Introduction

Postoperative cognitive dysfunction (POCD) is a common neurological complication following surgery, particularly among older patients (Liu et al., 2022a), and is characterized by impairments in memory, attention, executive function and information processing speed (Arefayne et al., 2023; Zhao et al., 2024). These cognitive disturbances may persist after hospital discharge, and negatively affect functional recovery and quality of life.

Although the mechanisms underlying POCD remain incompletely understood, neuroinflammation plays a key role in its development (Li et al., 2022; Yang et al., 2022b). Recently, neuroinflammation in POCD has been reported to be associated with dysbiosis in the gut (Wang et al., 2021b). Dysbiosis in the gut is defines as a condition of disruption of microbial diversity, leading to increasing potentially harmful microbiomes and decreasing beneficial microbiomes in the gut (Winter and Bäumler, 2023). Several attempts to control gut dysbiosis have shown improvement in neuroinflammation (Bairamian et al., 2022; Baizabal-Carvallo and Alonso-Juarez, 2020; Wang et al., 2021b). Emerging evidence suggests that modulation of gut dysbiosis and associated changes in microbiome-related metabolites are associated with reduced microglial activation and altered microglial polarization in the hippocampus during neuroinflammation (Erny et al., 2015; Johnson et al., 2019; Tang et al., 2023). Accordingly, Sugita et al. concluded that microbiome-targeted therapy decreased inflammation and appeared to have a positive effect on cognitive function, although the findings did not reach consensus (Sugita et al., 2023). Considering this evidence, agents that show preventive effects on neuroinflammation in POCD (Cho et al., 2024a, 2024b) might be associated with control of gut dysbiosis.

Ulinastatin, a urinary trypsin inhibitor, is purified from fresh healthy urine (Lv et al., 2026). It has anti-inflammatory effect, and protective effect against tissue injury via suppression of inflammatory signaling pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway inhibition and mitogen-activated protein kinase (MAPK) pathway modulation, reduction of oxidative stress, stabilization of vascular permeability, and modulation of coagulation process (Wang et al., 2021a; Yin et al., 2025). Therefore, it has been widely used for the treatment of inflammatory diseases, although it is available only in China, India, Japan, and Korea (Hey-Hadavi et al., 2023; Tong et al., 2024). Previous studies have also demonstrated that preoperative administration of ulinastatin has beneficial effects on postoperative cognitive decline in not only animal studies (Cho et al., 2024a, 2024b; Kim et al., 2023c) but also clinical situations (Duan et al., 2021; Liang et al., 2021). Considering the preventive effect of ulinastatin on cognitive decline via its own anti-inflammatory property and protective property against tissue injury, it might protect gut dysbiosis in occurrence of POCD. However, no study has investigated the effect of ulinastatin on gut dysbiosis in the context of POCD.

We hypothesised that the preventive effect of ulinastatin on POCD might be associated with control of gut dysbiosis. This study was designed to evaluate whether the preventive effect of ulinastatin on POCD was associated with control of gut dysbiosis.