On April 4th, 2025, Lei Guanghua, Zeng Chao, Wei Jie, Central South University, and Xie Cen, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, published a paper online in Science entitled "Osteoarthritis treatment via the GLP-1 - mediated gut-joint axis targets intestinal FXR signaling "research paper, the study for the first time systematically revealed that" intestinal bacteria - bile acid - intestinal FXR - GLP-1 - articular cartilage axis "plays an important role in OA, and the commercially available drug ursodeoxycholic acid can inhibit intestinal FXR in OA treatment. A new theory of the pathogenesis of OA "gut-joint axis" was systematically proposed, which broke through the traditional cognition that OA is a disease caused by local factors and opened up a new direction of clinical transformation.

Osteoarthritis (OA), a common localized joint disease often referred to as "wear and tear" arthritis, is a common and complex disease with multiple risk factors, including mechanical overload. OA is a leading cause of limited activity, disability and chronic pain, affecting more than 595 million people worldwide. Local factors (such as mechanical wear) have been considered to be the main cause of OA, while the role of systemic factors (such as systemic metabolism) in OA has been unclear.

Bile acids (BAs) are an important and abundant class of microbial metabolites that act as signaling molecules through receptors such as Farni X receptor (FXR) and Takeda G protein-coupled Receptor 5 (TGR5). These receptors affect multiple organs beyond the gut and play a key role in improving metabolic dysfunction. Given that BA receptors are promising drug targets for US FDA-approved ligands, understanding the importance of BA metabolism and signaling and its potential relevance to OA may provide better opportunities for conversion.

Multi-dimensional study reveals the mystery of "gut-joint axis" Based on BA metabolic profile analysis in OA of natural population

The research team performed a targeted metabolomic analysis on a total of 1868 individuals in two independent cohorts. In the "Xiangya Osteoarthritis Study", a natural population cohort independently established by Xiangya Hospital, they were pleasantly surprised to find that compared with the control group, the patients with osteoarthritis Blood levels of glycoursodeoxycholic acid (GUDCA, a bile acid) were significantly reduced, and this decrease was negatively correlated with OA and its severity. This finding was further validated in another self-established, independent population cohort (the Xiangya Step Study). These results suggest that GUDCA may play a key role in the pathogenesis of OA, providing important clues for subsequent research.

GUDCA slows the progression of OA by antagonizing FXR signaling in the gut

In order to further explore the mechanism of GUDCA's action, the research team conducted animal experiments. The results showed that GUDCA could delay the progression of OA in mice by selectively inhibiting the intestinal farnitol X receptor (FXR). When Fxr is knocked out of mouse intestinal stem cells, it promotes their proliferation and differentiation, thereby increasing the number of L-cells they differentiate into. The increase in the number of L-cells further promotes the production of glucagon-like peptide-1 (GLP-1) and ultimately increases serum GLP-1 levels. This series of responses reveals the important role of GUDCA in signaling between the gut and the joint, providing a new perspective for understanding the pathogenesis of OA.

Gut Fxr gene knockout alleviates OA by increasing the GLP-1-expressing EECs population and promoting glp-1 secretion

The research team further investigated and found that blood GLP-1 levels were reduced in OA patients and that blood was positively correlated with synovial GLP-1 levels. To verify the role of GLP-1 in the pathogenesis of OA, they performed a joint cavity injection experiment. The results showed that articular injection of GLP-1 receptor inhibitor exenatide could eliminate the therapeutic effect of GUDCA on OA mice, while articular or subcutaneous injection of GLP-1 receptor agonist liraglutide could delay the progression of OA mice. In addition, real-world studies have further validated that the use of GLP-1 receptor agonists is associated with a significantly reduced risk of disease progression in patients with OA. These results fully illustrate the potential value of GLP-1 in the treatment of OA.

Clostridium baumeri is a key intestinal microbe in producing UDCA in intestinal joint communication

To explore why GUDCA changes, the team conducted metagenomic sequencing of stool samples from 981 individuals. Sequencing revealed dysregulation of the gut microbiota in the natural population cohort, in particular a reduced relative abundance of intestinal Clostridium bolteae. Multiple omics studies showed that the relative abundance of Clostridium bornei had the strongest positive correlation with blood GUDCA levels. To further verify the role of C. botelli, the research team supplemented mice with C. botelli and found that it increased ursodeoxycholic acid (UDCA, a precursor of GUDCA) and GLP-1 levels, and delayed the progression of the disease in OA mice. This finding reveals the key role of C. botelli in intestinal joint communication and provides a theoretical basis for regulating intestinal microbiota in the treatment of OA.

UDCA alleviates OA progression via the entero-joint axis in mice and is associated with a reduced risk of OA progression in humans

In order to explore the clinical translation prospects of the research results, the research team conducted a study on UDCA, an already marketed drug with good safety. The results showed that UDCA could inhibit the activity of FXR, increase the number of L cells, promote the secretion of GLP-1 and delay the progression of OA in mice. In addition, in a real-world cohort study of 5,972 patients with OA, oral UDCA and use of GLP-1 receptor agonists were significantly associated with a reduced risk of disease progression in patients with OA. This result suggests the existence of "gut-joint axis" mechanism in the course of OA disease, and provides clinical supporting evidence for intestinal targeted intervention therapy of OA.

The gut microbial-bile acid-gut FXR-GLP-1 - combined pathway offers a potential treatment for OA

This study systematically revealed for the first time the important role of "Clostridium boveni - GUDCA - gut FXR - GLP-1 - articular cartilage axis" in the pathogenesis of OA, and clarified the new mechanism of inhibiting gut FXR to promote GLP-1 secretion by influencing the fate of stem cells. This discovery breaks through the traditional cognition that OA is a disease caused by local factors, and opens up a new way for the pathogenesis of OA.

At the same time, the study also found that UDCA, a marketed drug with good safety, is expected to treat OA by inhibiting intestinal FXR, which brings new treatment hope for OA patients. In addition, the study also provides a theoretical basis for the improvement of osteoarthritis shown by GLP-1 receptor agonists, such as Semaglutide, and provides a direction for the development of OA treatment drugs based on the "gut-joint axis" mechanism.