Metabolomics analysis of human plasma reveals decreased production of trimethylamine N‐oxide retards the progression of chronic kidney disease

D, Hu; Wu, Mingyu; Chen, Guang-Qi; Deng, Bing; Yu, Haibo; Huang, Jian; Luo, Ying; Li, Mengyuan; Liu, Jun-Yan

doi:10.1111/bph.15856

Cited by 23 publications

(9 citation statements)

References 49 publications

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“…For clinical use, one appropriate use case may involve an early detection of chronic kidney disease onset, especially as a microvascular complication from diabetes. 30 Multiple studies have probed metabolic differences related to chronic kidney progression using serum or urine metabolomics, [30][31][32][33][34][35] and we highlight some of the differences with our work. First, our work highlights that differences in serum metabolic profiles are not necessarily reflected in sweat.…”

Section: Discussionmentioning

confidence: 99%

Identification of end‐stage renal disease metabolic signatures from human perspiration

et al. 2023

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End-stage renal disease (ESRD), characterized by cessation in kidney function, has been linked to severe metabolic disturbances, caused by the buildup of toxic solutes in blood.To remove these solutes, ESRD patients undergo dialysis. As a proof of concept, we tested whether ESRD-related metabolic signatures can be detected in perspiration samples using a combined methodology. Our rapid methodology involves swabbing a glass slide across the patient's forehead, detecting the metabolites in the imprint using desorption electrospray ionization mass spectrometry, and identifying the key differences using machine learning methods. Based on collecting 42 healthy and 27 ESRD samples, we find saturated fatty acids are consistently suppressed in ESRD patients, with little change after dialysis. Moreover, our method enables the detection of uremic solutes, where we find elevated levels of uric acid (6.7 fold higher on average) that sharply decrease after dialysis. Beyond the study of individual metabolites, we find that a lasso model, which selects for 8 m/z fragments from 24,602 detected analytes, achieves area under the curve performance of 0.85 and 0.87 on training (n = 52) and validation sets (n = 17), respectively. Together, these results suggest that this methodology is promising for detecting signatures relevant for precision health. Key points• Combines physical measurements with statistical analysis based on machine learning.• Uses results to make medical predictions.• Learns about biological pathways.

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Section: Discussionmentioning

confidence: 99%

Identification of end‐stage renal disease metabolic signatures from human perspiration

et al. 2023

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“…Thus, the gender-specificity and clinical relevance of this CAR-FMO3-TMAO-platelet axis deserves further investigation. In addition to platelet function and thrombotic risk, an increase in the TMAO plasma concentration has also been shown to increase the risk of impaired glucose tolerance 59 , colorectal cancer 60 , chronic kidney disease 61 and overall mortality 62 . Whether drugs interacting with CAR could also influence these TMAO-dependent endpoints deserves further investigations.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological activation of constitutive androstane receptor induces female-specific modulation of hepatic metabolism

Huillet

Lasserre

Gratacap

et al. 2023

Preprint

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Background and Aims: The constitutive androstane receptor (CAR) is a nuclear receptor able to recognize a large panel of xenobiotics leading to the modulation of the expression of its target genes involved in xenobiotic detoxication and energy metabolism. While CAR hepatic activity is thought to be higher in women than in men, its response to an acute pharmacological activation has never been investigated in both sexes. Methods: Hepatic transcriptome, plasma and hepatic metabolome, have been analyzed in Car+/+ and Car-/- male and female mice treated either with the CAR-specific agonist, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), or with vehicle. Results: While 90% of TCPOBOP-sensitive genes were modulated in a sex- independent way, the remaining 10% were almost exclusively impacted in female liver specifically. These female-specific CAR-sensitive genes were mainly involved in xenobiotic metabolism, inflammation and extracellular matrix organization. CAR activation also induced higher hepatic oxidative stress and hepatocyte cytolysis in females than in males. Data mining on human data confirmed that CAR activation may be involved in sexually-dimorphic drug-induced liver injury. Hepatic expression of flavin monooxygenase 3 (Fmo3) was almost abolished and associated with a decrease of hepatic trimethylamine-N-oxide (TMAO) concentration in TCPOBOP-treated females. In line with a possible role in the control of TMAO homeostasis, CAR activation decreased platelet hyperresponsiveness in female mice supplemented with dietary choline. Conclusions: Our results demonstrate that more than 10% of CAR-sensitive genes are sex-specific and influence hepatic and systemic response such as platelet aggregation. Also, CAR activation may be an important mechanism of sexually- dimorphic drug-induced liver injury.

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“…Elevated plasma levels of TMAO and its precursors are associated with poor prognosis of CKD [22]. Da-Yong Hu et al reported that inhibiting the TMAO biosynthetic pathway attenuated renal injury in a murine model of CKD [23]. Yan-Ni Wang et al demonstrated that the dysregulation of phosphatidylcholine metabolism is involved in CKD pathology [17].…”

Section: Discussionmentioning

confidence: 99%

Investigation of the Metabolism of Astragaloside IV in a Puromycin-Damaged Rat Model by UPLC-Q-TOF-MS/MS Analysis

Zhang,

Huang,

Liu

et al. 2023

Planta Med

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Astragaloside IV (AS-IV) has been shown to provide renal protection in various kidney injury models. However, the metabolic profile variation of AS-IV in pathological models in vivo is not well established. This study aims to explore the metabolic pathway of AS-IV in vivo in the classical puromycin aminonucleoside (PAN)-induced kidney injury in a rat model. Twelve Wistar rats were randomly divided into the AS-IV (CA) and the PAN+AS-IV (PA) treatment groups. PAN was injected by a single tail intravenous (i. v.) injection at 5 mg/100 g body weight, and AS-IV was administered intragastrically (i. g.) at 40 mg/kg for 10 days. Fecal samples of these rats were collected, and metabolites of AS-IV were detected by ultra-performance liquid chromatography coupled with quadrupole/time-of-flight mass spectrometry (UPLC-Q-TOF-MS/MS) to explore the AS-IV metabolic pathway. The metabolic differences between the AS-IV and PAN+AS-IV groups were compared. A total of 25 metabolites were detected, and deglycosylation, deoxygenation, and methyl oxidation were found to be the main metabolic pathways of AS-IV in vivo. The abundance of most of these metabolites in the PAN+AS-IV group was lower than that in the AS-IV treatment group, and differences for seven of them were statistically significant. Our study indicates that AS-IV metabolism is affected in the PAN-induced kidney injury rat model.

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Metabolomics analysis of human plasma reveals decreased production of trimethylamine N‐oxide retards the progression of chronic kidney disease

Cited by 23 publications

References 49 publications

Identification of end‐stage renal disease metabolic signatures from human perspiration

Identification of end‐stage renal disease metabolic signatures from human perspiration

Pharmacological activation of constitutive androstane receptor induces female-specific modulation of hepatic metabolism

Investigation of the Metabolism of Astragaloside IV in a Puromycin-Damaged Rat Model by UPLC-Q-TOF-MS/MS Analysis

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