Unknown,Transcriptomics,Genomics,Proteomics

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Predicting and manipulating drug inactivation by the human gut microbiome

ABSTRACT: The trillions of microorganisms in the human gastrointestinal tract are an underexplored aspect of pharmacology. Despite numerous examples of microbial effects on drug efficacy and toxicity, there is often an incomplete understanding of the underlying mechanisms. Here, we dissect the inactivation of the commonly prescribed cardiac glycoside, digoxin, by Eggerthella lenta. Whole genome transcriptional profiling, comparative genomics, and culture-based assays revealed a cytochrome-encoding operon up-regulated by digoxin, absent in non-metabolizing E. lenta strains, and predictive of the efficiency of digoxin inactivation by the human gut microbiome. Digoxin inactivation was further enhanced by microbial interactions and inhibited by arginine. Pharmacokinetic studies using gnotobiotic mice revealed that increasing dietary protein reduces the in vivo metabolism of digoxin by E. lenta, with significant changes to drug concentration in the urine and serum. These results emphasize the importance of viewing pharmacology from the perspective of both our human and microbial genomes. RNA-Seq analysis of Eggerthella lenta cultured with or without digoxin.

ORGANISM(S): Eggerthella lenta DSM 2243

SUBMITTER: Peter Turnbaugh

PROVIDER: E-GEOD-43919 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Candida albicans is the most important fungal pathogen of humans, causing severe infections especially in nosocomial and immunocompromised settings. However, it is also the most prevalent fungus of the normal human microbiome, where it shares its habitat with hundreds of trillions of other microbial cells. Despite weak organic acids (WOAs) being among the most abundant metabolites produced by bacterial microbiota, little is known about their effect on C. albicans. Here we employed a sequencing-based profiling strategy to systematically investigate the transcriptional stress response of C. albicans to lactic, acetic, propionic and butyric acid at several time points after treatment. Our data reveal a complex transcriptional response, with individual WOAs triggering unique gene expression profiles and with important differences between acute and chronic exposure. In spite of all these dissimilarities, we found significant overlaps between the gene expression changes induced by each WOA, which lead us to uncover a core transcriptional signature that was unrelated to the general response to low pH. Genes commonly up-regulated by WOAs were enriched in several iron transporters, which was associated with an overall decrease in intracellular iron concentrations. Moreover, chronic exposure to any WOA lead to down-regulation of RNA synthesis and ribosome biogenesis genes, which resulted in significant reduction of total RNA levels in general and of ribosomal RNA in particular. In conclusion, this study suggests that GI microbiota might directly influence C. albicans physiology via production of WOAs, with possible implications of how this fungus interacts with its hosts in both health and disease. Transcriptional profiling of wild-type Candida albicans strain SC5314 under 6 differents condition (2 controls, 4 weak acids) at 4 time points by cDNA deep-sequencing, with 4 biological replicates, on the Illumina HiSeq 2000 platform. 96 total samples were sequenced (6 x 4 x 4).

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Predicting and manipulating drug inactivation by the human gut microbiome

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