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.
