Impact of a 7-day homogeneous diet on interpersonal variation in human gut microbiomes and metabolomes

Gut microbiota metabolism of dietary compounds generates a vast array of microbiome-dependent metabolites (MDMs), which are highly variable between individuals. The uremic MDMs (uMDMs) phenylacetylglutamine (PAG), p-cresol sulfate (PCS), and indoxyl sulfate (IS) accumulate during renal failure and are associated with poor outcomes. Targeted dietary interventions may reduce toxic MDM generation; however, it is unclear if inter-individual differences in diet or gut microbiome dominantly contribute to MDM variance. Here, we use a 7-day homogeneous average American diet to standardize dietary precursor availability in 21 healthy individuals. During dietary homogeneity, the coefficient of variation in PAG, PCS, and IS (primary outcome) did not decrease, nor did inter-individual variation in most identified metabolites; other microbiome metrics showed no or modest responses to the intervention. Host identity and age are dominant contributors to variability in MDMs. These results highlight the potential need to pair dietary modification with microbial therapies to control MDM profiles. [Display omitted] •Diet homogeneity did not decrease inter-individual variability in uremic MDMs•Homogeneous diet results in reduction of interpersonal variation in hippuric acid•Host identity and age, but not diet, are dominant contributors to variability in MDMs Guthrie et al. determine the extent to which diet or the gut microbiome contributes to interpersonal variation in microbiome-dependent metabolites that are high priority targets of nutritional strategies to minimize levels. Diet homogeneity decreases inter-individual variability in hippurate but not key uremic solutes phenylacetylglutamine, p-cresol sulfate, and indoxyl sulfate.