Efficacy of gut-brain neuromodulators in functional esophageal disorders: a systematic review

Patients with functional esophageal disorders exhibit symptoms such as chest pain, heartburn, dysphagia, globus sensation, or reflux hypersensitivity in the absence of structural abnormalities. This is characterized by dysregulated gut-brain interactions and visceral hypersensitivity.

A systematic search of the MEDLINE, EMBASE, Web of Science and the Cochrane central register of controlled trials databases was performed to December 31, 2025. Relevant randomized controlled trials (RCT) reporting the effects of gut-brain neuromodulator (GBN) therapy on functional chest pain (FCP), functional heartburn (FH), reflux hypersensitivity (RH), functional dysphagia (FD), and globus were analyzed.

Among 2538 screened records, 29 RCTs were included. Neuromodulators provided symptom relief in 18-67% of patients with FCP, with 52-71% achieving ≥ 50% symptom reduction. Moreover, 46-80% of patients experienced a globus reduction of more than 50%. In contrast, the number of included studies for RH and FH was small, and the evidence was inconsistent. In healthy individuals, human experimental models indicated that central or local sensory-modulatory pathways can mitigate acid-induced hyperalgesia, thereby offering a promising therapeutic strategy for RH. Convincing evidence to support the use of GBN in the treatment of FD is lacking. However, its effects on normal human esophageal motility also provides strategies for drug selection, although these outcome indicators vary substantially.

GBNs can alleviate FCP, improve globus, and to some extent regulate esophageal sensation. However, their effectiveness for FD, FH, and RH remains controversial. Accordingly, future well-designed and phenotype-specific RCTs are required to establish the role of GBNs in clinical management.