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The role of the gut-brain axis in depression: endocrine, neural, and immune pathways

A Correction to this article was published on 11 December 2020

This article has been updated


The aim of this article is to summarize the pathways connecting the gut and the brain and to highlight their role in the development of depression as well as their potential use as therapeutic targets. A literature search was conducted in PubMed using relevant keywords and their combinations up to the end of March 2020. Previously seen as a disease pertaining solely to the central nervous system, depression is now perceived as a multifactorial condition that extends beyond neurotransmitter depletion. Central to our understanding of the disease is our current knowledge of the communication between the gut and the brain, which is bidirectional and involves neural, endocrine, and immune pathways. This communication is facilitated via stress-mediated activation of the HPA axis, which stimulates the immune system and causes a decrease in microbial diversity, also known as dysbiosis. This change in the intestinal flora leads, in turn, to bacterial production of various substances which stimulate both the enteric nervous system and the vagal afferents and contribute to additional activation of the HPA axis. Concomitantly, these substances are associated with an increase in intestinal permeability, namely, the leaky gut phenomenon. The bidirectional link between the gut and the brain is of great importance for a more inclusive approach to the management of depression. It can thus be deployed for the development of novel therapeutic strategies against depression, offering promising alternatives to limited efficacy antidepressants, while combination therapy also remains a potential treatment option.

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Fig. 1
Fig. 2

Change history



adrenocorticotropic hormone






blood-brain barrier


brain-derived neurotrophic factor


cannabinoid receptor


central nervous system


corticotropin-releasing hormone


C reactive protein


enteroendocrine cell


fermentable oligo-, di-, and mono-saccharides, and polyols


gamma aminobutyric acid


glucagon-like peptide


G protein-coupled receptor 81










nuclear factor kappa-light-chain-enhancer of activated B cells




nitric oxide


neuropeptide Y


pancreatic polypeptide


paraventricular nucleus


peptide YY


retinoic acid


short-chain fatty acids


soluble interleukin 2 receptor


tumor necrosis factor






World Health Organization








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Correspondence to Stavroula A. Paschou.

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The original online version of this article was revised: Modifications have been made to Fig. 1, caption of Fig. 2 and the references. Full information regarding the corrections made can be found in the correction for this article.

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Makris, A.P., Karianaki, M., Tsamis, K.I. et al. The role of the gut-brain axis in depression: endocrine, neural, and immune pathways. Hormones 20, 1–12 (2021).

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  • Gut-brain axis
  • Gut microbiota
  • Depression
  • Psychological stress
  • Probiotics