Abstract
<title>Abstract</title> <p>Oral hyaluronan (HA) supplementation has shown clinical benefits, but its systemic effects remain insufficiently characterized. We focused on the systemic effects of oral HA (1.8 MDa) at 60 mg/day (SH60), 120 mg/day (SH120), or placebo for 12 weeks in 150 healthy donors. Within this randomized, double-blind, placebo-controlled study, plasma samples were analyzed to assess changes in immune and metabolic markers, as well as alterations in lipid metabolism, using high-quality, untargeted omics approaches with high information depth. The SH120 group significantly reduced pro-inflammatory markers, including CRP, IL-1b, and precursor of inflammatory mediators such as arachidonic acid, compared with placebo. Together with selective modulation in metabolic biomarkers, including fetuin-A, adipsin, mannopyranosyl tryptophan, 1,16-hexadecanedioic acid, and 3-hydroxydecanoic acid, supports the hypothesis that oral HA may promote an immune homeostasis and a “metabolically healthy” profile, exerting protective effects even in otherwise healthy individuals. Correlations between plasma markers and previously reported skin outcomes were generally weak, suggesting that modulation of systemic biomarkers can explain only partially the cutaneous effects of supplementation. Overall, oral HA was associated with selective changes in plasma biomarkers in healthy adults, which should be considered when evaluating the mechanisms underlying its clinical effects. Trial registration: NCT07065110.</p>