Compositional changes to the commensal bacterial communities of the human gastrointestinal tract are associated with a plethora of conditions, including inflammatory bowel disease, diabetes and obesity. Manipulating the structure of these communities, termed the microbiome, represents a promising avenue of therapeutic development. Diet has the ability to change the gastrointestinal microbiome, however there is limited knowledge on how dietary compounds impact the growth of individual bacterial species and underpin community structures. This has restricted our ability for targeted modulation of the microbiome through dietary interventions, and limited the scope for microbiome-based therapies broadly.
Applying a novel high-throughput screening technique, we investigated the functional response of 22 common and phylogenetically diverse gastrointestinal bacteria to 46 dietary compounds, defining over 1000 individual isolate-compound relationships. This work highlighted strain-level growth responses and nutrient dependencies in these isolates for the first time. We identified a group of four phenolic compounds, which are associated with health in the human diet, that were inhibitory to the growth of over 80% of the bacteria tested. Widespread growth inhibition by these phenolic compounds was confirmed through screening of a further 119 commensals, with 112 (94%) isolates inhibited in the presence of at least one of the four phenolic compounds. The most inhibitory compound was quercetin, with 83 isolates (70%) inhibited. In order to investigate the impact of quercetin on microbiome community structure, we sought to identify potential bacterial interactions that may prevent this compound induced inhibition for susceptible members of the community. Genomic analyses were applied to identify isolates carrying genes predicted to be involved in quercetin metabolism. Phenotypic validation of 20 bacterial species, with the genetic potential to break down quercetin, identified four isolates able to reduce quercetin concentration by greater than 50% over 24 hours. Co-culture experiments confirmed the role of these key species in preventing inhibition of susceptible commensals by quercetin, and highlighted the potential impact of species interactions on community response to quercetin. This work has contributed foundational understandings of the bacterial metabolic interactions that may greatly impact the use of dietary interventions as microbiome therapies.