The role of gut microbiota in neuropathic pain: insights into immune mechanisms

Neuropathic pain (NP), characterized by its complex pathophysiological mechanisms, has long posed a formidable therapeutic challenge. The burden of NP is further exacerbated by the increasing prevalence of chronic diseases. Emerging evidence highlights the pivotal role of gut microbiota in modulating immune responses, offering novel insights into NP pathogenesis. This review explores recent advancements in understanding how gut microbiota-derived metabolites - including short-chain fatty acids (SCFAs), bile acids, and tryptophan derivatives - regulate immune processes that influence neuroinflammation and nociceptive signaling. We focus on key immune mediators, including macrophages, microglia, T cells, and astrocytes, elucidating their involvement in microbiota-driven immune regulation via pathways such as TLR4/NF-κB signaling, histone deacetylase (HDAC) inhibition, and aryl hydrocarbon receptor (AhR) activation. Additionally, we examine emerging evidence of sex-specific immune mechanisms in NP. Despite promising preclinical findings on microbiota-targeted therapies, such as probiotics and fecal microbiota transplantation, translational challenges, such as microbiota heterogeneity and sex-specific responses, necessitate further investigation. This review aims to bridge microbiology, neuroimmunology, and pain research, offering a multidimensional perspective and actionable insights for the future management of NP.