Helicobacter pylori Infection in Rome IV Functional Dyspepsia: Association with the Epigastric Pain Syndrome Phenotype and Long-Term Response to Eradication

Background and Objectives: Functional dyspepsia (FD) is a heterogeneous disorder of gut–brain interaction with a multifactorial pathophysiology. Although Helicobacter pylori infection has been implicated in FD, its relationship with Rome IV FD subgroups and the extent to which successful eradication results in sustained symptomatic improvement remain unclear. This study aimed to evaluate the distribution of H. pylori infection across Rome IV FD subgroups and to assess long-term symptomatic response following successful eradication. Materials and Methods: This prospective, single-center observational cohort study included patients with dyspeptic symptoms who underwent evaluation according to the Rome IV criteria. Adult patients who completed the Rome IV gastroduodenal symptom questionnaire and underwent upper gastrointestinal endoscopy were evaluated. Patients fulfilling the Rome IV criteria for FD without an organic cause explaining their symptoms were classified as postprandial distress syndrome (PDS), epigastric pain syndrome (EPS), or overlapping PDS–EPS. H. pylori status was determined histopathologically using gastric antral and corpus biopsies. H. pylori-positive patients received 14-day bismuth-based quadruple therapy, and eradication was assessed using a stool antigen test 8–12 weeks after treatment. Symptomatic response was evaluated at month 2, 6, and 12 using Likert scale and clinical assessment. Results: Of 425 patients evaluated, 244 fulfilled the Rome IV criteria for FD, and 127 (52.0%) were H. pylori positive. The prevalence of H. pylori infection differed significantly among the Rome IV FD subgroups (p < 0.001) and was highest in the EPS subgroup (73.4%, 58/79), compared with the PDS (37.7%, 40/106) and overlapping (49.2%, 29/59) subgroups. H. pylori positivity was significantly higher in EPS than in both PDS and overlapping subgroups (p < 0.001 and p = 0.003, respectively). First-line eradication rates were 96.4% (106/110) per protocol and 83.5% (106/127) by intention to treat. Symptomatic response rates following successful eradication were 43.4% (46/106), 60.4% (64/106), and 70.2% (66/94) at month 2, 6, and 12, respectively, compared with 47.0% (55/117), 63.4% (71/112), and 78.4% (80/102) in H. pylori-negative patients. Between-group differences in symptomatic response were not statistically significant (p = 0.58, 0.64, and 0.18, respectively). In the conservative sensitivity analysis, month 12 response was lower in the H. pylori-positive cohort (55.1% vs. 68.4%, p = 0.03). Sustained complete symptom resolution occurred in 25.5% (24/94) of patients after successful eradication and 19.6% (20/102) of H. pylori-negative patients (p = 0.32). Conclusions: H. pylori infection was significantly more prevalent in the EPS phenotype, supporting the biological heterogeneity of Rome IV functional dyspepsia. Sustained complete symptom resolution occurred in 25.5% after successful eradication and 19.6% in the H. pylori-negative cohort. Despite successful eradication in 96.4% per protocol and 83.5% by intention to treat, no clear symptomatic advantage over the H. pylori-negative cohort was demonstrated. Differences in phenotype distribution, treatment exposure, and follow-up completeness limit direct comparisons and preclude conclusions of equivalence or attribution of symptom resolution to eradication alone.