Interplay between the gut microbiota and MAPK/NF-κ B/Nrf2 signaling in depression: pharmacological insights from traditional Chinese medicine

Depression is a major global health burden. However, conventional pharmacotherapies often face limitations in efficacy and tolerability. In recent years, the relationship between the gut microbiota and depression has gradually emerged as a major research hotspot, offering new perspectives for the treatment of depression. The gut microbiota and the brain are connected through a bidirectional communication system known as the microbiota–gut–brain axis. Within this regulatory network, gut microbiota dysbiosis can disrupt intestinal barrier integrity, triggering systemic and central neuroinflammation. This neuroinflammatory cascade forms the critical pathological basis of depression. These pathological mechanisms underlying depression are driven by the dysregulation of key immune-inflammatory and oxidative stress signaling pathways, such as the mitogen-activated protein kinase (MAPK), nuclear factor-κB (NF-κB), and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways. Therefore, targeting these pathways has become a promising strategy. Traditional Chinese Medicine (TCM), including botanical drug formulas and bioactive compounds, has demonstrated notable therapeutic efficacy. By altering the gut microbiota and strengthening the gut barrier, TCM can modulate the inflammatory signaling pathways mentioned above and decrease the levels of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and interleukin-6 (IL-6). Consequently, inflammation in the central nervous system can be alleviated, excessive microglial activation can be inhibited, and depressive symptoms can be effectively improved. Owing to its multitarget and multicomponent characteristics, TCM has unique advantages in reshaping the gut microbiota; regulating key signaling pathways, such as MAPK, NF-κB, and Nrf2; and providing a promising therapeutic strategy for depression.