Integrity of the Mucosa: effect of Amino acid formula on Gastrointestinal tract epithelium
in adult Eosinophilic esophagitis patients

Eosinophilic esophagitis (EoE) is an inflammatory disease of the esophagus
characterized by dysphagia, food impaction and strictures. Current treatment of
EoE is limited to topical or systemic corticosteroids and repeated endoscopic
dilations. The use of corticosteroid is accompanied by significant side-effects
that preclude long term treatment while dilations are painful, carry a risk of
perforation and, as underlying inflammation is not affected, recurrence often
occurs. Quality of life is significantly decreased in patients with EoE and
this persists up to 15 years after the first presentation, as there is
currently no acceptable treatment for patients with this disease.
We have recently completed a study using the Dutch pathology database (PALGA)
in which we demonstrate a huge increase in incidence of EoE in the Netherlands
from 0.01 in 1995 to 1.30 per 100 000 inhabitants in 2010 and still rising.
These numbers are in line with North American reports of a huge increase in
incidence. The majority of patients are young, otherwise healthy subjects
between 20 and 40 years of age and there are reasons to believe that many
patients are still not diagnosed yet.
The pathophysiology of EoE is largely unknown, although food allergy is
suggested to play an important role. Most EoE patients suffer from atopic
diseases and the majority of patients is polysensitized to food allergens. IgE
producing B cells and a high level of IgE bearing mast cells are present in the
esophageal mucosa of patients with EoE. We recently showed that the mucosal
barrier of patients with EoE is impaired and highly permeable to molecules with
the size of food allergens (data submitted). This impairment in mucosal
integrity can be primary, as observed in the skin disease atopic eczema where
an increased permeability is responsible for a high permeation of allergenic
molecules and subsequent activation of immune cells. Similarly, in atopic
eczema barrier dysfunction thus plays a role in initiating the inflammatory
process. However, it is also possible that the impaired mucosal integrity found
in EoE is only secondary to products produced by the inflammatory infiltrate,
and thus be the result of inflammation and not the initiator.

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 broad 6 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.
Elimination diets are also very effective in pediatric patients with EoE, with
patients often reaching complete symptomatic and histological remission. A
retrospective comparative report suggests that elementary diets are even more
effective than elimination diets with reported remission induction in 96% of
the treated children. The effect of elemental diet on adult patients with EoE
has only been investigated once. An American study by Peterson et al reported
that out of 18 patients that completed a trial with elementary diet (Elecare,
Abbott), only one patient did not respond. However, of the 29 patients that
were initially evaluated for the trial, 11 patients discontinued after starting
with elementary diet because of adherence failure leaving only 18 evaluable
patients. Adherence is thus an important point, when considering this
treatment.

More research on the role of elementary nutrition in adult patients with EoE is
thus required. In the current protocol we will also evaluate whether a
different formula with improved taste will enhance adherence.

Secondary, it will be crucial to study the effect of elementary nutrition on
esophageal mucosal integrity in EoE patients in order to get more insights into
pathophysiology. If, in the patients with complete remission, the mucosal
integrity will normalize, this will serve as evidence that mucosal integrity
changes are secondary to inflammation. However, if there is still decreased
mucosal integrity in the absence of inflammation, this could serve as an
indication that the observed mucosal integrity changes are a primary
characteristic of the esophageal mucosa of these patients.

Finally, in atopic dermatitis an increased permeability of the intestine is
observed. In this disease the increased intestinal permeability plays a role in
increased presentation of allergens to antigen presenting cells and triggers
limited local inflammation and a systemic T-helper 2 response with increased
levels of IL4, IL5, IL10 and IL13 after which stimulates inflammation in a
distant organ (i.e. the skin). It is very well possible that intestinal
permeability is also present in EoE. Increased permeability of food allergens
could also in EoE initiate a systematic T-helper 2 response, and stimulate or
aggravate inflammation in a distant organ, which is in case of EoE the
esophagus. Elementary formular diet could thus, next to a direct effect on
esophageal inflammation, also work beneficial indirectly through an effect on
the intestine.

Primary: To demonstrate that a liquid Neocate product (elemental nutrition)
study decreased esophageal eosinophil count to less than 15 eosinophils per
high-power field in adult patients with eosinophilic esophagitis.

Secondary: To study the effect of Neocate elemental nutrition on:
- Esophageal, duodenal and intestinal mucosal integrity
- Esophageal inflammation (mast cells and inflammatory cytokines)
- Esophageal endoscopic signs of EoE
- Esophageal symptoms, quality of life, and product acceptability
- Depending on former study outcomes the gastrointestinal microbiome will be
analyzed (esophagus, duodenum, saliva, feces)

Prospective intervention study

Elemental diet preceded by and followed by gastroscopy

Patients will be treated with an extensive diet. During the study patients are
not allowed to eat normal food. Patient adherence will be a big challenge. To
diminished a high dropout in the first days of dietary treatment we
incorporated an elemental diet test day of 24 hours.
Since the production of saliva, which plays an important role in maintaining
oral health, is diminished by a liquid diet, participants are allowed to use
sugar free chewing gum.

Patients will undergo gastroscopy twice; healthy volunteers once. The risk of
the performed procedures consists of the risk of esophageal biopsies, namely
bleeding and perforation.
There is no additional risk involved with the electrical tissue impedance
measurements.
Since participants are not allowed to use anti-inflammatory medication,
esophageal inflammation and symptoms might increase.
For the lactulose:mannitol absorption * urine excretion test, patients and
healthy volunteers need to collect urine and report fluid intake for 2 hours;
this test is safe and is not associated with additional risks.