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’ ( cgr) operon encoded by the gut Actinobacterium Eggerthella lenta to inactivation of the cardiac medication and plant natural product digoxin. Here, we compared the genomes of 25 E. lenta strains and close relatives, revealing an expanded 8-gene cgr-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 cgr2 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.
Trillions of microbes live within the human gut and influence our health. In particular, these microbes can modify food and drugs into compounds (metabolites) that humans cannot produce on their own. These compounds are often beneficial to the human host, but in some cases – for example, if the modification alters how a drug works – can be detrimental.
Digoxin is a toxic chemical produced by plants that, in low doses, can be used to treat heart conditions. It has been known for decades that the human gut bacterium Eggerthella lenta transforms digoxin into a metabolite that is an ineffective drug. Microbes use biological catalysts called enzymes to produce metabolites, but it was not known which enzymes enable E. lenta to modify digoxin.
Using biochemical and genomic techniques, Koppel et al. now show that an enzyme called Cgr2 inactivates digoxin and other related plant toxins. Data about the gut microbes in nearly 1,900 people from three continents revealed that bacteria that can produce Cgr2 were present in the guts of more than 40% of the individuals, although often in low abundance. Further experiments did not reveal any obvious benefits that E. lenta gains from modifying digoxin. Instead, Koppel et al. propose that the bacteria carry out this modification to protect their human host from plant toxins.
The results presented by Koppel et al. emphasise that the activities of gut microbes should be considered when designing new drugs or assessing how they work in the human body. The strategies used to identify Cgr2 could now be applied to discover other important gut microbe-drug interactions. Ultimately, this knowledge will help us to predict and control the activities of gut microbes in ways that could improve human health.