1. UVMHealth.org/MedCenter Functional dyspepsia (FD) is a common, disabling condition that affects up to 15% of the population [1]. However, our understanding of the pathogenesis of FD is poor which limits treatment options. Traditionally, abnormalities of gastric neuromuscular function were thought to be the main causes of FD. However, more recently duodenal abnormalities, including inflammation and immune activation, have been implicated as important steps in the pathogenesis of FD [2,3]. We and others have demonstrated altered 5-HT signaling in IBS, and others have demonstrated inflammation in FGIDs, but a causal relationship has not been demonstrated with the possible exception of post-infectious irritable bowel syndrome (IBS) [4]. Although this has not been shown to date in FD, previous studies have not investigated 5-HT signaling in the small intestine which has the greatest density of 5-HT producing cells in the gut [5,6]. INTRODUCTION 1.Determine whether low-grade inflammation and immune activation in the duodenum are features of FD. 2.Test whether altered 5-HT signaling in the duodenum is present in FD. OBJECTIVES Adult subjects who met Rome III criteria for FD including epigastric pain syndrome (EPS) and post-prandial distress syndrome (PDS) were enrolled. Subjects without symptoms of FD but underwent EGD for other reasons (e.g. Barrett’s surveillance, GERD) were recruited as controls. During the EGD, 6 mucosal biopsies were taken from the 2 nd portion of the duodenum. Tissue was placed immediately into a prepared Eppendorf tube, weighed, and processed for histology, immunohistology, 5-HT content, and RNA extraction. Comparisons amongst groups were made by ANOVA or t-test, as appropriate. Data are presented as mean ± SEM. Values were considered significantly different when p < 0.05. This research was supported by a grant from the American Neurogastroenterology and Motility Society. METHODS RESULTS SUMMARY OF RESULTS 32 subjects were enrolled (18 female, 14 male) 23 FD subjects were enrolled including EPS (n=14) and PDS (n=9). 9 controls undergoing EGD for other reasons were also recruited (Dysphagia n=4, Barrett’s surveillance n=3, anemia n=2). Inflammation/Immune Activation: There was no indication of inflammation or immune activation in FD. The number of eosinophils (Eos) was similar amongst the three groups (Table 1). RNA levels for TNF-α, IL-1β, and IL-10 were also similar amongst the three groups (Figure 1). 5-HT Signaling: Mean total enterochromaffin (EC) cells/total cells did not differ significantly amongst the three groups (Table 2). The TpH-1 RNA level was significantly lower in EPS compared with controls (p=0.02), but TpH-1 in the PDS group was comparable to controls (Figure 2). Other values related to 5-HT signaling, including SERT RNA levels, numbers of EC cells, and 5-HT content, were comparable amongst the three groups in the mucosal biopsies. CONCLUSIONS No changes in serotonin signaling or inflammatory condition were detected in FD. There was no differences in inflammatory markers identified. Although TpH-1 RNA level was reduced in the EPS group compared to controls, other readouts of 5-HT signaling, including EC cell numbers and 5-HT concentration, were not changed. Although the results suggest that symptoms of FD do not involve inflammatory or serotonergic abnormalities in the duodenal mucosa, this is a small population and further studies are needed to confirm these findings. REFERENCES 1.Tack, J., et al., Functional gastroduodenal disorders. Gastroenterology, 2006. 130(5): p. 1466-79. 2.Walker, M.M., et al., Duodenal mastocytosis, eosinophilia and intraepithelial lymphocytosis as possible disease markers in the irritable bowel syndrome and functional dyspepsia. Aliment Pharmacol Ther, 2009. 29(7): p. 765-73. 3.Kindt, S., et al., Immune dysfunction in patients with functional gastrointestinal disorders. Neurogastroenterol Motil, 2009. 21(4): p. 389-98. 4.Coates, M.D., et al., Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome. Gastroenterology, 2004. 126(7): p. 1657-64. 5.Foley, S., et al., Impaired uptake of serotonin by platelets from patients with irritable bowel syndrome correlates with duodenal immune activation. Gastroenterology. 140(5): p. 1434-43 e1. 6.Faure, C., et al., Serotonin signaling is altered in irritable bowel syndrome with diarrhea but not in functional dyspepsia in pediatric age patients. Gastroenterology. 139(1): p. 249-58. Allen Lee, 2 ; Brigitte Lavoie 1 ; Jonathan Pan 1 ; Jani Kim 1 ; Maryam Zenali 1 ; Rebecca Wilcox 1 ; Peter Callas 1 ; Peter Moses 1 ; Braden Kuo 3 ; Gary Mawe 1 1. University of Vermont College of Medicine, Burlington, VT. 2. University of Michigan Medical School, Ann Arbor, MI. 3. Massachusetts General Hospital, Boston, MA. ALTERED SEROTONERGIC SIGNALING AND IMMUNE ACTIVATION ARE NOT FEATURES OF FUNCTIONAL DYSPEPSIA Inflammation/Immune Activation: 5-HT Signaling Table 1. Number of Eos were similar amongst all three groups. Figure 1. RNA levels for IL-1β, TNF-α, and IL-10 were similar amongst all three groups. Table 2. Mean total EC cells/total epithelial cells did not differ significantly amongst all three groups. Figure 2. 5-HT content was similar amongst all three groups. SERT RNA level was comparable amongst all three groups. TpH-1 expression was similar amongst all three groups by ANOVA but TpH-1 expression in EPS was significantly decreased by t-test (p < 0.02).