ABSTRACT 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.
Tan et al. (2026) studied this question.