Leveraging glycan-metabolite interactions to shape structure and function of the gut microbiome

SUMMARY. From initially cataloging the microbiome, we can now causally link specific strains and metabolites of the microbiome with protective and pathogenic roles in a broad range of human disease. We are now faced with the challenge of shaping beneficial microbiomes, such as at the strain-level, and enhancing microbiome function, such as levels of microbiome-derived factors critical to the host, in order to harness the potential of the microbiome for human health. The Bacteroides are the most abundant Gram-negative bacteria of the human gut and play central roles in health and disease at the genus-, species- and strain- level, such as the role of pro- carcinogenic B. fragilis EBTF+ strains in colon cancer. This motivates the need of both a comprehensive understanding of the ecological factors impacting the Bacteroides and interventions to shape pro-health Bacteroides communities. The Bacteroides survive by utilizing glycans, the basis for using ‘prebiotic’ dietary glycans to target specific beneficial gut microbes such as members of the Bacteroides. Here, we reveal that butyrate, abundant in the gut and critical to host physiology, demonstrates strain-specific inhibition against the Bacteroides. Remarkably, butyrate inhibition is glycan dependent. Depending on the specific glycan used, a strain is rendered differentially vulnerable to butyrate. Within a Bacteroides species, the same glycan can render one strain vulnerable to butyrate and the other protected, suggesting that specific glycan-butyrate combinations may be exploited to enhance or suppress specific Bacteroides strains. Defense from butyrate is mediated by the activity of Acyl-CoA metabolic genes which differ among the Bacteroides. Unexpectedly, we find that extracellular butyrate is taken up and metabolized by members of the Bacteroides, demonstrating the Bacteroides as one of the first gut bacteria to take up butyrate and act as a potential microbial butyrate ‘sink’. Our findings revealing the impact of butyrate on the glycan-dependent and strain-specific survival of the Bacteroides and the ability of the Bacteroides to take-up and metabolize butyrate drive our central hypotheses: butyrate impacts the Bacteroides in vivo, we can leverage dietary glycan-butyrate interactions to shape strain-specific Bacteroides communities, and the Bacteroides modulate butyrate levels in the gut. To test these, we propose to: Aim 1. Define the impact of butyrate on the composition of the Bacteroides in vivo Aim 2. Determine the role of the Bacteroides in butyrate homeostasis in the gut Successful completion of this proposal will establish a new function for butyrate in gut microbial ecology, develop needed interventions to enhance/suppress Bacteroides strains by exploiting glycan-butyrate interactions, and establish both the role of microbial ‘sinks’ in gut butyrate homeostasis and the Bacteroides as a target to optimize butyrate levels in vivo. Our work is poised to have broad impact for our understanding of microbial ecology, diet- microbe-host interactions, microbial metabolism, and colonic health, with potential wide-ranging translational applications to shape Bacteroides communities and optimize butyrate levels in heath and disease.