P-Cresol Sulfate

What is p-Cresol Sulfate?

P-Cresol sulfate is commonly known as a uremic toxin and is derived from the secondary metabolism of p-cresol¹. Uremic toxins can be divided into three categories: 1) water-soluble, non-protein binding, low molecular weight compounds, 2) larger molecular weight compounds, and 3) protein binding, low molecular weight compounds. P-cresol sulfate belongs to the third group of uremic toxins, and due to strong protein binding, it is difficult to remove through dialysis².

Notably, p-Cresol sulfate is an important biomarker for chronic kidney disease and can accumulate in various organs. Uremic toxins like p-Cresol sulfate can trigger inflammatory responses and induce oxidative stress, thereby exacerbating renal damage.

P-Cresol sulfate is also a tyrosine metabolite produced by certain members of the gut microbiome³. In chronic kidney disease, increased production of P-Cresol sulfate in the gut, along with decreased clearance from the kidneys, results in toxicity that can affect multiple organs in the body.

P-Cresol Sulfate and cardiovascular health

Considering the close relationship between chronic kidney disease, metabolic health, and adverse cardiovascular outcomes, it is not surprising that p-Cresol sulfate could play a significant role in modulating overall metabolic health. Indeed, researchers have demonstrated that individuals with high levels of serum p-Cresol sulfate are at an increased risk for cardiovascular disease⁴. However, results can vary; one report found that serum levels of P-cresol sulfate were elevated in obese men while urine levels were decreased⁵.

Other studies have demonstrated no association between p-cresol sulfate itself and cardiovascular outcomes; however, there is an increased risk of cardiac death in individuals with low serum albumin (another indicator of kidney health) and high levels of p-cresol sulfate⁶.

P-Cresol Sulfate and gastrointestinal health

The production of p-Cresol sulfate gut microbes combined with decreased elimination during chronic kidney disease can cause severe organ damage. Several recent reports have begun to uncover the relationship between gastrointestinal health, chronic kidney disease, and p-Cresol sulfate. In one study using cats with chronic kidney disease, researchers found decreased fecal bacterial diversity associated with increased levels of uremic toxins such as p-Cresol sulfate⁷.

Others have identified a potential mechanism where chronic kidney disease triggers increased inflammation that breaks down epithelial tight junctions. Subsequently, gut-derived p-Cresol sulfate then diffuses through the “leaky gut” and induces widespread systemic inflammation⁸.

P-Cresol Sulfate and neuroscience

Type 1 diabetes is commonly known as a disease affecting peripheral physiology. However, recent data have identified a phenomenon known as gut-brain dysbiosis, where changes in gastrointestinal and metabolic health can directly affect the central nervous system.

One aspect of these changes is brain insulin resistance, where the central nervous system fails to effectively regulate insulin signaling. Interestingly, uremic toxins like p-Cresol sulfate can also have an effect on the brain. In one report examining lean vs. obese mice, researchers found increased levels of p-Cresol sulfate in the cerebrospinal fluid and brain tissue of obese mice. Furthermore, p-Cresol sulfate alters central insulin receptor function by increasing insulin receptor activation and downstream kinases⁹.

P-Cresol Sulfate and drug development

As a uremic toxin, p-Cresol sulfate levels have been useful in evaluating drug dosage during pharmaceutical development. One report investigated the relationship between urinary metabolite profiles and a widely used analgesic, acetaminophen. The findings revealed that individuals with high urinary levels of p-Cresol sulfate exhibited reduced efficiency in the sulfonation process of acetaminophen metabolism. In other words, p-Cresol sulfate competes with the body’s ability to metabolize acetaminophen efficiently, leading to changes in dose requirements for individuals with chronic kidney disease¹⁰.

References

1. National Library of Medicine, National Center for Biotechnology Information (2023). PubChem Compound Summary for p-Cresol sulfate (CID 4615423).
2. Liu WC, Tomino Y, and Lu KC. Impacts of Indoxyl Sulfate and p-Cresol Sulfate on Chronic Kidney Disease and Mitigating Effects of AST-120. Toxins (Basel) 2018;10(9):367.
3. Pascal Andreu V, Augustijn HE, Chen L et al. gutSMASH predicts specialized primary metabolic pathways from the human gut microbiota. Nat Biotechnol 2023.
4. Meijers BK, Bammens B, De Moor B et al. Free p-cresol is associated with cardiovascular disease in hemodialysis patients. Kidney Int 2008;73(10):1174–1180.
5. Yu HT, Fu XY, Xu B et al. Untargeted metabolomics approach (UPLC-Q-TOF-MS) explores the biomarkers of serum and urine in overweight/obese young men. Asia Pac J Clin Nutr 2018;27(5):1067–1076.
6. Shafi T, Sirich TL, Meyer TW et al. Results of the HEMO Study suggest that p-cresol sulfate and indoxyl sulfate are not associated with cardiovascular outcomes. Kidney Int 2017;92(6):1484–1492.
7. Summers SC, Quimby JM, Isaiah A et al. The fecal microbiome and serum concentrations of indoxyl sulfate and p-cresol sulfate in cats with chronic kidney disease. J Vet Intern Med 2019;33(2):662–669.
8. Lau WL, Kalantar-Zadeh K, and Vaziri ND. The Gut as a Source of Inflammation in Chronic Kidney Disease. Nephron 2015;130(2):92–98.
9. Leboucher A, Rath M, and Kleinridders A. Increased uremic toxins in cerebrospinal fluid of obese mice cause insulin resistance. Diabetologie und Stoffwechsel 2018;13(S 01):S21.
10. Clayton TA, Baker D, Lindon JC et al. Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism. Proc Natl Acad Sci U S A 2009;106(34):14728–14733.