The relationship between blood metabolites of the tryptophan pathway and kidney function: a bidirectional Mendelian randomization analysis

Cheng, Yu-Rong; Li, Yong; Benkowitz, Paula; Lamina, Claudia; Köttgen, Anna; Sekula, Peggy

doi:10.1038/s41598-020-69559-x

Cited by 30 publications

(30 citation statements)

References 92 publications

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“…The results from our exploratory metabolome profiling analysis revealed that VAKI patients had higher serum values of 5-methoxyindoleacetic acid (5-MIAA), anthranilic acid, IAA, kynurenine, quinolinic acid, and Kyn/Trp compared with non-VAKI patients (Figure 2B), and these findings were similar to those of a previous report in AKI patients [34]. However, Kyn/Trp might not be suitable for detecting VAKI because it tends to be higher in patients with infection and CKD compared with HCs [32,33,35,36]. Furthermore, Kyn/Trp and other metabolites of the kynurenine pathway would be affected by dietary conditions, including Trp supplementation [37].…”

Section: Discussionsupporting

confidence: 85%

Serum 5-Hydroxyindoleacetic Acid and Ratio of 5-Hydroxyindoleacetic Acid to Serotonin as Metabolomics Indicators for Acute Oxidative Stress and Inflammation in Vancomycin-Associated Acute Kidney Injury

et al. 2021

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The incidence of vancomycin-associated acute kidney injury (VAKI) varies from 5–43%, and early detection of VAKI is important in deciding whether to discontinue nephrotoxic agents. Oxidative stress is the main mechanism of VAKI, and serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) have been examined with respect to their involvement in ischemia/reperfusion damage in experimental animal models. In the current study, we assessed 5-HT and 5-HIAA as novel biomarkers for detecting VAKI in patients who have infections or compromised renal function, using a mass spectrometry–based metabolomics approach. We conducted amino acid profiling analysis and measurements of 5-HT and 5-HIAA using serum from subjects with VAKI (n = 28) and non-VAKI control subjects (n = 69), consisting of the infection subgroup (n = 23), CKD subgroup (n = 23), and healthy controls (HCs, n = 23). 5-HT was significantly lower in the VAKI group than in the non-VAKI groups, and the concentration of 5-HIAA and the ratio of 5-HIAA to 5-HT (5-HIAA/5-HT) showed higher values in the VAKI group. The infection subgroup presented a significantly greater 5-HIAA/5-HT ratio compared with the HC subgroup. Our study revealed that increased 5-HIAA/5-HT ratio has the potential to act as a VAKI surrogate marker, reflecting acute oxidative stress and inflammation.

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Section: Discussionsupporting

confidence: 85%

Serum 5-Hydroxyindoleacetic Acid and Ratio of 5-Hydroxyindoleacetic Acid to Serotonin as Metabolomics Indicators for Acute Oxidative Stress and Inflammation in Vancomycin-Associated Acute Kidney Injury

et al. 2021

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Section: Discussionmentioning

confidence: 99%

“…This suggests a clinically significant role of tryptophan metabolism in CKD. In contrast, Cheng and colleagues recently set out to evaluate the existence of a causal relationship between metabolites of the tryptophan pathway and kidney function using a bidirectional Mendelian randomization analysis, and they revealed that the increased blood levels of tryptophan metabolites were a consequence rather than a cause of a reduced eGFR [ 24 ]. However, it is becoming clear that IDO has a complex role in chronic inflammatory and metabolic diseases and remains an interesting therapeutic target [ 25 ], however, in-depth knowledge about its regulation and interconnection to other enzyme systems is essential in the development of effective therapies [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Local Inhibition of Indoleamine 2,3-Dioxygenase Mitigates Renal Fibrosis

Jensen

Tingskov

et al. 2021

Biomedicines

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Chronic kidney disease (CKD) is a major global health concern and renal fibrosis is an integral part of the pathophysiological mechanism underlying disease progression. In CKD patients, the majority of metabolic pathways are in disarray and perturbations in enzyme activity most likely contribute to the wide variety of comorbidities observed in these patients. To illustrate, catabolism of tryptophan by indoleamine 2,3-dioxygenase (IDO) gives rise to numerous biologically active metabolites implicated in CKD progression. Here, we evaluated the effect of antagonizing IDO on renal fibrogenesis. To this end, we antagonized IDO using 1-methyl-D-tryptophan (1-MT) and BMS-98620 in TGF-β-treated murine precision-cut kidney slices (mPCKS) and in mice subjected to unilateral ureteral obstruction (UUO). The fibrotic response was evaluated on both the gene and protein level using qPCR and western blotting. Our results demonstrated that treatment with 1-MT or BMS-985205 markedly reduced TGF-β-mediated fibrosis in mPCKS, as seen by a decreased expression of collagen type 1, fibronectin, and α-smooth muscle actin. Moreover, IDO protein expression clearly increased following UUO, however, treatment of UUO mice with either 1-MT or BMS-986205 did not significantly affect the gene and protein expression of the tested fibrosis markers. However, both inhibitors significantly reduced the renal deposition of collagen in UUO mice as shown by Sirius red and trichrome staining. In conclusion, this study demonstrates that IDO antagonism effectively mitigates fibrogenesis in mPCKS and reduces renal collagen accumulation in UUO mice. These findings warrant further research into the clinical application of IDO inhibitors for the treatment of renal fibrosis.

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“…Although we statistically corrected for age, the wide age range might still have influenced our results. Next, we did not measure renal function or dietary habits, which could be possible confounders [36] [-] [38]. However, none of the participants was known to have a history of kidney disease.…”

Section: This Figure Shows the Correlations Between The Non-motor Symptoms And Concentrations Of Metabolites In The Dystonia Group (Excl mentioning

confidence: 99%

Dopaminergic and serotonergic alterations in plasma in three groups of dystonia patients

Timmers

Faassen

Smit

et al. 2021

Parkinsonism & Related Disorders

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In dystonia, dopaminergic alterations are considered to be responsible for the motor symptoms. Recent attention for the highly prevalent non-motor symptoms suggest also a role for serotonin in the pathophysiology. In this study we investigated the dopaminergic, serotonergic and noradrenergic metabolism in blood samples of dystonia patients and its relation with (non-)motor manifestations. Methods: Concentrations of metabolites of dopaminergic, serotonergic and noradrenergic pathways were measured in platelet-rich plasma in 41 myoclonus-dystonia (M-D), 25 dopa-responsive dystonia (DRD), 50 cervical dystonia (CD) patients and 55 healthy individuals. (Non-)motor symptoms were assessed using validated instruments, and correlated with concentrations of metabolites. Results: A significantly higher concentration of 3-methoxytyramine (0.03 vs. 0.02 nmol/L, p < 0.01), a metabolite of dopamine, and a reduced concentration of tryptophan (50 vs. 53 μmol/L, p = 0.03), the precursor of serotonin was found in dystonia patients compared to controls. The dopamine/levodopa ratio was higher in CD patients compared to other dystonia groups (p < 0.01). Surprisingly, relatively high concentrations of levodopa were found in the untreated DRD patients. Low concentrations of levodopa were associated with severity of dystonia (r s = − 0.3, p < 0.01), depression (r s = − 0.3, p < 0.01) and fatigue (r s = − 0.2, p = 0.04). Conclusion:This study shows alterations in the dopaminergic and serotonergic metabolism of patients with dystonia, with dystonia subtype specific changes. Low concentrations of levodopa, but not of serotonergic metabolites, were associated with both motor and non-motor symptoms. Further insight into the dopaminergic and serotonergic systems in dystonia with a special attention to the kinetics of enzymes involved in these pathways, might lead to better treatment options.

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The relationship between blood metabolites of the tryptophan pathway and kidney function: a bidirectional Mendelian randomization analysis

Cited by 30 publications

References 92 publications

Serum 5-Hydroxyindoleacetic Acid and Ratio of 5-Hydroxyindoleacetic Acid to Serotonin as Metabolomics Indicators for Acute Oxidative Stress and Inflammation in Vancomycin-Associated Acute Kidney Injury

Serum 5-Hydroxyindoleacetic Acid and Ratio of 5-Hydroxyindoleacetic Acid to Serotonin as Metabolomics Indicators for Acute Oxidative Stress and Inflammation in Vancomycin-Associated Acute Kidney Injury

Local Inhibition of Indoleamine 2,3-Dioxygenase Mitigates Renal Fibrosis

Dopaminergic and serotonergic alterations in plasma in three groups of dystonia patients

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