Dynamic multi-omics mechanisms underpinning retinol tolerance: stage-specific reconstruction of skin barrier function and host-microbiome metabolic interactions.

Background: Retinol remains an essential component in anti-aging skincare; however, a subset of users develop intolerance, characterized by compromised barrier integrity and inflammation. The temporal dynamics of how skin microbiota and host metabolism co-evolve during retinol tolerance establishment remain poorly understood. Methods: We conducted a prospective 28-day longitudinal study with 18 Chinese women (aged 25-40): 9 retinol-intolerant subjects monitored at baseline, adverse reaction phase, and tolerance establishment, while baseline data from 9 retinol-tolerant individuals served as controls. We integrated cutaneous phenotypic measurements, metagenomic sequencing, and untargeted metabolomics. Results: In the intolerant group, skin phenotype assessment revealed a distinct biphasic response-an acute phase marked by increased stratum corneum hydration, reduced sebum secretion, lower skin pH, and improved wrinkle metrics, followed by a re-equilibration phase characterized by sustained barrier restoration. Metagenomic profiling of 969 microbial species demonstrated that, although overall microbial α-diversity remained stable across time points in both groups, key taxa in the intolerant group exhibited transient "rise-and-fall" dynamics. At baseline, the intolerant group exhibited overrepresentation of Cutibacterium acnes, whereas the tolerant group was enriched in potentially protective species, including Discussion: Integrated multi-omics correlation analyses further underscored the tightly interconnected regulation of host-microbe energy metabolism, antioxidant defenses, and membrane repair in response to retinol-induced stress. These findings elucidate the temporal interplay between host and microbial processes underpinning retinol tolerance and highlight baseline biomarkers that may facilitate personalized skincare interventions.