Reframing Osteoarthritis Therapy Through the Gut– <scp>GUDCA</scp> – <scp>FXR</scp> – <scp>GLP1</scp> Pathway: Opportunities and Limitations

Recent advances in immunometabolism and rheumatology have highlighted the role of gut-derived signals in modulating joint health. In particular, Yang et al. proposed that osteoarthritis (OA) may be influenced by intestinal bile acid metabolism through a mechanistic cascade involving the gut microbiota, Glycoursodeoxycholic acid (GUDCA), intestinal Farnesoid X receptor (FXR), and Glucagon-like peptide 1 (GLP-1) signaling. This emerging gut-to-joint communication axis invites new thinking about the pathogenesis and treatment of rheumatic diseases. The gut microbiome plays a crucial role in regulating systemic immunity and metabolism, primarily through its modulation of the bile acid (BA) pool. It influences the composition and transformation of both primary and secondary bile acids. This process was previously thought to occur only in the liver, but recent studies have shown that gut bacteria also perform these transformations, increasing the diversity of bile acids [1-3]. Secondary bile acids play crucial roles in modulating immune cell function and differentiation, impacting systemic immunity [4]. Recent findings further suggest that bile acids act as immunoregulatory signals in the gut environment, shaping both innate and adaptive immune responses by promoting regulatory T cell differentiation and suppressing pro-inflammatory T helper cell development [5]. GUDCA is a conjugated bile acid formed by the glycine-conjugation of the secondary bile acid ursodeoxycholic acid (UDCA). FXR, a nuclear receptor expressed in the liver and intestine, plays a vital role in regulating bile acid homeostasis, lipid metabolism, and intestinal barrier function. When antagonized by GUDCA in the ileum, FXR activity is reduced, resulting in upregulation of pro-secretory hormones such as Glucagon-like peptide-1 (GLP-1) from enteroendocrine L-cells [1]. Yan et al. explored this feedback and found that GUDCA-induced inhibition of intestinal FXR significantly boosted GLP-1 levels and improved gut barrier function and glucose metabolism in diabetic mouse models [6]. GLP-1, predominantly released by intestinal L-cells upon food consumption, while primarily known for its insulinotropic effects, also exerts anti-inflammatory and neuroprotective functions. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a class of therapeutic agents commonly prescribed for managing type 2 diabetes (T2D). Examples include exenatide, liraglutide, and semaglutide. These drugs exert their effects by imitating the activity of the naturally produced hormone GLP-1 [7]. Recent studies suggest that GLP-1RA may reduce joint inflammation through modulation of local immune responses [8, 9]. Yang et al. showed that targeting the gut-joint axis through FXR inhibition and GLP-1 modulation in osteoarthritis models led to pain reduction and improved joint pathology, hinting at the therapeutic scope of GLP-1 in rheumatic diseases [10]. The gut–joint axis refers to the immunometabolic connection whereby gut dysbiosis increases intestinal permeability, allowing microbial metabolites like lipopolysaccharide to enter circulation. This triggers systemic inflammation via Th1 and Th17 cells, ultimately contributing to joint damage in OA [11, 12]. The vagus nerve may mediate communication between the gut and joints, influencing inflammation and pain perception in OA [13]. Understanding these mechanisms supports the gut as a therapeutic target in rheumatology. The gut–GUDCA–FXR–GLP-1 axis offers novel therapeutic strategies for OA. Probiotics like Lactobacillus acidophilus improve gut microbiota composition, reducing joint inflammation and symptoms [11]. Bile acids such as GUDCA modulate NF-κB signaling, a key inflammatory pathway [14]. GLP-1 receptor agonists like liraglutide have demonstrated analgesic and cartilage-protective effects in OA models [8]. Recent evidence suggests that targeting intestinal FXR and enhancing GLP-1 signaling can prevent cartilage degradation [15]. While imeglimin, a mitochondrial modulator, does not directly link to OA, its metabolic effects may influence systemic inflammation [16]. The key components and therapeutic implications of the gut–GUDCA–FXR–GLP-1 pathway in osteoarthritis are summarized in Table 1. Despite the promising connections, there remain knowledge gaps. The specific microbial strains responsible for GUDCA synthesis, the extent of FXR's role in joint immunity, and the potential systemic effects of long-term FXR inhibition must be carefully assessed. Moreover, patient heterogeneity in microbiota composition presents challenges in universalizing microbiota-modulating interventions. Stratified approaches based on individual gut microbial signatures may be required. The gut–GUDCA–FXR–GLP1 signaling axis represents a compelling model that bridges gastrointestinal and rheumatologic systems. While the concept introduces new therapeutic directions, several mechanistic questions and translational hurdles must be addressed before clinical application. Encouragingly, ongoing research and drug repurposing strategies—such as the use of UDCA or GLP1 receptor agonists—may accelerate this process. Ultimately, this axis exemplifies how metabolic and immune cross-talk can inform the future of precision rheumatology. Shangqi Guan: Conceptualization, Literature Review, Writing – Original Draft Preparation. Yifang Mei: Supervision, Writing – Review and Editing, Correspondence, and Manuscript Revision. All authors have read and approved the final version of the manuscript. This work was supported by a strategy of precise targeted therapy for refractory rheumatoid arthritis using Adalimumab-Treg cell hydrogel (C2401029). The authors declare no conflicts of interest. Research data are not shared.