Spirulina and Kynurenine Pathway: IDO1, TDO2, Tryptophan Catabolism, and Immunosuppression

Tryptophan Catabolism: IDO1 and TDO2

The kynurenine pathway is the primary route of tryptophan catabolism (~95% in non-serotonin contexts). Two initial enzymes compete: IDO1 (indoleamine 2,3- dioxygenase 1, IFN-gamma/NF-kB/TLR inducible, expressed in DCs/macrophages/ placenta/tumour stroma) and TDO2 (tryptophan 2,3-dioxygenase, constitutive liver expression, heme-containing, glucocorticoid-inducible). Both convert L-tryptophan to N-formylkynurenine, which is further processed by kynurenine formamidase (AFMID) to kynurenine (KYN). KYN is the key branch point for downstream metabolites.

Downstream Kynurenine Metabolites

From kynurenine, two principal branches diverge: (1) kynurenine aminotransferases (KATs/CCBL1/2, GOT2) produce kynurenic acid (KYNA, NMDA/alpha7-nAChR antagonist, AhR ligand, anti-excitotoxic); (2) kynurenine 3-monooxygenase (KMO, FAD-dependent) produces 3-hydroxykynurenine (3-HK), then kynureninase (KYNU) to 3-hydroxyanthranilic acid (3-HAA), then 3-HAA dioxygenase (HAAO) to 2-amino-3-carboxymuconic semialdehyde (ACMS), which spontaneously cyclises to picolinic acid or is processed to quinolinic acid (QUIN) by ACMSD. QUIN (NMDA agonist, neurotoxic) is converted to nicotinic acid mononucleotide by QPRT (quinolinate phosphoribosyltransferase), entering the NAD+ de novo synthesis pathway.

AhR Activation by Kynurenines

Kynurenine and several downstream metabolites (FICZ, kynurenic acid) are endogenous ligands for the aryl hydrocarbon receptor (AhR/ARNT). AhR is a ligand-activated transcription factor: ligand binding displaces AhR from its HSP90/XAP2/p23 complex, dimerises with ARNT, and binds xenobiotic response elements (XREs: GCGTG). AhR target genes include CYP1A1/1A2/1B1 (xenobiotic metabolism, AhR ligand degradation), IDO1 (feedback amplification), and IL-10/TGF-beta (immune tolerance). In DCs, KYN-AhR drives IDO1 expression and Treg induction. Spirulina's IDO1/AhR- modulating effects are indirect: NF-kB suppression reduces IDO1 induction (which requires NF-kB+IFN-gamma), reducing KYN generation and AhR activation.

IDO1-Kynurenine in Tumour Immune Evasion

Tumour-expressed IDO1 depletes local tryptophan (activating GCN2 in T cells, causing T cell anergy via eIF2alpha phosphorylation) and accumulates KYN (activating AhR in T cells to induce FOXP3/Treg differentiation and suppressing effector T cell function). IDO1 inhibitors (epacadostat, BMS-986205) were explored as checkpoint combination partners (though clinical trials have had mixed results). Spirulina's NF-kB/IFN-gamma pathway modulation reduces IDO1 induction in tumour stroma, potentially limiting tumour KYN production, though direct spirulina-IDO1 tumour evidence is lacking.

NAD+ Biosynthesis from Quinolinate

The kynurenine/de novo pathway produces NAD+ via: QUIN (quinolinate) + PRPP → nicotinic acid mononucleotide (NaMN, by QPRT) → nicotinic acid adenine dinucleotide (NaAD) → NAD+ (by NAD+ synthetase, NADSYN1). This provides the only de novo NAD+ synthesis route, significant in cells with limited salvage capacity. Spirulina's NAMPT-driven NAD+ salvage (from nicotinamide) is a parallel, non-tryptophan route, reducing dependence on inflammatory IDO1-QUIN-QPRT de novo synthesis for NAD+ replenishment.

Serotonin and Melatonin: Competing Tryptophan Destinations

Tryptophan hydroxylase 1 (TPH1, peripheral, 5-HTP in gut) and TPH2 (neuronal, 5-HTP in brain) convert tryptophan to 5-hydroxytryptophan (5-HTP), then AADC to serotonin (5-HT). Serotonin is a precursor for melatonin (N-acetylserotonin by AANAT, then ASMT/HIOMT to melatonin). IDO1 induction (by inflammation) diverts tryptophan away from serotonin synthesis, contributing to depression comorbidity in chronic inflammatory disease. Spirulina's NF-kB/IDO1 suppression preserves tryptophan availability for serotonin synthesis, providing a mechanistic rationale for mood/cognitive effects of spirulina reported in some surveys and small trials.