*Effect of addition of elemental nutrition to an elimination diet on esophageal inflammation in adult eosinophilic esophagitis (EoE) patients: A randomized controlled trial

EoE is a chronic immune-mediated disorder of the esophagus in which dietary
allergens penetrate the esophageal mucosa and subsequently activate the immune
system with eosinophilic inflammation as a response. Clinical symptoms are
dysphagia and food impaction, and histologically the disease is characterized
by an esophageal infiltration of eosinophils.

Quality of life is significantly decreased in patients with insufficiently
treated EoE, which emphasizes the need for new treatment approaches as there is
currently no acceptable treatment for the growing group of patients suffering
from EoE. Current treatment of EoE is limited to topical or systemic
corticosteroids, endoscopic dilations and dietary elimination of food
allergens. Chronic use of corticosteroids is often not acceptable for young
patients and may be accompanied by side-effects that may preclude long term
treatment while dilations are painful, carry a risk of perforation and, as
underlying inflammation is not affected, needs to be repeated with time.
Dietary treatment seems a promising and safe drug free solution, although
patients adherence is challenging.

As mentioned, there is much data that suggests that food allergy plays an
important role in EoE and elimination diets have indeed been found to be
effective. Studies using the extensive six food elimination diet (exclusion of
milk, soy, egg, wheat, peanuts/tree nuts, and shellfish/fish) demonstrate a
clinical and pathologic response in 73-94% of patients. A less extensive
approach is the four food elimination diet (FFED) (exclusion of milk, soy, egg
and wheat), which has also shown to be effective. Histologic remission rates
vary from 54% in adults to 71% in children. Elemental diets with complete
elimination of all possible food allergens by exclusive use of amino acid-based
formulas are also very effective in pediatric and adult patients with EoE, with
histologic response rates up to 94% of patients.

A major obstacle in current dietary management is that it is unknown for which
allergens the patient is sensitized/allergic. Currently available allergy tests
do not provide sufficient sensitivity and specificity in causative allergen
detection. The ultimate goal is to exclusively eliminate the food(s)
responsible for triggering and maintaining the disease in each individual
patient. Therefore, most diets start with a very extensive empiric elimination
diet such as the six or four food elimination diets and then reintroduce food
groups step by step, with endoscopy 4-6 weeks after each change in diet. This
process spans several months and due to the high level of restrictions,
particular in the beginning, there is a significant risk of insufficient
caloric intake or accidental dietary mistakes. Addition of a formula feeding
may thus be helpful in order to maintain a healthy dietary intake.
Additionally, product food labels can be imprecise which may induce
cross-contamination and disappointing response rates. In specific situations it
may be easier to consume an easy to prepare amino acid-based formula without
causative allergens than consume a meal with a not completely known mix of
ingredients.

We have recently shown that a new formulation of amino acid-based nutrition,
when consumed as sole source nutrition, induces histological and clinical
remission within 4 weeks in the majority of EoE patients, showing that it is
very suitable as dietary treatment for these patients. Furthermore, it was well
tolerated in these adult EoE patients. Unfortunately, the use of
amino-acid-based formula as sole source nutrition is not feasible for adult
patients as a long-term dietary treatment. Aside from the removal of all food
allergens there is also data suggesting that amino acid-based nutrition has
anti-inflammatory effects itself. In non-allergic inflammatory bowel diseases,
such as Crohn*s disease elemental diet has shown to be effective in reducing
inflammation. The detailed mechanisms underlying this effectiveness is unclear,
however, it has been reported that some amino acids (glycine, histidine and
cysteine) exhibit anti-inflammatory effects and that the elemental diet reduces
the production of pro-inflammatory cytokines such as IL-1, IL-4, IL-6, IL-8,
IL-10, IL-12, GM-CSF and TNFa in Crohn*s disease. Additionally, another study
showed that cysteine and histidine exhibit anti-inflammatory effects in human
monocytes / macrophages. Also nutrients present in having anti-inflammatory
effects, may contribute to the anti-inflammatory effects of an amino-acid based
formula.
It is now increasingly recognized that foods and nutrients play an important
role in the maintenance or disruption of the mucosal integrity and the process
of inflammation through:
A. Local effects on epithelial integrity and mucosal epithelium and mucosal
immune system of the gastro-intestinal tract, vitamin A plays a critical role
in the differentiation of cells towards epithelial lineages important for
mucosal defense. Also zinc and iron have an essential role in the maintenance
of intestinal epithelial tight junction barrier via the regulation of claudin-3
and occluding expression.
B. Systemic effects on the immune system through micronutrients. According to
very strict criteria several nutrients such as copper, folate, iron, selenium,
vitamin A, B6, B12, C, D and zinc are recognized as having immunomodulatory
properties.
C. Long-chain polyunsaturated fatty acids (LCPUFA) are known because of their
immunomodulatory properties. These fatty acids serve as specific precursors of
immune regulatory eicosanoids. In general, n-6 LCPUFA are considered as being
pro-inflammatory and n-3 LCPUFA as being protective against inflammation.
An independent anti-inflammatory effect of the amino-acid based formula could
also in EoE contribute to the effect of the empiric elimination diet and would
thus make this an ideal combination.

We hypothesize that the addition of an amino acid-based nutritional supplement
to a FFED is more effective than FFED alone due to the: (1) anti-inflammatory
effect of the amino acids and anti-inflammatory nutrients (2) improving
patient*s adherence to the diet by increasing the feasibility of allergen
avoidance. Furthermore, we expect that the combination of amino acid-based
nutritional supplements and FFED leads to a higher acceptation of the diet and
a better quality of life.

Therefore, in the current protocol, we will evaluate whether the addition of
amino-acid based nutrition to FFED is superior to FFED alone in terms of
improvement of the esophageal eosinophilic inflammation, and improved patients*
adherence and acceptability of the diet. Secondary, it will be important to
study the effect of additional amino acid-based nutrition on symptoms as
measured by patient reported outcomes, weight loss prevention and quality of
life. In both arms the efficacy of the intervention will be controlled for the
total composition of the diet.

Finally, in order to investigate the anti-inflammatory effects of the addition
of amino-acid based nutritional supplements additional measurements are
performed on tissue and serum.

To investigate whether addition of amino acid-based nutritional supplements to
FFED is more effective in reducing esophageal eosinophilic inflammation
measured as reduction in absolute number of eosinophils than FFED alone, in
adult EoE patients.

Prospective randomized controlled intervention study

Standard elimination diet or elimination diet with addition of elemental
nutrition.

The extra burden of participation in the study is limited to one extra visit to
the hospital and filling out questionnaires. Elimination diet is an accepted
treatment for EoE and is accompanied by regular endoscopy to evaluate each
dietary step. There are no extra risks associated with the addition of
elemental nutrition.