Urinary Indoxyl Sulfate in Children: Age-Related Decline and Its Association with Bacteroidota in the Gut Microbiota

Urinary indoxyl sulfate (IS), a gut microbiota-derived uremic toxin, is associated with the adult gut microbiota and is elevated in children with autism spectrum disorder. However, its age-related trajectory and association with microbiota in healthy children remain uncharacterized. Therefore, we aimed to elucidate age-related changes in urinary IS in healthy children and to investigate the potential utility of urinary IS as a surrogate marker for their gut microbiota. We measured urinary IS/creatinine (Cr) ratios and analyzed the fecal gut microbiota composition (16S rRNA gene sequencing) in 102 healthy Japanese children aged 5 months to 12 years. Associations were assessed using Spearman's correlation. An empirical age-adjustment model (inverse proportional) was developed to derive an age-adjusted IS/Cr ratio (actual/predicted), thereby removing the strong age dependence before re-evaluating correlations with gut microbiota. The unadjusted IS/Cr ratio showed a strong negative correlation with age (rs=-0.47, p<0.001) and declined markedly during early childhood, stabilizing at approximately 5 years. Weak correlations with microbiota metrics were observed before adjustment; however, the age-adjusted IS/Cr ratio showed no correlation with age (rs=-0.03, p=0.768). Notably, age adjustment revealed significant positive correlations between the IS/Cr ratio and the phylum Bacteroidota (rs=0.26, p=0.008) and strengthened the correlation with the genus Bacteroides (rs=0.31, p=0.002), associations that were not apparent before adjustment. Correcting for this age-dependent variation is crucial, after which the IS/Cr ratio can serve as a potential non-invasive surrogate marker reflecting the abundance of Bacteroidota, particularly the genus Bacteroides, in the pediatric gut microbiota.