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

Introduction

The variability of the human gut microbiome (the 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 remains mostly descriptive due to several limiting factors.

Limitations in Current Research

1. Correlative Analyses: Most sequencing-based human microbiome studies rely on correlative analyses between microbiome composition and human phenotypes.
2. Incomplete Genome Annotations: These studies depend on largely incomplete microbial genome annotations and are not targeted to identify community-mediated functional traits.
3. Metabolite Origin: Many metabolites can be of both microbial and human origin, which makes it conceptually and methodologically challenging to disentangle metabolic microbiota-host interactions.

Proposed Strategy

To overcome these limitations, I propose a systematic bottom-up strategy to mechanistically study metabolic microbiota-host interactions by harnessing the gut microbiota’s capacity to biotransform (chemically modify) drug molecules.

Rationale for Using Medical Drugs

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

Methodology

We will combine the following approaches:

• High-throughput culturing protocols
• Genetics
• Metabolomics measurements
• Genomics analyses
• Gnotobiotic mouse work
• Computational modeling

These methods will help connect interpersonal differences in microbiome composition to differences in metabolic functions of individuals’ gut microbiota, ultimately linking them to molecular host phenotypes.

Importance of the Project

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.