Liddicoat, C.; Edwards, R. A.; Roach, M. J.; Robinson, J. M.; Wallace, K. J.; Barnes, A. D.; Brame, J.; Heintz-Buschart, A.; Cavagnaro, T. R.; Dinsdale, E. A.; Doane, M. P.; Eisenhauer, N.; Mitchell, G.; Rai, B.; Ramesh, S.; Breed, M. F.

Microbiomes are critical to the health and functioning of humans and ecosystems. Defining \'healthy microbiomes\', however, remains elusive. More advanced knowledge exists on health associations for the compounds used or produced by microbes. Because microbes, their feedstocks and micro-environments interact synchronously, using functional genes to facilitate chemical transformations, this presents an intriguing opportunity to examine microbiomes through their potential to process compounds associated with human health. There is also growing interest in environmental microbiota that might be efficient at processing health-associated compounds because these microbes may readily transfer to humans and environmental interventions could modulate our exposure to them. Here we propose a bioenergetic mapping approach to microbiome assessments that examines the compound processing potential imprinted in human gut and environmental soil metagenomes. From shotgun metagenomics functional profiling, we derive quantitative measures of compound processing potential for human health-associated compound classes (e.g., lipids, carbohydrates) and selected biomolecules of interest (e.g., vitamins, short-chain fatty acids). We mapped microbial functions to compounds using the complexity-reducing van Krevelen bioenergetic mapping framework, based on carbon-hydrogen-oxygen stoichiometry and principal axes that explain variation in microbial distribution and chemical speciation. We found differences in compound processing potential within gut metagenomes comparing health- and disease-associated samples, including atherosclerotic cardiovascular disease, colorectal cancer, type 2 diabetes and anxious-depressive behaviors. Patterns of compound processing potential in soil metagenomes were linked with ecosystem maturity. Assessment of compound processing potential offers a new lens to explore mechanisms of microbiome-mediated human health including connections to health-promoting environmental microbiomes.