Liupao Tea Extract Alleviates Rheumatoid Arthritis in Mice by Regulating the Gut–Joint Axis Mediated via Fatty Acid Metabolism

As a highly disabling chronic inflammatory disease, rheumatoid arthritis (RA) necessitates novel interventions. Liupao tea is a traditional Chinese dark tea known for its favorable anti-inflammatory properties. This study aims to elucidate the active ingredients and action mechanisms underlying the therapeutic effects of Liupao tea extract (LPTE) in RA. LPTE was preliminarily characterized by LC-MS technology. Network pharmacology and molecular docking predicted anti-RA compounds, targets, and pathways, with key compounds identified using chemical standards. The effect of LPTE on the collagen-induced arthritis mouse model was evaluated through serum biochemical analysis, micro-CT imaging, and histopathological analyses. Integrated serum metabolomics, 16S rRNA sequencing, MetOrigin analysis, SCFA metabolomics, and quantitative real-time PCR elucidated gut-joint axis mechanisms. LPTE effectively attenuated RA symptoms by reducing bone destruction and joint inflammation. Notably, LPTE reshaped gut microbiota by enriching key families such as <i>Monoglobaceae</i>, <i>Eggerthellaceae</i>, and <i>Desulfovibrionaceae</i>, thereby promoting SCFA production. Increased SCFA levels enhanced intestinal barrier integrity and exerted joint-protective and anti-inflammatory effects by upregulating tight junction proteins and activating SCFA receptors. LPTE also modulated arachidonic acid metabolism by affecting key genes such as <i>Alox5</i>, <i>Ptgs2</i>, and <i>Cbr1</i>. These effects collectively reduced the levels of pro-inflammatory cytokines and increased the expression of anti-inflammatory cytokines in joints. Additionally, quercetin, luteolin, ellagic acid, and kaempferol were identified as major anti-RA bioactive compounds in LPTE. Taken together, this study provides preliminary evidence that LPTE mitigates RA by regulating the gut-joint axis mediated via fatty acid metabolism.