Traditional Chinese medicine and plant metabolites for rheumatoid arthritis via modulating gut microbiota: a scoping review evaluating the transition from correlation to causality.

BACKGROUND

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovitis. The "gut-joint axis" proposes gut microbiota and metabolites modulate RA inflammation via mucosal and systemic immune responses. Botanical drugs (Traditional Chinese Medicine, TCM) and plant metabolites offer multi-target potential. However, most studies remain descriptive, demonstrating concurrent microbial shifts but lacking causal designs to verify mechanistic necessity.

OBJECTIVES

This scoping review examines TCM and plant metabolite interventions on RA gut microecology (2015-2025), focusing on the "microbiota-metabolite-immune" axis. It aims to classify evidence based on causal design rigor and identify steps to advance research from correlation to causality.

METHODS

We searched PubMed, Embase, and Web of Science (2015-2025). Studies reporting RA outcomes and gut microbiota changes following TCM interventions were included. We established a hierarchical classification system based on design rigor: antibiotic depletion (ABX), fecal microbiota transplantation (FMT), metabolite rescue, and blocking. Evidence was stratified: Level A (Closed-loop: ABX + FMT + rescue/blocking), Level A+ (plus in vitro blocking), Level B (Partial: ABX/FMT alone), and Level C (Correlational).

RESULTS

Of 25 included studies (24 animal, 1 clinical), only 2 were Level A, 1 Level A+, 3 Level B, and 19 Level C. While TCM improved RA phenotypes and altered microbiota, complete closed-loop verification remains rare. Short-chain fatty acids (SCFAs) show promise but inconsistent trends due to heterogeneity. Bile acids and tryptophan metabolites correlate with reduced inflammation, yet their mechanistic necessity remains largely untested.

CONCLUSION

Botanical drugs and plant metabolites demonstrate potential in modulating gut microbiota to improve RA. However, definitive causal links remain underexplored. Future research should prioritize "shortest closed-loop" strategies, including targeted quantification, rescue, and necessity validations. Longitudinal designs and systemic immune metrics are essential to transition from correlations to translatable mechanisms.