The Role of G Protein-Coupled Receptors in the Regulation of Orthopaedic Diseases by Gut Microbiota
Abstract
:1. Introduction
2. The Relationship Between Gut Microbiota and Orthopaedic Disease
2.1. Gut Microbiota and Rheumatoid Arthritis
2.2. Gut Microbiota and Osteoarthritis
2.3. Gut Microbiota and Osteoporosis
2.4. Gut Microbiota and Bone Metastasis
3. Interaction Between Metabolites of Gut Microbiota with GPCRs
3.1. GPCRs as Key Receptors for Sensing Gut Microbiota Metabolites
3.1.1. Response of GPR41, GPR43 and GPR109a to SCFAs
3.1.2. TGR5 Response to Bile Acids
3.1.3. GPR81 Response to Lactate
3.1.4. GPR84 Response to MCFAs
3.1.5. Response of GPR91 to Succinate
3.1.6. GPR4 Response to Acids
3.1.7. Response of GPR120 to Medium- and Long-Chain Unsaturated Fatty Acids
3.1.8. Response of GPR35 to Tryptophan Metabolites
3.1.9. Response of GPR78 to Hydrogen Sulphide
4. Role of Metabolites and GPCRs in Orthopaedic Diseases and Molecular Mechanisms
Signal Transduction Pathways and Their Effects on Orthopaedic Diseases
5. Mechanisms of GPCR Regulation of Gut Microbiota
5.1. Immune Regulation
5.2. Regulation of Bacterial Homeostasis by GPCRs
6. Research Progress of GPCR Activation in Orthopaedic Diseases
6.1. Drug Development
6.2. Exercise Regulates Gut Microbiota and Thus Activates GPCR
6.3. Dietary Modulation of Gut Microbiota and Thus Activation of GPCR
7. Future Research Directions
7.1. New GPCR Discovery
7.2. Strategies for Modulating the Gut Microbiota
7.3. Personalised Therapeutic Strategies
8. Conclusions
- (1)
- In terms of the discovery and function of new GPCRs, the discovery of new GPCRs is expected to provide new avenues for personalised treatment of orthopaedic diseases.
- (2)
- Moderate exercise and dietary interventions affecting the activity of GPCRs through the regulation of gut microbiota are expected to provide new protocols and strategies for personalised treatment of orthopaedic diseases.
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
AGE | advanced glycosylation end |
CIA | collagen-induced arthritis |
DHA | docosahexaenoic acid |
ERK | extracellular signal-regulated kinase |
FMT | faecal microbiota transplantation |
GPCRs | G protein-coupled receptors |
HA | hippuric acid |
IGF-1 | insulin-like growth factor 1 |
IL-6 | interleukin 6 |
IL-10 | interleukin-10 |
LPC | lysophosphatidyl choline |
MAPK | mitogen-activated protein kinase |
MCFAs | medium-chain fatty acids |
MMPs | matrix metalloproteinases |
MM | multiple myeloma |
micro-CT | micro-computed tomography |
MSCs | mesenchymal stem cells |
OA | osteoarthritis |
OM | osteogenic medium |
OP | osteoporosis |
OPN | Osteopontin |
OPG | Osteoprotegerin |
PI3K | phosphatidylinositol 3 kinase |
PLC | phospholipase C |
PGE2 | Prostaglandin E2 |
RA | rheumatoid arthritis |
RNS | reactive nitrogen species |
SCFAs | short-chain fatty acids |
SPC | phingosylphosphatidyl choline |
SPF | specific pathogen-free |
Tregs | T cells |
TMAO | Trimethylamine N-oxide |
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Type | Subject | Disease Model | Methods | Sample Size (n) | Changes in Gut Microbiota (Beneficial Bacteria) | Changes in Gut Microbiota (Pathogenic Bacteria) | Reference |
---|---|---|---|---|---|---|---|
RA | human | Rheumatoid arthritis patients | 16S rRNA sequencing | 52 | Fusicatenibacter ↓ Enterococcium ↓ | Escherichia ↑ Eisenbergiella ↑ Klebsiella ↑ | [59] |
RA | animal | Collagen-induced arthritis (CIA) rats | 16S rRNA sequencing | around 10–20 per group | Bifidobacterium ↓ Lactobacillus ↓ Pseudomonas fragilis ↓ | Fusobacterium nucleatum ↑ Streptococcus ↑ Escherichia coli ↑ Prevotella ↑ Bacteroidetes ↑ | [60,61,62,63,64] |
OA | human | Osteoarthritis patients | Metagenomic sequencing | 89 | Agathobacter ↓ Ruminococcus ↓ Roseburia ↓ Subdoligranulum ↓ Lactobacillus ↓ | Prevotella_7 ↑ Clostridium ↑ Flavonifractor ↑ Klebsiella ↑ | [63,65] |
OA | animal | Mono-iodine-acetic acid (MIA) induced OA animal models | Metagenomic sequencing or 16S rRNA sequencing | around 10–20 per group or 93 | Dictyostelium parvum ↓ Ackermannia ↓ Lactobacillus ↓ Bifidobacterium bifidum ↓ | Enterobacteriaceae ↑ Staphylococcus Proteus ↑ Clostridium ↑ | [66,67] |
OP | human | Osteoporosis patients | 16S rRNA sequencing | 2033 | Firmicutes ↓ Blautia ↓ Alistipes ↓ Megamonas ↓ Anaerostipes ↓ | Lactobacillus ↑ Ruminococcus ↑ Bacteroides of Bacteroidetes ↑ | [46] |
OP | animal | Ovariectomized (OVX) rats | 16S rRNA sequencing | around 10–20 per group | Bifidobacterium ↓ Lactobacillus ↓ Akkermansia muciniphila ↓ | Streptococcus sanguinis ↑ Streptococcus gordonii ↑ Actinomyces odontolyticus ↑ Actinomyces graevenitzii ↑ Escherichia coli ↑ Enterococcus ↑ Bacteroides ↑ | [68,69] |
BM | human | Tumour bone metastasis patients | Metagenomic DNA sequencing | 79 | Megamonas ↓ Clostridia ↓ Akkermansia ↓ Gemmiger ↓ Paraprevotella ↓ | Lactobacillales ↑ Bacilli ↑ Veillonella ↑ Streptococcus ↑ Campylobacter ↑ Epsilonproteobacteria ↑ Acinetobacter ↑ Pseudomonadales ↑ Moraxellaceae ↑ | [70] |
BM | animal | Inoculation of tumour cells into animal bones | Metagenomic DNA sequencing or 16S rRNA sequencing | around 10–20 per group | Bifidobacterium ↓ Lactobacillus ↓ Akkermansia muciniphila ↓ | Fusobacterium nucleatum ↑ Escherichia coli ↑ Enterococcus faecalis ↑ Fusobacterium ↑ | [49,71] |
Drug Development | Name of Drug | Mechanism of Action | Side Effects | Reference |
---|---|---|---|---|
Existing Drugs | Bisphosphonates | Used in the treatment of osteoporosis to increase bone density by activating the TGR5 | Studies have found that phosphonates are associated with an increased risk of atypical femur fractures, bisphosphonates have been associated with an increased risk of osteonecrosis of the jaw (ONJ), particularly in patients undergoing dental surgery, and oral bisphosphonates may cause oesophagitis and other gastro symptoms. | [162,163,164,165] |
Denosumab | A monoclonal antibody against RANKL used for the treatment of osteoporosis and bone metastases that reduces bone resorption by inhibiting the RANKL-RANK signalling pathway | Studies have found that Denosumab may affect the immune system and increase the risk of infection. Denosumab treatment may cause hypocalcaemia, especially in patients with vitamin D deficiency. | [166,167] | |
Prostaglandin | Used in the treatment of osteoarthritis to reduce inflammation and pain by activating EP2 and EP4 receptors | PGE2 analogues can cause gastro disturbances, increase the risk of cardiovascular events (especially in heart disease patients), and negatively impact renal function (especially in the elderly or those with kidney disease history). | [168,169] | |
New Drug Candidate Molecules | GPR41 and GPR43 Agonists | Activators of short-chain fatty acid receptors being investigated to promote osteoblast differentiation and inhibit osteoclast activity for the treatment of osteoporosis | [14] | |
TGR5 Agonists | Activators of the bile acid receptor in development to improve energy metabolism and bone density | [87] | ||
AhR Agonists | Activators of the aromatic hydrocarbon receptor, potentially used in the treatment of osteoarthritis by modulating immune response and inflammation | [170] |
Type | Changes in Gut Microbiota | Reference |
---|---|---|
High-intensity interval training | In bodybuilders, the genera Clostridium, Eisenbergiella, Faecalibacterium, Haemophilus, and Sutterella were more abundant, while Bifidobacterium and Parasutterella were less abundant. Probiotic species including Bifidobacterium adolescentis, Bifidobacterium longum, Latilactobacillus sakei, and SCFA-producing microorganisms (Blautia wexlerae, Eubacterium hallii) were less abundant in bodybuilders compared to controls. | [172] |
Endurance training | At the phylum level, Lentisphaerae and Acidobacteria were detected after running, with their functions in the human gut remaining unknown. At the family level, there was an increase in Coriobacteriaceae and Succinivibrionaceae, where Coriobacteriaceae are involved in bile salts and steroid hormones metabolism and activation of dietary polyphenols. At the genus level, half marathon running led to a decrease in the levels of Ezakiella, Romboutsia, and Actinobacillus, and an increase in Coprococcus and Ruminococcus bicirculans. | [173] |
Aerobic exercise | In a study by Durk et al. [174] on young healthy individuals, a higher Firmicutes/Bacteroidetes ratio was significantly correlated with higher VO2max. In a study on premenopausal women, participants with low VO2max had lower Bacteroides levels but higher Eubacterium rectale and Clostridium coccoides levels compared to those with high VO2max. A 12-week aerobic exercise training led to an increase in the relative abundance of intestinal Bacteroides and an improvement in cardiorespiratory fitness. | [174,175,176] |
Type | Changes in Gut Microbiota | Reference |
---|---|---|
Western Diet | This type of diet leads to a decrease in the abundance of several beneficial bacterial species, including Akkermansia muciniphila, Faecalibacterium prausnitzii, Roseburia spp., Eubacterium spp., and the bacteria in Clostridium cluster XIVa and IV. | [178,179] |
Ketogenic Diet | In obese patients, the Bacteroidetes/Firmicutes ratio was significantly altered. After a very-low-calorie ketogenic diet (VLCKD), there was a reduction in Eubacterium rectale and Roseburia, while the abundance of Akkermansia and Christensenellaceae increased. | [180,181] |
Vegan Diet | High intakes of indigestible carbohydrates (wheat bran and whole grain) typically lead to an increase in Lactobacillus spp. and Bifidobacterium spp. Whole grain barley and resistant starch are associated with an increase in Ruminococcus spp., Eubacterium rectale, and Roseburia spp., and a decrease in some Firmicutes phylum taxa such as Clostridium and Enterococcus species. | [182,183] |
Gluten-Free Diet | In healthy volunteers, one month of a gluten-free diet (GFD) led to the following microbiota changes: a decrease in the populations of Lactobacillus, Bifidobacterium, and Roseburia; an increase in E. coli, Enterobacteriaceae, Victivallaceae, and Clostridiaceae. | [184,185] |
Mediterranean Diet | In a study of twenty obese men, a one-year Mediterranean diet (MD) led to a decrease in Prevotella and an increase in Oscillospira and Roseburia. A long-term MD resulted in an increase in the relative abundance of Parabacteroides distasonis. A two-year MD had a positive effect, increasing the levels of Bacteroides, Prevotella, and some saccharolytic genera such as Roseburia, Faecalibacterium, and Ruminococcus. | [186,187] |
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Sun, P.; Liu, J.; Chen, G.; Guo, Y. The Role of G Protein-Coupled Receptors in the Regulation of Orthopaedic Diseases by Gut Microbiota. Nutrients 2025, 17, 1702. https://doi.org/10.3390/nu17101702
Sun P, Liu J, Chen G, Guo Y. The Role of G Protein-Coupled Receptors in the Regulation of Orthopaedic Diseases by Gut Microbiota. Nutrients. 2025; 17(10):1702. https://doi.org/10.3390/nu17101702
Chicago/Turabian StyleSun, Peng, Jinchao Liu, Guannan Chen, and Yilan Guo. 2025. "The Role of G Protein-Coupled Receptors in the Regulation of Orthopaedic Diseases by Gut Microbiota" Nutrients 17, no. 10: 1702. https://doi.org/10.3390/nu17101702
APA StyleSun, P., Liu, J., Chen, G., & Guo, Y. (2025). The Role of G Protein-Coupled Receptors in the Regulation of Orthopaedic Diseases by Gut Microbiota. Nutrients, 17(10), 1702. https://doi.org/10.3390/nu17101702