Tryptophan and the gut - Part 1 - Introduction to tryptophan metabolism

Tryptophan and the gut

Part 1: Introduction to tryptophan metabolism

Tryptophan is an essential amino acid and a precursor to many important molecules in the body. In this article series, I’ll talk about the various ways tryptophan is metabolized in the gut, and the implications this has for a wide range of chronic diseases.

If you’ve been reading my blog for any length of time, you’ve likely heard me talk about short-chain fatty acids (SCFAs). SCFAs, particularly butyrate, are often depleted in states of gut dysbiosis and chronic disease.

But SCFAs are just one of three major categories of gut metabolites. The other two categories – tryptophan metabolites and bile acids – play equally important roles in maintaining gut health. And it’s about time that I featured them on the blog!

In this first article, I’ll be covering what tryptophan is and introducing the three major pathways of tryptophan metabolism. In the next few articles in the series, I’ll go into each pathway in more detail and discuss the importance of balance among the three pathways. I’ll also talk about how this balance becomes skewed in chronic disease states, and of course, how we might use this information to restore balance and support gut and overall health. Let’s dive in!

What is tryptophan?

Meet tryptophan. Tryptophan is an amino acid – one of the many building blocks of protein in our body.

Tryptophan is also an important precursor to a number of other compounds in the body, including:

  • melatonin, a hormone that regulates sleep-wake cycles
  • niacin (vitamin B3), a nutrient that helps the body turn food into usable energy, and
  • serotonin, a neurotransmitter that plays a role in mood regulation and gut motility

As we’ll see, tryptophan is also a precursor to many other metabolites in the gut.

Getting adequate tryptophan: the importance of protein for gut health

Tryptophan is an essential amino acid, which means our body can’t synthesize it and we need a regular supply in our diet.

So where do we get tryptophan? Tryptophan can be found in most proteins, so a deficiency of tryptophan is most often due to inadequate dietary protein intake. In general, animal proteins tend to have higher amounts of tryptophan than plant proteins. While tryptophan can be taken in supplement form, it is best to get it as part of the complete protein in whole foods.

Sources of tryptophan include:

  • Meat, fish, and poultry
  • Eggs
  • Dairy products
  • Beans and legumes
  • Grains
  • Sesame seeds
  • Dark chocolate

Low tryptophan intake has been associated with depression, anxiety, poor mood, lower quality sleep, reduced visual cognition, and impaired learning and memory.1–4 It may also alter the gut microbiome and impair gut immunity.5

The three major fates of tryptophan in the gut

While most tryptophan is absorbed in the small intestine, some of it continues on to the large intestine, where it can be acted on by microbes and host cells.6 There are three major fates of tryptophan within the gut:

1) The indole/AhR pathway. Gut bacteria directly convert tryptophan to indoles and related molecules. Like a lock and key, some of these indole molecules bind to the aryl hydrocarbon receptor (AhR) on the surface of cells throughout the gut and other organs. This triggers a wide range of responses that promote gut homeostasis. The activity of this pathway depends on diet and the composition of the microbiota.

2) The kynurenine pathway. Some tryptophan is taken up by gut epithelial cells and immune cells, where it is converted by an enzyme called IDO1 into kynurenine. Kynurenine can be further metabolized to other molecules, such as quinolinic acid, which has neurotoxic effects. The activity of this pathway is increased by stress, inflammation, or infection.

3) The serotonin pathway. Tryptophan is also taken up into gut enteroendocrine cells, which is then converted to the neurotransmitter serotonin via the enzyme TpH1. Serotonin in the gut regulates gut motility, secretion and absorption, and plays a role in gut-brain signaling. The activity of this pathway is affected by fasting, diet, gut infection, and certain microbes.

The key, of course, is balance. In a healthy gut, these three pathways are balanced, resulting in optimal gut barrier function, motility, immunity, and neurological function.

Altered tryptophan metabolism in chronic disease

In chronic diseases, however, the balance of the three pathways above appears to be skewed, resulting in impaired gut function and systemic implications.

Here are just a few conditions that are characterized by altered tryptophan metabolism:

  • Inflammatory bowel disease7
  • Irritable bowel syndrome8
  • Obesity9
  • Metabolic syndrome10
  • Cardiovascular disease11
  • Depression12
  • Inflammatory skin conditions13
  • Allergies and autoimmunity14,15
  • Autism16
  • Celiac disease17
  • Multiple sclerosis18

Moreover, more and more studies are showing how we can modulate the microbiome or tryptophan metabolism to influence clinical outcomes in disease states. Diet and lifestyle factors, along with certain probiotics, plant compounds, and micronutrients can all be used to shift the balance of tryptophan metabolites. I’ll be covering many of these throughout this series.

In part 2, we’ll be taking a deep dive into the indole/AhR pathway and its implications for gut immunity, gut barrier function, and vagus nerve activity. Stay tuned!

  1. Lindseth, G., Helland, B. & Caspers, J. The Effects of Dietary Tryptophan on Affective Disorders. Archives of Psychiatric Nursing 29, 102–107 (2015).
  2. Voderholzer, U. et al. Impact of experimentally induced serotonin deficiency by tryptophan depletion on sleep EEC in healthy subjects. Neuropsychopharmacology 18, 112–124 (1998).
  3. Kałużna-Czaplińska, J., Gątarek, P., Chirumbolo, S., Chartrand, M. S. & Bjørklund, G. How important is tryptophan in human health? Critical Reviews in Food Science and Nutrition 59, 72–88 (2019).
  4. Tryptophan depletion in normal volunteers produces selective impairment in memory consolidation | SpringerLink. https://link.springer.com/article/10.1007/s002130050845.
  5. Yusufu, I. et al. A Tryptophan-Deficient Diet Induces Gut Microbiota Dysbiosis and Increases Systemic Inflammation in Aged Mice. International Journal of Molecular Sciences 22, 5005 (2021).
  6. Gibson, J. A., Sladen, G. E. & Dawson, A. M. Protein absorption and ammonia production: the effects of dietary protein and removal of the colon. Br J Nutr 35, 61–65 (1976).
  7. Nikolaus, S. et al. Increased Tryptophan Metabolism Is Associated With Activity of Inflammatory Bowel Diseases. Gastroenterology 153, 1504-1516.e2 (2017).
  8. Berstad, A., Raa, J. & Valeur, J. Tryptophan: ‘essential’ for the pathogenesis of irritable bowel syndrome? Scandinavian Journal of Gastroenterology 49, 1493–1498 (2014).
  9. Cussotto, S. et al. Tryptophan Metabolic Pathways Are Altered in Obesity and Are Associated With Systemic Inflammation. Frontiers in Immunology 11, 557 (2020).
  10. Natividad, J. M. et al. Impaired Aryl Hydrocarbon Receptor Ligand Production by the Gut Microbiota Is a Key Factor in Metabolic Syndrome. Cell Metab 28, 737-749.e4 (2018).
  11. Mangge, H. et al. Disturbed tryptophan metabolism in cardiovascular disease. Curr Med Chem 21, 1931–1937 (2014).
  12. Waclawiková, B. & El Aidy, S. Role of Microbiota and Tryptophan Metabolites in the Remote Effect of Intestinal Inflammation on Brain and Depression. Pharmaceuticals 11, 63 (2018).
  13. Di Meglio, P. et al. Activation of the Aryl Hydrocarbon Receptor Dampens the Severity of Inflammatory Skin Conditions. Immunity 40, 989–1001 (2014).
  14. Van der Leek, A. P., Yanishevsky, Y. & Kozyrskyj, A. L. The Kynurenine Pathway As a Novel Link between Allergy and the Gut Microbiome. Frontiers in Immunology 8, 1374 (2017).
  15. Choi, S.-C. et al. Gut microbiota dysbiosis and altered tryptophan catabolism contribute to autoimmunity in lupus-susceptible mice. Science Translational Medicine 12, eaax2220 (2020).
  16. Golubeva, A. V. et al. Microbiota-related Changes in Bile Acid & Tryptophan Metabolism are Associated with Gastrointestinal Dysfunction in a Mouse Model of Autism. EBioMedicine 24, 166–178 (2017).
  17. Lamas, B. et al. Aryl hydrocarbon receptor ligand production by the gut microbiota is decreased in celiac disease leading to intestinal inflammation. Science Translational Medicine 12, eaba0624 (2020).
  18. Nourbakhsh, B. et al. Altered tryptophan metabolism is associated with pediatric multiple sclerosis risk and course. Annals of Clinical and Translational Neurology 5, 1211–1221 (2018).
  19. Krishnan, S. et al. Gut Microbiota-Derived Tryptophan Metabolites Modulate Inflammatory Response in Hepatocytes and Macrophages. Cell Reports 23, 1099–1111 (2018).
  20. Lamas, B. et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nature Medicine 22, 598–605 (2016).
  21. Reigstad, C. S. et al. Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells. The FASEB Journal 29, 1395–1403 (2015).
  22. Monteleone, I. et al. Aryl Hydrocarbon Receptor-Induced Signals Up-regulate IL-22 Production and Inhibit Inflammation in the Gastrointestinal Tract. Gastroenterology 141, 237-248.e1 (2011).

About Lucy 

Lucy Mailing, PhD is an independent microbiome researcher and gut health science educator. She writes evidence-based articles about the microbiome, gut health, and nutrition science, inspired by her own health journey overcoming chronic eczema.

Tryptophan and the gut - Part 1 - Introduction to tryptophan metabolism

Tryptophan and the gut

Part 1: Introduction to tryptophan metabolism

Tryptophan is an essential amino acid and a precursor to many important molecules in the body. In this article series, I’ll talk about the various ways tryptophan is metabolized in the gut, and the implications this has for a wide range of chronic diseases.

If you’ve been reading my blog for any length of time, you’ve likely heard me talk about short-chain fatty acids (SCFAs). SCFAs, particularly butyrate, are often depleted in states of gut dysbiosis and chronic disease.

But SCFAs are just one of three major categories of gut metabolites. The other two categories – tryptophan metabolites and bile acids – play equally important roles in maintaining gut health. And it’s about time that I featured them on the blog!

In this first article, I’ll be covering what tryptophan is and introducing the three major pathways of tryptophan metabolism. In the next few articles in the series, I’ll go into each pathway in more detail and discuss the importance of balance among the three pathways. I’ll also talk about how this balance becomes skewed in chronic disease states, and of course, how we might use this information to restore balance and support gut and overall health. Let’s dive in!

What is tryptophan?

Meet tryptophan. Tryptophan is an amino acid – one of the many building blocks of protein in our body.

Tryptophan is also an important precursor to a number of other compounds in the body, including:

  • melatonin, a hormone that regulates sleep-wake cycles
  • niacin (vitamin B3), a nutrient that helps the body turn food into usable energy, and
  • serotonin, a neurotransmitter that plays a role in mood regulation and gut motility

As we’ll see, tryptophan is also a precursor to many other metabolites in the gut.

Getting adequate tryptophan: the importance of protein for gut health

Tryptophan is an essential amino acid, which means our body can’t synthesize it and we need a regular supply in our diet.

So where do we get tryptophan? Tryptophan can be found in most proteins, so a deficiency of tryptophan is most often due to inadequate dietary protein intake. In general, animal proteins tend to have higher amounts of tryptophan than plant proteins. While tryptophan can be taken in supplement form, it is best to get it as part of the complete protein in whole foods.

Sources of tryptophan include:

  • Meat, fish, and poultry
  • Eggs
  • Dairy products
  • Beans and legumes
  • Grains
  • Sesame seeds
  • Dark chocolate

Low tryptophan intake has been associated with depression, anxiety, poor mood, lower quality sleep, reduced visual cognition, and impaired learning and memory.1–4 It may also alter the gut microbiome and impair gut immunity.5

The three major fates of tryptophan in the gut

While most tryptophan is absorbed in the small intestine, some of it continues on to the large intestine, where it can be acted on by microbes and host cells.6 There are three major fates of tryptophan within the gut:

1) The indole/AhR pathway. Gut bacteria directly convert tryptophan to indoles and related molecules. Like a lock and key, some of these indole molecules bind to the aryl hydrocarbon receptor (AhR) on the surface of cells throughout the gut and other organs. This triggers a wide range of responses that promote gut homeostasis. The activity of this pathway depends on diet and the composition of the microbiota.

2) The kynurenine pathway. Some tryptophan is taken up by gut epithelial cells and immune cells, where it is converted by an enzyme called IDO1 into kynurenine. Kynurenine can be further metabolized to other molecules, such as quinolinic acid, which has neurotoxic effects. The activity of this pathway is increased by stress, inflammation, or infection.

3) The serotonin pathway. Tryptophan is also taken up into gut enteroendocrine cells, which is then converted to the neurotransmitter serotonin via the enzyme TpH1. Serotonin in the gut regulates gut motility, secretion and absorption, and plays a role in gut-brain signaling. The activity of this pathway is affected by fasting, diet, gut infection, and certain microbes.

The key, of course, is balance. In a healthy gut, these three pathways are balanced, resulting in optimal gut barrier function, motility, immunity, and neurological function.

Altered tryptophan metabolism in chronic disease

In chronic diseases, however, the balance of the three pathways above appears to be skewed, resulting in impaired gut function and systemic implications.

Here are just a few conditions that are characterized by altered tryptophan metabolism:

  • Inflammatory bowel disease7
  • Irritable bowel syndrome8
  • Obesity9
  • Metabolic syndrome10
  • Cardiovascular disease11
  • Depression12
  • Inflammatory skin conditions13
  • Allergies and autoimmunity14,15
  • Autism16
  • Celiac disease17
  • Multiple sclerosis18

Moreover, more and more studies are showing how we can modulate the microbiome or tryptophan metabolism to influence clinical outcomes in disease states. Diet and lifestyle factors, along with certain probiotics, plant compounds, and micronutrients can all be used to shift the balance of tryptophan metabolites. I’ll be covering many of these throughout this series.

In part 2, we’ll be taking a deep dive into the indole/AhR pathway and its implications for gut immunity, gut barrier function, and vagus nerve activity. Stay tuned!

  1. Lindseth, G., Helland, B. & Caspers, J. The Effects of Dietary Tryptophan on Affective Disorders. Archives of Psychiatric Nursing 29, 102–107 (2015).
  2. Voderholzer, U. et al. Impact of experimentally induced serotonin deficiency by tryptophan depletion on sleep EEC in healthy subjects. Neuropsychopharmacology 18, 112–124 (1998).
  3. Kałużna-Czaplińska, J., Gątarek, P., Chirumbolo, S., Chartrand, M. S. & Bjørklund, G. How important is tryptophan in human health? Critical Reviews in Food Science and Nutrition 59, 72–88 (2019).
  4. Tryptophan depletion in normal volunteers produces selective impairment in memory consolidation | SpringerLink. https://link.springer.com/article/10.1007/s002130050845.
  5. Yusufu, I. et al. A Tryptophan-Deficient Diet Induces Gut Microbiota Dysbiosis and Increases Systemic Inflammation in Aged Mice. International Journal of Molecular Sciences 22, 5005 (2021).
  6. Gibson, J. A., Sladen, G. E. & Dawson, A. M. Protein absorption and ammonia production: the effects of dietary protein and removal of the colon. Br J Nutr 35, 61–65 (1976).
  7. Nikolaus, S. et al. Increased Tryptophan Metabolism Is Associated With Activity of Inflammatory Bowel Diseases. Gastroenterology 153, 1504-1516.e2 (2017).
  8. Berstad, A., Raa, J. & Valeur, J. Tryptophan: ‘essential’ for the pathogenesis of irritable bowel syndrome? Scandinavian Journal of Gastroenterology 49, 1493–1498 (2014).
  9. Cussotto, S. et al. Tryptophan Metabolic Pathways Are Altered in Obesity and Are Associated With Systemic Inflammation. Frontiers in Immunology 11, 557 (2020).
  10. Natividad, J. M. et al. Impaired Aryl Hydrocarbon Receptor Ligand Production by the Gut Microbiota Is a Key Factor in Metabolic Syndrome. Cell Metab 28, 737-749.e4 (2018).
  11. Mangge, H. et al. Disturbed tryptophan metabolism in cardiovascular disease. Curr Med Chem 21, 1931–1937 (2014).
  12. Waclawiková, B. & El Aidy, S. Role of Microbiota and Tryptophan Metabolites in the Remote Effect of Intestinal Inflammation on Brain and Depression. Pharmaceuticals 11, 63 (2018).
  13. Di Meglio, P. et al. Activation of the Aryl Hydrocarbon Receptor Dampens the Severity of Inflammatory Skin Conditions. Immunity 40, 989–1001 (2014).
  14. Van der Leek, A. P., Yanishevsky, Y. & Kozyrskyj, A. L. The Kynurenine Pathway As a Novel Link between Allergy and the Gut Microbiome. Frontiers in Immunology 8, 1374 (2017).
  15. Choi, S.-C. et al. Gut microbiota dysbiosis and altered tryptophan catabolism contribute to autoimmunity in lupus-susceptible mice. Science Translational Medicine 12, eaax2220 (2020).
  16. Golubeva, A. V. et al. Microbiota-related Changes in Bile Acid & Tryptophan Metabolism are Associated with Gastrointestinal Dysfunction in a Mouse Model of Autism. EBioMedicine 24, 166–178 (2017).
  17. Lamas, B. et al. Aryl hydrocarbon receptor ligand production by the gut microbiota is decreased in celiac disease leading to intestinal inflammation. Science Translational Medicine 12, eaba0624 (2020).
  18. Nourbakhsh, B. et al. Altered tryptophan metabolism is associated with pediatric multiple sclerosis risk and course. Annals of Clinical and Translational Neurology 5, 1211–1221 (2018).
  19. Krishnan, S. et al. Gut Microbiota-Derived Tryptophan Metabolites Modulate Inflammatory Response in Hepatocytes and Macrophages. Cell Reports 23, 1099–1111 (2018).
  20. Lamas, B. et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nature Medicine 22, 598–605 (2016).
  21. Reigstad, C. S. et al. Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells. The FASEB Journal 29, 1395–1403 (2015).
  22. Monteleone, I. et al. Aryl Hydrocarbon Receptor-Induced Signals Up-regulate IL-22 Production and Inhibit Inflammation in the Gastrointestinal Tract. Gastroenterology 141, 237-248.e1 (2011).

About Lucy 

Lucy Mailing, PhD is an independent microbiome researcher and gut health science educator. She writes evidence-based articles about the microbiome, gut health, and nutrition science, inspired by her own health journey overcoming chronic eczema.