Researchers reveal how gut-microbiome-derived butyrate alleviates TMJ pain by reversing epigenetic and gene regulatory pathways in the brain

Temporomandibular joint (TMJ) pain is associated with disrupted gut microbiome metabolites. Researchers reveal that butyrate, administered as tributyrin, alleviates pain by restoring histone acetylation and reversing gene regulatory changes in the brain. The team identified key genes involved in pain modulation, such as Nop14 using a mouse model as well as single-cell multi-omics sequencing. Targeting butyrate-related epigenetic pathways may offer a promising non-opioid strategy for treating TMJ pain.

TMJ disorders are a major source of chronic orofacial pain, often arising from complex interactions between neural, inflammatory, and systemic factors. However, due to a large gap in the understanding of the underlying biological mechanisms of TMJ pain, current treatment options remain limited. Emerging evidence suggests that metabolites from the gut microbiome, especially short-chain fatty acids such as butyrate, play a key role in regulating inflammation and pain. Understanding these mechanisms could provide new therapeutic approaches for managing chronic pain conditions.

In an effort to understand this, a research team led by Drs. Sufang Liu and Feng Tao from the Department of Biomedical Sciences at Texas A&M University School of Dentistry, USA, conducted a comprehensive study using a mouse model of inflammatory TMJ pain. This study, published in the International Journal of Oral Science on April 17, 2026, investigates possible epigenetic and gene regulatory mechanisms through which butyrate modulates pain. The researchers found that oral administration of tributyrin, a prodrug that releases butyrate, significantly alleviated TMJ pain and restored the diminished butyrate levels in the gut, blood, and spinal trigeminal nucleus caudalis (Sp5C), which is a key region in the brain involved in processing trigeminal pain signals.

To further understand the underlying mechanisms, the team used single-cell multi-omics sequencing, integrating single-nucleus RNA sequencing (snRNA-seq) and chromatin accessibility profiling (snATAC-seq). This approach allowed them to map gene expression and gene activity changes at single-cell resolution within the Sp5C. They identified 12 distinct cell types, including various neuronal and glial cells, and observed that TMJ pain caused widespread changes in gene expression and chromatin accessibility across these cell types instead of changing cellular composition. Dr. Liu mentions, “Five key genes showed consistent regulatory changes in TMJ pain and were restored by tributyrin”.

Importantly, the study revealed that inflammatory TMJ pain disturbed the regulation of several key genes, such as Nop14, Matk, Idh3b, Ndst2, and Tomm6 across different cell subtypes. These genes demonstrated coordinated changes in both transcriptional activity and chromatin accessibility, suggesting that they play a central role in pain-related molecular pathways. Notably, tributyrin treatment reversed these changes and restored gene regulation to normal levels.

Further analysis revealed that TMJ pain is associated with reduced histone acetylation in the 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 via epigenetic regulation. Under pain conditions, acetylation and deacetylation-related genes were differentially regulated across cell types and normalized after treatment.

Nop14 emerged as a critical regulator. Researchers found that TMJ pain increased accessibility to chromatin and expression of Nop14, while tributyrin treatment reversed these effects. Further, knockdown of Nop14 in the Sp5C restored histone acetylation and significantly reduced TMJ pain in mice, supporting its role in epigenetic control of pain pathways. Dr. Tao explains, “Nop14 could be targeted to develop a novel therapy for TMJ pain”.

The study also uncovered complex regulatory networks involving transcription factors that regulate gene activity via changes in chromatin structure. These findings show that TMJ pain causes coordinated transcriptional and epigenetic shifts across specific neuronal cells, and that butyrate can counteract these changes.

This study emphasizes the critical role of gut microbiome-derived butyrate in regulating TMJ pain through cell-type-specific gene regulation and epigenetic mechanisms. The findings suggest that, by restoring disrupted molecular pathways in the central nervous system, butyrate and its derivatives may offer a promising non-opioid therapeutic strategy for chronic pain management.

Reference
Title of original paper: Single-cell multi-omics sequencing reveals cell-specific transcriptomic and chromatin accessibility profiles in gut microbiome metabolite butyrate-produced pain modulation
Journal: International Journal of Oral Science
DOI: https://doi.org/10.1038/s41368-026-00432-9

About TEXAS A&M University
Texas A&M University is a leading public research university headquartered in College Station, Texas, USA. Established in 1876, it was the first public institution of higher education in Texas and is one of the largest universities in the United States. The university is internationally recognized for excellence in research, education, and innovation across diverse disciplines including engineering, medicine, agriculture, life sciences, veterinary sciences, public health, and biomedical sciences. Through its extensive research programs and interdisciplinary collaborations, Texas A&M University contributes significantly to scientific advancement, healthcare innovation, and community impact worldwide. The university is also known for its strong emphasis on translational research, technology development, and global academic partnerships.
Website: https://www.tamu.edu/index.html

About Dr. Sufang Liu from TEXAS A&M University, USA
Dr. Sufang Liu is an assistant professor in the Department of Biomedical Sciences at Texas A&M University College of Dentistry, Dallas, TX, USA. Her research focuses on the neurobiological mechanisms of pain, especially temporomandibular joint (TMJ) disorders, trigeminal pain pathways, and gut-brain interactions, with an emphasis on neural circuit dissection and epigenetic regulation. With over a decade of research experience, Dr. Liu authored more than 50 peer-reviewed publications. Her notable achievements include contributions to advancing non-opioid pain therapeutics and her election to the Texas A&M Council of Principal Investigators.

About Professor Feng Tao from TEXAS A&M University, USA
Dr. Feng Tao is a professor in the Department of Biomedical Sciences at Texas A&M University School of Dentistry, Dallas, TX, USA. His research focuses on the neurobiological mechanisms of chronic pain, particularly central mechanisms of different types of orofacial pain conditions, as well as the involvement of gut microbiome and related metabolites. His work integrates advanced neuroscience and epigenetic approaches to understand pain regulation and develop non-opioid therapeutics. Dr. Tao has authored numerous peer-reviewed publications and received multiple National Institutes of Health (NIH) grants for supporting his pain research.

Funding information
This work was supported by the National Institutes of Health Grants R01DE031255
(Feng Tao), R01DE032061 (Feng Tao), and R03DE031822 (Sufang Liu)