Metabolic Feedback Inhibition Influences Metabolite Secretion by the Human Gut Symbiont Bacteroides thetaiotaomicron

Abstract

Microbial metabolism and trophic interactions between microbes give rise to complex multispecies communities in microbe-host systems. <i>Bacteroides thetaiotaomicron</i> (<i>B. theta</i>) is a human gut symbiont thought to play an important role in maintaining host health. Untargeted nuclear magnetic resonance metabolomics revealed <i>B. theta</i> secretes specific organic acids and amino acids in defined minimal medium. Physiological concentrations of acetate and formate found in the human intestinal tract were shown to cause dose-dependent changes in secretion of metabolites known to play roles in host nutrition and pathogenesis. While secretion fluxes varied, biomass yield was unchanged, suggesting feedback inhibition does not affect metabolic bioenergetics but instead redirects carbon and energy to CO₂ and H₂ Flux balance analysis modeling showed increased flux through CO₂-producing reactions under glucose-limiting growth conditions. The metabolic dynamics observed for <i>B. theta</i>, a keystone symbiont organism, underscores the need for metabolic modeling to complement genomic predictions of microbial metabolism to infer mechanisms of microbe-microbe and microbe-host interactions.<b>IMPORTANCE</b> <i>Bacteroides</i> is a highly abundant taxon in the human gut, and <i>Bacteroides thetaiotaomicron</i> (<i>B. theta</i>) is a ubiquitous human symbiont that colonizes the host early in development and persists throughout its life span. The phenotypic plasticity of keystone organisms such as <i>B. theta</i> is important to understand in order to predict phenotype(s) and metabolic interactions under changing nutrient conditions such as those that occur in complex gut communities. Our study shows <i>B. theta</i> prioritizes energy conservation and suppresses secretion of "overflow metabolites" such as organic acids and amino acids when concentrations of acetate are high. Secreted metabolites, especially amino acids, can be a source of nutrients or signals for the host or other microbes in the community. Our study suggests that when metabolically stressed by acetate, <i>B. theta</i> stops sharing with its ecological partners.