Germ-Free Conditions Modulate Host Purine Metabolism, Exacerbating Adenine-Induced Kidney Damage.
Germ-Free Conditions Modulate Host Purine Metabolism, Exacerbating Adenine-Induced Kidney Damage.
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DOI：
10.3390/toxins12090547
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发表时间：
2020-08-26
期刊：
影响因子：
4.2
通讯作者：
Abe T
中科院分区：
文献类型：
--
作者：
Mishima E;Ichijo M;Kawabe T;Kikuchi K;Akiyama Y;Toyohara T;Suzuki T;Suzuki C;Asao A;Ishii N;Fukuda S;Abe T
已知微生物群的改变会影响肾脏疾病。我们以前已经表明，无菌条件下加剧腺嘌呤诱导的小鼠肾损伤;然而，发生这种情况的机制尚未阐明。为了探讨这一机制，我们研究了无菌条件对嘌呤代谢和肾脏免疫反应的影响，这些反应与肾脏损伤有关。无菌小鼠表现出更高的嘌呤代谢酶表达水平，如黄嘌呤脱氢酶，它将腺嘌呤转化为肾毒性副产物2，8-二羟基腺嘌呤（2，8-DHA）。无菌小鼠还显示尿中尿囊素排泄增加，表明嘌呤代谢增强。代谢物组分析表明，无菌小鼠和有微生物群小鼠粪便中嘌呤代谢物水平存在显著差异。此外，与无菌条件不同，抗生素治疗不会增加嘌呤代谢酶的表达或加剧腺嘌呤诱导的肾损伤。考虑到肾免疫应答，无菌小鼠显示肾IL-17 A表达缺失。然而，野生型小鼠中腺嘌呤诱导的肾损伤与IL-17 A缺陷小鼠中的肾损伤相当，表明IL-17 A在疾病状况中不起主要作用。我们的研究结果表明，在无菌小鼠中，宿主嘌呤代谢的增强可能会促进给予的腺嘌呤转化为2，8-DHA，导致肾损伤加重。这进一步表明微生物群在调节宿主嘌呤代谢中的作用。
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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DOI：
10.1016/j.clim.2016.04.010
发表时间：
2017-12
期刊：
Clinical immunology (Orlando, Fla.)
影响因子：
--
作者：
Koga T;Ichinose K;Tsokos GC
通讯作者：
Tsokos GC
影响因子：
13.6
作者：
Li, Yan Jun;Chen, Xiaochen;Wu, Huiling
通讯作者：
Wu, Huiling
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
3.7
作者：
Mishima E;Jinno D;Akiyama Y;Itoh K;Nankumo S;Shima H;Kikuchi K;Takeuchi Y;Elkordy A;Suzuki T;Niizuma K;Ito S;Tomioka Y;Abe T
通讯作者：
Abe T
影响因子：
4.2
作者：
Koppe L;Fouque D;Soulage CO
通讯作者：
Soulage CO