Gut-brain axis and exosome-mediated communication in postoperative cognitive dysfunction associated with colorectal cancer

Abstract

Postoperative cognitive dysfunction (POCD) is a serious complication in patients undergoing colorectal cancer (CRC) surgery. It is characterized by significant impairments in memory, information processing and attention, and may also result in mood and personality changes, thereby increasing the risk of postoperative mortality. Currently, there are no effective interventions available, highlighting the need for further investigation into its pathogenesis. While the current literature has identified an association between gut microbiota dysregulation and cognitive deficits, the precise mechanisms involved remain insufficiently understood. This study hypothesizes that exosome-like (Exos-like) nanoparticles derived from the gut microbiota contribute to POCD by modulating autophagy-dependent ferroptosis in hippocampal neurons. In a rat model of CRC, significant alterations in the gut microbiota composition, including reduced microbial diversity and changes in the abundance of key taxa, are observed. Exosomes derived from these microbiota enhance neuronal uptake and trigger markers of ferroptosis, as evidenced by increased expressions of ATG5 and COX2, along with decreased levels of GPX4 and FTH1. These findings establish a mechanistic link between microbial dysbiosis, ferroptosis, and cognitive decline in POCD, providing new insights into potential therapeutic targets for CRC-associated POCD.

1. Introduction

Colorectal cancer (CRC) ranks as the third most prevalent cancer and the second leading cause of cancer-related mortality worldwide [1]. With the aging population and changes in lifestyle, the incidence and mortality rates of CRC in China continue to rise. CRC has become a significant malignant tumor affecting public health in China, imposing substantial medical and economic burdens [2]. According to the latest data released by the National Cancer Center of China, CRC is the fourth most prevalent malignant tumor, ranks third in incidence, and is the fifth leading cause of mortality among major malignancies in China [3]. A significant proportion of CRC patients are diagnosed at intermediate or advanced stages. However, with advancements in adjuvant chemoradiotherapy and immunotherapy, more CRC patients are receiving access to surgical treatments [4].

With advancements in anesthesia technology, the mortality rate and incidence of serious adverse events associated with anesthesia are progressively declining. However, numerous patients continue to experience varying degrees of complications [5]. Postoperative cognitive dysfunction (POCD) is a significant complication following surgical treatment for CRC. It not only results in substantial impairments in memory, information processing ability and attention, but also may lead to alterations in mood and personality [6]. The one-year mortality rate for patients experiencing POCD within three months following surgery is significantly higher than that for those without POCD, with the difference exceeding 2 folds [7]. The development of POCD is attributed to a multitude of predisposing factors, including patient-specific characteristics and aspects related to surgical anesthesia. The current understanding suggests that the pathogenesis of POCD primarily involves central neuroinflammation, oxidative stress, cholinergic system disorders, and amyloid deposition [8,9]. These pathological processes can result in increased neuronal apoptosis and reduced neuronal regeneration. While previous studies have explored neuroinflammation and oxidative stress in POCD patients, the role of exosome-mediated gut-brain communication remains underexplored. These factors may contribute to increased neuronal apoptosis, diminished regeneration, reduced synaptic plasticity, and other alterations in neurological function [6]; however, the specific pathological mechanisms remain inadequately understood. Existing interventions for POCD target neuroinflammation or oxidative stress. Identifying upstream regulators, such as exosomes, may offer more precise therapeutic targets.