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The kidney drug transporter OAT1 regulates gut microbiome–dependent host metabolism
Jeffry C. Granados, … , Geoffrey Chang, Sanjay K. Nigam
Jeffry C. Granados, … , Geoffrey Chang, Sanjay K. Nigam
Published January 24, 2023
Citation Information: JCI Insight. 2023;8(2):e160437. https://doi.org/10.1172/jci.insight.160437.
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Research Article Metabolism Nephrology

The kidney drug transporter OAT1 regulates gut microbiome–dependent host metabolism

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Abstract

Organic anion transporter 1 (OAT1/SLC22A6, NKT) is a multispecific drug transporter in the kidney with numerous substrates, including pharmaceuticals, endogenous metabolites, natural products, and uremic toxins. Here, we show that OAT1 regulates levels of gut microbiome–derived metabolites. We depleted the gut microbiome of Oat1-KO and WT mice and performed metabolomics to analyze the effects of genotype (KO versus WT) and microbiome depletion. OAT1 is an in vivo intermediary between the host and the microbes, with 40 of the 162 metabolites dependent on the gut microbiome also impacted by loss of Oat1. Chemoinformatic analysis revealed that the altered metabolites (e.g., indoxyl sulfate, p-cresol sulfate, deoxycholate) had more ring structures and sulfate groups. This indicates a pathway from gut microbes to liver phase II metabolism, to renal OAT1–mediated transport. The idea that multiple gut-derived metabolites directly interact with OAT1 was confirmed by in vitro transport and magnetic bead binding assays. We show that gut microbiome–derived metabolites dependent on OAT1 are impacted in a chronic kidney disease (CKD) model and human drug-metabolite interactions. Consistent with the Remote Sensing and Signaling Theory, our results support the view that drug transporters (e.g., OAT1, OAT3, OATP1B1, OATP1B3, MRP2, MRP4, ABCG2) play a central role in regulating gut microbe–dependent metabolism, as well as interorganismal communication between the host and microbiome.

Authors

Jeffry C. Granados, Vladimir Ermakov, Koustav Maity, David R. Vera, Geoffrey Chang, Sanjay K. Nigam

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Figure 1

Workflow of experiment and schematic of gut-derived metabolite transport by OAT1.

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Workflow of experiment and schematic of gut-derived metabolite transport...
Oat1-KO and WT mice were treated with an antibiotic cocktail to deplete the gut microbes. We then assessed the resulting changes on the serum metabolome and determined that many metabolites produced by commensal bacteria in the gut enter the blood stream, where their systemic levels are regulated in vivo by OAT1 in the kidney.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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