Emerging Insights into Postoperative Neurocognitive Disorders: The Role of Signaling Across the Gut-Brain Axis

Abstract

The pathophysiological regulatory mechanisms in postoperative neurocognitive disorders (PNCDs) are intricately complex. Currently, the pathogenesis of PNCDs has not been fully elucidated. The mechanism involved may include a variety of factors, such as neuroinflammation, oxidative stress, and neuroendocrine dysregulation. Research into the gut microbiota-induced regulations on brain functions is increasingly becoming a focal point of exploration. Emerging evidence has shown that intestinal bacteria may play an essential role in maintaining the homeostasis of various physiological systems and regulating disease occurrence. Recent studies have confirmed the association of the gut-brain axis with central nervous system diseases. However, the regulatory effects of this axis in the pathogenesis of PNCDs remain unclear. Therefore, this paper intends to review the bidirectional signaling and mechanism of the gut-brain axis in PNCDs, summarize the latest research progress, and discuss the possible mechanism of intestinal bacteria affecting nervous system diseases. This review is aimed at providing a scientific reference for predicting the clinical risk of PNCD patients and identifying early diagnostic markers and prevention targets.

Keywords: Anesthesia; Gut microbiota; Intestinal dysbacteriosis; Neuroinflammation; Postoperative neurocognitive disorders; Surgery.

Fig. 1

Nomenclature of PNCDs. PND including pre-existing neurocognitive dysfunction, POD (occurred within 1 week after surgery or before discharge), dNCR (cognitive decline within 7–30 days after surgery), PNCDs (mild and severe cognitive decline existed from 7 days to 12 months after surgery), and first diagnosed cognitive impairment 12 months after surgery

Fig. 2

The mechanism of the role of gut-brain axis in PNCDs. The gut microbiota plays a pivotal role in modulating communication between the gut and the brain, operating via immune responses, metabolites, and neurological and endocrine pathways. Disruption of the gut microbiota following anesthesia and surgery leads to the dysregulation of intestinal immune activity, resulting in the production of inflammatory cytokines. This initiates systemic inflammation, subsequently compromising both the intestinal barrier and the blood-brain barrier, allowing the infiltration of inflammatory agents into the central nervous system. Consequently, this cascade contributes to an escalation in aberrant microglial cell activation. These cytokines additionally stimulate the development of neuroinflammation and further activate the HPA axis. Disruptions in the gut microbiota can prompt alterations in the levels and functions of metabolites. This may involve a reduction in beneficial metabolites such as short-chain fatty acids (SCFAs) and vitamins, accompanied by an elevation in detrimental metabolites like trimethylamine N-oxide (TMAO) and lipopolysaccharides (LPS). These changes subsequently influence the onset of postoperative neurocognitive disorders (PNCDs). This also has the potential to reduce levels of gamma-aminobutyric acid (GABA), serotonin (5-HT), and acetylcholine (ACH). Aberrant metabolites, neurotransmitters, and inflammatory mediators are conveyed to the central nervous system through the gut-brain axis, inducing neuroinflammation and neuronal damage. Multiple pathways collaboratively contribute to the manifestation of neurocognitive dysfunction