Gut microbiota gate host exposure to metabolites from dietary Solanums

Dietary plants are molecularly rich but the fates of these compounds post-ingestion and their implications for human health are largely unknown. Here, we systematically characterized the major chemical contributions of widely consumed Solanum species (nightshades) to the human metabolome and established their mechanisms of production. Using untargeted metabolomics, we found a series of steroidal alkaloids resulting from tomatine, solanine, and chaconine that are dominant diet-derived compounds in systemic circulation following ingestion of potato and tomato. By comparing serum and tissue metabolomics of colonized and microbiome-depleted mice, we found that the gut microbiota metabolizes these compounds extensively, altering their absorption and gating host exposure to the diverse resulting metabolites. By screening metabolism with human stool samples, we established that steroidal glycoalkaloid metabolism varies inter-individually in a population. Further, using a collection of human commensal type strains, we found that a specific subset of strains in a community is responsible for steroidal glycoalkaloid metabolism, and chemical output of a community is determined by its strain-level composition. Microbial metabolism alters Solanum metabolite bioavailability and bioactivity in the context of acetylcholinesterase inhibition. The combination of dietary input and specific gut colonists dictate the composition of a variable component of the human metabolome. Our study provides insights into the molecular mechanisms of a diet-microbiome interaction and its effects on host physiology. ### Competing Interest Statement M.A.F. is a cofounder and director of Kelonia, a cofounder of Revolution Medicines, and a member of the scientific advisory boards of the Chan Zuckerberg Initiative and NGM Bio. The remaining authors declare no competing interests.