Engineering Microbiomes Using Physical-Organic Chemistry

The gut microbiome is complex: billions of bacteria from hundreds of species produce thousands of metabolites. How do we engineer such complex communities? Physical-organic chemistry—i.e. the science of establishing links between the molecular structure and function of a compound in a physical system—provides one simple approach. I will share two vignettes of this physical-organic approach: the first one studies the biological activity of a short-chain fatty acid (butyrate) and the second explores the impact of carbohydrates on the microbiome. Two of the biological activities of butyrate in the colon (suppression of proliferation of colonic epithelial stem cells and inflammation) correlate with the inhibition of histone deacetylases. Structure-activity relationships were compatible with the hypothesis that butyrate acts by binding to the Zn²⁺ in the catalytic site of histone deacetylases. In the second example, carbohydrates provide a method for tuning the composition of the microbiome and building future synbiotics (probiotics + prebiotics). These studies offer a starting point for guiding the desired outcomes from a “healthy” gut microbiome.