Type 2 Diabetes (T2D) prevalence increases with age and affects over 13.2% of the US
population by 2020. Studies show that microbiota composition and their metabolic genes are
different between healthy and T2D patients. However, it is challenging to unravel their causal
effects on host glucose homeostasis and T2D due to the lack of an efficient system to manipulate
their levels in vivo. Recently, we were able to toggle microbiota amino acid metabolic pathways
in vivo and found that some pathways affect host glucose homeostasis. We hypothesize that the
gut bacteria impact the host amino acid pool, which will further modulate host glucose
homeostasis. Herein we will identify the microbes that actively ferment dietary amino acids and
evaluate how they affect host glucose homeostasis in diseased mouse models. We will learn
more about the role of microbiota-mediated AA metabolism in the progress of T2D. Our work will
also lay the ground for generating a synthetic and engineered gut microbial community with
defined metabolic functions to prevent and cure T2D. There are three convergent motivations:
First, many microbiota molecular features are different between healthy and T2D patients, and
we need functional studies to causally connect them with T2D. We will combine bioinformatics,
metabolomics, bacterial genetics, and a gnotobiotic mouse model to modulate microbiome
metabolic pathways in the host. This approach will boost a systematic identification of T2D-
causing microbiota genes and pathways; our findings will also promote new therapeutic strategies
by targeting these previously unknown microbial metabolic avenues.
Second, gut microbiota metabolism significantly impacts host metabolic health. However, the
molecular mechanisms behind how microbiota regulates host amino acid homeostasis and
downstream biology remain largely unexplored. We believe that this approach has huge potential:
it can be used to regulate the microbiome metabolic functions at different body sites where host
and microbes interact. Our finding would also open the door to interrogating – and ultimately
controlling – one of the most concrete contributions that gut bacteria make to host biology.
Third, a synthetic microbial community with a defined and programmable metabolic function has
therapeutic potential for T2D. The gut microbiome is part of our ‘pan-genome,’ whose metabolic
functions are more tractable by genetic manipulation or adjusting microbiota composition. Our
approach will expedite the genomic and biological characterization of microbiota metabolic genes,
laying the basis for a synthetic community with a defined and programmable metabolic function
to prevent and cure T2D and other age-related metabolic diseases.
