Proton pump inhibitors (PPIs) improve functional dyspepsia (FD) by reducing duodenal eosinophils and mast cells, according to a prospective study.
Dr. Lucas Wauters
This suggests that the anti-inflammatory effects of PPIs are responsible for symptom improvement, and not barrier-protective or acid-suppressive effects, a finding that may guide future therapies and biomarkers, reported lead author Lucas Wauters, PhD, of University Hospitals Leuven (Belgium), and colleagues reported in Gastroenterology.
“FD is a common and unexplained disorder with unknown pathophysiology, hampering a conclusive diagnosis and the development of effective drugs,” the investigators wrote.
Although PPIs are currently used as first-line FD therapy, ostensibly for acid suppression, “the exact mechanism of action of PPIs in FD is unknown,” the investigators noted.
According to Dr. Wauters and colleagues, previous FD studies, such as a 2020 study published in Gut, have reported a variety of pathophysiological findings in the duodenum, including increased eosinophils and mast cells, as well as activation of duodenogastric reflexes, which suggests “a primary role for duodenal pathology in FD symptom generation.” Several drivers of this pathology have been proposed. Some, such as aberrations in bile salts and acidity, point to local, luminal changes, whereas others, such as dysregulated hypothalamic-pituitary-adrenal axis responsiveness and psychosocial factors, implicate a broader set of drivers, the investigators wrote.
The present study explored this landscape through a prospective trial that enrolled 30 healthy volunteers and 47 patients with FD (2 patients with FD did not complete the study).
Patients with FD were subgrouped into “FD-starters” who had not taken PPIs and/or acid suppression for at least 3 months leading up to the trial (n = 28) and “FD-stoppers” who had refractory symptoms after at least 1 month of daily PPI usage (n = 19). Among participants with FD, 25 had postprandial distress syndrome (PDS), 9 had epigastric pain syndrome (EPS), and 13 had subtype overlap.
For the trial, FD-starters and healthy volunteers took 4 weeks of pantoprazole 40 mg once daily, whereas FD-stoppers ceased PPI therapy for 8 weeks. Before and after these respective periods, certain study procedures were conducted, including duodenal biopsy collection, duodenal fluid aspiration, and questionnaires for symptoms and stress. The study also included use of Ussing chambers for biopsies, immunohistochemistry, and bile salt measurements.
FD-starters were significantly more symptomatic than healthy volunteers were at baseline. After starting PPIs, those with FD had symptom improvements, confirming “clinical efficacy of a standard course of PPIs in all FD subtypes,” whereas healthy volunteers showed no significant change in symptoms.
Similarly, baseline duodenal eosinophil counts were higher in FD-starters than in healthy volunteers. On starting PPIs, however, eosinophil counts in these two groups moved in opposite directions: FD-starters’ counts dropped from a mean of 331 to 183 eosinophils/mm2, whereas healthy volunteers’ counts rose from a mean of 115 to 229 eosinophils/mm2 (P < .0001). Changes in mast cells and paracellular passage followed the same pattern, falling in FD-starters and rising in healthy volunteers. On the other hand, symptoms actually improved in the FD-stoppers after they went off PPIs, although they did not reach symptom levels of the healthy volunteers.
“Differential effects of PPIs in healthy volunteers point to the role of luminal changes in determining low-grade mucosal immune activation in the duodenum, which can also occur in FD after long-term use and provide arguments against continued use in refractory patients,” the investigators wrote.
Dr. Wauters and colleagues suggested that their findings could guide future approaches to FD management.
“Our results suggest that quantification of duodenal eosinophils has the potential to become part of diagnostic workup and guide therapeutic decisions in FD,” they wrote. “Additional study of the underlying mediators might lead to the discovery of new potential biomarkers or novel therapeutic targets, potentially allowing the identification of subgroups responding to biologically targeted rather than symptom-based treatments.”
The study was supported by the clinical research fund of the University Hospitals Leuven. The investigators reported no conflicts of interest.