Integrated metabolomic and genetic profiling implicate loss of docosahexaenoic acid in the link between ultra-processed foods and Crohn's disease.

BACKGROUND AND AIMS: Increased intake of ultra-processed food (UPF) may elevate the risk of Crohn's disease (CD), yet the biological mechanisms remain unexplored. We aimed to profile UPF-related metabolomic features linked to incident CD and localize key mediators.

METHODS

This study involved two parts: construction of a UPF metabolic signature in the discovery cohort (n=10,229, UK Biobank), with internal (n=91,306) and external validation (n=7,893, Whitehall-II Study), and validation of key metabolic drivers in two Western and one Eastern cohort (n=752, ONE-IBD). High-throughput metabolomics platforms measured circulating metabolites. Elastic net regression was applied to derive UPF metabolic signature, and key metabolites were prioritized by integrating multivariable regression, network-based clustering, prospective association analyses, and mediation analyses. We further explored genetic mechanisms by Mendelian randomization, colocalization, and gene-environment analyses.

RESULTS

A UPF metabolic signature of 73 metabolites was constructed and validated across cohorts (Spearman ρ: 0.20-0.25). More pronounced UPF metabolic signature was associated with increased CD risk (HRper SD=2.65, 95% CI 1.57-4.48). Within the identified metabolite cluster, docosahexaenoic acid (DHA) was among the most consistently prioritized metabolites, mediating 17.1% of the UPF-CD association. Validation in ONE-IBD supported DHA linking UPF to CD incidence. Mendelian randomization revealed a protective effect of DHA on CD (OR=0.70, 95% CI 0.60-0.81), and colocalization implicated rs174546 in FADS1 as key genetic locus.

CONCLUSION

Our findings suggest lower circulating DHA may represent one metabolic pathway linking UPF intake to increased CD risk, apart from additive harm to metabolic depletion. This highlights potential targets for precision nutrition in CD prevention in future trials.