In this study, experimental results demonstrated that ZSSF could reduce anxiety-like behaviors, exert sedative–hypnotic effects, increase hippocampal 5-HT and 5-HTP, and enhance intestinal barrier function by inhibiting colon ZO-1, Claudin-1, and Occludin expression and TNF-α, IL-6, and IL-1β levels in CRS mice. Here, OCLN is linked to Anxiety.