Dissection of the host-microbe crosstalk that controls metabolism and physiology in intestinal symbiosis

Intestinal bacteria have been associated with the most diverse aspects of our physiology, and large efforts are being undertaken to determine how the metabolic repertoire of the microbiome impacts host nutrition and health. These efforts, however, face major obstacles.

First, we have a very poor understanding of how bacterial metabolism is regulated in the different sections of the gastrointestinal tract.

It is also becoming increasingly clear that symbionts support their hosts by means that extend beyond the provision of nutrients, and these effects can hardly be predicted from metagenomic analyses.

We will use ambitious approaches borrowed from several fields, including microbiology, genetics, and cell biology, to dissect how the crosstalk between hosts and their symbionts shapes metabolism and physiology at the scale of the holobiont.

We will leverage the relevant Drosophila gastrointestinal tract and use multi-omics approaches to dissect, in mechanistic depth, how the metabolism of a model enteric bacterium is regulated in the different sections of the digestive tract (Aim 1 The microbe).

In parallel, our work suggests that symbionts exert a broad control over intestinal digestive and metabolic activities, and act potentially through host bacterial sensing and epigenetic mechanisms to play these roles. We will dissect these regulatory links in Drosophila, and investigate their conservation in mammals (Aim 2 The host).

Finally, we have evidence that hosts cooperate with their symbionts to regulate gastrointestinal transit, a vital but underappreciated factor that shapes nutrition in both partners.

We will use two-sided genetic screens to uncover the bacterial metabolites and the host factors that regulate transit, and determine if this regulation involves the gut-brain axis (Aim 3 The holobiont).

Together, these studies will bring major advances in our understanding of the nutritional and metabolic interactions between hosts and their symbionts.