Defining the Quantitative Functional Mechanisms that Underly Gut Microbiome-Diet Interactions Contributing to Human Energy Balance

Project Summary The obesity epidemic continues to afflict populations globally. The literature is replete with observational studies purporting a role of the gut microbiome in body weight regulation. The main gap in the development of microbiome-targeted therapeutics to treat obesity is a deep understanding of the causal mechanisms by which

microbes impact energy balance in humans. In a first of its kind study, we implemented a quantitative bioenergetics paradigm in which human energy balance was deeply and precisely phenotyped (energy intake, expenditure and fecal energy loss) during an inpatient randomized controlled crossover feeding study. We

used diets that delivered minimal (Western Diet; WD) versus high (Microbiome Enhancer Diet; MBD) amounts of microbiota fermentable dietary substrates to the colon to reprogram the gut microbiome within individuals. We uncovered diet-host-microbe interactions that impacted human energy balance via increased fecal energy

loss and thus, lower metabolizable energy (ME) that was due in part to an increase in microbial biomass on the MBD as compared to the WD. To advance this work, we need to understand the quantitative and functional mechanisms by which the gut microbiome impacts ME when exposed to different diets. We propose two aims

to accomplish this. In Aim 1A, we will determine the amount of fecal energy loss that is due to shunting of energy from the human diet towards biomass expansion (and thus away from the host) to test the hypothesis that the dietary energy diverted from host towards biomass expansion is large enough to promote lower ME

(net negative energy balance) on the MBD vs. the WD. In Aim 1B, we will perform absolute quantification of microbial species to determine which ones are the dominant players in biomass expansion and their proportional contribution to fecal biomass energy. In Aim 2A, we will implement a novel integrated multi-omics

workflow aimed at determining microbial functions and substrate preferences in vivo. These data will tell us what the microbes “eat”, which specific species compete for the same dietary substrates, and the associated functions of the microbial community when specific dietary substrates are available. These data will be

validated in Aim 2B by performing ex vivo experiments to change the absolute abundance of specific microbes that contribute most to biomass by addition of the preferred substrates of those microbes. The overall outcome of this project is that we will have an unprecedented understanding of the quantitative microbial mechanisms

that drive human energy balance.