Tryptophan–kynurenine metabolites associate with inflammation and immunologic phenotypes in common variable immunodeficiency

BACKGROUND: A large proportion of patients with common variable immunodeficiency (CVID) have autoimmune and inflammatory manifestations characterized by chronic T-cell- and monocyte/macrophage activation of unknown etiology. The tryptophan-kynurenine pathway has previously been linked to immune activation involving T cells and monocytes/macrophages, as well as with gut microbial dysbiosis in some inflammatory diseases. OBJECTIVE: We aimed to characterize the tryptophan-kynurenine pathway in CVID and its potential association with clinical/immunologic phenotype and gut microbial dysbiosis. METHODS: Serum concentrations of a set of tryptophan-kynurenine pathway metabolites and neopterin were measured using liquid chromatography-tandem mass spectrometry in a discovery cohort (n = 40), a validation cohort (n = 53), and healthy controls (n = 60). B-cell phenotype was analyzed in both cohorts, whereas inflammatory markers (enzyme immunoassay), lipopolysaccharide, gut microbial composition, and food frequency questionnaire were measured in the discovery cohort. RESULTS: Compared to healthy controls, CVID patients had increased metabolism of the tryptophan-kynurenine pathway as assessed by increased kynurenine/tryptophan ratio, quinolinic acid, and 3-hydroxykynurenine in both the discovery and validation cohorts. The findings were most pronounced in the subgroup with autoimmune/inflammatory complications but was to some degree also observed in CVID patients with infection only. In CVID, the metabolites in the tryptophan-kynurenine pathway associated with soluble (s) markers of monocyte (sCD14, sCD163, neopterin) and T-cell (sCD25) activation as well as B-cell phenotype (eg, naïve B cells). Individual gut microbial taxa may influence tryptophan-kynurenine pathway metabolites, but not lipopolysaccharide or diet. CONCLUSION: We found altered levels of several metabolites in the tryptophan-kynurenine pathway in two different CVID cohorts associated with systemic inflammation and B-cell phenotype.