The interplay between microbiota and the gut-brain axis in treatment-resistant depression

Jun 11, 2026Progress in neuro-psychopharmacology & biological psychiatry

How gut bacteria and gut-to-brain communication relate to treatment-resistant depression

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Gut-Brain Axis on OpenScience ↗PubMed ↗DOI ↗

Abstract

Changes in gut microbiota composition may contribute to the development and persistence of treatment-resistant depression (TRD).

The microbiota-gut-brain axis connects gut microorganisms with the immune system and brain functions.
Alterations in gut microorganisms can impact neurotransmitter production and blood-brain barrier function.
Variations in short-chain fatty acid production and immune responses may influence TRD.
Disruptions in the hypothalamic-pituitary-adrenal axis and neurotransmitter signaling are associated with TRD.
Potential treatment strategies targeting the gut microbiome include modifications and probiotics.

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Major depressive disorder (MDD) is a common psychiatric condition, and many patients do not respond to standard antidepressant treatments, developing what is known as treatment-resistant depression (TRD). The microbiota-gut-brain axis (MGBA) encompasses the biological processes underlying MDD and TRD. This two-way communication system connects the gut microbiome, the immune system, the central nervous system, and hormone signaling. Changes in the composition and diversity of gut microorganisms can affect neurotransmitter production, blood-brain barrier (BBB) function, immune function, and metabolic processes. These changes may contribute to the development and persistence of TRD. This review describes how the MGBA may influence TRD through mechanisms including BBB function, changes in the kynurenine pathway, variations in short-chain fatty acid (SCFA) production, immune and inflammatory responses, imbalances in the hypothalamic-pituitary-adrenal (HPA) axis, and disruptions in neurotransmitter signaling. The review discusses treatment strategies, focusing on the gut microbiome, including modifications, probiotics, and other approaches.

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The interplay between microbiota and the gut-brain axis in treatment-resistant depression

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