Tryptophan Metabolism in Healthy Young Adults

Tryptophan is an essential amino acid and must be obtained from the diet. In addition to its essential role in protein synthesis, tryptophan has diverse and complex physiological functions via various metabolic pathways. Two primary metabolic pathways include the kynurenine and serotonin pathways. Tryptophan is the only precursor for both the kynurenine and serotonin pathways. Since these two pathways share tryptophan as the common nitrogenous substrate, a competition between these pathways is demonstrated. This can result in serotonin deficiency when kynurenine pathway is activated and may contribute to the pathophysiology of developing neurological disease. Furthermore, metabolites of the kynurenine pathway can exert neurotoxic effects because they can cross the blood brain barrier to reach the central nervous system (CNS). Evidence thus far indicates that the contribution of the different pathways of tryptophan metabolism can differ based on the physiological and pathological status. However, there is no clear evidence of whether the kynurenine pathway takes precedence over synthesis of protein (for growth) or serotonin during immune activation. There are also no investigations examining the impact of tryptophan intake during immune activation, for the purposes of this study meaning any activity by the immune system, on the production of neurotoxic metabolites of the kynurenine pathway.

Tryptophan uptake from parenteral nutrition fed to preterm neonates with current amino acid solutions may be about 2-2.5 times the estimated requirement based on data from neonatal piglets. Long-term effects of this excess intake in this vulnerable population are unknown. The potential adverse effects of increased catabolism via the kynurenine pathway during stress on growth and neurodevelopment of hospitalized preterm infants has not been explored. A method to quantify the partitioning of tryptophan between the different pathways will be highly beneficial but has not been established in humans. This will enable studies in parenterally fed neonates to assess whether tryptophan concentrations in current commercial amino acid solutions produce toxic metabolites or serotonin deficiency, which can contribute to neurocognitive deficits seen in this population.

Inclusion criteria

• Consent provided
• Aged 18 to 45 years old (inclusive)
• In good general health as evidenced by medical history, physical health and biochemistry
• Fasting blood glucose, hemoglobin A1c (HbA1c), urea, creatinine and CRP levels within normal ranges for age.

Exclusion criteria

• Presence of chronic disease and/or acute illness known to affect protein/amino acid metabolism (e.g. HIV, diabetes, cancer, liver or kidney disease, neurological conditions including depression and anxiety, hypo- / hyperthyroidism, inflammatory conditions,, anemia, acute cold or flu)
• Taking medications known to affect protein/AA metabolism (e.g. steroids, anti-inflammatory medications, acetaminophen, selective serotonin reuptake inhibitors (SSRI))
• Inability to tolerate the diet (i.e. allergy)
• Significant weight loss during the past month or consumption of weight reducing diets.
• Significant caffeine consumption (>2 cups per day)
• Significant consumption of alcohol (>1 drink per day i.e. 1 beer or ½ glass of wine).
• Unwilling to have blood drawn from a venous access or using a ventilated hood indirect calorimeter for the purposes of the study.