The gut bacterial natural product colibactin triggers induction of latent viruses in diverse bacteria

Silpe, Justin E.; Wong, Joel W. H.; Owen, Siân V.; Baym, Michael; Balskus, Emily P.

doi:10.1101/2021.05.24.445430

Cited by 3 publications

(1 citation statement)

References 69 publications

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“…The clb gene cluster is broadly distributed across Enterobacteriaceae , and while the study of the interactions of clb + bacteria with other commensals would allow for a topical knowledge of microbe–microbe interactions, it does not allow the effects of colibactin to be distinguished from other bacterial effectors. However, with a stable analog of colibactin now in hand, it is possible to directly study the effects of colibactin decoupled from other factors produced by the diverse array of bacteria that possess the clb gene cluster …”

Section: Discussionmentioning

confidence: 99%

Probing Microbiome Genotoxicity: A Stable Colibactin Provides Insight into Structure–Activity Relationships and Facilitates Mechanism of Action Studies

et al. 2021

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Colibactin is a genotoxic metabolite produced by commensal-pathogenic members of the human microbiome that possess the clb (aka pks) biosynthetic gene cluster. clb + bacteria induce tumorigenesis in models of intestinal inflammation and have been causally linked to oncogenesis in humans. While colibactin is believed underlie these effects, it has not been possible to study the molecule directly due to its instability. Herein, we report the synthesis and biological studies of colibactin 742 (4), a stable colibactin derivative. We show that colibactin 742 (4) induces DNA interstrand-cross-links, activation of the Fanconi Anemia DNA repair pathway, and G2/M arrest in a manner similar to clb + E. coli. The linear precursor 9, which mimics the biosynthetic precursor to colibactin, also recapitulates the bacterial phenotype. In the course of this work, we discovered a novel cyclization pathway that was previously undetected in MS-based studies of colibactin, suggesting a refinement to the natural product structure and its mode of DNA binding. Colibactin 742 (4) and its precursor 9 will allow researchers to study colibactin’s genotoxic effects independent of the producing organism for the first time.

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Section: Discussionmentioning

confidence: 99%

Probing Microbiome Genotoxicity: A Stable Colibactin Provides Insight into Structure–Activity Relationships and Facilitates Mechanism of Action Studies

et al. 2021

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Role of bacteriophages in shaping gut microbial community

Mahmud,

Tamanna,

Akter

et al. 2024

Gut Microbes

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Phages are the most diversified and dominant members of the gut virobiota. They play a crucial role in shaping the structure and function of the gut microbial community and consequently the health of humans and animals. Phages are found mainly in the mucus, from where they can translocate to the intestinal organs and act as a modulator of gut microbiota. Understanding the vital role of phages in regulating the composition of intestinal microbiota and influencing human and animal health is an emerging area of research. The relevance of phages in the gut ecosystem is supported by substantial evidence, but the importance of phages in shaping the gut microbiota remains unclear. Although information regarding general phage ecology and development has accumulated, detailed knowledge on phage-gut microbe and phage-human interactions is lacking, and the information on the effects of phage therapy in humans remains ambiguous. In this review, we systematically assess the existing data on the structure and ecology of phages in the human and animal gut environments, their development, possible interaction, and subsequent impact on the gut ecosystem dynamics. We discuss the potential mechanisms of prophage activation and the subsequent modulation of gut bacteria. We also review the link between phages and the immune system to collect evidence on the effect of phages on shaping the gut microbial composition. Our review will improve understanding on the influence of phages in regulating the gut microbiota and the immune system and facilitate the development of phage-based therapies for maintaining a healthy and balanced gut microbiota.

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Ecological stochasticity and phage induction diversify bacterioplankton communities at the microscale

Szabo

Pontrelli²,

Grilli

et al. 2021

Preprint

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In many natural environments, microorganisms self-assemble around heterogeneously distributed resource patches. The growth and collapse of populations on resource patches can unfold within spatial ranges of a few hundred micrometers or less, making such microscale ecosystems hotspots of biological interactions and nutrient fluxes. Despite the potential importance of patch-level dynamics for the large-scale evolution and function of microbial communities, we have not yet been able to delineate the ecological processes that control natural populations at the microscale. Here, we addressed this challenge in the context of microbially-mediated degradation of particulate organic matter by characterizing the natural marine communities that assembled on over one thousand individual microscale chitin particles. Through shotgun metagenomics, we found significant variation in microscale community composition despite the similarity in initial species pools across replicates. Strikingly, a subset of particles was highly populated by rare chitin-degrading strains; we hypothesized that their conditional success reflected the impact of stochastic colonization and growth on community assembly. In contrast to the conserved functional structures that emerge in ecosystems at larger scales, this taxonomic variability translated to a wide range of predicted chitinolytic abilities and growth returns at the level of individual particles. We found that predation by temperate bacteriophages, especially of degrader strains, was a significant contributor to the variability in the bacterial compositions and yields observed across communities. Our study suggests that initial stochasticity in assembly states at the microscale, amplified through biotic interactions, may have significant consequences for the diversity and functionality of microbial communities at larger scales.

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The gut bacterial natural product colibactin triggers induction of latent viruses in diverse bacteria

Cited by 3 publications

References 69 publications

Probing Microbiome Genotoxicity: A Stable Colibactin Provides Insight into Structure–Activity Relationships and Facilitates Mechanism of Action Studies

Probing Microbiome Genotoxicity: A Stable Colibactin Provides Insight into Structure–Activity Relationships and Facilitates Mechanism of Action Studies

Role of bacteriophages in shaping gut microbial community

Ecological stochasticity and phage induction diversify bacterioplankton communities at the microscale

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