PREILEAL · Decoding Ileal Metabolic Responses to Complex Dietary Structures for Precision Nutrition

The ileum is a pivotal yet under-characterized regulator of gut–brain metabolic signaling, rich in enteroendocrine cells (EECs) and a distinct facultative anaerobic microbiota. Its study has been constrained by the invasiveness of sampling, leaving major gaps in how food structure controls ileal metabolism. PREILEAL hypothesizes that plant-derived dietary assemblies undergo digestion and microbial fermentation in the ileum to yield metabolites that stimulate EEC hormone secretion directly or via microbiota-mediated pathways. To test this, we will build a unified causal pipeline: mechanistically defined food structure models of starch with varying digestion rates, biosynthesized plant cell wall analogues, and diverse polyphenol profiles (e.g. sourced from apple pomace, agricultural waste) will undergo standardized in vitro digestion (INFOGEST); the resulting chyme will be fermented with a novel synthetic ileal microbial consortium (SIMIC) to generate time-resolved metabolomic profiles (NMR, MS); these outputs will be applied to advanced transepithelial enterocyte–EEC co-cultures to quantify glucose transport, barrier integrity, and hormone release. Statistically identified drivers will be validated in vivo in mice, aligning ileal metabolic kinetics with systemic hormone and gut–brain axis responses. PREILEAL will deliver the first open-access, assay-ready framework for ileal nutrient sensing, including a metabolite atlas, validated EEC activation signatures, and a standardized causal model that repositions the ileum as a tractable target for precision nutrition. By pioneering a predictive in vitro screening platform linking dietary structures to host response, this project will reduce reliance on animal models and advance precision nutrition strategies for mitigating cardiometabolic disease through an integrative methodology spanning food chemistry, ileal microbiology, and translational physiology.