Functional dyspepsia (FD) is a chronic upper gastrointestinal (GI) disorder affecting over 7% of the population worldwide [1]. It is incompletely understood, but likely multifactorial pathophysiology complicates accurate diagnosis and effective treatment selection [2]. This lack of cost-effective therapeutic options results in high healthcare costs, implying a substantial economic burden [3]. Two subgroups, comprising postprandial distress syndrome (PDS) with predominant meal-related complaints and epigastric pain syndrome (EPS) with painful symptoms, can be distinguished as proposed by the Rome working group based on symptomatology, while an overlap between both also exists. By definition, no evidence of organic or structural disease explaining the symptoms is found during routine examination, including endoscopic or histological evaluation [4]. Following recent population-based evidence describing an important role of bidirectional gut–brain communication in FD pathophysiology [5], previously known functional GI disorders are now termed disorders of gut–brain interaction (DGBI), thereby better-reflecting pathophysiology [6].

Although gastric motility and sensitivity are altered in a substantial subgroup of patients, they are only poorly linked to the onset or worsening of symptoms [7]. While therapies directed against these disturbances, including acid-suppressive and prokinetic drugs, still remain the first treatment option, their (long-term) use has been contested due to lack of efficiency and various side effects, such as microbial dysregulation in case of proton pump inhibitors (PPI) [7,8] and cardiac or neurological side effects in case of specific prokinetics [9].

Over the last two decades, there has been decreasing support for the traditional paradigm of a primary gastric pathophysiology in FD with duodenal immune activation repeatedly being described in FD patients by different groups in various geographic areas [10]. Together with the involvement of duodenal microbial alterations [11], this reinforces the concept of an altered duodenal micro-environment as a major pathophysiological mechanism in FD [5,12], which could be targeted by a new spectrum of therapeutic approaches.

In this review, we summarize the existing treatment options for FD, classically targeting gastric abnormalities, before addressing the latest advances in FD pathophysiology research. We discuss the potential benefit of therapeutic interventions targeting duodenal alterations, including inflammation- or microbiota-based interventions in FD, and how these can offer renewed hope for FD patients through pathophysiology instead of symptom-based treatment selection.