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

ELife
Nitzan KoppelEmily P Balskus

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' (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.

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Datasets Mentioned

BETA
PRJNA412637
SRP018311

Methods Mentioned

BETA
biopsy
GAM
Electron paramagnetic resonance
Thermal melt
PCR
RNA-seq
electrophoresis
Protein Assay
gel filtration

Clinical Trials Mentioned

NCT03022682
NCT01967563
NCT01105143

Software Mentioned

R
BLASTP
Biostrings
DESeq2
HTSeq
clustalx
SAMtools
Bowtie
Trimmomatic
EFI

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