An oral tyrosine challenge test for functional phenotyping of microbiota-derived phenyl sulfate production.
Phenyl sulfate (PS), a gut microbiota-derived metabolite implicated in the pathogenesis of diabetic kidney disease, is generated through microbial conversion of dietary tyrosine to phenol, followed by hepatic sulfation via SULT1A1. We developed an oral tyrosine challenge test (OTyCT) to phenotype individual PS-producing capacity. Forty-eight healthy adults underwent a standardized tyrosine load with serial plasma PS levels measured over 48 h using LC-MS. OTyCT revealed substantial interindividual variability of PS production independent of baseline PS levels, highlighting marked heterogeneity in host-microbiome metabolic interactions. Sixteen participants in the highest tertile of the incremental area under the curve of PS were defined as high-PS producers. High PS producers exhibited distinct gut microbial signatures despite comparable abundances of known phenol-biosynthetic genes and host SULT1A1 genotypes. These findings suggest that susceptibility to PS-related complications may vary according to gut microbial profiles, supporting OTyCT as a practical tool for metabolic phenotyping and microbiome-informed precision nutrition. Clinical Trial registry name and registration number: Identification of P-Cresyl Sulfate Producer Phenotype by Oral Tyrosine Challenge Test: Interactions Among Diet, Gut Microbiota, and Host Genome, NCT04204174.