Acupuncture Ameliorates Depressive-Like Behaviors Via SCFA-Mediated TLR4 Signaling in the Gut-Brain Axis

Objective: To explore the possible mechanisms by which acupuncture improves depressive-like behaviors induced by chronic unpredictable mild stress (CUMS). Methods: Forty male C57BL/6J mice were randomly divided into Control, CUMS, CUMS + Acu, and CUMS + Acu + TAK-242 groups. Except for the Control group, the other groups received 4-week CUMS combined with isolation modeling; acupuncture was performed at Baihui, Yinzhang, and bilateral Zusanli points, with continuous intervention using 2 Hz/15 Hz sparse and dense waves; the TAK-242 group was given a TLR4-specific inhibitor in addition to acupuncture. Depression-like phenotypes were evaluated through sugar water preference test, forced swimming test, and tail suspension test. Short-chain fatty acids (SCFAs) in feces, inflammatory factors in the hippocampus, tight junction proteins of the intestinal barrier, and TLR4/NF-κB pathway proteins were detected using GC-MS, ELISA, and Western blot. Results: CUMS significantly reduced the sucrose preference rate, weight gain, acetic acid/propionic acid/butyric acid, and ZO-1/Occludin expression, and increased immobility time, TNF-α, IL-1β, IL-6, TLR4, and p-NF-κB levels. Acupuncture could systematically reverse these changes; after combined with TAK-242, behavioral and neuroinflammatory improvements were further enhanced, while SCFAs did not show corresponding upstream superposition. Conclusion: Acupuncture may improve depressive-like behaviors induced by CUMS by restoring the metabolic ecological niche of SCFAs, repairing the intestinal barrier, and inhibiting the amplification loop of TLR4/NF-κB inflammation in the hippocampus.