IntroductionGut-microbiota-brain axis is a potential treatment to decrease the risk of chronic traumatic encephalopathy following traumatic brain injury (TBI). Phosphoglycerate mutase 5 (PGAM5), a mitochondrial serine/threonine protein phosphatase, resides in mitochondrial membrane and regulates mitochondrial homeostasis and metabolism. Mitochondria mediates intestinal barrier and gut microbiome.ObjectivesThis study investigated the association between PGAM5 and gut microbiota in mice with TBI.MethodsThe controlled cortical impact injury was established in mice with genetically-ablatedPgam5(Pgam5−/−) or wild type, and WT male mice were treated with fecal microbiota transplantation (FMT) from malePgam5−/−mice orAkkermansia muciniphila(A. muciniphila). Then the gut microbiota abundance, blood metabolites, neurological function, and nerve injury were detected.ResultsTreated with antibiotics for suppressing gut microbiota inPgam5−/−mice partially relieved the role ofPgam5deficiency in the improvement of initial inflammatory factors and motor dysfunction post-TBI.Pgam5knockout exhibited an increased abundance ofA. muciniphilain mice. FMT from malePgam5−/−mice enabled better maintenance of amino acid metabolism and peripherial environment than that in TBI-vehicle mice, which suppressed neuroinflammation and improved neurological deficits, andA. muciniphilawas negatively associated with intestinal mucosal injury and neuroinflammation post-TBI. Moreover,A. muciniphilatreatment ameliorated neuroinflammation and nerve injury by regulating Nlrp3 inflammasome activation in cerebral cortex with TBI.ConclusionThus, the present study provides evidence that Pgam5 is involved in gut microbiota-mediated neuroinflammation and nerve injury, withA. muciniphila-Nlrp3 contributing to peripheral effects.