This study investigates the immunoregulatory role of gut microbiota in inflammatory depression, a treatment-resistant subtype of depression. The research begins by analyzing the gut microbiota composition, inflammatory factors, short-chain fatty acids (SCFAs), and intestinal permeability markers in patients with inflammatory depression. The results show that these patients have higher levels of *Bacteroides* and lower levels of *Clostridium*, with an increase in SCFA-producing species, particularly those involved in abnormal butanoate metabolism. To determine the causal role of gut microbiota, fecal microbiota transplantation (FMT) and probiotic supplementation (specifically *Clostridium butyricum*) are performed in animal experiments. After FMT, recipient mice exhibit increased peripheral and central inflammatory factors and intestinal mucosal permeability, along with depressive and anxiety-like behaviors. Administration of *Clostridium butyricum* normalizes the gut microbiota, reduces inflammatory factors, and displays antidepressant-like effects in the mouse model. These findings suggest that inflammatory processes derived from the gut microbiota contribute to neuroinflammation in inflammatory depression. The study highlights the potential of targeting gut microbiota as a therapeutic approach for inflammatory depression.This study investigates the immunoregulatory role of gut microbiota in inflammatory depression, a treatment-resistant subtype of depression. The research begins by analyzing the gut microbiota composition, inflammatory factors, short-chain fatty acids (SCFAs), and intestinal permeability markers in patients with inflammatory depression. The results show that these patients have higher levels of *Bacteroides* and lower levels of *Clostridium*, with an increase in SCFA-producing species, particularly those involved in abnormal butanoate metabolism. To determine the causal role of gut microbiota, fecal microbiota transplantation (FMT) and probiotic supplementation (specifically *Clostridium butyricum*) are performed in animal experiments. After FMT, recipient mice exhibit increased peripheral and central inflammatory factors and intestinal mucosal permeability, along with depressive and anxiety-like behaviors. Administration of *Clostridium butyricum* normalizes the gut microbiota, reduces inflammatory factors, and displays antidepressant-like effects in the mouse model. These findings suggest that inflammatory processes derived from the gut microbiota contribute to neuroinflammation in inflammatory depression. The study highlights the potential of targeting gut microbiota as a therapeutic approach for inflammatory depression.