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Engineered bacteria can function in the mammalian gut long-term as live diagnostics of inflammation.

ABSTRACT: Bacteria can be engineered to function as diagnostics or therapeutics in the mammalian gut but commercial translation of technologies to accomplish this has been hindered by the susceptibility of synthetic genetic circuits to mutation and unpredictable function during extended gut colonization. Here, we report stable, engineered bacterial strains that maintain their function for 6 months in the mouse gut. We engineered a commensal murine Escherichia coli strain to detect tetrathionate, which is produced during inflammation. Using our engineered diagnostic strain, which retains memory of exposure in the gut for analysis by fecal testing, we detected tetrathionate in both infection-induced and genetic mouse models of inflammation over 6 months. The synthetic genetic circuits in the engineered strain were genetically stable and functioned as intended over time. The durable performance of these strains confirms the potential of engineered bacteria as living diagnostics.

SUBMITTER: Riglar DT

PROVIDER: S-EPMC5658125 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Engineered bacteria can function in the mammalian gut long-term as live diagnostics of inflammation.

Riglar David T DT Giessen Tobias W TW Baym Michael M Kerns S Jordan SJ Niederhuber Matthew J MJ Bronson Roderick T RT Kotula Jonathan W JW Gerber Georg K GK Way Jeffrey C JC Silver Pamela A PA

Nature biotechnology 20170529 7

Bacteria can be engineered to function as diagnostics or therapeutics in the mammalian gut but commercial translation of technologies to accomplish this has been hindered by the susceptibility of synthetic genetic circuits to mutation and unpredictable function during extended gut colonization. Here, we report stable, engineered bacterial strains that maintain their function for 6 months in the mouse gut. We engineered a commensal murine Escherichia coli strain to detect tetrathionate, which is ...[more]

PMID: 28553941

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Project description:The mammalian intestine provides nutrients to hundreds of bacterial species. Closely related species often harbor homologous nutrient utilization genes and cocolonize the gut, raising questions regarding the strategies mediating their stable coexistence. Here we reveal that related Bacteroides species that can utilize the mammalian glycan chondroitin sulfate (CS) have diverged in the manner in which they temporally regulate orthologous CS utilization genes. Whereas certain Bacteroides species display a transient surge in CS utilization transcripts upon exposure to CS, other species exhibit sustained activation of these genes. Remarkably, species-specific expression dynamics are retained even when the key players governing a particular response are replaced by those from a species with a dissimilar response. Bacteroides species exhibiting distinct expression behaviors in the presence of CS can be cocultured on CS. However, they vary in their responses to CS availability and to the composition of the bacterial community when CS is the sole carbon source. Our results indicate that diversity resulting from regulation of polysaccharide utilization genes may enable the coexistence of gut bacterial species using a given nutrient.Genes mediating a specific task are typically conserved in related microbes. For instance, gut Bacteroides species harbor orthologous nutrient breakdown genes and may face competition from one another for these nutrients. How, then, does the gut microbial composition maintain such remarkable stability over long durations? We establish that in the case of genes conferring the ability to utilize the nutrient chondroitin sulfate (CS), microbial species vary in how they temporally regulate these genes and exhibit subtle growth differences on the basis of CS availability and community composition. Similarly to how differential regulation of orthologous genes enables related species to access new environments, gut bacteria may regulate the same genes in distinct fashions to reduce the overlap with coexisting species for utilization of available nutrients.

Dataset Information

Engineered bacteria can function in the mammalian gut long-term as live diagnostics of inflammation.

Publications

Engineered bacteria can function in the mammalian gut long-term as live diagnostics of inflammation.

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