Functional diversification of plant small molecules by the gut microbiome

Plants are composed of diverse secondary metabolites (PSMs) which are widely associated with human health. Whether and how the gut microbiome mediates such impacts of PSMs are poorly understood. Here we show that discrete phenolic glycosides, abundant health-associated PSMs, are utilized by distinct members of the human gut microbiome. Within the Bacteroides, the predominant Gram-negative bacteria of the Western human gut, we reveal a specialized multi-enzyme system dedicated to the processing of distinct glycosides based on structural differences in phenolic moieties. This Bacteroides metabolic system liberates chemically-distinct aglycones with diverse biological functions such as colonization resistance against the gut pathogen Clostridioides difficile, via anti-microbial activation of polydatin to the stilbene resveratrol, and intestinal homeostasis, via activation of salicin to the immunoregulatory aglycone saligenin. Together our results demonstrate an axis of plant-microbiome interactions via generation of biological diversity of phenolic aglycone “effector” functions by a distinct gut microbiome-encoded PSM-processing system.