Global metabolite profiling in feces, serum, and urine yields insights into energy balance phenotypes induced by diet-driven microbiome remodeling

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Background: Preclinical literature and behavioral human data suggest that diet profoundly impacts the human gut microbiome and energy absorption-a key determinant of energy balance. To determine whether these associations are causal, domiciled controlled feeding studies with precise measurements of dietary intake and energy balance are needed. Metabolomics-a functional readout of microbiome modulation-can help identify putative mechanisms mediating these effects. We previously demonstrated that a high-fiber, minimally processed Microbiome Enhancer Diet (MBD) fed at energy balance decreased energy absorption and increased microbial biomass relative to a calorie-matched fiber-poor, highly processed Western Diet (WD). Objective: To identify metabolic signatures distinguishing MBD from WD feeding and potential metabolomic mechanisms mediating the MBD-induced negative energy balance. Methods: We deployed global metabolomics in feces, serum, and urine using samples collected at the end of a randomized crossover controlled feeding trial delivering 22 days of an MBD and a WD to 17 persons without obesity. Samples were collected while participants were domiciled on a metabolic ward and analyzed using Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectroscopy. Linear mixed effects models tested metabolite changes by diet. Weighted gene network correlation analysis identified metabolite modules correlated with energy balance phenotypes. Results: Numerous metabolites consistently altered in the feces, fasting serum, and/or urine may serve as putative dietary biomarkers of MBD feeding. Fecal diet-microbiota co-metabolites decreased by an MBD correlated with reduced energy absorption and increased microbial biomass. An MBD shifted the urinary metabolome from sugar degradation to ketogenesis-evidence of negative energy balance. Conclusions: Precisely controlled diets disparate in microbiota-accessible substrates led to distinct metabolomic signatures in feces, fasting serum, and/or urine. These diet-microbiota co-metabolites may be biomarkers of a "fed" (MBD) or "starved" (WD) gut microbiota associated with energy balance. These findings lay the foundation for unveiling causal pathways linking diet-microbiota co-metabolism to energy absorption.

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