Osteoarthritis treatment via the GLP-1–mediated gut-joint axis targets intestinal FXR signaling
Yuanheng Yang; Cong Hao; Tingying Jiao; Zidan Yang; Hui Li; Yuqing Zhang; Weiya Zhang; Michael Doherty; Chuying Sun; Tuo Yang; Jiatian Li; Jing Wu; Mengjiao Zhang; Yilun Wang; Dongxing Xie; Tingjian Wang; Ning Wang; Xi Huang; Changjun Li; Frank J. Gonzalez; Jie Wei; Cen Xie; Chao Zeng; Guanghua Lei
INTRODUCTION
Although previous research has demonstrated the functional roles of gut microbiota–derived metabolites in systematic immune and metabolic disorders, few studies have explored the possible actions of these metabolites in conditions with localized effects, such as joint diseases. Osteoarthritis, a prevalent localized joint disease often referred to as “wear and tear” arthritis, affects more than 595 million people worldwide. Nevertheless, its underlying mechanism is not fully understood, and no disease-modifying drugs are available. Understanding the disease mechanisms of osteoarthritis and developing mechanism-based therapeutic approaches is an urgent yet unmet clinical need. Gut microbiota dysbiosis and several microbial metabolites have been implicated in osteoarthritis; however, whether a functional gut-joint axis exists has yet to be established.
RATIONALE
Bile acids, an important and abundant class of microbial metabolites, act as signaling molecules through receptors, such as farnesoid X receptor (FXR). FXR inhibition in L cells stimulates glucagon-like peptide 1 (GLP-1) production and secretion, and GLP-1 receptor (GLP-1R) agonists show anti–cartilage degrading effects in osteoarthritis, which suggests that GLP-1 is a potential mediator linking the intestine and the joint. These findings raise the possibility of a functional and targetable gut-joint axis. Given that bile acid receptors are promising targets with several available US Food and Drug Administration (FDA)–approved drugs, understanding the importance of bile acid metabolism and signaling and its relevance to osteoarthritis may offer previously unrealized translational opportunities.
RESULTS
Through targeted metabolomics analysis of two independent cohorts totaling 1868 individuals, we identified alterations in bile acid metabolism with reduced levels of glycoursodeoxycholic acid (GUDCA) in osteoarthritis patients compared with controls. Similar patterns were observed when correlating reduced GUDCA with osteoarthritis severity indicators. GUDCA supplementation mitigated osteoarthritis progression in mice, primarily through FXR inhibition. Knockout of Fxr in intestinal stem cells increased the number of GLP-1–positive L cells through enhanced stem cell proliferation, resulting in elevated serum levels of GLP-1. GLP-1R–positive cells—but not GLP-1–positive cells—are present in joints. Intra-articular injection of a GLP-1R antagonist, exendin 9-39 amide, abolished the therapeutic effects of GUDCA on osteoarthritis, which indicates that L cell–derived GLP-1 entered the joint to ameliorate osteoarthritis progression. Additionally, intra-articular injection of liraglutide, an FDA-approved GLP-1R agonist, mitigated cartilage degradation in mice. Furthermore, metagenomic sequencing of stool samples from 981 individuals revealed gut microbiota dysbiosis and a lower relative abundance of Clostridium bolteae in osteoarthritis patients. Additionally, C. bolteae showed the strongest positive correlation with GUDCA within the same cohort. In mice, colonization with C. bolteae increased the levels of ursodeoxycholic acid (UDCA) (a precursor of GUDCA) and alleviated the progression of osteoarthritis. Notably, UDCA (an FDA-approved drug) supplementation mitigated osteoarthritis progression through this gut-joint axis in mice, and UDCA use was also associated with a lower risk of clinically relevant end point of osteoarthritis-related joint replacement in a cohort of 5972 individuals.
CONCLUSION
We elucidated a pathway through which gut microbial metabolites influence osteoarthritis progression and uncovered the existence of a functional and targetable gut-joint axis. We suggest that orchestrating the gut microbiota–GUDCA–intestinal FXR–GLP-1–joint pathway offers a potential strategy for osteoarthritis treatment. Because FXR is a known druggable target, these findings provide the foundation for developing disease-modifying drugs for osteoarthritis.
EDITOR’S SUMMARY
Osteoarthritis is a common degenerative condition of the joints that is usually attributed to “wear and tear” and is managed by treating the symptoms. By performing metabolomic studies in hundreds of patients from independent clinical cohorts, Yang et al. identified specific differences in bile acids between people who did or did not have osteoarthritis (see the Perspective by Liu), identified the underlying signaling mechanism, and also linked the differences in bile acids to specific species among the intestinal microbiota.
Using a mouse model of osteoarthritis, the authors demonstrated the effectiveness of repurposing a clinically approved drug that targets bile acid metabolism. Moreover, human patients using this drug for other reasons had a lower risk of requiring a knee replacement for osteoarthritis, providing further support for potential clinical translation. —Yevgeniya Nusinovich
Link | PDF (Science)
Yuanheng Yang; Cong Hao; Tingying Jiao; Zidan Yang; Hui Li; Yuqing Zhang; Weiya Zhang; Michael Doherty; Chuying Sun; Tuo Yang; Jiatian Li; Jing Wu; Mengjiao Zhang; Yilun Wang; Dongxing Xie; Tingjian Wang; Ning Wang; Xi Huang; Changjun Li; Frank J. Gonzalez; Jie Wei; Cen Xie; Chao Zeng; Guanghua Lei
INTRODUCTION
Although previous research has demonstrated the functional roles of gut microbiota–derived metabolites in systematic immune and metabolic disorders, few studies have explored the possible actions of these metabolites in conditions with localized effects, such as joint diseases. Osteoarthritis, a prevalent localized joint disease often referred to as “wear and tear” arthritis, affects more than 595 million people worldwide. Nevertheless, its underlying mechanism is not fully understood, and no disease-modifying drugs are available. Understanding the disease mechanisms of osteoarthritis and developing mechanism-based therapeutic approaches is an urgent yet unmet clinical need. Gut microbiota dysbiosis and several microbial metabolites have been implicated in osteoarthritis; however, whether a functional gut-joint axis exists has yet to be established.
RATIONALE
Bile acids, an important and abundant class of microbial metabolites, act as signaling molecules through receptors, such as farnesoid X receptor (FXR). FXR inhibition in L cells stimulates glucagon-like peptide 1 (GLP-1) production and secretion, and GLP-1 receptor (GLP-1R) agonists show anti–cartilage degrading effects in osteoarthritis, which suggests that GLP-1 is a potential mediator linking the intestine and the joint. These findings raise the possibility of a functional and targetable gut-joint axis. Given that bile acid receptors are promising targets with several available US Food and Drug Administration (FDA)–approved drugs, understanding the importance of bile acid metabolism and signaling and its relevance to osteoarthritis may offer previously unrealized translational opportunities.
RESULTS
Through targeted metabolomics analysis of two independent cohorts totaling 1868 individuals, we identified alterations in bile acid metabolism with reduced levels of glycoursodeoxycholic acid (GUDCA) in osteoarthritis patients compared with controls. Similar patterns were observed when correlating reduced GUDCA with osteoarthritis severity indicators. GUDCA supplementation mitigated osteoarthritis progression in mice, primarily through FXR inhibition. Knockout of Fxr in intestinal stem cells increased the number of GLP-1–positive L cells through enhanced stem cell proliferation, resulting in elevated serum levels of GLP-1. GLP-1R–positive cells—but not GLP-1–positive cells—are present in joints. Intra-articular injection of a GLP-1R antagonist, exendin 9-39 amide, abolished the therapeutic effects of GUDCA on osteoarthritis, which indicates that L cell–derived GLP-1 entered the joint to ameliorate osteoarthritis progression. Additionally, intra-articular injection of liraglutide, an FDA-approved GLP-1R agonist, mitigated cartilage degradation in mice. Furthermore, metagenomic sequencing of stool samples from 981 individuals revealed gut microbiota dysbiosis and a lower relative abundance of Clostridium bolteae in osteoarthritis patients. Additionally, C. bolteae showed the strongest positive correlation with GUDCA within the same cohort. In mice, colonization with C. bolteae increased the levels of ursodeoxycholic acid (UDCA) (a precursor of GUDCA) and alleviated the progression of osteoarthritis. Notably, UDCA (an FDA-approved drug) supplementation mitigated osteoarthritis progression through this gut-joint axis in mice, and UDCA use was also associated with a lower risk of clinically relevant end point of osteoarthritis-related joint replacement in a cohort of 5972 individuals.
CONCLUSION
We elucidated a pathway through which gut microbial metabolites influence osteoarthritis progression and uncovered the existence of a functional and targetable gut-joint axis. We suggest that orchestrating the gut microbiota–GUDCA–intestinal FXR–GLP-1–joint pathway offers a potential strategy for osteoarthritis treatment. Because FXR is a known druggable target, these findings provide the foundation for developing disease-modifying drugs for osteoarthritis.
EDITOR’S SUMMARY
Osteoarthritis is a common degenerative condition of the joints that is usually attributed to “wear and tear” and is managed by treating the symptoms. By performing metabolomic studies in hundreds of patients from independent clinical cohorts, Yang et al. identified specific differences in bile acids between people who did or did not have osteoarthritis (see the Perspective by Liu), identified the underlying signaling mechanism, and also linked the differences in bile acids to specific species among the intestinal microbiota.
Using a mouse model of osteoarthritis, the authors demonstrated the effectiveness of repurposing a clinically approved drug that targets bile acid metabolism. Moreover, human patients using this drug for other reasons had a lower risk of requiring a knee replacement for osteoarthritis, providing further support for potential clinical translation. —Yevgeniya Nusinovich
Link | PDF (Science)
