Resolving metabolic interactions between the gut microbiota and the host with multi-omics-based modelling

Introduction

The gut microbiota is essential to human health: microorganisms in the human body help to digest nutrients, engage in host metabolism, immunity, behaviour, and brain functions. Since the gut microbiota, in contrast to the human genome, can be modified through dietary and therapeutic interventions, modulating the microbiota is a promising path to improve human health and to prevent or treat diseases.

Challenges in Understanding Microbiota

However, predicting the effects of microbiota perturbations on the host metabolic phenotype remains extremely challenging due to our limited understanding of:

1. Bacterial metabolic functions
2. Molecular interactions within microbial communities
3. The mechanisms of microbial interactions with the host

Proposed Approach

I propose to tackle these challenges with a combination of experimental and computational approaches in a synthetic community of 14 common human gut bacteria, which has been associated with over 150 health-relevant metabolites involved in amino acid, vitamin, and hormone metabolism in vivo.

Methodology

We will follow a bottom-up strategy to:

i) Systematically characterize the capacity of single bacteria to consume and produce metabolites of interest and identify the responsible enzymes.
ii) Investigate the metabolism of these compounds in compositionally diverse synthetic communities.
iii) Quantify and modulate microbiota contribution to the host metabolism of these compounds in mouse models.

Techniques and Integration

To this aim, we will combine:

• High-throughput bacterial culturing
• Metabolomics
• Transcriptomics
• Proteomics assays
• Genome-scale metabolic modelling
• Graph-based multi-omics integration methods
• Physiology-based models of microbiota-host interactions

Expected Outcomes

This project will provide a generalized framework to systematically resolve microbiota contributions to the host metabolic phenotype and elucidate the fundamental principles governing microbiota-host metabolic interactions. Thus, enabling targeted microbiota interventions to modulate the host metabolic phenotype and improve human health.