(582a) Activation of Plant Anticancer Compounds By the Gut Microbiota

Plant metabolites consumed through the diet have a broad range of chemopreventive activities, yet the effect depends on the composition of the gut microflora.  A prominent example is the glucosinolate class of compounds produced by vegetables in the genus Brassica (examples include broccoli, kale, and cabbage).[i]  These molecules are inactive ‘pro-nutrients’ that require deglycosylation to release the active nutrient.  A well-studied example is sulforaphane, which is derived from the glucosinolate glucoraphanin; this metabolite is a key player in both plant defense and human health.[ii]  The average per-person intake of glucosinolates is estimated to be 18 mg / day in the US, 50 mg / day in the UK, and several times higher in some Asian countries.[iii]  The role of gut bacteria in liberating sulforaphane is well documented, but no bacterial gene involved in glucosinolate metabolism has been identified to date.

Here we present bioinformatic analysis and biochemical characterization of a prominent gut microbe Bacteroides thetaiotaomicron (B. theta) capable of catalyzing the activation of glucosinolates.  High-resolution mass spectrometry established that sulforaphane is the primary product of glucoraphanin metabolism by B. theta.  Four independently isolated, sequenced B. theta strains exhibited differing abilities to metabolize glucosinolates, spanning 3 orders of magnitude.  Comparative genomic and transcriptomic strategies were employed toward identification of the gene responsible for this deglycosylation.  Additionally, a high-throughput screening method was developed that uses the inhibition of E. coli growth in B. theta–spent media to detect glucosinolate metabolism.  So far, a small-scale mutant screen has identified two candidate genes involved in glucosinolate activation, which has elucidated biochemical pathways related to sulforaphane release.

We conclude that B. theta acquired the ability to deglycosylate glucosinolates and release potent isothiocyanates (e.g. sulforaphane).  Further studies aim to test whether the antimicrobial and chemopreventive effects of our glucosinolate–B. theta system restrict the growth of enteric pathogens and cancerous cells in a mouse model.  The identification of specific microbial genes that process ingested plant metabolites is essential to predict how the gut microbiota influences nutrient uptake.  This type of information offers insight on how to best engineer plant-microbe interactions in the gut to lead to optimal health benefit.