Potential Role of PPARα in Ameliorating Neuropathic Pain by Gut Microbiota Alteration

Abstract

Abstract Background Neuropathic pain (NP) is a chronic disease state centred on neuroinflammation that severely affects the life and emotional state of patients. Peroxisome proliferator-activated receptor α (PPARα) has a bright future in NP management due to its promising anti-inflammatory properties. Emerging evidence suggests that the gut microbiome and its derived metabolites play a key role in NP. In this paper, we aimed to determine whether PPARα can influence the development and regression of NP by modulating gut microbes and serum nontarget metabolites. Methods A chronic constriction injury (CCI) pain model was established in C57BL/6J mice, and the PPARα agonist GW7647 (5 mg/kg) or PPARα inhibitor GW6471 (20 mg/kg) was injected intraperitoneally every other day to investigate whether PPARα could regulate NP through modulation of gut microbes. Pain behaviour tests were performed on mice, including the von Frey test and the hot plate test. Mice were sacrificed after 14 days and the corresponding tissues were collected in preparation for subsequent assays. Results The mice were divided into four groups: Sham + vehicle, CCI + vehicle, CCI + GW7647 and CCI + GW6471. 16S rDNA sequencing and liquid chromatography–mass spectrometry (LC-MS/MS) untargeted metabolomics analysis revealed significant changes in gut microbial and metabolite levels in CCI mice, and H&E staining revealed that the sciatic nerves of CCI mice showed significant inflammatory cell infiltration. Intraperitoneal injection of the PPARα agonist GW7647 (5 mg/kg) significantly attenuated mechanical allodynia and thermal hyperalgesia in CCI mice, whereas injection of the PPARα antagonist GW6471 (20 mg/kg) produced the opposite effect. Immunofluorescence showed a significant inhibitory effect of GW7647 on microglial activation. The distribution and abundance of intestinal microbial communities were significantly changed after the administration of GW7647 or GW6471 in CCI mice. Further serum LC‒MS/MS analysis revealed alterations in 258 potential serum metabolic biomarkers. The combined analysis showed that many alterations in serum metabolic biomarkers were closely associated with intestinal microorganisms. Conclusion This study demonstrates that PPARα can influence serum metabolite levels by modulating the abundance and community composition of gut microbes, which in turn modulates NP, providing a new idea for further research on the pathogenesis of NP.