Depressive disorder affects more than 350 million people worldwide, an increase of 18% over the past decade. Recent research suggests a link between dietary patterns and depression, with diets rich in seafood, vegetables, fruits and nuts may reduce the risk of depression, while an unbalanced diet could affect intestinal microbiota and promote the development of depression. In this review, a new strategy was proposed namely DIET crosslink (Depression and Diet, Intestinal microbiota, Enzyme and Traits of metabolism) to describe diet altering the enzymes produced by intestinal microbiota that influence traits of metabolism to treatment for depression. Patients exhibit changes in the abundance and composition of the gut microbiota, which produce numerous enzymes involved in the digestion and metabolism of dietary components, affect the production and absorption of exogenous metabolites by the body, affect the bioavailability of food and the progression of depression. DIET crosslink strategy underscores the significance of specific enzymes and metabolites in personalized depression treatment, providing a route to individualized care. Besides, this dynamic approach breaks from static studies, exploring the intricate interplay among diet, microbiota, enzymes, metabolism and disease, which provides a new perspective on researching how dietary influences impact changes in intestinal microbiota for disease treatment.