Postoperative cognitive dysfunction (POCD) is a significant clinical problem affecting millions annually, associated with increased mortality and healthcare costs. Advanced age is a known risk factor. While neuroinflammation is implicated in POCD, the underlying mechanisms remain unclear, and effective interventions are lacking. Emerging research highlights the gut microbiome's role in inflammation and its potential link to POCD. Animal studies have shown that gut microbiota alterations and dysbiosis are associated with cognitive impairment after surgery. Probiotics have shown promise in improving cognitive function, but direct evidence of the gut microbiome's involvement in POCD is limited. Previous studies suggest environmental enrichment, possibly through increased physical activity, can reduce postoperative cognitive decline. A recent study indicated that gut microbiota influences the effectiveness of exercise in improving glucose homeostasis and insulin sensitivity. Exercise itself has demonstrated cognitive benefits in humans and animals, although the relationship between exercise capacity and POCD remains unclear. Specifically, some studies have demonstrated that exercise can improve cognitive function after surgery in low-capacity runners, whereas the same protective effects may not be found in high-capacity runners, raising the question of an optimal exercise intensity for POCD prevention. This research aimed to investigate whether appropriate exercise levels could attenuate neuroinflammation and cognitive impairment after surgery, and to explore the role of gut microbiota in mediating these effects.

Existing literature established a strong correlation between POCD and factors like advanced age, neuroinflammation, and alterations in the gut microbiome. Studies demonstrated that surgery can induce systemic inflammation, leading to neuroinflammation in the brain and subsequent cognitive decline. The gut microbiome's crucial role in regulating inflammation was also highlighted. Several studies demonstrated links between gut dysbiosis, changes in gut microbiota diversity, and postoperative cognitive deficits in animal models. The potential benefits of pre-surgical probiotic treatment in mitigating cognitive decline were also explored, although direct evidence for gut microbiota's involvement in POCD remained scarce. Furthermore, previous research indicated that environmental enrichment, which often leads to greater physical activity, could reduce postoperative cognitive deficits, suggesting a potential role for exercise. However, the optimal intensity of exercise for POCD prevention, and its mechanism of action, particularly concerning the gut microbiome, needed further clarification.

The study utilized adult (9-week-old) and aged (19-month-old) male C57BL/6J mice. Mice were subjected to a 4-week treadmill exercise regimen at varying intensities (low, medium, and high, based on individual maximal exercise capacity determined beforehand). A control group received no exercise. After the exercise period, mice underwent a standardized surgical procedure (left carotid artery exposure) under isoflurane anesthesia. Cognitive function was assessed using the Barnes maze and novel object recognition tests. Gut microbiota composition was analyzed using 16S rRNA gene sequencing. Blood and fecal short-chain fatty acids (SCFAs) were measured by gas chromatography-mass spectrometry (GC-MS). Neuroinflammation was evaluated through immunostaining for Iba-1, IL-6, and IL-1β. Neuroplasticity markers, including BrdU incorporation (for neurogenesis), dendritic arborization (Golgi staining), and synaptic protein expression (Western blotting), were also assessed. Fecal microbiota transplantation experiments were conducted to determine the role of gut microbiota in the observed effects. Furthermore, experiments involving intraperitoneal and intracerebroventricular injections of valeric acid, a C3ar antagonist (SB290157), and a C3ar agonist were performed to investigate the underlying mechanisms. Finally, the role of GDNF was examined in the context of these effects.

Low-intensity exercise significantly improved learning and memory in mice after surgery, as measured by Barnes maze and novel object recognition tests. This improvement was observed in both adult and aged mice. Middle and high-intensity exercise did not yield the same protective effects, suggesting that an optimal exercise intensity exists for POCD prevention. Exercise also attenuated surgery-induced neuroinflammation, as indicated by reduced Iba-1, IL-6, and C3 levels in the hippocampus. Furthermore, exercise prevented surgery-induced reductions in neurogenesis, dendritic arborization, and synaptic protein expression. Fecal transplantation experiments demonstrated that the beneficial effects of exercise could be transferred to non-exercised mice receiving feces from exercised mice, highlighting the crucial role of the gut microbiome. Valeric acid levels were significantly decreased in the blood of exercised mice and positively correlated with certain bacteria associated with gut dysbiosis. Intraperitoneal injection of valeric acid blocked the positive effects of exercise on learning and memory, neuroinflammation, and neuroplasticity, suggesting a detrimental role for valeric acid. Experiments with C3ar antagonists and agonists revealed a key role for C3 signaling in POCD development. Exercise also preserved GDNF levels, and GDNF's neuroprotective role was confirmed.

This study provides strong evidence supporting the hypothesis that appropriate levels of exercise can mitigate POCD through modulation of the gut microbiome. The key finding of valeric acid's detrimental role, coupled with the positive effects of exercise-induced changes in the gut microbiome composition, significantly advances our understanding of POCD pathogenesis. The transferability of exercise's beneficial effects via fecal transplantation underscores the importance of the gut-brain axis in POCD. The involvement of C3 signaling further elucidates the underlying neuroinflammatory mechanisms. Furthermore, the neuroprotective role of GDNF suggests potential therapeutic targets for POCD intervention.

This study demonstrates that low-intensity exercise is a promising strategy for preventing POCD in mice by stabilizing gut microbiota, reducing blood valeric acid levels, and inhibiting neuroinflammation. The findings suggest that manipulating the gut microbiome and targeting C3 signaling could be potential therapeutic avenues for POCD. Future research should focus on translating these findings to humans and exploring the detailed mechanisms of valeric acid's effects on the brain and the optimal exercise regimens for POCD prevention across different age groups and exercise capacities.

While this study provides compelling evidence, several limitations exist. The study was conducted in mice, and the findings may not directly translate to humans. The precise mechanisms by which valeric acid exerts its detrimental effects on the brain warrant further investigation. The study focused on low-intensity exercise and did not fully elucidate the reasons for the lack of beneficial effects of higher-intensity exercise. The use of pooled fecal samples for transplantation may mask some individual variation in gut microbiota responses. Finally, the study did not investigate the long-term effects of exercise on POCD prevention.