Gut microbiome and serum metabolites in neuropathic pain: The PPARα perspective

Abstract

Neuropathic pain (NP) is a chronic disease state centred on neuroinflammation with a high prevalence and limited effective treatment options. Peroxisome proliferator-activated receptor α (PPARα) has emerged as a promising target for NP management due to its anti-inflammatory properties. Recent evidence highlights the critical role of the gut microbiome and its metabolites in NP pathogenesis. This study aimed to investigate whether PPARα modulates the development and alleviation of NP by influencing gut microbial communities and serum metabolites. 16S rDNA sequencing and liquid chromatography-mass spectrometry (LC-MS/MS) untargeted metabolomics analyses performed 14 days after the establishment of a chronic constriction injury (CCI) pain model in C57BL/6 J mice showed significant changes in gut microbial and metabolite levels in CCI mice. 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 analysis revealed that GW7647 effectively suppressed microglial activation. Additionally, PPARα agonist and antagonist treatments markedly altered the composition and abundance of intestinal microbial communities in CCI mice. Further serum LC-MS/MS analysis identified 258 potential serum metabolic biomarkers, many of which correlated with changes in gut microbial composition. These findings demonstrate that PPARα influences serum metabolite profiles by modulating gut microbiota composition, which subsequently affects NP progression. This study provides novel insights into the mechanisms underlying NP and suggests potential therapeutic avenues targeting PPARα and gut microbiota.