Bidirectional Communication of the Gut-Brain Axis in Pain Regulation: From Microbial Metabolites to Neuroinflammation.

Chronic pain is increasingly recognized not merely as a physiological symptom of tissue damage, but as a multidimensional pathological state involving sensory, emotional, and cognitive components. Central to its modulation is the gut-brain axis (GBA), a bidirectional communication network linking the enteric nervous system (ENS), the active intestinal epithelium, gut microbiota, and central nervous system (CNS) through neural, endocrine, immune, and metabolic pathways. Despite growing clinical evidence linking microbial dysbiosis to conditions such as irritable bowel syndrome (IBS), migraine, and fibromyalgia (FM), important gaps remain in understanding the molecular mechanisms that govern gut microenvironmental signaling in pain regulation. This review comprehensively summarizes the current literature on GBA-mediated pain regulation, with a focus on the molecular mechanisms by which microbial metabolites, such as short-chain fatty acids (SCFAs), and brain-gut peptides (BGPs) influence peripheral and central sensitization. Available evidence suggests that microbiota-derived inflammatory mediators, including lipopolysaccharide (LPS) and pro-inflammatory cytokines, contribute to neuroinflammation by activating glial cells and increasing blood-brain barrier (BBB) permeability. In addition, host intestinal epithelial and enteroendocrine cells (EECs), particularly enterochromaffin cells (ECs), are not merely passive barriers but active signaling interfaces, capable of releasing 5-hydroxytryptamine (5-HT), glutamate derived from neuropod cells, and multiple endocrine peptides involved in gut-brain communication and nociceptive regulation. The interplay between the hypothalamic-pituitary-adrenal (HPA) axis and the endogenous cannabinoid system (ECS) may act as an important regulatory "filter" in descending pain modulation. This review also discusses how reprogramming of the gut microbiota through probiotics and dietary interventions may influence the pain matrix and help alleviate comorbid affective symptoms. Overall, this review provides an integrated perspective on chronic pain as a disorder influenced by multi-level gut-brain interactions and potentially sustained by a bidirectional pathogenic feedback loop, thereby offering a theoretical basis for the development of gut microenvironment-targeted analgesic strategies.