(13)C-tryptophan breath test detects increased catabolic turnover of tryptophan along the kynurenine pathway in patients with major depressive disorder

Toshiya Teraishi, Hiroaki Hori, Daimei Sasayama, Junko Matsuo, Shintaro Ogawa, Miho Ota, Kotaro Hattori, Masahiro Kajiwara, Teruhiko Higuchi, Hiroshi Kunugi, Toshiya Teraishi, Hiroaki Hori, Daimei Sasayama, Junko Matsuo, Shintaro Ogawa, Miho Ota, Kotaro Hattori, Masahiro Kajiwara, Teruhiko Higuchi, Hiroshi Kunugi

Abstract

Altered tryptophan-kynurenine (KYN) metabolism has been implicated in major depressive disorder (MDD). The L-[1-(13)C]tryptophan breath test ((13)C-TBT) is a noninvasive, stable-isotope tracer method in which exhaled (13)CO2 is attributable to tryptophan catabolism via the KYN pathway. We included 18 patients with MDD (DSM-IV) and 24 age- and sex-matched controls. (13)C-tryptophan (150 mg) was orally administered and the (13)CO2/(12)CO2 ratio in the breath was monitored for 180 min. The cumulative recovery rate during the 180-min test (CRR0-180; %), area under the Δ(13)CO2-time curve (AUC; %*min), and the maximal Δ(13)CO2 (Cmax; %) were significantly higher in patients with MDD than in the controls (p = 0.004, p = 0.008, and p = 0.002, respectively). Plasma tryptophan concentrations correlated negatively with Cmax in both the patients and controls (p = 0.020 and p = 0.034, respectively). Our results suggest that the (13)C-TBT could be a novel biomarker for detecting a subgroup of MDD with increased tryptophan-KYN metabolism.

Figures

Figure 1. Schematic view of 13 C-tryptophan…
Figure 1. Schematic view of 13C-tryptophan metabolism.
After utilization for protein synthesis, over 90% of dietary tryptophan is converted to KYN by one of two rate-limiting enzymes: by TDO in the liver under healthy conditions and by IDO in various human tissues (e.g., intestines, lungs, placenta, kidneys, spleen, blood, and brain) under inflammatory conditions. The 13CO2 derived from 13C-tryptophan is produced by the conversion of 3-OH-KYN into 3HAA via the KYN–NAD pathway (box with solid line) as the post-KYN metabolism. In addition, although 13CO2 is produced to a minor degree in the tryptophan–serotonin and anthranilic acid pathways, it is not produced by the KA (box with dotted line) or xanthurenic acid pathways. Bold arrows indicate quantitatively major pathways. Minor pathways and pathways without release of 13CO2 are omitted. Red circles indicate the 13C-labeled carbon. Abbreviations: IDO, indoleamine 2,3-dioxygenase; KA, kynurenic acid; KYN, kynurenine; NAD, nicotinamide adenine dinucleotide; TDO, tryptophan 2,3-dioxygenase; 3HAA, 3-hydroxyanthranilic acid; 3-OH-KYN, 3-hydroxy-l-kynurenine.
Figure 2
Figure 2
(a) Time course for the Δ13CO2 in expired air after the 13C-tryptophan breath test was applied to patients with major depressive disorder (MDD) and to healthy controls. (b) Time course for the cumulative recovery rate (CRR; %) in expired air for patients with MDD and for healthy controls. Abbreviations: MDD, major depressive disorder group; CON, control group; Time, time after ingesting the solution of 13C-tryptophan (150 mg).

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