Gut microbiota drug biotransformation as a tool to unravel the mechanisms of metabolic microbiota-host interactions

The variability of the human gut microbiome (entirety of microorganisms inhabiting the intestine) far exceeds human genome variability, and has been connected to various aspects of human health.

Although microbiome differences are often linked to altered metabolism, the current view on metabolic interactions between the microbiota and the host remain mostly descriptive due to several limiting factors.

First, most sequencing-based human microbiome studies rely on correlative analyses between microbiome composition and human phenotypes, depend on largely incomplete microbial genome annotations, and are not targeted to identify community-mediated functional traits.

Second, many metabolites can be both of microbial and human origin, which makes it conceptually and methodologically challenging to disentangle metabolic microbiota-host interactions.To overcome these limitations, I propose a systematic bottom-up strategy to mechanistically study metabolic microbiota-host interactions by harnessing gut microbiotas capacity to biotransform (chemically modify) drug molecules.

The large chemical diversity and exogenous origin makes medical drugs ideally suited for experimental in vitro and in vivo approaches to probe microbiota-host interactions in a controlled way.

We will combine high-throughput culturing protocols, genetics, metabolomics measurements, genomics analyses, gnotobiotic mouse work, and computational modeling to connect interpersonal differences in microbiome composition to differences in metabolic functions of individuals gut microbiota, and ultimately link them to molecular host phenotypes.

Generating these mechanistic insights and transformational resources is essential to understand the fundamental principles of the microbiota-host relationship.

In addition, this project has direct medical relevance, as it provides actionable microbiome-based links to interpersonal differences in medical drug response, which remain a widespread problem in clinical practice.