Schaerer, M. R.; Yu, Y.; Grawe, A.; Christensen, J. K.; Robinson, S. L.; Bokulich, N. A.

The growing prevalence of synthetic organofluorine substances in agrochemicals, food packaging, and consumer products has led to increasing gastrointestinal exposure, with potential consequences for human health. Despite the extreme stability of fluorinated compounds, several microbial pathways for their transformation are known, including by laccases, a type of multicopper oxidase. However, the functionality of laccases in the gut microbiome, a natural contact point between food-associated chemicals and microbial biotransformation pathways, is poorly defined. Through a multi-study analysis of 1578 human gut metagenomes spanning a global gradient from hunter-gatherer societies to industrialized urban populations, we found that laccase-coding genes are widely distributed in the human gut microbiome. We identified a significant association between both the abundance of laccase-coding genes and the phylogeny of laccase amino acid sequences with the degree of urbanization along a gut microbiome gradient from hunter-gatherer societies to highly industrialized urban populations. As gut microbial laccase activity had not been experimentally demonstrated, eight gut metagenome-derived laccases were heterologously expressed and screened for activity with a redox mediator system. Six of the eight laccases demonstrated activity. One of these gut microbial laccases and three previously characterized laccases were then tested for their capacity to biotransform 11 different food-associated chemicals. All four effectively depleted the agrochemicals cyflumetofen and fluazinam, as well as the industrial chemical bisphenol AF to a lesser extent. By linking global gut metagenomes with activity assays, this work demonstrates that microbial laccases can actively modify various agricultural and industrial chemicals.