ABSTRACT: Background. The mechanisms by which environmental risk factors (eg, stress) predispose to symptoms and gastric emptying (GE) disturbances in non-ulcer dyspepsia (NUD) is unknown. Our aims were to compare the circulating leukocytes’ epigenome between NUD patients with normal versus delayed and normal versus rapid GE. Methods. In 24 NUD patients, we evaluated gastrointestinal symptoms, GE (scintigraphy) and 3 promoter/enhancer-associated histone modifications (H3K4me3, H3K9ac, and H3K27ac) by chromatin immunoprecipitation-sequencing in buffy coats, then compared the genome-wide binding of histone marks between patients with normal versus delayed and normal versus rapid GE. Key results. GE was normal (9 patients), delayed (6 patients), or rapid (9 patients). Compared to normal GE, there was differential binding of H3K4me3, which marks active promoters, at 100 genes in delayed and 233 genes in rapid GE (FDR < 0.05). Delayed GE was associated with increased H3K4me3 binding at several genes that regulate T cell functions (eg, CD247, IL2RA, CD69, CD96, ICOS, ITK, and GRAP2); conversely, binding was reduced at genes that regulate neuronal synapses (ie, SYT6, SYT12, CDH2, CDH11, EFNB3, CAMK2B, and SHISA6) and neuronal nitric oxide synthase (NOS1). In rapid GE, genes related to opioid signaling (OPRD1, MAPK4, CAMK2B, and PDE1C), neuronal development, and synaptic functions bound less H3K4me3. No or few genes were differentially enriched with H3K9ac and H3K27ac. Conclusions. H3K4me3 discriminates among patients with normal, rapid, and delayed GE. Delayed GE is associated with alterations that suggest increased T-cell functions. Rapid GE is associated with changes suggesting reduced opioid signaling.
