Tryptophan

Tryptophan is an essential amino acid, i.e., not produced in the body and hence must be obtained from our diet or by other methods of supplementation. Foods high in tryptophan include milk, turkey, chicken, fish, eggs, pumpkin seeds, beans, peanuts, cheese, and leafy green vegetables. Inside the human body, a small amount of tryptophan is used for protein synthesis. Most dietary tryptophan goes through one of the three branches of tryptophan catabolism: kynurenine degradation in the brain, liver, and gut; serotonin synthesis in the central system and the gut; and indole synthesis in the gut.

Some of the end products of these metabolic processes have beneficial effects because  they regulate  emotional and cognitive behavior, the immune system, and the sleep-wake cycle, while some tryptophan degradation products can be potentially harmful to body functions. Hence, obtaining the right balance between tryptophan utilization and breakdown pathways is essential to maintaining good metabolic function and health benefits, which can be achieved through stress release, diet, controlled sleep patterns, physical exercise, and, in some cases, tryptophan supplements.

Tryptophan and the gut microbiome

After eating foods rich in animal or plant proteins, the free tryptophan, and other essential amino acids, are  released into the intestines. Here, some tryptophan is absorbed and enters the circulation as albumin-bound tryptophan. Unabsorbed and excess dietary tryptophan is consumed and processed by gut microbes¹.

From dietary tryptophan, gut microbes produce serotonin and indole and their derivates. Serotonin is an important signaling molecule in the gut that helps to regulate inflammation, stabilize the gut wall, and promote peristalsis. Additionally, gut microbes produce indole, indole derivates, and tryptamine from a small portion of dietary tryptophan. These compounds support immune homeostasis in the gastrointestinal tract and promote the growth of beneficial gut bacteria¹.

By producing important signaling molecules and neurotransmitters from the amino acid tryptophan, the gut microbiota directly links the health of the gut to the health of the brain in the gut-brain axis. This is also why patients with gastrointestinal disorders, like irritable bowel disease, often show alterations in tryptophan plasma concentrations, which can be linked to elevated stress levels and migraines².

Tryptophan and sleep

After absorption and release into the blood circulation, dietary tryptophan crosses the blood-brain barrier, reaching the central nervous system. In the brain, tryptophan is converted to serotonin, and in other organs, such as the pineal gland, from serotonin to melatonin. These hormones, or neurotransmitters, regulate sleep, emotions, mood, and appetite.

The amount of serotonin and melatonin produced directly depends on the ratio of free tryptophan to large neutral amino acids. This relationship is  supported by studies showing that diets rich in carbohydrates as well as supplementing the diet with tryptophan improve sleep quality, mood swings, insomnia, and post-exercise recovery³.

Tryptophan and physical activity

While a small portion of dietary tryptophan is converted to indole and serotonin and their derivates, a large percentage of tryptophanundergoes biochemical conversions to metabolites via the kynurenine pathway. This degradation pathway generates both neuroprotective and neurotoxic compounds including nicotinamide adenine dinucleotide, an important small molecule directly involved in influencing cellular bioenergetics.

While the molecular mechanisms are not fully understood, physical activity seems to shift the kynurenine pathway toward the production of energy sources, neuroprotective compounds, and serotonin⁴. This change in muscle tryptophan metabolic functions has further beneficial impacts on adipose tissue, the immune response, and the central nervous system, with therapeutic indications for patients with major depressive disorder⁵.

Tryptophan and disease

​Concomitant alterations in tryptophan degradation pathways and the gut microbiome have been shown to be directly and indirectly linked to several diseases, including neuropsychiatric, cardiovascular, and gastrointestinal conditions. Decreased serotonin levels and increased activation of the kynurenine pathways are central symptoms of patients with major depression⁵. Additionally, neurotoxic kynurenine products trigger inflammation in the brain and damage neurons. Dietary tryptophan supplementation was shown to ameliorate these inflammatory effects, lower stress levels and improve cognitive performance⁶.

Similarly, changes in the composition of the gut microbiome, and, therefore, in tryptophan degradation have been observed in patients with inflammatory bowel syndrome and migraines. In both conditions, patients have decreased levels of kynurenine and elevated levels of tryptophan, with the underlying mechanisms not being fully understood yet⁷.

Several gut microbiome-derived tryptophan metabolites, such as indole and indole-3-propionic acid, directly regulate blood pressure and hypertension. At the same time, tryptophan-derived serotonin is important for cardiovascular regulation in the human body, while a disbalance in tryptophan catabolism was found to promote atherosclerosis⁸.

Tryptophan in research

As of July 2023, there are over 5,700 citations for “propionic acid” in research publications (*excluding books and documents) on PubMed. The extensive number of publications linking tryptophan to mental health disorders suggests that any researcher interested in the link between this metabolite and brain health may consider including quantitative analyses of tryptophan in  their study. Similarly, due to the well-recognized links between tryptophan and the gut microbiome, any studies aiming to better understand how the microbiome influences health and disease may benefit from tryptophan quantification.

References

1. Gao K, Mu CL, Farzi A, et al. Tryptophan Metabolism: A Link Between the Gut Microbiota and Brain. Adv Nutr 2020;11(3):709-723.
2. Gao J, Xu K, Liu H, et al. Impact of the Gut Microbiota on Intestinal Immunity Mediated by Tryptophan Metabolism. Front Cell Infect Microbiol 2018;8:13.
3. Sutanto C, Loh WW, and Kim JE. The Impact of Tryptophan Supplementation on Sleep Quality: A Systematic Review, Meta-Analysis and Meta-Regression. Curr Dev Nutr 2021;5:373.
4. Martin KS, Azzolini M, Lira Ruas J. The kynurenine connection: how exercise shifts muscle tryptophan metabolism and affects energy homeostasis, the immune system, and the brain. Am J Physiol Cell Physiol 2020; 318(5):C818-C830.
5. Agus A, Planchais J, and Sokol H. Gut Microbiota Regulation of Tryptophan Metabolism in Health and Disease. Cell Host Microbe 2018;23(6):716-724.
6. Clarke G, Grenham S, Scully P, et al. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry 2013;18(6):666-73.
7. Fila M, Chojnacki J, Pawlowska E, et al. Kynurenine Pathway of Tryptophan Metabolism in Migraine and Functional Gastrointestinal Disorders. Int J Mol Sci 2021;22(18):10134.
8. Paeslack N, Mimmler M, Becker S, et al. Microbiota-derived tryptophan metabolites in vascular inflammation and cardiovascular disease. Amino Acids 2022;54(10):1339-1356.