Uncovering the biological basis of probiotic non-response in preterm gut health (360G-Wellcome-329980_Z_25_Z)

This project aims to revolutionise probiotic therapy in preterm infants by uncovering why some individuals fail to respond to current treatments. Our unpublished data shows ‘non-response’ to treatment increases the risk of necrotising enterocolitis (NEC), an inflammatory bowel disease that represents a leading cause of death in preterm infants. The absence of specific maternal milk bioactive components and/or infant-related factors likely contribute. This will be investigated through three key aims: 1) Identify dietary and host factors associated with probiotic response, focusing on bioactive components in mother’s milk and infant immune/metabolic profiles. 2) Determine how diet and gut microbiome influence probiotic growth and function, using high- throughput microbial assays and metabolomics to test milk components and microbial interactions. 3) Mechanistically study host-microbe interactions using preterm intestinal organoids and a novel anaerobic co-culture system to assess how probiotics and milk components affect inflammation and gut health. The latter stages of the project will validate the results using other probiotics/cohorts and uncover the mechanisms using genetic manipulation approaches. This project leverages extensive biobank resources, advanced multi-omics, microbiology, and cutting-edge organoid models to generate fundamental discoveries. The outcomes will guide the development of personalised probiotic, prebiotic, and/or postbiotic therapies to improve preterm infant gut health.