Resveratrol alleviates temporomandibular joint inflammatory pain by recovering disturbed gut microbiota
Introduction
Patients with temporomandibular disorders (TMDs) suffer from persistent facial pain, a condition characterized by painful temporomandibular joint (TMJ) sounds and limited or asymmetric mandibular motion, and the pain is often localized in the TMJ and muscles of mastication (Scrivani et al., 2008). Nonsteroidal anti-inflammatory drugs are frequently used to manage inflammatory TMD pain (Dionne et al., 1997, Ta and Dionne, 2004). However, TMD pain management requires different therapeutic strategies due to diverse causes of this disorder (Wieckiewicz et al., 2015). Therefore, it is necessary to identify new targets and develop novel therapies for TMD pain.
Accumulating evidence in preclinical studies indicates that the dysregulated expression of a variety of pronociceptive mediators, such as pro-inflammatory cytokines, released from activated microglia in trigeminal nociceptive system is crucial to the development and maintenance of TMJ inflammation and trigeminal pain (Magni et al., 2018, Villa et al., 2010). Although inhibition of these pronociceptive cytokines and chemokines in animal models has shown its efficiency in the treatment of this type of pain, the analgesic effect is usually short-lasting and not always robust. Thus, targeting the mechanisms that cause the production of pronociceptive cytokines in the trigeminal nociceptive system rather than inhibiting these molecules may be a better therapeutic strategy for treating such pain.
The emerging role of gut microbiota in neurological disorders has recently been demonstrated. Growing evidence suggests that the disturbance of gut microbiota significantly influences microglia maturation and its function (Erny et al., 2015, Erny et al., 2017). Moreover, short-chain fatty acids (SCFAs), including acetic acid, propionic acid and butyric acid, are derived from bacterial fermentation of nondigestible carbohydrates in the gut (Koh et al., 2016). And these SCFAs have important roles in regulating microglia morphology and function. Specifically, Bacteroidetes account for approximately 23% of gut bacteria and members of this phylum mainly produce acetic and propionic acids (den Besten et al., 2013), and Lachnospiraceae mainly produces butyric acid in the gut (Meehan and Beiko, 2014). Thus, the gut microbiome may serve as a vital mediator for TMJ inflammation through the regulation of microglial activation in the trigeminal nociceptive system.
Resveratrol (RSV) is a natural bioactive compound found in various plants, especially in grape skins and red wines (Bastianetto et al., 2015, Yu et al., 2012). Due to its anti-oxidant, anti-inflammatory properties, RSV has been proved to improve pathological and behavioral outcomes in the treatment of different neurological disorders including trigeminal neuropathic pain in rats (Yang et al., 2016) and chronic neuropathic pain in mice (Tao et al., 2016). In addition, a recent study shows that RSV is able to alter gut microbiome in obese mice, which is the vital mechanism underlying its effect on glucose homeostasis (Sung et al., 2017). These studies suggest that RSV may be used to treat TMJ inflammatory pain by restoring normal gut microbiota and thereafter regulating microglial activation and the release of pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNFα).
In the present study, we hypothesized that gut microbiota is a potential target to develop an effective therapy for TMJ inflammatory pain. We showed that RSV significantly inhibits complete Freund's adjuvant (CFA)-induced TMJ inflammation, reverses CFA-caused reduction of SCFAs and the relevant gut bacteria, restores the integrity of the blood–brain barrier (BBB), inhibits the activation of microglia and decreases the release of TNFα in the spinal trigeminal nucleus caudalis (Sp5C). Furthermore, we found that fecal microbiota transplantation (FMT) with feces from RSV-treated mice significantly diminishes the CFA-induced TMJ inflammatory pain. Together, our results suggest that gut microbiome perturbation is critical for the development of TMJ inflammation and that recovering gut microbiome to normal levels could be a new therapeutic approach for treating TMJ inflammatory pain.
Section snippets
Animals
Eight-week-old male C57BL/6 mice (The Jackson Laboratory) were used in this study. We chose male mice in this study to avoid the influence of estrogen level alteration on systemic RSV-produced treatment of TMJ inflammation. Animals were housed under standard conditions with 12 h light/dark cycle and allowed access to water and food ad libitum. All behavioral tests were performed by an investigator blinded to the assignment of animal groups, and mice were acclimated with the test environment
RSV dose-dependently inhibits CFA-induced TMJ inflammation
To determine whether RSV can treat TMD-like facial pain, we administered (i.p.) it (40 mg/kg and 80 mg/kg) once a day for consecutive 4 days starting from 1 h after intra-TMJ injection of CFA. The CFA-induced TMJ inflammatory pain was assessed by measuring mechanical hypersensitivity with von Frey filaments. We observed that bilateral injection of CFA robustly decreased head withdrawal threshold in both sides of trigeminal nerve V3 branch-innervated facial skin area (Fig. 1A and B). In the
Discussion
Accumulating evidence has suggested an important role of gut microbiome in nociceptive response and the pathogenesis of different types of pain (Amaral et al., 2008, Moloney et al., 2016, Tang et al., 2019). Gut microbial dysbiosis is common in people suffering from chronic pain, and restoring gut microbiome composition and its function leads to great amelioration of such pain (Aamodt et al., 2008, Minerbi et al., 2019, Schott et al., 2018). It has been shown that alterations in gut microbiota
Conclusions
Our results in this study demonstrated that gut microbiome perturbation is crucial for TMJ inflammation. By restoring disturbed gut microbiome-caused dysregulation of SCFAs in the gut, BBB integrity, and microglia activation and TNFα release in the Sp5C, RSV can alleviate TMJ inflammation. Therefore, targeting gut microbiota could be a promising strategy for developing a new therapy for TMD pain.
Acknowledgments
This work was supported by National Institutes of Health Grants R01 DE022880 (F.T.) and K02 DE023551 (F.T.) as well as Texas A&M University Interdisciplinary Faculty T3 Award (F.T.).
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