Mechanisms of microbiota-gut-brain axis communication in anxiety disorders

Abstract

Anxiety disorders, prevalent mental health conditions, receive significant attention globally due to their intricate etiology and the suboptimal effectiveness of existing therapies. Research is increasingly recognizing that the genesis of anxiety involves not only neurochemical brain alterations but also changes in gut microbiota. The microbiota-gut-brain axis (MGBA), serving as a bidirectional communication pathway between the gut microbiota and the central nervous system (CNS), is at the forefront of novel approaches to deciphering the complex pathophysiology of anxiety disorders. This review scrutinizes the role and recent advancements in the MGBA concerning anxiety disorders through a review of the literature, emphasizing mechanisms via neural signals, endocrine pathways, and immune responses. The evidence robustly supports the critical influence of MGBA in both the development and progression of these disorders. Furthermore, this discussion explores potential therapeutic avenues stemming from these insights, alongside the challenges and issues present in this realm. Collectively, our findings aim to enhance understanding of the pathological mechanisms and foster improved preventative and therapeutic strategies for anxiety disorders.

Keywords: MGBA; anxiety disorders; endocrine pathways; gut microbiota; immune pathways; neural signal.

Figure 1

Neural signaling pathways. Gut microbiota contribute to anxiety regulation through two distinct neural pathways: one pathway transmits sensory signals from the intestinal wall to brain regions involved in emotional regulation through the vagus nerve (VN); the other pathway involves neurotransmitters produced by microbial metabolism that traverse the gut and blood–brain barrier (BBB), altering the equilibrium of original neurotransmitters. Both pathways result in altered neurotransmitter levels and changes in the function of brain regions involved in emotional regulation, ultimately affecting the development and progression of anxiety. Supplementary explanation of acronyms used in figure: 5-HT, 5-hydroxytryptamine; ACC, anterior cingulate cortex; Ach, acetylcholine; DA, dopamine; GABA, y-aminobutyric acid; Glu, glutamate; LC, locus coeruleus; Nac, nucleus accumbens; NE, norepinephrine; NTS, nucleus tractus solitarius; PFC, prefrontal cortex.

Figure 2

Endocrine pathways. Gut microbiota metabolites, including glucocorticoids (GCs), sex hormones, thyroid hormones, growth hormones, short-chain fatty acids (SCFAs), Trp-2,3-dioxygenase (TDO), indoleamine-2,3-dioxygenase (IDO), kynurenine (KYN), vitamin K2, water-soluble B vitamins, fatty acid amides (FAAs), a-melanocyte-stimulating hormone (a-MSH), 4-ethylphenylsulfate (4EPS), and secondary bile acids (SBAs), can cross the gut barrier and the BBB into specific regions of the brain associated with mood regulation under certain conditions. These metabolites mediate anxiety through diverse mechanisms, and their interactions create a complex and layered system that collectively influences the development and management of anxiety. Supplementary explanation of acronyms used in figure: BDNF, brain-derived neurotrophic factor; ClpB, caseinolytic protease B; CNS, central nervous system; GH, growth hormone; GLP-1, glucagon-like peptide-1; HPA, hypothalamic–pituitary–adrenal; IGF-1, insulin-like growth factor-1; KYNA, kynurenic acid; NMDA, N-methyl d-aspartate; QUIN, quinolinic acid; SigR1, Sigmar-1 receptor; a7-nACh, a7-nicotinic ACh.

Figure 3

Immune pathways. Pro-inflammatory and anti-inflammatory metabolites produced by gut microbiota are crucial in modulating anxiety emotions through immune pathways. Inflammatory mediators, including lipopolysaccharides (LPS), indole derivatives, and lipid metabolites, can compromise the integrity of the intestinal mucosal barrier, facilitating their entry into the bloodstream and crossing the BBB, thereby initiating neuroinflammation. Conversely, anti-inflammatory agents like SCFAs may counter these effects. The cumulative immune responses of these metabolites affect the function of brain regions and neurotransmitter levels involved in mood regulation, thereby influencing the brain’s ability to modulate anxiety emotions. Supplementary explanation of acronyms used in figure: AHR, aryl hydrocarbon receptor; GluAl, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor A1; INKT, invariant natural killer T; Kv1.2, voltage-gated potassium channel subfamily A member 2; NO, nitric oxide; PG, prostaglandin; PSD-95, postsynaptic density-95; Pyk2, proline-rich tyrosine kinase 2.