High Humidity Exacerbates Rheumatoid Arthritis in Mice via Prevotella stercorea-Mediated Chondroitin Sulfate...

Background: Rheumatoid arthritis (RA) is influenced by environmental exposures. High humidity has been clinically associated with worsened joint symptoms, but the microbial and metabolic mechanisms remain unclear. We investigated whether a gut microbiota-metabolism axis contributes to humidity-associated aggravation of collagen-induced arthritis (CIA). Methods: CIA mice were maintained under normal or high relative humidity. We integrated 16S rRNA and metagenomic sequencing, liquid chromatography-tandem mass spectrometry metabolomics, and intestinal barrier assessments. Fecal microbiota transplantation (FMT) was performed to evaluate microbiota dependency. Based on multi-omics findings, we quantified chondroitin sulfate (CS) and conducted functional experiments involving Prevotella stercorea (P. stercorea) supplementation, CS administration, and in vitro degradation assays. Results: High humidity aggravated arthritis severity and systemic inflammation, including increased interleukin-6, interleukin-17A, and granulocyte colony-stimulating factor, and was accompanied by impaired intestinal barrier integrity. FMT supported a microbiota-dependent contribution. Metagenomic analysis identified enrichment of P. stercorea and glycosaminoglycan degradation pathways under high humidity. CS abundance was reduced in articular cartilage, P. stercorea degraded CS in vitro and was associated with cartilage CS loss in vivo, and CS supplementation attenuated arthritis under high humidity and reduced the arthritis-promoting effects associated with P. stercorea. Conclusions: High humidity is associated with microbiota-dependent functional remodeling, enhanced CS degradation, and aggravated arthritis in CIA mice. These findings suggest that humidity-associated alterations in microbial CS metabolism may link environmental exposure to cartilage disruption and joint inflammation.