Oral hyaluronan modulates small intestinal microbiota and improves metabolic health: Insights from multi-omics analysis

Dietary polysaccharides are increasingly recognized as modulators of host metabolism through intestinal interactions, yet not all exert comparable systemic effects. In this context, dietary hyaluronan (HA) is distinguished by its clinical efficacy on connective tissues. We investigated whether oral HA modulates the small-intestinal microbiome, systemic metabolome, and lipid metabolism, and compared its effects with pectin. Using a healthy murine model, we combined 16S rRNA sequencing, metabolomics, lipidomics and correlation analyses. Oral HA triggered profound and previously undescribed shifts in the small-intestinal microbiome, while pectin’s effects were markedly weaker. Both supplements increased microbial diversity, with HA specifically enriching taxa such as Turicibacter, Clostridium, and Lachnoclostridium. HA also elevated systemic metabolites, enhancing redox status. Hydroxybutyrate and related metabolites increased, consistent with enhanced lipolysis. HA reduced glycogen degradation without affecting synthesis, whereas pectin lowered glycogen synthesis without altering degradation. Notably, only HA modulated plasma and hepatic lipid metabolism, while pectin had no effect. Specifically, lipid mediators playing roles in organismal homeostasis, inflammation, and pain modulation were altered. Collectively, these findings indicate that oral HA exerts a unique effect among dietary polysaccharides on the intestinal microbiome, systemic metabolome, and lipidome