IDDF2024-ABS-0279 Inter-relationship between pathological mechanisms in functional dyspepsia: insights from systematic clustering and correlation analysis

<h3>Background</h3> Multiple pathophysiologies were proposed for functional dyspepsia (FD), including mucosal microinflammation, barrier dysfunction, visceral hypersensitivity, and psychological factors. However, none of the studies has explored the relationship between mechanisms. This study aimed to identify FD subclusters with different pathophysiologies and investigate the interrelationship between different mechanisms. <h3>Methods</h3> A total of 57 FD patients who met the Rome IV criteria and 10 healthy controls (HCs) were included. Symptom and psychological evaluations were fulfilled at baseline. The biopsies of gastric fundus and duodenum were taken for histological analysis. Histological indices of inflammation (count of eosinophil, mast cells (MC)), barrier function (Claudin 2 (CLDN2), Occulin (OCLN) and Zonula occluden-1 (ZO-1)), visceral hypersensitivity (5-HT-positive cells, 5-HT receptors (5-HT1AR and 5-HT3R), nociceptors transient receptor potential vanilloid 1 (TRPV1), transient receptor potential vanilloid 4 (TRPV4) and acid-sensing ion channel 1 (ASIC1)) were analyzed. Unsupervised cluster analysis was used to identify potential FD subclusters, and explore the coexistence or exclusive relationship between mechanisms. <h3>Results</h3> Gastroduodenal microinflammation, altered visceral hypersensitivity, barrier dysfunction and higher psychological burden were observed in FD patients as compared to HC groups. Systematic clustering categorized FD patients into 3 subclusters: cluster 1 (n=32, 56.1%, IDDF2024-ABS-0279 Figure 1 (A)) was characterized by impaired barrier function but normal visceral sensitivity; Cluster 2 (n=7, 12.3%, IDDF2024-ABS-0279 Figure 1 (B)) by higher symptom burden, along with barrier dysfunction and altered visceral hypersensitivity; and cluster 3 (n=18, 31.6%, IDDF2024-ABS-0279 Figure 1 (C)) by increased mast cell infiltration, but normal barrier function and sensitivity. Correlation analysis showed a significant correlation in histological indices between visceral hypersensitivity and barrier function, while microinflammation was a relatively independent pathologic mechanism (IDDF2024-ABS-0279 Figure 2). <h3>Conclusions</h3> Three different subclusters with different pathological mechanisms were identified in FD. Visceral hypersensitivity and barrier dysfunction might coexist and contribute to a higher symptom burden, while microinflammation was an independent pathological factor for FD.