Bacterial exopolysaccharides mediate activation of flavin-containing monooxygenase 2 to extend lifespan in Caenorhabditis elegans

The gut microbiota plays a pivotal role in modulating host physiology and longevity through the production of microbial-derived molecules. Among these, bacterial exopolysaccharides (EPS) represent a structurally diverse group of surface polysaccharides with emerging roles in regulating host well-being. Here, we investigated the role of Lactobacillus strains with the capability to produce EPS, using Caenorhabditis elegans as a model organism. Results revealed significant lifespan extension in worms fed with EPS-producing bacteria, accompanied by improved health-span markers such as enhanced pharyngeal pumping and reduced lipofuscin accumulation. Transcriptomic profiling identified robust upregulation of the host detoxification and immune defense pathways, highlighting the flavin-containing monooxygenase gene fmo-2, as one of the major mediators of longevity and stress resistance triggered by EPS-producing lactobacilli. The effect was confirmed using fmo-2p::GFP reporter animals and was abrogated in fmo-2, hlh-30, and nhr-49 mutant backgrounds. Mechanistically, we demonstrated that EPS acts through a conserved transcriptional network that primarily relies on the activation of nhr-49/PPAR-α, with purified EPS being sufficient to activate fmo-2 expression. Our findings reveal that bacterial EPS activates host xenobiotic pathways to modulate aging, positioning it as a potential tool for microbiota-based longevity interventions. These insights show how microbial products can modulate fundamental biological processes across species, opening new strategies for age-related health interventions.