Hyaluronic acid alleviates rheumatoid arthritis symptoms in a molecular weight-dependent manner by modulating gut microbial composition and intestinal barrier functions via the microbiota-gut-joint axis, as confirmed by fecal microbiota transplantation experiments.
Key Findings
Results
Oral administration of hyaluronic acid (HA) improved osteochondral health and cartilage injury in collagen-induced arthritis (CIA) rats in a molecular weight-dependent manner.
CIA Wistar rats received HAs of three different molecular weights (2 kDa, 300 kDa, and 3000 kDa) by oral gavage.
Improvements were characterized by alleviated foot swelling, enhanced motor capacity, and reduced pro-inflammatory mediator levels.
Effects were observed to be MW-dependent, with higher molecular weight HAs showing greater efficacy.
Results
High-molecular-weight HA upregulated beneficial gut bacteria while inhibiting harmful bacteria in CIA rats.
Beneficial bacteria upregulated by high-MW HA included Lactobacillus, Clostridium sensu stricto 1, and Turicibacter.
Harmful bacteria inhibited included Desulfovibrio and the NK4A214 group.
Multi-omics analysis of gut microbiota was used to characterize these compositional changes.
Results
HA treatment modulated gut microbial composition, microbial interactions, phenotype, and intestinal barrier functions in a molecular weight-dependent manner.
Multi-omics analysis of gut microbiota and joint transcriptomic studies were used to reveal these effects.
High-MW HA upregulated arginine and proline metabolism pathways.
High-MW HA inhibited ECM-receptor interaction pathways.
Changes in intestinal barrier functions were among the key mechanisms identified.
Results
Fecal microbiota transplantation (FMT) from high-MW HA-treated donors reproduced alleviation of RA symptoms in pseudo-germ-free (PGF) recipient rats.
PGF rats received FMT from donors in the high-MW HA treatment group.
Recipients showed alleviation of RA symptoms similar to that observed in the original high-MW HA treatment group.
Similar characteristics of the gut microbiota were observed in FMT recipients compared to donors.
This experiment confirmed that gut microbiota mediates the anti-rheumatic effect of HA.
Results
The gut microbiota was identified as a mediator of the anti-rheumatic effects of HA on the microbiota-gut-joint axis.
The microbiota-gut-joint axis influences systematic and local inflammation via the gut microbiota.
FMT experiments provided direct evidence that gut microbiota mediates the anti-rheumatic effects of HA.
The findings provide insight into structure-property relationships of HA in RA therapy.
The study builds on prior work showing that HA with specific molecular weights affects human gut microbiota in simulated batch fermentation systems.
What This Means
This research suggests that hyaluronic acid (HA), a naturally occurring molecule often used in joint health products, can reduce symptoms of rheumatoid arthritis when taken orally, and that its effectiveness depends on the size (molecular weight) of the HA molecules. In rats with experimentally induced arthritis, larger HA molecules were more effective at reducing joint swelling, improving movement, and lowering inflammation compared to smaller molecules. The researchers found that HA appears to work partly by changing the community of bacteria living in the gut — increasing helpful bacteria like Lactobacillus and decreasing harmful ones like Desulfovibrio — and by strengthening the intestinal barrier.
To confirm that the gut bacteria were actually responsible for these benefits, the researchers performed fecal microbiota transplants: they transferred gut bacteria from HA-treated rats into rats that had their own gut bacteria cleared. The recipient rats showed similar improvements in arthritis symptoms, demonstrating that the gut microbiome plays a key role in carrying the anti-inflammatory effects of HA to the joints — a pathway sometimes called the 'microbiota-gut-joint axis.' High-molecular-weight HA also influenced metabolic pathways related to amino acids (arginine and proline) and reduced signals that drive tissue damage in joints.
This research suggests that the molecular size of HA in food or supplement products matters significantly for its health effects, and that at least part of how oral HA may benefit joint health is through reshaping gut bacterial communities rather than through direct absorption into the joints. These findings could inform future development of HA-based dietary strategies or therapies for inflammatory joint conditions, though further research in humans would be needed.
Zhu H, Gao X, Zhou X, Qian H, Yang Z, Liu Y. (2026). Hyaluronic acid from C. glutamicum repairs cartilage and joint injuries molecular weight-dependently via the microbiota-gut-joint axis.. Food & function. https://doi.org/10.1039/d6fo02328b