FNDC5/irisin mediates hallmark brain alterations and cognitive impairment in acute intestinal injury/disease

Abstract

Abstract Intestinal ischemia/reperfusion (II/R) injury is a highly-lethal clinical problem and communication between intestine-brain axis is vital. Unfortunately, the mechanisms underlying the changes are yet unclear. The present study aimed to determine whether FNDC5/irisin plays a role in the progressive cerebral injury and cognitive deficit following II/R and reveal the mechanisms. Herein, the II/R-treated FNDC5/irisin knockout mice models demonstrated that FNDC5/irisin deficiency aggravates cognitive deficit, the pro-inflammation microglia activation, oxidative injury, inflammatory response, and neuronal apoptosis, while recombinant FNDC5/irisin promotes the beneficial phenotype polarization of microglia and improves the 7-day survival rate, cognitive deficit, and cerebral injury after II/R. Mechanistically, TXNIP/NLRP3 pathway was activated in the II/R-induced cerebral injury and was deteriorated in FNDC5/irisin knockout mice. However, supplementing with recombinant FNDC5/irisin suppressed the TXNIP/NLRP3 pathway. The in vitro results showed that FNDC5/irisin promotes the M2 microglial phenotype in lipopolysaccharide (LPS)-treated BV2 cells, thereby alleviating the LPS-induced neurotoxic effects of BV2 cells on hippocampal HT22 neurons. Furthermore, the overexpression of TXNIP abolished the recombinant FNDC5/irisin-mediated improvements, in vivo and in vitro. These data provided novel insights into the pathogenesis of II/R-induced cerebral injury and cognitive deficit, and defined FNDC5/irisin as a promising therapeutic target for improving II/R-mediated acute neuropsychiatric phenotypes.