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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

Abstract

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

Abbreviations

ACTH:

adrenocorticotropic hormone

AEA:

N-arachydonoylethanolamine/anandamide

ARC:

arcuate

BBB:

blood-brain barrier

BDNF:

brain-derived neurotrophic factor

CB:

cannabinoid receptor

CNS:

central nervous system

CRH:

corticotropin-releasing hormone

CRP:

C reactive protein

EEC:

enteroendocrine cell

FODMAP:

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

GABA:

gamma aminobutyric acid

GLP:

glucagon-like peptide

GPR81:

G protein-coupled receptor 81

HPA:

hypothalamic-pituitary-adrenal

HPT:

hypothalamic-pituitary-thyroid

IL:

interleukin

INF-a:

interferon-alpha

NF-κB:

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

NMDA:

N-methyl-D-aspartate

NO:

nitric oxide

NPY:

neuropeptide Y

PP:

pancreatic polypeptide

PVN:

paraventricular nucleus

PYY:

peptide YY

RA:

retinoic acid

SCFA:

short-chain fatty acids

sIL2-R:

soluble interleukin 2 receptor

TNF:

tumor necrosis factor

T3:

triiodothyronine

T4:

thyroxine

WHO:

World Health Organization

2-AG:

2-arachydonoylglycerol

5-HT:

5-hydroxytrypramine

5-HTTP:

5-hydroxytryptophan

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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). https://doi.org/10.1007/s42000-020-00236-4

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Keywords

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