Methamphetamine, one of the most frequently used illicit drugs worldwide, can induce psychosis in a large fraction of abusers and it is becoming a major problem for the health care institutions. There is some evidence that genetic and epigenetic factors may play roles in methamphetamine psychosis. In this study, we examined methamphetamine‐induced epigenetic and expression changes of several key genes involved in psychosis. RNA and DNA extracted from the saliva samples of patients with methamphetamine dependency with and without psychosis as well as control subjects (each group 25) were analyzed for expression and promoter DNA methylation status of DRD1, DRD2, DRD3, DRD4, MB‐COMT, GAD1, and AKT1 using qRT‐PCR and q‐MSP, respectively. We found statistically significant DNA hypomethylation of the promoter regions of DRD3 (P = 0.032), DRD4 (P = 0.05), MB‐COMT (P = 0.009), and AKT1 (P = 0.0008) associated with increased expression of the corresponding genes in patients with methamphetamine psychosis (P = 0.022, P = 0.034, P = 0.035, P = 0.038, respectively), and to a lesser degree in some of the candidate genes in non‐psychotic patients versus the control subjects. In general, methamphetamine dependency is associated with reduced DNA methylation and corresponding increase in expression of several key genes involved in the pathogenesis of psychotic disorders. While these epigenetic changes can be useful diagnostic biomarkers for psychosis in methamphetamine abusers, it is also consistent with the use of methyl rich diet for prevention or suppression of psychosis in these patients. However, this needs to be confirmed in future studies.

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.

Major depressive disorder (MDD) is a complex disorder and a leading cause of disability in 280 million people worldwide. Many environmental factors, such as microbes, drugs, and diet, are involved in the pathogenesis of depressive disorders. However, the underlying mechanisms of depression are complex and include the interaction of genetics with epigenetics and the host immune system. Modifications of the gut microbiome and its metabolites influence stress-related responses and social behavior in patients with depressive disorders by modulating the maturation of immune cells and neurogenesis in the brain mediated by epigenetic modifications. Here, we discuss the potential roles of a leaky gut in the development of depressive disorders via changes in gut microbiota-derived metabolites with epigenetic effects. Next, we will deliberate how altering the gut microbiome composition contributes to the development of depressive disorders via epigenetic alterations. In particular, we focus on how microbiota-derived metabolites such as butyrate as an epigenetic modifier, probiotics, maternal diet, polyphenols, drugs (e.g., antipsychotics, antidepressants, and antibiotics), and fecal microbiota transplantation could positively alleviate depressive-like behaviors by modulating the epigenetic landscape. Finally, we will discuss challenges associated with recent therapeutic approaches for depressive disorders via microbiome-related epigenetic shifts, as well as opportunities to tackle such problems.

Multiple lines of evidence have shown that lactate-mediated pH alterations in the brains of patients with neuropsychiatric diseases such as schizophrenia (SCZ), Alzheimer’s disease (AD) and autism may be attributed to mitochondrial dysfunction and changes in energy metabolism. While neuronal activity is associated with reduction in brain pH, astrocytes are responsible for rebalancing the pH to maintain the equilibrium. As lactate level is the main determinant of brain pH, neuronal activities are impacted by pH changes due to the binding of protons (H⁺) to various types of proteins, altering their structure and function in the neuronal and non-neuronal cells of the brain. Lactate and pH could affect diverse types of epigenetic modifications, including histone lactylation, which is linked to histone acetylation and DNA methylation. In this review, we discuss the importance of pH homeostasis in normal brain function, the role of lactate as an essential epigenetic regulatory molecule and its contributions to brain pH abnormalities in neuropsychiatric diseases, and shed light on lactate-based and pH-modulating therapies in neuropsychiatric diseases by targeting epigenetic modifications. In conclusion, we attempt to highlight the potentials and challenges of translating lactate-pH-modulating therapies to clinics for the treatment of neuropsychiatric diseases.

Obesity (OB) has become a serious health issue owing to its ever-increasing prevalence over the past few decades due to its contribution to severe metabolic and inflammatory disorders such as cardiovascular disease, type 2 diabetes, and cancer. The unbalanced energy metabolism in OB is associated with substantial epigenetic changes mediated by the gut microbiome (GM) structure and composition alterations. Remarkably, experimental evidence also indicates that OB-induced epigenetic modifications in adipocytes can lead to cellular “memory” alterations, predisposing individuals to weight regain after caloric restriction and subsequently inducing inflammatory pathways in the liver. Various environmental factors, especially diet, play key roles in the progression or prevention of OB and OB-related disorders by modulating the GM structure and composition and affecting epigenetic mechanisms. Here, we will first focus on the key role of epigenetic aberrations in the development of OB. Then, we discuss the association between abnormal alterations in the composition of the microbiome and OB and the interplays between the microbiome and the epigenome in the development of OB. Finally, we review promising strategies, including prebiotics, probiotics, a methyl-rich diet, polyphenols, and herbal foods for the prevention and/or treatment of OB via modulating the GM and their metabolites influencing the epigenome.