Voedselgeïnduceerde immuunactivatie in het duodenum: Een trigger voor symptomen en therapeutisch aangrijpingspunt bij functionele dyspepsie

Functional Dyspepsia (FD) is a highly prevalent disorder of gut-brain interaction (DGBI) with a complex and multifactorial disease mechanism. Besides alterations in stomach motility, alterations have been found in the duodenum in the last decade with impaired barrier function and increase immune cell infiltration. Although some progress has been made in understanding these mechanisms, therapeutic options remain limited, with only Helicobacter pylori eradication and proton pump inhibitors (PPIs) endorsed in recent consensus guidelines. This thesis addressed knowledge gaps in the epidemiology, symptomatology, genetics, disease mechanisms, and treatment strategy of FD. In a first epidemiological analysis using Belgian data from the Rome Foundation Global Epidemiology Study regional variations were revealed in DGBI prevalence, with French-speaking participants reporting higher rates of FD, functional bloating, and functional diarrhea, as well as increased anxiety. These findings underscore the influence of linguistic, cultural and psychosocial factors on symptom expression within a single country. FD is traditionally subdivided in a postprandial distress syndrome (PDS) subtype - characterized by postprandial fullness and early satiation - and an epigastric pain syndrome (EPS) subtype which is characterized by epigastric pain and epigastric burning. In a second multicenter cohort study of 483 FD patients we demonstrated that nausea, besides the cardinal Rome IV symptom, is frequently reported. This should be taken into consideration when investigating new treatments for FD. In a separate study we validated a new instrument to measure epigastric pain and epigastric burning. The Leuven Epigastric Pain Syndrome scale (LEPS) provides a novel patient-reported outcome measure for assessing EPS symptoms, with strong reliability and responsiveness and can be used in future clinical trials. Genetic susceptibility was explored through the FunDysGWAS consortium, with identification of FD-associated single nucleotide polymorphisms (SNPs). Future work is needed to establish functional consequences through gene expression and protein-level studies in affected tissues. Dietary interventions were also investigated. We studied FD-patients during a low-FODMAP diet and showed significantly improvement of duodenal transepithelial electrical resistance (TEER), suggesting improvement of barrier function. Although no significant changes in immune cell counts were observed, symptom improvements correlated with reductions in eosinophil and mast cell numbers. Histamine measured in the urine, showed preliminary associations with mucosal mast cell activation, though larger studies are required for validation. A mechanistic FODMAP challenge study using MRI revealed altered small bowel water content and reduced gut hormone (GLP-1, GIP) responses in FD patients compared to healthy controls, pointing to altered nutrient sensing in patients with FD. Therapeutically, the prokinetic agent itopride demonstrated a favorable long-term safety profile over 52 weeks. Symptom improvement was reported in nearly 78% of participants completing treatment. As a new treatment option we investigated palmitoylethanolamide (PEA), a naturally occurring anti-inflammatory compound. PEA did not significantly improve overall FD symptoms in a placebo-controlled trial. However, PEA significantly enhanced duodenal barrier function in patients concurrently using PPIs, suggesting a possible interaction that merits further investigation. This thesis advances understanding of functional dyspepsia by highlighting regional and symptom variability, validating new patient-reported outcome tools, and linking diet to duodenal barrier dysfunction and immune activation. These findings suggest a key interplay between symptoms, barrier integrity, and immunity—pointing to a promising and necessary direction for future FD research.