Progress in neuro-psychopharmacology & biological psychiatryJun 11, 2026

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

Gut-Brain Axis Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 27, 2026

Abstract

Essence

The gut-brain microbiota axis may help explain persistence and treatment opportunities in treatment-resistant depression.

Evidence

This review summarizes proposed links among gut microbiome diversity, blood-brain barrier function, kynurenine metabolism, short-chain fatty acids, immune and inflammatory signaling, HPA-axis imbalance, and neurotransmitter signaling in MDD and TRD.

Caveat

The article is a mechanistic review, so microbiome-focused treatments such as probiotics or other modifications are discussed rather than tested as clinical outcomes here.

Simplified

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.