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.
Highlights
Recent evidence has highlighted the importance of gut microbiota in the pathophysiology of kidney diseases and proposed a relationship between the gut and kidney, named the gut-kidney axis [1,2]
When excessive adenine is administered, it is converted into 2,8-DHA by xanthine dehydrogenase (XDH), which converts hypoxanthine into uric acid (Figure 1a,b)
To examine effect of microbiota on the host purine microbiota host purine metabolism, we evaluated thethe expression levels of purine metabolizing metabolism, evaluated the expression levelsdiet of purine enzymes and between enzymes andwe allantoin, between
Summary
Recent evidence has highlighted the importance of gut microbiota in the pathophysiology of kidney diseases and proposed a relationship between the gut and kidney, named the gut-kidney axis [1,2]. Owing to the various roles played by the microbiota, its depletion either by germ-free conditions or by treatment with antibiotics can influence every kidney disease differently. The extent of the influence of microbiota on kidney diseases appears to vary depending on the model used and methods of microbial depletion (germ-free condition or antibiotic treatment). The alteration of the host purine metabolism by loss of microbiota may contribute to the more severe adenine-induced kidney damage in the GF mice. To clarify this causative mechanism, we examined: (i) the effect of microbiota on the host purine metabolism; and (ii) the influence of loss of microbiota on the kidney damage and renal immune response in the adenine-induced
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