Temporomandibular joint disorders (TMD) are a collective term for a group of conditions affecting the temporomandibular joint and/or surrounding muscles, characterized by pain and dysfunction (Scrivani et al., 2008; Andre et al., 2022; Thomas et al., 2023). TMD are highly prevalent among people, with children and adolescents also being susceptible to the condition (Kopp et al., 2023). Approximately 5% to 12% of Americans are affected by TMD, with annual total costs for treating TMD reaching around $4 billion (Schiffman et al., 2014; Manrriquez et al., 2021). Women have a higher risk of developing TMD, with prevalence rates ranging from 25% to 40% in population (Murphy et al., 2013; Calixtre et al., 2014; Valesan et al., 2021). Nearly half of individuals diagnosed with TMD experience persistent or recurring symptoms, often leading to a diminished quality of life (List and Axelsson, 2010; Maixner et al., 2011). Treating TMD poses many challenges. Comorbidities are highly prevalent among TMD patients, including headaches, widespread pain, fibromyalgia, neck and back pain, and psychosocial disorders like stress, anxiety, depression (Aggarwal et al., 2006). Prospective and risk assessment studies on oral and facial pain support the biological psychological social model of TMD, emphasizing the role of comprehensive treatment (Fillingim et al., 2018). Traditionally, treatment methods for TMD include cognitive–behavioral therapy, anti-inflammatory drug therapy, splint therapy, minimally invasive, arthroscopic, or open surgery (Manrriquez et al., 2021; Valesan et al., 2021). Despite the availability of numerous treatments for TMD, they often fail to prevent the occurrence or recurrence of the condition. The etiological factors of TMD are still unclear.

The human gut harbors thousands of microbial species, forming a complex ecological community, called the gut microbiome (Lagier and Raoult, 2016). These microorganisms are major mediators of body homeostasis, influencing various physiological activities such as metabolism, barrier homeostasis, inflammation, and hematopoiesis through intestinal and parenteral actions. Recently, the gut microbiota has recently been classified as a “vital organ” due to its establishment of multidirectional and communicative links or axes with other organs through neural, endocrine, humoral, immune, and metabolic pathways. Changes in the microbiome can lead to gut-related problems, but also affects other organ-related diseases, although the actual mechanisms of gut-organ interaction are not fully understood. A recent study had revealed a correlation between the occurrence of TMD and the deregulation of microbial metabolites (Ma et al., 2020). Extensive research on the brain-gut axis underscores the pivotal role of gut microbiota in adjusting the secretion of inflammatory neurotransmitters, which could lead to the release of diverse proinflammatory mediators in the process of TMD (Shrivastava et al., 2021; Aburto and Cryan, 2024).

Widespread debate still exists regarding whether there is a causal relationship between abnormal microbial communities associated with diseases. The substitution of a nucleotide in the genome can significantly alter the function of an organism. Single nucleotide polymorphisms (SNPs) are commonly present in microorganisms and can endow bacteria with antibiotic resistance or the ability to infect new host species. The diversity of SNPs may reflect the correlation between host microbial interactions. Current research lacks comprehensive evidence to confirm between gut bacteria and TMD. Mendelian randomization (MR) is a crucial instrument for exploring the potential causal relationship between exposure and outcomes using instrumental variables (IV) (Davey and Hemani, 2014; Swerdlow et al., 2016; Bowden and Holmes, 2019). This approach is based on the fair and random allocation of alleles to the next generation, and has emerged as a powerful tool for exploring the intricate connections between complex traits and diseases (Bowden and Holmes, 2019). MR is currently widely used in oncology, neuroscience, cardiovascular and genetics. Its advantage in exploring causal relationships makes it have broad prospects (Swerdlow et al., 2016; Bowden and Holmes, 2019; Ouyang et al., 2022). With the continuous advancement of technology and the ongoing refinement of research methods, such as Genome-wide association studies, MR becomes an important method in the biomedical fields. In this research, we aimed to explore the causality between the intestinal microbiome and TMD by Mendelian randomization.

According to recent epidemiological, cellular biology, and genomics research, a significant portion of the external influences on the human body appears to mediated by the gut microbiota. The gut microbiota, being the largest microbial community, exerts a substantial influence on training host immunity, regulating intestinal endocrine function, promoting neurotransmitter release, modulating drug action and metabolism, eliminating toxins, and producing numerous compounds that affect the host. Extensive debate exists regarding whether abnormal microbial communities associated with diseases are causally related to the diseases (i.e., susceptibility, initiation, or progression) (Davies et al., 2018; Fan and Pedersen, 2021). An important finding is that the abundance of Bacteroidetes and Lachnospiraceae in the gut of TMJ mice significantly decreased (Ma et al., 2020). In another study, 16S rRNA sequencing of TMJ mice revealed significant changes in Bacteroidetes, TM7, Actinobacteria, Tenericutes, Verrucomicrobia, Cyanobacteria, Spirochaetes, and Elusimicrobia (Shen et al., 2023). Additionally, arthritis patients displayed an enrichment of genera such as Anaerostipes, Bifidobacterium, Brachyspira, and Eggerthella, while healthy controls had higher levels of genera such as Faecalibacterium, Lachnoclostridium, Phascolarctobacterium, and Paraprevotella (Jeyaraman et al., 2023). Using IVW estimation, a statistical method that uses the reciprocal of the variance of the results (square of standard error) as a weight for fitting is used to evaluate the causal impact of 211 gut microbiota on TMD. The analysis of the data in this article suggests that the abundance of 12 bacteria were found to have causal relationships with the progression of TMD. Among them, 11 species of bacteria were found to exacerbate TMD, while Peptococcaceae seemed to had a protective effect. In subsequent stability tests, removing SNP loci that influenced the results did not alter the stability of the outcomes. Therefore, the relationship of the above microbial communities on TMD to be stable and reliable. Reverse MR revealed no evidence of causal effect of TMD on the on the identified gut microbiome.

The relationship between gut microbiota and TMD may be based on the susceptibility to TMD caused by dysbiosis of gut microbiota, or the microbiota and its metabolites acting as promoting factors for TMD. Increasing evidence suggested an association between the family Lachnospiraceae and the genus Ruminococcus with inflammatory diseases. Ruminococcus is a Gram-positive anaerobic bacterium belonging to the phylum Firmicutes, and it is one of the 57 species present in 90% of individuals at a median abundance of around 0.1% (Aguilera et al., 2012; Crost et al., 2023). An increase in the abundance of Ruminococcus has been observed in patients with ankylosing spondylitis (Vereecke and Elewaut, 2017). Additionally, a correlation exists between the prevalence of musculoskeletal pain (MSKP) in elderly community members and Ruminococcus (Shmagel et al., 2018).

Costello et al. observed alterations in the composition of gut microbiota from patients with ankylosing spondylitis (AS), where the increased abundance of bacteria from the Lachnospiraceae, Ruminococceae, Rikenellaceae, Porphyromonadae, and Bacteroideae appeared at AS (Costello et al., 2015). This study similarly suggested that Lachnospiraceae ucg-010 and the Ruminococcus may play a promoting role in TMD.

In this study, Peptococcaceae may have a mitigating or protective effect on the occurrence of TMD. This effect may be associated with their impact on metabolic products. Wen et al. confirmed the correlation of Peptococcaceae with various metabolic pathways, including tryptophan and tyrosine, derived from metabolomic and 16S rRNA gene sequencing analyses (Wen et al., 2019).

The analysis of the data in this article also provides some new insights into the effects of drugs in TMD treatment. TMD treatment targets both pain relief and functional improvement. The reports described that a large number of TMD patients had used medication, including anti-inflammatory drugs, over-the-counter painkillers, and even antidepressants, anti-anxiety drugs, and muscle relaxants (Gauer and Semidey, 2015). Although the standard of drug treatment for TMD still lacks evidence-based support, nonsteroidal anti-inflammatory drugs are considered the first choice, and other drugs mentioned above have also been used in combination (Ta and Dionne, 2004). The differences in the abundance of intestinal microorganisms among different populations may lead to different responses to TMD drug treatment. Lachnospiracea, a diverse obligate anaerobic bacteria, is abundant in the human gut. In rats administered with low-dose aspirin, alterations in the Lachnospiracea family and its interactions with the Ruminococcaceae family were observed (Chi et al., 2021). When using medication to treat TMD, changes in the aforementioned bacteria may be potential evaluation indication. Some microbial communities may synergize with malocclusion. Malocclusion is an important cause of TMD, resulting from multiple factors such as genes, occlusal training, and nutritional factors that affect growth and development (Masucci et al., 2020). The synthesis of butyrate by human gut microbiota has significantly improve skeletal muscle mass (Lv et al., 2021). Skeletal muscles, especially chewing muscles and some head and neck muscle groups, have a promoting or inhibiting effect on the development of maxillofacial bones, which may lead to excessive or insufficient development of the jawbone, further leading to malocclusion (Rot et al., 2014). Peptococcaceae has been demonstrated to enhance muscle strength through the synthesis of butyric acid, and occlusal muscle strength is an important factor affecting maxillofacial development (Joshi et al., 2014; Parada et al., 2019; Leszczyszyn et al., 2021). The increase in the abundance of Turicibacter may reduce the content of bile acids such as lithocholic acid, which in turn leads to a decrease in the intestinal absorption of vitamin D (Guida et al., 2020; Hao et al., 2022). Skeletal development is another factor that affects malocclusion. This article suggests that malocclusion played a partial mediating role in the effects of Turcicactor, Victivalis, and Peptococcaceae on TMD. Regulating the gut microbiota is expected to become a part of the precise therapy of TMD, relying on reducing the inflammatory response around the joints, and providing a suitable microenvironment for the regeneration of surrounding chondrocytes.

This study focuses on exploring the causal relationship between gut microbiota and TMD without delving into the specific regulatory mechanisms. Given the complex interplay among gut microbiota and the broad spectrum of pathogenic factors associated with TMD, there may be intricate cross-interactions among these factors. This underscores the necessity for further comprehensive research to achieve precision in treating TMD. Additionally, the study relies on GWAS data grouped based on epidemiological surveys rather than specific TMD pathology group, which hinders further research on the pathogenic factors of different pathological states of TMD. Therefore, the interpretation of the result still needs to be cautious. Moreover, given that the majority of participant are European descent, extending these research conclusions to other populations requires broader data support.

In conclusion, this study represents a view in understanding the connections between temporomandibular joint disorders and gut microbiota. These identified microbial signatures associated with TMD contribute to reveal the mechanistic and explore novel therapeutic avenues for individuals precise therapy.