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

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.