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

Mar 5, 2026European journal of pharmacology

Gut bacteria-produced indole compounds in depression: how they may work and treatment possibilities

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Abstract

Gut microbiota-derived indole metabolites are significantly reduced in depression.

The microbial indole pathway plays a crucial role in tryptophan metabolism influenced by gut microbiota.
Reduced levels of indole-3-propionic acid (IPA) and indole-3-aldehyde (IAld) are linked to depression.
Indole metabolites may enhance the integrity of the intestinal and blood-brain barriers.
These metabolites could suppress neuroinflammation and promote neuroplasticity, potentially alleviating depressive symptoms.
Interventions such as probiotics, prebiotics, dietary changes, and fecal microbiota transplantation may help restore indole metabolite levels.

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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.