Discovery of an ene-reductase for initiating flavone and flavonol catabolism in gut bacteria

Gut microbial transformations of flavonoids, an enormous class of polyphenolic compounds abundant in plant-based diets, are closely associated with human health. However, the enzymes that initiate the gut microbial metabolism of flavones and flavonols, the two most abundant groups of flavonoids, as well as their underlying molecular mechanisms of action remain unclear.

 Here, we discovered a flavone reductase (FLR) from the gut bacterium, Flavonifractor plautii ATCC 49531 (originally assigned as Clostridium orbiscindens DSM 6740), which specifically catalyses the hydrogenation of the C2–C3 double bond of flavones/flavonols and initiates their metabolism as a key step. Crystal structure analysis revealed the molecular basis for the distinct catalytic property of FLR. Notably, FLR and its widespread homologues represent a class of ene-reductases that has not been previously identified. Genetic and biochemical analyses further indicated the importance of FLR in gut microbial consumption of dietary and medicinal flavonoids, providing broader insight into gut microbial xenobiotic transformations and possible guidance for personalized nutrition and medicine.

a Proposed microbial metabolic pathway for flavones and flavonols. b A sequence similarity network (SSN) for the ene-reductases. c Crystal structure of FLR dimmer and its interface. d A screening of the substrate spectrum of FLR

Human intestinal tract hosts thousands of microbial species, and the prevalence of the flr genes in this microbial community may be due to the horizontal gene transfer. However, the factors that determine the specific distribution of these genes in the microbial community remain unclear. Nevertheless, considering that a large number of flavone and flavonol compounds have been used as clinical drugs, it seems imperative to probe the potential impact of gut microbial transformations on the efficacy of these drugs. The flr genes may be useful predictive biomarkers for assessing the flavone and flavonol drug transformation in different individuals, thereby guiding personalized medicine.

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