Cyclic exclusive enteral nutrition and the nebulous diet landscape in Crohn’s disease

Diet pattern and food choice for patients with inflammatory bowel disease (IBD) are often central to disease management on a personal level (1). Unfortunately, navigating diet in IBD is also characterized by uncertainty, avoidance/restriction behaviors, and social isolation (2,3). This contributes to a high prevalence of avoidant/restrictive food intake disorder (ARFID) within IBD (4). The implications of restrictive intake behaviors, even if they do not rise to the level of a formal ARFID diagnosis, are an increased risk of malnutrition and nutrient disorders in a patient population already susceptible to nutrition-related conditions such as reduced muscle mass and bone density (5,6).

Much of this clinical vulnerability stems from profound patient frustration, as the dietary advice patients with IBD receive is often inconsistent and largely observational (7,8). While both patients and providers rank diet as a top research priority in IBD (9), strategies that account for the heterogeneous diet patterns and food environments of patients are often neglected (10). Paradoxically, the most established dietary strategy, included in European pediatric IBD guidelines (11,12), is exclusive enteral nutrition (EEN) therapy, which demands absolute food restriction. EEN is an intensive nutritional regimen that provides 100% of nutritional needs from a select formula, by oral or nasogastric tube, and (typically) does not allow for additional food intake. Therefore, while effective in the short-term (weeks to months), it historically has not been considered as a reasonable long-term maintenance therapy. Therefore, we congratulate Pigneur and colleagues [2026] for developing and testing a novel cyclic EEN (C-EEN) approach that allowed patients to consume a free diet with recurring 2-week EEN intervals over the course of a year (13).

This study was an open-label, randomized, multicenter trial in pediatric patients (aged 6–18) with Crohn’s disease comparing C-EEN (n=49, 2-week cycles of EEN every 8-weeks) to PEN (n=51, supplemental nutrition at 25% daily calories) for maintenance of clinical remission at 52 weeks. All enrolled participants had achieved clinical remission following 6–12 weeks of EEN induction therapy. The formula used for both induction therapy and the intervention trial was Modulen IBD, which is a cow’s milk protein-based, fiber-free formula commonly selected for EEN and partial enteral nutrition (PEN) trials (14-17). Those in the C-EEN arm had a clinically significant reduction in disease relapse compared to the PEN arm [49% vs. 76%; OR 0.29, 95% confidence interval (CI):: 0.13–0.70] at 12 months, but interpretation of these findings is complicated by comparable secondary endpoints such as mucosal healing (55% C-EEN and 58% PEN) and transmural healing (29% C-EEN and 40% PEN). While the true biological effect of the C-EEN intervention remains unclear, the study highlights the need to better understand the broader relationship between diet and IBD activity.

A strength of the study by Pigneur et al. was the use of an “unrestricted diet” outside of the EEN windows for those randomized to C-EEN, reflecting true patient preferences. This approach, where participants are allowed to follow their baseline diet, is appealing from a clinical application standpoint. Participants were only asked to track volumes of formula consumed during each 2-week EEN interval (and the associated 2-week interval for those on the PEN arm). Consequently, the data was limited to the percent and volume of formula consumed rather than nutrient intake or foods consumed. The C-EEN or PEN intervention may have influenced overall nutrient intake and food choices differently in the groups, and this is an important unknown.

Although no statistical difference was observed in overall growth trajectories between the cohorts, the distribution for weight Z-scores [C-EEN: −0.40 (−1.30 to 0.00) vs. PEN: −0.40 (−0.90 to 0.20)] reveals subtle nuances that may be clinically relevant. However, because continuous data from relapsing patients was not included in analyses, and there were more relapses in the PEN arm (76% vs. 49%), growth metrics in the PEN arm may be inflated because growth data only reflects the top 24% of non-relapsing, highly responsive patients. Regardless, the lower limit for weight Z-score was higher (−0.90 vs. −1.30) in the PEN group, and a subset of patients managed to reach positive thresholds (0.20), reflecting an upward trend not observed in the C-EEN arm. On the other hand, the height Z-score distribution [C-EEN: −0.15 (−0.80 to 0.40); PEN: −0.10 (−1.10 to 0.60)] reflected a more heterogeneous response within the PEN cohort, indicated by its wider interquartile range (PEN: 1.7 vs. C-EEN: 1.2). Whether one intervention supported a more consistent overall caloric intake, however, remains unknown, as dietary intake data outside the formulas was not collected.

Notably, tracking the interplay between daily nutrient intake and disease activity fell outside the primary scope of this trial, which was designed strictly to evaluate C-EEN as a therapeutic agent to support maintenance of clinical remission. While the findings in support of a C-EEN approach as a potential maintenance therapy are encouraging, they require cautious interpretation (18). Future studies should consider incorporating detailed dietary records to fully explore how these interventions alter long-term food selection and overall dietary patterns. Given that Pigneur et al. documented an adverse event of anorexia, dietary intake data can also help determine whether intermittent, exclusionary diet therapy risks exacerbating disordered eating behaviors common in IBD (3,19,20).

The C-EEN intervention represents a literal “food as medicine” intervention, but risks overlooking a diet landscape that may be contributing to disease activity (21,22). Because it allows an unaltered background diet, this approach fails to address intake of diet patterns high in ultra-processed foods and emulsifiers that have been linked to IBD development and disease activity (23,24).

There is immense confusion regarding the role of diet in IBD, driven in part by the paradox of EEN. Despite meeting the purest definition of ultra-processed and containing the additives and emulsifiers identified as being of particular concern in IBD (17,25,26), EEN is consistently effective as an induction therapy in Crohn’s disease. Meanwhile, current recommendations of dietary patterns have been developed on the premise that western diet features such as ultra-processed foods and, more specifically, food additives such as emulsifiers increase disease activity (25-27). Mechanistically, these dietary components are thought to erode the mucus layer, increase tight junctions permeability, and drive expansion of pathobionts (28,29). This aligns with the broader understanding of the role of diet in intestinal health, which typically recommend a less processed diet rich in fruits and vegetables (30). The consistent success of EEN therapy for induction, and now potentially C-EEN for maintenance, directly challenges this whole-food framework. It is at this juncture that there is immense opportunity to advance the understanding of diet in management of Crohn’s disease and distinguish between approaches like EEN that represent more traditional medical treatment vs diet more broadly as therapy.

Similar to the work by Pigneur et al., there is a dearth of robust dietary records in diet-based intervention trials in Crohn’s disease (14,17,25,26). Adherence to the intervention is commonly assessed, but foods consumed are rarely captured. Further, when they are, they are often reduced to nutrients (25) or a pre-defined “healthy” eating index score (26). But this overlooks food choice as a variable unto itself, which could better define the mechanism of action for interventions like EEN and diet more broadly (31). The importance of capturing food choice is increasingly appreciated in the field of diet-microbiome research (32-34) but has historically been overlooked in diet intervention studies, both within and outside of IBD. Recent cross-sectional work by Bolte et al. demonstrates the potential of a food-based approach by linking intake of specific food patterns and combinations with metabolic and inflammatory pathways (35). This highlights the need for detailed dietary data collection in future trials to better understand how diet impacts IBD.

The work by Pigneur et al. represents an important milestone in advancing dietary strategies as potential IBD treatments, moving beyond induction to long-term maintenance therapy. Future studies, however, should look to capture more granular dietary intake data to enable food-based modeling capable of targeting the role of individual foods or food patterns on IBD activity. In the meantime, these findings by Pigneur et al. offer an encouraging direction that demands further exploration, as this cyclic approach stands to potentially improve both patient care and clinical outcomes.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-26-0118/prf

Funding: This work was supported by the National Institutes of Health’s National Center for Advancing Translational Sciences, grants Nos. K12TR004373 and 1UM1TR004405-01A1. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health’s National Center for Advancing.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-26-0118/coif). The authors have no conflicts of interest to declare.

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