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Remote effects of kidney drug transporter OAT1 on gut microbiome composition and urate homeostasis
Vladimir S. Ermakov, … , Jeffry C. Granados, Sanjay K. Nigam
Vladimir S. Ermakov, … , Jeffry C. Granados, Sanjay K. Nigam
Published November 8, 2023
Citation Information: JCI Insight. 2023;8(21):e172341. https://doi.org/10.1172/jci.insight.172341.
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Research Article Nephrology

Remote effects of kidney drug transporter OAT1 on gut microbiome composition and urate homeostasis

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Abstract

The organic anion transporter OAT1 (SLC22A6, originally identified as NKT) is a multispecific transporter responsible for the elimination by the kidney of small organic anions that derive from the gut microbiome. Many are uremic toxins associated with chronic kidney disease (CKD). OAT1 is among a group of “drug” transporters that act as hubs in a large homeostatic network regulating interorgan and interorganismal communication via small molecules. The Remote Sensing and Signaling Theory predicts that genetic deletion of such a key hub in the network results in compensatory interorganismal communication (e.g., host-gut microbe dynamics). Recent metabolomics data from Oat1-KO mice indicate that some of the most highly affected metabolites derive from bacterial tyrosine, tryptophan, purine, and fatty acid metabolism. Functional metagenomic analysis of fecal 16S amplicon and whole-genome sequencing revealed that loss of OAT1 was impressively associated with microbial pathways regulating production of urate, gut-derived p-cresol, tryptophan derivatives, and fatty acids. Certain changes, such as alterations in gut microbiome urate metabolism, appear compensatory. Thus, Oat1 in the kidney appears to mediate remote interorganismal communication by regulating the gut microbiome composition and metabolic capability. Since OAT1 function in the proximal tubule is substantially affected in CKD, our results may shed light on the associated alterations in gut-microbiome dynamics.

Authors

Vladimir S. Ermakov, Jeffry C. Granados, Sanjay K. Nigam

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Figure 2

Beta diversity analysis reveals compositional differences between the Oat1-KO and WT gut microbiomes.

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Beta diversity analysis reveals compositional differences between the Oa...
(A) Venn diagram of OTUs assigned to Oat1-KO and WT samples (n = 9 each). (B) Principal coordinate analysis (PCoA) based on Bray-Curtis distances. The 95% CI ellipses are included for both groups. PC1 and PC2 account for 61% of variability in the species between the groups. (C) Biplot based on Deicode, a modified Aitchison distance calculation. Arrows represent the top 8 species that contribute to the variability in beta diversity. (D) Analysis of Compositions of Microbiomes (ANCOM) volcano plot of the Oat1-KO and WT OTUs. Features above a W statistic of 708 were deemed significant. Values colored blue represent features significantly increased in the WT, and those colored red represent features significantly elevated in the Oat1 KO. Clr is the centered log-ratio of the KO with respect to WT. Thirty features were found to be significantly altered between the 2 groups, with many of the features belonging to the family Muribaculaceae. Members belonging to Alistipes and Akkermansia were elevated in the WT. Abundance of archaea was not measured. (E) Microbial differential ranks estimated from multinomial regression with Prevotellacae, Turicibacter, Lactobacillus, and Lachnospiraceae highlighted. The y axis represents the log-ratio of abundance between KO and WT samples, and the x axis numerically orders the ranks of each taxon in the analysis; ranks further down the x axis represent greater abundance in WT microbiomes, with respect to other taxa. Features belonging to Turicibacter appear to constitute a greater proportion of the WT microbiomes when compared with the Oat1 KO, while Prevotellacae constitute a greater proportion of the Oat1-KO microbiomes. Lactobacillus appears to make up a greater proportion of the Oat1-KO microbiomes. Lachnospiraceae does not favor either genotype.

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