NUTRITION REVIEWS IN GASTROENTEROLOGY, SERIES #1

Exclusive Enteral Nutrition in Inflammatory Bowel Disease: An Under-Appreciated Therapeutic Gem

January 2023 • Volume XLVII, Issue 1
Kelly Issokson,Eric Vasiliauskas

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Patients with inflammatory bowel disease (IBD) experience periods of disease flares and remission throughout their lives. Despite advances in medical therapy that provide increasing treatment options to help patients achieve and maintain remission, complementary diet strategies can work synergistically to improve the clinical course in IBD. Exclusive enteral nutrition (EEN) is a nutritional therapy that has shown promise as a low-risk therapeutic approach to improve symptoms and reduce inflammation, with the potential to heal gut mucosa, heal fistulas, and decrease perioperative complications, all while providing nourishment to the individual. Current underutilization of EEN in the clinical setting may be related to a myriad of factors, including lack of provider awareness and experience, insufficient support staff, or assumed high rate of non-adherence. The aim of this review is to discuss the evidence supporting EEN in adults with IBD and provide practical suggestions for the implementation of this nutritional therapy.

INTRODUCTION

Inflammatory bowel diseases (IBD) are chronic diseases for which there are no known cure. The two main subtypes of IBD include Crohn’s disease (CD) and ulcerative colitis (UC). Individuals with IBD experience periods of disease flares and remission throughout their lives and are commonly managed with medications, which have become increasingly effective for inducing and maintaining remission.

A significant subset of patients does not adequately respond to medical therapies, and it is not uncommon for patients to experience a loss of therapeutic response over time. Further, medications that are traditionally used to induce rapid reduction in symptoms or remission, such as corticosteroids, come with significant potential side effects that increase with long-term use. The European Society of Parenteral and Enteral Nutrition (ESPEN) guidelines for IBD recommend the use of Exclusive Enteral Nutrition (EEN) as primary therapy for inducing remission in pediatric Crohn’s disease, and in adults when steroids are not tolerated or are contraindicated.1

When used as adjunctive therapy, nutritional therapeutics can work synergistically to improve the clinical course in IBD by nourishing the patient, while also reducing symptoms, decreasing inflammation, and synergistically augmenting response to medical therapy. An increasing number of studies in adults with IBD suggest that EEN shows promise as a low-risk therapeutic agent with the potential to not only improve symptoms, but to also reduce inflammation, and even to heal both gut mucosa and fistulas, as well as to decrease perioperative complications. Despite the evidence supporting EEN’s potential benefits, current underutilization in both the inpatient and outpatient clinical settings may be related to a myriad of factors, including lack of clinician awareness and experience, insufficient support staff, or assumed high rate of non-adherence.

What is EEN?

EEN is a nutritional therapy that involves consuming a complete nutrition liquid formula as a sole source of nutrition for 1-12 weeks. Formula is usually taken by mouth but can also be infused via enteric tube. The type of formula and duration of therapy depends on the indication for use, patient history, allergies, budget, tolerance, taste and ingredient preference, and availability. See Table 1 for a list of complete nutrition formula options that are commercially available.

The wider variety of formula flavors and compositions, including more organic and vegan options has improved patient acceptance and preference. Formula types that are available include: polymeric (whole, intact proteins), semielemental (hydrolyzed proteins) and elemental (free amino acids). The more palatable polymeric formulas are effective for induction of remission, but patients with allergies, impaired absorption, or prior resections may require a semi-elemental or elemental formula.

Shorter durations of EEN can be used to reduce clinical symptoms or for nutritional optimization in preparation for planned surgery; longer durations are needed to induce endoscopic and histologic remission and healing gut mucosa. EEN has historically been used in children and adolescents with Crohn’s disease, and although its efficacy has been demonstrated in adults, EEN is underutilized as an adjunctive therapy. While the experience with EEN in UC is emerging, to date there remains a paucity of literature for its potential roles in UC management.

EEN for Induction of Remission

Corticosteroid therapy has traditionally been used to induce remission in active IBD. While often effective, the short- and long-term side effects, including hyperglycemia, fluid retention, changes in mood, insomnia, hypertension, glaucoma, cataracts, osteoporosis, avascular necrosis, and effects on wound healing and body distortion such as rapid weight gain, moon facies and stretch marks remain a concern to patients and providers, so reducing exposure to corticosteroids is

imperative. EEN provides an opportunity to limit steroid exposure, and has the added benefits of nourishing the individual, correcting dysbiosis seen in active disease, decreasing inflammatory cytokine production, and promoting mucosal healing.2 EEN can be particularly beneficial for those desiring to avoid steroids, those who are intolerant to steroids, and those who are pregnant.

EEN has been predominantly studied in pediatric Crohn’s disease, where durations of therapy of 6-12 weeks have demonstrated remission (clinical and potentially biochemical, endoscopic, radiologic) in up to 80% of cases.3 While the mechanics of EEN are thought to be the same in adults, a recent Cochrane meta-analysis found EEN was slightly less effective than steroids for remission induction in adults with Crohn’s disease.4 It is important to consider the studies used for this meta-analysis were of low quality and had a high rate of non-adherence to EEN.5 Low adherence and underutilization are likely multifactorial and may be due to palatability of formula, lack of insurance coverage, lack of knowledgeable support staff, and lack of training, experience, and conviction of efficacy among providers. A recent prospective study of children and adults on EEN, mucosal healing was reported in 79% of patients on EEN for an average of 123 days (range 50-212 days).6 Thus, emerging evidence supports the role of EEN as a very safe, effective option for primary induction therapy for adult Crohn’s disease patients who are flaring.

While the literature surrounding the effectiveness of EEN in pregnancy is limited, a recent retrospective study demonstrated the potential to achieve clinical remission in patients with Crohn’s disease who were pregnant and consumed a peptide-based EEN formula for 12 weeks.7 A recent randomized controlled trial of 62 adults hospitalized for acute severe ulcerative colitis flares found that 7 days of EEN using a semielemental formula augmented response to steroids, reduced hospital length of stay, and resulted in reduced colectomy and re-hospitalization at 6 months compared to those who received standard of care.8 That being said, there remains a paucity of published evidence for the potential roles of EEN in UC.

It should be acknowledged that replacing food with formula exclusively can be too challenging for some patients to implement in real life. Thus, it is important to recognized that evidence suggests that even partial enteral nutrition (PEN) strategies (formula combined with foods) may be effective as a combination therapy along with biologics for inducing and maintaining remission in patients with Crohn’s disease. A meta-analysis of four studies in adults with Crohn’s disease (n=342) found the PEN approach as combination therapy with a biologic (infliximab) resulted in 69% of patients achieving clinical remission versus 45% on a biologic as monotherapy. The study authors pointed out that that amounts to over a 2-fold increase in the odds of achieving clinical remission amongst patients on combination therapy with PEN added to infliximab compared with those on infliximab monotherapy alone. Further, 74% on infliximab/ PEN combination therapy remained in clinical remission at one year, compared to 49% of those on infliximab monotherapy and the probability of maintaining clinical remission on combination therapy appeared to extend beyond 1 year.9

EEN and Fistulizing Disease

A severe complication of Crohn’s disease includes fistula formation. A fistula is an abnormal connection between the gut and another organ (e.g., bladder, vagina, skin, or other part of the intestinal tract). In IBD, fistulas can form as a result of inadequately treated inflammation. Medical therapy traditionally involves starting or adjusting immunosuppressive/ biologic medications, surgery, and/or local control with the placement of setons (flexible tubing or material inserted within the fistula tract that keeps the fistula open to allow it to drain). Studies investigating EEN in patients with Crohn’s disease demonstrate high rates of remission and fistula closure after 4-12 weeks of EEN therapy. A single-center prospective study (n=41) of patients with entero-cutaneous fistulas (ECF) found 80% achieved full clinical remission and 75% had fistula closure after 12 weeks on EEN.10 Another study (n=48) found similar rates of ECF closure at 62% after 3 months on EEN using a semi-elemental formula, with an average fistula closure time around 32 days. Additionally, they found improvements in nutrition with increases in weight, BMI, and hemoglobin, and identified lower baseline CRP and higher baseline BMI as predictors of response to EEN.11

EEN in Elective Surgery

A recent meta-analysis of contemporary studies found a 5-year cumulative risk of surgery of 7% in UC and 18% in Crohn’s disease.12 Importantly, in patients heading towards surgery malnutrition is frequently identified and increases the risk for post-op complications and mortality. Therefore, clinical guidelines recommend nutrition support for optimization perioperatively in those with weight loss >10% in 6 months, BMI <18.5 kg/m2, or an albumin of <3 g/dL, and delaying surgery for 7-14 days if feasible to allow for nutrition optimization.1 Administration of EEN 4-6 weeks perioperatively may serve as a tool to improve nutrition status pre-operatively, decrease inflammation, improve post-operative outcomes, and a small, but significant subset of patients may even be able to avoid surgery when treated with perioperative EEN. The latter was highlighted by a retrospective study (n=51) of adult patients with complicated Crohn’s disease in which 25% of patients who received EEN as part of their preoperative management for an average of 6 weeks were able to avoid surgery. In those who proceeded with surgery, there was a significant decrease in length of time in the operating room, anastomotic leak, and abscess formation.13 The positive findings from this study are limited by the design (retrospective, single center, small study population). Another single center study (n=87) found 4 weeks of EEN taken via naso-gastric tube decreased risk for surgery over a 2-year follow-up period in adult patients with Crohn’s disease and intra-abdominal abscess compared to those who received standard care (26% vs. 56%, p=0.01).14 Furthermore, a meta-analysis found pre-op EEN significantly reduced post-operative complications compared to those who did not receive EEN (21% vs. 73%, p<0.001), with a number needed to treat of 2.15 While larger, prospective trials are needed to confirm these results, these studies do highlight the use of EEN as a promising potentially effective tool to improve surgical outcomes.

PRACTICAL APPLICATIONS
Commencement of EEN

The primary reason EEN is not used as widely in adults is the lack of multidisciplinary support. Many, if not most, gastroenterologists and surgeons who care for adult patients with IBD are not well-educated on the potential benefits of enteral nutrition, nor are convinced of its potential efficacy, and few have the experience to effectively initiate, guide, and monitor patients on EEN. Optimizing success with EEN therapy involves much more that writing a prescription for EEN. A registered dietitian (RD) who is experienced in IBD and experienced with EEN is a vital member on the care team who can provide a comprehensive nutrition assessment and guide patients who are appropriate for and desire EEN as therapy (see Figure 1 for an EEN algorithm). Small studies suggest that adult patients with IBD do not have increased energy requirements above the general population, therefore standard predictive equations (e.g., Mifflin St. Jeor) can be used when estimating nutrition needs.1 Importantly, additional calories may very well be needed to assist with wound healing, perioperative needs, or weight gain. Similarly, while protein needs are comparable to the general population in quiescent disease (1 gm/kg), they are increased during active disease (1.2-1.5 grams/kg) due to increased proteolysis, enteric losses, or effects of disease treatments such as corticosteroids.1

Ideal candidates for EEN include not only those who are malnourished, but also those motivated patients with active disease, disease complications (e.g., fistulas, strictures), those who are planning for potential surgery, and those desiring to limit corticosteroid exposure (e.g., those intolerant or non-responsive to corticosteroids, or those who are pregnant). It is also important to consider psycho-social factors, as EEN can be cognitively and emotionally demanding. Researchers found that those with greater levels of conscientiousness were more adherent to therapy.16 Access to a social worker,psychologist and/or psychiatrist – ideally as part of the multidisciplinary IBD team, or at least familiar with IBD – is important for supporting patients during disease flares and may help with successful completion of EEN therapy. Once a nutrition prescription has been developed, the next step in initiating EEN is to choose a formula. Consider nutrition content, cost, availability, allergies/intolerances, medical/ surgical history (length of functional intestine remaining), palatability, and patient preference when selecting a formula. It may be beneficial for patients to try multiple formula options before deciding on which to use for their EEN treatment, as palatability, tolerance, and cost are important

factors for adherence. Some patients desire organic formulas or formulas with less sugar, and some desire concentrated formulas to allow nutrient needs to be met in a smaller volume. Formulas for EEN are not often covered by insurance companies but writing a prescription along with a letter of medical necessity can increase the odds of formula coverage. This is important for the patient to know upfront so they can determine if EEN is an affordable therapy in the event they must pay out of pocket. The cost of formulas vary; with standard 1 kcal/mL formulas being the most cost-effective and concentrated or semi-elemental or elemental being the most expensive (see Table 1 for commercially available formulas). When discussing the cost of EEN or PEN therapy, it can be helpful to point out that the formula will be replacing what they would normally spend on meals, snacks, and beverages consumed at home or when eating out. During the initial consultation, the patient should receive instruction on the anticipated duration of EEN, which will be determined by the indication for use. The route of administration can be oral or via a small diameter flexible enteric feeding tube (self-inserted or inserted by staff). Monitoring patients on EEN may include weekly update on weight and symptoms, and periodic labs or stool tests to monitor disease activity and nutrition status (e.g., chemistry panel, c-reactive protein, sedimentation rate, fecal calprotectin, iron studies and complete blood count, zinc, vitamin D (25-OH), vitamin B6).

After selecting a formula, the patient should be provided with instruction on how to start EEN. If the patient regularly consumes caffeine, he or she may want to wean off caffeine in the days before starting EEN to avoid caffeine-withdrawal symptoms. While there is no consensus on how to start EEN, a gradual transition onto EEN over a few days may help with tolerance (e.g., replace one meal each day with 2-3 formula shakes until completely on EEN and off solid foods). This approach would also be recommended if the patient is severely malnourished or at high risk for refeeding syndrome.

Encourage strict adherence to EEN (no other food or beverage except water), as efficacy decreases with exposure of other foods and beverages. Patients should be advised to stop all other nutrition supplements (e.g., multivitamin, calcium) as the nutrition formulas are considered “complete” and fortified, usually providing 100% of the recommended dietary allowance in about 1 liter.

Clinical symptoms, such as bloating, pain, diarrhea, urgency, constipation, may occur during the transition period off food and onto EEN, thus patients should be reassured that such symptoms should subside and improve within 1-2 weeks. Drinking the formula slowly (over 30-60 minutes) and spacing the formula out throughout the day can help with tolerance. If symptoms persist at two weeks, consider alternate formula or alternate route of administration (e.g., small bore nasogastric feeding tube) or alternate therapy. Hydration is important to emphasize. To optimize tolerance and success, patients who struggle with any aspect of EEN should be encouraged to contact their RD for support and guidance as issues arise. At our center, patients are given instructions to provide weekly updates to the RD through a secure patient portal to ensure the patient is tolerating EEN, weight goals are met, symptoms are improving, and that EEN remains an appropriate treatment. The weekly patient updates allow the RD to intervene early if changes to the treatment plan are needed, such as increases in formula volume goal to support weight gain, or to provide support if patients are having difficulty implementing EEN at home or in social settings.

Navigating Life on EEN

Relying on a liquid diet as a sole source of nutrition for weeks at a time can be emotionally and cognitively challenging. Eating food is how we nourish our bodies, both physically and emotionally. The ritual of eating plays a large part in how we experience cultures, celebrate with friends, socialize with colleagues, connect with family, and grieve. Acknowledge the impact EEN will have on patients. For some, EEN may feel isolating. For others, EEN may be liberating by allowing them to be more active and social because the symptoms they had been experiencing prior to EEN are improved by EEN.

With the reduction in inflammatory cytokines, mucosal healing, and the full nourishment of the patient, an increase in quality of life is to be expected. Patients should be encouraged to engage in activities that bring them joy (e.g., hiking, biking, swimming, going to the beach, seeing family or friends). If activities involve food, it may be best to arrive full (drink shakes beforehand) or bring shakes to the event to allow nourishment at the same time others are eating and drinking.

The formulas can become monotonous in both flavor and texture. Encourage patients to choose different flavors of formula to help decrease monotony. Mixing flavors (chocolate, vanilla) can also provide a little extra variety. Some find freezing formula in ice cube trays to blend with formula from the can is a fun way to add different texture. Other creative options include freezing formula in popsicle molds to serve as a cool treat on a hot day, or warming chocolate formula in a mug can provide some soothing comfort on a cold night. Some formulas can be difficult to purchase from the store and transport home. Writing a prescription for EEN and connecting the patient with a home health company may help increase the odds that the formula will be covered, all or in part, by their insurance. Additionally, patients will receive supplies of formula shipped directly to their home, ensuring they have enough formula for their EEN. In our center, we also provide travel letters to patients who will be going through security checkpoints. This allows them to carry their formula with them during their travels instead of having to go without.

Transitioning from EEN

EEN is not a sustainable long-term therapy for most individuals. There is a lack of evidence to recommend an evidence-based specific strategy for food reintroduction after EEN. Discussions about how to transition off EEN can happen at any point during the patient’s journey but should commence prior to the end date for EEN.

A single center study in pediatric patients with Crohn’s disease found no difference in rates of clinical remission at 12 months with a gradual food reintroduction over 5 weeks versus rapid reintroduction of food over 3 days.17 While this study was done in children and not adults, it provides some reassurance that a rapid food reintroduction doesn’t worsen disease outcomes and may be the best approach, as long and drawnout food reintroductions may result in inadequate intake, weight loss, or nutrient imbalances. It may be prudent to advise patients to start with small portions of low fat and well-cooked foods (see Table 2 for examples) to assist with tolerance when initially re-introducing foods.

Research suggests specific diet therapies may assist with maintenance of remission; these include adoption of longer-term PEN, a semi-vegetarian diet, or a diet that follows guidelines from the International Organization of the Study for IBD (IOIBD); it is beyond the scope of this article to review these diets. Thus, transitioning from EEN to such an adjunctive nutritional strategy should be considered beyond just maintenance medicinal strategies alone. Regardless of the strategy, a follow-up visit with the RD a few weeks before stopping EEN or after starting foods is recommended to ensure diet balance and tolerance.

Conclusion

EEN is a safe and effective therapy for IBD with the potential to induce clinical, endoscopic, and histologic remission, heal fistulas, and when used perioperatively, to improve nutrition status and surgical outcomes, while avoiding steroid side effects. While most studies have shown the benefit of EEN in pediatric IBD, an increasing number of small studies and meta-analyses show benefits in the adult population as well. EEN is currently underutilized and should be considered in patients as an adjunctive therapeutic tool in the expanding treatment armamentarium. Thoughtful implementation of EEN guided by and supported by the multidisciplinary IBD team is likely to maximize adherence and therapeutic success.

References

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