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      Germ-Free Conditions Modulate Host Purine Metabolism, Exacerbating Adenine-Induced Kidney Damage

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          Abstract

          Alterations in microbiota are known to affect kidney disease conditions. We have previously shown that germ-free conditions exacerbated adenine-induced kidney damage in mice; however, the mechanism by which this occurs has not been elucidated. To explore this mechanism, we examined the influence of germ-free conditions on purine metabolism and renal immune responses involved in the kidney damage. Germ-free mice showed higher expression levels of purine-metabolizing enzymes such as xanthine dehydrogenase, which converts adenine to a nephrotoxic byproduct 2,8-dihydroxyadenine (2,8-DHA). The germ-free mice also showed increased urinary excretion of allantoin, indicating enhanced purine metabolism. Metabolome analysis demonstrated marked differences in the purine metabolite levels in the feces of germ-free mice and mice with microbiota. Furthermore, unlike the germ-free condition, antibiotic treatment did not increase the expression of purine-metabolizing enzymes or exacerbate adenine-induced kidney damage. Considering renal immune responses, the germ-free mice displayed an absence of renal IL-17A expression. However, the adenine-induced kidney damage in wild-type mice was comparable to that in IL-17A-deficient mice, suggesting that IL-17A does not play a major role in the disease condition. Our results suggest that the enhanced host purine metabolism in the germ-free mice potentially promotes the conversion of the administered adenine into 2,8-DHA, resulting in exacerbated kidney damage. This further suggests a role of the microbiota in regulating host purine metabolism.

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          The gut microbiota and the brain–gut–kidney axis in hypertension and chronic kidney disease

          Crosstalk between the gut microbiota and the host has attracted considerable attention owing to its involvement in diverse diseases. Chronic kidney disease (CKD) is commonly associated with hypertension and is characterized by immune dysregulation, metabolic disorder and sympathetic activation, which are all linked to gut dysbiosis and altered host-microbiota crosstalk. In this Review, we discuss the complex interplay between the brain, the gut, the microbiota and the kidney in CKD and hypertension and explain our brain-gut-kidney axis hypothesis for the pathogenesis of these diseases. Consideration of the role of the brain-gut-kidney axis in the maintenance of normal homeostasis and of dysregulation of this axis in CKD and hypertension could lead to the identification of novel therapeutic targets. In addition, the discovery of unique microbial communities and their associated metabolites and the elucidation of brain-gut-kidney signalling are likely to fill fundamental knowledge gaps leading to innovative research, clinical trials and treatments for CKD and hypertension.
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            Gut Bacteria Products Prevent AKI Induced by Ischemia-Reperfusion.

            Short-chain fatty acids (SCFAs) are fermentation end products produced by the intestinal microbiota and have anti-inflammatory and histone deacetylase-inhibiting properties. Recently, a dual relationship between the intestine and kidneys has been unraveled. Therefore, we evaluated the role of SCFA in an AKI model in which the inflammatory process has a detrimental role. We observed that therapy with the three main SCFAs (acetate, propionate, and butyrate) improved renal dysfunction caused by injury. This protection was associated with low levels of local and systemic inflammation, oxidative cellular stress, cell infiltration/activation, and apoptosis. However, it was also associated with an increase in autophagy. Moreover, SCFAs inhibited histone deacetylase activity and modulated the expression levels of enzymes involved in chromatin modification. In vitro analyses showed that SCFAs modulated the inflammatory process, decreasing the maturation of dendritic cells and inhibiting the capacity of these cells to induce CD4(+) and CD8(+) T cell proliferation. Furthermore, SCFAs ameliorated the effects of hypoxia in kidney epithelial cells by improving mitochondrial biogenesis. Notably, mice treated with acetate-producing bacteria also had better outcomes after AKI. Thus, we demonstrate that SCFAs improve organ function and viability after an injury through modulation of the inflammatory process, most likely via epigenetic modification.
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              Gut microbiome-derived phenyl sulfate contributes to albuminuria in diabetic kidney disease

              Diabetic kidney disease is a major cause of renal failure that urgently necessitates a breakthrough in disease management. Here we show using untargeted metabolomics that levels of phenyl sulfate, a gut microbiota-derived metabolite, increase with the progression of diabetes in rats overexpressing human uremic toxin transporter SLCO4C1 in the kidney, and are decreased in rats with limited proteinuria. In experimental models of diabetes, phenyl sulfate administration induces albuminuria and podocyte damage. In a diabetic patient cohort, phenyl sulfate levels significantly correlate with basal and predicted 2-year progression of albuminuria in patients with microalbuminuria. Inhibition of tyrosine phenol-lyase, a bacterial enzyme responsible for the synthesis of phenol from dietary tyrosine before it is metabolized into phenyl sulfate in the liver, reduces albuminuria in diabetic mice. Together, our results suggest that phenyl sulfate contributes to albuminuria and could be used as a disease marker and future therapeutic target in diabetic kidney disease.
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                Author and article information

                Journal
                Toxins (Basel)
                Toxins (Basel)
                toxins
                Toxins
                MDPI
                2072-6651
                26 August 2020
                September 2020
                : 12
                : 9
                : 547
                Affiliations
                [1 ]Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan; eikan@ 123456med.tohoku.ac.jp (E.M.); mariko.ichi@ 123456med.tohoku.ac.jp (M.I.); koichikikuchi@ 123456med.tohoku.ac.jp (K.K.); yukako.akiyama@ 123456med.tohoku.ac.jp (Y.A.); toyohara@ 123456med.tohoku.ac.jp (T.T.); suzuki2i@ 123456med.tohoku.ac.jp (T.S.); chitose@ 123456med.tohoku.ac.jp (C.S.)
                [2 ]Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan; kawabet@ 123456med.tohoku.ac.jp (T.K.); aasao@ 123456med.tohoku.ac.jp (A.A.); ishiin@ 123456med.tohoku.ac.jp (N.I.)
                [3 ]Institute for Advanced Biosciences, Keio University, Tsuruoka 997-0052, Japan; sfukuda@ 123456sfc.keio.ac.jp
                [4 ]Intestinal Microbiota Project, Kanagawa Institute of Industrial Science and Technology, Kawasaki 210-0821, Japan
                [5 ]Transborder Medical Research Center, University of Tsukuba, Tsukuba 305-8575, Japan
                [6 ]Division of Medical Science, Tohoku University Graduate School of Biomedical Engineering, Sendai 980-8574, Japan
                [7 ]Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
                Author notes
                [* ]Correspondence: takaabe@ 123456med.tohoku.ac.jp ; Tel.: +81-22-717-7163; Fax: +81-22-717-7168
                Author information
                https://orcid.org/0000-0002-3706-2745
                https://orcid.org/0000-0001-7655-3005
                https://orcid.org/0000-0001-5161-9880
                Article
                toxins-12-00547
                10.3390/toxins12090547
                7551802
                32859011
                f648709b-21c4-4a8f-bdde-33bc05890b33
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 16 July 2020
                : 24 August 2020
                Categories
                Article

                Molecular medicine
                microbiota,uremic toxins,xanthine dehydrogenase,xanthine oxidase,uric acids,chronic kidney disease,gut-kidney axis,il-17,th17

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