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

Loganic acid markedly and dose-dependently attenuated disease severity in collagen-induced arthritis (CIA) mice.

• Disease severity was assessed by clinical arthritis scores, systemic inflammatory cytokines, and synovial tissue damage.
• The attenuation of disease severity was described as both marked and dose-dependent.
• The CIA mouse model was used as the experimental system for in vivo testing.
• Loganic acid is a major iridoid glycoside derived from Gentiana macrophylla Pall.

Loganic acid reshaped the gut microbiota, and fecal microbiota transplantation (FMT) from LA-treated donors partially reproduced its protective effects.

• FMT from LA-treated donors partially reproduced the protective effects of LA in recipient CIA mice.
• This FMT result indicated 'a causal contribution of the altered microbial community' to LA's therapeutic effects.
• The gut microbiota reshaping was identified as a key component of LA's mechanism of action.

Loganic acid selectively enriched OTUs annotated as Lactobacillus murinus and increased levels of the microbial tryptophan metabolite indole-3-acetic acid (IAA).

• L. murinus was specifically identified among the gut microbiota changes induced by LA treatment.
• IAA is described as a microbial tryptophan metabolite whose levels were increased following LA treatment.
• The enrichment of L. murinus was described as selective, suggesting specificity of LA's effect on the microbiome.
• The L. murinus-IAA relationship forms what the authors call an 'L. murinus-associated microbial IAA axis.'

Both loganic acid and IAA activated aryl hydrocarbon receptor (AhR) signaling and suppressed TNF-α-induced inflammatory responses in human synoviocytes.

• Both LA and IAA were shown to activate AhR signaling.
• The suppression of inflammation was demonstrated in tumor necrosis factor-α (TNF-α)-induced inflammatory responses in human synoviocytes as an in vitro model.
• In vivo, both LA and IAA enhanced IAA-AhR-interleukin-10 (IL-10) signaling in arthritic joints.
• These findings link both the direct compound and its microbially-derived metabolite to the same signaling pathway.

Pharmacological inhibition of AhR with CH223191 substantially reversed LA's therapeutic effects, demonstrating that AhR signaling plays a critical role in LA's anti-arthritic activity.

• The AhR inhibitor used was CH223191.
• Reversal of LA's therapeutic effects upon AhR inhibition was described as 'substantial.'
• This pharmacological inhibition experiment provided mechanistic evidence that AhR is a critical mediator of LA's effects.
• The result confirms AhR signaling as necessary, not merely correlative, to LA's anti-arthritic activity.

LA's anti-arthritic mechanism operates through a dual pathway: direct AhR activation in joint tissues and indirect AhR reinforcement via the L. murinus-IAA microbial axis.

• The dual mechanism involves both direct action on joint tissue AhR and indirect action through gut microbiota-derived metabolites.
• The study highlights 'a gut microbiota-metabolite-AhR pathway as a key mediator of LA's anti-arthritic effects.'
• The authors conclude that LA represents 'a promising microbiota-informed therapeutic candidate for RA.'
• The pathway is characterized as: L. murinus enrichment → increased IAA production → AhR activation → IL-10 upregulation in arthritic joints.