Molecular mechanisms behind microbiota regulation of host amino acid and glucose homeostasis

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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.