With the development of clinical nutrition and in-depth understanding of body metabolism, some scholars proposed the concept of Immunonutrition, which regulates metabolism according to different metabolic characteristics of organ tissues and emphasizes the nutritional effects of special nutrients, using their pharmacological effects to achieve the purpose of regulating body metabolism and improving immune function.
The basic research of immune nutrition was carried out in 1980s. From the level of immunology and molecular biology, it was recognized that the body produces systemic inflammatory response syndrome (SIRS) to external aggression, which further develops into dysfunction of the nervous and endocrine systems and multiple organs. At the same time, the intestinal barrier becomes dysfunctional in response to stress, and bacteria and endotoxins enter the body through the mucosal barrier, which then leads to a series of changes such as SIRS and MODS.
I. Concept of enteral immune nutrition
A new approach to nutritional support by adding nutrients with immunomodulatory effects, such as glutamine, arginine, ω-3 fatty acids, nucleotides, and dietary fiber, to standard nutritional formulas. It can play a positive regulatory role in immunosuppression after severe burns and major surgical procedures by improving the cellular immune function of the body, promoting short half-life protein synthesis, regulating local and systemic cytokine production, maintaining the structural and functional integrity of the intestinal mucosa, improving nutritional status, increasing tolerance to surgery and chemotherapy, reducing the occurrence of postoperative complications, and promoting tissue repair and wound healing.
Enteral eco-immunonutrition adds to the immunonutritional support therapy the application of ecological agents based on probiotic synergists to enhance the effect of nutritional support, reduce EN-related complications and decrease the infection rate in critically ill patients, and improve patient prognosis, and this approach is called eco-immunonutrition. Compared with the traditional enteral immunonutrition, the significant feature of the new enteral ecological immunonutrition is the addition of probiotics based on live lactobacilli and dietary fiber based on oats.
II. Immunonutrition components and functions
1.Glutamine.
Glutamine is the most abundant free amino acid in blood circulation and body amino acid pool, is the conditionally essential amino acid in the traumatic stress state of the body, and is the fuel used preferentially by lymphocytes, liver cells and intestinal mucosa. Gln deficiency does not occur in normal humans and animals, but in tumor states and severe traumatic stress conditions, the concentration of Gln in blood and tissues can drop significantly and become undersupplied.
(1) Maintaining the immune system: Glutamine has potential immune functions and promotes phagocytosis of neutrophils. Mucosal immune defenses are dependent on acquired glutamine. Studies have shown that parenteral nutrition containing glutamine protects colonic IgA concentrations and prevents mucosal atrophy by maintaining cell numbers and preserving function.
(2) Metabolism in the catabolic state: Glutamine flow from muscle to the intestine, immune cells and kidneys is significantly reduced to 20 to 50% of normal levels in the state of prolonged starvation, after elective surgery and severe trauma. The amount and duration of glutamine deficiency is directly proportional to the severity of the condition. The decrease of glutamine will last 20-30d after major surgery.
(3) Regulation of the body’s antioxidant and protection of the intestine: glutamine is a precursor substance of glutathione, and trauma and severe disease are associated with significant glutamine and glutathione deficiency. Glutathione is the main intracellular antioxidant, and glutamine regulates the body’s antioxidation and prevents cells from damage by ischemia and repeated perfusion. Glutamine dipeptide supplementation attenuates the decrease of glutathione content in muscle after trauma.
(4) Potential effect on hyperglycemia: In recent years, the hyperglycemic condition of critically ill patients has been paid attention to. Patients whose blood glucose level can be maintained at 6 mmol/L or lower have significantly reduced mortality. Animal experiments have found that in patients with hyperglycemia due to hyperinsulinism, increased glutamine intake makes insulin insensitive to glucose production and promotes insulin-mediated glucose utilization.
(5) Improved clinical prognosis: GriffithsE et al. reported that the mortality rate at 6 months after discharge was significantly lower in critically ill patients on glutamine enteral nutrition compared with those on conventional total parenteral nutrition, and concluded that the improved ICU survival was mainly related to the reduction in mortality due to M0F. WilmoreEB defines glutamine as “a uniquely important nutrient that is both a vital metabolite and a metabolic regulator, essential to human health and survival.
2. omega-3 fatty acids.
Omega-3 fatty acids mainly include α-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid. In recent years, or3 fatty acids have become important nutritional additions for patients with severe trauma, showing anti-inflammatory properties in trauma patients and preventing the body from falling into an excessive inflammatory state. Numerous experiments have demonstrated that or3 fatty acids reduce excessive inflammatory responses, improve host responses, improve visceral blood flow and intestinal barrier function, and prevent tumor growth. Immunonutrition is recommended early in severe trauma to counteract the hypercatabolic and immunosuppressed state of the patient. Diets rich in omega-3 fatty acids may result in increased cytokine production and increased cell-mediated immune and regulatory effects, along with increased antigen-induced lymphocyte production. These effects both attenuate excessive inflammatory responses and maintain the body’s systemic and cellular defenses.
3. Arginine.
Arginine-containing immunonutrition improves cellular immunity in patients undergoing preoperative or post-traumatic stress. alogac state et al. reviewed 13 prospective, randomized clinical studies in which patients in 12 experimental groups had improved prognosis, particularly length of hospitalization and ICU stay, duration of mechanical ventilation, and number of infections decreased with arginine use.
(1) Effects on the immune system: Arginine prevented thymus destruction and T-cell dysfunction in traumatized rats, and also increased thymus weight and T-cell mitosis in non-traumatized rats, resulting in increased numbers of thymic T cells. Clinical studies have found that arginine supplementation (30 g/d) for several days can promote mitogenic responses, and this effect can last for 2-3 weeks.
(2) Effects on intestinal barrier function: Stress reactions such as severe trauma and infection can damage the intestinal mucosal barrier system and cause intestinal-derived infections to occur with bacterial translocation, and the inflammatory response of the body can be aggravated in a vicious cycle. In the intestine, arginine is converted into polyamines by the action of arginase and ornithine decarboxylase, which increases the total thickness of intestinal mucosa and the number of small intestinal villi, and provides nutritional support for normal intestinal flora to maintain the normal ratio of intestinal intrinsic bacteria and maintain the intestinal microbial barrier. Arginine can also stimulate the release of various gastrointestinal hormones, which can also promote the proliferation and differentiation of intestinal mucosal cells, thus maintaining the intestinal barrier function.
(3) Promote wound healing: The healing-promoting effect of arginine is closely related to the arginase system. Polyamines and proline catalyzed by arginase are involved in trauma cell proliferation and collagen synthesis; after trauma, arginine can protect tissues and organs by reducing the aggregation and activation of neutrophils, down-regulating the inflammatory response and reducing cytokines and cell mediators. The trauma repair effect of arginine is related to the function of macrophages. Angele et al. found that arginine improved the function of macrophages suppressed after trauma and bleeding and reduced the release of IL-6. Wittmann et al. concluded that arginine promotes wound healing, is a useful nutrient in trauma and fluid resuscitation after acute blood loss, and reduces trauma complications.
(4) Safety: The use of arginine in critically ill patients has caused considerable controversy. Some studies have suggested that SIRS in critically ill patients may be amplified by immune enhancers such as arginine, so it is recommended that immune enhancers should not be used in patients with SIRS. It has also been suggested that there is insufficient evidence that enteral supplementation with arginine and other immunologically active substances in critically ill ICU patients is associated with high mortality. heylandE et al. concluded after a comprehensive meta-analysis of arginine that immune nutrition in surgical and critically ill patients may reduce the incidence of infection. An analysis of patients with severe trauma, burns, and ICU found increased mortality with arginine application in patients with shock, sepsis, and organ failure. In patients with SIRS and sepsis following trauma, arginine-containing enteral nutrition resulted in transient hypotension, elevated cardiac index, and decreased systemic and pulmonary vascular compliance. The mechanism by which arginine causes harm needs to be studied in depth.
4. Cysteine and taurine
Glutathione is an important intracellular non-protein sulfur group, the most abundant low molecular peptide in the body, which can regulate many enzymatic reactions, and the glutathione level of the body is closely related to the immune function status of the body. Cysteine is a sulfur-containing conditionally essential amino acid, which is synthesized in the liver from methionine. As a precursor of glutathione, cysteine is involved in all redox reactions. Adding glutamine and cysteine to enteral nutritional support can improve postoperative glutathione levels in gastric cancer patients, which in turn improves the body’s immune function. Taurine is a widely distributed intracellular sulfur-containing β-amino acid that is involved in membrane stabilization and Ca2+ transport across the membrane, and has positive inotropic, anti-arrhythmic and anti-lipid peroxidative damage effects. Under stress conditions such as trauma and infection, intracellular and extracellular taurine levels are reduced, and supplementation of taurine can inhibit the production of TNFα and NO in macrophages, which has anti-inflammatory and immunomodulatory effects.
5.Nucleotide
Nucleotides are the basic units of DNA and RNA and are involved in all cellular activities in the body. Nucleotides can induce the release of IL 1β, TNF α, INF γ, enhance the number and function of circulating T lymphocytes, improve macrophage activity and stimulate the cytotoxic effect of NK cells. Under the condition of adequate protein supply, nucleotides can rapidly promote the recovery of immune function in malnourished animals. Polynucleotide (PAPU) is a biological response modulator. Cancer patients receiving PAPU therapy after surgery can improve the number and cytotoxic activity of circulating NK cells, prolong tumor-free survival and overall survival, and reduce the risk of tumor recurrence.
6.Dietary fiber
Dietary fiber is a carbohydrate in food that cannot be directly hydrolyzed by digestive enzymes. Dietary fiber can absorb and preserve water, stimulate intestinal peristalsis, dilute the concentration of carcinogenic substances in the intestine and promote discharge. Short-chain fatty acids (SCFA), the enzymatic products of dietary fiber, are the main source of energy for colonic mucosal cells, increase blood supply to intestinal mucosa, promote the proliferation and differentiation of intestinal mucosal cells, maintain the integrity of the morphological structure of intestinal villi, and have nutritional and protective effects on intestinal mucosal barrier. High intake of cereal fiber can significantly reduce the risk of pancreatic cancer. The addition of dietary fiber after major abdominal surgery can significantly reduce the incidence of intestinal bacterial translocation and infection.
III. Commonly used enteral immunonutrition agents
1.1 Supportan is an enteral immune nutritional preparation specially designed for oncology patients, which is rich in immune enhancing substances: nucleotides, omega-3 polyunsaturated fatty acids and antioxidants. Each 100 ml of supportan contains 546 kJ of energy, l0.4 g of carbohydrate, 7.1 g of protein, 7.2 g of fat, 2.9 g of saturated fatty acids, 0.9 g of unsaturated fatty acids, 1.25 g of arginine, 0.3 g of omega-3 fatty acids, 0.13 g of nucleotides and various minerals, trace elements and vitamins.
1.2 Stresson Each 100 ml of Stresson contains 523 kJ of energy, 14.5 g of carbohydrate, 7.5 g of protein, 41.7 g of fat, 3.45:1 of co-6:oJ-3 (g), 0.89 g of arginine, 1.3 g of glutamine, 0.13 g of nucleotide, and 0.9 g of dietary fiber.
1.3 Indinapac (Impact) Each 100 ml of Indinapac contains 418 kJ of energy, 13.4 g of carbohydrate, 5.6 g of protein, 2.8 g of total fat, of which ω-3 fatty acids account for 10.5 of total fat, ω-3 fatty acids account for 8.3, 1.25 g of arginine, 0.12 g of nucleotides.
IV. Timing of enteral immunonutrition implementation
Early postoperative enteral nutrition support has become a consensus: “enteral nutrition should be preferred as long as the intestine is functional” has become a consensus in recent nutrition therapy. At present, there are still some controversies about when to start enteral nutrition. However, recent studies have found that postoperative gastrointestinal paralysis is limited to the stomach and colon, while the peristaltic, digestive and absorptive functions of the small intestine return to normal a few hours after surgery. Therefore, from the theoretical point of view, if the function of small intestine is normal before surgery, it can receive the input of nutrients 6-12 h after surgery, but in fact, the internal environment is not yet completely stable, so if enteral nutrition is given too early, the body may not have the ability to digest and absorb it completely; on the contrary, it may produce abdominal distension due to intolerance of enteral nutrition, and abdominal distension may aggravate postoperative discomfort and complications. Most scholars believe that the ideal enteral nutrition should be started within 24-48 h after surgery. Some studies have shown that early postoperative enteral immune nutrition can enhance the body’s immune response, improve the incidence of postoperative infectious complications and reduce the length of hospital stay. The fast-track surgery advocated by Nanjing General Hospital emphasizes early postoperative enteral immunonutrition.
V. Problems to be noted in immunonutrition treatment
Current research suggests that immunonutrition as a therapeutic measure should be used to maximize its benefits and minimize its risks. Three problems should be noted while performing immunonutrition therapy.
1. The dose is too low, which leads to ineffective immunonutrition therapy and fails to achieve the pharmacological effect of immunomodulation, which is one of the main factors affecting the clinical effect of immunonutrition. The implementation of immunonutrition therapy needs to reach a minimum limit in order to play its immunomodulatory role, but there is no definite answer to the current study, and some studies suggest that burn patients may need to reach two to seven times the amount of healthy people.
2. The timing of application, as with enteral nutrition, should be started early, preferably within 72 hours after surgery, to avoid early excessive inflammatory response.
3, The severity of the disease is another major factor affecting the effectiveness of immunonutrition therapy. Immunonutrition therapy for critically ill patients with severe sepsis, shock, and multiple organ insufficiency may instead aggravate the disease and increase mortality. Therefore, immunonutrition should not be implemented in such patients. To sum up, two aspects should be considered when applying immunonutrition therapy in clinical practice: first, the tolerance of patients to immunonutrition; second, the severity of the disease. Immunonutrition should be administered in patients who need enteral nutrition and can tolerate a certain dose of enteral nutrition, and should be used with caution or not in patients with severe SIRS and MODS. For immunonutrition treatment in patients with severe trauma, it is best to control their acute physiological and chronic health status score (APACHE) II.