TO THE EDITOR
Inflammatory bowel disease (IBD) is characterized by chronic relapsing and remitting inflammation of the gastrointestinal (GI) tract that increases the risk of irreversible structural damage and colorectal malignancies[1]. In recent years, the therapeutic goals in IBD have shifted from clinical remission as such to achieving mucosal healing that is otherwise called deep remission. The latter proved to be associated with improved long-term clinical outcomes[2-4]. The paper published by Ovadia et al[5] is a prospective study comparing the effects of a nutritional intervention (Modulen) to a pharmaceutical conventional therapy (budesonide) on clinical response and mucosal healing, in adult patients with newly diagnosed mild to moderate Crohn’s disease (CD) The present article examines and comments on the novel findings by Ovadia et al[5].
Background and physiological grounds for investigation
In the past, the treatment of CD had typically focused on controlling clinical symptoms. With the introduction of advanced therapeutic options such as biologics and oral small molecules, the therapeutic goals have evolved to clinical as well as endoscopic remission. Moreover, there is a trend in recent clinical trials to assess the outcomes of achieving histological remission[6]. The scoring systems used to assess endoscopic response to treatment of CD were the CD Activity Index and the CD Endoscopic Index of Severity[6]. This was further highlighted in the Selecting Therapeutic Targets in IBD expert committee therapeutic targets that were updated in 2021 in the Selecting Therapeutic Targets in IBD-II initiative as follows[7]: The recommended treat-to-target strategy consists of escalating treatment until the target is reached, defined by both objective and subjective criteria[8]. In a cohort study done by Ardizzone et al[9] in 2011, patients with ulcerative colitis without complete mucosal healing had higher rates of hospitalization, and a higher likelihood of undergoing colectomy compared to patients with complete mucosal healing. These results emphasize the importance of targeting treatment with the goal of mucosal healing, ultimately leading to a less aggressive disease course.
Non-invasive biomarkers are also used to assess mucosal healing[10]. C-reactive protein (CRP) is a routinely used biomarker, but the caveat is that 25% of patients with active CD on endoscopy do not express elevated CRP levels[11]. Fecal calprotectin is another biomarker measured in the stool. Although it has an increased specificity to depict inflammatory intestinal processes, there is a high variability among different patients, and single measurements should be looked at in the context of longitudinal measurements[4]. The CALM trial, an open-label randomized controlled phase 3 study done from 2011 to 2016, was the first study to demonstrate that timely treatment escalation with an anti-tumor necrosis factor based on a combination of clinical symptoms and biomarkers assessment results in better clinical and endoscopic outcomes than symptoms alone driven decisions[12].
While there is emerging evidence supporting the role of dietary interventions in managing CD, the certainty of evidence remains low to very low. The American Gastroenterological Association recommends that all patients with IBD, including CD, follow a Mediterranean diet rich in fresh fruits and vegetables, monounsaturated fats, complex carbohydrates, and lean proteins, while low in ultra processed foods, added sugar, and salt for overall health and well-being[13]. This diet has been shown to be well-tolerated and may improve symptoms in some patients. Other dietary interventions, such as the specific carbohydrate diet and low-fermentable oligosaccharides, disaccharides, monosaccharides, and polyols diet, have been explored, but the evidence supporting their use is less robust. The specific carbohydrate diet has shown similar efficacy to the Mediterranean diet in some studies, while the low-fermentable oligosaccharides, disaccharides, monosaccharides, and polyols diet may help reduce symptoms in patients with concomitant irritable bowel syndrome-like symptoms[14]. Enteral nutrition (EN), containing macro and micronutrients, has been also explored as a low-risk and minimally invasive therapy. It is a well-established first-line therapy in pediatric CD, with remission rates of up to 80%[15]. Exclusive EN (EEN) is the use of a complete liquid diet without normal dietary components for a certain period of time in patients with CD[16]. Multiple studies have investigated the efficacy of EEN in inducing clinical remission, with remission rates varying from 20 to 100%[17]. However, the main obstacle to successful treatment is the low adherence to EEN due to taste intolerance, cost and GI symptoms, with a rate of noncompliance reaching up to 41%[4]. Hence EN is still largely under-utilized in adults with CD[15].
Modulen IBD (Nestle, Vevey, Switzerland), created in 2001, is an oral polymeric diet with casein being its protein source, and is enriched with transforming growth factor beta (TGF-β)[18]. It contains 14% proteins, 44% carbohydrates and 42% fat[19]. It has adequate amounts of vitamins, minerals and trace elements. It is lactose-free, with limited amounts of preservatives[19]. In 2019, Agin et al[20] examined the effect of Modulen IBD supplementation for 8 weeks in 73 pediatric patients with IBD (35 CD and 38 ulcerative colitis patients), in addition to their medical treatment. Among the patients with CD, 88% of those who got Modulen IBD achieved remission, compared to 42% of patients who did not receive Modulen IBD. This study demonstrated that TGF-β-rich EN support in children with IBD is an effective and reliable approach with an earlier remission success[20]. In a study done by Watanabe et al[21] in 2010, 29 adult patients with active CD received Modulen IBD as an exclusive diet over a 4-week period. 69% of these patients had clinical amelioration, stabilized their weight, and had an improved general well-being score.
It is believed that the Modulen IBD effects are mainly due to its TGF-β2 contents[22]. Modulen IBD is casein-based, which can protect TGF-β2 from duodenal enzymatic degradation[22]. Casein is rich in two essential amino acids: Leucine, which promotes cryptidin-1 production by Paneth cells, enhancing a defense mechanism against bacteria; and lysine which has anti-inflammatory properties[23,24]. It also contains one non-essential amino acid glutamic acid, which regulates apoptotic and inflammatory cellular pathways, tight junction proteins, and enhances intestinal integrity[25]. In addition, TGF-β2 stimulates intestinal cells to down-regulate inflammatory cytokines such as interleukin-6, promotes immunoglobulin A production, and forkhead box P3 regulatory T cells, and prevents goblet cell depletion[26]. In CD, healing pathways mediated by TGF-β2 are inhibited due to the mucosal inflammatory cells expressing Smad7, the endogenous intracellular inhibitor of TGF-α signaling[27].
Moreover, budesonide, a synthetic steroid from the glucocorticoid family, has a high topical anti-inflammatory activity. It is available in enteric-coated formulations that resist gastric acid degradation which helps deliver it to the small intestine and the proximal colon[28]. It is generally well tolerated, with minimal side effects compared to traditional glucocorticoids[28]. It is also well studied for its efficacy during induction and short-term maintenance therapy in CD[28]. The mode of action and pathophysiological consequences of Modulen IBD need further exploration. The study by Ovadia et al[5] provides valuable insights into this area, comparing the impacts of Modulen and budesonide on clinical response and mucosal healing in adult patients with newly diagnosed mild to moderate CD. By comparing a nutritional to a pharmaceutical intervention, the study addresses an important question on whether dietary interventions can match or even surpass traditional medications in promoting mucosal healing in CD.
Key findings from the prospective study
The study enrolled 30 patients in total, with 21 patients assigned to the Modulen group and 9 to the budesonide group. While initial patient preference favored the nutritional intervention, the Modulen group experienced a notably high withdrawal rate of 52.3%, with only 11 patients completing the full eight-week treatment. The most common reasons for withdrawal included difficulties with taste, cost considerations, and GI symptoms. In contrast, the budesonide group maintained better retention, with 7 out of 9 patients completing the study. The Modulen group demonstrated significant clinical improvements in both intention-to-treat and per-protocol analyses. In the intention-to-treat analysis of 21 patients, there were marked improvements in CD Activity Index, IBD Questionnaire scores, and total symptoms scores throughout the treatment period. The endoscopic evaluation revealed a significant reduction in the total inflammatory score, though the Lewis score improvement did not reach statistical significance. Notably, laboratory parameters remained largely unchanged in this analysis. In contrast, the per-protocol analysis of 11 patients in the Modulen group showed significant improvements in both clinical and endoscopic parameters. Treatment compliance was satisfactory, with patients consuming an average of three portions during the first month and 2.8 portions in the second month.
On the other hand, in the budesonide group, the intention-to-treat analysis of 9 patients showed a temporary positive clinical response, with CD Activity Index showing significant improvement only during the first month before losing statistical significance in the last four weeks. However, laboratory parameters showed more consistent improvement, particularly in calprotectin levels. The per-protocol analysis of 7 patients revealed significant improvements in calprotectin, hemoglobin, and CRP levels. However, endoscopic parameters showed no significant improvements. Safety profiles were favorable for both treatments, with no significant adverse events reported in either group. The capsule endoscopy procedures were largely successful, with only one incomplete study and no cases of capsule retention. All patients but one underwent capsule studies before and after the intervention, providing reliable endoscopic assessment of treatment effects.
This study provides a comprehensive assessment approach, combining clinical, laboratory, and endoscopic measures. The study’s focus on newly diagnosed patients with mild to moderate CD is particularly valuable, as early intervention during this crucial window may prevent disease progression and improve long-term prognosis. For these newly diagnosed patients, who often struggle with dietary choices to prevent flares, the study offers practical insights into nutritional management. Moreover, the use of small bowel capsule endoscopy is relatively a novel method for the evaluation of mucosal healing, offering an accurate picture of treatment effectiveness compared to traditional imaging methods.
Limitations of the study
Several important limitations must be acknowledged when interpreting this study’s findings. First, the small sample size, and uneven distribution of participants (9 patients in the budesonide group compared to 21 in the Modulen group), raises concerns about statistical power and generalizability. Discrepancies in sample sizes between treatment arms can potentially skew results, limiting statistical power and increasing the risk of type II errors, where genuine effects might be undetected. The nutritional status of the patients was not accounted for, including total energy and nutrient intake. Also, the study’s reliance on capsule endoscopy results may introduce selection bias, as a significant portion of patients who did not undergo this procedure were excluded. This again limits the generalizability of findings to the broader CD population.
Second, the remarkably high withdrawal rate in the Modulen group (52.3%) may have affected the study’s internal validity and would as well reflect potential challenges in maintaining dietary interventions for the duration of therapy. It highlights the presence of practical obstacles when implementing nutritional therapy in clinical practice. While the authors of the paper attributed this mainly to taste and cost, it would be beneficial to investigate the impact of other potential cofounding factors such as the socioeconomic background, and variations in baseline disease activity. Financial toxicity, which includes financial hardship due to medical bills, cost-related medication nonadherence, and personal financial distress, is prevalent among IBD patients and can significantly impact their ability to afford and adhere to nutritional interventions[29,30]. Additionally, patients with higher baseline disease activity are generally more motivated to adhere to treatment initially but may struggle with long-term adherence due to disease burden and psychological factors. Several studies highlight these dynamics. For instance, Khanna et al[31] found that patients experiencing a current flare were more likely to be nonadherent in the future, suggesting that acute symptoms might initially drive adherence, but the chronic nature of the disease can lead to fatigue and eventual nonadherence. Similarly, Adriaanse et al[32] demonstrated that high disease activity negatively impacts IBD control, mediated by reduced self-efficacy and self-management behaviors, indicating that patients with active disease may struggle with maintaining long-term adherence due to decreased confidence in managing their condition. In addition, it would be beneficial to suggest strategies to increase Modulen adherence such as nutritional education, taste and texture improvement, and supportive counseling[33,34].
Third, the study’s interpretation indicating no improvement in endoscopy in the budesonide group, offers a preliminary view of budesonide’s effects but may overlook critical nuances affecting these observations. Initial colonoscopy results showed no colonic inflammation in most participants and only minimal inflammation in the remaining, suggesting predominant inflammation in the small intestine. Also, the Lewis score was used as it is used to especially to assess small bowel inflammation in CD via capsule endoscopy in comparison to the Simple Endoscopic Score for CD that is used for evaluating disease activity in the ileum and colon[31,32]. However, budesonide acts mainly in the proximal colon and terminal ileum, depending on the formulation used[35,36]. Therefore, these are the areas where endoscopic improvements might be expected with its use, and the use of other assessment tools with greater sensitivity might be necessary for a more complete evaluation of the drug’s effectiveness when medically indicated.
Moreover, the study’s short follow up period may be insufficient to fully understand the long-term implications of either treatment approaches. This is particularly relevant for the Modulen intervention, where the long-term sustainability of dietary modifications and their impact on the disease course and overall patients’ health remain uncertain. The effects on the quality of life of the patients is also an important aspect to be further investigated. Finally, Ovadia et al[5] analyze the impact of Modulen and budesonide on CD by examining changes in inflammatory markers and disease activity within each treatment group. However, the study lacks a direct comparison between the Modulen and budesonide groups regarding these indicators, limiting conclusions about their relative effectiveness. Such a comparison would substantially strengthen the analysis and provide valuable insights into the optimal treatment approach. It would be beneficial to also compare and investigate the potential advantages of patients receiving combined therapy.
Clinical implications of the study
The study’s results suggest distinct and potentially complementary roles for Modulen and budesonide therapy. Modulen appeared more effective in achieving clinical response and mucosal healing, particularly in the middle small bowel segment where it is primarily absorbed. Budesonide, while showing more modest clinical effects, showed superior ability to improve inflammatory markers. This dichotomy in treatment effects suggests that a combination approach might be beneficial for some patients, challenging the traditional reliance on pharmacological interventions alone. Despite initial patient enthusiasm for nutritional therapy, the higher withdrawal rate in the Modulen group (52.3%) compared to the budesonide group (22.2%) underscores the challenges of maintaining dietary interventions in daily practice. This observation serves as an important reminder for clinicians about the importance of considering patient’s adherence when selecting treatment strategies and tailoring these treatments to achieve the best outcomes possible with respect to patients’ preferences.
Future research directions
Looking forward, this study opens several avenues for future research. Larger randomized controlled trials are needed to confirm these findings. Longer follow-up periods would provide insights into the durability of treatment effects and possible long-term side effects. Additionally, investigating factors to mitigate noncompliance and improve adherence to nutritional therapy could enhance its practical use. It is also important to ensure balanced sample sizes or utilize statistical correction techniques, such as stratified random sampling or variance analysis adjustments, to improve the reliability and interpretability of the findings. Future research should investigate the potential benefits of combining Modulen and budesonide, given their complementary effects on mucosal healing and systemic inflammation, respectively. Furthermore, it would be interesting to evaluate the role of nutritional therapy in severe CD, where patients often require complex, multi-disciplinary approach. Understanding how nutritional interventions can be integrated into intensive treatment protocols for severe IBD could significantly enhance patients’ quality of life.
In the future, the high dropout rate witnessed in the Modulen group should also be addresses and efforts should be made to lower this number as much as possible. This can be done by addressing the taste and cost concerns by offering palatable flavor options, providing financial assistance, and developing cheaper formulations. Managing potential GI side effects through monitoring, dose adjustments, and dietary counseling is also crucial. Moreover, patient education and support, potentially including a pre-screening period could help identify those who are unlikely to tolerate it due to taste or GI issues.
Finally, while Ovadia et al’s study[5] suggests that the effect observed in the Modulen group is attributed to a specific ingredient in Modulen (TGF-β2), it seems that this conclusion might not be drawn definitively. This is because EN by itself, is already proven to effectively induce remission and mucosal healing in CD, particularly in children, achieving clinical remission comparable to corticosteroids (60%-80%) and even higher mucosal healing rates[37-39]. In adults, data is less robust, with some studies reporting remission rates exceeding 70%[40]. Hence it might be helpful to directly compare Modulen with regular EN (which does not contain TGF-β2) to better highlight the potential advantages of TGF-β2-containing nutrition formulas.
Conclusion
In conclusion, Ovadia et al’s study[5] is a key step in the future of CD management. By demonstrating the differing effects of Modulen and budesonide on clinical response, laboratory parameters, and mucosal healing, it highlights the complexity of CD management and the potential benefits of a multi-faceted treatment approach. As we continue to strive in optimizing our strategies for achieving and maintaining mucosal healing in CD, such studies encourage clinicians to consider individualized treatment strategies that might incorporate both nutritional and pharmacological interventions, taking into account patient preferences, compliance factors, and personal therapeutic goals. While further research is needed to build upon these findings, this study provides a valuable foundation for future investigations and underscores the potential of personalized treatment approaches in CD management.
