Tryptophan metabolism

Once absorbed, tryptophan is metabolized along three major pathways: the kynurenine pathway (via host cells), the serotonin pathway (via host cells), and the indole pathway (via gut microbiota).  

1. The kynurenine pathway is the dominant route accounting for over 95% of dietary tryptophan catabolism. While it primarily occurs in the liver (via TDO), it is also activated in immune and barrier tissues (via IDO), especially under immune stress and activation. This pathway yields a variety of bioactive intermediates and ultimately contributes to the endogenous synthesis of NAD+, a vital cofactor involved in mitochondrial energy metabolism, redox balance, and DNA repair.
   When immune stress is sustained, more tryptophan is directed into this pathway, and imbalances can occur. Under favorable conditions, downstream metabolism favors the production of beneficial metabolites like kynurenic acid (KYNA), while also supporting efficient NAD+ synthesis. When the balance shifts – due to enzyme bottlenecks, oxidative stress, micronutrient insufficiencies, or prolonged immune activation – metabolism becomes skewed toward intermediates such as quinolinic acid (QA) and 3-hydroxykynurenine (3-OH-KYN). 
   
   QA acts on NMDA receptors and can amplify excitatory signaling in the brain.
   3-OH-KYN promotes oxidative stress and lipid peroxidation.
   Reduced flow through the NAD+-producing end of the pathway can result in relative NAD+ depletion, challenging mitochondrial efficiency, cellular energy, and overall resilience. 
   
   Such patterns are often seen in contexts of persistent immune stress and metabolic imbalance.
    
2. The serotonin pathway converts tryptophan into serotonin (5-HT). Though it uses only 1-2%              ryptophan, it plays a significant role in regulating mood, gut motility, and circadian rhythms. Shifts in this pathway may influence mood balance, digestive function, and sleep quality. 
    
3. The indole pathway is driven by microbial metabolism in the colon. Certain gut bacteria express tryptophanase enzymes that convert tryptophan into indole and its derivatives, including indole-3-propionic acid (IPA). These metabolites are ligands for the aryl hydrocarbon receptor (AhR), Supporting gut barrier integrity, immune tolerance, and systemic balance. 
    

The balance between these metabolic pathways is not simply a biochemical curiosity; it reflects both the functional state of gut microbial activity and the presence of systemic immune stress. Together, they determine whether tryptophan is routed toward protective or stress-associated metabolic products (metabolites) – with downstream consequences for gut, immune, and metabolic health. 
 

A healthy, fiber-rich diet promotes the microbial production of IPA, which then supports gut barrier integrity and metabolic resilience. Conversely, systemic inflammation, stress, and dysbiosis shift the balance in tryptophan metabolism toward an excessive flux through the kynurenine route, increasing the production of stress-associated metabolites.  
 

This is why tryptophan metabolism is now viewed as a molecular bridge linking the gut microbiome to systemic health. By examining these metabolic pathways, we gain a novel lens through which to assess lifestyle and diet’s impact on for example  immunity, mood and metabolism. 

Quick summary

• Tryptophan is metabolized into different products by the host (your body) and microbiota (the microbes living inside your body), depending on how it is processed – and each of these products has unique functions in the body. 
• The kynurenine pathway dominates during immune stress, while the indole pathway flourishes in gut health. 
• This metabolic balance links diet and microbiome activity to immunity, mood, and metabolism.