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

1
Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
2
Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
3
Institute for Advanced Biosciences, Keio University, Tsuruoka 997-0052, Japan
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 to whom correspondence should be addressed.
Toxins 2020, 12(9), 547; https://doi.org/10.3390/toxins12090547
Received: 16 July 2020 / Revised: 21 August 2020 / Accepted: 24 August 2020 / Published: 26 August 2020
(This article belongs to the Special Issue Gut Microbiota Dynamics and Uremic Toxins)
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. View Full-Text
Keywords: microbiota; uremic toxins; xanthine dehydrogenase; xanthine oxidase; uric acids; chronic kidney disease; gut-kidney axis; IL-17; Th17 microbiota; uremic toxins; xanthine dehydrogenase; xanthine oxidase; uric acids; chronic kidney disease; gut-kidney axis; IL-17; Th17
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Mishima, E.; Ichijo, M.; Kawabe, T.; Kikuchi, K.; Akiyama, Y.; Toyohara, T.; Suzuki, T.; Suzuki, C.; Asao, A.; Ishii, N.; Fukuda, S.; Abe, T. Germ-Free Conditions Modulate Host Purine Metabolism, Exacerbating Adenine-Induced Kidney Damage. Toxins 2020, 12, 547.

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