Reframing chronic pain through the microbiota-gut-brain axis: from mechanisms to clinical meaning

Chronic pain is increasingly accepted in the scientific literature as a multidimensional disorder shaped by dynamic interactions between peripheral tissues, the nervous system, and immune pathways, rather than as a direct consequence of structural pathology alone. Within this evolving framework, the microbiota-gut-brain axis has emerged as a compelling systems-level model capable of integrating nociceptive, neuropathic, and nociplastic mechanisms into a unified biological context. This narrative review reframes chronic pain through this axis, synthesizing current evidence on how gut microbial ecosystems influence pain processing via interconnected epithelial, immune, neural, and neuroendocrine pathways. We examine key mechanistic domains, including intestinal barrier integrity, microbial-derived metabolites such as short-chain fatty acids and tryptophan products, vagal and autonomic signaling, hypothalamic-pituitary-adrenal axis modulation, and neuroimmune reprogramming involving glial and peripheral immune cells. These pathways converge to modulate nociceptor sensitivity, central sensitization, and symptom clusters frequently accompanying chronic pain, including fatigue, mood disturbance, and bowel dysfunction. Evidence from human observational studies, translational experiments, Mendelian randomization analyses, and early interventional trials suggest that microbiota-related alterations are not merely epiphenomenal but may contribute to pain vulnerability and persistence across selected phenotypes, with the most consistent and clinically supported evidence observed in visceral pain disorders such as irritable bowel syndrome, while evidence in other conditions, including fibromyalgia, neuropathic pain, and cancer-related pain, remains more heterogeneous or predominantly translational. Despite growing mechanistic plausibility, clinical translation remains constrained by heterogeneity in study design, inconsistent microbial signatures, and limited high-quality interventional data. Accordingly, we propose a pragmatic interpretation for clinicians, emphasizing microbiome-informed adjunctive strategies within multimodal pain management rather than standalone therapeutic approaches. The microbiota-gut-brain axis should therefore be viewed not as a discrete target, but as a regulatory network that refines our understanding of chronic pain complexity and opens avenues for personalized, systems-based care.