Table 1.

Different dietary regimes and their effects on DNA methylation and the resulting changes in the brain. Abbreviations: AMPA, amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; GluR1, glutamate receptor 1; DA, dopamine; LTP, long-term potentiation; AD, Alzheimer’s disease; PP2A, protein phosphatase; Hcy, homocysteine; DNMT, DNA methyltransferase; DAT, dopamine active transporter; D1R/D2R, dopamine 1/2 receptor; BDNF, brain-derived neurotrophic factor; CDK5, cyclin-dependent kinase 5; Tph1A, tryptophan 5-monooxygenase; PPARα, peroxisome proliferator-activated receptor alpha.

Diet/Supplementation	Changes in Methylation Patterns	Physiological and Behavioural Effects
MCD/MCFD diet	○Global hypermethylation [123] ○Specific methylation of AMPA subunit promotors and GluR1 [32]	Impaired fear extinction [124] and hippocampal-dependent memory [32]. Reduction in GluR1 expression, which increased DA levels in the striatum, resulting in schizophrenia-like behaviours. Reductions in LTP and deficits in synaptic plasticity [32,128,129].
Supplementation of Methionine/Choline	○Global DNA hypermethylation [33]	Ameliorated depressive-like symptoms resulting from maternal deprivation in rats [33]. Choline improved visual attention tasks/affective neural functioning and hippocampal neurogenesis. Evidence to suggest it may mitigate the pathogenesis of schizophrenia/AD [161,162].
Choline Deficiency	○Changes in global methylation patterns [100]	Learning and memory deficits [100].
Folate Deficiency	○Hypomethylation [160] ○Reduced methylation of PP2A gene [158,159]	Cognitive impairment [96], increased Hcy and oxidative stress [160]. Impaired abstract reasoning, visuospatial memory and attention [163,164,165] Hyperphosphorylated tau (associated with AD) and increased DNMT1 mRNA [158,159].
High Fat Diet	○Global DNA hypermethylation [127,135,136,137] ○Hypermethylation of dopaminergic genes: DAT, tyrosine hydroxylase, D1R and D2R [34,125] ○Hypermethylation of BDNF [133,134] ○Hypomethylation of dopaminergic genes in hypothalamus [125] ○Hypomethylation of CDK5 [153]	Hypermethylation: Downregulation of D2Rs in the striatum (rescued by oryzanol) [34] and the VTA, which was reported to give rise to anhedonia and addiction-like behaviours [125,127], as well as exacerbation of schizophrenia symptoms [135], hyperactivity and cognitive impairment [136,137]. Hypomethylation: increased CDK5 expression and resulting tau hyperphosphorylation. Followed by memory impairments in mice [153]. Increase of DRs in hypothalamus resulting in compulsive eating [125].
SCFAs	○Reversal of exon IV BDNF hypermethylation (Omega-3) [143,144]	Increased BDNF expression, and improvement in spatial learning and memory [145,146]. Dysregulation associated with suicide status via p38 mitogen kinase pathway [147,148].
Caloric Restriction	○Changes in the pattern of CG and CH methylation [36]	Improved cognition and neurogenesis in mice [36]
Probiotics	○Global changes in DNA methylation patterns including BDNF and Tph1A [76]	Improved behaviour, mood and cognition [76,77,78]
Low Protein	○Hypermethylation of (potential) PPARα enhancer [154]	Reductions in PPARα increase amyloid fibrils (associated with AD) [154]. There is evidence to suggest that an increase in PPARα improves memory and anxiety in AD mice [157].
Zinc Deficiency	○BDNF exon IX hypermethylation	Decreased expression of BDNF and DMNT3a and upregulation of DNMT1 [138]. Implicated in depression, particularly treatment-resistant [139,142].
Vitamin B
Pan-vitamin B Supplementation	○Hypermethylation of Redox Genes [119]	Improved cognitive performance [119]
Vitamin B2 Supplement (Riboflavin)	○Unexplored	Improved global cognitive function in elderly human subjects [99]
Vitamin B6 Deficiency	○Hypomethylation [reviewed in [166]	Increased brain levels of Hcy, exacerbating AD pathology and symptoms of cognitive impairment [167].
Vitamin B12 Supplement	○Unexplored	Improved cognition, decreased Hcy [168,169]
Vitamin B12 Deficiency	○Unexplored	Correlates with paresthesia, peripheral neuropathy and psychosis in vegetarians [170].