Aryl Hydrocarbon Receptor and Uremic Toxins from the Gut Microbiota in Chronic Kidney Disease Patients: Is There a Relationship between Them?

Hypertension and chronic kidney disease (CKD) can originate during early-life. Tryptophan metabolites generated by different pathways have both detrimental and beneficial effects. In CKD, uremic toxins from the tryptophan-generating metabolites are endogenous ligands of the aryl hydrocarbon receptor (AHR). The interplay between AHR, nitric oxide (NO), the renin–angiotensin system (RAS), and gut microbiota is involved in the development of hypertension. We examined whether tryptophan supplementation in pregnancy can prevent hypertension and kidney disease programmed by maternal CKD in adult offspring via the aforementioned mechanisms. Sprague–Dawley (SD) female rats received regular chow or chow supplemented with 0.5% adenine for 3 weeks to induce CKD before pregnancy. Pregnant controls or CKD rats received vehicle or tryptophan 200 mg/kg per day via oral gavage during pregnancy. Male offspring were divided into four groups (n = 8/group): control, CKD, tryptophan supplementation (Trp), and CKD plus tryptophan supplementation (CKDTrp). All rats were sacrificed at the age of 12 weeks. We found maternal CKD induced hypertension in adult offspring, which tryptophan supplementation prevented. Maternal CKD-induced hypertension is related to impaired NO bioavailability and non-classical RAS axis. Maternal CKD and tryptophan supplementation differentially shaped distinct gut microbiota profile in adult offspring. The protective effect of tryptophan supplementation against maternal CKD-induced programmed hypertension is relevant to alterations to several tryptophan-metabolizing microbes and AHR signaling pathway. Our findings support interplay among tryptophan-metabolizing microbiome, AHR, NO, and the RAS in hypertension of developmental origins. Furthermore, tryptophan supplementation in pregnancy could be a potential approach to prevent hypertension programmed by maternal CKD.

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Association of Sarcopenia and Gut Microbiota Composition in Older Patients with Advanced Chronic Kidney Disease, Investigation of the Interactions with Uremic Toxins, Inflammation and Oxidative Stress

Toxins ◽

10.3390/toxins13070472 ◽

2021 ◽

Vol 13 (7) ◽

pp. 472

Author(s):

Elisabetta Margiotta ◽

Lara Caldiroli ◽

Maria Luisa Callegari ◽

Francesco Miragoli ◽

Francesca Zanoni ◽

...

Keyword(s):

Oxidative Stress ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Gut Microbiota ◽

Inflammatory Cytokines ◽

Interleukin 10 ◽

Uremic Toxins ◽

Interleukin 12 ◽

European Working ◽

And Oxidative Stress

Background: Sarcopenia is a prevalent condition in chronic kidney disease (CKD). We determined gut microbiota (gMB) composition in CKD patients with or without sarcopenia. Furthermore, we investigated whether in these patients, there was any association between gMB, uremic toxins, inflammation and oxidative stress. Methods: We analyzed gMB composition, uremic toxins (indoxyl sulphate and p-cresyl sulphate), inflammatory cytokines (interleukin 10, tumor necrosis factor α, interleukin 6, interleukin 17, interleukin 12 p70, monocyte chemoattractant protein-1 and fetuin-A) and oxidative stress (malondialdehyde) of 64 elderly CKD patients (10 < eGFR < 45 mL/min/1.73 m2, not on dialysis) categorized as sarcopenic and not-sarcopenic. Sarcopenia was defined according to European Working Group on Sarcopenia in Older People 2 criteria. Results: Sarcopenic patients had a greater abundance of the Micrococcaceae and Verrucomicrobiaceae families and of Megasphaera, Rothia, Veillonella, Akkermansia and Coprobacillus genera. They had a lower abundance of the Gemellaceae and Veillonellaceae families and of Acidaminococcus and Gemella genera. GMB was associated with uremic toxins, inflammatory cytokines and MDA. However, uremic toxins, inflammatory cytokines and MDA were not different in sarcopenic compared with not-sarcopenic individuals, except for interleukin 10, which was higher in not-sarcopenic patients. Conclusions: In older CKD patients, gMB was different in sarcopenic than in not-sarcopenic ones. Several bacterial families and genera were associated with uremic toxins and inflammatory cytokines, although none of these latter substantially different in sarcopenic versus not-sarcopenic patients.

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Identification of endogenous 1‐aminopyrene as a novel mediator of progressive chronic kidney disease via aryl hydrocarbon receptor activation

British Journal of Pharmacology ◽

10.1111/bph.15062 ◽

2020 ◽

Vol 177 (15) ◽

pp. 3415-3435 ◽

Cited By ~ 5

Author(s):

Hua Miao ◽

Gang Cao ◽

Xia‐Qing Wu ◽

Yuan‐Yuan Chen ◽

Dan‐Qian Chen ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Aryl Hydrocarbon Receptor ◽

Receptor Activation ◽

Aryl Hydrocarbon

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Tryptophan-Derived Uremic Toxins and Thrombosis in Chronic Kidney Disease

Toxins ◽

10.3390/toxins10100412 ◽

2018 ◽

Vol 10 (10) ◽

pp. 412 ◽

Cited By ~ 19

Author(s):

Tawfik Addi ◽

Laetitia Dou ◽

Stéphane Burtey

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Cardiovascular Events ◽

Elevated Risk ◽

Uremic Toxins ◽

Extrinsic Pathway ◽

Coronary Syndrome ◽

Aryl Hydrocarbon ◽

Hemodialysis Vascular Access ◽

No Bioavailability

Patients with chronic kidney disease (CKD) display an elevated risk of thrombosis. Thrombosis occurs in cardiovascular events, such as venous thromboembolism, stroke, and acute coronary syndrome, and is a cause of hemodialysis vascular access dysfunction. CKD leads to the accumulation of uremic toxins, which exerts toxic effects on blood and the vessel wall. Some uremic toxins result from tryptophan metabolization in the gut through the indolic and the kynurenine pathways. An increasing number of studies are highlighting the link between such uremic toxins and thrombosis in CKD. In this review, we describe the thrombotic mechanisms induced by tryptophan-derived uremic toxins (TDUT). These mechanisms include an increase in plasma levels of procoagulant factors, induction of platelet hyperactivity, induction of endothelial dysfunction/ impairment of endothelial healing, decrease in nitric oxide (NO) bioavailability, and production of procoagulant microparticles. We focus on one important prothrombotic mechanism: The induction of tissue factor (TF), the initiator of the extrinsic pathway of the blood coagulation. This induction occurs via a new pathway, dependent on the transcription factor Aryl hydrocarbon receptor (AhR), the receptor of TDUT in cells. A better understanding of the prothrombotic mechanisms of uremic toxins could help to find novel therapeutic targets to prevent thrombosis in CKD.

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The Impact of CKD on Uremic Toxins and Gut Microbiota

Toxins ◽

10.3390/toxins13040252 ◽

2021 ◽

Vol 13 (4) ◽

pp. 252

Author(s):

Jacek Rysz ◽

Beata Franczyk ◽

Janusz Ławiński ◽

Robert Olszewski ◽

Aleksanda Ciałkowska-Rysz ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Microbial Community ◽

Kidney Disease ◽

Gut Microbiota ◽

Intestinal Inflammation ◽

Adverse Outcomes ◽

Uremic Toxins ◽

Dietary Interventions ◽

Stress Injury ◽

The Impact

Numerous studies have indicated that the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD) is strictly associated with the accumulation of toxic metabolites in blood and other metabolic compartments. This accumulation was suggested to be related to enhanced generation of toxins from the dysbiotic microbiome accompanied by their reduced elimination by impaired kidneys. Intestinal microbiota play a key role in the accumulation of uremic toxins due to the fact that numerous uremic solutes are generated in the process of protein fermentation by colonic microbiota. Some disease states, including CKD, are associated with the presence of dysbiosis, which can be defined as an “imbalanced intestinal microbial community with quantitative and qualitative changes in the composition and metabolic activities of the gut microbiota”. The results of studies have confirmed the altered composition and functions of gut microbial community in chronic kidney disease. In the course of CKD protein-bound uremic toxins, including indoxyl sulfate, p-cresyl glucuronide, p-cresyl sulfate and indole-3-acetic acid are progressively accumulated. The presence of chronic kidney disease may be accompanied by the development of intestinal inflammation and epithelial barrier impairment leading to hastened systemic translocation of bacterial-derived uremic toxins and consequent oxidative stress injury to the kidney, cardiovascular and endocrine systems. These findings offer new therapeutic possibilities for the management of uremia, inflammation and kidney disease progression and the prevention of adverse outcomes in CKD patients. It seems that dietary interventions comprising prebiotics, probiotics, and synbiotics could pose a promising strategy in the management of uremic toxins in CKD.

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Aryl hydrocarbon receptor is activated in patients and mice with chronic kidney disease

Kidney International ◽

10.1016/j.kint.2017.11.010 ◽

2018 ◽

Vol 93 (4) ◽

pp. 986-999 ◽

Cited By ~ 26

Author(s):

Laetitia Dou ◽

Stéphane Poitevin ◽

Marion Sallée ◽

Tawfik Addi ◽

Bertrand Gondouin ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Aryl Hydrocarbon Receptor ◽

Aryl Hydrocarbon

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Aryl hydrocarbon receptor (AhR) and its endogenous agonist – indoxyl sulfate in chronic kidney disease

Postępy Higieny i Medycyny Doświadczalnej ◽

10.5604/01.3001.0010.3843 ◽

2017 ◽

Vol 71 (1) ◽

pp. 0-0 ◽

Cited By ~ 7

Author(s):

Tomasz Kamiński ◽

Małgorzata Michałowska ◽

Dariusz Pawlak

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Aryl Hydrocarbon Receptor ◽

Biological Effects ◽

P53 Protein ◽

Free Fraction ◽

High Reactivity ◽

Indoxyl Sulfate ◽

Aryl Hydrocarbon ◽

Tryptophan Degradation

The indoxyl sulfate (IS, indoxyl sulphate) is the end product of dietary tryptophan degradation by indole pathway and significantly higher serum and tissue concentrations of this compound is observed in patients with impaired renal function. Despite the high albumin binding affinity, the remaining free fraction of IS has a number of biological effects related to the generation of oxidative stress andactivation of signaling pathways related to NF-кB, p53 protein, STAT3, TGF-β and Smad2/3. IS induces the inflammatory process, exerts nephrotoxic activity and is also a factor impairing the cardiovascular system.Its high concentrations are associated with the occurrence of cardiovascular incidents, whose frequency is significantly higher in patients with chronic kidney disease. Evaluation of the mechanisms that underlie the high reactivity of indoxyl sulfate and its biological effects showed that this compound is an agonist of the aryl hydrocarbon receptor (AhR). This receptor plays an important role in maintaining homeostasis Moreover, AhR exerts high transcriptional activity, so ligands of obciążethis receptor may exert different biological effects. The following paper describes the role of indoxyl sulfate as AhR ligand in the context of the excessive accumulation, which appears as one of the symptoms associated with chronic kidney disease.

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