# Indoxyl sulfate

Indoxyl sulfate, also known as 3-indoxylsulfate and 3-indoxylsulfuric acid, is a metabolite of dietary L-tryptophan that acts as a cardiotoxin and uremic toxin. High concentrations of indoxyl sulfate in blood plasma are known to be associated with the development and progression of chronic kidney disease and vascular disease in humans. As a uremic toxin, it stimulates glomerular sclerosis and renal interstitial fibrosis.

## Biosynthesis

Indoxyl sulfate is a metabolite of dietary L-tryptophan that is synthesized through the following metabolic pathway:
    L-tryptophan → indole → indoxyl → indoxyl sulfate
Indole is produced from L-tryptophan in the human intestine via tryptophanase-expressing gastrointestinal bacteria. Indoxyl is produced from indole via enzyme-mediated hydroxylation in the liver; in vitro experiments with rat and human liver microsomes suggest that the CYP450 enzyme CYP2E1 hydroxylates indole into indoxyl. Subsequently, indoxyl is converted into indoxyl sulfate by sulfotransferase enzymes in the liver; based upon in vitro experiments with recombinant human sulfotransferases, SULT1A1 appears to be the primary sulfotransferase enzyme involved in the conversion of indoxyl into indoxyl sulfate.
* Tryptophan metabolism by human gut microbiota (vte)
* Tryptophan
* Clostridium sporogenes
* Lacto- bacilli
* Tryptophanase- expressing bacteria
* IPA
* I3A
* Indole
* Liver
* Brain
* IPA
* I3A
* Indole
* Indoxyl sulfate
* AST-120
* AhR
* Intestinal immune cells
* Intestinal epithelium
* PXR
* Mucosal homeostasis: ↓TNF-α ↑Junction protein- coding mRNAs
* L cell
* GLP-1
* T J
* Neuroprotectant: ↓Activation of glial cells and astrocytes ↓4-Hydroxy-2-nonenal levels ↓DNA damage –Antioxidant –Inhibits β-amyloid fibril formation
* Maintains mucosal reactivity: ↑IL-22 production
* Associated with vascular disease: ↑Oxidative stress ↑Smooth muscle cell proliferation ↑Aortic wall thickness and calcification
* Associated with chronic kidney disease: ↑Renal dysfunction –Uremic toxin
* Kidneys
* This diagram shows the biosynthesis of bioactive compounds (indole and certain other derivatives) from tryptophan by bacteria in the gut. Indole is produced from tryptophan by bacteria that express tryptophanase. Clostridium sporogenes metabolizes tryptophan into indole and subsequently 3-indolepropionic acid (IPA), a highly potent neuroprotective antioxidant that scavenges hydroxyl radicals. IPA binds to the pregnane X receptor (PXR) in intestinal cells, thereby facilitating mucosal homeostasis and barrier function. Following absorption from the intestine and distribution to the brain, IPA confers a neuroprotective effect against cerebral ischemia and Alzheimer's disease. Lactobacillaceae (Lactobacillus s.l.) species metabolize tryptophan into indole-3-aldehyde (I3A) which acts on the aryl hydrocarbon receptor (AhR) in intestinal immune cells, in turn increasing interleukin-22 (IL-22) production. Indole itself triggers the secretion of glucagon-like peptide-1 (GLP-1) in intestinal L cells and acts as a ligand for AhR. Indole can also be metabolized by the liver into indoxyl sulfate, a compound that is toxic in high concentrations and associated with vascular disease and renal dysfunction. AST-120 (activated charcoal), an intestinal sorbent that is taken by mouth, adsorbs indole, in turn decreasing the concentration of indoxyl sulfate in blood plasma.

## Clinical significance

Occasionally in urinary tract infections, bacteria produce indoxyl phosphatase which splits indoxyl sulfate forming indigo and indirubin creating dramatic purple urine. Indoxyl sulfate is also a product of indole metabolism, which is produced from tryptophan by intestinal flora, such as Escherichia coli.