Study on Crohn's disease and elementary nutrition

Relation

Levine A, Wein E, Assa A, et al. Crohn's disease exclusion diet plus partial enteral nutrition induces sustained remission in a randomized controlled trial.Gastroenterology. 2019;157(2):440-450.

Draft

Prospective, randomized clinical trial

Participant

Study participants included 78 children and adolescents aged 4 to 18 years with mild to moderately active luminal Crohn's disease as determined by the Pediatric Crohn's Disease Activity Index (PCDAI). The PCDAI is calculated based on symptoms, a physical examination, and laboratory values ​​(hematocrit, erythrocyte sedimentation rate, and serum albumin). The authors conducted two arms of the study, one in Canada and one in Israel.

Exclusion criteria included recent use of steroids or biologics, recent change or initiation of immunomodulators, and rectal or anal disease. Participants were allowed to use antibiotics (excluding quinolones or metronidazole) as needed during the first 10 days of treatment. They were also allowed to continue taking a stable dose of immunomodulators while enrolled in the study.

Interventions

The Crohn's disease exclusion diet (CDED), partial enteral nutrition (PEN) and exclusive enteral nutrition (EEN). PEN and EEN consisted of an elemental nutritional supplement ( Modules from Nestle).

Study parameters assessed

Participants were randomized into 2 groups: Group 1 participants received 50% of their calories from CDED and 50% from PEN in weeks 1-6. At weeks 7–12, this group continued Phase II of CDED for 75% of their calories and received 25% of their calories from PEN. Group 2 received EEN for the first 6 weeks and then no dietary restrictions plus 25% of their calories from PEN for weeks 7-12.

Primary outcome measures

The primary endpoint of this study was diet tolerability. Other studies have shown that EEN is effective in inducing remission, but it is poorly tolerated and requires tube feeding in 50% to 60% of cases.

Secondary outcome measures examined response to treatment. These measures included a 12.5 point decrease in PCDAI or remission; a decrease or normalization of inflammatory markers (CRP, ESR, calprotectin) at week 6; the lactulose/mannitol ratio (L/M ratio); and compliance.

The researchers also assessed changes in the gut microbiome over the course of the study.

Key insights

Primary outcome

Of the 78 patients who started the study, 4 randomly discontinued EEN within 48 hours because they refused to take modules orally. After the first 48 hours, 39 of 40 participants (97.5%) in the CDED+PEN arm (Group 1) successfully tolerated their regimen, while 28 of 38 participants (73.7%) in the EEN arm (Group 2) did.

Secondary results

At week 3, the L/M ratio had improved for CDED+PEN patients, but there was no change in the L/M ratio for EEN patients.

At week 6, there was no statistical difference in treatment response between the two groups; 85% of participants in both groups were in corticosteroid-free remission (as determined by the PCDAI score), although remission rates were strongly associated with good adherence to the regimen. Normal CRP was present in 51.3% of group 1 participants and 55.8% of group 2 participants. Calprotectin levels also fell significantly in both groups. Analysis of the microbiome in patients who achieved remission in both groups showed a specific pattern in certain species that waxed and waned over 6 weeks.

At week 12, 75.9% of group 1 patients had normal CRP, versus 47.6% of group 2 patients. Of those in remission at week 6, 87.5% of group 1 patients and 56% of group 2 patients were still in remission at week 12. Calprotectin levels continued to decrease between weeks 7 and 12 in group 1, but increased slightly in group 2. The microbiome of those who achieved remission in group 1 continued to change in a similar pattern to the first 6 weeks, while the microbiome of those who achieved remission in group 2 returned to pre-treatment levels.

Practice implications

Several other studies have examined the effectiveness of elemental-only diets (EED) for inducing and maintaining remission of Crohn's disease. EED has been shown to reduce inflammation, increase absorption, and prevent recurrence.^2-5However, EED is restrictive, generally unpleasant, and costly. For example, a typical 1,500 calorie/day EED program costs more than $1,000/month. Modules are not readily available in the United States, but a 1-month supply through Amazon appears to cost almost $2,000. For these reasons, compliance tends to be low in the long term. Finding nutritional strategies that provide the clinical benefit of EEN while providing the patient with real nutritional options would significantly improve quality of life and compliance.

In the subjects in this study who used CDED+PEN, inflammatory markers, disease severity and microbiome were more positively affected than in the subjects who used EEN and then PEN plus an unrestricted diet, particularly in weeks 7 to 12. CDED is based on the premise that a diet rich in animal fats, sugars, gluten, emulsifiers and thickeners and is low in fiber, depletes the mucous layer of the gastrointestinal tract, allowing bacteria to invade the intestinal lining and cause inflammation and intestinal permeability. A number of studies have used this protocol and shown positive results.^6.7The diet removes elements that increase inflammation and microbial permeability and includes foods that improve microbial diversity and reduce inflammation. (See the Nutritional Protocol.) The specific components of the diet plan include the following.

Fiber and pectins from fruits and vegetableswhich contribute to the production of butyrate and other short-chain fatty acids and reduce inflammation in the intestines.⁶A diet low in fiber, on the other hand, promotes the penetration of pathogenic bacteria into the intestinal mucosa.

Extremely limited animal fats and moderate intake of fats from plant sources. Diets high in animal fat are associated with a higher incidence of inflammatory bowel disease (IBD), while diets high in omega-3 fatty acids reduce the risk.⁸High-fat diets also promote the buildup of secondary bile acids, which inhibit the growth of healthy bacteria.⁶

Exclusion of grains containing gluten. The specific carbohydrate diet, which excludes all grains, is a popular option for Crohn's disease patients seeking dietary treatment and has shown some clinical success.⁹The authors of this study specifically describe gluten and wheat as alpha-amylase/trypsin inhibitors that promote inflammation in the gut and promote intestinal permeability.⁶

Exclusion of processed foods. A number of food additives have been shown to affect intestinal permeability and GI mucosal integrity. These include two common emulsifiers, carboxymethylcellulose (CMC) and polysorbate-80, as well as thickeners such as maltodextrin and carrageenan.¹⁰Martino JV et al. write: "Animal studies consistently report that carrageenan and CMC induce histopathological features typical of IBD while altering the microbiome, disrupting the intestinal epithelial barrier, inhibiting proteins that provide protection against microorganisms, and stimulating the development of pro-inflammatory cytokines."¹¹

The L/M ratio is a test of intestinal permeability in which subjects are given a loading dose of both lactulose and mannitol and then the urine is tested for the clearance of these sugars. Lactulose is a large sugar and is not absorbed by an intact intestine; The appearance in the urine then signals a greater permeability of the lining of the gastrointestinal tract. Mannitol is better absorbed the more intact the villi in the intestine are, and therefore will be present in greater quantities as the intestine heals.¹Intestinal intestinal permeability improved only in group 1, as indicated at week 3.

Although not a primary outcome measure, this study examined the role of microbiome composition in Crohn's disease. The results showed a significant change in the microbiome between the start of the study and week 6 in the subjects who went into remission. At week 12, the microbiome returned to original levels in subjects who reintroduced an unrestricted diet. Subjects with active disease show a greater number of types, such as: B. pathogenicEscherichia colispp,Bilophilaspp and several species in the phyla Proteobacteria. They also have less healthy species such as:Bifidobacteriaspp and those from the Firmicutes phylum.¹²However, studies of probiotics, including fecal transplants, and antibiotics for Crohn's disease have had mixed results at best.^13-17This leads to an intriguing set of questions about whether the composition of the microbiome is causative of symptoms or just coincidental; whether adding the appropriate probiotic bacteria or killing dysbiotic bacteria makes sense; and whether the food we eat is the most important factor influencing the microbiome in the pathogenesis of Crohn's disease.

I also have a few questions about the study itself. While the diet specifically excludes dairy products and butterfat, the protein source in modules is casein and the primary fat source is milk fat. This leads me to question how dairy products affect Crohn's disease and whether products with more hydrolyzed forms of protein would produce different clinical outcomes. The main funding for this study came from Nestlé, the module manufacturer, and the principal researchers receive compensation for consulting from Nestlé.