A/E E. coli depletes host cell DNA mismatch repair (MMR) proteins in colonic cell lines and has been detected in colorectal cancer (CRC) patients. However, until now, a direct link between infection and host mutagenesis has not been fully demonstrated. Here we show that the EPEC-secreted effector protein EspF is critical for complete EPEC-induced depletion of MMR proteins. The mechanism of EspF activity on MMR protein was posttranscriptional and dependent on EspF mitochondrial targeting. EPEC infection also induced EspF-independent elevation of host reactive oxygen species levels. Moreover, EPEC infection significantly increased spontaneous mutation frequency in host cells, and this effect was dependent on mitochondrially targeted EspF. Taken together, these results support the hypothesis that A/E E. coli can promote colorectal carcinogenesis in humans. IMPORTANCE There is mounting evidence linking the gut microbiota with the induction of colorectal tumorigenesis. We previously described the downregulation of host cell mismatch repair (MMR) protein levels upon enteropathogenic Escherichia coli (EPEC) infection and speculated that this depletion may lead to an ablated DNA repair system. In this work, we identify EspF, a translocated EPEC effector protein, as one of the factors required for this phenotype and show that this effector protein must be targeted to the mitochondria in order to exert its effect. Furthermore, we found that the impaired mismatch repair system resulting from EPEC infection led to the generation of spontaneous mutations within host DNA at a site of microsatellite instability, a trait typical of colorectal tumors. Thus, this work provides a novel means by which enteric bacteria may promote colorectal carcinogenesis.

Escherichia coli and colorectal cancer: Unfolding the enigmatic relationship

2021 ◽  
Vol 22 ◽  
Author(s):  
Rogayeh Nouri ◽  
Alka Hasani ◽  
Kourosh Masnadi Shirazi ◽  
Mohammad Reza Aliand ◽  
Bita Sepehri ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Escherichia Coli ◽  
Mammalian Cells ◽  
Chromosomal Rearrangements ◽  
Current Evidence ◽  
Dna Breaks ◽  
Colon Cells ◽  
E Coli ◽  
Dna Mismatch ◽  
Double Strand Dna Breaks

: Colorectal cancer (CRC) is one of the deadliest cancers in the world. Specific strains of intestinal Escherichia coli (E. coli) may influence the initiation and development of CRC by exploiting virulence factors and inflammatory pathways. Mucosa-associated E. coli strains are more prevalent in CRC biopsies in comparison to healthy controls. Moreover, these strains can survive and replicate within macrophages and induce a pro-inflammatory response. Chronic exposure to inflammatory mediators can lead to increased cell proliferation and cancer. Production of colobactin toxin by the majority of mucosa-associated E. coli isolated from CRC patients is another notable finding. Colibactin-producing E. coli strains, in particular, induce double-strand DNA breaks, stop the cell cycle, involve in chromosomal rearrangements of mammalian cells and are implicated in carcinogenic effects in animal models. Moreover, some enteropathogenic E. coli (EPEC) strains are able to survive and replicate in colon cells as chronic intracellular pathogens and may promote susceptibility to CRC by downregulation of DNA Mismatch Repair (MMR) proteins. In this review, we discuss current evidence and focus on the mechanisms by which E. coli can influence the development of CRC.

scholarly journals Multidrug-Resistant Avian Pathogenic Escherichia coli Strains and Association of Their Virulence Genes in Bangladesh

2020 ◽  
Vol 8 (8) ◽  
pp. 1135
Author(s):  
Otun Saha ◽  
M. Nazmul Hoque ◽  
Ovinu Kibria Islam ◽  
Md. Mizanur Rahaman ◽  
Munawar Sultana ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Virulence Genes ◽  
Multidrug Resistant ◽  
Avian Pathogenic Escherichia Coli ◽  
E Coli ◽  
Molecular Approaches ◽  
Clade B ◽  
Pathogenic Escherichia Coli ◽  
Resistance Patterns

The avian pathogenic Escherichia coli (APEC) strains are the chief etiology of colibacillosis worldwide. The present study investigated the circulating phylotypes, existence of virulence genes (VGs), and antimicrobial resistance (AMR) in 392 APEC isolates, obtained from 130 samples belonged to six farms using both phenotypic and PCR-based molecular approaches. Congo red binding (CRB) assay confirmed 174 APEC isolates which were segregated into ten, nine, and eight distinct genotypes by RAPD assay (discriminatory index, DI = 0.8707), BOX-PCR (DI = 0.8591) and ERIC-PCR (DI = 0.8371), respectively. The combination of three phylogenetic markers (chuA, yjaA and DNA fragment TspE4.C2) classified APEC isolates into B23 (37.36%), A1 (33.91%), D2 (11.49%), B22 (9.20%), and B1 (8.05%) phylotypes. Majority of the APEC isolates (75–100%) harbored VGs (ial, fimH, crl, papC, and cjrC). These VGs (papC and cjrC) and phylotypes (D2 and B2) of APEC had significant (p = 0.004) association with colibacillosis. Phylogenetic analysis showed two distinct clades (clade A and clade B) of APEC, where clade A had 98–100% similarity with E. coli APEC O78 and E. coli EHEC strains, and clade B had closest relationship with E. coli O169:H41 strain. Interestingly, phylogroups B2 and D2 were found in the APEC strains of both clades, while the strains from phylogroups A1 and B1 were found in clade A only. In this study, 81.71% of the isolates were biofilm formers, and possessed plasmids of varying ranges (1.0 to 54 kb). In vitro antibiogram profiling revealed that 100% isolates were resistant to ≥3 antibiotics, of which 61.96%, 55.24%, 53.85%, 51.16% and 45.58% isolates in phylotypes B1, D2, B22, B23, and A1, respectively, were resistant to these antimicrobials. The resistance patterns varied among different phylotypes, notably in phylotype B22, showing the highest resistance to ampicillin (90.91%), nalidixic acid (90.11%), tetracycline (83.72%), and nitrofurantoin (65.12%). Correspondence analysis also showed significant correlation among phylotypes with CRB (p = 0.008), biofilm formation (p = 0.02), drug resistance (p = 0.03), and VGs (p = 0.06). This report demonstrated that B2 and A1 phylotypes are dominantly circulating APEC phylotypes in Bangladesh; however, B2 and D2 are strongly associated with the pathogenicity. A high prevalence of antibiotic-resistant APEC strains from different phylotypes suggest the use of organic antimicrobial compounds, and/or metals, and the rotational use of antibiotics in poultry farms in Bangladesh.

scholarly journals Microsatellite Instability: Diagnosis, Heterogeneity, Discordance, and Clinical Impact in Colorectal Cancer

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1567 ◽  
Author(s):  
Evrard ◽  
Tachon ◽  
Randrian ◽  
Karayan-Tapon ◽  
Tougeron
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Therapeutic Strategy ◽  
Immune Checkpoint Inhibitor ◽  
Dna Mismatch ◽  
Stage Ii Colorectal Cancer ◽  
Tumor Dna ◽  
Standard Techniques ◽  
Mmr Proteins

Tumor DNA mismatch repair (MMR) deficiency testing is important to the identification of Lynch syndrome and decision making regarding adjuvant chemotherapy in stage II colorectal cancer (CRC) and has become an indispensable test in metastatic tumors due to the high efficacy of immune checkpoint inhibitor (ICI) in deficient MMR (dMMR) tumors. CRCs greatly benefit from this testing as approximately 15% of them are dMMR but only 3% to 5% are at a metastatic stage. MMR status can be determined by two different methods, microsatellite instability (MSI) testing on tumor DNA, and immunohistochemistry of the MMR proteins on tumor tissue. Recent studies have reported a rate of 3% to 10% of discordance between these two tests. Moreover, some reports suggest possible intra- and inter-tumoral heterogeneity of MMR and MSI status. These issues are important to know and to clarify in order to define therapeutic strategy in CRC. This review aims to detail the standard techniques used for the determination of MMR and MSI status, along with their advantages and limits. We review the discordances that may arise between these two tests, tumor heterogeneity of MMR and MSI status, and possible explanations. We also discuss the strategies designed to distinguish sporadic versus germline dMMR/MSI CRC. Finally, we present new and accurate methods aimed at determining MMR/MSI status.

scholarly journals Sub-lethal Concentrations of Phytochemicals (Carvacrol and Oregano) Select for Reduced Susceptibility Mutants of Escherichia coli O23:H52

2020 ◽  
Vol 69 (1) ◽  
pp. 121-125
Author(s):  
AFNAN A. AL-MNASER ◽  
MARTIN J. WOODWARD
Keyword(s):  
Escherichia Coli ◽  
Antibiotic Resistance ◽  
Coli Strain ◽  
Whole Genome ◽  
Avian Pathogenic Escherichia Coli ◽  
Antibiotic Resistant ◽  
E Coli ◽  
Pathogenic Escherichia Coli ◽  
Survival Mechanisms

In vitro studies aimed at studying the mechanism of action of carvacrol and oregano as natural anti-bacterial agents to control multiple antibiotic-resistant avian pathogenic Escherichia coli (APEC) strain O23:H52 isolated from chicken were performed. Derivatives with increased minimum inhibitory concentrations (MIC) to the phytochemicals were selected after growing Escherichia coli (E. coli) strain O23:H52 at sub-lethal concentrations of carvacrol and oregano for a period of 60 days. Whole-genome sequencing (WGS) of two derivatives revealed a missense mutation in cadC and marR: the genes responsible for survival mechanisms and antibiotic resistance by efflux, respectively.

scholarly journals Role of Deoxyribose Catabolism in Colonization of the Murine Intestine by Pathogenic Escherichia coli Strains

2009 ◽  
Vol 77 (4) ◽  
pp. 1442-1450 ◽  
Author(s):  
Vanessa Martinez-Jéhanne ◽  
Laurence du Merle ◽  
Christine Bernier-Fébreau ◽  
Codruta Usein ◽  
Amy Gassama-Sow ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Biochemical Characterization ◽  
Pathogenic Potential ◽  
E Coli ◽  
Intestinal Epithelia ◽  
Gut Colonization ◽  
Pathogenic Escherichia Coli ◽  
Increased Risk ◽  
Evolutionary Step

ABSTRACT We previously suggested that the ability to metabolize deoxyribose, a phenotype encoded by the deoK operon, is associated with the pathogenic potential of Escherichia coli strains. Carbohydrate metabolism is thought to provide the nutritional support required for E. coli to colonize the intestine. We therefore investigated the role of deoxyribose catabolism in the colonization of the gut, which acts as a reservoir, by pathogenic E. coli strains. Molecular and biochemical characterization of 1,221 E. coli clones from various collections showed this biochemical trait to be common in the E. coli species (33.6%). However, multivariate analysis evidenced a higher prevalence of sugar-metabolizing E. coli clones in the stools of patients from countries in which intestinal diseases are endemic. Diarrhea processes frequently involve the destruction of intestinal epithelia, so it is plausible that such clones may be positively selected for in intestines containing abundant DNA, and consequently deoxyribose. Statistical analysis also indicated that symptomatic clinical disorders and the presence of virulence factors specific to extraintestinal pathogenic E. coli were significantly associated with an increased risk of biological samples and clones testing positive for deoxyribose. Using the streptomycin-treated-mouse model of intestinal colonization, we demonstrated the involvement of the deoK operon in gut colonization by two pathogenic isolates (one enteroaggregative and one uropathogenic strain). These results, indicating that deoxyribose availability promotes pathogenic E. coli growth during host colonization, suggest that the acquisition of this trait may be an evolutionary step enabling these pathogens to colonize and persist in the mammalian intestine.

scholarly journals The Polyamine Spermidine Modulates the Production of the Bacterial Genotoxin Colibactin

mSphere ◽  
2019 ◽  
Vol 4 (5) ◽  
Author(s):  
Camille V. Chagneau ◽  
Christophe Garcie ◽  
Nadège Bossuet-Greif ◽  
Sophie Tronnet ◽  
Alexander O. Brachmann ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Escherichia Coli ◽  
Colorectal Carcinogenesis ◽  
Eukaryotic Cells ◽  
Cancer Tissue ◽  
Dna Double Strand Breaks ◽  
Content Type ◽  
E Coli ◽  
Genotoxic Activity ◽  
New Perspective

ABSTRACT Colibactin is a polyketide/nonribosomal peptide produced by Escherichia coli strains that harbor the pks island. This toxin induces DNA double-strand breaks and DNA interstrand cross-links in infected eukaryotic cells. Colibactin-producing strains are found associated with colorectal cancer biopsy specimens and promote intestinal tumor progression in various murine models. Polyamines are small polycationic molecules produced by both microorganisms and eukaryotic cells. Their levels are increased in malignancies, where they contribute to disease progression and metastasis. In this study, we demonstrated that the endogenous spermidine synthase SpeE is required for full genotoxic activity of colibactin-producing E. coli. Supplying spermidine in a ΔspeE pks+ E. coli strain restored genotoxic activity. Spermidine is involved in the autotoxicity linked to colibactin and is required for direct damaging activity on DNA. The production of the colibactin prodrug motif is impaired in ΔspeE mutants. Therefore, we demonstrated that spermidine has a direct impact on colibactin synthesis. IMPORTANCE Colibactin-producing Escherichia coli strains are associated with cancerous and precancerous colorectal tissues and are suspected of promoting colorectal carcinogenesis. In this study, we describe a new interplay between the synthesis of the genotoxin colibactin and the polyamine spermidine. Polyamines are highly abundant in cancer tissue and are associated with cell proliferation. The need for spermidine in genotoxic activity provides a new perspective on the role of these metabolites in the pathogenicity of colibactin-producing E. coli strains in colorectal cancer.

scholarly journals Orally Fed Recombinant Lactococcus lactis Displaying Surface Anti-Fimbrial Nanobodies Protects Piglets against Escherichia coli Causing Post-Weaning Diarrhea

Agriculture ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 186
Author(s):  
Emmanuel Okello ◽  
Kristof Moonens ◽  
Joseph Erume ◽  
Henri De Greve
Keyword(s):  
Escherichia Coli ◽  
Lactococcus Lactis ◽  
Heavy Chain ◽  
Passive Immunization ◽  
Weaned Piglets ◽  
E Coli ◽  
Gut Colonization ◽  
Recombinant Lactococcus Lactis

Post-weaning diarrhea (PWD) and edema disease (ED), caused by enterotoxigenic and Shiga toxin producing Escherichia coli (ETEC and STEC) strains, are important diseases of newly weaned piglets worldwide. The objective of this study is to develop a passive immunization strategy to protect piglets against PWD and ED using recombinant Lactococcus lactis added to piglet diet at weaning. The Variable Heavy chain domains of Heavy chain antibodies (VHHs) or Nanobodies (Nbs), directed against the fimbrial adhesins FaeG (F4 fimbriae) and FedF (F18 fimbriae) of E. coli were cloned and expressed on the surface of L. lactis. In vitro, the recombinant L. lactis strains agglutinated and inhibited adhesion of cognate F4 or F18 fimbriae expressing E. coli to pig villous preparation. In vivo, the anti-F4 L. lactis protected weaned piglets against a challenge with an F4-positive ETEC strain. Piglets supplemented with oral anti-F4 L. lactis showed reduced fecal E. coli shedding. We concluded that the surface expressed Nanobodies on L. lactis neutralized the adhesins of targeted E. coli and abrogated gut colonization, the first step in disease pathogenesis. As a proof of concept, we demonstrated the potential of passive immunization with recombinant L. lactis as a viable alternative to antibiotic prophylaxis in preventing piglet-post-weaning diarrhea.

scholarly journals A nadA mutation confers nicotinic acid auxotrophy in pro-carcinogenic intestinal Escherichia coli NC101

2021 ◽  
Author(s):  
Lacey R. Lopez ◽  
Cassandra J. Barlogio ◽  
Christopher A. Broberg ◽  
Jeremy Wang ◽  
Janelle C. Arthur
Keyword(s):  
Colorectal Cancer ◽  
Escherichia Coli ◽  
Nicotinic Acid ◽  
Intestinal Microbiota ◽  
Inflammatory Bowel Diseases ◽  
E Coli ◽  
Functional Studies ◽  
Bowel Diseases ◽  
Inflammatory Bowel

AbstractInflammatory bowel diseases and inflammation-associated colorectal cancer are linked to blooms of adherent-invasive Escherichia coli (AIEC) in the intestinal microbiota. AIEC are functionally defined by their ability to adhere/invade epithelial cells and survive/replicate within macrophages. Changes in micronutrient availability can alter AIEC physiology and interactions with host cells. Thus, culturing AIEC for mechanistic investigations often involves precise nutrient formulation. We observed that the pro-inflammatory and pro-carcinogenic AIEC strain NC101 failed to grow in minimal media (MM). We hypothesized that NC101 was unable to synthesize a vital micronutrient normally found in the host gut. Through nutrient supplementation studies, we identified that NC101 is a nicotinic acid (NA) auxotroph. NA auxotrophy was not observed in the other non-toxigenic E. coli or AIEC strains we tested. Sequencing revealed NC101 has a missense mutation in nadA, a gene encoding quinolinate synthase A that is important for de novo NAD biosynthesis. Correcting the identified nadA point mutation restored NC101 prototrophy without impacting AIEC function, including motility and AIEC-defining survival in macrophages. Our findings, along with the generation of a prototrophic NC101 strain, will greatly enhance the ability to perform in vitro functional studies that are needed for mechanistic investigations on the role of intestinal E. coli in digestive disease.ImportanceInflammatory bowel diseases (IBD) and colorectal cancer (CRC) are significant global health concerns that are influenced by gut resident microbes, like adherent-invasive Escherichia coli (AIEC). Nutrient availability influences specialized metabolite production, AIEC-defining functional attributes, and AIEC:host interactions. NC101 is a pro-inflammatory and pro-carcinogenic AIEC strain commonly used for studies on IBD and CRC. We identified that NC101 growth in vitro requires a micronutrient found in the host gut. By correcting an identified mutation, we generated an NC101 strain that no longer has micronutrient restrictions. Our findings will facilitate future research that necessitates precise nutrient manipulation, enhancing AIEC functional studies and investigations on other auxotrophic intestinal microbiota members. Broadly, this will improve the study of bacterial:host interactions impacting health and disease.

Oligosaccharide-Mediated Inhibition of the Adhesion of Pathogenic Escherichia coli Strains to Human Gut Epithelial Cells In Vitro

2008 ◽  
Vol 71 (11) ◽  
pp. 2272-2277 ◽  
Author(s):  
J. RHOADES ◽  
K. MANDERSON ◽  
A. WELLS ◽  
A. T. HOTCHKISS ◽  
G. R. GIBSON ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Desulfovibrio Desulfuricans ◽  
Viable Count ◽  
Intestinal Epithelial ◽  
E Coli ◽  
Control Value ◽  
Pathogenic Escherichia Coli ◽  
Pectic Oligosaccharides ◽  
Ht29 Cell Line

The aim of the study was to investigate the ability of pectic oligosaccharides (POS) to inhibit adhesion of three strains of verotoxigenic Escherichia coli, three strains of enteropathogenic E. coli, and one nonclinical strain of Desulfovibrio desulfuricans to human intestinal epithelial cell cultures. Lactobacillus acidophilus and Lactobacillus gasseri were included for comparison. Attachment was determined in the human HT29 cell line by viable count of adherent bacteria. POS in buffer at pH 7.2 were antiadhesive at a dose of 2.5 mg ml−1, reducing adhesion of enteropathogenic E. coli and verotoxigenic E. coli strains to less than 30% of control values. Concentrations resulting in 50% inhibition ranged from 0.15 to 0.46 mg ml−1. L. acidophilus was not significantly affected, but adhesion of L. gasseri was reduced to 29% of the control value. POS reduced the adhesion of D. desulfuricans to 0.33% of the control value. POS also had a protective effect against E. coli verocytotoxins VT1 and VT2 at concentrations of 0.01 and 1 μgml−1, respectively.

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