| Summary: | <b>A</b><b>bstract</b>: This study was aimed to gain new insights into the molecular mechanisms used by <i>Lactobacillus plantarum</i> WCFS1 to respond to hydroxytyrosol (HXT), one of the main and health-relevant plant phenolics present in olive oil. To this goal, whole genome transcriptomic profiling was used to better understand the contribution of differential gene expression in the adaptation to HXT by this microorganism. The transcriptomic profile reveals an HXT-triggered antioxidant response involving genes from the ROS (reactive oxygen species) resistome of <i>L. plantarum</i>, genes coding for H<sub>2</sub>S-producing enzymes and genes involved in the response to thiol-specific oxidative stress. The expression of a set of genes involved in cell wall biogenesis was also upregulated, indicating that this subcellular compartment was a target of HXT. The expression of several MFS (major facilitator superfamily) efflux systems and ABC-transporters was differentially affected by HXT, probably to control its transport across the membrane. <i>L. plantarum</i> transcriptionally reprogrammed nitrogen metabolism and involved the stringent response (SR) to adapt to HXT, as indicated by the reduced expression of genes involved in cell proliferation or related to the metabolism of (p)ppGpp, the molecule that triggers the SR. Our data have identified, at genome scale, the antimicrobial mechanisms of HXT action as well as molecular mechanisms that potentially enable <i>L. plantarum</i> to cope with the effects of this phenolic compound.
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