Preventive effect of ulinastatin on postoperative cognitive dysfunction through modulation of the gut microbiome: evidence from short-chain fatty acids.

BACKGROUND

Increasing evidence indicates that gut dysbiosis and gut-brain axis dysfunction contribute to postoperative cognitive dysfunction (POCD) following general anaesthesia. Although ulinastatin, a urinary trypsin inhibitor, has been reported to exert anti-inflammatory and neuroprotective effects, its role in the gut microbiome and microbiome-related metabolites in POCD remains unclear.

METHODS

A total of 30 18-month-old male Sprague-Dawley rats were randomly allocated to the Ulinastatin group or the Control group. Ulinastatin (50,000 U/mL) or normal saline (1 mL) was intraperitoneally administered before general anaesthesia, which was maintained with isoflurane 1.5 vol% for 2 h. Cognitive function was assessed using the Y-maze test. Lactobacillus viable counts, short-chain fatty acid (SCFA) levels and nuclear factor erythroid 2-related factor 2 (Nrf2) expression were evaluated by microbiological analysis, enzyme-linked immunosorbent assay (ELISA) and immunohistochemical staining, respectively.

RESULTS

Y-maze performance did not differ between groups before general anaesthesia. However, a significant decline after anaesthesia was observed only in the Control group (p < 0.001). Lactobacillus viable counts showed a similar pattern, with a significant reduction in the Control group but preservation in the Ulinastatin group (p < 0.001). The Ulinastatin group had significantly higher SCFA levels in the gut, blood, and brain than did the Control group (all p < 0.001). Nrf2 expression in both the gut and brain was also significantly higher in the Ulinastatin group (both p = 0.0001).

CONCLUSION

Preoperative administration of ulinastatin prevented cognitive decline after general anaesthesia. The protective effect of ulinastatin was associated with control of gut dysbiosis.