Short-chain fatty acids from gut microbiota restore Th17/Treg balance in rheumatoid arthritis: Mechanisms and therapeutic potential

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by synovial inflammation and joint destruction. Dysregulation of the Th17/Treg balance is a key immunological hallmark of RA. Emerging evidence highlights the critical role of gut microbiota-derived short-chain fatty acids (SCFAs) in maintaining immune homeostasis. This review systematically elucidates how SCFAs modulate the Th17/Treg equilibrium through three synergistic mechanisms: (1) metabolic reprogramming via AMPK/mTOR signaling, (2) epigenetic regulation by inhibiting HDAC, and (3) modulation of cytokine cascades. We integrate preclinical and clinical evidence showing that SCFAs reduce synovial inflammation by suppressing NLRP3 inflammasome activation, resulting in a 70 % decrease in IL-1β levels, while enhancing Treg suppressive function with a threefold increase in IL-10. Notably, butyrate exhibits circadian fluctuations that negatively correlate with morning stiffness severity (r = −0.82, p < 0.01), suggesting novel chronotherapeutic opportunities. Therapeutically, we evaluate promising microbiota-targeted strategies including high-fiber diets (which increase butyrate levels by 240 % and reduce Disease Activity Score 28 (DAS28) by 1.8 points), engineered nanoparticle delivery systems (achieving 89 % colonic retention), probiotic interventions (Bifidobacterium-mediated reduction of CCR9-positive Th17 cells), and precision combination therapies (showing a 40 % greater efficacy than monotherapy). Our work establishes a comprehensive translational roadmap, spanning molecular insights to clinical applications. We propose microbiome-guided personalized medicine as a paradigm shift in RA management, supported by the first systematic integration of multi-omics methods-metabolomics, single-cell sequencing, and spatial transcriptomics-to decode the gut-joint axis and identify actionable therapeutic targets for this refractory autoimmune condition.