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
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Research Article Nephrology

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

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 4

16S and WGS pathway analyses reveal microbial pathways enriched in the Oat1 KO.

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16S and WGS pathway analyses reveal microbial pathways enriched in the O...
(A) Bar chart of the predicted MetaCyc pathways from the 16S PICRUSt2 analysis of Oat1-KO and WT mice (n = 9 each). Pathways enriched in the Oat1 KO are represented by a positive log fold-change (LogFC). A voom differential expression analysis was performed to generate fold-changes and P values. P values were adjusted for multiple comparisons using the Benjamini-Hochberg correction. Of 346 total detected MetaCyc pathways, those charted had an Padj < 0.1. Pathways annotated with an asterisk represent those with an Padj < 0.05. (B) Tyrosine degradation, tryptophan metabolism, and LCFA synthesis pathways summarizing the abundance of enzymes reconstructed from WGS metagenome. Enzymes with a > 2-fold increase in abundance in the KO were annotated with a dark green arrow. Integer values inside the arrows represent the difference in hits an enzyme had in the KO versus WT. Tyrosine degradation, tryptophan metabolism, and LCFA synthesis are favored in the Oat1-KO microbiomes. (C) Volcano plot of gene enrichment from KEGG ontology annotated genes in PICRUSt2. Red points highlight genes present in the adjacent pathway diagram (B). Positive log fold-changes reflect an increased abundance of a gene in the Oat1 KO. Both WGS and 16S pathway analyses reflect increases in tyrosine degradation, tryptophan metabolism, and LCFA production in the Oat1 KO. Fold-change and P values were generated using voom. (D) Serum abundance of metabolites from Oat1-KO (n = 4) mice were correlated with MetaCyc pathways detected from the 16S PICRUSt2 analysis. Cells in heatmap are annotated with a Pearson’s R correlation coefficient. Serum microbe-derived metabolites correlate well with associated pathway enrichment in the microbiome. Therefore, pathways in the microbiome may have a predictive value for serum concentrations of gut-derived compounds.