Epigenetic Aberrations in Major Psychiatric Diseases Related to Diet and Gut Microbiome Alterations

Abstract

Nutrition and metabolism modify epigenetic signatures like histone acetylation and DNA methylation. Histone acetylation and DNA methylation in the central nervous system (CNS) can be altered by bioactive nutrients and gut microbiome via the gut-brain axis, which in turn modulate neuronal activity and behavior. Notably, the gut microbiome, with more than 1000 bacterial species, collectively contains almost three million functional genes whose products interact with millions of human epigenetic marks and 30,000 genes in a dynamic manner. However, genetic makeup shapes gut microbiome composition, food/nutrient metabolism, and epigenetic landscape, as well. Here, we first discuss the effect of changes in the microbial structure and composition in shaping specific epigenetic alterations in the brain and their role in the onset and progression of major mental disorders. Afterward, potential interactions among maternal diet/environmental factors, nutrition, and gastrointestinal microbiome, and their roles in accelerating or delaying the onset of severe mental illnesses via epigenetic changes will be discussed. We also provide an overview of the association between the gut microbiome, oxidative stress, and inflammation through epigenetic mechanisms. Finally, we present some underlying mechanisms involved in mediating the influence of the gut microbiome and probiotics on mental health via epigenetic modifications.

Keywords: DNA methylation; epigenetic; histone acetylation; mental disease; microbiome; nutrition.

Figure 1

Complex interactions among environmental factors, gut microbiome, genome, and epigenome. Diverse environmental factors affect food quality and microbial habitat, thus influencing gut microbiome construction and composition that in turn alter the way they process food generating bioactive compounds and nutrients which affect the human epigenome and gene expression levels. However, external environmental factors and genetic construction can modify the epigenetic landscape as well, which in turn affects both gene expression levels and the gut microbiome community.

Figure 2

Microbiota-gut-brain axis. The gut and brain are linked together in three ways, (1) the Vagus nerve; (2) blood which is controlled by the BBB and (3) other tissues that produce varus metabolites and hormones (e.g., insulin). The Vagus nerve creates a direct reciprocal connection between the enteric nervous system (ENS) and the central nervous system (CNS). There are different types of bacteria in the gut either with useful or harmful effects which directly and indirectly may influence the brain functions. Bacterial fermentation metabolic byproducts such as short-chain fatty acids, vitamin B12, folate, choline, methionine, and anti-inflammatory cytokines have useful effects. These metabolic byproducts participate in immune modulation, BBB permeability regulation, optimization of mitochondrial function, neurotransmitter synthesis, neuroprotection, and reprogramming of the cellular epigenome. Harmful bacteria by producing toxins and inflammatory cytokines may cause dysbiosis and leaky gut increasing intestinal barrier permeability, which plays crucial roles in the pathophysiology of different diseases, including mental disorders by translocation of pro-inflammatory factors, chemokines, and pathogens into the blood stream and subsequently disrupting the BBB functions. Green Arrows address beneficial effects and bule arrows address harmful effects.

Figure 3

Schematic representation of the factors that affect the gut microbiome and epigenetic programing in offspring and subsequently influence brain functions and cognition. Diet and other environmental factors such as medications, toxins, contaminants, stress, smoking, addiction, and infection influence the maternal microbiome and epigenome, which in turn alter the offspring’s gut microbiome composition, microbiome-derived metabolites, and epigenetic landscape. These alterations affect brain functions and cognition leading to the development of mental diseases in offspring.

Figure 4

Illustration of the cascade of events during which epigenetically active food-microbiome products finally affect the brain’s molecular events and function, thus cognition. Epithelial cells of the intestinal wall are the first barriers determining which gut compositions can pass through blood circulation. In the next step, blood–brain barrier (BBB) defines what can pass through endothelial cells reaching to brain cells/tissue. A leaky gut or affected BBB may allow unhealthy materials to penetrate through these very important barriers altering the functional status of the affected cells/tissues. Downward arrows indicate decrease and upward arrows indicate increase.