Proteomic signatures of a microbiota-supportive dietary pattern are associated with reduced risk of inflammatory bowel disease

Environmental factors play an important role in the natural history of Inflammatory bowel disease (IBD). As a key modifiable environmental factor, diet profoundly influences gut microbiota, mucosal barrier integrity, and host immunity, making dietary strategies an attractive target for IBD prevention and management. Nevertheless, the potential of microbiota-supportive dietary strategies for reducing disease incidence remains unclear. Furthermore, the proteomic signatures linking such a dietary pattern to IBD risk require further exploration. We examined the association between adherence to a microbiota-supportive dietary pattern, quantified using the Dietary Index for Gut Microbiota (DI-GM), and incident IBD in a prospective cohort ( n = 208,143). High-throughput plasma proteomic data from a subset ( n = 21,919) were further integrated to identify diet-associated circulating proteins, followed by exploratory mediation analysis to investigate candidate proteomic signatures underlying the observed association. Over a mean follow-up of 10.77 years, higher adherence to the microbiota-supportive dietary pattern was associated with a 16% lower risk of incident IBD compared with lower adherence. The inverse association was more pronounced for ulcerative colitis (UC), whereas no statistically significant association was observed for Crohn’s disease (CD). Proteomic profiling identified 429 plasma proteins associated with the microbiota-supportive dietary pattern, primarily enriched in immune-inflammatory responses, cytokine-mediated signaling, and tissue repair processes. Exploratory mediation analysis identified 9 proteins with nominal mediation signals for the diet-IBD association, however, none remained significant after FDR correction ( q < 0.05), indicating exploratory findings. Higher adherence to the microbiota-supportive dietary pattern was associated with a modestly lower incidence of IBD, primarily UC. The identified plasma protein signatures are exploratory and require validation in studies incorporating temporally ordered dietary, proteomic, and direct microbiome measurements.