Rapid Lymphatic Absorption of Orally Administered Low-Molecular-Weight Hyaluronic Acid: A Pathway to the Bloodstream via Mesenteric Nodes

Background: The 35 kDa low-molecular-weight hyaluronic acid (HA35) injection has shown efficacy in alleviating various types of pain, reducing inflammation and edema, and exhibiting potential in lipolysis and cosmetic applications. Compared to injectable forms, oral administration offers greater convenience and improved patient compliance. However, the absorption mechanism of orally administered low-molecular-weight hyaluronic acid (LMWHA, <100 kDa) remains poorly understood. This study investigates the absorption pathways of two LMWHA—HA35 and HA70—which differ in their cellular binding affinity but exhibit similar tissue permeability, with a particular focus on the role of the mesenteric lymphatic system. Methods: Rats were administered high oral doses of HA35 and HA70. Blood and tissue samples were collected at predefined time points following administration. The concentrations of hyaluronic acid (HA) in serum, mesenteric lymph nodes, liver, and spleen were quantified using enzyme-linked immunosorbent assay (ELISA) to monitor absorption kinetics and tissue distribution. Results: Both HA35 and HA70 were rapidly absorbed into the systemic circulation, predominantly via the mesenteric lymphatic pathway, bypassing the conventional intestinal absorption route through the portal vein and liver. HA levels in the mesenteric lymph nodes increased significantly within 30 minutes post-administration and remained elevated over time. No significant increases in free HA were observed in the liver or spleen, reinforcing lymphatic uptake as the principal route of absorption. Conclusion: In contrast to high-molecular-weight hyaluronic acid (HMWHA, >1000 kDa), which requires degradation prior to absorption, this study demonstrates for the first time that LMWHA molecules (HA35 and HA70, <100 kDa) can be directly absorbed through the intestinal lymphatic system. This alternative absorption route is significant, as it enables compounds to bypass hepatic first-pass metabolism, potentially enhancing bioavailability and prolonging systemic exposure. These findings provide new insights into the absorption mechanisms of LMWHA and suggest promising opportunities for developing oral therapeutics that leverage lymphatic transport pathways for the improved delivery of bioactive macromolecules.