Dietary Modulation of The Human Small Intestine Metabolome and Microbiome

The human gastrointestinal tract (GIT) is central to human physiology, yet our understanding of the metabolite, microbial, and hormonal spatiotemporal dynamics in humans is limited. How these environments respond to complex food structures and homeostatic mechanisms they generate is unknown in humans. Here, we employ naso-enteral intubation to generate a spatiotemporally resolved, multimodal dataset spanning the oral cavity (salivary fluids), stomach, duodenum, and ileum of ten healthy participants. In a randomised study, participants consumed legume-based meals with different cellular structure (intact versus broken), revealing that food structure remarkedly altered metabolites and dominant microbe spatiotemporal trajectories in the GIT, driving distinct enteroendocrine hormone responses (GIP, GLP-1 and PYY). Broken-cell meals produced early glucose and maltose peaks in the GIT fluid associated with rapid GIP responses, whereas intact-cell meals elevated duodenal amino acids and ileal sugars, amino acids and formate, enhancing GLP-1 and PYY responses. We showed that quantified metabolites from the 1HNMR profiles and microbial profiles exhibit rapid spatial reorganisation, with evidence of transmission of oral bacterial strains to the ileum, where their abundance was associated with local metabolites and release of PYY. These findings suggest an underappreciated route for oral bacteria to reach the ileum via the food bolus and impact metabolism. Our unique dataset allows us to explore the interplay between local and systemic metabolism, microbiota, and host physiology, with implications for metabolic health. ISRCTN registration: ISRCTN18097249.