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      Targeted metabolomics study of serum bile acid profile in patients with end-stage renal disease undergoing hemodialysis

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          Abstract

          Background

          Bile acids are important metabolites of intestinal microbiota, which have profound effects on host health. However, whether metabolism of bile acids is involved in the metabolic complications of end-stage renal disease (ESRD), and the effects of bile acids on the prognosis of ESRD remain obscure. Therefore, this study investigated the relationship between altered bile acid profile and the prognosis of ESRD patients.

          Methods

          A targeted metabolomics approach based on ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to determine the changes in serum bile acids between ESRD patients ( n = 77) and healthy controls ( n = 30). Univariate and multivariate statistical analyses were performed to screen the differential proportions of bile acids between the two groups.

          Results

          Six differentially expressed bile acids were identified as potential biomarkers for differentiating ESRD patients from healthy subjects. The decreased concentrations of chenodeoxycholic acid, deoxycholic acid and cholic acid were significantly associated with dyslipidemia in ESRD patients. Subgroup analyses revealed that the significantly increased concentrations of taurocholic acid, taurochenodeoxycholic acid, taurohyocholic acid and tauro α-muricholic acid were correlated to the poor prognosis of ESRD patients.

          Conclusions

          The serum bile acid profile of ESRD patients differed significantly from that of healthy controls. In addition, the altered serum bile acid profile might contribute to the poor prognosis and metabolic complications of ESRD patients.

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          Most cited references27

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          Identification of a nuclear receptor for bile acids.

          Bile acids are essential for the solubilization and transport of dietary lipids and are the major products of cholesterol catabolism. Results presented here show that bile acids are physiological ligands for the farnesoid X receptor (FXR), an orphan nuclear receptor. When bound to bile acids, FXR repressed transcription of the gene encoding cholesterol 7alpha-hydroxylase, which is the rate-limiting enzyme in bile acid synthesis, and activated the gene encoding intestinal bile acid-binding protein, which is a candidate bile acid transporter. These results demonstrate a mechanism by which bile acids transcriptionally regulate their biosynthesis and enterohepatic transport.
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            Microbiota-Modulated Metabolites Shape the Intestinal Microenvironment by Regulating NLRP6 Inflammasome Signaling.

            Host-microbiome co-evolution drives homeostasis and disease susceptibility, yet regulatory principles governing the integrated intestinal host-commensal microenvironment remain obscure. While inflammasome signaling participates in these interactions, its activators and microbiome-modulating mechanisms are unknown. Here, we demonstrate that the microbiota-associated metabolites taurine, histamine, and spermine shape the host-microbiome interface by co-modulating NLRP6 inflammasome signaling, epithelial IL-18 secretion, and downstream anti-microbial peptide (AMP) profiles. Distortion of this balanced AMP landscape by inflammasome deficiency drives dysbiosis development. Upon fecal transfer, colitis-inducing microbiota hijacks this microenvironment-orchestrating machinery through metabolite-mediated inflammasome suppression, leading to distorted AMP balance favoring its preferential colonization. Restoration of the metabolite-inflammasome-AMP axis reinstates a normal microbiota and ameliorates colitis. Together, we identify microbial modulators of the NLRP6 inflammasome and highlight mechanisms by which microbiome-host interactions cooperatively drive microbial community stability through metabolite-mediated innate immune modulation. Therefore, targeted "postbiotic" metabolomic intervention may restore a normal microenvironment as treatment or prevention of dysbiosis-driven diseases.
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              A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis.

              Bile acids repress the transcription of cytochrome P450 7A1 (CYP7A1), which catalyzes the rate-limiting step in bile acid biosynthesis. Although bile acids activate the farnesoid X receptor (FXR), the mechanism underlying bile acid-mediated repression of CYP7A1 remained unclear. We have used a potent, nonsteroidal FXR ligand to show that FXR induces expression of small heterodimer partner 1 (SHP-1), an atypical member of the nuclear receptor family that lacks a DNA-binding domain. SHP-1 represses expression of CYP7A1 by inhibiting the activity of liver receptor homolog 1 (LRH-1), an orphan nuclear receptor that is known to regulate CYP7A1 expression positively. This bile acid-activated regulatory cascade provides a molecular basis for the coordinate suppression of CYP7A1 and other genes involved in bile acid biosynthesis.
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                Author and article information

                Contributors
                Journal
                PeerJ
                PeerJ
                PeerJ
                PeerJ
                PeerJ
                PeerJ Inc. (San Diego, USA )
                2167-8359
                17 June 2019
                2019
                : 7
                : e7145
                Affiliations
                [1 ]Department of Nephrology, Second Affiliated Hospital of Chongqing Medical University , Chongqing, China
                [2 ]Chongqing Key Laboratory of Ultrasound Molecular Imaging, Ultrasound Department of the Second Affiliated Hospital of Chongqing Medical University , Chongqing, China
                Author information
                http://orcid.org/0000-0002-9356-159X
                Article
                7145
                10.7717/peerj.7145
                6585905
                d61e3065-96ab-4d49-a9ec-1147f32c3bd2
                © 2019 Li et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited.

                History
                : 23 January 2019
                : 18 May 2019
                Funding
                Funded by: China Postdoctoral Science Foundation funded project
                Award ID: 2018M633630XB
                Funded by: Science and Technology Research Program of Chongqing Municipal Education Commission
                Award ID: KJQN201800403
                This work was supported by the China Postdoctoral Science Foundation funded project (No. 2018M633630XB) and the Science and Technology Research Program of Chongqing Municipal Education Commission (Grant No. KJQN201800403). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Internal Medicine
                Nephrology

                bile acids,end-stage renal disease,dyslipidemia,targeted metabolomics,uplc-ms/ms

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