Letter: Disappearing Microbe, Emerging Disease? Nuancing the Protective Effects of Helicobacter pylori Against Eosinophilic Oesophagitis

Abstract

We commend Spinelli et al. [1] for their comprehensive meta-analysis of 19 studies encompassing 1.7 million subjects, which substantially advances our understanding of Helicobacter pylori (Hp) infection's potential protective role against eosinophilic oesophagitis (EoE). Their findings demonstrate a notable 46% reduction in the odds of EoE development among Hp-exposed individuals. Notwithstanding the meticulous synthesis of existing data, several methodological refinements and research directions warrant consideration to further elucidate this intriguing epidemiological relationship.

First, stratification by Hp virulence factors and strain specificity could illuminate mechanistic insights. While the meta-analysis aggregated all Hp infections, growing evidence suggests strain-specific immunomodulatory effects—particularly cagA+ strains, which elicit more robust Th1 responses [2]. Subgroup analyses comparing cagA+ versus cagA− infections might reveal differential protection against EoE, as observed in other Th2-mediated conditions such as asthma [3]. Second, geographic heterogeneity warrants deeper exploration. Although Spinelli et al. [1] found comparable odds reductions in Eastern (odds ratio: 0.53) and Western (odds ratio: 0.52) cohorts, Hp infection prevalence diverged remarkably (43% vs. 14%, respectively). This paradox suggests region-specific confounders, such as genetic factors or endemic helminth infections synergising with Hp's immunoregulatory effects [4]. Regression models accounting for regional socioeconomic indices, sanitation standards and antibiotic stewardship could disentangle these interactions further. Third, temporality in the Hp–EoE relationship remains unresolved. The stronger inverse association in post-2019 studies (56% vs. 37% reduction) [1] is in accordance with EoE's rising incidence but raises questions about birth cohort effects [5]. Case–control studies nested within longitudinal birth cohorts could clarify whether early-life Hp acquisition may confer greater protection than adult exposure, as hypothesised for allergic diseases. Additionally, Mendelian randomisation studies using genetic variants as proxies for Hp susceptibility might better establish causality whilst minimising confounding [6]. Fourthly, the meta-analysis did not elaborate on mucosal cytokine profiles, transcriptomic alterations, or microbiome signatures associated with EoE and their potential modification by Hp infection. We further contend that non-invasive biomarkers of EoE, including autoantibodies and inflammatory mediators [7], warrant comprehensive investigation in relation to Hp. pylori status. Finally, within existing clinical trials involving EoE patients [8-10], it would be valuable to analyse the prevalence of Hp infection and to examine how it might influence therapeutic outcomes.

In conclusion, broadening investigations to encompass strain-specific effects, geospatial determinants, life course exposures, biomarkers and the potential confounding influence of Hp. pylori infection in clinical trials could transform the epidemiological signal highlighted by Spinelli et al. [1] into actionable biological insights and preventative strategies. Notably, the declining Hp prevalence resulting from eradication campaigns necessitates urgent translational research, including animal models that evaluate whether Hp-derived molecules mitigate eosinophilic oesophageal inflammation—potentially offering novel therapeutic approaches.