Introduction

According to the 2020 Global Cancer Statistics, 560,000 new colorectal cancer (CRC) cases and 290,000 deaths were recorded in China. CRC is the second-most common cancer and the fifth-most common cause of cancer-related mortality.1 Surgery remains the main treatment for resectable CRC,2 but the high catabolism,3 preoperative tension and anxiety of patients together with surgery-induced intestinal ischemia-reperfusion injury, postoperative pain, nausea and vomiting, and intestinal dysfunction often cause delayed oral intake, impairing nutrient uptake and absorption;4,5 moreover, perioperative application of antibiotics can cause an imbalance of the intestinal flora and disruption of the intestinal barrier.6 The prevalence of malnutrition in patients with CRC ranges from 29% to 60% and may increase during hospitalization.7,8 Previous studies have shown that malnutrition is associated with poor clinical outcomes such as decreased immune function, increased inflammatory response, and delayed or failed wound healing. Malnutrition predicts prolonged postoperative length of hospital stay (LOS),9 which significantly increases medical costs.10 Therefore, perioperative nutritional support is crucial for patients with CRC, especially those undergoing surgical treatment.11

Since the 1990s, immunonutrition supported by specific nutrients, mainly glutamine (Gln), has been recognized to provide the necessary energy, improve the nutritional status of patients with cancer, and increase the number of intestinal lymphocytes, thereby regulating immune function, compared with traditional nutritional support.12,13 Immunonutrition attenuates the increased intestinal permeability14 and bacterial translocation15 and regulates the inflammatory response,16 nitrogen balance, and protein synthesis,17 reducing the incidence of postoperative complications and shortening the LOS.18,19 In the hypercatabolic situation of surgical stress, the requirement for Gln increases while the production capacity is impaired; consequently, the Gln obtained from dietary intake and endogenous synthesis is insufficient to meet the needs of the body,20,21 and additional Gln supplementation is therefore required.

An aqueous solution of Gln is unstable Consequently, an alanyl-Gln (Ala-Gln) dipeptide was developed for intravenous supplementation of Gln. Ala-Gln has been used as a Gln source for total parenteral nutrition (TPN) without side effects.22 In 1989, Ala-Gln was first applied clinically, and Stehle et al reported that Ala-Gln supplementation as TPN could maintain the Gln concentration of postoperative muscle cells in patients with CRC preoperatively and maintain the nitrogen balance.17 In 1999, Jian et al reported that parenteral nutrition (PN) supplemented with Ala-Gln could improve the nitrogen balance, protect the intestinal barrier, and be safe for patients after major abdominal surgery.23 Song et al reported that Gln-enriched PN improved postoperative immune function and protein metabolism in patients with CRC and enhanced the efficacy of PN.24 In 2007, researchers reported that combined parenteral and enteral Ala-Gln supplementation during the perioperative period reduced the incidence of postoperative complications and shortened the LOS in patients with CRC.25 Yang et al in 2021 showed that surgical site infection, anastomotic leakage, and LOS in a Gln supplementation group were significantly lower than those in the control group after radical resection of CRC.26 This may be due to the inhibition of the production of pro-inflammatory factors TNF-α and IL-6 in the process of inflammatory response, which protects the intestinal mucosa and reduces the translocation of bacteria and toxins into the blood, thereby reducing the occurrence of postoperative complications and ultimately improving the prognosis of patients.27

However, clinical trials have yielded inconsistent results. A prospective, double-blind registered clinical trial by Lobo et al showed that the incidence of infectious complications in experimental and control groups was 57.4% and 44.4%, respectively, after the early use of immunomodulatory feeding containing Gln in 54 patients with upper gastrointestinal tumors after surgery, and did not find any advantage of the immunonutritional diet over enteral feeding with a standard formula.28 Sandini et al showed that parenteral Gln supplementation reduced the LOS in patients undergoing elective major abdominal surgery but did not affect the incidence of complications.29 In recent years, domestic and foreign guidelines and consents have become inconsistent in the application of perioperative immunonutrition; the 2019 Chinese Expert Consensus on Perioperative Nutritional Therapy for Colorectal Cancer does not recommend the routine application of immunonutrition during the perioperative period for patients with CRC.30 The 2021 edition of the Chinese Expert Consensus on Perioperative Whole-Procedure Nutritional Management of Gastrointestinal Surgery Patients concluded that Gln supplementation is beneficial to most patients undergoing gastrointestinal surgery.31 In 2021, the European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines recommended the application of immunonutrition in the perioperative period for gastrointestinal malignant tumors.32 However, the mechanism by which parenteral Gln supplementation has a positive effect on CRC remains unclear.33 Additionally, Lee et al has questioned whether the routine use of immunonutrition during the perioperative period for colon cancer is unreasonable.34 Because they found that preoperative immunonutrition did not reduce the incidence of postoperative infectious or overall complications, nor did it reduce LOS.

Therefore, the clinical application of immunonutrition remains controversial in major guidelines and clinical trials, and further research is needed to verify the effects of immunonutrition as represented by Gln. Consequently, in this study, we reviewed the administration of Gln-enriched PN in patients with CRC to evaluate the incidence of postoperative complications, postoperative recovery, perioperative nutritional status, immune function, inflammation level, and safety indicators compared with traditional nutritional support to provide a reference for parenteral Gln supplementation in patients with CRC.

Materials and Methods Materials Inclusion Criteria

Inclusion criteria were: (1) Age 18–85 years old, sex was not limited; (2) CRC was diagnosed by pathology and met the diagnostic criteria of the American Joint Committee on Cancer (AJCC) (8th edition, 2017) for CRC; (3) radical R0 resection of the CRC was performed; (4) no preoperative radiotherapy or other treatments for CRC were administered; (5) no use of immunosuppressants or enhancers within 6 months before surgery; (6) patients were unable to take oral food within seven days after surgery and required parenteral nutrition; or if the energy and protein provided by oral feeding combined with enteral nutrition is less than 60% of the body’s target requirement, and parenteral nutrition is needed.

Exclusion Criteria

Exclusion criteria were: (1) Presence of distant metastases; (2) complications that included organic heart disease, pulmonary infection, and other serious cardiopulmonary dysfunctions; severe liver and kidney diseases such as active hepatitis, cirrhosis, and uremia; or intestinal obstruction, intestinal perforation, intestinal bleeding, and other emergencies; and (3) presence of severe preoperative malnutrition, uncontrolled diabetes, and/or coagulation disorders. The study flow is shown in Figure 1.

Figure 1 Study flow chart.

Abbreviations: PN, Parenteral nutrition; TPN, Total parenteral nutrition; EN, Enteral nutrition; SPN, Supplemental parenteral nutrition.

General Clinical Data

The clinical data of 178 patients with CRC who underwent radical resection of colorectal cancer in the same surgical treatment group in department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, from January 2019 to December 2021 were retrospectively collected, and the general clinical data of the patients were recorded. Among them, 58 patients received Gln-enhanced parenteral nutrition support after operation and were set as the observation group. 120 cases received postoperative traditional nutritional support, which was set as control group. Data included sex, age, weight, tumor location, TNM stage, surgical method, ASA classification, surgical year, surgical time, intraoperative blood loss, intraoperative blood transfusion, preoperative nutritional status, and postoperative PN support time. This study was approved by the Ethics Committee of the Affiliated Hospital of Zunyi Medical University (number: KLL-2023-186). Since the study was retrospective and would not adversely affect the rights and health of the subjects, the ethical committee waived the informed consent requirement. Our study complies with the Declaration of Helsinki.

Nutritional Support Nutritional Support Methods Used in the Control Group

All patients diagnosed with CRC underwent surgical resection according to the tumor resection standards. Postoperative nutritional support for patients was based on the patient’s body weight and postoperative intestinal recovery conditions to determine parenteral and enteral intake, and energy supply was supplied according to 25–30 kcal/(kg∙d). During this period, basic treatments such as anti-infection, acid control, rehydration, and maintenance of the acid-base balance were routinely administered. PN was administered via peripheral or central venous drip at a drip rate of 50–60 drops per min and an infusion time of 10–12 h. Prescription components and dosage principles of PN nutrient solution after CRC surgery are summarized in Table 1.

Table 1 Prescription Components and Dosage Principles of PN Nutrient Solution After CRC Surgery

Nutritional Intervention Methods Used in the Observation Group

For nutritional support in the observation group, on the basis of the control group, a 50-mL volume of Aln-Gln injection (50 mL) was dissolved in a compound amino acid injection (250 mL) or a 100-mL volume was dissolved in a fat emulsion amino acid glucose injection (1440 mL), and the infusion time was controlled within 12–24 h through the peripheral or central vein. The duration was ≥7 days.

Observing Indicators General Indicators

Sex, age, weight, tumor location, TNM stage, surgical method, ASA, year of operation, surgical time, intraoperative blood loss, intraoperative blood transfusion, preoperative nutritional status, and postoperative PN support time.

Main Indicators

Postoperative complications: total complications (anastomotic leakage, anastomotic bleeding, pulmonary infection, abdominal infection, incision infection, etc.) and severe postoperative complications (Clavien-Dindo grade ≥III complications: surgery, endoscopy, radiological intervention, etc.; Life-threatening complications (including central nervous system complications) requiring ICU admission; Death, etc).

Secondary Indicators

(1) Postoperative recovery: first exhaust time, first defecation time, first liquid diet time, LOS, and 30-day readmission rate. (2) Perioperative nutritional status: total protein, albumin, and prealbumin levels preoperatively and 1, 3, and 7 days postoperatively. (3) Perioperative immune function: peripheral blood lymphocyte counts preoperatively and at 1, 3, and 7 days postoperatively. (4) Perioperative inflammatory factors: white blood cell count, neutrophilic granulocyte percentage, and neutrophil/lymphocyte ratio preoperatively and at 1, 3, and 7 days postoperatively. (5) Perioperative safety indicators: alanine aminotransferase, aspartate aminotransferase, total bilirubin, endogenous creatinine clearance, and urea nitrogen levels preoperatively and 1, 3, and 7 days postoperatively.

Statistical Methods

Statistical analyses were performed using SPSS version 29.0. The measurement data of the normal distribution were expressed as mean ± SD, and comparisons between groups were performed by an independent sample t-test and repeated measures ANOVA. The measurement data of the skewed distribution were expressed as M (P25, P75), and the Mann–Whitney U-test was used for comparison between groups. Enumeration data were expressed as percentages [n(%)], and the chi-square test or Fisher’s method was used for comparison between groups. A P-value of <0.05 was considered significant.

Results Comparison of the General Clinical Data

A total of 178 patients (121 males and 57 females) were included in the study, all of whom underwent radical resection of CRC. The age range was 22–85 years, with a mean age of 61 years. In total, 58 patients who received Gln-enhanced PN support after surgery were included in the observation group, while 120 patients received traditional nutritional support after surgery and were set as the control group. No significant differences were present in sex, age, weight, tumor location, TNM staging, surgical method, ASA, surgical year, surgical time, intraoperative blood loss, intraoperative blood transfusion, preoperative nutritional status, or postoperative PN support time between the two groups (P >0.05). The results are summarized in Table 2. The PN energy supply ratio and protein energy supply of the two groups were compared, with no statistical difference (P>0.05). The results are shown in Table 3.

Table 2 Comparison of General Data Between the Two Groups

Table 3 Comparison of the Proportion of PN Energy Supply and Protein Energy Supply Between the Two Groups

Comparison of Main Endpoint Comparison of Postoperative Complications

A total of 37 patients in the two groups had postoperative complications, including 7 cases of anastomotic leakage, of which 6 cases healed after reoperation, and 1 case was improved after conservative treatment such as non-surgical drainage. Anastomotic bleeding occurred in 2 cases and healed after reoperation. 16 cases had pulmonary infection, of which 9 cases were improved after symptomatic treatment such as active anti-infection, 7 cases were transferred to ICU and improved after treatment. There were 7 cases of abdominal infection, of which 4 cases were improved after conservative treatment, and 3 cases were improved after ICU care. There were 5 cases of incision infection, of which 4 cases were improved after symptomatic treatment such as active anti-infection, and 1 case was improved after surgical treatment. In summary, the overall incidence of postoperative complications in the control group and the observation group was 22.50% (27/120) and 17.24% (10/58), respectively, and there was no significant difference between the two groups (P=0.42). The incidence of postoperative complications of Clavien-Dindo grade ≥III in the control group and the observation group was 14.17% (17/120) and 3.45% (2/58), respectively, and the difference between the two groups was statistically significant (P=0.03).The results are summarized in Tables 4 and 5.

Table 4 Comparison of Total Complications Between Groups

Table 5 Comparison of the Incidence of Severe Postoperative Complications (Clavien-Dindo Grade ≥III) Between the Two Groups

Comparison of Secondary Endpoints Comparison of Postoperative Recovery Rates

Compared with the control group, the observation group exhibited an early recovery time of first exhaust (P = 0.02), time of first defecation (P = 0.02), time of first fluid diet (P = 0.03), and a shortened LOS (P = 0.04). No significant difference was observed in the 30-day readmission rate (P = 0.39) between the two groups. The results are summarized in Table 6.

Table 6 Comparison of Postoperative Recovery Between the Two Groups

Comparison of the Perioperative Nutritional Status

No significant differences were observed in the levels of total protein (P = 0.70), albumin (P = 0.80), or prealbumin (P = 0.10) between the two groups on preoperative and postoperative days 1, 3, and 7. This suggests that Gln intervention does not improve the perioperative nutritional status of patients with CRC. The results are shown in Table 7.

Table 7 Comparison of Perioperative Nutritional Status Indexes Between the Two Groups

Comparison of the Perioperative Immune and Inflammatory Indices

Significant differences were observed in the trends in lymphocyte count (P = 0.03), leukocyte count (P = 0.03), and neutrophil percentage (P = 0.01) between the two groups in the preoperative period and on postoperative days 1, 3, and 7, whereas no significant difference was observed in the neutrophil/lymphocyte ratio between the two groups (P = 0.59). Gln supplementation has been suggested to enhance immune function and reduce postoperative inflammation. Results are represented in Table 8.

Table 8 Comparison of Perioperative Immune and Inflammatory Indexes Between the Two Groups

Comparison of Perioperative Safety Indices

For liver function, significant differences were observed in alanine aminotransferase levels (P = 0.01) and total bilirubin levels (P <0.05) on preoperative and postoperative days 1, 3, and 7 between the two groups; however, aspartate aminotransferase (P = 0.30) levels did not significantly differ. For renal function, significant differences were observed in the trend in urea nitrogen levels preoperatively and on postoperative days 1, 3, and 7 between the two groups (P <0.05) but not in the endogenous creatinine clearance rate (P = 0.79). These results suggest that the Gln application impairs liver and kidney function. Results are represented in Tables 9 and 10.

Table 9 Comparison of Perioperative Liver Function Between the Two Groups

Table 10 Comparison of Perioperative Renal Function Between the Two Groups

Discussion

Gln is the most abundant free amino acid in the human body and plays important roles in intermediary metabolism, ammonia-nitrogen transport between tissues, and pH homeostasis.35 Gln is an essential nutrient for lymphocyte proliferation and cytokine production, phagocytosis and secretion by macrophages, and the bactericidal activity of neutrophils.36 The release and utilization of Gln in circulation are mainly controlled by key metabolic organs, such as the gut, liver, and skeletal muscle. During high levels of catabolism, Gln is essential for metabolic function, but its availability is mostly limited because of the impaired homeostasis of amino acid metabolism between tissues.37 Initially, Gln supplementation was mostly used in critically ill or surgical patients. In a meta-analysis of 40 randomized controlled trials involving 3107 critically ill or postoperative patients, Bollhalder et al reported that parenteral Gln supplementation significantly reduced the incidence of infectious complications and LOS; a trend toward lower short-term mortality was observed, but this difference was not significant.38 In recent years, the incidence of malnutrition among oncology patients has been increasing annually, and approximately 30–80% of oncology patients are at risk of malnutrition,39 which is an independent risk factor for complications after gastrointestinal surgery.40 Therefore, Gln is now included in clinical nutritional supplementation programs.

To explore the effect of Gln application on postoperative complications in patients with CRCs, many previous studies have used total infectious complications, and noninfectious complications as observational indicators. A retrospective study in 2021 included 1004 CRC surgical patients (of whom 660 received intravenous Gln supplementation) and reported that the postoperative total complication incidence in the Gln and control groups was 14.9% and 36.8%, respectively, and that the incidence of postoperative infectious complications was significantly lower in the Gln group than that in the control group (10.5% versus 28.9%).41 A retrospective study by Wei et al reported that Gln-enhanced PN reduced the incidence of complications in older adult patients with CRC (7.50% versus 17.50%, P <0.05), accelerated perioperative recovery, and improved patient prognosis.42 In recent years, the Clavien–Dindo classification has been used as an observation index of postoperative complications in clinical practice for improved assessment and management of postoperative complications.43 Therefore, our current retrospective study investigated the effect of postoperative Gln on the severity of postoperative complications by observing whether this had been provided parenterally to patients with CRC after surgery. The results showed that parenteral Gln supplementation reduced the incidence of postoperative complications of Clavien-Dindo grade ≥III, which confirmed the effectiveness of Gln in patients with CRC. Previous studies showed that Gln supplementation reduced the incidence of postoperative infectious and non-infectious complications, and found its effect on improving the severity of postoperative complications. Our study also found that parenteral Gln supplementation had a tendency to reduce postoperative complications such as anastomotic leakage, bleeding and postoperative infection, but the difference did not reach statistical significance, which may be due to the small number of subjects included in the study, and further study with larger sample should be continued.

For postoperative recovery, our study observed that the time to first flatus (P = 0.02), first defecation (P = 0.02), first liquid diet (P = 0.03), and LOS (P = 0.04) in the observation group were earlier than those in the control group, suggesting that Gln improved gastrointestinal function, which is consistent with results of previous studies. In 2019, Chaidez et al reported that intravenous infusion of Gln after gastrointestinal tumor surgery changed the assessment of gastrointestinal function from severe to mild dysfunction in the supplemented group (P = 0.0001) and that the non-supplemented group progressed from moderate to severe dysfunction, suggesting that supplementation of Gln by PN can improve gastrointestinal function.44 Gln can activate the mammalian target of rapamycin, increase the expression of ornithine decarboxylase, and promote intestinal repair.45 Gln can upregulate the expression of antiapoptotic proteins Bcl-2 and CD45RO and downregulate that of proapoptotic proteins Fas and Fas ligands in the human T lymphocyte Jurkat cell line.46 In this study, no significant difference was observed in the 30-day readmission rates (P = 0.39) between the groups. We believe that the maintenance time in this study was mainly 7–10 days, which is a short-term application of immunonutrition therapy, and may have had minimal effect on relatively long-term observation indicators.

Gln oxidation can provide a nitrogen source for protein synthesis.47 Our study showed that the preoperative nutritional status did not differ between the two groups, with no significant difference in the change trends of total protein, albumin, and prealbumin levels on postoperative days 1, 3, and 7 between the groups (P >0.05), suggesting that Gln intervention did not improve the nutritional status of patients in the short term. This is inconsistent with the results of recent studies. Kai Xiong et al reported that nutritional status indicators (albumin, prealbumin, and nitrogen balance) were significantly improved after Gln treatment in patients with CRC undergoing radical resection.48 Gang Tang et al enrolled 1004 patients with CRC undergoing elective surgery and reported that Gln supplementation attenuated the decline in albumin (P <0.001), total protein (P <0.001), and prealbumin levels (P <0.001).49 The decrease in serum protein levels after CRC surgery is affected by many factors, one of which may be the increase in capillary permeability caused by the inflammatory effect of surgical stimulation, causing the leakage of plasma proteins through capillaries.50 The half-life of albumin is approximately 21 days, and the short-term monitoring of nutritional status within 7 days after surgery in our study may not reflect the true plasma level. Our findings suggest that postoperative Gln supplementation enhances immune function and reduces postoperative inflammation to an extent. This is consistent with previous studies, and an earlier clinical trial reported that Gln caused an increase in total lymphocyte count, CD8+, CD4+, IgA, and IgG levels, and a decrease in C-reactive protein levels in immunocompromised patients.51 The mechanism whereby Gln exerts an anti-inflammatory effect may be via the inhibition of various inflammatory response pathways such as NF-kB, p38MAPK, ERK, and MKP-1; Gln has an inhibitory effect on the increase in iNOS expression.16 In addition, Gln plays a role in controlling cell proliferation in the immune system by activating proteins such as ERK and JNK,36 maintaining Paneth and goblet cell numbers, normalizing Th2 cytokines, and increasing resistance to bacterial mucosal invasion.52 Finally, in terms of safety indicators, we defined the clearance rate of transaminase, total bilirubin, urea nitrogen and creatinine. Glutamine is usually metabolized by the liver, and it is necessary to dynamically monitor the liver and kidney function of CRC patients when glutamine preparation is applied in clinical. Our study showed that the application of Gln after surgery in CRC patients can damage liver function to a certain extent while increasing the nitrogen levels in the body, but this statistical difference has no clinical significance.

Our study has several advantages. First, by comparing the effects of general nutritional support and Gln-enriched PN on the clinical outcomes of patients with CRC, the advantages of Gln were verified to provide a clinical basis for perioperative nutritional support programs for patients with CRC. Second, this study classified the main endpoints as grade I–II and ≥III concurrently according to the Clavien–Dindo classification, which is more in line with clinical practice and better reflects the improvement of postoperative complications in patients with CRC. Third, We reviewed studies in other fields and found that for patients with liver cancer, pancreatic cancer et al during the perioperative period, glutamine supplementation also had a positive effect on reducing the incidence of postoperative complications, shortening LOS, and ultimately improving the prognosis of patients.53,54 Therefore, we believe that the study population and the findings can be generalized to other types of surgeries or patient demographics. This study had a limitation, this is a single-center retrospective study, which inevitably has some confounding factors or selection bias. In order to minimize the influence of these factors or bias, we formulated and implemented strict inclusion and exclusion criteria, and the patients were precisely set as the control and the observation group according to the different nutritional support methods in the past. And our team is considering to conduct a follow-up prospective randomized controlled study on related topics to improve the reliability of the conclusion.

Conclusion

Compared with traditional nutritional support therapy, postoperative PN with glutamine supplementation can reduce the incidence of Clavien-Dindo≥III complications in patients with CRC, promote the recovery of intestinal function, shorten LOS, improve immune function, and reduce inflammation to a certain extent. This is closely related to the function of glutamine to protect the intestinal barrier and reduce the translocation of bacteria and toxins into the blood. Due to the limitations of a retrospective study, we could not control variables in advance to completely eliminate the confounding factors of this study, so future implementation of a multicenter prospective study is warranted. Secondly, the universality of glutamine in other settings should also be explored, and the positive effects of its application in patients with other tumors or surgery should be explored to bring the greatest benefits to hospitalized patients and give full play to the advantages of glutamine as an immunonutrient. Finally, the specific mechanism of action, application time, optimal dose of glutamine, and the efficacy of adjuvant therapy such as radiotherapy and chemotherapy are the focus of future research.

Data Sharing Statement

The first author is available to provide data and materials upon request.(Yong Huang, Email:[email protected]).

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

This research was funded by the National Natural Science Foundation of China (funding number: 81960105), Zunyi Science and Technology Plan Project (Zun City Science and Technology HZ [2023]304), and the Training Plan for Clinical Famous Doctors of Zunyi Medical University (RC220230405).

Disclosure

The authors report no conflicts of interest in this work.

References

1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–249.

2. Benson AB, Venook AP, Al-Hawary MM, et al. Colon cancer, version 2.2021, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2021;19(3):329–359. doi:10.6004/jnccn.2021.0012

3. Batista MJ, Peres SB, McDonald ME, et al. Adipose tissue inflammation and cancer cachexia: possible role of nuclear transcription factors. Cytokine. 2012;57(1):9–16. doi:10.1016/j.cyto.2011.10.008

4. Cui JW, Zhuo WL, Huang L, et al. Guidelines for tumor immunonutrition therapy. J Can Metabol Nutrit. 2020;7(02):160–168.

5. Deng YY, Zhou K, Lu Z, et al. Research progress of perioperative nutritional support therapy in patients with colorectal cancer. Cancer Progress. 2020;21(18):1978–1981.

6. Ban K, Kozar RA. Glutamine protects against apoptosis via downregulation of Sp3 in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol. 2010;299(6):G1344–G1353. doi:10.1152/ajpgi.00334.2010

7. van der Werf A, Arthey K, Hiesmayr M, et al. The determinants of reduced dietary intake in hospitalised colorectal cancer patients. Support Care Cancer. 2018;26(6):2039–2047. doi:10.1007/s00520-018-4044-1

8. Kim JY, Wie GA, Cho YA, et al. Development and validation of a nutrition screening tool for hospitalized cancer patients. Clin Nutr. 2011;30(6):724–729. doi:10.1016/j.clnu.2011.06.001

9. Tokunaga R, Sakamoto Y, Nakagawa S, et al. Prognostic nutritional index predicts severe complications, recurrence, and poor prognosis in patients with colorectal cancer undergoing primary tumor resection. Dis Colon Rectum. 2015;58(11):1048–1057. doi:10.1097/DCR.0000000000000458

10. Kiss N, Hiesmayr M, Sulz I, et al. Predicting hospital length of stay at admission using global and country-specific competing risk analysis of structural, patient, and nutrition-related data from nutritionDay 2007-2015. Nutrients. 2021;13(11):1.

11. Huhmann MB, August DA. Perioperative nutrition support in cancer patients. Nutr Clin Pract. 2012;27(5):586–592.

12. Burke DJ, Alverdy JC, Aoys E, et al. Glutamine-supplemented total parenteral nutrition improves gut immune function. Arch Surg. 1989;124(12):1396–1399. doi:10.1001/archsurg.1989.01410120042009

13. Kudsk KA, Wu Y, Fukatsu K, et al. Glutamine-enriched total parenteral nutrition maintains intestinal interleukin-4 and mucosal immunoglobulin A levels. JPEN J Parenter Enteral Nutr. 2000;24(5):270–274. doi:10.1177/0148607100024005270

14. De-Souza DA, Greene LJ. Intestinal permeability and systemic infections in critically ill patients: effect of glutamine. Crit Care Med. 2005;33(5):1125–1135. doi:10.1097/01.ccm.0000162680.52397.97

15. Li JY, Lu Y, Hu S, et al. Preventive effect of glutamine on intestinal barrier dysfunction induced by severe trauma. World J Gastroenterol. 2002;8(1):168–171. doi:10.3748/wjg.v8.i1.168

16. Singleton KD, Beckey VE, Wischmeyer PE. Glutamine prevents activation of nf-kappab and stress kinase pathways, attenuates inflammatory cytokine release, and prevents acute respiratory distress syndrome (ards) following sepsis. Shock. 2005;24(6):583–589. doi:10.1097/01.shk.0000185795.96964.71

17. Stehle P, Zander J, Mertes N, et al. Effect of parenteral glutamine peptide supplements on muscle glutamine loss and nitrogen balance after major surgery. Lancet. 1989;1(8632):231–233. doi:10.1016/s0140-6736(89)91254-3

18. Souba WW. Nutritional support. N Engl J Med. 1997;336(1):41–48. doi:10.1056/NEJM199701023360107

19. Mariette C. Immunonutrition. J Visc Surg. 2015;152:S14–S17. doi:10.1016/S1878-7886(15)30005-9

20. Fläring UB, Rooyackers OE, Wernerman J, et al. Glutamine attenuates post-traumatic glutathione depletion in human muscle. Clin Sci (Lond). 2003;104(3):275–282. doi:10.1042/CS20020198

21. Parry-Billings M, Evans J, Calder PC, et al. Does glutamine contribute to immunosuppression after major burns? Lancet. 1990;336(8714):523–525. doi:10.1016/0140-6736(90)92083-t

22. Fürst P, Pogan K, Stehle P. Glutamine dipeptides in clinical nutrition. Nutrition. 1997;13(7–8):731–737.

23. Jian ZM, Cao JD, Zhu XG, et al. The impact of alanyl-glutamine on clinical safety, nitrogen balance, intestinal permeability, and clinical outcome in postoperative patients: a randomized, double-blind, controlled study of 120 patients. JPEN J Parenter Enteral Nutr. 1999;23(5 Suppl):S62–S66. doi:10.1177/014860719902300516

24. Song JX, Qing SH, Huang XC, et al. Effect of glutamine-enhanced parenteral nutrition on postoperative immune function in patients with colorectal cancer. Lingnan Mod Clin Surg. 2002;2002:(2):46–48.

25. Oguz M, Kerem M, Bedirli A, et al. L-alanin-L-glutamine supplementation improves the outcome after colorectal surgery for cancer. Colorectal Dis. 2007;9(6):515–520. doi:10.1111/j.1463-1318.2006.01174.x

26. Yang T, Yan X, Cao Y, et al. Meta-analysis of glutamine on immune function and post-operative complications of patients with colorectal cancer. Front Nutr. 2021;8:765809. doi:10.3389/fnut.2021.765809

27. Coeffier M, Marion R, Leplingard A, et al. Glutamine decreases interleukin-8 and interleukin-6 but not nitric oxide and prostaglandins e(2) production by human gut in-vitro. Cytokine. 2002;18(2):92–97. doi:10.1006/cyto.2002.1027

28. Lobo DN, Williams RN, Welch NT, et al. Early postoperative jejunostomy feeding with an immune modulating diet in patients undergoing resectional surgery for upper gastrointestinal cancer: a prospective, randomized, controlled, double-blind study. Clin Nutr. 2006;25(5):716–726. doi:10.1016/j.clnu.2006.04.007

29. Sandini M, Nespoli L, Oldani M, et al. Effect of glutamine dipeptide supplementation on primary outcomes for elective major surgery: systematic review and meta-analysis. Nutrients. 2015;7(1):481–499. doi:10.3390/nu7010481

30. Dong M, Zhou JP, Yao HW. Chinese expert consensus on perioperative nutritional therapy for colorectal cancer (2019 edition). Chinese J Pract Sur. 2019;39(06):533–537.

31. Wu GH, Tan SJ. Chinese expert consensus on perioperative nutrition management of patients with gastrointestinal surgery (2021 edition). Chin J Practical Surgery. 2021;41(10):1111–1125.

32. Muscaritoli M, Arends J, Bachmann P, et al. ESPEN practical guideline: clinical Nutrition in cancer. Clin Nutr. 2021;40(5):2898–2913. doi:10.1016/j.clnu.2021.02.005

33. Weimann A, Braga M, Carli F, et al. ESPEN practical guideline: clinical nutrition in surgery. Clin Nutr. 2021;40(7):4745–4761.

34. Lee SY, Lee J, Park HM, et al. Impact of preoperative immunonutrition on the outcomes of colon cancer surgery: results from a randomized controlled trial. Ann Surg. 2023;277(3):381–386. doi:10.1097/SLA.0000000000005140

35. Griffiths RD, Jones C, Palmer TE. Six-month outcome of critically ill patients given glutamine-supplemented parenteral nutrition. Nutrition. 1997;13(4):295–302.

36. Scheppach W, Loges C, Bartram P, et al. Effect of free glutamine and alanyl-glutamine dipeptide on mucosal proliferation of the human ileum and colon. Gastroenterology. 1994;107(2):429–434. doi:10.1016/0016-5085(94)90168-6

37. Cruzat V, Macedo RM, Noel KK, et al. Glutamine: metabolism and Immune Function. Supplem Clin Translat Nutr. 2018;10(11):1.

38. Bollhalder L, Pfeil AM, Tomonaga Y, et al. A systematic literature review and meta-analysis of randomized clinical trials of parenteral glutamine supplementation. Clin Nutr. 2013;32(2):213–223. doi:10.1016/j.clnu.2012.11.003

39. Song CH, Wang KH, Guo ZQ, et al. Nutritional status of patients with common malignant tumors in China. Sci China Life Sci. 2020;50(12):1437–1452.

40. Jeejeebhoy KN, Keller H, Gramlich L, et al. Nutritional assessment: comparison of clinical assessment and objective variables for the prediction of length of hospital stay and readmission. Am J Clin Nutr. 2015;101(5):956–965. doi:10.3945/ajcn.114.098665

41. Gupta A, Gupta E, Hilsden R, et al. Preoperative malnutrition in patients with colorectal cancer. Can J Surg. 2021;64(6):E621–E629. doi:10.1503/cjs.016820

42. Wei XL, Zhao TY, Liu JN, et al. Effect of glutamine-enriched parenteral nutrition on intestinal function and stress state in elderly patients with colorectal cancer after surgery. Chin J Food Nutrit. 2012;28(04):83–86.

43. Tamura S, Sugawara Y, Kaneko J, et al. Systematic grading of surgical complications in live liver donors according to Clavien’s system. Transpl Int. 2006;19(12):982–987. doi:10.1111/j.1432-2277.2006.00375.x

44. Beltrán CY, Reyes BD, Flores MM, et al. Effect of parenteral glutamine in patients with gastrointestinal cancer undergoing surgery. Nutr Hosp. 2019;36(1):5–12. doi:10.20960/nh.1816

45. Wang JY. Polyamines and mRNA stability in regulation of intestinal mucosal growth. Amino Acids. 2007;33(2):241–252. doi:10.1007/s00726-007-0518-z

46. Chang WK, Yang KD, Chuang H, et al. Glutamine protects activated human T cells from apoptosis by up-regulating glutathione and Bcl-2 levels. Clin Immunol. 2002;104(2):151–160. doi:10.1006/clim.2002.5257

47. Kim M, Wischmeyer PE. Glutamine. World Rev Nutr Diet. 2013;105:90–96. doi:10.1159/000341276

48. Xiong K, Li G, Zhang Y, et al. Effects of glutamine on plasma protein and inflammation in postoperative patients with colorectal cancer: a meta-analysis of randomized controlled trials. Int J Colorectal Dis. 2023;38(1):212. doi:10.1007/s00384-023-04504-8

49. Tang G, Pi F, Qiu YH, et al. Postoperative parenteral glutamine supplementation improves the short-term outcomes in patients undergoing colorectal cancer surgery: a propensity score matching study. Front Nutr. 2023;10:1040893. doi:10.3389/fnut.2023.1040893

50. Norberg Å, Rooyackers O, Segersvärd R, et al. Albumin kinetics in patients undergoing major abdominal surgery. PLoS One. 2015;10(8):e136371.

51. Chuntrasakul C, Siltharm S, Sarasombath S, et al. Metabolic and immune effects of dietary arginine, glutamine and omega-3 fatty acids supplementation in immunocompromised patients. J Med Assoc Thai. 1998;81(5):334–343.

52. Wang X, Pierre JF, Heneghan AF, et al. Glutamine improves innate immunity and prevents bacterial enteroinvasion during parenteral nutrition. JPEN J Parenter Enteral Nutr. 2015;39(6):688–697. doi:10.1177/0148607114535265

53. Yao J. Effects of glutamine nutritional support on perioperative inflammatory factors and immune function in patients with liver cancer. J Clin Rat Drug Use. 2021;14(19):169–171.

54. Niu X, Liu J, Zhang DQ. Effects of alanyl glutamine on immune function and blood Gln and urine L/M ratio in patients after pancreatic cancer resection. Chongqing Med. 2022;51(15):2596–2599+2604.