The bridging role of gut microbiota-derived metabolites in neuropathic pain comorbid with anxiety

Neuropathic pain (NP) is a chronic pain condition caused by damage or disease of the somatosensory system and often forms a comorbid state with anxiety, severely affecting patients' quality of life. The occurrence of this comorbidity involves the interplay of multiple mechanisms, including neuroinflammation, metabolic abnormalities, the hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and imbalances in central neurotransmitter systems. In recent years, research on the mechanisms by which gut microbiota-derived metabolites regulate NP and anxiety via the "gut-brain axis" has garnered increasing attention. Among the numerous gut microbiota-derived metabolites, lipopolysaccharide (LPS), short-chain fatty acids (SCFAs), bile acids (BAs), serotonin (5-HT), and γ-aminobutyric acid (GABA) are considered key signaling molecules. They collectively participate in the pathological process of NP-anxiety comorbidity by regulating immune responses, metabolic pathways, and neural pathways. This review focuses on these five metabolites, analyzing the bridging role of their functional abnormalities in this comorbidity and future directions in this field.