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Research Article: Dietary index for gut microbiota and risk of incident gastroesophageal reflux disease: a prospective cohort analysis integrating plasma proteomics in the UK Biobank

Date Published: 2026-07-07

Abstract:
Gastroesophageal reflux disease (GERD) is a common chronic digestive disorder, and diet is an important modifiable risk factor. The Dietary Index for Gut Microbiota (DI-GM) reflects dietary patterns considered favorable to the gut microbiota; however, the gut microbiome itself was not measured, and evidence on whether DI-GM is associated with GERD risk is limited. We aimed to evaluate the association between DI-GM and incident GERD and to explore potential intermediate pathways using mediation analysis and plasma proteomics. We included 133,915 UK Biobank participants free of GERD at baseline. DI-GM scores (range 0–14) were calculated from the Oxford WebQ 24-h dietary recall and grouped into four categories (0–3, 4, 5, ?6). Incident GERD was identified from the UK Biobank first-occurrence records (ICD-10 K21). Cox proportional hazards regression was complemented by restricted cubic spline (RCS), subgroup, and Cox weighted quantile sum (WQS) analyses, counterfactual mediation analysis, integrated plasma proteomics (Olink Explore 3072), and a range of sensitivity analyses. During a median follow-up of 13.6 years, 12,271 incident GERD cases occurred. In the fully adjusted model, each 1-point increase in DI-GM was associated with an approximately 4% lower hazard of GERD [hazard ratio (HR) 0.956, 95% CI 0.947–0.965; P < 0.001], and the highest DI-GM group (?6) had a lower hazard than the lowest (0–3) (HR 0.812, 95% CI 0.774–0.851; P for trend < 0.001). RCS analysis showed a modest inverse dose–response relationship that was most apparent at higher DI-GM scores, and WQS analysis indicated that the association was driven by a few key components rather than shared equally across the index. BMI (proportion mediated 21.43%) and phenotypic age acceleration (7.53%) both significantly mediated the association (both P < 0.001). Integrated proteomic analysis identified 13 shared proteins; the nine positively associated with DI-GM and inversely associated with GERD showed exploratory enrichment in neurodevelopment- and cell-adhesion-related processes. Higher DI-GM was associated with a lower incidence of medically attended GERD, with mediation analysis suggesting that BMI and biological aging may partly account for this association. Exploratory proteomic analyses identified shared protein correlates, including adiposity-related and, tentatively, neurodevelopment- and cell-adhesion-related proteins; these are hypothesis-generating and require confirmation. Because the gut microbiome was not measured, the diet–microbiota link remains inferential, and these findings should be interpreted as associations rather than established mechanisms.

Introduction:
Gastroesophageal reflux disease (GERD) is one of the most common chronic digestive disorders worldwide, with an estimated global prevalence of approximately 13% in adults and a continuing upward trend ( 1 ). GERD substantially impairs quality of life and is closely linked to esophagitis, Barrett's esophagus, and esophageal adenocarcinoma, contributing to a growing medical burden ( 2 ). Identifying modifiable risk factors for GERD is therefore of considerable public health importance. Diet is considered one of…

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