Nutritional Management of Crohn’s Disease: Present and Future Approaches

In the near future, we will refine and improve nutritional approaches to IBD. This might include broadening the range of settings in which it is used, advancing the science of nutritional therapy, conducting more clinical trials and incorporating dietary therapies into more guidelines for treatment of IBD.

Nutritional Therapy: What, Why and How?

Eytan Wine, Professor of Pediatrics and Physiology, University of Alberta, Canada

IBD patients are often given dietary guidance, but nutritional therapy goes beyond this.¹  Therapy requires a good epidemiologic and mechanistic rationale; indeed, diet is involved in pathogenesis and therefore, dietary change could help induce or maintain remission. However, confirming the utility of a sound, evidence-based dietary therapy can be challenging.

There is a vast body of literature around diet and IBD. However, this material is not always solid enough or reflective of the latest scientific understanding. 

RCT-supported nutritional therapies for CD include exclusive enteral nutrition (EEN), partial enteral nutrition (PEN) and specific diets such as the Crohn’s Disease Exclusion Diet (CDED). 

EEN has now been used for several decades and is recommended by ECCO-ESPGHAN as a first-line treatment for induction of remission in children with active luminal CD.² 

In 2019, a randomised controlled trial established evidence for use of CDED plus PEN to induce sustained remission in paediatric CD.³ Tolerance of CDED at 6 weeks was found to be significantly better than EEN and those using CDED+PEN had higher rates of sustained remission at 12 weeks. A further study confirmed applicability to adults.⁴ 

New ESPEN Guidelines recommend that CDED should be considered as an alternative to EEN for induction of remission for both paediatric and adult patients.⁵

Despite this progress, challenges remain. These include understanding the mechanism of how nutritional therapy for IBD works, supporting patients in complying with a restrictive diet, selection of best candidates and extending application of dietary therapy. Cost, access, and cultural adaptation are also important considerations. In addition, there are some concerns that exclusion diets can lead to development of avoidant-restrictive food intake disorder (ARFID).

An expert review recently published sets out a CDED use algorithm as well as giving a clear outline of research gaps.⁶ Although many challenges remain, experts agree that CDED nutritional therapy is an important part of treating IBD.

Conclusions

Dietary therapy has been around for decades and is now recommended as a first-line treatment for some CD patients. However, there is still a relative lack of awareness amongst clinicians and challenges for wide implementation in systematic clinical practice remain. 

Next Generation Enteral Nutrition Therapy

Konstantinos Gerasimidis, Professor of Human Nutrition, School of Medicine, Dentistry and Nursing, University of Glasgow, UK

EEN for induction of remission in active CD should be considered as a primary therapy in both adults and children.⁷ EEN is very effective as a treatment, improving disease symptoms in up to 85% of patients, working at least as well as oral steroids. It also improves blood disease markers, replenishes nutritional deficit, improves muscle mass and induces mucosal healing in more patients than steroids.^{8 9 10 11 12 13 14 15 16 17 18}  These benefits are without the side effects of other drug treatments.

However, EEN is a very restrictive diet for patients, and they need to consume a significant volume of EN for a long period. A drawback of EEN is that after gut inflammatory markers have improved, they often rebound to baseline levels soon after solid food is reintroduced.¹⁹

The introduction of advanced therapies has given clinicians more options in treating patients. Patients are often now put on biologic treatments without considering EEN. In the 2021 edition the ECCO/ESPGHAN guidelines changed to recommend EEN only for patients with mild-moderate, uncomplicated disease and set the option to start biologics early in the management of those patients.²⁰

However, there is potential for the use of PEN with or without exclusion diets for induction of remission, use of EEN in complicated disease, maintaining remission with PEN therapy post-EEN induction, peri-surgical use of EEN and combination therapies using biologics alongside EEN or PEN.

Studies on the use of PEN for maintenance of remission have mixed results. A recent study found that there was a dose-response relationship between the amount of PEN consumed and the clinical benefit derived; if >35% of total nutrition comes from PEN, the rate of relapse is lower.²¹ A further ongoing systematic review and meta-analysis found a clear dose-benefit effect.²²

Figure 1: Dose-dependent effect of PEN on maintenance of remission. Clinical relapse rates according to amount of PEN consumed over 1 year.²³ MEN: maintenance enteral nutrition

The concept of using a high dose of PEN (above 50% of daily energy requirements) to prolong remission in children with low-risk CD has recently been introduced into ECCO-ESPGHAN guidelines.²⁴ A note of caution is that for PEN to be effective it should be used as a diet replacement, rather than a supplement.

There is a lot of interest in pre-surgical use of EEN in CD. A study found that this reduces C-reactive protein (CRP) at surgery, makes operations quicker and reduces complications. Moreover, 25% patients could avoid surgery altogether.²⁵

It is worth remembering that the use of EEN around surgery was established in 1973 by surgeons who wanted to enable their patients’ bowels to rest in preparation for surgery.²⁶

Most studies in this area are retrospective; however, in the UK a major NIHR-funded prospective study (OCEaN) is underway with almost 620 participants. Patients will be randomised between six weeks’ pre-operative EEN or a control arm with no EEN. A full range of outcomes will be reported. 

Combination therapy offers opportunities to associate treatments with distinct modes of action. For example, a biologic treatment that inhibits the activation of the immune system could be used alongside nutritional therapy that works by removing environmental factors for CD.²⁷

In retrospective trials, this combination therapy approach has been shown to result in better remission and maintenance rates. A prospective RCT is now comparing 50% partial EN and adalimumab to adalimumab monotherapy.²⁸ Preliminary data indicate that almost twice as many patients achieve normalised faecal calprotectin (<100 mg/kg) when using combined therapy.²⁹ 

EEN is often seen as unsuitable for complicated CD; however, two recent studies from China found that it could be effective in patients with non-fibrotic strictures.^{30 31} There is historic precedent for this. A study from 1973 showed that a patient with severe CD and perianal fistula experienced fistula closure after four weeks of EEN.³² 

It is likely that EEN will still be recommended for patients with mild-moderate CD. Moreover, combination of biologics and nutritional therapy will probably be recommended more and more for patients in the future. EEN/MEN (maintenance enteral nutrition) may also be used more frequently when biologics do not prove effective or patients lose response to them, and for peri-operative optimisation.

Conclusions

EN is an effective treatment but has limitations, including the impact of monotony on patient compliance. Dietary therapy based on whole foods has been recommended as an alternative. Altogether, there are multiple nutrition-based options in the armamentarium accessible to clinicians for treating CD. 

The Current State of Evidence for Novel Dietary Therapies

Rotem Sigall Boneh, Clinical and research dietitian, Wolfson Medical Center, Tel Aviv, Israel

In recent years, dietitians have moved from a supportive role in addressing nutritional deficiencies to a more active role in treatment of inflammation. Dietitians are now looking at how whole food diets can improve treatment, care and quality of life for patients.

Evidence on novel dietary interventions is still emerging and many studies are small in scale or have other limitations. Further randomised controlled trials (RCTs) are required before evidence-based recommendations can be made. However, findings can be summarised in the table below: 

In recent years, CDED+PEN has been found to achieve a similar response to EEN by week six in paediatric patients, but with better tolerability (97% versus 73.7%).³³ In adult patients, those using CDED+PEN showed great response and sustained remission.³⁴ Inflammatory markers were also improved in both adults and children.^{35 36}    

Since CDED was proposed in 2014,³⁷ series of studies have confirmed that it is well tolerated and effective in management of mild-moderate CD. Studies are now required to ascertain whether CDED can be used more widely, for example in more severe cases, complex cases and with perianal disease. Initial findings show that CDED can be beneficial in some of those cases.³⁸ 

In the DIETOMICS-CD trial, mild to severe paediatric CD patients were put on 2 weeks of EEN and then randomized to CDED+PEN up to 24 weeks or continued on EEN to complete an 8-week course, followed by PEN+ free diet up to 24 weeks. Patients were followed up to week 52. The CDED+PEN group showed better remission rates but this did not reach significance. Also, 44% and 25% of patients on CDED+PEN continued CDED+PEN without immunomodulators; 90% and 100% achieved clinical remission at week 14 and week 24, respectively.³⁹ 

CDED has been shown to induce remission in patients with pouch inflammation in a small-scale study.⁴⁰ A pilot RCT in Argentina looked at asymptomatic paediatric patients who had achieved remission using biologics but had elevated FCP levels. CDED+PEN was found to reduce FCP levels at 12 weeks whereas a free diet did not achieve a reduction.⁴¹

CDED can also be used for patients who stop responding to biologics. An Israeli study found that 77% of patients who added CDED alongside a biologic returned to remission, meaning they didn’t need to initiate a new biologic.⁴² A Spanish retrospective study found similar results.⁴³

Improving long-term dietary habits has to be a key goal for dietitians. Patients who used CDED showed lower levels of ultra-processed food consumption at 52 weeks compared to baseline.⁴⁴

Substantial research has now been gathered for CDED to progress into guidelines and clinical practice for induction and maintenance of remission in children and adults with CD.⁴⁵ The contribution of dietitians is crucial in implementing CDED in practice.  

Figure 2: CDED Pyramid of Evidence-based Medicine

Conclusions

Recent years have seen an evolution from EEN to whole food diets for CD patients, with extensive research into CDED in particular. More investigation is required to determine the effectiveness of CDED across different phenotypes, populations and clinical indications.

References

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