Gut bacterial nutrient preferences quantified in vivo

Abstract

Great progress has been made in understanding gut microbiome’s products and their effects on health and disease. Less attention, however, has been given to the inputs that gut bacteria consume. In the first part of the thesis, we start with quantitatively examination of inputs and outputs of the mouse gut microbiome, using isotope tracing. This revealed that main input to microbial carbohydrate fermentation is dietary fiber, and to branched-chain fatty acids and aromatic metabolites is dietary protein. In addition, circulating host lactate, 3-hydroxybutyrate and urea (but not glucose or amino acids) feed the gut microbiome. To determine nutrient preferences across bacteria, we traced into genus-specific bacterial protein sequences. We find systematic differences in nutrient use: Most genera in the phylum Firmicutes prefer dietary protein, Bacteroides dietary fiber, and Akkermansia circulating host lactate. Such preferences correlate with microbiome composition changes in response to dietary modifications. Thus, diet shapes the microbiome by promoting the growth of bacteria that preferentially use the ingested nutrients (Zeng et al., 2022). Following the part I, we developed an ex vivo biochemical assay to assess protein digestibility, and we show that protein digestibility is an important determinant of circulating levels of microbiota-associated metabolites. We anticipate future efforts will be focused on understanding how different protein digestibility shape microbiome composition, and therefore regulating immune status of the gastrointestinal system. In the third part of the thesis, using a comprehensive fluxomic approach, we show that despite distinct changes in whole-body circulatory fluxes, tissue fuel preferences remain conserved in an obesity and insulin resistance model.