Effects of specific nutrients on immune modulation in patients with gastrectomy

Abstract Gastric cancer (GC) is one of the most prevalent and lethal malignant neoplasms worldwide. The main treatment for GC is gastrectomy, which generally causes considerable metabolic stress to patients. To modulate cell function, maintain homeostasis of the immune response, reduce postoperative complications, and obtain favorable outcomes, physicians prescribe specific nutrients with immunomodulatory properties as supplementation to enteral or parenteral formulas, indicating immunonutrition. In the formulas, among the immunonutrients, glutamine, arginine, and n‐3 polyunsaturated fatty acids are the most commonly used either alone or in combination. The present review summarizes and focuses on the evidence obtained from clinical trials and animal studies supporting the role of immunonutrients supplemented enterally or parenterally in total or subtotal gastrectomy. In addition, this review describes the possible molecular mechanisms underlying the protective action of these immunonutrients, which may contribute to therapeutic approaches to improve postoperative outcomes of gastrectomy. Combination of conventional therapy with immunonutrition seems to be a useful strategy to achieve synergistic effects in the treatment of GC patients.


| INTRODUC TI ON
Gastric cancer (GC) is one of the most prevalent malignancies causing mortality worldwide. It remains among the top 10 causes of cancer-related death for both genders in many Asian countries. The primary therapeutic method for resectable GC is gastrectomy, which generally causes massive metabolic stress to patients. Patients undergoing major surgery may have an inflammatory reaction and postoperative immunosuppression, making them highly susceptible to infection. 1 Furthermore, radical cancer surgery may result in an intestinal hypodynamic state and impair the secretion of intestinal enzymes. These conditions may compromise early recovery of the gastrointestinal tract. Most patients who undergo gastrectomy experience preoperative protein-energy malnutrition, and adequate postoperative oral intake is achieved late. Thus, artificial nutritional support is essential for these patients. According to the consensus guidelines for enhanced recovery after gastrectomy and as recommended by the Enhanced Recovery after Surgery Society, malnourished patients should be optimized with oral supplements or enteral nutrition (EN) preoperatively. Patients who are clearly malnourished or those who cannot meet 60% of the daily requirement by postoperative day 6 should be given individualized nutritional support. 2 For all postoperative patients who have a functioning gastrointestinal (GI) tract but cannot tolerate oral intake, standard EN is generally recommended because it is less expensive, safer, and more physiological to maintain the barrier function of the intestines than any artificial nutritional support. Meta-analysis reports suggest that EN is conducive to a lower infection rate and a shorter hospital stay than parenteral nutrition (PN) in GI surgical patients. 3,4 However, if patients cannot receive adequate EN as a result of GI incompetency such as ileus, bowel ischemia, severe GI bleeding, or critical illness with poor enteral tolerance, then PN is required. In our previous study, we found that compared with patients without nutritional support, morbidity and mortality of malnourished gastrectomy patients with peri-or postoperative total parenteral nutrition (TPN) significantly decreased. 5 To reduce postoperative complications and achieve immune homeostasis through regulating cell function, physicians introduce enteral or parenteral formulas supplemented with nutrients having immunomodulatory properties. This type of supplementation is termed immunonutrition. Commonly in the formulas, some of the immunonutrients, such as glutamine (GLN), arginine (Arg), n-3 polyunsaturated fatty acids (PUFA), and nucleotides, are supplemented alone or in combination. Previous meta-analyses found that immunonutrition reduces overall postoperative complications and shortens hospital stay in adult patients with major abdominal surgery. 6,7 According to a meta-analysis specifically for total gastrectomy patients with GC, enteral immunonutrition improves cellular immunity, modulates inflammatory response, and reduces postoperative complications. 8 Previous studies using immunonutritional regimens were conducted using either one specific nutrient or in different combinations of nutritional components. In the present review, we explored and summarized the evidence obtained from clinical trials and animal studies supporting the role of immunonutrients supplemented enterally or parenterally in total or subtotal gastrectomy. This review also describes the possible molecular mechanisms underlying the protective action of these immunonutrients, which may contribute to the therapeutic approaches to improve postoperative outcomes of gastrectomy.

| Effects of specific nutrient combination on gastrectomy
Although immunonutrition has agreeably favorable effects, different time points of intervention may influence the outcomes after gastrectomy. In a previous study, an enteral immune-enhancing formula enriched with Arg, n-3 fatty acids (FA), and ribonucleic acid (RNA), named "Impact (Novartis Nutrition, Bern, Switzerland)," was given to patients with GC in two distinct time periods; then, the potential benefits of perioperative versus postoperative treatments on host defense and protein metabolism were evaluated. Compared with postoperative dosage, perioperative supplementation of immunonutrition had more metabolic advantages in modulating postoperative immune and inflammatory responses in gastrectomy patients with GC. 9 However, early postoperative EN with Impact supplementation increased collagen synthesis, thereby promoting wound healing 10 and improving the clinical and immunological outcomes of these patients. 11 Okamoto et al 12 found that preoperative EN with Impact supplementation maintained CD4 + T-cell levels, shortened the duration of systemic inflammatory response syndrome, and decreased the incidence of postoperative infectious complications in patients with GC. In another study, Impact was included in a normal diet for 5 consecutive days before gastrectomy; however, preoperative enteral immunonutrition did not show any benefits in the clinical outcomes of patients with GC. 13 Meanwhile, a prospective randomized clinical trial showed that routine postoperative immunonutrition given enterally or parenterally had no advantages in well-nourished patients undergoing elective gastrectomy or pancreaticoduodenectomy. 14 Peker et al 15 investigated the effects of immunonutrition on infiltrative lymphocytes and angiogenesis in resected gastric adenocarcinoma tissues. They found that compared with the samples obtained from patients with standard nutrition, the samples from patients consuming Impact for 7 preoperative days resulted in a lower CD4 + /CD8 + ratio and in a higher CD105 level. The low CD4 + / CD8 + ratio in tumor-infiltrating lymphocytes could be an indicator that tumor progression has been prevented. However, CD105 is a marker of microvascular intensity and is used to indicate neovascularity. The abovementioned findings indicated that preoperative immunonutrition regulates the balance between CD4 + and CD8 + T cells but its prolonged use increases tumor angiogenesis. 16 In a clinical trial, malnourished patients were given preoperative PN for 2 weeks initially. Then, gastrectomy or pancreatectomy patients were randomly assigned to either a postoperative immunomodulating diet or a standard oligopeptide diet. Immunomodulating diet  19 A meta-analysis concluded that among the immunonutrients used for enteral immunonutrition, namely, Arg, GLN, n-3 FA, and RNA, RNA and n-3 FA are the most effective in reducing infectious complications and length of hospital stay in patients with GC suffering from gastrectomy. 20 In a rodent sarcopenia model induced by total gastrectomy, Haba et al 21

investigated the effect of oral
branched-chain amino acids (BCAA) and/or GLN supplementation on skeletal muscle atrophy after surgery. They found that combined use of BCAA and GLN was more effective in inhibiting muscle atrophy than providing BCAA or GLN alone. Considering that several immunonutrients are combined in enteral immunonutrition formulas, the influence of each immunonutrient on gastrectomy cannot be confirmed. Therefore, we summarized the studies that used the most commonly used immunonutrients, and we describe the roles of these immunonutrients on gastrectomy.  As for animal studies, rats were infused with GLN-containing PN before and after gastrectomy to investigate the efficacy of GLN on surgery. As a result, TPN supplemented with GLN improved nitrogen balance and enhanced abdominal macrophage phagocytic activity in rats with partial gastrectomy. 45 In a previous study, we gave GLN parenterally to investigate the role of GLN on cellular adhesion molecule and inflammatory cell recruitment in rats with total gastrectomy. We found that GLN-enriched PN attenuated leukocyte integrin expression and elicited a more rapid immune response to injury after gastrectomy. 46

| Effects of Arg on gastrectomy
Arginine is a nonessential amino acid that serves as the precursor of various metabolites, such as nitric oxide (NO), citrulline, creatine, ornithine, urea, and polyamines. 47 Arg stimulates anabolic hormone release and improves nitrogen balance. 48 It also shows immunoregulatory characteristics 49 and can attenuate an inflammatory response in stressful conditions. 50 Conversely, Arg deficiency or unavailability inhibits T-lymphocyte proliferation, resulting in diverse impairments in the immune system and response. 51 The resulting immune cally ill patients. 52 Arg is considered a conditionally essential amino acid for catabolic patients. 53,54 However, Arg supplementation remains controversial, especially for patients with sepsis. Although meta-analysis studies found that Arg supplementation has no effect on infectious complications and may deteriorate outcomes in critically ill patients, Arg supplementation is associated with reduced infectious complication rates and a short length of hospital stay with no adverse effects on mortality in patients receiving elective surgery. 55 Recently, in human studies, Arg has been found to decrease clinical infections, postoperative hospital stay, intra-abdominal abscess and anastomotic leak, and mortality. 53,56 A review reported that the dosage of Arg available in commercial formulations is nontoxic and that parenteral delivery of Arg is also safe at clinical levels.

TA B L E 1 Studies on enteral immunonutrition in gastrectomy
Therefore, Arg should be considered for inclusion in immunonutri-  However, most studies reviewed in this report suggested that immunonutrients that are provided either alone or in combination have favorable effects in improving patient outcomes, except that the exclusive use of arginine is rare and needs to be confirmed in gastrectomy patients with GC. Conventional therapy in combination with immunonutrition pre-and/or postoperatively may be an important strategy to achieve favorable synergistic effects in the management of GC patients.

D I SCLOS U R E
Conflicts of Interest: Authors declare no conflicts of interest for this article.