Heritability and clinical determinants of serum indoxyl sulfate and p-cresyl sulfate, candidate biomarkers of the human microbiome enterotype

Abstract

Background: Indoxyl sulfate and p-cresyl sulfate are unique microbial co-metabolites. Both co-metabolites have been involved in the pathogenesis of accelerated cardiovascular disease and renal disease progression. Available evidence suggests that indoxyl sulfate and p-cresyl sulfate may be considered candidate biomarkers of the human enterotype and may help to explain the link between diet and cardiovascular disease burden.

Objective and design: Information on clinical determinants and heritability of indoxyl sulfate and p-cresyl sulfate serum is non-existing. To clarify this issue, the authors determined serum levels of indoxyl sulfate and p-cresyl sulfate in 773 individuals, recruited in the frame of the Flemish Study on Environment, Genes and Health Outcomes (FLEMENGHO study).

Results: Serum levels of indoxyl sulfate and p-cresyl sulfate amounted to 3.1 (2.4-4.3) and 13.0 (7.4-21.5) μM, respectively. Regression analysis identified renal function, age and sex as independent determinants of both co-metabolites. Both serum indoxyl sulfate (h2 = 0.17) and p-cresyl sulfate (h2 = 0.18) concentrations showed moderate but significant heritability after adjustment for covariables, with significant genetic and environmental correlations for both co-metabolites.

Limitations: Family studies cannot provide conclusive evidence for a genetic contribution, as confounding by shared environmental effects can never be excluded.

Conclusions: The heritability of indoxyl sulfate and p-cresyl sulfate is moderate. Besides genetic host factors and environmental factors, also renal function, sex and age influence the serum levels of these co-metabolites.

Figure 1. Distribution of indoxyl sulfate and p-cresyl sulfate.

The vertical line is the limit of quantification.

Figure 2. Indoxyl sulfate and p-cresyl sulfate according to age.

The dots indicate the geometric means of indoxyl sulfate (IndS) and p-cresyl sulfate (PCS) in decades of age (<30 years, 30–39 years, 40–49 years, 50–59 years, 60–69 years and ≥70 years). The numbers above the horizontal axis are the number of subjects in the various age classes. The curves are calculated from a regression model with log IndS and log PCS as dependent variables and age and age-squared as independent variables. For IndS the P-values of the linear and squared terms were 0.035 and 0.0024 respectively. The corresponding P-values for PCS were 0.070 and 0.004.