Protein-Bound Uremic Toxins and Immunity

Rocchetti, Maria Teresa; Cosola, Carmela; Ranieri, Elena; Gesualdo, Loreto

doi:10.1007/978-1-0716-1507-2_15

Cited by 17 publications

(9 citation statements)

References 70 publications

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“…In this report, we provide evidence that GDBSs are enriched in memory CD4 + T cells (PCS) and in the plasma of INR (PCS and IS), possibly impeding CD4 + T cell recovery. PCS is the most studied toxin and was reported to have a pleiotropic effect on multiple cell types in vitro (37). PCS is proinflammatory and alters endothelial cell function (46).…”

Section: Discussionmentioning

confidence: 99%

“…Four GDBSs are generated by gut microbiota and have been extensively studied in combination with adverse clinical outcomes: (a) PCS is generated from tyrosine and phenylalanine as p-cresol by the gut microbiota and then acquires the sulfate group in the colon and the liver; (b) IS is generated from tryptophan by the gut bacterial tryptophanase enzyme, which transforms tryptophan to indole and then acquires the sulfate group in the colon and liver as well; (c) phenylactylglutamine (PAG) is generated by the gut microbiota from phenylalanine; and (d) trimethylamine N-oxide (TMAO) is generated by the gut microbiota from dietary amines, choline, betaine, and carnitine (36). Few studies have addressed the implication of these GDBSs in the modulation of immune responses (37) or whether GDBSs have a role in CD4 + T cell depletion in INRs.…”

Section: Introductionmentioning

confidence: 99%

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Gut-derived bacterial toxins impair memory CD4+ T cell mitochondrial function in HIV-1 infection

Ferrari¹,

Silva²,

Liu³

et al. 2022

Journal of Clinical Investigation

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gut-derived bacterial toxins impair memory CD4+ T cell mitochondrial function in HIV-1 infection

Ferrari¹,

Silva²,

Liu³

et al. 2022

Journal of Clinical Investigation

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“…Gut-derived PBUTs are bioactive microbiota metabolites originating exclusively from protein fermentation realized by the gut flora; they enter the blood circulation, where they are sulfated in the liver ( 36 ). Current clinical data indicated that the plasma level of PBUTs is rather low in the healthy population (HA: 16 μM, IS: 2 μM, PCS: 10 μM), but their average concentrations increase sharply in patients with CKD (HA: 398 μM, IS: 108 μM, PCS: 111 μM), as well as their highest concentrations (HA: 2,631 μM, IS: 940 μM, PCS: 219 μM) ( 27 , 37 ).…”

Section: Discussionmentioning

confidence: 99%

Short-Chain Fatty Acids Alleviate Hepatocyte Apoptosis Induced by Gut-Derived Protein-Bound Uremic Toxins

Deng

et al. 2021

Front. Nutr.

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Chronic kidney disease (CKD) is characterized with the influx of uremic toxins, which impairs the gut microbiome by decreasing beneficial bacteria that produce short-chain fatty acids (SCFAs) and increasing harmful bacteria that produce gut-derived protein-bound uremic toxins (PBUTs). This study aimed to assess the proapoptotic effects of three major gut-derived PBUTs in hepatocytes, and the effects of SCFAs on apoptosis phenotype in vitro. HepG2 (human liver carcinoma cells) and THLE-2 (immortalized human normal liver cells) cell line were incubated with 0, 2, 20, 200, 2000 μM p-cresol sulfate (PCS), indoxyl sulfate (IS), and hippuric acid (HA), respectively, for 24 h. Flow cytometry analysis indicated that three uremic toxins induced varying degrees of apoptosis in hepatocytes and HA represented the highest efficacy. These phenotypes were further confirmed by western blot of apoptosis protein expression [Caspase-3, Caspase-9, B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X protein (Bax)]. Human normal hepatocytes (THLE-2) are more sensitive to PBUTs-induced apoptosis compared with human hepatoma cells (HepG2). Mechanistically, extracellular HA could enter hepatocytes, increase reactive oxygen species (ROS) generation, and decrease mitochondrial membrane potential dose-dependently in THLE-2 cells. Notably, coculture with SCFAs (acetate, propionate, butyrate) for 24 h significantly improved HA-induced apoptosis in THLE-2 cells, and propionate (500 μM) represented the highest efficacy. Propionate reduction of apoptosis was associated with improving mitochondria dysfunction and oxidative stress in a manner involving reducing Caspase-3 expression, ROS production, and increasing the Bcl-2/Bax level. As such, our studies validated PBUTs accumulation might be an important cause of liver dysfunction in patients with CKD, and supplementation of SCFAs might be a viable way to protect the liver for patients with CKD.

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“…There are 25 known gut-derived PBUTs [ 83 ]. PBUTs are accumulated in CKD patients despite dialysis and hemofiltration due to their association with proteins which hinders their clearance from the plasma [ 84 ]. Characteristic representatives of this group include advanced glycation end products (AGEs), p-cresyl sulfate, indoxyl sulfate, indole acetic acid, kynurenines and phenylacetic acid which have the highest global toxicity score in terms of several biological systems affected and overall experimental and clinical evidence [ 37 ].…”

Section: Effects Of Alterations In the Intestinal Flora In Chronic Ki...mentioning

confidence: 99%

Homeostasis in the Gut Microbiota in Chronic Kidney Disease

Bhargava

Merckelbach

Noels

et al. 2022

Toxins

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The gut microbiota consists of trillions of microorganisms, fulfilling important roles in metabolism, nutritional intake, physiology and maturation of the immune system, but also aiding and abetting the progression of chronic kidney disease (CKD). The human gut microbiome consists of bacterial species from five major bacterial phyla, namely Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, and Verrucomicrobia. Alterations in the members of these phyla alter the total gut microbiota, with a decline in the number of symbiotic flora and an increase in the pathogenic bacteria, causing or aggravating CKD. In addition, CKD-associated alteration of this intestinal microbiome results in metabolic changes and the accumulation of amines, indoles and phenols, among other uremic metabolites, which have a feedforward adverse effect on CKD patients, inhibiting renal functions and increasing comorbidities such as atherosclerosis and cardiovascular diseases (CVD). A classification of uremic toxins according to the degree of known toxicity based on the experimental evidence of their toxicity (number of systems affected) and overall experimental and clinical evidence was selected to identify the representative uremic toxins from small water-soluble compounds, protein-bound compounds and middle molecules and their relation to the gut microbiota was summarized. Gut-derived uremic metabolites accumulating in CKD patients further exhibit cell-damaging properties, damage the intestinal epithelial cell wall, increase gut permeability and lead to the translocation of bacteria and endotoxins from the gut into the circulatory system. Elevated levels of endotoxins lead to endotoxemia and inflammation, further accelerating CKD progression. In recent years, the role of the gut microbiome in CKD pathophysiology has emerged as an important aspect of corrective treatment; however, the mechanisms by which the gut microbiota contributes to CKD progression are still not completely understood. Therefore, this review summarizes the current state of research regarding CKD and the gut microbiota, alterations in the microbiome, uremic toxin production, and gut epithelial barrier degradation.

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Protein-Bound Uremic Toxins and Immunity

Cited by 17 publications

References 70 publications

Gut-derived bacterial toxins impair memory CD4+ T cell mitochondrial function in HIV-1 infection

Gut-derived bacterial toxins impair memory CD4+ T cell mitochondrial function in HIV-1 infection

Short-Chain Fatty Acids Alleviate Hepatocyte Apoptosis Induced by Gut-Derived Protein-Bound Uremic Toxins

Homeostasis in the Gut Microbiota in Chronic Kidney Disease

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