Microbiome, inflammation, epigenetic alterations, and mental diseases

Abstract

Major mental diseases such as autism, bipolar disorder, schizophrenia, and major depressive disorder are debilitating illnesses with complex etiologies. Recent findings show that the onset and development of these illnesses cannot be well described by the one-gene; one-disease approach. Instead, their clinical presentation is thought to result from the regulative interplay of a large number of genes. Even though the involvement of many genes are likely, up regulating and activation or down regulation and silencing of these genes by the environmental factors play a crucial role in contributing to their pathogenesis. Much of this interplay may be moderated by epigenetic changes. Similar to genetic mutations, epigenetic modifications such as DNA methylation, histone modifications, and RNA interference can influence gene expression and therefore may cause behavioral and neuronal changes observed in mental disorders. Environmental factors such as diet, gut microbiota, and infections have significant role in these epigenetic modifications. Studies show that bioactive nutrients and gut microbiota can alter either DNA methylation and histone signatures through a variety of mechanisms. Indeed, microbes within the human gut may play a significant role in the regulation of various elements of "gut-brain axis," via their influence on inflammatory cytokines and production of antimicrobial peptides that affect the epigenome through their involvement in generating short chain fatty acids, vitamin synthesis, and nutrient absorption. In addition, they may participate in-gut production of many common neurotransmitters. In this review we will consider the potential interactions of diet, gastrointestinal microbiome, inflammation, and epigenetic alterations in psychiatric disorders.

Keywords: epigenetics; inflammation; microbiome; nutrition; psychiatric disorders.

FIGURE 1

Interplay of nutrition, microbiome, and epigenome. This is a simplified depiction of what happens in the GI tract, and how the outcome in the form of metabolites and byproducts can ultimately affect the epigenetics in other tissues of the body. This change can be the result of direct interaction between these metabolites or secondary to activation of an immune response

FIGURE 2

Cell-cell interactions in an immune response. When Antigen Presenting Cell (APC) comes in contact with Th0 (naïve T cell) the faith of immune response is decided. Th0 have the potential to differentiate to inflammatory Th1 cells or Th2 helper cells. This is done by cytokines in the environment, which are influenced by the antigen being presented via APC. Antigen induced IL4 production favors Th2 generation while IL12 favors Th1 cells. Once the faith of immune pathway is decided other Interleukins will inhibit the alternative pathways. IFN produced by Th1 will inhibit the differentiation of Th2 and in return IL4 produced by Th2 will inhibit Th1. Th17 is another subset of helper T cells. Th17 is a part of adoptive immune response and also play a significant role in maintaining mucosal barriers and contribute to pathogen clearance at mucosal surfaces. TGFβ, IL6, IL21, and IL23 contribute to Th17 differentiation. Another subpopulation of T cells is regulatory T cells (Th-reg). These actively suppress activation of the immune system and prevent pathological self-reactivity, that is, autoimmune disease. In the presence of TGFβ and IL4 naïve T cells can transform to T9 helper cells. The main product of Th9 is IL9, which is one of the major interleukins in mast cell production and T cell growth. It also stimulates mast cell accumulation in tissues, promotes ILC survival, enhances class-switching to IgE in B cells and alters haematopoietic progenitor cell activity.T Follicular Helper (Tfh) Cells are the T cells responsible for antigen specific B-Cell immunity. Tfh helps B-cells to produce antigen specific antibodies and form long term memory cells. Solid arrows indicate stimulatory and dashed arrows indicate inhibitory effects