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

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.

Quantifying the impact of gut microbiota on inflammation and hypertensive organ damage

“…38 SCFA have been shown to have anti-inflammatory properties in several cell types 39-42 , which could contribute to the lessened damage in COL mice, since only mice harboring microbiota have significant SCFA production within the gastrointestinal tract (Figure 5C). Our results are highly compatible with previous studies showing that GF status exacerbates kidney damage in the context of IRI 43 and adenine-induced chronic kidney disease 20, 44 .…”

“…Perivascular fibrosis analyzed by Masson’s trichrome staining was accentuated in GF mice but not statistically different between the groups using two-way ANOVA; although when comparing the relative increase from sham to HTN, there was a significant difference between GF and COL (Supplemental Figure S3E). Similar to what was previously shown 20 , GF mice tended to have lower baseline values for several damage markers when comparing sham-treated GF and COL mice. Overall, renal pathology upon HTN induction was greater in GF mice when compared to their COL littermates.…”

The faecal metabolome in COVID-19 patients is altered and associated with clinical features and gut microbes

“…Therefore, a reduction in faecal purine metabolites may result from increasing demands for nucleic acids to repair the intestinal epithelial damage caused by SARS-CoV-2 infection. On the other hand, as the gut microbiota can produce and release large quantities of purines [ 30 ], the reduction in faecal purine metabolites may also be related to alterations in the gut microbiota. Consistent with this phenomenon, our results revealed positive correlations between several COVID-19-depleted microbes and purine metabolites, such as between Anaerostipes and Faecalibacterium and hypoxanthine and between Aspergillus tritici and inosine.…”

Intestinal microbiota dysbiosis in acute kidney injury: novel insights into mechanisms and promising therapeutic strategies

“…The intestinal microbiota composition of humans changes continuously over the life of the host, based on lifestyle, including eating habits, age, administration of antibiotics, and presence or absence of diseases [ 16 ]. The balance of the intestinal microbiota is essential for the integrity of the intestinal epithelial barrier [ 17 ], executing energy metabolism [ 18 , 19 ], and regulating immune health [ 20 ]. It also promotes the maturation of the intricate enteric nervous system (ENS) [ 21 ].…”