Appropriate exercise level attenuates gut dysbiosis and valeric acid increase to improve neuroplasticity and cognitive function after surgery in mice

Abstract

Postoperative cognitive dysfunction (POCD) affects the outcome of millions of patients each year. Aging is a risk factor for POCD. Here, we showed that surgery induced learning and memory dysfunction in adult mice. Transplantation of feces from surgery mice but not from control mice led to learning and memory impairment in non-surgery mice. Low intensity exercise improved learning and memory in surgery mice. Exercise attenuated surgery-induced neuroinflammation and decrease of gut microbiota diversity. These exercise effects were present in non-exercise mice receiving feces from exercise mice. Exercise reduced valeric acid, a gut microbiota product, in the blood. Valeric acid worsened neuroinflammation, learning and memory in exercise mice with surgery. The downstream effects of exercise included attenuating growth factor decrease, maintaining astrocytes in the A2 phenotypical form possibly via decreasing C3 signaling and improving neuroplasticity. Similar to these results from adult mice, exercise attenuated learning and memory impairment in old mice with surgery. Old mice receiving feces from old exercise mice had better learning and memory than those receiving control old mouse feces. Surgery increased blood valeric acid. Valeric acid blocked exercise effects on learning and memory in old surgery mice. Exercise stabilized gut microbiota, reduced neuroinflammation, attenuated growth factor decrease and preserved neuroplasticity in old mice with surgery. These results provide direct evidence that gut microbiota alteration contributes to POCD development. Valeric acid is a mediator for this effect and a potential target for brain health. Low intensity exercise stabilizes gut microbiota in the presence of insult, such as surgery.

Preoperative environment enrichment preserved neuroligin 1 expression possibly via epigenetic regulation to reduce postoperative cognitive dysfunction in mice

“…Our previous study has shown that surgery increases HDAC activity and reduced brain‐derived neurotrophic factor in the hippocampus 7 . Our most recent study has shown that surgery decreases postsynaptic density protein 95 and synapsin 1, two synaptic proteins, and preoperative exercise attenuates this decrease 38 …”

“…7 Our most recent study has shown that surgery decreases postsynaptic density protein 95 and synapsin 1, two synaptic proteins, and preoperative exercise attenuates this decrease. 38 Thus, surgery can reduce multiple proteins in addition to neuroligin 1. These affected proteins include other synaptic proteins, such as synapsin 1 and postsynaptic density 95.…”

Neuroinflammation as the Underlying Mechanism of Postoperative Cognitive Dysfunction and Therapeutic Strategies

“…These pathological mechanisms could be ameliorated by the increase of beneficial bacteria in the gut, such as Bifidobacterium , Lactobacillus , and Galactose oligosaccharide ( Jeong et al, 2015 ; Kobayashi et al, 2017 ; Yang et al, 2018 ). Furthermore, the latest research has shown that proper exercise improved postoperative neuroplasticity and cognitive function by ameliorating the gut dysbiosis and valeric acid increase ( Lai et al, 2021 ). However, it is still unclear how the gut microbiota and neurons in the brain mutually interacted and how these interactions affected normal brain cognitive function ( Chen et al, 2021 ).…”

Does Preoperative Cognitive Optimization Improve Postoperative Outcomes in the Elderly?

“…Comprehensive behavioral and neurophysiological studies in preclinical animal models are essential to understand the effect of preoperative interventions on the pathophysiology of PND [16]. Preoperative exercise and enriched environment have been shown to attenuate postoperative cognitive impairment in multiple aged rodent studies [81][82][83][84]. Both exercise and enriched environment appear to prevent neuroinflammation in these animal models [82,84].…”