Tryptophan Metabolism in Allergic Disorders

Abstract

Allergic diseases such as asthma and rhinitis, as well the early phase of atopic dermatitis, are characterized by a Th2-skewed immune environment. Th2-type cytokines are upregulated in allergic inflammation, whereas there is downregulation of the Th1-type immune response and related cytokines, such as interferon-γ (IFN-γ). The latter is a strong inducer of indoleamine 2,3-dioxygenase-1 (IDO-1), which degrades the essential amino acid tryptophan, as part of an antiproliferative strategy of immunocompetent cells to halt the growth of infected and malignant cells, and also of T cells - an immunoregulatory intervention to avoid overactivation of the immune system. Raised serum tryptophan concentrations have been reported in patients with pollen allergy compared to healthy blood donors. Moreover, higher baseline tryptophan concentrations have been associated with a poor response to specific immunotherapy. It has been shown that the increase in tryptophan concentrations in patients with pollen allergy only exists outside the pollen season, and not during the season. Interestingly, there is only a minor alteration of the kynurenine to tryptophan ratio (Kyn/Trp, an index of tryptophan breakdown). The reason for the higher tryptophan concentrations in patients with pollen allergy outside the season remains a matter of discussion. To this regard, the specific interaction of nitric oxide (NO∙) with the tryptophan-degrading enzyme IDO-1 could be important, because an enhanced formation of NO∙ has been reported in patients with asthma and allergic rhinitis. Importantly, NO∙ suppresses the activity of the heme enzyme IDO-1, which could explain the higher tryptophan levels. Thus, inhibitors of inducible NO∙ synthase should be reconsidered as candidates for antiallergic therapy out of season that may abrogate the arrest of IDO-1 by decreasing the production of NO∙. Considering its association with the pathophysiology of atopic disease, tryptophan metabolism may play a relevant role in the pathophysiology of allergic disorders.

A tryptophan metabolite of the skin microbiota attenuates inflammation in patients with atopic dermatitis through the aryl hydrocarbon receptor

“…Indole and indole derivatives are mainly catabolized by the microbiota, and 5-HTP and KYN are produced by both the microbiota and the host cells. 13,14,16 Thus the decreased level of IAId, but not 5-HTP and KYN, on the skin surfaces of patients with AD indicates that Trp metabolism by the skin microbiota is attenuated, which is consistent with the metagenomics results obtained by Chng et al 18 and with our unpublished data.…”

“…However, KYN, 5-HTP, or IAA, the major metabolites of Trp, did not have any effects on the MC903-induced skin inflammation (see Fig E4, A-E, in this article's Online Repository at www.jacionline.org), although previous studies showed that some of the metabolites had inhibitory effects in various inflammatory conditions. [13][14][15] The interference of DMSO, the dissolvent of IAId, on the effect of MC903 was excluded because there was no difference between the mice treated with MC903 and those treated with MC903 plus DMSO (see Fig E4, F-J).…”

“…12 The essential amino acid Trp, an energy source for microbiota, is involved in immune modulation through various metabolites, including indole and indole derivatives. 13,14 Indole mediates the interaction between Escherichia coli and mammalian hosts and tightens gut epithelial cell junctions. 15 Indole-3-aldehyde (IAId), a major indole derivative, promotes IL-22 transcription and regulates intestinal inflammation, which is dependent on the aryl hydrocarbon receptor (AhR).…”

Orchestration of Tryptophan‐Kynurenine Pathway, Acute Decompensation, and Acute‐on‐Chronic Liver Failure in Cirrhosis

“…Accordingly, measuring the serum levels of these metabolites provides comprehensive information on KP activity. In addition, the KYN to Trp ratio (KYN/Trp) is used widely to estimate the TDO and IDO activity . Table A lists the serum levels of these metabolites, as measured by LC‐MS and expressed in relative units corresponding to chromatographic peak areas, in healthy controls and patients with compensated cirrhosis, AD, and ACLF.…”

“…In addition, the KYN to Trp ratio (KYN/Trp) is used widely to estimate the TDO and IDO activity. (20) Table 1A lists the serum levels of these metabolites, as measured by LC-MS and expressed in relative units corresponding to chromatographic peak areas, in healthy controls and patients with compensated cirrhosis, AD, and ACLF. In patients with compensated cirrhosis, the KP activity was not significantly different from healthy controls.…”