I: Functional dyspepsia (FD) is a chronic gastrointestinal (GI) disorder with incompletely understood pathophysiology. The duodenal mucosal immunological environment has previously been implicated through histology, while flow cytometric evaluation suggested a T-helper (Th)2/17 signature (Burns et al. Front Immunol. 2023). However, previously reported anti-inflammatory effects of first-line therapy proton pump inhibitors (PPI) are rarely taken into consideration. Therefore, well-designed studies untangling the response to PPI from pathophysiological alterations in FD are needed. Here, we aimed to study mucosal lymphocyte populations in the duodenum of FD and evaluate the local immunomodulatory effects of high-dose PPI in FD.

M: Upper GI endoscopy with duodenal biopsies was performed in Rome IV FD patients and healthy controls (HC), repeated in FD after high-dose PPI (pantoprazole 40mg bid, 4 weeks). GI symptoms were scored using the PAGI-SYM questionnaire. Duodenal lamina propria cells were isolated, stained for surface markers and acquired on an LSR Fortessa (BD). Symptom scores were analyzed by non-parametric tests. Flow cytometry data were transformed and analyzed by linear (baseline) or mixed (treatment) models.

R: Data were obtained from 28 FD patients (75% F, mean±SD age 32±13 yr.) and 30 HC (77% F, 30±10 yr.). Symptoms were higher in FD (P<.0001), and decreased after PPI (P=.002). Effector memory (EM) Th17.1 cells tended to be higher in FD vs HC (P=.068). Postprandial distress syndrome (PDS) patients had lower EM Th2 (P=.017) and numerically lower EM Th17 cells (P=.083), but tended to have higher EM Th1 cells (P=.068) compared to combined epigastric pain syndrome (EPS) and PDS/EPS overlap (Figure 1). High-dose PPI tended to decrease follicular Th cells (P=.070), but increased B cells (P=.034) in FD. Clinical responders (CR, 54%) (improvement of ≥1 point in postprandial distress or upper abdominal pain PAGI-SYM subscores after PPI) had similar baseline PAGI-SYM (sub)scores with equal distribution of FD subtypes vs non-responders (CNR) (χ² test, P=.46). Naive Th cells were lower in CR vs CNR at baseline (P=.013), while total EM Th (P=.016) and EM Th17.1 cells (P=.056) were higher in CR (Figure 2A). In CR but not CNR, the improvement in PAGI-SYM scores after PPI correlated to the decrease in EM Th17.1 cells (r= .59; P=.027) (Figure 2B).

C: Here, we expand the knowledge on duodenal immunological alterations in FD with a potential role for Th17.1 effector memory cells. Altered effector memory Th populations between FD subtypes suggests differences in their underlying pathophysiology. Lastly, decreased Th17.1 effector memory cells were associated with a symptom decrease in response to PPI, which warrants further research into the anti-inflammatory effects of PPI, but can also present new opportunities for Th17.1 targeted therapies in FD.

Figure 1: Different effector memory T-helper cell profiles between postprandial distress syndrome (PDS), and combined epigastric pain syndrome (EPS) and PDS/EPS overlap.

Figure 2: A. Different naive and effector memory (EM) T-helper cell profiles between clinical responders (CR) to proton pump inhibitors (PPI) and clinical non-responders (CNR). B. Positive correlation between improvement in PAGI-SYM scores after PPI and decreased EM Th17.1 cells in clinical responders.

Matthias Ceulemans

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