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Review
. 2022 Dec 23;12(1):54.
doi: 10.3390/cells12010054.

The Role of Gut Dysbiosis in the Pathophysiology of Neuropsychiatric Disorders

Nikhilesh Anand  1 , Vasavi Rakesh Gorantla  2 , Saravana Babu Chidambaram  3   4
Affiliations
Review

The Role of Gut Dysbiosis in the Pathophysiology of Neuropsychiatric Disorders

Nikhilesh Anand et al. Cells. .

Abstract

Mounting evidence shows that the complex gut microbial ecosystem in the human gastrointestinal (GI) tract regulates the physiology of the central nervous system (CNS) via microbiota and the gut-brain (MGB) axis. The GI microbial ecosystem communicates with the brain through the neuroendocrine, immune, and autonomic nervous systems. Recent studies have bolstered the involvement of dysfunctional MGB axis signaling in the pathophysiology of several neurodegenerative, neurodevelopmental, and neuropsychiatric disorders (NPDs). Several investigations on the dynamic microbial system and genetic-environmental interactions with the gut microbiota (GM) have shown that changes in the composition, diversity and/or functions of gut microbes (termed "gut dysbiosis" (GD)) affect neuropsychiatric health by inducing alterations in the signaling pathways of the MGB axis. Interestingly, both preclinical and clinical evidence shows a positive correlation between GD and the pathogenesis and progression of NPDs. Long-term GD leads to overstimulation of hypothalamic-pituitary-adrenal (HPA) axis and the neuroimmune system, along with altered neurotransmitter levels, resulting in dysfunctional signal transduction, inflammation, increased oxidative stress (OS), mitochondrial dysfunction, and neuronal death. Further studies on the MGB axis have highlighted the significance of GM in the development of brain regions specific to stress-related behaviors, including depression and anxiety, and the immune system in the early life. GD-mediated deregulation of the MGB axis imbalances host homeostasis significantly by disrupting the integrity of the intestinal and blood-brain barrier (BBB), mucus secretion, and gut immune and brain immune functions. This review collates evidence on the potential interaction between GD and NPDs from preclinical and clinical data. Additionally, we summarize the use of non-therapeutic modulators such as pro-, pre-, syn- and post-biotics, and specific diets or fecal microbiota transplantation (FMT), which are promising targets for the management of NPDs.

Keywords: gut dysbiosis; gut microbiota; inflammation; microbiota gut–brain axis; neuropsychiatric disorders; oxidative stress.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Gut–brain axis regulatory model. Healthy composition of gut microbiota (termed as eubiosis) maintains the integrity of the intestinal mucosa and mucus secretion, and regulates the endocrine, neural and immune signaling through the MGB axis. Healthy GM and GM-derived metabolic profiles regulate the immune function, the production of neurotransmitters and stress hormones, and maintains the function of glial cells, synaptic pruning and myelination. Thus, the MGB axis influences higher psychological functions such as mood, emotion, cognition and memory by regulating the neural circuits. Abnormal composition of gut microbiota (termed as dysbiosis) disrupts the intestinal membrane integrity and dysregulates the functions of endocrine, neural and immune system through MGB axis. Aberrated GM and GM-derived metabolic profile results in immune-driven inflammatory response, inadequate secretion of neurotransmitters, and increased stress response, immature and dysfunctional glial cells, impaired synaptic pruning, and myelination. Thus, deregulation of the MGB axis affects the higher psychological functions such as mood, emotion, cognition and memory by altered neural circuitry.
Figure 2
Figure 2
Composition and relative abundance of gut microbiota of mice subjected to chronic unpredictable mild stress (CUMS). The four groups are mice divided into no CUMS, CUMS (CUMS+ vehicle (0.9% saline)), CUMS mice treated with imipramine (CUMS + imipramine), and alkaloids (CUMS + alkaloids). (A) Chao1 index of imipramine and alkaloids-treated mice was reduced, but there was no significant difference in their diversity compared to saline treated CUMS mice. (B) The principal coordinates analysis (PCoA) based on the Bray–Curtis distance for GM showed a significant difference in microbial clusters among CUMS + imipramine and CUMS + alkaloids groups. Ellipses refer to 95% confidence intervals between treatments. (C) Taxonomic tree of GM represented in packed circles. The phylum level is denoted by the largest circles, while the inner circles are denoted by class, order, family, and genus. Firmicutes, Bacteroidetes, and Proteobacteria are found to be the dominant phyla. (D) Treatment with imipramine and alkaloids increased the Firmicutes, and decreased Bacteroidetes and Proteobacteria content. (E) Bar chart represents the specific changes in the relative abundance of GM between CUMS, CUMS + imipramine and CUMS + alkaloids groups at the genus level. * Denotes significant differences in specific microbes between groups. (F) Linear discriminant analysis scores on the cladograms of amplicon sequence variant is more than 2 based on linear discriminant analysis effect size [156].
Figure 3
Figure 3
Gut microbiota diversity in healthy control and bipolar disorder subjects before and after treatment (Quetiapine, atypical antipsychotic medication). (A) α-diversity between control and untreated or treated subjects. (B) α-diversity between untreated and quetiapine treated subjects. As per the Shannon (A1), Simpson (A2) or obs (A3) indexes analyses, there is no significant difference in GM diversity between control and bipolar disorder subjects before treatment. However, treatment with quetiapine produced a significant difference in α-diversity between control and treated subjects. On the other hand, treatment with quetiapine improved the α-diversity in bipolar subjects when compared to the untreated subject. This effect was observed with the Shannon (B1) and obs (B3) indexes, but not in the Simpson index (B2) (the figure is reused as per journal copyright permission [245]).
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