(EA02-08-25) Metabolomic Biomarkers of Diet-Host-Gut Microbiome Interactions Are Associated With Energy Balance

Scientific conference where the work was recently presented: Central Florida Triangle Metabolism Meeting

Date on which the work was previously presented at the scientific conference listed: March 7, 2025

Objectives: Preclinical and behavioral human data suggest that the gut microbiota partly mediates the effects of diet on energy balance, a key driver of obesity. Metabolomics—a functional readout of microbiome modulation—can help identify biomarkers and putative mechanisms by which gut microbes exert their effects. We previously demonstrated that a high-fiber Microbiome Enhancer Diet (MBD) fed at energy balance decreased energy absorption and increased microbial biomass relative to a calorie-matched, fiber-poor Western Diet (WD). The two diets reprogrammed the gut microbiome, with the WD “starving” the gut microbiota. We aimed to identify metabolic signatures of MBD and WD feeding and potential 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 volunteers 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 altered in the feces, fasting serum, and/or urine that have links to obesity, mucin degradation, and ketogenesis may serve as putative biomarkers of a “fed” (MBD) or a “starved” (WD) gut microbiota. 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, suggestive of negative energy balance and fat utilization.

Conclusions: Diets discordant in microbiota-accessible substrates distinctly altered metabolomic signatures associated with obesity/energy balance and substrate utilization. These findings provide testable hypotheses for unveiling causal pathways linking diet-microbiota co-metabolism to energy absorption and obesity.

Funding Sources: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (R01DK105829).