Skatol (3-Methylindol): the pathway in the body

Skatol (3-Methylindol) is part of the pathway “Protein fermentation in the colon”. This page shows the whole pathway; the station of Skatol (3-Methylindol) is highlighted.

Where this laboratory value sits: Skatole — 3-methylindole. The bacterial enzyme indoleacetate decarboxylase removes carbon dioxide from indole-3-acetic acid, producing skatole, which shapes the smell of stool. Some is absorbed, converted in the liver and excreted in urine. Source 9, 18

In brief

Protein fermentation is the bacterial breakdown of protein that reaches the colon undigested. It produces iso-fatty acids, indole, skatole and p-cresol; the gut wall and liver attach sulfate or glycine to some of them, and the kidneys excrete them in urine.

The pathway step by step

Each station states what the compound does there. Three signs: ↑ supplies — builds up or makes available · ↓ depletes — inhibits, consumes or withholds · ↕ both, depending on amount. Behind it stands what the statement rests on: established physiology, observed in studies, or contested. The signs do not grade; they name the direction.

1. Protein in the colon → BCAAs (Val, Leu, Ile) Bacteria split the protein into peptides and amino acids with their own proteases. Valine, leucine and isoleucine carry a branched carbon chain; they give rise to the iso-fatty acids. Source 5, 1↑ supplies The branched-chain amino acids supply the bacteria with carbon skeletons and energy. Their branched chain is kept during breakdown and reappears in the iso-fatty acids. established physiology Source 5, 4
   ⚖ When the balance tips

   too much — If more branched-chain amino acids are available in the colon, the bacteria form more iso-fatty acids.

   too little — If few are available, hardly any iso-fatty acids are formed; the short-chain fatty acids in stool then come almost entirely from carbohydrates.

   established physiology · Source 5, 1

2. Protein in the colon → Tryptophan Bacterial proteases Tryptophan carries an indole ring. Whatever is released in the colon is broken down by bacteria along several routes: to indole, to indole-3-acetic acid and on to skatole. Source 7, 6↑ supplies In the colon, tryptophan supplies the starting material for all bacterial indole compounds. Which of them are formed depends on which species with which enzymes live there. established physiology Source 7
   ⚖ When the balance tips

   too much — If more tryptophan reaches the colon, more indole, indole-3-acetic acid and skatole are formed.

   too little — If little arrives, few indole compounds are formed; most of the tryptophan has then already been absorbed in the small intestine.

   established physiology · Source 7, 6

3. Protein in the colon → Tyrosine Tyrosine carries a phenol ring. In the colon, gut bacteria break it down via 4-hydroxyphenylacetate to p-cresol; phenylalanine also yields phenolic breakdown products. Source 11, 6↑ supplies In the colon, tyrosine supplies the starting material for p-cresol and other phenols. Many bacterial families can begin this breakdown, only a few carry it all the way to p-cresol. established physiology Source 11, 6
   ⚖ When the balance tips

   too much — If more tyrosine reaches the colon, more phenols such as p-cresol are formed.

   too little — If little arrives, few phenols are formed; dietary tyrosine is then almost entirely absorbed in the small intestine.

   established physiology · Source 11, 2

4. BCAAs (Val, Leu, Ile) → Iso-fatty acids Deamination Bacteria remove the amino group from the branched-chain amino acids and shorten the skeleton. This gives isobutyrate from valine, isovalerate from leucine and 2-methylbutyrate from isoleucine. They are measured in stool. Source 5, 3↑ supplies Iso-fatty acids arise only from protein, not from fibre; they therefore indicate how much protein is being fermented. Gut cells can use them as fuel like other short-chain fatty acids. observed in studies Source 5, 2
   ⚖ When the balance tips

   too much — If more protein is fermented, iso-fatty acids rise with it; ammonia, phenols and indoles form alongside them. Their share increases from the proximal to the distal colon.

   too little — If little protein is fermented, for instance because plenty of fibre keeps the bacteria busy, few iso-fatty acids are formed.

   established physiology · Source 3, 2

5. Tryptophan → Indole Tryptophanase · Vitamin B6 (PLP) The bacterial enzyme tryptophanase splits tryptophan into indole, pyruvate and ammonia. It needs pyridoxal phosphate, the active form of vitamin B6. Escherichia coli and Bacteroides carry the enzyme. Source 7, 8↕ both, depending on amount Indole is a signalling molecule between bacteria and binds to the aryl hydrocarbon receptor (AhR) of gut cells. What passes into the blood is converted by the liver into indoxyl sulfate; the more indole, the more follows this route. observed in studies Source 7, 4
   ⚖ When the balance tips

   too much — If more indole is formed, more of it reaches the liver via the portal vein, and more indoxyl sulfate is produced.

   too little — If little indole is formed, for instance because few tryptophanase carriers live in the gut, little indoxyl sulfate is produced as well.

   established physiology · Source 7, 14

6. Tryptophan → Indole-3-acetic acid Indole-pyruvate route Other bacteria convert tryptophan via indole-3-pyruvate into indole-3-acetic acid. Some of it enters the blood and is excreted by the kidneys; some is broken down further in the gut to skatole. Source 7↕ both, depending on amount Like indole, indole-3-acetic acid binds to the AhR of gut and immune cells. At the same time it is the starting material for skatole; how much goes on depends on the bacteria carrying the enzyme IAD. observed in studies Source 7
   ⚖ When the balance tips

   too much — If more indole-3-acetic acid is formed, more is available for skatole formation and more enters the blood; the kidneys absorb it via the transporter OAT1 and excrete it.

   too little — If little is formed, skatole formation also stays low because its starting material is missing.

   observed in studies · Source 7, 15

7. Tyrosine → p-Cresol 4-HPA decarboxylase Bacteria break tyrosine down to 4-hydroxyphenylacetate. The enzyme 4-hydroxyphenylacetate decarboxylase, which works only without oxygen, removes carbon dioxide from it, producing p-cresol. Source 10, 11↓ depletes In cell culture, free p-cresol acts on the cells of the gut lining. The gut wall and liver rapidly attach sulfate; in the blood it is therefore present almost only as p-cresyl sulfate. observed in studies Source 11, 2
   ⚖ When the balance tips

   too much — If more p-cresol is formed, the gut wall has to link more of it with sulfate, and p-cresyl sulfate in the blood rises.

   too little — If little is formed, for instance because few bacteria carry the enzyme, p-cresyl sulfate also stays low.

   observed in studies · Source 11, 2

8. Polyphenols → Benzoic acid Bacterial enzymes Gut bacteria break polyphenols down step by step to benzoic acid. Benzoic acid also arrives with food as a preservative. It is absorbed and reaches the liver via the blood. Source 16↑ supplies Benzoic acid supplies the liver with the starting material for hippuric acid. It must first be bound to coenzyme A; then GLYAT attaches glycine. established physiology Source 16, 17
   ⚖ When the balance tips

   too much — If a lot of benzoic acid arrives, it ties up much coenzyme A in liver mitochondria until GLYAT passes it on with glycine; more glycine is used in the process.

   too little — If little arrives, the liver forms little hippuric acid, and coenzyme A and glycine remain free for other pathways.

   established physiology · Source 17

9. Indole-3-acetic acid → Skatole Indoleacetate decarb. The bacterial enzyme indoleacetate decarboxylase removes carbon dioxide from indole-3-acetic acid, producing skatole, which shapes the smell of stool. Some is absorbed, converted in the liver and excreted in urine. Source 9, 18↕ both, depending on amount In liver cells, skatole binds to the AhR and switches on genes for cytochrome P450 enzymes that break it down. The same enzymes can convert it into reactive intermediates. observed in studies Source 19, 18
   ⚖ When the balance tips

   too much — If more skatole is formed, stool smells stronger, and more of it reaches the liver, where it switches on the breakdown enzymes.

   too little — Without bacteria carrying the enzyme IAD, or without their starting material indole-3-acetic acid, hardly any skatole is formed; stool then smells weaker.

   observed in studies · Source 9, 19

10. Indole → Indoxyl sulfate CYP2E1, SULT1A1 · PAPS (sulfate donor) In the liver, mainly CYP2E1 oxidises indole to indoxyl. The sulfotransferase SULT1A1 attaches a sulfate group donated by PAPS. This forms indoxyl sulfate, which is measured in urine as indican. Source 12, 13↓ depletes In the blood, indoxyl sulfate is almost entirely bound to albumin. In cell culture and animal models it acts on kidney and vascular cells via the AhR and oxygen radicals; in humans the effect is not established. observed in studies Source 14
    ⚖ When the balance tips

    too much — If much indole forms in the gut, indoxyl sulfate rises in blood and urine. If the kidneys excrete more slowly, it stays longer in the blood, because albumin binding slows filtration.

    too little — If little indole is formed, little indoxyl sulfate is made; no task is known that would then go unfulfilled in the body.

    observed in studies · Source 14, 7

    Field of research — Indoxyl sulfate is studied in research on kidney and vascular disease. Source 14

11. p-Cresol → p-Cresyl sulfate SULT1A1 · PAPS (sulfate donor) Already in the gut wall and then in the liver, SULT1A1 links p-cresol with sulfate; a small part is attached to glucuronic acid. In the blood, p-cresyl sulfate is largely bound to albumin. Source 11↓ depletes The sulfate group makes p-cresol water-soluble and excretable. In cell culture and animal models, p-cresyl sulfate releases oxygen radicals in kidney and vascular cells; in humans this is not settled. observed in studies Source 11
    ⚖ When the balance tips

    too much — If more p-cresol is formed or the kidneys excrete more slowly, p-cresyl sulfate builds up in the blood; bound to albumin, it is barely filtered.

    too little — If little p-cresol is formed, p-cresyl sulfate also stays low; no task is known that would then go unfulfilled.

    observed in studies · Source 11

    Field of research — p-Cresyl sulfate is studied in research on kidney disease. Source 11

12. Benzoic acid → Hippuric acid GLYAT · Glycine, Coenzyme A In the mitochondria of liver and kidney, benzoic acid is bound to coenzyme A. The enzyme glycine N-acyltransferase (GLYAT) exchanges coenzyme A for glycine, producing hippuric acid. Source 16, 17↓ depletes Forming hippuric acid uses up glycine and frees coenzyme A again. In this way benzoic acid becomes water-soluble and leaves the body via the urine. established physiology Source 17, 16
    ⚖ When the balance tips

    too much — If more benzoic acid comes from the gut and food, hippuric acid in urine rises with it, as long as glycine and GLYAT keep up.

    too little — If little benzoic acid arrives, for instance because few polyphenols are fermented, little hippuric acid appears in the urine.

    established physiology · Source 16, 17

13. Indoxyl sulfate → Excretion in urine Because they are bound to albumin, these compounds are barely filtered. Kidney tubule cells absorb them from the blood via the transporters OAT1 and OAT3 and release them into the urine. Source 15, 14↓ depletes The kidney tubules actively remove indoxyl sulfate, p-cresyl sulfate, hippuric acid and indole-3-acetic acid from the blood. What appears in urine reflects formation in the gut and excretion at the same time. established physiology Source 14, 15
    ⚖ When the balance tips

    too much — If more is formed in the gut, the kidneys excrete correspondingly more, and the urine values rise.

    too little — If the kidney tubules excrete less, less appears in urine, and the compounds stay longer in the blood.

    established physiology · Source 14, 11

    Field of research — The excretion of these compounds is studied in research on kidney disease. Source 14, 11

14. Skatole → Excretion in urine Because they are bound to albumin, these compounds are barely filtered. Kidney tubule cells absorb them from the blood via the transporters OAT1 and OAT3 and release them into the urine. Source 15, 14↓ depletes The kidney tubules actively remove indoxyl sulfate, p-cresyl sulfate, hippuric acid and indole-3-acetic acid from the blood. What appears in urine reflects formation in the gut and excretion at the same time. established physiology Source 14, 15
    ⚖ When the balance tips

    too much — If more is formed in the gut, the kidneys excrete correspondingly more, and the urine values rise.

    too little — If the kidney tubules excrete less, less appears in urine, and the compounds stay longer in the blood.

    established physiology · Source 14, 11

    Field of research — The excretion of these compounds is studied in research on kidney disease. Source 14, 11

15. p-Cresyl sulfate → Excretion in urine Because they are bound to albumin, these compounds are barely filtered. Kidney tubule cells absorb them from the blood via the transporters OAT1 and OAT3 and release them into the urine. Source 15, 14↓ depletes The kidney tubules actively remove indoxyl sulfate, p-cresyl sulfate, hippuric acid and indole-3-acetic acid from the blood. What appears in urine reflects formation in the gut and excretion at the same time. established physiology Source 14, 15
    ⚖ When the balance tips

    too much — If more is formed in the gut, the kidneys excrete correspondingly more, and the urine values rise.

    too little — If the kidney tubules excrete less, less appears in urine, and the compounds stay longer in the blood.

    established physiology · Source 14, 11

    Field of research — The excretion of these compounds is studied in research on kidney disease. Source 14, 11

16. Hippuric acid → Excretion in urine Because they are bound to albumin, these compounds are barely filtered. Kidney tubule cells absorb them from the blood via the transporters OAT1 and OAT3 and release them into the urine. Source 15, 14↓ depletes The kidney tubules actively remove indoxyl sulfate, p-cresyl sulfate, hippuric acid and indole-3-acetic acid from the blood. What appears in urine reflects formation in the gut and excretion at the same time. established physiology Source 14, 15
    ⚖ When the balance tips

    too much — If more is formed in the gut, the kidneys excrete correspondingly more, and the urine values rise.

    too little — If the kidney tubules excrete less, less appears in urine, and the compounds stay longer in the blood.

    established physiology · Source 14, 11

    Field of research — The excretion of these compounds is studied in research on kidney disease. Source 14, 11

Further stations

• Protein in the colon — undigested remnants Part of dietary protein is not fully broken down and absorbed in the small intestine. It reaches the colon together with protein from shed cells, mucus and digestive enzymes. Source 1, 4↑ supplies Protein arriving in the colon supplies the bacteria there with nitrogen and amino acids. They use them to build their own protein, to gain energy and for further breakdown pathways. established physiology Source 4, 1
  ⚖ When the balance tips

  too much — If more protein reaches the colon, the bacteria ferment more of it. This happens mainly in the distal colon, where the sugars from dietary fibre have largely been used up.

  too little — If little protein arrives, few putrefaction products are formed; the bacteria then draw their nitrogen mainly from mucus and shed cells.

  established physiology · Source 2, 3

• Polyphenols — from fruit, tea, coffee Polyphenols are plant compounds found in fruit, vegetables, tea and coffee. Many of them reach the colon unchanged, where bacteria break them into smaller acids. Source 16↑ supplies Polyphenols supply the bacteria with starting materials from which benzoic acid, among others, is formed. They are the main source of hippuric acid, not protein. established physiology Source 16
  ⚖ When the balance tips

  too much — If more polyphenols reach the colon, the bacteria form more benzoic acid, and more hippuric acid appears in the urine.

  too little — If few arrive, little benzoic acid is formed; hippuric acid then comes mainly from benzoic acid used as a preservative in foods.

  established physiology · Source 16

Cofactors in this pathway

• Tryptophan — Starting material from which bacteria form indole, indole-3-acetic acid and skatole Source 7In the ORY catalogue as a laboratory value: Tryptophan
• Tyrosine — Starting material from which bacteria form p-cresol via 4-hydroxyphenylacetate Source 11, 10In the ORY catalogue as a laboratory value: Tyrosin
• Leucine — Starting material from which bacteria form isovalerate Source 5In the ORY catalogue as a laboratory value: Leucin
• Valine — Starting material from which bacteria form isobutyrate Source 5In the ORY catalogue as a laboratory value: Valin
• Isoleucine — Starting material from which bacteria form 2-methylbutyrate Source 5In the ORY catalogue as a laboratory value: Isoleucin
• Vitamin B6 (PLP) — As pyridoxal phosphate, cofactor of bacterial tryptophanase, which splits tryptophan into indole Source 8In the ORY catalogue as a laboratory value: Vitamin B6
• Glycine — Attached by GLYAT to benzoyl-CoA, forming hippuric acid Source 17, 16In the ORY catalogue as a laboratory value: Glycin
• Sulfate (PAPS) — PAPS supplies SULT1A1 with the sulfate group for indoxyl sulfate and p-cresyl sulfate Source 13, 11

Sources

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3. Macfarlane GT, Gibson GR, Cummings JH. Comparison of fermentation reactions in different regions of the human colon. J Appl Bacteriol 1992 · PubMed 1541601
4. Blachier F. Amino Acid-Derived Bacterial Metabolites in the Colorectal Luminal Fluid: Effects on Microbial Communication, Metabolism, Physiology, and Growth. Microorganisms 2023 · PubMed 37317289
5. Ríos-Covián D, Ruas-Madiedo P, Margolles A et al. Intestinal Short Chain Fatty Acids and their Link with Diet and Human Health. Front Microbiol 2016 · PubMed 26925050
6. Smith EA, Macfarlane GT. Formation of Phenolic and Indolic Compounds by Anaerobic Bacteria in the Human Large Intestine. Microb Ecol 1997 · PubMed 9115181
7. Roager HM, Licht TR. Microbial tryptophan catabolites in health and disease. Nat Commun 2018 · PubMed 30120222
8. Högberg-Raibaud A, Raibaud O, Goldberg ME. Kinetic and equilibrium studies on the activation of Escherichia coli K12 tryptophanase by pyridoxal 5'-phosphate and monovalent cations. J Biol Chem 1975 · PubMed 1091651
9. Liu D, Wei Y, Liu X et al. Indoleacetate decarboxylase is a glycyl radical enzyme catalysing the formation of malodorant skatole. Nat Commun 2018 · PubMed 30310076
10. Selmer T, Andrei PI. p-Hydroxyphenylacetate decarboxylase from Clostridium difficile. A novel glycyl radical enzyme catalysing the formation of p-cresol. Eur J Biochem 2001 · PubMed 11231288
11. Gryp T, Vanholder R, Vaneechoutte M, Glorieux G. p-Cresyl Sulfate. Toxins (Basel) 2017 · PubMed 28146081
12. Banoglu E, Jha GG, King RS. Hepatic microsomal metabolism of indole to indoxyl, a precursor of indoxyl sulfate. Eur J Drug Metab Pharmacokinet 2001 · PubMed 11808865
13. Banoglu E, King RS. Sulfation of indoxyl by human and rat aryl (phenol) sulfotransferases to form indoxyl sulfate. Eur J Drug Metab Pharmacokinet 2002 · PubMed 12064372
14. Leong SC, Sirich TL. Indoxyl Sulfate-Review of Toxicity and Therapeutic Strategies. Toxins (Basel) 2016 · PubMed 27916890
15. Deguchi T, Kouno Y, Terasaki T et al. Differential contributions of rOat1 (Slc22a6) and rOat3 (Slc22a8) to the in vivo renal uptake of uremic toxins in rats. Pharm Res 2005 · PubMed 15846470
16. Lees HJ, Swann JR, Wilson ID et al. Hippurate: the natural history of a mammalian-microbial cometabolite. J Proteome Res 2013 · PubMed 23342949
17. Badenhorst CP, van der Sluis R, Erasmus E, van Dijk AA. Glycine conjugation: importance in metabolism, the role of glycine N-acyltransferase, and factors that influence interindividual variation. Expert Opin Drug Metab Toxicol 2013 · PubMed 23650932
18. Ruangyuttikarn W, Appleton ML, Yost GS. Metabolism of 3-methylindole in human tissues. Drug Metab Dispos 1991 · PubMed 1686246
19. Rasmussen MK, Balaguer P, Ekstrand B et al. Skatole (3-Methylindole) Is a Partial Aryl Hydrocarbon Receptor Agonist and Induces CYP1A1/2 and CYP1B1 Expression in Primary Human Hepatocytes. PLoS One 2016 · PubMed 27138278

Whole pathway: Protein fermentation in the colon

Related pathways

• Dopamine, noradrenaline, adrenaline — tyrosine
• Kynurenine pathway — tryptophan
• NAD⁺ — tryptophan
• Serotonin and melatonin — tryptophan
• Alanine — Leucin, Vitamin B6

As of 2026-10-05. Draft written by Claude to schema v2; sources checked in PubMed; expert approval pending
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