Hyaluronic Acid from C. Glutamicum Repairs Cartilage and Joint Injuries Molecular Weight-Dependently Via the Microbiota-Gut-joint Axis.

The microbiota-gut-joint axis influences systematic and local inflammation via the gut microbiota. Our previous investigations have revealed that hyaluronic acid (HA) with specific molecular weight (MW) affects the human gut microbiota in a simulated batch fermentation system. However, the structure-property relationships and mechanism by which HA alleviates rheumatoid arthritis (RA) by modulating the gut microbiota remain unexplored. In this study, collagen-induced arthritis (CIA) Wistar rats received HAs of different MWs (2 kDa, 300 kDa, 3000 kDa) by oral gavage. HAs MW-dependently improved osteochondral health and cartilage injury, characterized by alleviated foot swelling, enhanced motor capacity and reduced pro-inflammatory mediator levels. Muti-omics analysis of the gut microbiota and joint transcriptomic studies revealed that HAs regulate the gut microbial composition, interactions, phenotype and intestinal barrier functions. High-MW HA upregulated beneficial bacteria (i.e., Lactobacillus, Clostridium sensu stricto 1 and Turicibacter) and arginine and proline metabolism while inhibiting harmful bacteria (i.e., Desulfovibrio and the NK4A214 group) and ECM-receptor interactions. Furthermore, alleviation of RA symptoms and similar characteristics of the gut microbiota were observed in a pseudo-germ-free (PGF) rat model after fecal microbiota transplantation (FMT) from donors of the high-MW HA group. These findings proved that the gut microbiota mediates the anti-rheumatic effect of HAs on the microbiota-gut-joint axis, providing a new opportunity to understand the structure-property relationships in RA therapy.