Disrupted Tryptophan Metabolism Linked to Psoriasis Severity, Multiple Comorbidities

For people living with psoriasis, the metabolic processes driving skin inflammation may also be fueling depression, joint disease, and metabolic dysfunction through a shared biological mechanism—one that several already-approved therapies appear to modulate.¹

A review published in the Journal of Advanced Research synthesized current evidence on how tryptophan (Trp) metabolism is altered in psoriasis and its associated conditions, identifying key enzymes and metabolites as both disease biomarkers and candidate therapeutic targets.

Why the Research Was Needed: A Chronic Condition With Systemic Reach

Psoriasis affects approximately 2% to 3% of the global population and carries no known cure, according to the World Health Organization. Although biologic therapies have improved outcomes for many patients, the metabolic mechanisms connecting psoriasis to its comorbidities—including psoriatic arthritis (PsA), depression, metabolic syndrome (MetS), and inflammatory bowel disease—have not been fully characterized.

Tryptophan is an essential amino acid available only through diet. It is metabolized through 3 primary pathways: the kynurenine (Kyn) pathway, the serotonin pathway, and the indole pathway. Disruptions in these pathways have previously been associated with conditions ranging from depression and inflammatory bowel disease to liver cancer, making their role in psoriasis a logical area of inquiry.

Kynurenine Pathway Consistently Overstimulated Across Psoriasis Phenotypes

The review authors analyzed metabolic data across multiple psoriasis subtypes, drawing on studies with sample sizes ranging from 13 to 182 patients. In a 2025 case-control study of 60 people with psoriasis vulgaris, the most common form of the disease, serum and urine levels of Kyn, kynurenic acid (KYNA), and quinolinic acid (QA) were significantly higher than in matched controls.² Activity of indoleamine-2,3-dioxygenase (IDO), a rate-limiting enzyme in the Kyn pathway, correlated positively with both the Psoriasis Area and Severity Index (PASI) score and circulating IL-17A levels.

In 20 people with erythrodermic psoriasis, serum Trp levels were lower and negatively correlated with PASI score, consistent with systemic Trp depletion driven by chronic immune activation.¹ Among 24 people with generalized pustular psoriasis, Trp depletion was observed to activate counter-regulatory amino acid response pathways, suggesting the metabolite may simultaneously drive and restrain inflammation in this subtype.

Comorbidities Reflect a Shared Metabolic Profile

The comorbidity burden associated with psoriasis was substantial across the reviewed literature. PsA was estimated to affect 17.58% of people with psoriasis, while MetS was present in 20% to 50%, with prevalence escalating alongside disease severity. Depression and anxiety affected approximately 20% and 21% of patients, respectively.

Among 113 people with psoriasis vulgaris, serum serotonin correlated significantly with PASI scores only in those with comorbid depression symptoms (r = 0.50), suggesting a link between neurotransmitter dysregulation and skin disease activity. Urinary analysis in 182 people with MetS revealed elevated levels of Kyn, KYNA, QA, and xanthurenic acid compared with controls.

"Trp metabolism is consistently shifted toward the kynurenine pathway, resulting in Trp depletion, neurotransmitter imbalance, and immune dysregulation," the authors wrote.

Approved Treatments Already Alter Tryptophan Catabolism

Several currently approved therapies were found to affect Trp catabolism. Tapinarof 1% cream, a topical aryl hydrocarbon receptor (AhR) modulator approved for adult plaque psoriasis, rebalanced T-helper-cell differentiation and downregulated IL-23/IL-17 signaling by antagonizing endogenous Kyn pathway ligands. Biologic agents—etanercept and ustekinumab—were associated with significantly decreased kynureninase (KYNU) expression after 12 weeks of treatment. Dimethyl fumarate and its active metabolite, monomethyl fumarate, inhibited IDO activity and reduced KYNU expression through NF-κB signaling pathway-dependent mechanisms.

A population-based cohort study found that selective serotonin reuptake inhibitors were associated with a decreased need for systemic psoriasis treatment (95% CI, 0.28-0.68), suggesting potential benefit for patients with comorbid depression.

Diet, Exercise, and Probiotics as Adjunct Strategies

Mediterranean diet adherence was inversely correlated with psoriasis disease severity scores, in part through effects on gut microbiota and downstream Trp catabolism. Physical exercise was shown to increase KYNA synthesis by activating kynurenine aminotransferases, with potential anti-inflammatory effects. Probiotic interventions, including Bifidobacterium longum, supported indole pathway metabolism from Trp and helped maintain intestinal barrier integrity.

Study Limitations and Future Directions

The review had several limitations. Much of the cited clinical data was cross-sectional, limiting causal inference. Referenced primary studies were small, with sample sizes ranging from 13 to 182 patients, reducing generalizability across heterogeneous psoriasis populations.

The authors acknowledged challenges in drug delivery, particularly achieving tissue-specific enzyme inhibition, and called for more precise delivery systems and long-term safety monitoring for AhR modulators. The review also did not conduct formal meta-analyses, precluding quantitative synthesis of effect sizes across studies.

References

1. He X, Mo Y, Shi P, et al. Tryptophan metabolism in psoriasis and its complications: Future opportunities. J Adv Res. 2026;84:883-894. doi:10.1016/j.jare.2025.09.034
2. Stepaniuk A, Baran A, Hermanowicz JM, et al. Peripheral kynurenine pathway metabolites in patients with psoriasis. Int J Mol Sci. 2025;26(7):3139. doi:10.3390/ijms26073139