The central role of the duodenal microenvironment in functional dyspepsia.

Functional dyspepsia is a common gastrointestinal disorder,
characterized by upper abdominal symptoms in the absence of a
clear organic cause. Nevertheless, the pathophysiology is still
unclear and the available treatment options are limited and poorly
efficacious. In the recent years, several groups, including my own,
have demonstrated increased permeability of the duodenal mucosa
and increased presence of eosinophils and mast cells in the
duodenum. However, the cause of the duodenal immune activation
and its relevance to symptom generation are still unknown. In the
proposed project we will first provide a detailed characterization of
the mucosal immune activation by flow cytometry of lamina propria
leukocytes and measurement of local cytokine profiles. We will also
investigate whether these local or systemic (plasma and feces) signs
of immune activation can be used as a biomarker. We will study the
role of locally produced soluble mediators and luminal factors in this
inflammatory response. In the second part of the project we will
answer the question whether and how the duodenal immune
activation leads to sensitization of the submucosal neurons (calcium
imaging), which would add another layer of evidence for its
importance in symptom generation. Finally, treatment studies
investigating the anti-inflammatory mechanism and clinical effect of
proton-pump inhibitors (PPI) and the locally active corticosteroid
budesonide, will be undertaken.