Challenges with interpreting pre-operative immunonutrition research

Immunonutrition has become a well-recognised intervention aimed at improving clinical outcomes within the perioperative setting. Immunonutrition refers to nutrients that are known to have an impact on immune function and most commonly include ω-3 fatty acids, glutamine, arginine and nucleotides (1). These substrates all have unique actions but result in anti-inflammatory, immune enhancing properties (1).

Early immunonutrition studies and subsequent systematic reviews and meta-analyses have shown positive outcomes on post-operative infectious complications and reduced length of hospital stay with the use of pre-operative immunonutrition supplementation (2-4). Many guidelines now recommend oral pre-operative immunonutrition for people undergoing elective colorectal surgery (5,6).

The challenge of immunonutrition is that each nutrient can be administered as an individual supplement but more commonly, multiple nutrients are included in an oral or enteral formula. Different combinations of immune nutrients may be included and doses can vary significantly. When included within an oral or enteral formula, many other nutrients are also included which have also been shown to influence perioperative outcomes. Of particular note, standard oral nutrition, including additional calories and protein, have been shown to improve nutritional status and reduce cancer and surgical-related complications (7-9). Further to this, due to changes in flavour and texture consistency, compliance with immunonutrition when administered as a part of an oral formula has been shown to be a major barrier (10).

Hence the challenge of interpreting immunonutrition research is determining whether dosing and compliance was adequate, and whether the study had adequately matched control interventions to ensure that the research is measuring the impact of immunonutrition as opposed to other nutrition components. To date much of the research published in this area have failed to adequately consider these confounding factors. Many study designs have compared immunonutrition added to an oral formula (with additional calories, protein, and micronutrients) to ‘usual’ diet. Usual diet is often not measured or quantified. This has the potential to lead to more favourable outcomes attributed to immunonutrition, where these outcomes may actually be attributable to overall nutrient adequacy. Much of the literature reviewing the evidence for immunonutrition has not taken this possible bias into consideration.

In the current issue of this journal, Markar et al. (11) provide a double-blind randomised controlled multicentre clinical trial assessing the impact of an oral formula including immunonutrition on quality of life. In this study the control oral formula was reported to be similar to the intervention and isocalorically matched. Compliance was reported although how compliance was measured is unclear. Unfortunately, this well-designed study was terminated early due to challenges in measuring quality of life in advanced cancer patients. For the 300 people already randomised there were no differences in quality of life, measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (Core-30 items) (EORTC QLQ-C-30) (11). However, this paper provides an opportunity to review the reporting standards associated with immunonutrition research. To allow adequate assessment of immunonutrition, reporting needs to include detailed nutrient analysis of intervention formulas and/or oral intake as well as control therapies. This should include a nutrient analysis of any oral formulas used as a control, and a dietary analysis of usual intake. Compliance should be measured including details on how this is measured. Inclusion of these details will allow a clearer analysis of the role of immunonutrition in improving clinical outcomes within the perioperative setting.

As research within the immunonutrition sphere continues with the possibility of significant benefits, future immunonutrition research should focus on adequate matching of non-immunonutrition nutrients so that the ‘real’ impact of immunonutrition can be assessed.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Esophagus. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://aoe.amegroups.com/article/view/10.21037/aoe-2026-1-0007/coif). The author has no conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Grimble R. Basics in clinical nutrition: Immunonutrition – Nutrients which influence immunity: Effect and mechanism of action. E Spen Eur E J Clin Nutr Metab 2008;4:e10-e13.
2. Waitzberg DL, Saito H, Plank LD, et al. Postsurgical infections are reduced with specialized nutrition support. World J Surg 2006;30:1592-604. [Crossref] [PubMed]
3. Ricci C, Serbassi F, Alberici L, et al. Immunonutrition in patients who underwent major abdominal surgery: A comprehensive systematic review and component network metanalysis using GRADE and CINeMA approaches. Surgery 2023;174:1401-9. [Crossref] [PubMed]
4. Khan A, Wong J, Riedel B, et al. The Impact of Peri-operative Enteral Immunonutrition on Post-operative Complications in Gastrointestinal Cancer Surgery: A Meta-Analysis. Ann Surg Oncol 2023;30:3619-31. [Crossref] [PubMed]
5. Weimann A, Bezmarevic M, Braga M, et al. ESPEN guideline on clinical nutrition in surgery - Update 2025. Clin Nutr 2025;53:222-61. [Crossref] [PubMed]
6. Gustafsson UO, Scott MJ, Hubner M, et al. Guidelines for Perioperative Care in Elective Colorectal Surgery: Enhanced Recovery After Surgery (ERAS(®)) Society Recommendations: 2018. World J Surg 2019;43:659-95. [Crossref] [PubMed]
7. Liu Y, Wu Z, Shao T, et al. Application of oral nutritional supplements to control body weight loss in postoperative patients suffering from solid tumors: a systematic review and meta-analysis. Front Nutr 2025;12:1476463. [Crossref] [PubMed]
8. Habibi S, Talebi S, Khosravinia D, et al. Oral nutritional supplementation in cancer patients: A systematic review and dose-response meta-analysis. Clin Nutr 2025;47:28-39. [Crossref] [PubMed]
9. Ciesielka J, Jakimów K, Majewska K, et al. The Association Between Preoperative Sarcopenia and Sarcopenic Obesity and the Occurrence of Postoperative Complications in Patients Undergoing Pancreaticoduodenectomy for Periampullary Malignancies-A Literature Review. Nutrients 2024;16:3569. [Crossref] [PubMed]
10. Hogan S, Solomon M, Rangan A, et al. Bridging the gap between research and practice for nutrition support after pelvic exenteration surgery. Asia Pac J Clin Nutr 2019;28:486-94. [Crossref] [PubMed]
11. Markar S, Mariette C, Bonnetain F, et al. Immunonutrition to improve the quality of life of upper gastrointestinal cancer patients undergoing neoadjuvant treatment prior to surgery (NEOIMMUNE): double-blind randomized controlled multicenter clinical trial. Dis Esophagus 2025;38:doae113. [Crossref] [PubMed]