Discovery and characterization of a prevalent human gut bacterial enzyme sufficient for the inactivation of a family of plant toxins.

Abstract

Although the human gut microbiome plays a prominent role in xenobiotic transformation, most of the genes and enzymes responsible for this metabolism are unknown. Recently, we linked the two-gene 'cardiac glycoside reductase' (<i>cgr</i>) operon encoded by the gut Actinobacterium <i>Eggerthella lenta</i> to inactivation of the cardiac medication and plant natural product digoxin. Here, we compared the genomes of 25 <i>E. lenta</i> strains and close relatives, revealing an expanded 8-gene <i>cgr</i>-associated gene cluster present in all digoxin metabolizers and absent in non-metabolizers. Using heterologous expression and in vitro biochemical characterization, we discovered that a single flavin- and [4Fe-4S] cluster-dependent reductase, Cgr2, is sufficient for digoxin inactivation. Unexpectedly, Cgr2 displayed strict specificity for digoxin and other cardenolides. Quantification of <i>cgr2</i> in gut microbiomes revealed that this gene is widespread and conserved in the human population. Together, these results demonstrate that human-associated gut bacteria maintain specialized enzymes that protect against ingested plant toxins.