Exerkine irisin mitigates cognitive impairment by suppressing gut-brain axis-mediated inflammation

Introduction: Exercise has been recognized to improve cognitive performance by optimizing gut flora and up-regulating exerkine irisin.

Objective: Although exercise-induced irisin is beneficial to cognitive improvement, whether this benefit is achieved by optimizing gut microbiota and metabolites is not fully explored.

Methods: After aerobic exercise and exogenous irisin interventions for 12 weeks, the 16S rRNA and metabolites in feces of 21-month-old mice were analyzed. Meanwhile, the differential miRNAs and mRNAs in hippocampal tissues were screened by high-throughput sequencing. Relevant mRNAs and proteins were evaluated by RT-PCR, Western blot, and immunofluorescence.

Results: Compared with the young control mice, irisin levels and cognitive capacity of aged mice revealed a significant reduction, while aerobic exercise and intraperitoneal injection of exogenous irisin reversed aging-induced cognitive impairment. Similarly, 147 up-regulated and 173 down-regulated metabolites were detected in aged mice, while 64 and 45 up-regulated and 225 and 187 down-regulated metabolites were detected in aged mice with exercise and irisin interventions, respectively. Moreover, during hippocampal miRNA and mRNA sequencing analysis, 9 differential gut flora and 35 differential genes were identified to be correlated with the inflammatory signaling mediated by the TLR4/MyD88 signal pathway.

Conclusion: Aging-induced cognitive impairment is due to insulin resistance induced by TLR4/MyD88 signaling activation in hippocampal tissues mediated by gut microbiota and metabolite changes. Myokine irisin may be an important mediator in optimizing gut microbiota and metabolism for an improved understanding of mitigated aging process upon exercise interventions.