Essential Minerals And Metabolic Adaptation Of Immune Cells Part 1

Abstract:

Modern lifestyles deviated considerably from the ancestral routines towards major shifts in diets and increased sedentarism. The trace elements status of the human body is no longer adequately supported by micronutrient-inferior farmed meats and crop commodities produced by the existing agricultural food systems. This is particularly evident in the increased obesogenic adipogenesis and low-grade inflammation that fails to resolve with time. The metabolically restrictive environment of the inflamed tissues drives activation and proliferation of transient and resident populations of immune cells in favor of pro-inflammatory phenotypes, as well as a part of the enhanced autoimmune response. 

The relationship between obesity and immunity is very complicated. Most studies have shown that obesity can lead to abnormalities in the immune system, which in turn increases the risk of certain diseases, such as diabetes, cardiovascular disease, and some cancers. Antibody levels to certain infectious diseases. The following is the specific relationship between obesity and immunity:

1. Obesity can lead to chronic inflammation, which in turn affects the regulatory function of the immune system and reduces immunity. This is because obese fat secretes a series of cytokines and inflammatory factors, such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), etc., which Factors cause an inflammatory response, and chronic inflammation can damage the immune system.

2. Fat cells will secrete some unhealthy lipid substances, such as free fatty acids and inflammatory lipid substances. The existence of these substances will interfere with the immune system and reduce its resistance.

3. Obesity will lead to an increase in the number of pro-inflammatory cells, such as macrophages, natural killer cells, and obesity-related T cells, which can release a large number of cytokines and inflammatory factors, further aggravating the inflammatory state of the body.

4. Excessive proliferation of adipocytes leads to immune cell infiltration, which further leads to chronic inflammation and immune system dysregulation.

In conclusion, obesity and fat can negatively affect the immune system, which in turn increases the risk of certain diseases. Therefore, losing weight, improving your eating habits, and maintaining good health can help boost your immune system. From this point of view, we need to pay special attention to the improvement of our immunity. Cistanche can significantly improve immunity. Meat ash contains a variety of biologically active components, such as polysaccharides, two mushrooms, Huang Li, etc. Stimulate various cells of the immune system and increase their immune activity.

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As different stages of the immune activation and resolution depend on the availability of specific minerals to maintain the structural integrity of skin and mucus membranes, activation and migration of immune cells, activation of the complement system, and the release of pro-inflammatory cytokines and chemokines, this review discusses recent advances in our understanding of the contribution of select minerals in optimizing the responses of innate and adaptive immune outcomes. An abbreviated view of the absorption, transport, and delivery of minerals to the body tissues as related to metabolic adaptation is considered.

Keywords:

micronutrient; malnutrition; macrophage polarization; intestinal immunity; mucosal integrity; dietary intervention.

1. Introduction

A new lifestyle has evolved in the last 80 years, owing mostly to changes in dietary habits and a rise in sedentarism. These conditions have resulted in a dramatic increase in the prevalence of non-communicable diseases, including chronic disorders associated with four key metabolic and physiological changes (raised blood glucose, raised LDL cholesterol, excess body weight or obesity, and high blood pressure). Centers for Disease Control and Prevention maps effectively tracked the rise of obesity in the US during this time, with an estimated average gain of 15 kg of body mass, 4.5 BMI units, and 18 cm of waist circumference for an average adult [1]. Excess adiposity has thus almost become the norm, and trends in diagnosed diabetes trailed the obesity data with a 15–20 year delay owing to progressive damage from sustained hyperglycemia and impaired insulin action in the target tissues [2]. 

Only 6.8% of US adults had optimal cardiometabolic health in 2018 [3], a critical issue that was brought into the spotlight one more time by the striking relationship between metabolic health and the risk of severe COVID-19 outcomes associated with immune-mediated dysfunction that leads to the development of pneumonia (15%) and severe disease (5%) in unvaccinated individuals [4]. This association between excessive adiposity and deteriorated immune phenotypes is now observed worldwide, as 50–60% of the population is routinely classified as overweight or obese, and 9–12% as diabetic, in both Europe [5], the Middle East, and Gulf region [6], and East Asia [7].

Although the four metabolic risk factors have very different pathophysiological signatures, inflammation, and oxidative stress are the common central players in their development [8–10]. Metabolic states directly affect systemic markers of chronic low-grade inflammation and correlate with immune activation in tissues such as fat, liver, pancreas, and vasculature [11]. The innate immune system (granulocytes and myeloid cells) allows for a rapid proinflammatory response to injury or infection via activation of pattern recognition receptors; however, its resolution is substantially delayed in unhealthy metabolic states. 

The adaptive immune system (B and T lymphocytes) in turn critically depends on the innate immune cells for antigen presentation and receptor-mediated activation, otherwise unable to effectively control for autoimmune reactions. In tissues, this process seems to be maintained by the transient tissue macrophages, as well as mature tissue macrophages derived from embryonic precursors seeded in place before birth and self-renewed [12].

Failure to maintain metabolic homeostasis results in a maladaptive metabolic state that relies on tissue-resident macrophages to propagate inflammation [13]. Expansion of adipose tissue and ectopic storage of triglycerides in the liver, muscle, and pancreas is also achieved by local inflammatory reactions that allow for increased perfusion and remodeling of otherwise structurally rigid tissues [14]. This is achieved by chronic upregulation of complex signaling cascades that include vasoactive amines (histamine and serotonin), eicosanoids—lipid mediators that define pro-inflammatory (prostaglandins and thromboxanes) or anti-inflammatory (leukotrienes, lipoxins, resolvins) polarization, as well as cytokines with similar polarization effects. A core cluster of effector molecules that drives pro-inflammatory responses seems to include TNF-α, IL-1β/IL-6/IL-17, IL-18/INF-γ/MCP-1 [15], and the messengers of prolonged activation (NF-κB, COX-2, iNOS) [16]. It is currently not clear to what extent the nature of an inflammatory trigger dictates the type of mediator induced.

This situation is further complicated by an alteration in the two-way relationship between the richness and diversity of microbiota that occupies mucosal surfaces of the gastrointestinal tract or lungs, and the underlying immune tissues [17]. One common evolutionary approach to maintaining tissue integrity and healthy metabolism is sensing the effector molecules (enzymes/substrates, receptors/ligands) from sequestrated cells that normally do not overlap spatially, as seen at the surface epithelium, vascular endothelium, basement membranes (epithelial-mesenchymal connection), and plasma membranes [13]. Assembly of NALP3 inflammasome in response to leaked intracellular ATP/toxins via activation of macrophage purinoceptors [18], as well as differentiation of intestinal regulatory T cells in response to metabolites secreted by the commensal microbial community [19], indicate dual regulation of the metabolic status and maintenance of a fine balance between immunity and tolerance in the gastrointestinal tract.

Finally, another variable in the relationship between metabolic and immune health is food. The modern agricultural food systems achieved significant advances in breeding crops with increased macronutrient profiles and energy density, as well as developed an extensive set of manufacturing and processing routines that improved the affordability, shelf life, and safety of contemporary food products. This was achieved, however, at a profound loss of several important phytonutrients including dietary fiber, micronutrients (vitamins and essential minerals), and phytochemicals such as phenolic metabolites [20]. Mineral malnutrition is especially widespread but difficult to quantify. Reduced consumption of organ meats, changes in the geographical origin of foods, new varieties, agroecological methods of farming and preserving soils, and widespread environmental changes are in part responsible for the observed reductions [21]. The important role of minerals as a part of a healthy diet as it applies to metabolic and immune health has stimulated research into altered cellular metabolism, often driven by mitochondrial dysfunction to produce metabolic disparity, which in turn influences inflammation and energy balance. These areas are the focus of the present review.

2. Inflammation and Metabolic Dysfunction

Inflammation is a physiological response to adverse stimuli, which may be physical, chemical, or biological. The response normally leads to the restoration of homeostasis and apoptosis of malfunctioning or necrotic cells by macrophages. In this process, macrophages undergo activation as polarization towards two opposite states, the M1 or classical (pro-inflammatory), and the M2 or alternative (pro-resolution) phenotype [22]. In addition to the pathogen defense, M2 macrophages clear apoptotic cells and mitigate inflammatory response to IL-4, IL-10, IL-13, and TGF-β signaling [23]. 

If the noxious stimuli are not neutralized and removed, or if the apoptotic inflammatory cells are not cleared from the inflamed tissue, the inflammatory mechanism continues, and a condition of chronic inflammation or autoimmunity can develop with the recruitment of T lymphocytes and the formation of lymphoid infiltrates in the metabolic tissues [24]. This process is especially evident in the metabolic state of morbid obesity which is characterized by constant activation of the innate immune system that leads to acute inflammation [25]. Sustaining the M2 state of tissue-resident macrophages would be an interesting approach to reduce circulating inflammatory mediators and thus alleviate the metabolic disorders associated with chronic inflammation.

2.1. Inflammation in Obesity

Obesity is a confounding factor in many metabolic disorders. Excessive lipids in the circulation, whether they are dietary or genetically determined, trigger hyperplasia, remodeling, and hypertrophy of the adipose tissue, and result in increased fat mass as an adaptation to extra energy storage. These processes have significant inflammatory underpinnings, and inflammation is linked to all stages of metabolic alterations. Metabolic dysfunction is generally observed together with low-grade local inflammation, deficient insulin receptor signaling, and metabolic homeostasis disruption [26]. However, the precise contribution of individual macronutrients (carbohydrates, fats, proteins) to the development of obese and pro-inflammatory metabolic states has not been established.

While there is a broad consensus that increased levels of fructose-containing carbohydrates, saturated long-chain fatty acids, and branched-chain amino acids impair metabolic health, the views on their different roles are extremely polarized. This is highlighted by a generally recognized U-shaped association between mortality risk and carbohydrate consumption, with the epidemiological data from the PURE study at one extreme [27] and the Blue Zone Diets at the other [28]. These inconsistencies arise from the inherent limitations of the single-nutrient approaches, and the inability to correlate findings with concurrent nutrient intakes. For example, when protein is diluted in the diet by readily digestible carbohydrates and fats in the form of processed foods, protein “leverage” results in excess calorie intake, leading to rising levels of obesity and metabolic disease [29].

On the molecular level, the processes are mediated in part by increased de novo lipogenesis in the liver, reduced fat oxidation in mitochondria, accumulation of toxic ceramides and diacylglycerides, and activation of mTOR that ultimately degrade the insulin receptor substrate-1 (IRS-1) substrate and lead to malfunction of insulin-sensitive tissues [30]. In a remarkable overlap, deficiencies in IRS-1 substrate drive the proinflammatory phenotypes of the target tissues [31]. Similar to metabolic mediators, inflammatory cytokines like TNF-α, IL-6, and IL-1β also impair the insulin signaling pathway leading to insulin-resistant metabolic conditions [32]. Both IL-6 and TNF-α promote hepatic production of C-reactive protein (CRP), a major nonspecific reactant for the acute inflammatory phase, that is also increased in obese subjects. This further stimulates the complement system, mediates phagocytosis, and controls inflammation in the target tissues [33].

Cytokines, endothelial adhesion molecules, and chemotactic mediators within adipose tissue originate from both adipocytes, as well as resident or transitory macrophages that infiltrate the tissue [34]. These signals also activate another molecular pathway, called inflammasome, in myeloid cells which mediates the maturation and secretion of IL-1β and IL-18 by macrophages [35]. The signaling messengers have local effects on adipocytes and other resident immune cells (e.g., neutrophils, B cells, and T cells), and circulate in the periphery, where they affect the liver and skeletal muscle. In the liver, this translates to increased infiltration with resident Kupffer cells and monocyte-derived recruited hepatic macrophages [36], while skeletal muscle experiences increased pro-inflammatory M1 macrophage infiltration [37].

2.2. Inflammation in Diabetes

The relationship between immunity and carbohydrate metabolism is bidirectional, encompassing both inflammation's role in the pathogenesis of metabolic disorders and the impact of the metabolic condition, including inflammatory signaling, on immune cell regulation [38]. At the pathophysiological level, type 2 diabetes (T2D) is primarily characterized by peripheral insulin resistance and progressive exhaustion/destruction of insulin-producing pancreatic beta cells [39]. These alterations are also associated with elevated oxidative stress, which leads to the additional dysregulation of the polyol, hexosamine, and protein kinase C (PKC) pathways, as well as a rise in the formation of advanced glycation end products (AGEs) [40]. Indeed, increased oxidative stress has been a major risk factor for the most prevalent diabetic microvascular complications, including nephropathy, retinopathy, and neuropathy at the later stages of T2D. Importantly, in diabetic patients, this consistently elevated oxidative stress condition results in low-grade pathological inflammation [40].

Several markers of inflammation are elevated in patients with diabetes, including the leukocyte count, IL-6, TNF-α, and CRP [41]. Similar to obesity, TNF-α produces metabolic perturbation in diabetic states by inducing insulin resistance via activation of IκB kinase β (IKKβ), the c-Jun aminoterminal kinase (JNK), and inhibitory phosphorylation of IRS-1 at Ser 307 [42]. A close connection between obesity and insulin resistance is exemplified by the fact that a gradual weight loss of 5–15% of the original body weight over 3–10 months is sufficient to improve β-cell function and insulin sensitivity in all key metabolically active tissues: liver, skeletal muscle, and fat [43]. It has also been long recognized that anti-inflammatory treatments attenuate insulin resistance as observed with salicylic acid [44], salicylates [45], or aspirin [46], likely via inhibition of κB in the NF-κB inflammatory pathway. Inflammasome-activated IL-1β and IL-18 are the major cytokines implicated in the development of obesity- and diabetes-related insulin resistance, and some conflicting results were reported for IL-6 and the downstream STAT pathway [47].

2.3. Inflammation in the Gastrointestinal Disorders

Another bidirectional interaction between gastrointestinal tissues, microbiota in the gastrointestinal lumen, and host immunity, in which inflammation is critically involved, has recently been stated to have a compounding effect on metabolic diseases [48]. The gastrointestinal tract represents a major component of the immune system that maintains immune homeostasis by supporting the integrity of the intestinal epithelial barrier and recognizing the food and microbial antigens. Disruption of the epithelial barrier occurs when a double (stomach or colon) or a single (small intestine) layer of the gastrointestinal mucus is diminished [49], and the tight junction protein complexes are misassembled to allow for increased penetration of dietary components and microbial metabolites via the paracellular transport pathway [50]. 

This creates a unique antigen presentation environment where under normal conditions specialized epithelial microfold (M) cells recognize luminal antigens and present them to the mononuclear phagocytes (dendritic cells and macrophages) and B cells to trigger antigen-specific secretory IgA, as well as systemic IgG production [51]. In humans, these areas are more frequently localized in the distal part of the small intestine (ileum) where microbial loads start to increase [52]. 

This allows for timely activation and differentiation of the effector and regulatory Th cells mostly via IL-10 and TGF-β signaling to suppress the inflammatory responses of B and T cells initiated by normal food, commensal microbes, and environmental antigens [53]. The epithelial layer also expressed a significant number of extraoral bitter taste receptors family (TAS2R, 25 members in humans) that do not support the bitter sensing in the gut, but instead, provide a chemosensing environment to detect and respond to dietary and microbial chemical constituents and modify their absorption [54].

In addition to ectopic lipid accumulation and chronic inflammation in the key metabolic tissues, excessive metabolic states also promote inflammation of the gastrointestinal tissues. As different parts of the gut perform distinct functions in the digestion and absorption of nutrients, the health outcomes of gastrointestinal inflammatory disorders are highly variable. In a normal state, the duodenum supports the digestion of foods with pancreatic and bile secretions, as well as iron, calcium, and magnesium absorption. The jejunum absorbs most nutrients, vitamins, and minerals. 

The ileum reabsorbs bile acids and fluids, and the colon completes the absorption of fluid and electrolytes. This functional separation is partially responsible for different manifestations associated with gastrointestinal disorders, as a celiac disease primarily affects the duodenum/jejunum, Crohn’s disease is centered in the ileum and spreads to the colon, and ulcerative colitis affects primarily colon starting at the anus. For this reason, primary mineral inadequacies in celiac patients are iron, calcium, magnesium, and to a lesser degree zinc, copper, and selenium [55]. 

Mineral malabsorption in Crohn's patients is variable but generally includes iron, calcium, magnesium, and zinc [56]. Patients with ulcerative colitis are less susceptible to mineral deficiencies but require larger amounts of zinc, copper, and selenium to promote wound healing [57]. The altered epithelial barrier function is present in all IBD conditions and presents as increased leak-flux of water and solutes that leads to elevated antigen presentation, tissue inflammation, and diarrhea [58].

3. Immune Cell Metabolism and Metabolic Reprogramming

The immune system has various types of cells in its stable state, which become active in different situations to respond to infection, inflammation, and changes in metabolic fluxes. These responses include multiple changes in signal transduction pathways and gene expression networks to perform suitable functions like the production of cytokines, tissue remodeling enzymes, mediators, and toxic gases, to be able to migrate through tissues and/or undergo cellular division and proliferation. Such changes are supported by abrupt modifications of basic metabolic processes that provide immune cells with energy and bio-precursors to correlate with required immune functions. Cellular bioenergetics, therefore, serves as both a sensor and fundamental effector of the immune response, and this becomes even more evident in pathological metabolic states.

3.1. Inflamed Tissue Is a Metabolically Restrictive Environment

Cellular metabolism involves a network of biochemical reactions that utilize nutrients and microelements to generate energy, redox equivalents, and macromolecules specific to the cell type and function. This is typically achieved first via glycolysis in the cytosol and the subsequent mitochondrial oxidative phosphorylation in the presence of oxygen. However, rapidly proliferating cells such as tumors and activated immune cells require faster energy supplies and achieve them by lowering their metabolic efficiency and relying nearly exclusively on the faster glycolytic reactions in the cytosol. 

This allows them to outcompete other cells and tissues for essential nutrients and microelements critical to their survival [59]. Aerobic glycolysis and pentose phosphate pathways are the main metabolic modes of activated M1 macrophages, neutrophils (respiratory burst and chemotaxis), iNOSexpressing dendritic cells, lymphocytes (effector T cells, LPS-stimulated B lymphocytes) and natural killer cells. Alternatively, activated immune cells geared towards the resolution of inflammation such as M2 macrophages and the regulatory T cells rely on oxidative phosphorylation from fatty acid oxidation instead [60].

Survival of activated immune cells in the metabolically restrictive environment depends on the competitive uptake of glucose and the expression of corresponding transporters on the cell surface. For this reason, many pro-inflammatory pathologies induce at least transitory, but often long-lasting state of insulin resistance in the host tissues. This is observed in patients with sepsis [61], burn injury [62], and normal pregnancy [63].

The resulting increased availability of glucose for aerobic glycolysis provides the biosynthetic precursors essential for the synthesis of nucleotides, amino acids, and lipids of rapidly growing and proliferating cells. The metabolic shifts are supported in part by the interaction of glycolytic enzymes such as GAPDH with the translation of IFN-γ and IL-2 mRNA to ensure unconstrained generation of pro-inflammatory signaling once glycolysis is upregulated [64], as well as activity of the glycolytic regulators such as HIF-1α under the conditions of microenvironment hypoxia [65].

3.2. Metabolic Reprogramming during Activation of Immune Cells

Active selection of metabolic pathways enables immune cells to adapt to their functional requirements, but at the same time, the metabolic state of the host directly affects the phenotype and function of immune cells. Several minerals are important for adequate transition between resting and activated states of the immune system, activity of the rate-limiting enzymes in respective biochemical pathways, and transcriptional factors responsible for activation of the target gene expression networks (Figure 1).

3.2.1. Neutrophils

Neutrophils are a subpopulation of granulocytes (leukocytes) abundant in the blood and rare in healthy tissues. These immune cells are one of the earliest transitory responders that propagate the pro-inflammatory states via secretion of elastase 2, TNF-α, and MCP-1 [47]. Neutrophils phagocytose debris, promote angiogenesis, and allow for tissue expansion and repair. They consume very low amounts of oxygen and rely primarily on aerobic glycolysis to generate ATP. A high flux through the glycolytic pathway upon activation is channeled via the pentose phosphate pathway to generate NADPH and superoxide anions (oxidative burst). Neutrophils also maintain some levels of fatty acid oxidation and glutaminolysis [66].

3.2.2. Mast Cells

Mast cells are another class of highly granulated tissue resident hematopoietic cells that are major effectors of IgE-mediated allergies, but also disorders of the brain, gastrointestinal, and adipose tissues. They undergo early-phase degranulation and late-phase activation by releasing histamine, leukotrienes, TNF-α, and Th2-associated cytokines such as IL-4, IL-6, IL-10, and IL-13. Both oxidative phosphorylation and glycolysis appear to be critical for rapid allergic reactions, while glycolysis is a predominant energy pathway for non-IgE activation [67].

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