Published online Jun 27, 2026. doi: 10.4240/wjgs.118979
Revised: January 30, 2026
Accepted: April 7, 2026
Published online: June 27, 2026
Processing time: 160 Days and 1.3 Hours
Nutritional deficiency and immunosuppression after radical colorectal cancer (CRC) surgery persist long term, rather than being confined to the immediate postoperative period, and may even worsen after hospital discharge. However, most research exploring immunonutrition (IMN) efficacy has been concentrated on the short-term perioperative phase, culminating in a significant dearth of long-term evidence for its effects on the immunonutritional status of postdischarge CRC patients.
To assess the influence of prolonged oral administration postdischarge on the immunonutritional status of patients undergoing radical CRC surgery.
In June 2023, a two-parallel-arm, multicenter randomized controlled trial (ChiCTR2300071078) was launched in CRC patients across 20 tertiary Chinese medical centers. For a consecutive 30 days postdischarge, patients in the in
We collated and analyzed data from the trial’s lead center up to May 2024, with a total of 447 patients enrolled. Baseline demographic characteristics were well balanced between the two study arms (P > 0.05). After intervention, significant intergroup differences were observed in Patient-Generated Subjective Global Assessment scores and serum albumin concentrations (P < 0.05). Moreover, the IMN group had a significant post-intervention elevation in absolute lymphocyte count and the levels of immunoglobulin G and immunoglobulin M compared with the control group (all P < 0.05). Although the total incidence of complications did not differ significantly between the two arms, the IMN group presented a markedly lower incidence of postoperative infectious complications (P < 0.05).
The present trial demonstrated that prolonged post-surgical oral IMN supplementation in patients with CRC resulted in improved nutritional status, enhanced immune function, and a reduced incidence of postoperative infectious complications.
Core Tip: This randomized controlled trial compared long-term immunonutrition (IMN) with conventional oral nutritional supplements in postdischarge colorectal surgery patients. Radical colorectal cancer surgery induces persistent nutritional deficiency and immunosuppression that may worsen after discharge, yet most IMN studies focus on the short-term perioperative phase, resulting in a notable lack of long-term postdischarge data. After the intervention, nutritional and immunological parameters were comparable between the groups, while the IMN group had a significantly lower incidence of postoperative infectious complications. Our findings confirmed that prolonged postoperative oral IMN optimizes nutritional profiles, enhances immune competence, facilitates subsequent therapy preparation and reduces infection risk in colorectal cancer patients.
- Citation: Bao MD, Huang F, Cheng P, Zheng ZX. Effects of long-term immunonutrition on postdischarge colorectal cancer surgery patients. World J Gastrointest Surg 2026; 18(6): 118979
- URL: https://www.wjgnet.com/1948-9366/full/v18/i6/118979.htm
- DOI: https://dx.doi.org/10.4240/wjgs.118979
According to the 2024 cancer statistics released by China’s National Cancer Center, there were 4.8247 million new cancer cases nationwide in 2022. Among these, colorectal cancer (CRC) accounted for 10.72% of the new cases, making it the second most commonly diagnosed malignancy. CRC also represents 9.32% of all cancer-related deaths and ranks fourth in terms of mortality[1]. Furthermore, survey data from China reveal a high prevalence of malnutrition among cancer patients. Nearly 80% are affected, with the incidence of moderate-to-severe cases reaching 58%. Patients with digestive tract tumors report the highest rates of malnutrition[2]. Severe malnutrition in CRC patients not only predisposes them to serious postoperative complications and mortality but also significantly exacerbates their financial burden[3]. Long-term tumor consumption and reduced intake due to symptoms such as anorexia and diarrhea predispose patients to malnutrition, with a prevalence of 45%-60% of this population experiencing malnutrition, which significantly increases after radical surgery[4]. The interplay between malnutrition and surgical insult - which induces systemic inflammatory response syndrome and further immune impairment - is responsible for a significant proportion of postoperative complications[5,6]. These complications, in turn, negatively influence short-term outcomes - particularly by prolonging the length of stay and increasing costs - as well as long-term oncological results and quality of life[7]. Therefore, the treatment for severe malnutrition should focus not only on improving the patient’s nutritional status but also on enhancing the immune system and reducing inflammatory responses.
To date, the special nutrients generally termed immunonutrition (IMN) and predominantly utilized in clinical practice consist mainly of omega-3 fatty acids, glutamine, arginine, dietary fiber, nucleosides, and RNA[8]. Omega-3 fatty acids may help mitigate platelet adhesion to the endothelium and reduce the production of proinflammatory eicosanoids[9]. Arginine is the sole precursor for the synthesis of nitric oxide, a critical component of the innate immune response against pathogens and an essential element of the host’s primary defense system[10]. Glutamine serves as a primary energy source for macrophages, lymphocytes, and enterocytes. It can increase glutathione levels in the gut mucosa, thereby decreasing free radical activity and inflammation[11].
Accumulating research evidence has confirmed that short-term perioperative IMN intervention for CRC patients undergoing surgical procedures is capable of ameliorating short-term prognosis, including a reduction in the occurrence of infectious complications and hospitalization duration[12,13]. Moya et al[14] implemented a multicenter randomized controlled study recruiting 244 CRC patients, who were randomly assigned to two cohorts: The study cohort receiving immune-enhancing nutrition and the control cohort administered a hypercaloric-hypernitrogenous supplement. This intervention regimen persisted for 7 days prior to colorectal resection and was continued for 5 days following surgery. The outcomes revealed a decline in the overall number of complications in the IMN cohort relative to the control cohort, mainly resulting from a substantial reduction in infectious complications (23.8% vs 10.7%, P = 0.0007). Mingliang et al[15] conducted a meta-analysis of seven randomized controlled trials (RCTs) that compared perioperative enteral IMN to standard nutrition and reported that the relative risk of anastomotic leakage was reduced by 41%, with associated confidence intervals crossing the line of no effect [5.4% vs 9.4%, relative risk = 0.59, 95% confidence interval (CI): 0.33-1.04; P = 0.07].
However, studies have revealed that the immunosuppression and malnutrition status experienced by patients due to tumors is a long-term phenomenon. It does not dissipate immediately after tumor excision but involves a prolonged recovery process. Studies indicate that this process usually persists for more than one month, and in some cases, it may even extend to more than four months[16]. Furthermore, current investigations into the effects of IMN in patients following CRC surgery are predominantly restricted to the two-week perioperative period. Large-scale, well-designed RCT are warranted to clarify whether prolonged oral IMN administration can improve immunonutritional status, strengthen immune responses, and consequently enhance the prognosis of patients who have undergone radical CRC resection.
A multicenter, two-parallel-arm RCT was initiated in June 2023 at 20 Chinese medical centers, led by the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. The trial was registered as ChiCTR2300071078 on the ChiCTR (www.chictr.org.cn) subsequent to ethical approval by local research ethics committees, and all patients provided written informed consent after receiving a full explanation of study participation details before enrollment.
The primary endpoints were nutritional and immunologic parameters after intervention, and the secondary endpoint was the incidence of infectious complications after surgery.
The study enrolled patients aged 18-75 years who were diagnosed with colorectal adenocarcinoma and underwent radical surgery. The key inclusion criteria were a body mass index (BMI) of 18.5-28 kg/m2, a hemoglobin concentration ≥ 90 g/L, an albumin (ALB) concentration ≥ 2.5 g/dL, and the absence of blood products during the week prior to enrollment.
The exclusion criteria included receiving radiotherapy or chemotherapy prior to surgery; having a protective ileostomy; having chronic inflammatory bowel diseases; having active infection, thyroid disorders, or medically managed diabetes; having congenital or acquired immunodeficiency; or having significant insufficiency of renal (creatinine ≥ 2 × upper limits of normal or hemodialysis), cardiac (New York Heart Association class > III), hepatic (alanine aminotransferase or total bilirubin ≥ 2 × upper limits of normal), or respiratory (PaO2 < 70 mmHg) systems.
The nutritionist provided all patients with individualized guidance on intake recording, enabling precise calculation of daily calories and intake. The intervention was as follows: (1) Identical education: All patients received comprehensive postoperative nutritional education; and (2) Group-specific supplementation.
IMN group: Patients supplemented their diet with 500 mL/day of IMPACT Oral® (enriched with protein, arginine, omega-3, and RNA) for 30 days. IMPACT Oral® contains high concentrations of protein, arginine, omega-3 fatty acids, and RNA. The detailed composition of the supplement is provided in Supplementary Table 1.
No-IMN group: Patients who received standard dietary counseling without specialized IMN supplements.
Baseline demographic and disease-related characteristics of each cohort at the time of surgery were prospectively collected, including sex, age, BMI, American Society of Anesthesiologists physical status classification score, tumor location, tumor-node-metastasis stage, and history of previous abdominal surgery.
We additionally assessed the following nutritional and immunological parameters at two time points: The 1st postdischarge day (defined as “baseline”), the day when patients began to take IMPACT Oral®, and the 30th day after the first dose (defined as “endline”): BMI, patient-generated subjective global assessment (PG-SGA), transferrin (TFN), serum ALB, prealbumin (PA), glucose (GLU), absolute lymphocyte count (ALC), and C-reactive protein, and serum immunoglobulin (Ig) G, IgM, and IgA levels.
The incidence of postoperative complications occurring between baseline and endline was meticulously recorded, including a range of adverse events such as surgical site infections, abdominal abscesses, anastomotic fistulas, and intestinal obstructions. Complications were defined as any deviation from the normal postoperative recovery course and were categorized into minor and major complications as previously described[17]. Minor complications - including bedside-managed surgical site infections, urinary tract infections, and postoperative ileus - were classified as Clavien-Dindo grades I-II. Major complications, whereas, included life-threatening events and those requiring surgical, endo
The sample size was determined on the basis of a previous multicenter randomized trial conducted in China. The hazard ratio for this study was 0.8, the expected percentage of events during the study period was 0.7, and the proportion allocated to patients in the experimental group was 0.66. A superiority test with a cutoff value of 5% was used, and α = 0.05 and β = 0.2 were used. A two-sided Z test was adopted, with a total of 800 cases in the study group vs 400 cases in the control group. Considering that approximately 20% of the evaluation data were invalid for reasons such as dropout and loss to follow-up, a total of 1340 patients actually needed to be included (960 patients in the IMN group vs 480 patients in the control group). The formula for calculating sample size is as follows.
Centralized randomization was executed through an electronic data capture (EDC) system (https://edc-cloud.medsci.cn). Eligible patients were assigned unique study IDs, with automatic allocation to the IMN or control group at a 2:1 ratio. Stratified randomization was used by tumor location (colon vs rectum), with 1:1 allocation within each stratum to maintain balance. Allocation sequence was concealed until group assignment, blinding investigators to avoid predictable patient grouping.
Statistical analyses were conducted using SPSS software version 27.0 for Windows (SPSS Inc., Chicago, IL, United States). Continuous data were presented as mean ± SD and compared between groups using the independent samples t-test. Categorical data were expressed as frequencies and percentages, and intergroup comparisons (IMN group vs control group) were performed using the χ2 test. A two-tailed P value < 0.05 was considered statistically significant, indicating that the observed differences were not attributable to random chance.
From June 2023 to May 2024, a total of 480 patients were initially enrolled in the main centers in this study. Following this, 12 patients were excluded for not meeting the inclusion criteria (n = 8), declining participation (n = 3), or other reasons (n = 1). Compared with 2 patients in the control group, 9 patients in the IMN group did not receive the intervention because of incorrect supplement intake or refusal. Furthermore, 7 patients in the IMN group were lost to follow-up because of incomplete contact information or refusal, whereas 3 patients in the control group were lost. Thus, a total of 447 patients were enrolled in the final interim evaluation, with 296 participants assigned to the IMN group and 151 to the control group. The complete CONSORT flowchart is presented in Figure 1.
As shown in Table 1, the independent samples t-test demonstrated that baseline demographic characteristics were comparable between the IMN group and the control group (non-IMN group). In both the IMN and control groups, males accounted for a higher proportion than females, with no statistically significant difference in gender distribution between the two groups (P = 0.911). The mean age of all enrolled patients was 60 years, and there were no significant intergroup differences in age (P = 0.227). Similarly, the two groups exhibited comparable BMI distributions, showing no notable variations (P = 0.761). Additionally, the two groups had comparable baseline data for other key variables, including American Society of Anesthesiologists score (P = 0.329), tumor location (P = 0.523), and tumor-node-metastasis. stage (P = 0.472). In addition, no significant difference was observed between the two groups in terms of history of prior abdominal surgery (P = 0.461).
| Category | IMN group (n = 296) | No-IMN group (n = 151) | P value |
| Gender | 0.911 | ||
| Male | 180 (60.8) | 91 (60.3) | |
| Female | 116 (39.2) | 60 (39.7) | |
| Median age; years (range) | 60 (28-75) | 59 (30-75) | 0.227 |
| ≤ 44 | 15 (6.8) | 19 (12.6) | |
| 45-59 | 115 (38.9) | 57 (37.7) | |
| 60-75 | 161 (54.3) | 75 (49.7) | |
| BMI | 0.761 | ||
| < 18.5 | 15 (5.1) | 4 (2.7) | |
| 18.5-23.9 | 125 (42.2) | 71 (47.0) | |
| 24-27.9 | 123 (41.6) | 55 (36.4) | |
| ≥ 28 | 33 (11.1) | 21 (13.9) | |
| ASA score | 0.329 | ||
| I | 36 (12.2) | 19 (12.6) | |
| II | 192 (64.9) | 96 (63.6) | |
| III | 62 (20.9) | 33 (21.9) | |
| IV | 6 (2.0) | 3 (1.9) | |
| Tumor site | 0.523 | ||
| Rectum | 175 (59.1) | 94 (62.3) | |
| Colon | 121 (40.9) | 57 (37.7) | |
| TNM stage | 0.472 | ||
| Carcinoma in situ | 15 (5.1) | 8 (5.3) | |
| I-II | 145 (49.0) | 75 (49.7) | |
| III-IV | 136 (45.9) | 68 (45.0) | |
| Previous abdominal surgery | 0.461 | ||
| Yes | 74 (25.0) | 33 (21.9) | |
| No | 222 (75.0) | 118 (78.1) | |
Nutritional parameters were analyzed, and detailed data are presented in Table 2. The comparison of baseline levels at the start of the intervention showed that there were no statistically significant differences in all indicators between the two groups (all P values > 0.05), suggesting that the baseline nutritional status and physical condition were comparable, effectively eliminating the interference of baseline confounding factors on the subsequent evaluation of intervention effects. Among them, BMI (kg/m2) was 22.98 ± 3.14 and 22.55 ± 2.97 for the two groups (P = 0.306, 95%CI: -0.40 to 1.26); the nutritional risk score (PG-SGA) was 4.96 ± 2.60 and 5.41 ± 2.35 (P = 0.159, 95%CI: -1.08 to 0.18). In the blood nutrition-related indicators, the P values of TFN, ALB, PA, and GLU were 0.208, 0.077, 0.227, and 0.724 respectively, and the 95%CI all included 0, fully confirming the homogeneity of the baseline status of the two groups. Post-intervention, no significant differences were detected in BMI, TFN, PA, or GLU between the IMN and control groups (all P > 0.05). In contrast, as illustrated in Figure 2, significant intergroup disparities emerged in PG-SGA scores and serum ALB concentrations following intervention (both P < 0.05), suggesting that oral IMN supplementation led to significant improvements in both subjective nutritional assessment and objective nutritional markers.
| Category | IMN group (n = 296) | No-IMN group (n = 151) | P value | 95%CI | |
| BMI (kg/m2) | Baseline | 22.98 ± 3.14 | 22.55 ± 2.97 | 0.306 | -0.40 to 1.26 |
| Endline | 23.45 ± 3.21 | 23.12 ± 2.94 | 0.399 | -0.43 to 1.08 | |
| PG-SGA | Baseline | 4.96 ± 2.60 | 5.41 ± 2.35 | 0.159 | -1.08 to 0.18 |
| Endline | 2.22 ± 1.11 | 2.65 ± 2.11 | 0.031a | -0.04 to 0.82 | |
| TFN (mg/L) | Baseline | 185.38 ± 38.46 | 180.86 ± 31.09 | 0.208 | -0.25 to 1.16 |
| Endline | 267.17 ± 49.08 | 262.4 ± 54.27 | 0.409 | -0.16 to 0.66 | |
| ALB (g/L) | Baseline | 34.24 ± 3.34 | 33.67 ± 2.90 | 0.077 | -0.06 to 1.19 |
| Endline | 42.23 ± 3.02 | 41.29 ± 3.08 | 0.004a | -0.30 to 1.57 | |
| PA (g/L) | Baseline | 16.18 ± 4.20 | 15.65 ± 4.13 | 0.227 | -0.33 to 1.39 |
| Endline | 27.57 ± 5.80 | 27.83 ± 5.42 | 0.736 | -1.79 to 1.27 | |
| GLU (mmol/L) | Baseline | 6.13 ± 1.91 | 6.07 ± 1.53 | 0.724 | -0.29 to 0.42 |
| Endline | 5.80 ± 1.28 | 5.83 ± 1.20 | 0.847 | -0.33 to 0.27 | |
Immunologic parameters were analyzed, with detailed results summarized in Table 3. At baseline, the IMN group and control group exhibited comparable levels of key immunologic indicators, including ALC, IgG, IgM, and IgA (all P > 0.05). Post-intervention, as shown in Figure 3, the IMN group demonstrated a significant elevation in ALC, IgG, and IgM concentrations compared with the control group (all P < 0.05). In contrast, no significant intergroup differences were observed in C-reactive protein levels or IgA concentrations either at baseline or post-intervention (all P > 0.05).
| Category | IMN group (n = 296) | No-IMN group (n = 151) | P value | 95%CI | |
| ALC (× 109/L) | Baseline | 1.22 ± 0.47 | 1.16 ± 0.49 | 0.203 | -0.03 to 0.15 |
| Endline | 1.79 ± 0.60 | 1.59 ± 0.54 | 0.001a | -0.08 to 0.31 | |
| CRP (mg/L) | Baseline | 5.91 ± 4.73 | 5.06 ± 4.95 | 0.077 | -0.09 to 1.81 |
| Endline | 1.28 ± 4.51 | 1.02 ± 3.45 | 0.543 | -0.58 to 1.10 | |
| IgG (g/L) | Baseline | 8.90 ± 1.85 | 8.66 ± 1.99 | 0.222 | -0.15 to 0.64 |
| Endline | 13.10 ± 2.70 | 12.24 ± 2.41 | 0.003a | -0.29 to 1.42 | |
| IgM (g/L) | Baseline | 0.82 ± 0.40 | 0.76 ± 0.37 | 0.101 | -0.01 to 0.15 |
| Endline | 1.37 ± 0.48 | 1.22 ± 0.54 | 0.007a | -0.04 to 0.26 | |
| IgA (g/L) | Baseline | 2.20 ± 0.85 | 2.08 ± 0.80 | 0.174 | -0.05 to 0.29 |
| Endline | 2.94 ± 0.95 | 2.77 ± 0.74 | 0.084 | -0.02 to 0.36 | |
Postoperative complications were assessed, and comprehensive data regarding these complications are presented in Table 4. While the total incidence of complications in the IMN group was numerically reduced compared with the control group (15.9% vs 21.2%), this difference failed to achieve statistical significance (P = 0.172). When stratified by compli
| Category | IMN group (n = 296) | No-IMN group (n = 151) | P value |
| Infectious complications | 28 (9.5) | 24 (15.9) | 0.045a |
| Respiratory tract | 3 (1.0) | 4 (26) | 0.188 |
| Surgical site infection | 14 (4.7) | 14 (8.2) | 0.061 |
| Urinary tract | 2 (0.7) | 1 (0.7) | 0.987 |
| Abdominal abscess | 9 (3.0) | 5 (3.3) | 0.876 |
| Noninfectious | 19 (6.4) | 8 (5.3) | 0.638 |
| Anastomotic fistula | 9 (3.0) | 4 (2.6) | 0.816 |
| Bleeding | 2 (0.7) | 1 (0.7) | 0.987 |
| Intestinal obstruction | 4 (1.4) | 1 (0.7) | 0.512 |
| Wound dehiscence | 4 (1.4) | 2 (1.3) | 0.981 |
| Total incidence of complication | 47 (15.9) | 32 (21.2) | 0.172 |
CRC significantly impairs patient nutrition and immunity. A large majority (up to 80%) of these patients are malnourished at the time of diagnosis because of tumor-related symptoms and treatment side effects[2]. This malnutri
Although early nutritional support has demonstrated modest benefits for patients following CRC surgery, it yields only limited improvements in postoperative immune function[1-3]. With ongoing research and exploration, accumulating evidence has indicated that supplementing standard enteral nutrition formulas with specific bioactive nutrients can yield additional clinical benefits[4-6]. IMN, in addition to the regular nutritional components (proteins, carbohydrates, fats), also adds immunologically active components such as arginine, glutamine, omega-3 polyunsaturated fatty acids, and nucleotides. Theoretically, it can achieve the dual goals of “nutritional support and immune regulation” by repairing the intestinal barrier, promoting protein synthesis, and regulating immune function. Omega-3 polyunsaturated fatty acids are essential fatty acids for the human body and include mainly eicosapentaenoic acid and docosahexaenoic acid. The core functions of omega-3 polyunsaturated fatty acids are anti-inflammatory activity and immune regulation. They can exert their effects through various pathways: First, as important components of cell membranes, they increase the fluidity and stability of cell membranes; second, they can compete to inhibit the metabolism of omega-6 polyunsaturated fatty acids, reducing the production of inflammatory mediators; third, they can inhibit the activation of inflammatory signaling pathways such as nuclear factor kappa-B, lowering the levels of inflammatory factors; and fourth, they can regulate the differentiation and function of immune cells and enhance antitumor immune responses[19]. Glutamine is not only an energy substrate for rapidly proliferating cells such as intestinal mucosal cells and lymphocytes but also a precursor of the antioxidant glutathione, which can alleviate oxidative stress damage. Moreover, glutamine can increase the expression of heat shock protein 70, inhibit the activation of inflammatory signaling pathways, and exert anti-inflammatory, immunoregulatory and intestinal barrier protective effects[20]. Arginine is involved in various physiological processes in the body. Its role in the immunonutritional therapy of CRC mainly includes the following: First, it promotes the proliferation and activation of immune cells. Arginine can enhance the functions of T lymphocytes and macrophages by activating the nuclear factor kappa-B pathway and improving the clearance ability of natural killer cells against tumor cells. Second, it promotes wound healing. Arginine can be metabolized into polyamines, which promote collagen production and accelerate the repair of surgical incisions and intestinal mucosal injuries. Third, it exerts antitumor effects. Under the action of inducible nitric oxide synthase, arginine generates nitric oxide, which can induce tumor cell apoptosis by downregulating Survivin expression or upregulating the p53 gene. Fourth, it protects the intestinal mucosal barrier and reduces the translocation of intestinal bacteria[10]. Nucleotides are the basic units that constitute nucleic acids and are involved in physiological processes such as cell structure composition, metabolic regulation, and energy supply. Exogenous supplementation of nucleotides can exert immune nutritional effects by regulating the functions of immune cells, such as increasing the production of interleukin-12, inhibiting antigen-specific IgE reactions, increasing the activity of T lymphocytes and macrophages, and improving the body’s anti-infection ability[12].
Extensive clinical and preclinical studies have validated the efficacy of IMN not only in improving postoperative nutritional status but also in strengthening host cellular and humoral immune responses. Two separate meta-analyses have evaluated the role of IMN in patients who have recovered from gastrointestinal cancer surgery[21,22]. The first, involving 1124 patients, indicated that compared with standard enteral nutrition, IMN significantly increased the PA concentration (mean difference: 24.98, 95%CI: 3.21-46.74; P = 0.02; I2 = 92%). Second, a systematic review of 12 RCTs encompassing 1864 patients confirmed that IMN provides comprehensive postoperative benefits, including improved serum ALB concentration (Δ = 3.2 g/L; P = 0.001), a lower rate of infectious complications (odds ratio = 0.42; 95%CI: 0.31-0.57), and a shorter hospital stay (P < 0.01). Our trial demonstrated that post-intervention, serum ALB concentrations in the IMN group increased significantly, while PG-SGA scores were markedly lower than those in the control group (both P < 0.05). These findings therefore suggest that prolonged post-discharge oral IMN administration following radical CRC surgery can effectively improve nutritional status, reduce the risk of postoperative malnutrition, and potentially enhance clinical prognosis in CRC patients. A meta-analysis of 20 studies involving 1613 patients indicated that supplementation with omega-3 fatty acids was associated with significant improvements in key markers of humoral and cellular immunity. Specifically, notable increases were observed in immunoglobulin levels (IgA, IgM, and IgG) and T-cell subsets (CD3+, CD4+, and the CD4+/CD8+ ratio), with all standardized mean differences and their 95% confidence intervals indicating statistically significant positive effects[23]. In a prospective trial, sixty patients with gastrointestinal cancer were randomized to receive either an IMN diet or a conventional diet for seven days prior to surgery. The results indicated that postoperative IgG levels were markedly higher in the IMN group in comparison to the control group[24]. Huang and Wang[25] conducted a retrospective analysis of 102 perioperative patients, who were assigned to either the IMN diet group (n = 52) or the conventional diet group (n = 50). In comparison to the control group, the IMN diet group displayed substantially increased levels of IgA, IgG, IgM, complement C3, and complement C4 on both the 1st and 7th postoperative days (all P < 0.05). Further, our research found that 30 days of consecutive oral IMN intake starting from the 1st day after discharge led to considerable enhancements in ALC, IgG, and IgM levels in the IMN group as opposed to the control group (all P < 0.05). Taken together, these observations imply that continuous postoperative IMN intervention can produce long-term favorable impacts on improving patients’ nutritional and immune status.
Nevertheless, a key question persists: Whether the long-term potentiation of postoperative immune function and regulation of inflammatory reactions can bring about clinical benefits and ultimately optimize patient prognosis? Growing evidence supports this possibility. Lymphocytes are widely acknowledged as vital cellular elements of the human immune system. When identifying potential pathogens related to surgical injury, lymphocytes trigger host immune reactions and proliferate extensively to eliminate these pathogens, thereby lowering the incidence of postoperative infection, promoting wound repair, and hastening patient recovery. Clinically, the primary indicators used to assess host humoral immune function are immunoglobulins, namely IgA, IgM, and IgG. Immunoglobulins constitute a unique category of antibody-active proteins present in human serum and body fluids, possessing intrinsic antibacterial and antiviral capacities, along with the capability to boost cellular phagocytic activity. Additionally, with the assistance of the complement cascade, immunoglobulins can inactivate and break down pathogenic microbes, thereby serving a pivotal function in host humoral immunity. In detail, IgG is closely involved in antibacterial, antiviral, and antitoxic processes, and plays a substantial role in immune modulation[26]. The gastrointestinal tract serves as the main site of IgA synthesis and secretion, and IgA acts as a critical antibody in gastrointestinal mucosal immune responses[27]. IgM antibodies are characterized by high efficacy and potent bactericidal activity, particularly towards gram-negative bacteria (e.g., Escherichia coli). Of note, IgM is the initial antibody produced during humoral immune responses against pathogens that multiply in vivo and cause infections[28].
In the present study, prolonged postoperative administration of IMN in the IMN group led to enhanced cellular immunity (as reflected by an increased ALC) and humoral immunity (as reflected by elevated levels of IgG, IgA, and IgM). While the overall incidence of postoperative complications did not differ significantly between the two groups (15.9% in the IMN group vs 21.2% in the control group; P = 0.172), the marked improvement in immunonutritional status conferred by IMN translated to a significant reduction in infectious complications (9.5% vs 15.9%; P = 0.045). These findings hold considerable clinical significance and align with the primary goal of postoperative IMN intervention, particularly in patients with CRC.
As emphasized in the Introduction, CRC patients are inherently susceptible to malnutrition (prevalence: 45%-60%) and immune dysfunction, attributed to prolonged tumor-associated catabolism and surgical stress. Infectious complications (e.g., surgical site infection, abdominal abscess, and urinary tract infection) constitute 50%-70% of preventable postope
Although formal analyses of hospital length of stay and medical costs were not performed in our study, the significant reduction in infectious complications provides robust evidence supporting the clinical value of prolonged oral IMN following CRC surgery. This benefit is particularly critical for optimizing short-term recovery and long-term prognosis in CRC patients, especially those with advanced disease (stage III-IV) or preoperative malnutrition (PG-SGA score ≥ 4).
The current investigation is associated with several limitations. Frist, this study was carried out at a single institution with a comparatively limited sample size, which restricts the generalizability of our results and prevents the drawing of definitive conclusions. Second, regarding cellular immunity, our analysis was limited to ALC; specific lymphocyte subsets and other critical immune cells (e.g., T cells, B cells, natural killer cells, and macrophages) were not assessed. Third, our investigation centered on the impact of long-term postoperative IMN intervention on the short-term prognosis of CRC patients, and observational evidence concerning its influence on long-term survival remains insufficient. By June 2026, we will complete data collection from all 20 centers, reaching the precalculated target sample size of 1340 patients (960 in the IMN group vs 480 in the control group). Additionally, although the current significant increases in ALC, IgG, and IgM (P < 0.05) provide preliminary evidence of improved cellular and humoral immunity, the planned detection of subsets will further clarify the immunomodulatory pathway of IMN (e.g., whether CD4+ T-cell expansion contributes to infection reduction). Finally, we extended the follow-up period to 1–3 years for all the enrolled patients. Long-term outcome indicators will include overall survival, disease-free survival, and recurrence rate - key endpoints to verify whether the IMN-induced reduction in infectious complications translates to improved long-term oncological outcomes.
Based on our findings, long-term oral administration of IMN - formulated with bioactive components including omega-3 fatty acids, glutamine, arginine, and RNA - can effectively ameliorate nutritional status and enhance immune responses in patients with CRC. While future studies involving multiple centers and larger sample sizes are warranted to further validate the impact of sustained oral IMN on long-term survival outcomes, our results clearly indicate that this nutritional intervention can reduce the incidence of postoperative infectious complications and improve short-term clinical prognosis in CRC patients.
The authors are thankful to all the patients who participated in the present study.
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