Potential Microbiota-Immune-Neural Axis Mechanisms in Orthopedic Chronic Post-Surgical Pain

Chronic Post-Surgical Pain (CPSP) represents a prevalent complication following orthopedic surgery, significantly compromising patient recovery and quality of life. Emerging evidence indicates that the microbiota-immune-neural axis may play a contributory role in the pathogenesis and progression of CPSP, though direct causal evidence in patients undergoing orthopedic surgery remains limited. At the level of microbiota, gut dysbiosis may disrupt gut barrier integrity, potentially facilitating the translocation of bacterial products such as lipopolysaccharides into systemic circulation and thereby triggering systemic inflammatory responses. At the immunological level, microbial metabolites, particularly short-chain fatty acids, have been hypothesized to modulate the neuroimmune microenvironment through regulation of Treg/Th17 equilibrium. Activation of microglia and astrocytes may induce the release of pro-inflammatory cytokines, which may contribute to central sensitization. Concurrently, infiltration of peripheral immune cells at surgical sites may establish neuroinflammation, potentially resulting in persistent nociceptor activation. At the neural level, the vagus nerve and ascending spinal pathways constitute bidirectional communication conduits between the microbiota and brain. Gut dysbiosis may influence pain-modulating centers, including the amygdala and anterior cingulate cortex, via the gut-brain axis, thereby altering pain perception and emotional processing. It must be emphasized that much of the evidence discussed herein is indirect, associative, or derived from preclinical models, and should be interpreted accordingly. Therefore, in addition to introducing the proposed pathophysiology of CPSP, this review also presents possible microbiota-targeted intervention strategies and emphasizes the need for rigorous, orthopedically-specific randomized controlled trials before these strategies are implemented clinically.