Microbial signatures of pain: the microbiome-immune-neural axis in pain chronification

Chronic pain is increasingly recognized as a complex neuroimmune disorder rather than a purely nociceptive phenomenon. Emerging evidence suggests that microbial ecosystems, particularly the gut microbiota, act as upstream modulators of immune and neural signaling pathways that shape pain perception and chronification. This narrative review synthesizes current mechanistic and translational evidence supporting the concept of a microbiome-immune-neural axis in acute and chronic pain conditions. We examine how dysbiosis and epithelial barrier dysfunction promote systemic translocation of microbial-derived molecules, including lipopolysaccharide and other pathogen-associated molecular patterns, leading to activation of innate immune pathways (e.g., Toll-like receptor 4, inflammasomes) and sustained cytokine release. These immune signals sensitize peripheral nociceptors, prime spinal microglia, and alter descending inhibitory circuits, thereby facilitating peripheral and central sensitization. Attention is given to nociplastic pain syndromes, neuropathic pain, musculoskeletal disorders, and cancer-related pain, where low-grade inflammation and immune dysregulation intersect with microbial alterations. We further discuss microbial metabolites, short-chain fatty acids, tryptophan-kynurenine derivatives, secondary bile acids, and endocannabinoid-modulating compounds, as bidirectional regulators of neuroimmune homeostasis. Developmental immune imprinting, stress-related dysbiosis, and epigenetic mechanisms are explored as potential contributors to long-term vulnerability to pain chronification. Finally, we evaluate translational implications, including microbiome-derived biomarkers of pain phenotypes, dietary and probiotic interventions, fecal microbiota transplantation, and integration with artificial intelligence-based profiling strategies. While causality remains incompletely established and methodological heterogeneity limits definitive conclusions, converging data support a model in which microbial-immune signaling functions as a mechanistic amplifier of pain persistence. Positioning chronic pain within a microbial-immunological framework may redefine therapeutic targets and open precision-medicine pathways aimed at restoring neuroimmune and microbial homeostasis.