Oral and Gut Health, (Neuro) Inflammation, and Central Sensitization in Chronic Pain: A Narrative Review of Mechanisms, Treatment Opportunities, and Research Agenda.

Given the limited efficacy of current interventions and the complexity of chronic pain, identifying perpetuating factors is crucial for uncovering new mechanistic pathways and treatment targets. The oral and gut microbiome has emerged as a potential modulator of pain through immune, metabolic, and neural mechanisms. Contemporary evidence indicates that chronic pain populations exhibit altered oral and gut microbiota, characterized by reduced short-chain fatty acid (SCFA)-producing taxa and an overrepresentation of pro-inflammatory species. These compositional changes affect metabolites such as SCFAs, bile acids, and microbial cell wall components, which interact with host receptors to promote peripheral and central sensitization. Microbiota-derived metabolites modulate peripheral sensitization by altering nociceptive neuron excitability and stimulating immune cells to release pro-inflammatory cytokines that increase blood-brain barrier permeability, activate microglia, and amplify neuroinflammation. Activated microglia further disrupt the balance between excitatory and inhibitory neurotransmission by enhancing glutamatergic activity and weakening GABAergic signaling, thereby contributing to the induction and maintenance of central sensitization. While observational studies establish associations between dysbiosis and chronic pain, animal models and early human fecal microbiota transplantation studies suggest a potential causal role of dysbiosis in pain, although human evidence remains preliminary and influenced by diet, lifestyle, and comorbidities. Overall, microbiota appears to regulate pain via peripheral and central mechanisms, and targeting it through specific interventions, such as dietary modulation to enhance SCFA production, alongside broader lifestyle measures like sleep, physical activity, stress management, and oral hygiene, may represent a new therapeutic strategy for the management of chronic pain.