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.

Keywords: Gut-joint axis; Microbiome-guided therapy; Multi-omics; Rheumatoid arthritis; Short-chain fatty acids; Th17/Treg balance.

Fig. 1

Triple immunomodulatory mechanisms of SCFAs in RA: Metabolic reprogramming, epigenetic modulation, and cytokine regulation. SCFAs regulate the Th17/Treg balance through three synergistic axes. These are: (i) metabolic reprogramming, (ii) epigenetic remodeling, and (iii) cytokine network modulation. Each is detailed below. Abbreviations: AMPK, AMP-activated protein kinase; mTOR, Mechanistic target of rapamycin; GPR, G protein-coupled receptor; HIF-1α, hypoxia inducible factor-1α; HDAC, Histone deacetylase; FOXP3, Forkhead box protein P3; lncRNAs, long non-coding RNAs; AS1, Antisense RNA 1; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3, NOD-, LRR- and pyrin domain-containing protein 3; RANKL, Receptor Activator of Nuclear Factor Kappa-B Ligand; OPG, Osteoprotegerin.

Fig. 2

Gut flora-SCFAs-Th17/Treg regulatory axis. This figure illustrates the pivotal role of gut microbiota-derived SCFAs, including butyric, propionic, and acetic acid, in modulating immune homeostasis and joint inflammation. SCFAs, produced by commensal bacteria such as Bacteroidetes and Firmicutes, activate receptors GPR41 and GPR43 on immune cells. This signaling promotes the differentiation and function of anti-inflammatory Tregs and the production of cytokines IL-10 and TGF-β, while inhibiting the pro-inflammatory Th17/Th1 response and the production of IL-17, TNF-α, and IFN-γ. Concurrently, SCFAs can suppress osteoclastogenesis via the RANKL pathway and modulate dendritic cell (DC) and macrophage function, thereby restoring immune balance and mitigating the inflammatory processes that characterize RA.

Fig. 3

Translational pipeline of SCFA-based therapies for RA. This flowchart illustrates the progression from mechanistic discovery to the application of precision medicine. Each stage is crucial in translating fundamental research into clinical practice, ultimately aiming to enhance patient care through personalized treatment strategies.1).Mechanistic Discovery: This is the initial phase where the underlying disease mechanisms are explored. In this context, the discovery that Short-Chain Fatty Acids (SCFAs) regulate the balance between Th17 and Treg cells is highlighted. This finding is pivotal as it provides a novel understanding of immune cell regulation, which can potentially be targeted for therapeutic interventions. 2. Preclinical Validation: Following the mechanistic discovery, the next step involves preclinical validation. This stage is critical for confirming the findings from the discovery phase under controlled laboratory conditions. The focus here is on assessing how nanoparticles can enhance the delivery to synovial joints, which is crucial for conditions like rheumatoid arthritis. The use of nanoparticles aims to improve the efficacy and specificity of drug delivery, thereby reducing side effects and enhancing treatment outcomes. 3. Clinical Development: Once the preclinical data are validated, the findings move into clinical development. This phase involves conducting clinical trials to test the safety and efficacy of the interventions in human subjects. The transition from preclinical to clinical development is marked by a rigorous process of regulatory approval and ethical considerations, ensuring that the treatments are safe and beneficial for patients. 4. Precision Medicine: The final stage in this flowchart is the implementation of precision medicine. This approach involves tailoring medical treatment to the individual characteristics of each patient. In this context, microbiome-guided dosing is emphasized, suggesting that treatment protocols can be personalized based on an individual’s microbiome composition. This personalized approach aims to optimize treatment efficacy and minimize adverse effects, leading to better patient outcomes.

Fig. 4

Schematic Representation of Multi-omics Technologies in Spatiotemporal Analysis of SCFAs in RA. This schematic diagram illustrates the application of multi-omics technologies in the spatiotemporal analysis of SCFAs in RA. The diagram is divided into four main sections, each representing a different omics technology and its specific applications in understanding the roles and therapeutic targets of SCFAs in RA. This diagram effectively captures the complex interactions between SCFAs, the microbiome, and the immune system in RA, highlighting the potential for multi-omics technologies to advance our understanding and treatment of this disease.