Elucidating heritable, gut microbe-driven host epigenetic changes and their role in metabolic disease susceptibility

The trillions of microbes within our gut play crucial roles in human health and disease. Changes in gut microbiota are associated with metabolic diseases, including type 2 diabetes and obesity.

My host has shown that gut microbiota and metabolites regulate the host epigenome in a diet-dependent manner, and isolated studies have shown that early life environments impact gut microbial community composition, host epigenetic programming, and metabolic disease susceptibility across generations.

However, no studies have linked these phenomena together.

I propose to determine 1) whether the maternal microbiome impacts the epigenome of offspring and the heritability across generations, 2) the impact of diet on the gut microbe-host epigenome relationship, and 3) the role of heritable gut microbe-driven epigenetic changes on susceptibility to metabolic disease.

I will use a tissue bank consisting of >400 neonatal and adult male and female mice across 4 generations, 3 microbial conditions, and 2 diets using histone proteomics, transcriptomics, and metabolomics in the Mostoslavsky and Krautkramer groups at the Massachusetts General Hospital/Harvard Medical School.

This work will provide key knowledge about gut microbial control of the host epigenome across generations and its impact on susceptibility to metabolic disease and will reveal novel microbe- and epigenome-based therapeutic targets to combat metabolic disease.