Loganic Acid Ameliorates Rheumatoid Arthritis via the Lactobacillus murinus-Inodole-3-Acetic Acid-AhR-IL-10 Axis

Loganic acid (LA), a major iridoid glycoside from Gentiana macrophylla Pall., possesses anti-inflammatory and immunomodulatory properties, but its therapeutic potential in rheumatoid arthritis (RA) and its interaction with the gut microbiota remain poorly defined. Here, we show that LA markedly and dose-dependently attenuates disease severity in collagen-induced arthritis mice, as evidenced by reduced clinical arthritis scores, systemic inflammatory cytokines, and synovial tissue damage. LA reshaped the gut microbiota, and fecal microbiota transplantation from LA-treated donors partially reproduced its protective effects, indicating a causal contribution of the altered microbial community. In particular, LA selectively enriched OTUs annotated as Lactobacillus murinus (L. murinus) and increased levels of the microbial tryptophan metabolite indole-3-acetic acid (IAA). Both LA and IAA activated aryl hydrocarbon receptor (AhR) signaling, suppressed tumor necrosis factor-α-induced inflammatory responses in human synoviocytes, and, in vivo, enhanced IAA-AhR-interleukin-10 (IL-10) signaling in arthritic joints. Pharmacological inhibition of AhR with CH223191 substantially reversed LA's therapeutic effects, demonstrating that AhR signaling plays a critical role in its anti-arthritic activity. Collectively, these findings demonstrate that LA protects against RA through a dual mechanism: direct activation of AhR in joint tissues and indirect reinforcement of AhR signaling through an L. murinus-associated microbial IAA axis. This study highlights a gut microbiota-metabolite-AhR pathway as a key mediator of LA's anti-arthritic effects and supports LA as a promising microbiota-informed therapeutic candidate for RA.