Mechanism of the AMPK/SIRT1 pathway in gut dysbiosis–mediated postoperative cognitive dysfunction in aged mice

Oct 1, 2025The international journal of neuropsychopharmacology

Role of the AMPK/SIRT1 pathway in gut imbalance linked to memory problems after surgery in aged mice

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Abstract

Aged mice with (POCD) showed significant cognitive impairments and neuroinflammation.

Prolonged escape latency and reduced platform crossings were observed in aged POCD mice on postoperative day 7.
Severe hippocampal CA1 damage and increased numbers of activated microglia and astrocytes were detected.
Elevated levels of proinflammatory cytokines were noted in the hippocampus of aged POCD mice.
Treatment with the probiotic VSL#3 improved gut microbiota balance and alleviated cognitive deficits and neuroinflammation.
Gut microbiota from POCD mice worsened cognitive impairments in aged mice, while its clearance led to improved outcomes.
Activation of the was associated with the mitigation of POCD in aged mice.

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OBJECTIVE: (POCD) is a prevalent complication in older patients who undergo surgery that requires anesthesia. This study explored the role of the adenosine monophosphate-activated protein kinase (AMPK)/silent information regulator factor 2-related enzyme 1 (SIRT1) pathway in -mediated POCD in aged mice.

METHODS: POCD was induced in aged male mice via open tibial fracture surgery under isoflurane anesthesia. Mice then received the probiotic VSL#3, the SIRT1 inhibitor EX527, and the AMPK/SIRT1 activator resveratrol. Fecal microbiota transplantation was conducted in aged POCD mice. Mouse cognitive function was assessed using the Morris water maze and novel object recognition tests. Mouse histopathological changes were observed via hematoxylin-eosin staining. Iba1+/GFAP+ activation was assessed via immunofluorescence, and proinflammatory cytokines (tumor necrosis factor alpha, interleukin [IL]-1β, and IL-6) in the hippocampus were determined via enzyme-linked immunosorbent assay. Gut microbiota compositions were detected via 16S rRNA sequencing. Hippocampal pAMPK/AMPK and SIRT1 levels were assessed by western blot.

RESULTS: Aged POCD mice exhibited prolonged escape latency, reduced platform crossings, and an impaired object discrimination rate on postoperative day 7. Severe hippocampal CA1 damage, increased Iba1+/GFAP+ cell numbers, elevated proinflammatory cytokines, and gut dysbiosis were also observed. The probiotic VSL#3 ameliorated gut dysbiosis, alleviated POCD, and reduced neuroinflammation. Gut microbiota from POCD mice exacerbated cognitive deficits and neuroinflammation in aged mice, while clearance of the gut microbiota improved outcomes. VSL#3 improved POCD in aged mice by balancing the gut microbiota through the . The AMPK/SIRT1 pathway activation mitigated POCD.

CONCLUSION: VSL#3 balanced the gut microbiota and suppressed neuroinflammation in the hippocampal CA1 region by activating the AMPK/SIRT1 pathway, thereby alleviating POCD in aged mice. Significance Statement Postoperative cognitive dysfunction (POCD) is a common complication in older adults after surgery, causing memory loss and difficulty thinking. In this study, using aged male mice (Mus musculus) we found that an imbalance in gut bacteria can worsen POCD by increasing brain inflammation. Treatment with the probiotic VSL#3 restored healthy gut bacteria, reduced brain inflammation, and improved memory through the AMPK/SIRT1 pathway. These findings suggest that targeting the gut-brain connection may help prevent POCD in older surgical patients.

Key numbers

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Increase in platform crossings

Platform crossings in the Morris water maze test for + VSL#3 group vs. group.

120 s

Prolonged escape latency

Escape latency in the Morris water maze test for group.

Reduction in TNF-α levels

ELISA detection of TNF-α levels in the hippocampus for + VSL#3 group.

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Mechanism of the AMPK/SIRT1 pathway in gut dysbiosis–mediated postoperative cognitive dysfunction in aged mice

Abstract

Key numbers

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