Dietary Modulation of the Immune System

Abstract

Recent insights into the influence of nutrition on immune system components have driven the development of dietary strategies targeting the prevention and management of major metabolic-inflammatory diseases. This review summarizes the bidirectional relationship between nutrition and immunocompetence, beginning with an overview of immune system components and their functions. It examines the effects of nutritional status, dietary patterns, and food bioactives on systemic inflammation, immune cell populations, and lymphoid tissues, as well as their associations with infectious and chronic disease pathogenesis. The mechanisms by which key nutrients influence immune constituents are delineated, focusing on vitamins A, D, E, C, and B, as well as minerals including zinc, iron, and selenium. Also highlighted are the immunomodulatory effects of polyunsaturated fatty acids as well as bioactive phenolic compounds and probiotics, given their expanding relevance. Each section addresses the implications of nutritional and nutraceutical interventions involving these nutrients within the broader context of major infectious, metabolic, and inflammatory diseases. This review further underscores that, while targeted nutrient supplementation can effectively restore immune function to optimal levels, caution is necessary in certain cases, as it may increase morbidity in specific diseases. In other instances, dietary counseling should be integrated to ensure that therapeutic goals are achieved safely and effectively.

Keywords: chronic diseases; immunity; infection; inflammation; nutrients.

Figure 1

A schematic representation of the anatomical localization of the components of the immune system and leucocyte differentiation in the bone marrow and thymus. The skin and mucosal membranes form the first line of defense, acting as physical barriers that prevent pathogen entry. These surfaces are coated with beneficial microorganisms that secrete antimicrobial substances and mucus to inhibit pathogen colonization. Immune cells originate from hematopoietic stem cells (HSCs) in bone marrow, differentiating into myeloid progenitor cells (MPCs) or lymphoid progenitor cells (LPCs) based on microenvironmental signals. MPCs produce eosinophils, basophils, neutrophils, and monocytes, with monocytes further maturing into dendritic cells or macrophages. LPCs give rise to T cells, B cells, and NK cells. T cells complete their differentiation in the thymus, becoming regulatory (Treg), helper (Th), or cytotoxic cells (Tc), while B cells mature in the bone marrow and later differentiate into plasma cells that secrete antibodies upon antigen exposure. Secondary lymphoid organs support antigen presentation, lymphocyte activation, and immune response generation. Gut-associated lymphoid tissue (GALT) is the largest component of the immune system, while the liver and white adipose tissue (WAT) contribute to immunity by producing innate immune proteins, cytokines, and immunomodulatory molecules.

Figure 2

Malnutrition and obesity profoundly affect the bone marrow, thymus, and mucosa, disrupting their structure, cellular composition, and function. In primary lymphoid organs, malnutrition induces atrophy and hypocellularity, significantly reducing hematopoietic stem cells and thymocytes. In the mucosa, it leads to epithelial atrophy and impaired integrity, which compromises secretion, absorption, and cellular renewal. Obesity, on the other hand, increases adiposity in the bone marrow and thymus, accelerating age-related involution and impairing lymphopoiesis and immune function. It also heightens mucosal inflammation and permeability. Deficiencies in zinc, iron, selenium, and B vitamins lead to the bone marrow and thymus changes seen in malnutrition, while deficits in vitamins A, D, and C are linked to mucosal dysfunction. Importantly, immune organ impairments associated with obesity are induced and further exacerbated by high-fat or Western diets (detailed information is provided in the following sections).

Figure 3

Macrophage activation (1) involves migration (2), phagocytosis (3), and the destruction of engulfed antigens (4). Pro-inflammatory signals such as cytokines or lipopolysaccharides (LPS) activate Toll-like (TLR) or interleukin receptors (IR), respectively, leading to the translocation of NF-κB to the nucleus, enhancing the transcription of pro-inflammatory genes. Simultaneously, cytosolic phospholipase A2 (cPLA2) releases arachidonic acid (AA) from membrane phospholipids, which is metabolized by cyclooxygenase-2 (COX-2) into prostaglandin E2 (PGE2). PGE2 acts in a paracrine manner through prostaglandin E2 receptor (EP2), further activating NF-κB and amplifying inflammatory responses. The cytokines produced reinforce pro-inflammatory activity by increasing oxidative stress and recruiting additional immune cells, thereby amplifying inflammation. Nutrients play a critical role in modulating these pathways. Vitamin C, vitamin D, and selenium exert antioxidant effects, inhibiting COX-2 activity and reducing oxidative damage caused by the respiratory burst that liberates reactive oxygen species (ROS). Omega-3 fatty acids (Ω-3) compete with AA for COX-2, producing PGE3, resolvins (D-series and E-series) that promote inflammation resolution. Vitamin D enhances the expression of antimicrobial peptides such as defensins and cathepsins. Iron supports the activity of myeloperoxidase (MPO), whereas zinc is vital for the functionality of the NADPH oxidase complex, both enzymes crucial to producing hypochlorous acid and superoxide to kill pathogens in the phagolysosome. Immune components rely on these nutrients for optimal function, and deficiencies impair the immune response, increasing susceptibility to infections or exacerbating collateral tissue damage caused by excessive inflammation.

Figure 4

Commensal microorganisms and probiotics enhance mucosal integrity and promote anti-inflammatory processes in gut-associated lymphoid tissue. They are detected by receptors such as TLR (Toll-like receptor) and GPR (G protein-coupled receptor), enzymes like HDAC (histone deacetylase), and transcription factors such as AhR (aryl hydrocarbon receptor). Upon activation, these pathways stimulate epithelial differentiation and the production of structural proteins, defensins, and mucus, strengthening the mucosal barrier. Critical microbial products include polysaccharide A (PSA), short-chain fatty acids (SCFAs), phenolic compound metabolites, and bacteriocins. Unmetabolized polyphenols also exhibit antiviral and antimicrobial properties and promote epithelial differentiation. Probiotics and polyphenols further modulate immunity by driving the development of tolerogenic dendritic cells (DCs), which secrete anti-inflammatory cytokines like TGF-β and IL-10. DCs promote B-cell differentiation into IgA-secreting cells and induce T cells to adopt a regulatory phenotype (Tregs), creating an anti-inflammatory environment and enhancing barrier defenses. Additionally, omega-3 fatty acids (Ω-3), vitamin D, and vitamin A support tolerogenic DC development through their interactions with transcription factors peroxisome proliferator-activated receptor gamma (PPAR-γ), RXR (retinoic X receptor), and VDR (vitamin D receptor), respectively. These vitamins are also crucial for mucosal differentiation and function, emphasizing their essential role in maintaining gastrointestinal health.