Vagus Nerve Mediates the Effect of Tributyrin Supplementation on Inflammatory Temporomandibular Joint Pain in Mice

The modulation of orofacial pain through the gut-brain axis represents a novel approach in pain management. Our previous study has shown that short-chain fatty acids (SCFAs) in the gut contribute to inflammatory temporomandibular joint (TMJ) pain. However, the underlying mechanism remains unclear. In the present study, we investigated whether the vagus nerve is involved in the effect of SCFA supplementation on inflammatory TMJ pain. We performed oral gavage of tributyrin (0.2 ml, 5 g/kg body weight), a precursor of SCFA butyrate, for 10 consecutive days and tested its effect in a complete Freund’s adjuvant (CFA)-induced inflammatory TMJ pain mouse model. The tributyrin treatment started at 5 days before intra-TMJ injection of CFA (10 microliters, 5 mg/ml). We further performed vagotomy (ipsilateral to CFA injection side) to examine the role of vagus nerve-linked gut-brain crosstalk in the tributyrin treatment. We measured evoked and spontaneous pain behaviors with von Frey and Mouse Grimace Scale (MGS), respectively. Open field and Rotarod tests were performed for measuring locomotor function of the mice. We observed that oral administration of tributyrin significantly inhibited CFA-induced inflammatory TMJ pain, and that ipsilateral vagotomy blocked the tributyrin-produced inhibition of evoked pain, but not spontaneous pain, on day 5 post-CFA compared to the sham control group. We also observed that all the treatments had no effects on mouse locomotor function. In conclusion, our results suggest that vagus nerve and related gut-brain communication play a critical role in gut SCFA butyrate-produced inhibition of inflammatory TMJ pain. Supported by the National Institutes of Health Grants R01DE031255 (F.T.) and R01DE032061 (F.T.).