Links between short-chain fatty acids and osteoarthritis from pathology to clinic via gut-joint axis

Abstract

Short-chain fatty acids (SCFAs), the primary metabolites produced by the microbial fermentation of dietary fibers in the gut, have a key role in protecting gut health. Increasing evidence indicates SCFAs can exert effects on distant tissues and organs beyond the gut via blood circulation. Osteoarthritis (OA) is a chronic inflammatory joint disease that severely diminishes the physical function and quality of life. However, effective clinical treatments for OA remain elusive. Recent studies have shown that SCFAs can exert beneficial effects on damaged joints in OA. SCFAs can mitigate OA progression by preserving intestinal barrier function and maintaining the integrity of cartilage and subchondral bone, suggesting that they have substantial potential to be the adjunctive treatment strategy for OA. This review described the SCFAs in the human body and their cellular signaling mechanism, and summarized the multiple effects of SCFAs (especially butyrate, propionate, and acetate) on the prevention and treatment of OA by regulating the gut-joint axis, providing novel insights into their promising clinical applications.

Keywords: Butyrate; Dietary fibers; Fecal microbiota transplantation; Gut-Joint Axis; Osteoarthritis; Probiotics and prebiotics; Short-chain fatty acids.

Fig. 1

SCFAs in the human body. Complex carbohydrates, such as dietary fibers, are metabolized by the gut microbiota, resulting in the production of SCFAs. SCFAs in the gut lumen are mostly absorbed by colon epithelium via passive diffusion and monocarboxylate transporters such as MCT1, MCT4, and SMCT1 or through exchange with bicarbonate. Once inside the colonic epithelial cells, SCFAs are partly oxidized in mitochondria to produce ATP, serving as an energy source for these cells. The unmetabolized SCFAs can reach extraintestinal organs and tissues, including the liver, white adipose tissue, skeletal muscle, heart, brain, and lung, where they exert various biological effects. MCT1, monocarboxylate transporter 1; MCT4, monocarboxylate transporter 4; SMCT1, sodium-coupled monocarboxylate transporter 1

Fig. 2

Molecular mechanisms of SCFAs signaling. Outside of the cell, SCFAs function as agonists for G-protein-coupled receptors (GPCRs), including GPR41, GPR43, and GPR109A. SCFAs stimulation of GPCRs activates the mammalian target of rapamycin (mTOR), mitogen-activated protein kinases (MAPKs), and nuclear factor-κB (NF-κB) pathways. In addition to acting as a ligand for GPCRs on the cell surface, SCFAs can enter cells via several monocarboxylate transporters such as hydrogen-coupled transporters (MCT1, MCT4), and sodium-coupled monocarboxylate transporters (SMCT1). Intracellular SCFAs can promote gene transcription by inhibiting histone deacetylases (HDACs) and activating histone acetyltransferases (HATs). These processes can occur in colonocytes as well as in any cell within a tissue accessible to SCFAs

Fig. 3

The gut-joint axis in the inflammatory joint diseases. The dysbiosis of gut microbiota contributes to an inflammatory microenvironment in the intestine and an increased level of zonulin. Zonulin is an enterotoxin that can lead to the disassembly of the tight junctions in the intestinal epithelium. In addition, the degradation of mucus and epithelial damage can also disrupt intestinal integrity. Due to the impaired gut barrier and increased permeability, the gut microbiota and inflammatory mediators migrate into the systemic circulation through the “leaky gut”. This process can result in chronic low-grade inflammation, which may influence the occurrence and progression of inflammatory joint diseases, such as rheumatoid arthritis, spondyloarthropathy, and osteoarthritis

Fig. 4

The effects of SCFAs on osteoarthritis. SCFAs can alleviate the progression of OA through multiple mechanisms. SCFAs can inhibit the NF-κB, MAPK, and PI3K signaling pathways, alleviate inflammation and oxidative damage in chondrocytes, and reduce cartilage matrix degradation. SCFAs can decrease subchondral bone loss and bone resorption by promoting macrophage M2 polarization, inhibiting NLRP3 inflammasome activation, and reducing osteoclast differentiation. Meanwhile, SCFAs can induce the senescence of synovial fibroblasts and decrease the necroptosis and inflammation in synovial tissue. In addition to being involved in the protection of articular cartilage, bone, and synovium in OA, SCFAs can also indirectly improve OA by reducing obesity and systemic inflammation. SCFAs contribute to weight loss by improving hepatic lipid metabolism, inducing browning of white fat, and suppressing appetite. Moreover, SCFAs can maintain normal gut barrier function and permeability, resulting in reduced risk of endotoxemia and systemic low-grade inflammation. Therefore, SCFAs have the potential to be a promising strategy for the prevention and treatment of OA. ROS, reactive oxygen species; TNF-α, tumor necrosis factor alpha; IL-1β, interleukin-1beta; iNOS, inducible nitric oxide synthase; MCP-1, monocyte chemoattractant protein 1; MMPs, matrix metalloproteinases; Arg-1, Arginase-1; Fizz1, found in inflammatory zone 1; Trap, tartrate resistant acid phosphatase; Oscar, osteoclast associated Ig-like receptor; Ctsk, cathepsin K; BMD, bone mineral density; BV/TV, bone volume/total volume; Tb.Th, trabecular bone thickness; Tb.N, trabecular number; RIPK1, receptor interacting protein kinase-1; MLKL, mixed lineage kinase domain-like; PPARγ, peroxisome proliferator-activated receptor gamma; Pgc1α, PPARγ coactivator-1α; Ucp1, uncoupling protein 1; Cidea, cell death-inducing DFFA-like effector a; Nrg4, neuregulin 4; PYY, peptide YY; GLP-1, glucagon-like peptide-1

Fig. 5

The strategies for supplementing SCFAs and their therapeutic implications. Current strategies for supplementing SCFAs include direct SCFAs administration, diet therapy, probiotics, prebiotics, and fecal microbiota transplantation. SCFAs can reduce intestinal inflammation, and protect the intestinal barrier and microenvironment, thereby inhibiting the onset and development of osteoarthritis