Host-Specific Adaptive Diversification of Crohn’s Disease-Associated Adherent-Invasive Escherichia coli

Elhenawy, Wael; Tsai, Caressa N.; Coombes, Brian K.

doi:10.1016/j.chom.2018.12.010

Cited by 57 publications

(85 citation statements)

References 70 publications

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“…[65][66][67] Some of these genes appear to allow for enhanced fitness across phylogenetic backgrounds under inflammatory conditions in the gut and likely encode the AIEC phenotypes that we and others have studied. 64,68,69 Together, these ideas and observations strongly suggest that the expansion of E. coli strains with AIEC characteristics likely results from an inflammatory environment.…”

Section: Discussionmentioning

confidence: 90%

“…E. coli lineages are not stably maintained within hosts-they switch hosts and even host species regularly. 55 Consequently, E. coli are not consistently exposed, over evolutionary time-scales, to the inflammatory conditions that locally and temporally select for AIEC phenotypes, 69 not even in IBD patients who experience episodes of remission and relapse. In contrast, the adherence phenotype, which was not associated with disease, showed remarkably little variability among strains, possibly because all the strains in our study were isolated from mucosal biopsies.…”

Section: Discussionmentioning

confidence: 99%

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Establishing the phenotypic basis of adherent-invasiveEscherichia coli(AIEC) pathogenicity in intestinal inflammation

Kittana

Gomes-Neto

Heck

et al. 2019

Preprint

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Background & Aims: Adherent-invasive Escherichia coli (AIEC) are enriched in ileal Crohn's disease patients and implicated in disease etiology. However, AIEC pathogenesis is poorly understood, and it is unclear if the expansion of these organisms contributes to inflammatory bowel disease (IBD). Questions also remain as to what extent the various in vitro phenotypes used to classify AIEC are pathologically relevant. Methods: We utilized a combination of in vitro phenotyping and a murine model of intestinal inflammation to systematically relate AIEC phenotypes to pathogenicity for 30 mucosa-associated humanderived E. coli strains. In vitro assays used included survival/replication in and TNF-α production by J774 macrophages as well as invasion/replication in Caco2 intestinal epithelial cells.Results: AIEC do not form a phenotypic group that is clearly separated from non-AIEC.However, E. coli strains displaying in vitro AIEC phenotypes caused, on average, more severe intestinal inflammation. Survival/replication of strains in J774 and Caco2 cells were positively correlated with disease in vivo, while adherence to Caco2 cells and TNF-α production by J774 cells were not. Importantly, co-colonization with adherent non-AIEC strains ameliorated AIECmediated disease. Conclusion: Our findings do not support the existence of an AIEC pathovar that can be clearly separated from commensal E. coli. However, intracellular survival/replication phenotypes do contribute to murine intestinal inflammation, suggesting that the AIEC overgrowth observed in human IBD makes a causal contribution to disease. The ability to differentiate pathologically-relevant AIEC phenotypes from those that are not provides an important foundation for developing strategies to predict, diagnose and treat human IBD through characterizing and modulating patient E. coli populations.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Establishing the phenotypic basis of adherent-invasiveEscherichia coli(AIEC) pathogenicity in intestinal inflammation

Kittana

Gomes-Neto

Heck

et al. 2019

Preprint

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“…Non-motile AIEC have significantly reduced virulence in in vivo models [45,46,66], and host-adapted AIEC are hyper-motile [59], suggesting flagella motility is critical in AIEC virulence. We therefore assayed the in vivo virulence of LF82 and LF82 Δ LF82_314 using an established C. elegans survival assay [66].…”

Section: Resultsmentioning

confidence: 99%

“…The mechanisms of intracellular replication remain to be elucidated, with only one protein – the oxidoreductase dsbA – known to be required [55]. In addition to canonical adhesion and invasion traits explored in the first descriptions of AIEC, biofilm formation [56–58], motility [44–46,59], and the ability to utilise short-chain fatty acids (SCFA’s) as carbon sources [59–61] are becoming understood as determinants of AIEC pathogenesis. The discovery of elevated mucosa-associated biofilms in CD patients [29] suggests biofilms may be of specific importance in AIEC pathogenesis, warranting further investigation.…”

Section: Introductionmentioning

confidence: 99%

A conserved protein, BcmA, mediates motility, biofilm formation, and host colonisation in Adherent InvasiveEscherichia coli

Cogger-Ward

Collins

McLean

et al. 2019

Preprint

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25Adherent Invasive Escherichia coli (AIEC) is a non-diarrhoeagenic intestinal E. coli pathotype 26 associated with Crohn's Disease. AIEC pathogenesis is characterised by biofilm formation, 27 adhesion to and invasion of intestinal epithelial cells, and intracellular replication within 28 epithelial cells and macrophages. Here, we identify and characterise a protein in the 29 prototypical AIEC strain LF82 which is required for efficient biofilm formation and dispersal -30 LF82_p314. LF82 ΔLF82_314 have defective swimming and swarming motility, indicating 31 LF82_p314 is important for flagellar-mediated motility, and thus surface colonisation and 32 biofilm dispersal. Flagellar morphology and chemotaxis in liquid appear unaffected by 33 deletion of LF82_314, suggesting LF82_p314 does not elicit an effect on flagella biogenesis or 34 environmental sensing. Flagellar motility has been implicated in AIEC virulence, therefore we 35 assessed the role of LF82_p314 in host colonisation using a Caenorhabditis elegans model. 36 We found that LF82 ΔLF82_314 have an impaired ability to colonise the C. elegans compared 37 to wild-type LF82. Phylogenetic analysis showed that LF82_314 is conserved in several major 38 enterobacterial pathogens, and suggests the gene may have been acquired horizontally in 39 several genera. Our data suggests LF82_p314 may be a novel component in the flagellar 40 motility pathway and is a novel determinant of AIEC colonisation. Our findings have potential 41 implications not only for the pathogenesis of Crohn's Disease, but also for the course of 42 infection in several major bacterial pathogens. We propose a new designation for LF82_314, 43 biofilm coupled to motility A, or bcmA. 44 Author summary 45 Adherent Invasive Escherichia coli (AIEC) are a group of bacteria implicated in the 46 pathogenesis of Crohn's Disease, a chronic inflammatory bowel disease with no cure. Critical 47 48 colonise the host surface using specialised, propeller-like appendages called flagella. In this 49 paper, we describe a novel protein -LF82_p314 (BcmA) -which is required for efficient 50 flagella-mediated motility and surface colonisation in AIEC. Using a nematode worm 51 (Caenorhabditis elegans) infection model, we show that LF82_p314 enables effective 52 colonisation of the C. elegans gut, suggesting a role for the protein during human infection. 53 These findings indicate BcmA is significant for initial colonisation of the human gut by AIEC, 54 and therefore the onset of Crohn's Disease. 55 Introduction 56 Crohn's Disease (CD) is a chronic and relapsing inflammatory bowel disease presenting with 57 frequent bloody diarrhoea, bowel obstruction, abdominal pain, and extraintestinal 58 manifestations affecting the eyes, skin, joints, and liver (reviewed in [1-3]). CD is a complex 59 syndrome which is understood as an unchecked and inappropriate inflammatory response to 60 intestinal bacteria, potentiated by carriage of one or several of over 180 predisposing 61 immune-related alleles [4-13] and their inter...

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“…Among these, we found dnaE and cadC , which had been identified as adaptive via direct experiments or through parallelism across hosts, suggesting that the method is capable of identifying beneficial mutations. Additionally, one of the mutational targets is rho , which has also been detected during adaptation of adherent-invasive E. coli to the mouse gut [81] and appears in a non-mutator clone.…”

Section: Partial Selective Sweeps Structure the High Polymorphism Of mentioning

confidence: 99%

Low Mutational Load Allows for High Mutation Rate Variation in Gut Commensal Bacteria

Ramiro

Durão

Bank

et al. 2019

Preprint

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Bacteria generally live in species-rich communities, such as the gut microbiota. Yet, little is known about bacterial evolution in natural ecosystems. Here, we followed the long-term evolution of commensal Escherichia coli in the mouse gut. We observe the emergence of polymorphism for mutation rate, ranging from wild-type levels to 1000-fold higher. By combining experiments, whole-genome sequencing and in silico simulations, we identify the molecular causes and evolutionary conditions that allow these hypermutators to emerge and coexist within a complex microbiota. The hypermutator phenotype is caused by mutations in DNA polymerase III, which increase mutation rate by~1000-fold (a mutation in the proofreading subunit) and stabilize hypermutator fitness (mutations in the catalytic subunit). The strong mutation rate variation persists for >1000 generations, with coexistence between lineages carrying 4 to >600 mutations. This in vivo molecular evolution pattern is consistent with deleterious mutations of~0.01-0.001% fitness effects, 100 to 1000-fold lower than current in vitro estimates. Despite large numbers of deleterious mutations, we identify multiple beneficial mutations that do not reach fixation over long periods of time. This indicates that the dynamics of beneficial mutations are not shaped by constant positive Darwinian selection but by processes leading to negative frequency-dependent or temporally fluctuating selection. Thus, microbial evolution in the gut is likely characterized by partial sweeps of beneficial mutations combined with hitchhiking of very slightly deleterious mutations, which take a long time to be purged but impose a very weak mutational load. These results are consistent with the pattern of genetic polymorphism that is emerging from metagenomics studies of the human gut microbiota, suggesting that we identified key evolutionary processes shaping the genetic composition of this community.

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Host-Specific Adaptive Diversification of Crohn’s Disease-Associated Adherent-Invasive Escherichia coli

Cited by 57 publications

References 70 publications

Establishing the phenotypic basis of adherent-invasiveEscherichia coli(AIEC) pathogenicity in intestinal inflammation

Establishing the phenotypic basis of adherent-invasiveEscherichia coli(AIEC) pathogenicity in intestinal inflammation

A conserved protein, BcmA, mediates motility, biofilm formation, and host colonisation in Adherent InvasiveEscherichia coli

Low Mutational Load Allows for High Mutation Rate Variation in Gut Commensal Bacteria

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