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Principal Investigator: Seth Rakoff-Nahoum
Organization: BOSTON CHILDREN'S HOSPITAL
Fiscal Year: 2024
Award: $663,173
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
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.
Terms: <Acyl CoA><Acyl Coenzyme A><Address><Affect><Autoregulation><B fragilis><B. fragilis><Bacteria><Bacteroides><Bacteroides fragilis><Basic Research><Basic Science><Bionomics><Butyrates><Cataloging><Cell Body><Cells><Clinical><Collection><Colon><Colon Cancer><Colon Carcinoma><Communities><Complex><Data><Diabetes Mellitus><Diet><Disease><Disorder><Ecology><Engineering><Fatty Acyl CoA><Feces><GI microbiome><GI microbiota><Gastrointestinal microbiota><Genes><Genetic><Glycans><Gnotobiotic><Gnotobiotics><Goals><Gram-Negative Bacteria><Health><Health Promotion><Homeostasis><Human><Human Microbiome><Immune><Immunes><Intermediary Metabolism><Intervention><Intervention Strategies><Link><Long-Chain Acyl CoA><Mediating><Metabolic><Metabolic Processes><Metabolism><Metabolite Interaction><Microbe><Mission><Modern Man><Molecular><NIAID><NIDDK><National Institute of Allergy and Infectious Disease><National Institute of Diabetes and Digestive and Kidney Diseases><Nerve Degeneration><Neuron Degeneration><Pathogenicity><Personal Satisfaction><Physiological Homeostasis><Physiology><Play><Polysaccharides><Prevention><Production><Publishing><Resistance><Role><Salutogenesis><Shapes><Source><Structure><Testing><Work><bacteria in the gut><cancer in the colon><carcinogenicity><develop therapy><diabetes><dietary><diets><digestive tract microbiome><enteric microbial community><enteric microbiome><enteric microbiota><extracellular><fitness><gastrointestinal microbial flora><gastrointestinal microbiome><gut bacteria><gut commensal><gut community><gut flora><gut microbe community><gut microbes><gut microbial community><gut microbial composition><gut microbial consortia><gut microbial species><gut microbiome><gut microbiota><gut microbiotic><gut microflora><gut-associated microbiome><host microbe association><host microbe relationship><host-microbe interactions><host-microbial interactions><host-microorganism interactions><human disease><human-associated microbiome><in vivo><intervention development><interventional strategy><intestinal biome><intestinal flora><intestinal microbes><intestinal microbiome><intestinal microbiota><intestinal microflora><intestinal tract microflora><member><microbial><microbiome><microbiome components><microbiome members><mouse model><murine model><neural degeneration><neurodegeneration><neurodegenerative><neurological degeneration><neuronal degeneration><prebiotics><promoting health><resistant><social role><stool><sugar><therapy development><translational applications><treatment development><well-being><wellbeing>