Intestinal bile acid metabolism involving ursodeoxycholic acid (UDCA) and glycoursodeoxycholic acid (GUDCA) promotes glucagon-like peptide 1 (GLP-1) manufacturing by L cells. GLP-1 reaches the joints, the place it doubtlessly protects in opposition to osteoarthritis by interacting with joint cell varieties, together with chondrocytes. Credit score: Chuan-ju Liu, et al. (Science, 2025)
Osteoarthritis (OA) is likely one of the most prevalent circumstances affecting tens of thousands and thousands of U.S. adults, historically understood as a illness pushed primarily by mechanical put on and tear. This attitude is being reshaped by rising analysis that highlights the contribution of metabolic pathways to OA improvement and development.
New analysis lately printed within the journal Science, revealed compelling proof of a gut-joint axis involving bile acid metabolism and glucagon-like peptide 1 (GLP-1) signaling in OA improvement. This examine marks a big development in understanding the metabolic underpinnings of OA and opens thrilling new avenues for remedy together with doubtlessly new potentialities for arthritis analysis at Yale.
Charles W. Ohse Professor of Orthopedics & Rehabilitation, Chuan-Ju Liu, Ph.D., serves because the vice chair of Analysis for the Division of Orthopedics & Rehabilitation and principal investigator on the Liu Lab for Translational Orthopedic Analysis.
His analysis efforts at Yale are centered on vital features of musculoskeletal well being and problems, significantly irritation, age-related adjustments in joints and bones, and skeletal illnesses. Of the numerous circumstances he and his lab workforce prioritize, OA is paramount.
Liu, whose arthritis analysis is globally-recognized, was lately invited by the journal Science to write down a Perspective article sharing his insights on this physique of labor.
Liu says, “The study by Yang et al shifts our understanding of osteoarthritis from a purely mechanical perspective to one that includes metabolic processes, potentially revolutionizing how we approach treatment.”
The function of bile acid metabolism and GLP-1 signaling
In accordance with Liu, the analysis by Yang and colleagues highlights the essential function of bile acid metabolism, significantly glycoursodeoxycholic acid (GUDCA), in OA. Their preclinical research showcased that reductions in GUDCA accelerated OA development, whereas GUDCA supplementation mitigated these results. This protecting impact was primarily because of the inhibition of the intestinal farnesoid X receptor (FXR).
FXR, a key regulator of bile acid synthesis, lipid, and glucose metabolism, when inhibited, enhanced the proliferation of intestinal stem cells. This led to an elevated variety of enteroendocrine cells that secrete GLP-1, a hormone that enters the bloodstream and reaches the joints, thereby providing safety in opposition to OA by regulating cartilage-producing chondrocytes and different joint cells.
The affect of intestine microbiome on osteoarthritis
The intestine microbiome, significantly the bacterium Clostridium bolteae, performs an influential function in FXR signaling and GLP-1 modulation. Liu notes that Yang et al. demonstrated that C. bolteae disrupted bile acid stability, affected GLP-1 secretion, and altered OA development. This intricate connection between the intestine microbiome and joint well being underscores the potential of focusing on gut-derived pathways for OA remedy.
“The gut-joint axis is a relatively new concept but holds tremendous potential,” Liu provides. “Understanding the role of the gut microbiome in osteoarthritis can lead to innovative therapeutic strategies.”
Therapeutic potential of UDCA and GLP-1 receptor agonists
One of the crucial promising features of the findings, in line with Liu, is the therapeutic potential of ursodeoxycholic acid (UDCA), a clinically authorised drug for liver problems. UDCA supplementation restored bile acid composition, elevated GLP-1 ranges, and subsequently decreased joint irritation and cartilage degradation in preclinical trials.
Provided that UDCA is already in medical use, these findings supply a promising path for translation into OA remedy. Furthermore, GLP-1 receptor agonists, equivalent to semaglutide and liraglutide, broadly used for diabetes and weight problems, present potential in assuaging OA-related ache and could possibly be explored additional for his or her results on cartilage integrity and joint construction.
Future instructions and analysis alternatives
Whereas UDCA has proven promise in mitigating OA development in preclinical research and observational human research, additional analysis is essential to find out its long-term security and efficacy in OA sufferers. Key questions stay, nevertheless, concerning the optimum dosing, period of remedy, and the variability of responses amongst completely different affected person subgroups primarily based on their intestine microbiome composition.
“Longitudinal clinical trials and advanced metabolomic profiling should be the focus of future research to refine patient selection criteria and optimize treatment protocols,” says Liu.
“The concept of a gut-joint axis opens intriguing possibilities beyond osteoarthritis, potentially extending to other joint disorders such as rheumatoid arthritis and spondyloarthritis,” he concludes. “The interplay between gut microbiota, bile acids, glucose homeostasis, and systemic immune responses is an emerging field that could uncover common therapeutic targets across multiple musculoskeletal diseases.”
The evolving understanding of OA as greater than a mechanical dysfunction, together with insights into the gut-joint axis, bile acid metabolism, and GLP-1 signaling, spotlight a pivotal shift within the foundational understanding of the situation, which could be utilized to develop new, simpler therapeutic interventions that might considerably enhance affected person outcomes.
Extra data:
Yuanheng Yang et al, Osteoarthritis remedy through the GLP-1–mediated gut-joint axis targets intestinal FXR signaling, Science (2025). DOI: 10.1126/science.adt0548
Chuan-ju Liu, Past put on and tear on the joint, Science (2025). DOI: 10.1126/science.adw4656
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Rising metabolic pathways in osteoarthritis: Insights from current research and therapeutic avenues (2025, April 16)
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