A systematic literature search was conducted in PubMed/MEDLINE, Scopus, and Cochrane up to December 2024. We also searched Google Scholar to increase search sensitivity, manually screening the first 200 results and carefully excluding duplicates and low-quality sources that did not meet our inclusion criteria. We searched the following keywords and Medical Subject Headings (MeSH): “Preoperative assessment” AND “diet” AND “infection,” “Prevention” AND “healthcare-associated” AND “infections” AND “diet,” (“Prevention of HAIs” AND “diet”), (prevention surgical infection [MeSH Terms]) combined with specific terms (glutamine [MeSH Terms], milk [MeSH Terms], arginine [MeSH Terms], Vitamin [MeSH Terms], Nutrient [MeSH Terms], Selenium [MeSH Terms], zinc [MeSH Terms], Glycine [MeSH Terms], probiotic [MeSH Terms]). MeSH terms were selected following the National Center for Biotechnology Information (NCBI) guidelines, with wild-card operators employed when appropriate. No backward or forward citation tracking (snowballing) was performed.

Inclusion criteria: (1) exploring the effect of immunonutrition, synbiotics, probiotics and protein integration on HAI prevention in surgical patients; (2) reporting clinically relevant outcomes such as Infectious complication, BSI, SSIs, UTI, Pneumonia, LOS; (3) retrospective cohort studies, prospective cohort studies, single-center or multicenter prospective studies, RCT, or case-control studies.

Exclusion criteria: (1) studies not directly addressing the research question; (2) articles lacking sufficient quantitative data; (3) case reports, editorials, narrative reviews, feasibility studies, pilot studies or commentaries; (4) studies that did not meet the following PICOS criteria (Table 1):

No limits were set on publication date or language. The oldest included study was published in 1999, thus our evidence base spans from 1999 to December 2024.

Following the title and abstract screening, potentially relevant articles were retrieved in full and assessed for eligibility criteria. This selection process was carried out independently by four reviewers, conflicts have been solved with the help of a fifth reviewer when needed. A standardized data extraction form was used to collect information on study design, population characteristics, type and dosage of supplements, primary and secondary outcomes, and follow-up duration.

The methodological quality and potential risk of bias of the included studies were assessed independently by four researchers using National Institutes of Health (NIH) Quality Assessment Tool (12) tailored to each study type.

Of the included RCT, 16 publications were classified as having “Low risk of bias,” 9 “Moderate risk of bias” and on “High risk of bias.” Among the analytical studies, 6 publications were identified as having “Low risk of bias,” 4 “Moderate risk of bias,” and 3 “High risk of bias.” Results were displayed graphically using the Traffic Light Plot (Supplementary Figure 1) and a Summary Plot (Supplementary Figure 2), respectively. Blinding bias was not deemed critical, as outcomes were objective.

GRADE approach (13) was used to assess the certainty of the evidence. Two reviewers independently assessed the certainty of the evidence and resolved disagreements by discussion; all decisions have been justified and reported in the footnotes. Results have been reported following the recommendations from the GRADE Guidance (14) and classified in four levels based on the confidence that the true value of the estimate is on one side of a threshold of interest or within a specific range:

We acknowledge that definitions of postoperative infections (SSI, BSI, UTI, pneumonia) and surveillance methods may vary across included studies, potentially affecting the comparability of pooled effect estimates. This heterogeneity in outcome ascertainment represents an important limitation of our analysis. We used the GRADEpro software¹ to create the summary of findings table.

Both qualitative and quantitative data synthesis were performed. Four researchers independently conducted the synthesis, resolving any discrepancies through discussion and consensus. Meta-analysis was performed using STATA SE 19 (StataCorp LLC, College Station, Texas, United States). While assessing heterogeneity an I² value of 25, 50%, or 75% was classified as low, moderate, or high heterogeneity, respectively. A random-effects model was used when heterogeneity was significant; otherwise, a fixed-effects model was applied. Summary outcome measures included OR with 95% confidence intervals (CIs) for binary outcomes and MD for continuous outcomes. For studies reporting continuous outcomes in terms of medians and interquartile ranges, the corresponding mean and standard deviation were estimated using the methods provided by Luo et al. (15) and Wan et al. (16). Sensitivity analyses were performed to evaluate result stability by sequentially excluding individual studies. Publication bias was not assessed because less than 10 studies contributed to each analysis. All statistical analyses were conducted following established guidelines to ensure robustness and reproducibility.

The meta-analysis included a total of 39 publications [26 RCTs (17–42) and 13 analytical studies (43–55)] (Figure 1) that evaluated the efficacy of nutritional supplements in patients undergoing surgical procedures, primarily oncological interventions. In three of these publications (20, 43, 51), multiple comparisons were reported (each of these studies included two intervention groups and one control group, with the intervention groups differing, for example, in the timing of integration or in the type of surgical procedure) and were therefore analyzed separately in the meta-analysis. Geographically, the studies were distributed as follows: 43.6% in Asia, 33.3% in Europe, 12.8% in North America, and 10.3% in South America.

Regarding surgical approach, 28 studies involved only laparotomic procedures, 5 mixed surgical interventions (including both laparotomic and laparoscopic procedures within the same study), and the remaining 6 referred to other types of surgeries (orthopedic, cardiac, and mixed surgical approaches).

The mean age of patients was relatively evenly distributed, with 53.9% of participants younger than 65 years, 33.3% older than 65 years, and 12.8% of unspecified age. The routes of supplement administration were predominantly oral (66.7%), while 12.8% were enteral, 2.6% parenteral, and the remaining 17.9% involved a combination of these modalities.

The main characteristics of the studies included in the meta-analysis are reported in Supplementary Table 1, summarizing study design, location, type of nutritional integration, and participant demographics (sample size, age, and sex). Supplementary Table 2 outlines outcome data, showing the absolute and relative frequencies of infectious complications, SSIs, BSIs, UTIs, and pneumonia in both intervention and control groups. These tables provide a clear comparison of effect estimates, reflecting variations in study populations, integration protocols, and outcome definitions.

Regarding the maturity of evidence and clinical adoption, immunonutrition represents the most established intervention with relatively standardized formulations and established clinical protocols, particularly in oncological surgery. Probiotics and synbiotics remain more experimental, with substantial heterogeneity in strain selection, dosing regimens, and administration protocols across studies. Protein supplementation is the least studied intervention with limited data available.

Summary effect estimates for each integration type, along with subgroup analyses, are presented in the main text and detailed in Supplementary Tables 3–7.

Of the 39 included studies, 23 (12 RCTs and 11 analytical studies) did not clearly report on the adverse events of the interventions (21, 25, 27–29, 32, 35, 37, 39–45, 47, 49–55). Nine studies (all RCTs) reported no therapy-related adverse effects (18, 20, 22–24, 30, 31, 34, 36). The seven studies (five RCTs, two on immunonutrition (17, 33), two on synbiotics (19, 26), one on protein supplementation (38), and two analytical studies (46, 48) on immunonutrition) that reported adverse events highlighted the gastrointestinal side effects of the therapies. The most common symptoms were diarrhea, nausea, and vomiting, even though there were usually non-significant differences between the intervention and control groups.

This systematic review and meta-analysis confirms that perioperative nutritional interventions reduce postoperative infectious complications in surgical patients, with evidence strength varying by intervention type and outcome. Immunonutrition shows the strongest evidence base. RCT data demonstrate robust efficacy in preventing SSIs (OR 0.35, 95% CI 0.17–0.71, moderate certainty evidence) and reducing overall infectious complications (OR 0.36, 95% CI 0.21–0.62, low certainty evidence) in surgical oncology patients. This represents clinically meaningful risk reduction with moderate confidence in the effect estimate.

Probiotics demonstrate protective effects across multiple infection types: SSIs (OR 0.61, low certainty), pneumonia (OR 0.42, low certainty), UTIs (OR 0.32, low certainty), and BSIs (OR 0.42, low certainty). However, evidence certainty is consistently lower than for immunonutrition, reflecting greater heterogeneity in study designs and probiotic formulations.

Synbiotics showed non-significant trends toward benefit across outcomes, with insufficient evidence to support clinical recommendations.

Protein supplementation demonstrated statistical significance for SSI reduction (OR 0.36, 95% CI 0.17–0.75) but carries very low certainty evidence based on only four studies with substantial methodological limitations. This precludes any clinical recommendations until large, well-designed RCTs validate these preliminary findings.

Critically, analytical studies consistently showed weaker and often non-significant effects compared to RCTs. For immunonutrition’s effect on SSIs, observational studies yielded OR 0.58 (95% CI 0.31–1.07) versus RCT evidence of OR 0.35 (95% CI 0.17–0.71). This discordance underscores that practice-changing recommendations must be based primarily on randomized evidence, which provides more reliable causal inference through randomization and blinding.

For clinical practice, immunonutrition in high-risk oncological surgery represents an evidence-based intervention ready for implementation as standard of care, based on RCT evidence of moderate certainty. Healthcare systems should prioritize establishing preoperative immunonutrition pathways for appropriate surgical populations, integrated within comprehensive infection prevention bundles alongside established measures (antibiotic prophylaxis, aseptic technique, glycemic control).

Probiotics may serve as complementary interventions, particularly in settings where immunonutrition faces implementation barriers or for lower-risk procedures, though their effects are supported by lower certainty evidence. Protein supplementation shows promise but cannot be recommended for infection prevention based on current very low certainty evidence.

National health authorities and surgical societies should establish standardized immunonutrition protocols specifying evidence-based formulations (particularly those containing L-arginine, omega-3 fatty acids, RNA nucleotides, and soluble fiber), preoperative administration timing (based on our subgroup analyses showing superior effects), and clearly defined target populations. Integration into enhanced recovery pathways and surgical safety bundles will facilitate systematic adoption. Healthcare administrators should conduct institution-specific cost-effectiveness analyses to prioritize implementation across surgical services, focusing initially on high-risk gastrointestinal and oncological surgery. While our illustrative economic projections suggest potential substantial savings, actual cost-effectiveness will vary by institution and should be empirically evaluated.

Immunonutrition use in eligible surgical populations should be established as a quality indicator and monitored through national surgical and infection surveillance systems to ensure implementation fidelity and enable ongoing effectiveness evaluation in real-word settings.

Research priorities must address critical evidence gaps. Large pragmatic multicenter RCT evaluating system-level implementation strategies, real-world effectiveness, and cost-effectiveness across diverse healthcare settings are urgent needed. Studies specifically addressing implementation in low- and middle- income countries are essential to ensure equitable access and avoid exacerbating global health inequities.

For protein supplementation, large well-designed RCTs are prerequisite before any clinical recommendations can be made, given current very low certainty evidence. For probiotics and synbiotics, research must focus on standardizing formulations, dosing, and administration protocols to reduce heterogeneity.

Future studies must adopt standardized, internationally recognized definitions for postoperative infections (SSIs, BSIs, UTIs, pneumonia) to improve comparability and enable more precise meta-analyses.

Long-term outcomes including antimicrobial resistance patterns, healthcare utilization, functional recovery, and patient-reported outcomes should be incorporated. Economic evaluations must accompany effectiveness studies to inform resource allocation decisions.

Enhancing HAI surveillance systems to systematically capture nutritional intervention use (such as national registries linking surgical procedures, nutritional interventions, and infection) will enable post-implementation effectiveness monitoring and identify optimization opportunities.