A literature search was conducted to identify relevant peer-reviewed articles, reviews, and key seminal papers. Primary databases included PubMed/MEDLINE, Web of Science Core Collection, and Scopus. The search period spanned from 2008 to 2025, ensuring the inclusion of foundational and highly contemporary research within the rapidly evolving fields of immunometabolism and nutritional immunology.

The search strategy combined controlled vocabulary (e.g., MeSH terms) and free-text keywords organized into three conceptual domains relevant to the scope of this review.

Domain 1 (Immunometabolism): “immunometabolism,” “immune cell metabolism,” “metabolic reprogramming,” “glycolysis,” “oxidative phosphorylation,” “fatty acid oxidation,” “macrophage polarization,” “T cell metabolism.”

Domain 2 (Nutrition/Diet): “diet,” “nutrition,” “macronutrient,” “micronutrient,” “Mediterranean diet,” “Western diet,” “ketogenic diet,” “fasting,” “probiotics,” “prebiotics,” “polyphenols.”

Domain 3 (Disease and physiology): “metaflammation,” “obesity,” “type 2 diabetes,” “NAFLD/NASH,” “atherosclerosis,” “insulin resistance,” “adipose tissue inflammation,” “gut microbiota.”

Boolean operators (AND, OR) were used to combine these domains to identify studies linking diet, immune metabolism, and metabolic disease (e.g., (Domain 1) AND (Domain 2)). The reference lists of identified key review articles and seminal papers were manually scanned (backward snowballing) to ensure inclusion of foundational and highly relevant studies not captured by the initial database search.

Identified records were screened for relevance in a two-stage process based on title/abstract and subsequent full-text review.

Studies were included when they met the following criteria:

1.

Publication in English in a peer-reviewed journal.

Studies were excluded if they focused exclusively on:

1.

Undernutrition or protein-energy malnutrition without a metabolic disease link.

Data from included studies were extracted and organized thematically according to the pre-defined structure of this review (e.g., foundational metabolic pathways, macronutrient effects, gut microbiota axis, disease-specific mechanisms).

For each thematic area, key findings, mechanistic insights, and experimental models were summarized to construct an integrated conceptual framework linking diet to immune metabolic programming.

Given the narrative and integrative scope of this review, a formal quantitative meta-analysis was not performed. Instead, a qualitative synthesis was employed to identify consensus views, elucidate mechanistic frameworks, highlight contradictory findings, and pinpoint emerging trends across the literature.

Particular emphasis was placed on integrating evidence from molecular studies, preclinical models, and human research to bridge mechanistic insights and clinical relevance in metabolic diseases. Figures were created using PowerPoint and Inkscape, which are widely used for scientific diagram preparation and do not require external image licensing.

As a broad-scope narrative review, this work has inherent limitations. The vast and interdisciplinary nature of the topic precludes an exhaustive citation of all relevant literature.

While the literature search followed structured conceptual domains, the selection of studies inevitably reflects an interpretive synthesis rather than a strictly systematic review methodology.

Furthermore, the synthesis of evidence is interpretive, drawing connections across different experimental systems (cell culture, animal models, human studies) with varying levels of physiological relevance. These limitations are acknowledged, and the review aims to provide a conceptual roadmap and a state-of-the-art synthesis to inform future hypothesis-driven research and systematic reviews on more focused questions within this field.

Although many mechanistic insights into immunometabolism originate from cellular and animal studies, translation to human physiology remains challenging because of species differences in immune regulation, diet handling, and gut microbiome structure [34–36].

Immune cells dynamically toggle between several core metabolic pathways, with the balance primarily dictated by activation status, environmental cues, and cellular function.

Glycolysis is the cytosolic breakdown of glucose to pyruvate, yielding a rapid but low-efficiency ATP gain. Its critical role in immunity extends far beyond energy production. Rapid glycolytic upregulation is a hallmark of innate immune cell activation (e.g., in macrophages, dendritic cells) and effector T cell responses, a process potentiated by HIFs [38, 39]. This so-called “aerobic glycolysis” or the Warburg effect provides swift ATP and, crucially, generates metabolic intermediates for biosynthetic pathways (pentose phosphate pathway for nucleotides, glycerol for lipids) necessary for cell growth, proliferation, and cytokine production [40]. In T cells, glycolysis is indispensable for robust activation and function; it fuels phosphoinositide 3-kinase (PI3K) signaling to bolster clonal expansion and effector cytokine production [41]. Conversely, its inhibition can lead to functional exhaustion [42, 43]. In innate cells like macrophages and natural killer (NK) cells, glycolytic flux is essential for pro-inflammatory (M1) polarization, antimicrobial activity, and cytotoxic function [44, 45]. However, this pathway is also co-opted in pathological states, contributing to autoimmunity and providing an immunosuppressive milieu in the tumor microenvironment [46–48].

OXPHOS is the high-yield ATP production pathway in mitochondria, coupling the electron transport chain (ETC) with ATP synthase. It is the dominant metabolic mode in quiescent, memory, and anti-inflammatory immune cells, supporting long-term survival and homeostasis. Naïve and memory T cells rely on OXPHOS fueled by fatty acid oxidation (FAO) and pyruvate from glycolysis [49]. Regulatory T cells (Tregs) also depend on robust OXPHOS for their suppressive function and stability. Impairment of mitochondrial OXPHOS, often due to persistent antigen exposure, is a key driver of T cell exhaustion, limiting their proliferative and effector potential [50, 51]. In macrophages, OXPHOS is characteristic of alternatively activated (M2) cells, supporting their tissue-reparative functions [52]. Recent evidence indicates that enhanced mitochondrial OXPHOS in B cells is associated with increased antibody production and disease progression in conditions such as systemic lupus erythematosus [53]. Furthermore, OXPHOS is vital for the function of B cells and plasma cells, supporting antibody production and, when dysregulated, contributing to inflammatory pathologies like lupus and multiple sclerosis [53–55]. Its role is complex in cancer, as it can both support antitumor immune functions and confer therapy resistance [56, 57].

FAO is the mitochondrial process of breaking down fatty acids into acetyl-CoA for entry into the Krebs cycle to fuel OXPHOS. It is a critical metabolic pathway for immune cells requiring sustained energy and resilience. Memory CD8+ T cells and Tregs heavily utilize FAO to maintain their longevity and functional fitness [49]. In macrophages, FAO is a metabolic signature of M2 polarization and is crucial for their anti-inflammatory and tissue-remodeling activities. For instance, peroxisome proliferator-activated receptor gamma (PPARγ)-dependent induction of FAO is central to alternative macrophage activation [58, 59]. Conversely, inhibition of FAO can promote a more pro-inflammatory, antimicrobial macrophage phenotype, as seen in responses to Mycobacterium tuberculosis [60, 61]. In pathological contexts, tumor-associated macrophages (TAMs) and glioblastoma cells can use FAO to support immunosuppression and resistance to therapy [62, 63].

Amino acid metabolism is indispensable for protein synthesis, but specific amino acids also serve as key signaling molecules and fuel for the Krebs cycle (anaplerosis). Glutamine is the most abundant amino acid and a primary anaplerotic substrate. Its metabolism supports nucleotide biosynthesis and redox balance (via glutathione production), making it vital for proliferating effector T cells and activated macrophages [64]. Arginine metabolism creates a critical bifurcation: it can be metabolized by inducible nitric oxide synthase (iNOS) in M1 macrophages to produce nitric oxide (NO, antimicrobial), or by arginase-1 in M2 macrophages and myeloid-derived suppressor cells (MDSCs) to produce ornithine and polyamines, promoting tissue repair and immunosuppression, respectively [65]. Tryptophan catabolism, particularly via the enzyme indoleamine 2,3-dioxygenase (IDO), depletes this essential amino acid and generates immunosuppressive kynurenines, shaping T cell responses and promoting tolerance [66]. The uptake and metabolism of these amino acids are tightly regulated by specific transporters and enzymes, presenting key nodes for immune modulation in cancer and autoimmunity [67, 68].

The differential engagement of these core pathways underlies the functional specialization of immune cell subsets. The key mechanisms underlying these immune cell metabolic states are summarized in Table 1 and supported by prior studies on glycolysis, OXPHOS, FAO, and amino acid metabolism.

1.

Beyond macronutrients, essential micronutrients and dietary bioactive compounds serve as critical cofactors and signaling molecules that fine-tune immunometabolism, ensuring optimal immune responses while preventing excessive inflammation [103].

The synergistic and antagonistic interactions between individual nutrients are integrated at the level of whole dietary patterns, which exert sustained effects on systemic immunometabolism.

The Western diet, characterized by high intake of saturated fats, refined sugars, processed meats, and low fiber, is a primary driver of metaflammation [98, 116]. This pattern promotes pro-inflammatory immune activation through excess metabolic substrates and gut microbiota disruption, contributing to chronic low-grade inflammation and metabolic disease development [117].

In stark contrast, the Mediterranean diet, rich in fruits, vegetables, whole grains, legumes, nuts, olive oil, and fatty fish, is a paradigm of an anti-inflammatory dietary pattern [100]. Its benefits are attributed to high fiber intake, favorable fatty-acid composition, and abundant polyphenols, which support regulatory immune responses and reduced inflammatory biomarkers [101, 118].

Ketogenic diets and intermittent fasting represent dietary interventions that impose a metabolic shift from glucose toward fatty acid and ketone metabolism. These interventions promote metabolic flexibility and can suppress inflammatory signaling pathways while supporting mitochondrial function and immune regulation [102, 119].

Plant-based diets, when well planned, are rich in fiber, polyphenols, and unsaturated fats while low in saturated fat. These diets promote beneficial gut microbiota activity and the production of immunoregulatory metabolites that support balanced immune metabolism [120].

CR without malnutrition is another dietary intervention associated with improved metabolic and immune regulation [120]. CR enhances insulin sensitivity and mitochondrial efficiency while reducing inflammatory mediators and age-related immune dysfunction [121–123].

The relationship between dietary patterns, microbial metabolites, and immune cell metabolic programming is illustrated in Figure 1.

Long-term dietary patterns imprint distinct microbial signatures. Diets rich in fiber and plant polyphenols, such as the Mediterranean diet, promote the abundance of SCFA-producing bacteria (e.g., Faecalibacterium, Roseburia) and increase microbial diversity [124]. In contrast, the Western diet, high in saturated fats and refined sugars, drives a state of dysbiosis characterized by reduced microbial diversity and expansion of pro-inflammatory microbes [121, 125]. This dysbiotic shift compromises intestinal barrier integrity and facilitates translocation of microbial products such as LPS into circulation, contributing to metabolic endotoxemia and systemic inflammation [126].

The fermentation of dietary fiber by commensal bacteria yields SCFAs, principally acetate, propionate, and butyrate [121]. These metabolites influence immune function by regulating gene expression through histone deacetylase inhibition and activation of G-protein-coupled receptors such as G protein-coupled receptor 43 (GPR43) and GPR109A [62]. Certain vitamins influence the composition of the gut microbiota [103]. SCFAs contribute to immune regulation and intestinal homeostasis while influencing inflammatory responses through microbiota-mediated metabolic pathways [127, 128].

In obesity and metabolic syndrome, dysbiosis is a hallmark feature that contributes to disease pathogenesis [52]. Altered microbial composition is associated with reduced SCFA production, increased gut permeability, and elevated systemic inflammation [99]. This disruption affects the gut-liver axis, promoting hepatic steatosis and inflammatory signaling, and may also influence appetite regulation through the gut-brain axis [129, 130]. Microbiota alterations induced by high-fat diets can further promote inflammatory macrophage accumulation in adipose tissue and impair insulin signaling. Consequently, dietary strategies aimed at restoring microbial balance, including increased fiber intake and microbiota-targeted interventions, may help correct immunometabolism dysfunction [120, 130]. Recent advances in multi-omics approaches have enabled deeper characterization of the microbiome and its association with metabolic and inflammatory diseases [131].

The key immunomodulatory metabolites derived from the gut microbiota, their dietary origins, and their mechanisms of action are summarized in Table 3.

mTOR complex 1 acts as a central metabolic regulator activated by nutrients and growth signals [144]. In immune cells, mTOR signaling promotes glycolytic metabolism and supports differentiation of pro-inflammatory immune subsets such as Th1, Th17, and M1 macrophages. Conversely, reduced mTOR activity, such as during CR, favors oxidative metabolism and regulatory immune phenotypes, including Tregs and M2 macrophages [145].

AMPK functions as a cellular energy sensor activated during nutrient scarcity or energetic stress. It counteracts mTOR signaling and promotes catabolic metabolism, including FAO and mitochondrial biogenesis [146]. AMPK activation also suppresses inflammatory signaling pathways and supports anti-inflammatory macrophage polarization, with potential therapeutic relevance in metabolic diseases such as NASH [147, 148].

HIF-1α is a transcriptional regulator that promotes glycolysis under hypoxic or inflammatory conditions [39, 71]. Stabilization of HIF-1α enhances glucose uptake and glycolytic enzyme expression, thereby promoting pro-inflammatory immune responses in macrophages and effector T cells [71]. Metabolic stress in tissues such as obese adipose tissue can therefore reinforce inflammatory immune activation through sustained HIF-1α signaling [149].

PPAR family members (PPARα, β/δ, and γ) regulate lipid metabolism and inflammatory gene expression. PPARγ promotes fatty-acid metabolism and supports alternative macrophage activation while repressing NF-κB-mediated inflammatory signaling [76]. Disruption of PPAR signaling by unhealthy dietary patterns may therefore contribute to metabolic inflammation [128].

SIRTs are NAD⁺-dependent deacylases that link cellular metabolic state to transcriptional and epigenetic regulation. SIRT1 activation during energy restriction enhances mitochondrial biogenesis through PGC-1α and suppresses inflammatory pathways, including NF-κB and HIF-1α signaling [144, 145]. These actions connect dietary restriction with improved metabolic and immune regulation [147].

NF-κB is a central transcription factor controlling inflammatory gene expression. It is activated by pattern-recognition receptor signaling and metabolic stress signals such as SFAs [148]. Activation of NF-κB drives production of cytokines, including TNF-α, IL-1β, and IL-6. In contrast, several dietary components—including polyphenols, omega-3 fatty acids, and microbial metabolites—can suppress NF-κB activity and thereby reduce inflammatory signaling [148, 149].

Recent studies (2023–2026) indicate that dietary interventions may modulate immunometabolism through epigenetic mechanisms and microbiota-derived metabolites. Early clinical evidence suggests that targeting these pathways through dietary strategies could improve inflammatory and metabolic outcomes.

Obesity is characterized by chronic low-grade inflammation originating primarily from the expansion and dysfunction of white adipose tissue (WAT). As adipocytes enlarge under nutrient excess, they release inflammatory mediators and stress signals that recruit immune cells to adipose tissue [88, 152]. Circulating monocytes differentiate into pro-inflammatory adipose tissue macrophages (ATMs), which accumulate around damaged adipocytes and secrete cytokines such as TNF-α, IL-6, and IL-1β [153, 154]. This inflammatory signaling disrupts insulin signaling pathways and promotes systemic metabolic inflammation that contributes to insulin resistance and other obesity-associated complications [155, 156].

T2D develops through a combination of insulin resistance and progressive pancreatic β-cell dysfunction, both strongly influenced by immune-mediated inflammation. Macrophage-derived cytokines such as TNF-α and IL-1β impair insulin signaling pathways in metabolic tissues, thereby exacerbating systemic insulin resistance [157, 158]. Persistent inflammatory signaling within pancreatic islets further contributes to β-cell stress, reduced insulin secretion, and eventual β-cell apoptosis [159, 160]. These processes link chronic metabolic inflammation with the progression from insulin resistance to overt diabetes.

The progression from simple steatosis to inflammatory NASH is largely mediated by liver immune cells, particularly Kupffer cells. Dietary lipids and gut-derived endotoxins activate Kupffer cells, which produce inflammatory cytokines and recruit additional monocytes to the liver [161, 162]. These immune responses promote hepatocyte injury and activate hepatic stellate cells, leading to liver inflammation and fibrosis [163, 164]. Persistent immunometabolism dysregulation therefore drives disease progression from benign fat accumulation to more severe hepatic pathology.

Atherosclerosis is a chronic inflammatory disease of the vascular wall characterized by interactions between lipid metabolism and immune activation. Circulating monocytes are recruited to the arterial intima, where they differentiate into macrophages that accumulate modified lipids and form foam cells, a defining feature of atherosclerotic plaques [165]. These foam cells release inflammatory mediators that promote plaque growth and instability [166–168]. Dietary factors that increase circulating lipids can accelerate this process, whereas anti-inflammatory dietary components may help reduce vascular inflammation and improve plaque stability [169, 170].

A comparative overview of the immunometabolism dysregulation in key diet-related diseases is presented in Table 4, which highlights the tissue-specific immune players, dietary drivers, and consequent pathogenic outcomes discussed below.

Targeted supplementation with vitamins, minerals, and bioactive compounds can support immune metabolism and reduce inflammatory signaling when deficiencies are present. For example, vitamin D influences antimicrobial responses and Treg differentiation, while zinc and polyphenols modulate immune signaling pathways linked to inflammation and insulin sensitivity [29, 174].

Dietary patterns such as the Mediterranean diet, ketogenic diets, and intermittent fasting can influence immunometabolism pathways through alterations in nutrient availability and metabolic signaling. These approaches have been associated with improvements in inflammatory markers, metabolic flexibility, and cardiometabolic health outcomes [175, 176].

Probiotics, prebiotics, synbiotics, and postbiotics aim to restore beneficial gut microbial activity and enhance production of immunoregulatory metabolites such as SCFAs, thereby influencing systemic immune and metabolic regulation [177–179]. Nutritional strategies targeting immunometabolism regulation are summarized in Table 5.

The effects are often strain-specific, dose-dependent, and subject to high inter-individual variability based on the host’s existing microbiota, underscoring the need for a personalized approach [184].

Precision nutrition seeks to tailor dietary strategies to an individual’s metabolic, genetic, and microbiome profile in order to improve metabolic and immune outcomes [185]. Approaches may incorporate biomarker profiling, microbiome analysis, and individualized dietary planning to optimize metabolic responses and inflammatory regulation [124, 186–192]. Advances in omics technologies, including genomics, metabolomics, and microbiome analysis, have enabled the development of personalized nutrition strategies based on gene–diet interactions and individual metabolic profiles [193].