Gut-Derived Indole-3-Propionic Acid Protects Against Neuroinflammation After Traumatic Brain Injury Through the NLRP3 Signaling Pathway

Abstract

Traumatic brain injury (TBI) poses a significant threat to human and veterinary health, with secondary neuroinflammation driven by the gut-brain axis exacerbating brain damage. This study aimed to investigate the role of gut microbiota-derived indole-3-propionic acid (IPA) in mitigating neuroinflammation following traumatic brain injury (TBI) and to elucidate its mechanism. TBI models were established using controlled rotational acceleration. Gut microbiota composition and serum metabolites were analyzed via 16S rRNA sequencing and untargeted metabolomics. Fecal microbiota transplantation (FMT) from TBI rats to antibiotic-treated healthy rats was performed to validate microbiota-dependent effects. IPA was orally administered post-TBI and neuroinflammation was assessed by immunofluorescence, qRT-PCR and proteomics. Our results demonstrate that TBI induces dysbiosis of gut commensals (e.g., Alistipes, Allobaculum) and reduces serum IPA levels. Supplementation with IPA suppressed microglial activation and NLRP3 inflammasome signaling, highlighting its therapeutic potential for neuroinflammatory disorders. These findings reveal a novel gut-microbiota-neuroinflammation axis, supporting IPA-based interventions for TBI management in both humans and companion animals.