Indoxyl sulfate (IS) has been implicated in the pathogenesis of cardiovascular diseases. IS is converted from indole, a metabolite of dietary tryptophan through the action of gut microbial tryptophanase, by two hepatic enzymes: CYP2E1 and SULT1A1. We hypothesized that the effect of tryptophan intake on IS production might differ from person to person. We enrolled 72 healthy persons (33 ± 7 years; 54.2% women) to undergo an oral tryptophan challenge test (OTCT), in which 7 blood samples were collected at 0, 4, 8, 12, 24, 36, and 48 h following oral administration of L-tryptophan 2000 mg. We observed high interindividual variability of IS production in the response to an OTCT. Twenty-four subjects in the lowest tertile of the baseline-adjusted area under the curve of IS were defined as low-IS producers, whereas 24 subjects in the highest tertile were defined as high-IS producers. There was no significant difference in baseline characteristics or CYP2E1 and SULT1A1-SNP genotyping distributions between the two IS-producing phenotypes. However, distinct differences in gut microbial composition were identified. In addition, the abundance of tryptophanase was significantly higher in the high-IS producers than in the low-IS producers (P = 0.01). The OTCT may serve as personalized dietary guidance. High-IS producers are more likely to be at greater risk of cardiovascular diseases and may benefit from consuming foods low in tryptophan. Potential clinical applications of the OTCT in precision nutrition warrant further investigation.
© 2025. The Author(s).