The gut-joint axis is a bidirectional communication and interaction between the gastrointestinal tract (gut) and the joints. It involves the gut microbiome, intestinal permeability, immune responses, and ultimately, the joint health.
Osteoarthritis is a complex joint disease with a multifaceted pathogenesis, presenting a persistent challenge to medical researchers.
However, recent investigations into the gut microbiota have unveiled an intriguing connection with arthritis, giving rise to the concept of the “gut-joint axis”.
Short-chain fatty acids produced by gut microorganisms have emerged as potential players in maintaining bone homeostasis and reducing inflammation. The gut mycobiome (fungi) and virome (viruses) in OA remain largely unexplored, presenting exciting opportunities for future investigations. The emerging understanding of the gut-joint axis offers promising avenues for innovative OA prevention and treatment strategies, though further research is needed to fully elucidate these complex interactions.
A recent paper in Science (1) reported on the possibility that some bile acids, such as glycoursodeoxycholic acid GUDCA (Figure 1) use was associated with lower risk of osteoarthritis-related joint replacement in humans.
Figure 1. structure of glycoursodeoxycholic acid
These findings suggest that regulation of the gut microbiota-GUDCA-intestinal FXR*-GLP-1-joint pathway offers a potential strategy for osteoarthritis treatment. (*FXR, stands for the Farnesoid X receptor, a bile acid-sensing receptor playing a critical role in the regulation of bile acid metabolism, glucose and lipid homeostasis, and other metabolic processes.)
Osteoarthritis in one of the most common form of arthritis affecting millions of people worldwide. Whether a gut-joint axis exists to affect and regulate osteoarthritis is yet not entirely known. In two independent cohorts, authors of Science paper identified altered microbial bile acid metabolism with reduced glycoursodeoxycholic acid (GUDCA) in osteoarthritis. Suppressing farnesoid X receptor glycoursodeoxycholic acid alleviated osteoarthritis through intestine-secreted glucagon-like peptide 1 (GLP-1) in mice. GLP-1 receptor blockade attenuated these effects, whereas GLP-1 receptor activation mitigated osteoarthritis.
But, where are the microbes?
Osteoarthritis patients were found to exhibit a lower relative abundance of microbe Clostridium bolteae, which promoted the formation of ursodeoxycholic acid (UDCA), a precursor of glycoursodeoxycholic acid. Treatment with microbe Clostridium bolteae and the Food and Drug Administration-approved bile acid, UDCA alleviated osteoarthritis through the gut FXR-joint GLP-1 axis in mice. These new findings suggest that affecting the gut microbiota-GUDCA-intestinal FXR-GLP-1-joint pathway offers a potential new strategy for osteoarthritis treatment.
Independently from the above results, similar observations were reported by studying the effect of well-known tirzepatide (2). Tirzepatide (see Figure 2) is a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, so this API is a promising therapeutic option for treatment of type 2 diabetes.
Fig. 2 Two- and three-dimension structures of Tirzepatide, built up with 39 amino acids (source PubChem)
Nevertheless, its effect and underlying mechanism on hepatic steatosis (termed also fatty liver) remain ambiguous. Chinese scientists explored the impact of tirzepatide on improving hepatic steatosis in diabetic mice, with a particular focus on the gut microbiota and bile acids using animal models. (2) Tirzepatide was found effectively reduce body weight, improved insulin resistance, decreased serum and hepatic lipid levels, and mitigated liver injury.
Cyclodextrin (CD) bile acid interaction
Currently, there are about 500 papers and patents dedicated to the interaction between cyclodextrins and bile acids. We learned that bile acids and CDs can form both 1:1 and 2:1 host:guest inclusion complexes, with relatively high association constants.
The higher the lipophilicity of bile acids, the stronger the molecular interaction with CDs. This strong interaction may play a role in the oral absorption of CD-enabled drug complexes, as in the GI tract significant competitive events occur due to the presence of lipids and bile acids, thus affecting oral bioavailability of complexed drugs. So, designing a CD-enabled API for oral administration, one should consider the effect of bile acid competitors in GI tract. (3)
Regarding structural details and strength of interaction with series of bile acids and beta-CD derivatives, a thorough paper written by Finnish colleagues is recommended to read. (4)
The interactions of cholate, deoxycholate, glycocholate, and taurocholate with methyl-β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin were studied by means of isothermal titration calorimetry and molecular modeling. The binding constants, standard molar enthalpy, Gibbs free energy, and entropy changes were determined for the formation of bile salt/cyclodextrin inclusion complexes. Authors observed a 1:1 stoichiometry for all inclusion complexes and could demonstrate marked differences in binding affinity between the different bile salt and cyclodextrins. The dihydroxy bile salt deoxycholate showed significantly higher affinity toward methyl-β-cyclodextrin (K = 6276 ± 164 M-1) and 2-hydroxypropyl-β-cyclodextrin (K = 4429 ± 34 M-1) compared to the trihydroxy bile salt cholate (K = 2693 ± 25 M-1 and K = 2510 ± 98 M-1, respectively). The conjugation of cholate with glycine or taurine lowered its affinity markedly toward methyl-β-cyclodextrin (K= 1958 ± 178 M-1 and K= 2148 ± 33 M-1, respectively). The molecular modeling and docking data suggested that the most probable mode of binding would be the insertion of the bile salt A-ring into the rim of the cyclodextrin containing the secondary alcohol moieties. These results show that bile salt binding to cyclodextrin is influenced both by the degree of bile salt hydroxylation and by bile salt conjugation.
References
- Yuanheng Yang et al. Osteoarthritis treatment via the GLP-1-mediated gut-joint axis targets intestinal FXR signaling. Science 2025 Apr 4;388(6742):eadt0548. https://doi.org/10.1126/science.adt0548.
- Weiting Hu et al. Dual GIP and GLP-1 receptor agonist tirzepatide alleviates hepatic steatosis and modulates gut microbiota and bile acid metabolism in diabetic mice. Int. Immunopharmacol. 2025 Feb 6:147:113937. https://doi.org/10.1016/j.intimp.2024.113937.
- Arianna Cuoco et al. When Interactions Between Bile Salts and Cyclodextrin Cause a Negative Food Effect: Dynamic Dissolution/Permeation Studies with Itraconazole (Sporanox®) and Biomimetic Media. J. Pharm. Sci. 2023;112(5):1372-1378. https://doi.org/10.1016/j.xphs.2022.12.010.
- Fredrik Ollila et al. Characterization of Bile Salt/Cyclodextrin Interactions Using sothermal Titration Calorimetry. Langmuir 2001, 17, 22, 7107–7111 https://doi.org/10.1021/la0109258
Featured image: The gut-joint axis (W. Guo et al. Chinese Journal of Analytical Chemistry, 52, 2024, 100354)