The Role of Gut Microbiome in Temporomandibular Joint Disorder Pathogenesis

Due to the unclear etiology and pathogenesis of temporomandibular joint disorders (TMDs), current treatments often fail to provide long-term relief or halt disease progression. Therefore, this study aims to explore the underlying etiologic mechanisms by focusing on the causal relationship between the gut microbiome (GM) and TMD through a multi-omics approach. This includes mendelian randomization (MR) analysis of GM, metabolomics, and TMD data, as well as transcriptomic analysis. In accordance with MR guidelines, we utilized summary-level genome-wide association study data to perform bidirectional MR, identifying 28 gut microbial taxa with causal effects on TMD. The following species had the strongest associations with TMD incidence: RUG147 sp900315495 (odds ratio [OR], 2.016; 95% CI, 1.219 to 3.333; P = 0.006), CAG-194 sp002441865 (OR, 0.713; 95% CI, 0.555 to 0.916; P = 0.008), CAG-145 sp000435615 (OR, 1.166; 95% CI, 1.040 to 1.308; P = 0.009), and CAG-81 sp000435795 (OR, 1.150; 95% CI, 1.036 to 1.276; P = 0.009). To explore the mediating role of metabolites, a 2-step mediation MR approach was employed, revealing that lipid-related metabolites serve as key mediators in the GM-TMD interaction. Specifically, total cholesterol in high-density lipoprotein 3 was identified as a mediator of CAG-145 sp000435615 on TMD (−4.13%). Further analysis based on transcriptomic data identified differentially expressed and shared genes between GM and TMD, with the AGE-RAGE (advanced glycation end products–receptor for advanced glycation end products) and processes related to cell adhesion and inflammation emerging as significant pathways. These findings highlight the role of GM dysbiosis in TMD pathogenesis, potentially through disruptions in lipid metabolism and inflammatory processes, suggesting new therapeutic strategies targeting GM and its associated pathways.