Gastroparesis (GP) is a chronic gastric motility disorder that is frequently underdiagnosed and underestimated, with a major impact on quality of life. The underlying tissue mechanisms remain poorly defined. G-POEM is an emerging endoscopic therapy for refractory GP, but robust predictors of response are lacking. This study aimed to characterize gastric transcriptomic and metatranscriptomic profiles in patients with refractory idiopathic or diabetic GP and to correlate these features with post–G-POEM outcomes.

In this single-center prospective study, we enrolled adults with refractory idiopathic or diabetic GP undergoing G-POEM (clinical cohort). All patients underwent standardized additional mucosal gastric biopsies from the antrum, body, and fundus. Clinical success at 3 months after G-POEM was defined as a ≥1.0-point reduction in total GCSI and a ≥25% improvement in at least one GCSI subscale.

A nested molecular cohort (9 GP patients) was selected for RNA sequencing. A control group of patients without GP symptoms, undergoing EGD for non–motility-related indications, underwent the same biopsy protocol; nine controls were age- (±3 years) and sex-matched to GP cases. Host transcriptomic and microbial metatranscriptomic data were analyzed using differential expression, GSEA, UMAP, cell-type deconvolution, microbial alpha-diversity, and species-level differential analyses. Correlations with G-POEM outcomes were also assessed.

Between February 2023 and June 2025, 21 refractory GP patients (57% idiopathic, 43% diabetic; median age 52 years; 71.4% female) undergoing G-POEM and 16 controls were enrolled. Clinical and functional success rates after G-POEM were 47.6% and 42.9%, respectively. G-POEM significantly improved GCSI, SF-36, and GES parameters.

In the molecular cohort, a marked and region-specific transcriptional shift was observed in the antrum of GP patients (1,793 genes upregulated and 1,006 downregulated vs controls). Pathway enrichment in the antrum revealed upregulation of programs related to tissue remodeling, cell migration and adhesion, vascular regulation, and neuromuscular organization. Microbial alpha-diversity was preserved across groups and regions, although a distinct, region-specific shift in bacterial community composition at the species level was identified in the antrum of GP patients. No significant correlations emerged between molecular features and G-POEM outcomes.

In refractory GP, G-POEM provides a moderate short-term clinical and functional benefit. GP patients exhibit a distinct, antral-specific transcriptomic reprogramming together with localized alterations in bacterial community composition. These findings support the concept of a regionally confined, functionally oriented molecular phenotype in GP, which may contribute to disease mechanisms and help inform future, more personalized therapeutic strategies.