Nutritional Requirements for Immunity

3. Nutritional Requirements for Immunity

During the Development Period

The first and perhaps most significant effect of nutrition on immunity occurs during the development of the immune system (Cunningham-Rundles et al., 2005). Cells of the immune system develop in utero, but this is followed by an important period of maturation soon after birth, continuing to develop throughout life. Deficiencies of zinc, protein, essential amino acids, vitamin A, and copper are only some of the many nutritional variables that can impair development of the immune system in young, growing animals. Micronutrient deficiencies affect the adaptive immune responses, and innate responses (Table 2). Thymic and splenic lymphocyte numbers can be greatly reduced by maternal deficiencies, most notably zinc. Serum antibody responses in young animals to vaccination can be affected by maternal deficiencies of nutrients such as of zinc, iron, copper, selenium, and magnesium.

The net effects of malnutrition during development are altered microbial colonization of mucosal surfaces, impaired responses to commensals and pathogens, increased susceptibility to infection, and decreased ability to resolve infection once established. Such defects may last well beyond the initial period of malnutrition and alter an animal’s immunophenotype for life.

Essential Nutrients for Fuel

Glucose

Glucose is essential for monocytes, neutrophils, and lymphocytes. Following activation of macrophages and neutrophils, or stimulation of lymphocyte proliferation, glucose oxidation increases dramatically, although it is only partially oxidized, with lactate being the predominant end product (Figure 7). Glutamine is another vital fuel for both cell types, and at rest, may account for more than 50% of ATP production by these cells. Like glucose, glutamine is only partially oxidized, with glutamate, aspartate, and lactate as the end products, and only a small amount being oxidized completely to CO2, H2O, and NH3. Although fatty acids and ketones can be oxidized for ATP production, cellular activation and proliferation of leukocytes does not increase the rate of usage of either substrate (Newsholme et al., 1987; Newsholme & Newsholme, 1989).

Figure 7. Anerobic glycolytic pathway.

Incomplete oxidation of glucose and glutamine occurs despite the presence of mitochondria and functioning citric acid cycles. This is consistent with the need for these cells to operate in areas of low oxygen availability (e.g., ischemic tissue, or unvascularized spaces). The high rates of glucose and glutamine utilization is partly to provide intermediates for the biosynthesis of purine and pyrimidine nucleotides which are required for the synthesis of DNA and mRNA by these cells, and partly to maintain high rates of metabolic flux through the pathways to allow for rapid large changes in utilization that follows activation.

Glutamine

Plasma glutamine concentrations affect the susceptibility of cells to different apoptosis triggers: where glutamine-starving cells are more sensitive to apoptosis (Oehler and Roth, 2003). In contrast, glutamine may protect activated T cells from apoptosis. A similar protective effect against apoptosis has been demonstrated in neutrophils, in which glutamine also appears to positively regulate the expression of the NADPH oxidase. The immunosuppressive effect of asparaginase has been shown to be due to its ability to hydrolyse glutamine, rather than to the reduction of asparagines (Kitoh et al., 1992). In addition, states associated with low plasma glutamine concentrations are also associated with suppression of both innate and adaptive immunity.

Plasma glutamine is almost entirely derived from skeletal muscle, since dietary glutamine is either utilized by the intestine or the liver, and plasma glutamine only rises very slightly following a meal. During inflammatory responses, muscle catabolism increases in response to low plasma insulin, or muscle insulin resistance induced by cortisol and catabolic cytokines (Kotler, 2000). This provides a source of glutamine both for hepatic gluconeogenesis, but also directly to leukocytes. Thus feeding in systemic inflammatory disease states with glutamine free amino acid sources would be expected to inhibit muscle glutamine release, suppress plasma glutamine concentrations, and thus lead to relative immunosuppression. Conversely, glutamine supplementation enhances macrophage phagocytic activity, helps maintain circulating T lymphocyte numbers, and normalizes lymphocyte function in models of severe sepsis. Predictably, glutamine supplementation of TPN solutions has been shown to reduce morbidity in some septic human patients (Fuentes-Orozco et al., 2004).

When glutamine is supplemented orally, the form of glutamine that is administered is important. Glutamine utilization is significantly more efficient when glutamine is consumed as part of a polypeptide than when it is consumed as a free amino acid (Boza et al., 2000).

Glutamine Absorption

Absorption and utilization of amino acids differs when they are fed as free amino acids or as part of intact polypeptides. A mixture of small peptides is of greater nutritive value than a mixture of free amino acids with a similar composition for both growth and recovery from malnutrition. When starved rats are re-fed, body weight gain is greater, and the plasma concentration of total amino acids -especially glutamine- is significantly higher in rats fed a whey protein hydrolysate-based diet compared with those fed an amino acid-based diet (Boza et al., 2000).

In addition, energy conversion efficiency, protein efficiency ratio, and nitrogen retention are significantly higher in hydrolysate-fed rats. In humans, the glutamine concentration in the duodenal mucosa increases with the enteral supplementation of glutamine-rich proteins compared with a free glutamine solution, despite there being no difference in plasma glutamine concentrations (Preiser et al., 2003). Potential explanations for these findings include poor solubility of certain free amino acids in the intestinal lumen, rapid absorption of free amino acids leading to an increase in hepatic oxidation, altered intestinal oxidation, and increased catabolism by intestinal flora of free amino acids over polypeptides.

Glutamine can be fed as a free amino acid supplement, as part of a polypeptide in a hydrolysed protein diet, or as part of an intact protein in a conventional food protein source. The combination of glutamine availability, digestibility, and reduced antigenicity may make moderately hydrolysed protein diets ideal for enteral feeding in severe inflammatory disease states.

Cell Division

Other than essential amino acids and sufficient substrate for fuel, several vitamins are required for leukocyte function and replication (Table 3). During an immune response, this is particularly important for lymphocytes.

Deficiencies in any of the essential nutrients listed in Table 2 will limit cell proliferation, and hence alter cell mediated and humoral immune responses.

Glutamine warrants special mention again, since its availability is often reduced in severe illness, and low plasma concentrations are correlated with morbidity in humans and experimental studies. The major use of glutamine by replicating lymphocytes is not simply as a fuel, but also for nucleotide synthesis (Figure 8), whereby low glutamine concentrations inhibit, and increased concentrations stimulate lymphocyte proliferation following stimulation. In addition, this effect of glutamine on replicating lymphocytes is enhanced by the amino acid arginine.

Figure 8. Glutamine and cellular replication.

Antioxidants

Generally speaking, dietary antioxidants fulfill two roles in immune responses. Firstly they protect leukocytes against endogenously derived free radical damage, and secondly they protect the host against bystander damage from the same free radicals (Figure 9). The requirement for increased intracellular antioxidant capacity in neutrophils and macrophages has been discussed above. This requirement is met by taurine, glutathione, ascorbate, and tocopherol. Glutathione plays a pivotal role as an antioxidant both through direct interaction with free radicals, but also as a substrate for the regeneration of ascorbate. Glutamine availability can limit glutathione production, and supplementation of glutamine can increase superoxide production by neutrophils.

Figure 9. Antioxidants: mode of action.

In addition, several other dietary antioxidants have been shown to have an effect on immunity. Notable amongst them, are the carotenoids (Figure 9). Both b-carotene and lutein are incorporated into lymphocytes and neutrophils of both cats and dogs, especially mitochondrial membranes, where they probably function to protect the lipid membranes from endogenous free-radical damage (Chew & Park, 2004).

Extracellular (plasma) antioxidants are also important for limiting damage to whole tissues and the vascular endothelium during an immune response. Taurine, ascorbate, tocopherol, glutathione, and carotenoids, all contribute to whole organ defense against free radicals produced by activated phagocytes.