FODMAP intake, gut microbiota, and gastroesophageal reflux disease: a triangulated study of Mendelian randomization and clinical validation.

BACKGROUND

Dietary factors related to fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) and gut microbiota may influence gastroesophageal reflux disease (GERD), but causal evidence and clinical consistency remain uncertain.

OBJECTIVE

We tested whether FODMAP-related and GERD-relevant dietary traits influence GERD risk using Mendelian randomization (MR), and whether gut microbiota mediate these associations.

METHODS

We integrated UK Biobank dietary GWAS, MiBioGen microbiota GWAS, and FinnGen GERD summary statistics using inverse-variance weighted MR, multivariable MR, Benjamini-Hochberg false discovery rate (BH-FDR) correction, MR-Steiger filtering, and two-step mediation analysis. A 525 matched-pair retrospective case-control cohort provided clinical validation.

RESULTS

After BH-FDR correction, genetically predicted cheese, cereal, oily fish, fresh/dried fruit, and salad/raw vegetables were associated with lower GERD risk (ORs, 0.46-0.77), whereas tea and poultry were associated with higher risk (ORs, 1.28-2.14). Microbiota-wide and mediation signals did not survive FDR correction. The oily fish-Erysipelatoclostridium indirect effect was small and statistically imprecise (indirect effect, -0.015; 95% CI, -0.034 to 0.005), corresponding to a mediated proportion of 4.1% (95% CI, -1.2 to 9.5%); therefore, it was interpreted as an exploratory signal rather than evidence of a confirmed microbial pathway. Clinical data directionally supported the main dietary signals: tea, poultry, processed meat, and sweets were associated with higher GERD risk (ORs, 1.04-1.19), while cheese, cereal, fruit, and oily fish were protective (ORs, 0.80-0.94).

CONCLUSION

Dietary associations with GERD were more robust than microbiota-associated signals. These findings suggest that oily fish-related dietary patterns may be associated with lower GERD risk, while exploratory analyses provide preliminary evidence that gut microbiota may contribute to these associations. Further studies are required to validate these potential biological pathways.