The causal impact of gut microbiota on allergic rhinitis mediated by cerebrospinal fluid metabolites: A study based on Mendelian randomization and mediation analysis.

In recent years, the role of gut microbiota (GM) in the pathogenesis of allergic diseases (ADs) has garnered increasing attention, yet the influence of the brain and its metabolites (such as cerebrospinal fluid [CSF] metabolites) remains unclear. This study aims to investigate whether GM mediates its effect on allergic rhinitis (AR) through CSF metabolites and to quantify this mediating effect, while systematically evaluating the causal relationships between brain functional networks/CSF metabolites and multiple ADs to elucidate the potential roles of brain-related factors in allergic mechanisms. Using large-scale genome-wide association study data, including GM (n = 7738), brain functional networks (n = 47,276), CSF metabolites (n = 291), and 7 categories of AD (Finnish R12 database), we applied Mendelian randomization (MR) for causal inference. Specifically, we performed: mediation MR to test the GM-CSF metabolites-AR pathway; and 2-sample MR to assess causal relationships between brain functional networks/CSF metabolites and ADs. Genetically predicted analyses revealed significant associations between GM and both CSF metabolites and AR. Mediation MR confirmed that Peptococcia abundance exerts a positive causal effect on AR (odds ratio [OR] = 1.55, 95% confidence interval [CI] = 1.23-1.95, P = .0002), which was partially mediated by CSF methyl succinoyl-carnitine levels, with a mediation proportion of 9.02%. Extended analyses indicated that CSF metabolites are positively associated with allergic contact dermatitis and pollen allergy: specifically, methyl succinoyl-carnitine levels correlated positively with pollen allergy, and indoleacetate levels with allergic contact dermatitis (both significant after false discovery rate correction). Brain functional network analyses showed allergic urticaria was negatively correlated with 9 functional networks, including the occipital-precuneus and postcentral gyrus. This study is the first, via MR, to demonstrate that GM may partially influence AR risk through CSF metabolites (e.g., methyl succinoyl-carnitine); concurrently, brain functional networks regulate specific ADs. These findings deepen understanding of the "gut-brain-immune" axis mechanism and provide new directions for future precise interventions targeting metabolites and neuroimmune pathways.