Temporomandibular joint (TMJ) pain is associated with disruption of gut microbiota metabolites. Researchers have shown that butyrate, administered as tributyrin, reduces pain by restoring histone acetylation and reversing changes in gene regulation in the brain. The research team identified key genes involved in pain regulation, including: No.14 We use a mouse model and single-cell multi-omics sequencing. Targeting the butyrate-related epigenetic pathway may provide a promising non-opioid strategy for the treatment of temporomandibular joint pain.
Temporomandibular joint disorders are a major cause of chronic orofacial pain and often result from a complex interaction between neurological, inflammatory, and systemic factors. However, current treatment options remain limited due to large gaps in our understanding of the biological mechanisms underlying TMJ pain. Emerging evidence suggests that metabolites of the gut microbiota, particularly short-chain fatty acids such as butyrate, play an important role in regulating inflammation and pain. Understanding these mechanisms may provide new therapeutic approaches for managing chronic pain conditions.
To understand this, a research team led by Drs. Sufang Liu and Feng Tao of the Texas A&M University School of Dentistry’s Department of Biomedical Sciences conducted a comprehensive study using a mouse model of inflammatory temporomandibular joint pain. The study was published in the International Journal of Oral Science on April 17, 2026. We are investigating the epigenetic and genetic regulatory mechanisms by which butyrate may modulate pain. Researchers found that oral administration of tributyrin, a butyrate-releasing prodrug, significantly reduced temporomandibular joint pain and restored reduced butyrate levels in the gut, blood, and the spinal trigeminal caudal nucleus (Sp5C), a key region of the brain involved in processing trigeminal neuralgia signals.
To further understand the underlying mechanisms, the research team used single-cell multi-omics sequencing that integrated single nuclear RNA sequencing (snRNA-seq) and chromatin accessibility profiling (snATAC-seq). This approach allowed us to map changes in gene expression and gene activity at single-cell resolution within Sp5C. They identified 12 different cell types, including a variety of neurons and glial cells, and observed that TMJ pain caused widespread changes in gene expression and chromatin access across these cell types, rather than altering cellular composition. Dr. Liu said: “Five important genes showed consistent regulatory changes in temporomandibular joint pain and were restored by tributyrin.”
Importantly, this study revealed that inflammatory TMJ pain disrupts the regulation of several important genes, including: Nop14, Matk, Idh3b, Ndst2, and tom 6 across different cell subtypes. These genes showed coordinated changes in both transcriptional activity and chromatin accessibility, suggesting that these genes play a central role in pain-related molecular pathways. Remarkably, tributyrin treatment reversed these changes and restored gene regulation to normal levels.
Further analysis revealed that temporomandibular joint pain is associated with decreased histone acetylation at Sp5C, an epigenetic mechanism associated with transcriptional regulation. At the same time, tributyrin treatment restored histone acetylation levels, suggesting that butyrate exerts its analgesic effects through epigenetic regulation. Under pain conditions, acetylation- and deacetylation-related genes were differentially regulated by cell type and normalized after treatment.
No.14 It has emerged as an important regulatory authority. Researchers found that temporomandibular joint pain increases chromatin access and chromatin expression. No.14On the other hand, tributyrin treatment reversed these effects. Additionally, knockdown No.14 Sp5C restored histone acetylation and significantly reduced temporomandibular joint pain in mice, supporting the role of Sp5C in epigenetic regulation of pain pathways. Dr. Tao explains: “Nop14 could be targeted to develop new treatments for temporomandibular joint pain.”
The study also revealed a complex regulatory network involving transcription factors that regulate gene activity through changes in chromatin structure. These findings indicate that temporomandibular joint pain causes coordinated transcriptional and epigenetic changes across specific neurons and that butyrate can counteract these changes.
This study highlights the important role of gut microbiome-derived butyrate in controlling temporomandibular joint pain through cell type-specific gene regulation and epigenetic mechanisms. This finding suggests that butyrate and its derivatives may provide a promising non-opioid therapeutic strategy for chronic pain management by restoring disrupted molecular pathways in the central nervous system.
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Reference magazines:
Tao, R. Others. (2026). Single-cell multi-omics sequencing reveals cell-specific transcriptomic and chromatin accessibility profiles in pain modulation produced by the gut microbiome metabolite butyrate. International Journal of Oral Sciences. DOI: 10.1038/s41368-026-00432-9. https://www.nature.com/articles/s41368-026-00432-9
