Gut microbiota-derived tryptophan metabolism mediates renal fibrosis by aryl hydrocarbon receptor signaling activation

Liu, Jingru; Miao, Hua; Deng, Deqiang; Vaziri, Nosratola D.; Li, Ping; Zhao, Ying-Yong

doi:10.1007/s00018-020-03645-1

Cited by 125 publications

(102 citation statements)

References 104 publications

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“…Moreover, the metabolites of tryptophan metabolism can act as the ligands binding to specific receptors to elicited various pathologic cellular process. For example, kynurenine, serotonin and indole derivatives may bind to aryl hydrocarbon receptor (AHR), a cytoplasmic ligand-activated transcription factor, to trigger oxidative stress, inflammation in chronic kidney disease [ 38 ]. via UPLC-based metabolomics technology, we constructed the important position of tryptophan metabolism once again and revealed novel metabolites derived from tryptophan in DG, which may provide fruitful insights into the study on DG pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Untargeted serum metabolomics and tryptophan metabolism profiling in type 2 diabetic patients with diabetic glomerulopathy

et al. 2021

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Diabetic glomerulopathy (DG) remains the prevalent microvascular complication and leading cause of shortened lifespan in type-2 diabetes mellitus (T2DM) despite improvement in hyperglycemia control. Considering the pivotal role of kidney in metabolism, using untargeted metabolomic techniques to globally delineate the serum metabolite profiles will help advance understanding pathogenetic underpinnings of renal biopsy-confirmed DG from the perspective of metabolism specifically. Fourteen pathologically diagnosed DG patients secondary to T2DM and 14 age-and gender-matched healthy controls (HCs) were recruited for study. We employed mass spectrometry-based untargeted metabolomic methods to reveal the metabolite profiles of serum samples collected from all included subjects. We identified a total of 334 and 397 metabolites in positive and negative ion mode respectively. One hundred and eighty-two important differential metabolites whose variable importance in projection (VIP) > 1 and p value <0.05 were selected and annotated to metabolic pathways. KEGG pathway enrichment analysis revealed tryptophan metabolism enriched most significantly. Among the tryptophan derivatives, L-tryptophan (L-Trp) and serotonin were relatively accumulated in DGs compared with HCs, while 5-hydroxyindoleacetic acid (5-HIAA) and indole-3-acetamide were depleted. Correlation analysis showed serotonin and L-Trp are negatively correlated with 24 h urine protein and glycosylated hemoglobin (Ghb). To exclude the interference of preexisting T2DM on DG exacerbation, we selected 5-HIAA and 3-(3-hydroxyphenyl) propionic acid (3-OHPPA) which are not correlated with Ghb and analyzed their correlation relationship with crucial renal indices. We found 3-OHPPA is positively correlated with urine total protein and creatinine ratio (T/Cr) and 24 h urine protein, 5-HIAA is positively correlated with serum creatinine and urea.

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Section: Discussionmentioning

confidence: 99%

Untargeted serum metabolomics and tryptophan metabolism profiling in type 2 diabetic patients with diabetic glomerulopathy

et al. 2021

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“…According to the latest global kidney disease health report released by the World Kidney Conference in 2021, 1 out of 10 people in the world suffers from kidney disease [25]. In recent years, more and more evidence has shown that there are disorders of intestinal ora and impaired intestinal barrier function in patients with chronic kidney disease [26][27][28][29][30]. Therefore, more and more scienti c experiments are investigated the mechanism of the intestinal-renal axis in CKD, hoping to delay its progress by regulating the intestinal ora.…”

Section: Discussionmentioning

confidence: 99%

Lanthanum Hydroxide Protects Kidney Through Gut-Metabolite-Kidney Axis in a Rat Model of CKD

Gao

Wang

Sun

et al. 2021

Preprint

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Background: Recent evidence suggests alterations in the gut-kidney axis may drive chronic kidney disease (CKD). Results: In the present study, we observed that administration of adenine to rats induced CKD, gut microbial dysbiosis, kidney pathology, and amino acid metabolism. In this model of CKD hyperphosphatemia, lanthanum hydroxide improved kidney function in CKD rats by restoring gut microbial homeostasis, thereby increasing urine ammonium metabolism. These findings demonstrated that lanthanum hydroxide improves kidney function in a CKD model in mice by restoring homeostasis of the gut-metabolite-kidney axis, which alleviated an amino acid imbalance. Lanthanum hydroxide thus shows therapeutic potential for patients with CKD, through reshaping the composition of gut microbiota.Conclusions: Lanthanum hydroxide plays a kidney protective role through the gut-metabolite-kidney axis in a rat model of chronic kidney disease caused by adenine.

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“…Therefore, an adenine-induced rats model provides a potential platform to study the progression of CRF. In the past few decades, substantial advances have been made in understanding the underlying pathophysiology of CRF, leading to the development of novel pharmaceuticals and interventional therapies [6,7]. Tragically, efficient treatment in the clinical setting are scarce and often ineffective to either stop or reverse progression of CRF, underscoring the importance of novel therapeutics on disease intervention.…”

Section: Introductionmentioning

confidence: 99%

The Dysregulation of Eicosanoids and Bile Acids Correlates with Impaired Kidney Function and Renal Fibrosis in Chronic Renal Failure

Wang

Zhang

et al. 2021

Metabolites

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Chronic renal failure (CRF) is an irreversible deterioration of the renal functions that characterized by fluid electrolyte unbalance and metabolic-endocrine dysfunctions. Increasing evidence demonstrated that metabolic disturbances, especially dyslipidemia and profound changes in lipid and lipoprotein metabolism were involved in CRF. Identification of lipids associated with impaired kidney functions may play important roles in the understanding of biochemical mechanism and CRF treatment. Ultra-performance liquid chromatography coupled with high-definition mass spectrometry-based lipidomics was performed to identify important differential lipids in adenine-induced CRF rats and investigate the undergoing anti-fibrotic mechanism of Polyporus umbellatus (PPU) and ergone (ERG). Linear correlation analysis was performed between lipid species intensities and creatinine levels in serum. Adenine-induced rats exhibited declining kidney function and renal fibrosis. Compared with control rats, a panel of lipid species was identified in the serum of CRF rats. Our further study demonstrated that eight lipids, including leukotrienes and bile acids, presented a strong linear correlation with serum creatinine levels. In addition, receiver operating characteristics analysis showed that eight lipids exhibited excellent area under the curve for differentiating CRF from control rats, with high sensitivity and specificity. The aberrant changes of clinical biochemistry data and dysregulation of eight lipids could be significantly improved by the administration of PPU and ergone. In conclusion, CRF might be associated with the disturbance of leukotriene metabolism, bile acid metabolism and lysophospholipid metabolism. The levels of eicosanoids and bile acids could be used for indicating kidney function impairment in CRF. PPU could improve renal functions and either fully or partially reversed the levels of eicosanoids and bile acids.

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Gut microbiota-derived tryptophan metabolism mediates renal fibrosis by aryl hydrocarbon receptor signaling activation

Cited by 125 publications

References 104 publications

Untargeted serum metabolomics and tryptophan metabolism profiling in type 2 diabetic patients with diabetic glomerulopathy

Untargeted serum metabolomics and tryptophan metabolism profiling in type 2 diabetic patients with diabetic glomerulopathy

Lanthanum Hydroxide Protects Kidney Through Gut-Metabolite-Kidney Axis in a Rat Model of CKD

The Dysregulation of Eicosanoids and Bile Acids Correlates with Impaired Kidney Function and Renal Fibrosis in Chronic Renal Failure

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