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CME Author: Vicki Brower

Study Authors: V. Svolos, R. Hansen, et al.

Target Audience and Goal Statement:

Gastroenterologists, pediatricians, internists, and family medicine specialists

The goal is to determine whether it is possible to substitute an individualized, food-based diet, known as CD-TREAT, for exclusive enteral nutrition (EEN) in patients with Crohn's disease (CD) to bring them into remission. CD-TREAT is similar in composition to EEN.

Questions Addressed:

• Does the CD-TREAT diet reproduce changes in symptoms and gut biota that are seen in healthy adults, children with CD, and an animal (rat) model of CD, all of whom are put on EEN in order to treat acute IBS?
• Is CD-TREAT more palatable and any easier to adhere to than EEN?
• How do the results in rats, healthy adults, and children with CD compare on EEN and CD-TREAT?

Study Synopsis and Perspective:

While successful in about 80% of patients, the gut-healing EEN regimen in CD patients is very restrictive, and acceptability is low among patients over the long term. "It is therefore of critical importance that we use our understanding of CD pathogenesis and the mechanism of EEN action to develop new effective dietary therapies that are more acceptable and tolerable," the authors wrote, adding that this currently unmet need was prioritized as one of 10 top in inflammatory bowel disease by healthcare providers and patient groups.

This study demonstrates that an ordinary diet based on commonly eaten solid foods can replicate the physiological effects of EEN, the established but challenging dietary treatment for CD, according to the researchers.

This small proof-of-principle study that compared the effects of a bland, basic whole-food diet without gluten, lactose, and alcohol, and EEN in three experimental populations found "robust" evidence that CD-TREAT, the individualized, ordinary food-based diet similar in nutritional composition to EEN, was easier to tolerate and adhere to than EEN, but had comparable effects on the gut microbiome, inflammation reduction, and clinical response in children with relapsing CD, in rats, and in healthy adults.

For the study. researchers randomized 25 healthy adults to receive EEN or CD-TREAT for 7 days, followed first by a 14-day washout period, and then by crossover to the alternate diet. The adults had a mean age of 24.5 and a mean BMI of 22.4; 52% were female. Fecal samples were collected before and after each experimental diet for a total of four samples per participant. Fecal bacteria metabolites were measured, as was the fecal metabolome.

The nutritional intake of CD-TREAT was more similar to that of EEN than to the participants' habitual diet: participants consumed more total and saturated fat, and less fiber and carbohydrates compared with their usual regimen, the researchers wrote. Their protein intake was also higher than the habitual diet during CD-TREAT. The authors saw no significant changes in participants' weight. Fecal microbiome and metabolome were assessed before and after each diet.

The microbiome composition, fecal pH, short-chain fatty acids, total sulfide, fecal bacterial load, and fecal metabolome significantly changed in the same direction for both regimens. The mean total sulfide increases on EEN and CD-TREAT were 133.0 vs 54.3 nmol/g, and the pH increase was 1.3 vs 0.9. Decreases (μmol/g) were as follows:

• Short-chain fatty acid acetate: 27.4 vs 21.6
• Propionate 5.7 vs 5.2
• Butyrate: 7.0 vs 10.2

The healthy adult participant group reported that CD-TREAT was easier to comply with and more satiating than EEN, produced less hunger and less desire to eat between meals.

Five pediatric patients with active relapsing CD also received CD-TREAT for 8 weeks, and clinical activity and fecal calprotectin were evaluated after that period of treatment. The primary endpoint was clinical response at 8 weeks or clinical remission. Secondary endpoints was changes in fecal calprotectin, serum albumin, and C-reactive protein.

While GI symptoms were uncommon in this group of pediatric patients, among the children receiving CD-TREAT, four (80%) had a clinical response and three (60%) entered remission, with significant concurrent reductions in fecal calprotectin (mean decrease 918 mg/kg, P=0.002).

For both human groups, many parallel changes in specific metabolites and species were observed, the authors noted.

In the third part of the study, HLA-B7 and HLA-B27 heterozygous transgenic adult rats with gut inflammation received EEN, CD-TREAT, or standard feed for 4 weeks. A control group of B7 rats did not have gut inflammation. Rats were fed regular chow, EEN, and CD-TREAT consecutively. Researchers analyzed fecal, luminal, and tissue microbiome, fecal metabolites, and gut inflammation. They found that CD-TREAT and EEN produced similar changes in bacterial load, short-chain fatty acids, microbiome, and ileitis severity histopathology scores.

Taken together, researchers observed many parallel changes in specific metabolites and species.

Like EEN and antibiotics, CD-TREAT may deplete nutrients such as fiber that promote bacterial growth or create a luminal microenvironment that suppresses the functionality of inflammatory microbes, blunting activation of the gut-associated immune response in CD patients, the researchers stated.

Source Reference: , Dec. 7, 2018; DOI: 10.1053/j.gastro.2018.12.002

Study Highlights: Explanation of Findings

EEN is currently the sole established dietary treatment used for pediatric patients with CD, especially those in Europe. While effective, it is not practical or pleasant for patients.

CD-TREAT is an alternative to EEN for bringing patients into remission, and is based on Modulen IBD, which is used widely in Europe. "If successful, CD-TREAT has the potential to be used interchangeably with EEN, particularly in adults where EEN uptake is low, and raises the prospect of long-term dietary maintenance therapy," wrote Konstantinos Gerasimidis, PhD, of the University of Glasgow, and colleagues.

Jason K. Hou, MD, of Baylor College of Medicine in Houston, called the study "fascinating as an early demonstration of concept showing mechanistically how components of the gut microbiome can be modified by mimicking the effects of EEN with whole foods."

"This is important because while the best data comes from EEN studies, for many patients, EEN is not a practical option," said Hou, who was not involved in the study.

Many individuals are not able to tolerate EEN and some may even require feeding tubes. "While the study is not large enough to show a real difference and justify patients going on [CD-TREAT], it lays the groundwork for larger clinical trials," he added.

A typical day's menu in the CD-TREAT diet for a male, age 15 years, with CD included the following foods (all lactose- and gluten-free):

• Breakfast: full-fat milk, rice breakfast cereal, and apple juice
• Lunch: white bread, cheddar, and cream cheese; lettuce, peeled cucumber, and chicken with rice soup
• Dinner: grilled salmon, mashed potatoes, cheese sauce
• Snacks: pineapple juice, peeled apple, rice pudding

Along with restricting certain foods, CD-TREAT also excludes maltodextrin, an artificial glucose polymer and most common form of carbohydrates in EEN foods that is not present in whole foods. Substituted in its place were foods high in starch and low in fiber.

"As approximately 10% of food starch resists digestion (i.e., resistant starch), and so reaches the colon, this is likely to influence the gut microbiome in a different way than EEN," the authors stated. They explained that they purposely decreased the carbohydrate in CD-TREAT, and complex carbohydrates in particular, in favor of protein. Ultimately, both protein and carbohydrate stayed within the composition range of other EEN compounds, which have been shown to be effective. Micronutrients found in EEN were supplemented for the CD-TREAT diet by a multivitamin.

The researchers noted that the concentration of total fecal bacteria significantly decreased after both diets: 48.3% of the EEN effect was replicated by CD-TREAT, and 73.7% of the CD-TREAT effect was seen in EEN, they wrote.

Among the preliminary study's other limitations was its reliance solely on fecal samples for microbiome analysis in the healthy volunteers, which may not have reflected the mucosal microbiome. Moreover, some of the outcome measures for which equivalence between EEN and CD-TREAT was inferred may have needed a larger sample size. In addition, the dietary interventions lasted 7 days in human adults and 4 weeks in rats, which is considerably shorter than the 6 to 8 weeks of EEN that CD patients typically receive.

Original story for 名媛直播 by Diana Swift

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