Heritability and Clinical Determinants of Serum Indoxyl Sulfate and p-Cresyl Sulfate, Candidate Biomarkers of the Human Microbiome Enterotype

Abstract

BackgroundIndoxyl 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 DesignInformation 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).ResultsSerum 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.LimitationsFamily studies cannot provide conclusive evidence for a genetic contribution, as confounding by shared environmental effects can never be excluded.ConclusionsThe 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.

Plasma metabolite profiles in children with current asthma

“…[34] Gut microbes have long been hypothesized to interact with the immune system in ways that may alter risk of allergies and asthma, and a number of publications now show compositional differences in the gut microbiome when allergic disease risk factors or allergic disease phenotypes are present. [31–34] It has been hypothesized that p-cresol sulfate may indicate a gut microbiome enterotype dominated by Bacteroides ,[34] a genera containing multiple taxa including B. Fragilis , a species with strong experimental evidence for restoring Th1/Th2 imbalance. [35] While our observed association between p-cresol sulfate and asthma status is intriguing, further research is required to uncover the connection between the gut microbiome, the circulating metabolome, and their combined relationship to asthma.…”

“…p-cresol sulphate is a microbial metabolite that may reflect gut microbiome composition. 32 Gut microbes have long been hypothesized to interact with the immune system in ways that may alter risk of allergies and asthma, and a number of publications now show compositional differences in the gut microbiome when allergic disease risk factors or allergic disease phenotypes are present. [33][34][35][36][37][38] It has been hypothesized that p-cresol sulphate may indicate a gut microbiome enterotype dominated by Bacteroides, 32 and asthma status is intriguing, further research is required to uncover the connection between the gut microbiome, the circulating metabolome, and their combined relationship to asthma.…”

Linking gut microbiota to cardiovascular disease and hypertension: Lessons from chronic kidney disease

“…Concentrations of PCS and IndS increase along the progression of CKD [32][33][34], both as a consequence of decreased elimination and increased production [35], to reach concentration in patients with ESRD are 10-50 fold higher than in healthy controls. Concentrations of PCS and IndS also rise with ageing [36].…”

“…However also in individuals with preserved kidney function, clear associations between PCS and IndS concentrations and cardiovascular endpoints have been reported. E.g., in a population-based study, the prevalence of hypertension increased along PCS and IndS quartiles [36]. Increased exposure to PCS and IndS may be hypothezised to be in the causal pathway between a diet rich in red meat and poor renal [49] and cardiovascular outcomes.…”

Unsupervised integration of multimodal dataset identifies novel signatures of health and disease

“…In addition, we observed novel associations between the metabolite p---cresol sulfate (pCS) and the microbiome genus Intestinimonas as well as an unclassified genus in the Erysipelotrichaceae family (p = 2.92E---24 and p = 2.98E---20 respectively; Figure 2B). pCS is a known microbial metabolite 14,15 that is associated with accelerated cardiovascular disease and renal disease progression, and is considered a potential uremic toxin 14,[16][17][18] . It is a sulfated phenolic compound generated in the colon by the bacterial fermentation of tyrosine.…”