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.

膳食化合物的肠道微生物群代谢产生大量微生物组依赖性代谢物 (MDM)，这些代谢物在个体之间差异很大。尿毒症 MDMs (uMDMs) 苯乙酰谷氨酰胺 (PAG), p甲酚硫酸盐 (PCS) 和硫酸吲哚酚 (IS) 在肾功能衰竭期间蓄积并与不良预后相关。有针对性的饮食干预可能会减少有毒 MDM 的产生；然而，尚不清楚饮食或肠道微生物组的个体差异是否主要导致 MDM 差异。在这里，我们使用 7 天同质平均美国饮食来标准化 21 名健康个体的膳食前体可用性。在饮食同质化期间，PAG、PCS 和 IS（主要结果）的变异系数没有降低，大多数已鉴定代谢物的个体间变异也没有降低；其他微生物组指标显示对干预没有反应或反应不大。主机身份和年龄是 MDM 可变性的主要贡献者。