Dietary modulation of the gut–immune–brain axis: nutritional immunoepigenomics for immune regulation in autoimmunity, cancer, and infection

The gut microbiota is emerging as a master regulator of immune homeostasis across infections, cancer, and neuroinflammatory disorders. Dietary inputs dynamically shape microbial ecosystems and induce durable epigenetic reprogramming of host immunity a convergence now defined as nutritional immunoepigenomics. This review posits that specific nutrients (e.g., soluble fibers, omega-3 fatty acids, polyphenols) promote anti-inflammatory microbial profiles that generate metabolites such as short-chain fatty acids and tryptophan catabolites. These act as epigenetic modifiers regulating histone marks (H3K27ac, H3K9me3) and DNA methylation in Tregs, Th17 cells, dendritic cells, and microglia thus modulating immune tolerance and neuroimmune surveillance. I further explore how ketogenic diets and intermittent fasting influence microbiota epigenome signaling. Integrating findings from preclinical and human studies, and highlight translational advances in spectroscopy and multi-omics for non-invasive monitoring of diet-induced immunoepigenetic states. This review advocates precision dietary strategies as programmable modulators of the gut–immune–brain axis to enhance immunological resilience and therapeutic potential. Gut–Brain–Immune Axis: Communication, Modulation, and Disease Outcomes- This graphical abstract illustrates the multidirectional interplay among the gut, brain, immune system, and diet, emphasizing how microbial, immune, neuroendocrine, and epigenetic pathways coalesce to shape systemic and central nervous system (CNS) health. A. Communication Pathways of the Gut–Brain Axis - This section outlines the primary signaling axes that bridge the gut and brain: Nervous System : The vagus nerve and enteric nervous system relay microbial and neurochemical signals (e.g., GABA, serotonin, amino acids) to the CNS. Immune System: Cytokines such as IL-1β, IL-6, TNF-α, and IL-10 transmit peripheral immune activity to the brain, influencing neuroinflammation. Endocrine System : The hypothalamic–pituitary–adrenal (HPA) axis and gut hormones (e.g., cortisol, leptin, GLP-1) modulate neuroimmune signaling. Microbial Products : Metabolites like short-chain fatty acids (SCFAs: butyrate, propionate, acetate) impact both immune and neuronal circuits. Systemic and CNS Circulation : Pro-inflammatory cytokines and immune cell trafficking influence microglial activation and brain homeostasis. Intestinal Interface : Dietary tryptophan metabolism, microbial neurotransmitters (5-HT, GABA), and epithelial cell crosstalk shape immune tone through the gut-associated lymphoid tissue (GALT) . B. Neuroimmune Outcomes in Disease Context- Dysregulation of gut–brain–immune signaling is linked to a spectrum of diseases: Autoimmune Disorders (e.g., MS): Aberrant T cell responses attack CNS tissues. Infectious Diseases: Gut or systemic infections can prime immune activation and secondary CNS involvement. Cancer: Immunoediting and systemic inflammation influence tumor immune evasion. Neuroinflammation: Elevated TSPO expression (PET imaging) marks activated microglia; gut dysbiosis and “leaky gut” contribute to systemic inflammation and CNS effects. C: Epigenetic Rewiring of Immune Cells- This panel highlights the role of dietary and microbial signals in modulating immune cell plasticity via epigenetic changes: Histone Modifications : Marks like H3K27ac (activation) and H3K9me3 (repression) govern gene expression in T cells and dendritic cells. Treg Induction: SCFAs and polyphenols inhibit histone deacetylases (HDACs), favouring regulatory T cell (Treg) development and tolerance induction. D: Dietary Patterns and Bioactive Nutrients - Diet shapes microbiota composition and immune function: Mediterranean and High-Fiber Diets : Promote microbial diversity, SCFA production, and anti-inflammatory immunity. Ketogenic Diet: Alters microbiota and immune metabolism through high-fat intake. Ultra-Processed Foods: Rich in saturated fats and low in fiber, associated with microbial dysbiosis and pro-inflammatory responses. The cumulative influence of these dietary patterns modulates host immunity via microbial metabolites, epigenetic regulators, and neuroimmune crosstalk , thus contributing to disease resilience or susceptibility. DC (dendritic cell), EC (epithelial cell), EEC (enteroendocrine cell)