The Brain-Gut Axis and Chronic Pain: Mechanisms and Therapeutic Opportunities

Tim Ho ^1,2* Lucy Kocanda ³ Katherine Brain ³ Omer Elma ⁴ Thao Lam ¹ Tejas Kanhere ⁵ Huan-Ji Dong ⁶

• ¹ The University of Sydney, Darlington, Australia
• ² Western Sydney Local Health District, Sydney, New South Wales, Australia
• ³ The University of Newcastle, Callaghan, New South Wales, Australia
• ⁴ Bournemouth University, Poole, England, United Kingdom
• ⁵ University of New South Wales, Kensington, New South Wales, Australia
• ⁶ Linköping University, Linköping, Östergötland, Sweden

The Brain-Gut Axis (BGA) is emerging as a critical mediator in chronic pain, involving bidirectional communication between the central nervous system and the gastrointestinal system. The "Pain Matrix" is associated with microbial dysbiosis, vagus nerve dysfunction, and hypothalamic-pituitary-adrenal (HPA) axis dysregulation, driving neuroinflammation and central sensitization. Key mechanisms include microbial diversity loss, leaky gut, and altered neuroactive signaling via Short-Chain Fatty Acids (SCFAs) and vagal pathways. This narrative review explores the intricate interplay between BGA mechanisms and chronic pain, highlighting therapeutic opportunities such as restoring dysbiosis, modulating vagus nerve activity, and regulating endocrine pathways. These interventions target inflammation, autonomic balance, and stress/reward pathway modulation, offering a promising path toward integrative pain management. Further research is required to validate these strategies and improve patient outcomes.