Gut microbiota-derived indole metabolites in depression: mechanisms and therapeutic potential

Depression, a prevalent neuropsychiatric disorder with complex pathophysiology and often insufficient treatment efficacy, is increasingly associated with disruptions in the gut-brain axis. This review focuses on the underappreciated role of the microbial indole pathway, a key route in tryptophan metabolism orchestrated by the gut microbiota. We synthesize recent evidence demonstrating that gut microbiota-derived indole metabolites, such as indole-3-propionic acid (IPA) and indole-3-aldehyde (IAld), are significantly reduced in depression. These metabolites exert multifaceted antidepressant effects by enhancing intestinal and blood-brain barrier integrity, suppressing neuroinflammation, and promoting neuroplasticity. Furthermore, we explore the therapeutic potential of targeting this axis through interventions like specific probiotics, prebiotics, dietary modifications, and fecal microbiota transplantation to restore microbial ecology and indole metabolite levels. By highlighting the microbiota-indole-brain pathway as a critical mechanistic and therapeutic frontier, this review provides a novel perspective on the pathogenesis and treatment of depression, moving beyond conventional monoaminergic theories.