Abstract： The author integrates ZHU Danxi's theory of "depression leading to disease" with male diseases to summarize the "extreme depression leads to change" theory. Based on this theory and focusing on the brain-gutreproductive axis， this study explores the implications of depression for the clinical diagnosis and treatment of male infertility by investigating the neuroregulatory mechanisms of the brain-gut-reproductive axis. This research connects the "extreme depression leads to change" theory with modern science to further demonstrate its rationality，scientific nature， and research significance. Depression and gut microbiota mutually influence and promote each other，jointly lead to the development and changes of male infertility. By relying on the brain-gut-reproductive axis to explain the scientific connotations of "extreme depression leads to change"， this study provides a modern theoretical bridge between depression and change. The brain-gut- reproductive axis is one of the important mediators from depression to change. The mutual influence between depression and gut microbiota propels the occurrence， development， and outcome of male infertility. This insight suggests that for clinical practitioners，starting from depression and regulating the balance of gut microbiota is of significant importance for the diagnosis and treatment of male infertility.