A new approach to attenuate breast-cancer risk may be found by exploiting the metabolic capabilities of the trillions of microbes living in the human gastrointestinal tract—the gut microbiota. Bacteria inhabiting this niche are the only known producers of phytoestrogenic enterolactone (ENL)—a metabolite associated with decreased breast-cancer risk in epidemiological studies and reduced breast-cancer tumor burden in mice. Because of compositional variation in the bacterial communities inhabiting individuals’ guts, it is difficult to forecast which people will produce ENL. As a metabolite of commonly consumed dietary lignans, the potential for ENL production may be predicted by identifying the bacterial genes encoding its synthesis. Identifying the genes responsible for the multi-step conversion of lignans to ENL will serve as a biomarker to predict individuals who may benefit from a lignan-rich diet. Some strains of Eggerthella lenta, a gut-residing Actinobacterium, can perform the first chemical reaction—benzyl-ether reduction—in the four-step pathway converting pinoresinol (PINO, one of the most consumed lignans) to ENL. To identify the gene responsible for this activity, we collected 27 strains of E. lenta and its close relatives and cultured each with PINO. In 66% of strains, we detected PINO metabolism. We next used comparative genomics to identify two genes, a reductase and a transcriptional regulator, that are only present in metabolizing strains. Heterologous expression of this reductase in non-PINO-metabolizing Escherichia coli conferred benzyl ether-reducing function. We have identified the first gene in the gut microbiome, benzyl ether reductase (ber), that encodes a secreted enzyme for the metabolism of dietary lignans. The identification of ber is the first steps towards predicting the extent of lignan bioactivation by human-associated microbial communities. We are expanding this tool by elucidating the genes responsible for the remaining three chemical transformations in the lignan-bioactivation pathway. Due to variation in the strains of bacteria inhabiting individuals’ gastrointestinal tracts, discovery of the genes encoding the lignan-to-ENL transformation is an important step towards a personalized approach to nutrition that accounts for differences in host and microbial metabolism.

Discovery of a bacterial gene in the gut microbiome encoding metabolism of dietary lignans

253rd National Meeting (2017)

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