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

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 5

Treatment and genotype overlap in their impact on 40 circulating metabolites.

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Treatment and genotype overlap in their impact on 40 circulating metabol...
(A) Of the 103 metabolites affected by loss of Oat1 and the 162 metabolites affected by microbiome depletion, 40 metabolites overlapped. (B) The 40 metabolites belonged to 19 unique subpathways, with 11 belonging to the Benzoate Metabolism subpathway. (C) The levels of the 40 metabolites are shown, with the scaled intensity of each metabolite being scaled to range from 0 to 3 for improved visualization, though there are some metabolites that have higher scaled intensities. The individual groups of mice are shown on the y axis, and the individual metabolites are shown on the x axis. KOU, Oat1-KO untreated; KOT, Oat1-KO treated; WTU, WT untreated; WTT, WT treated. (D) Linear discriminant analysis (LDA) shows clear separation between the 4 groups of metabolites altered by both loss of Oat1 and microbiome depletion. Thirty-one of the 40 overlapping metabolites have available chemical structures (Group 1, 5 metabolites with structures; Group 2, 17 metabolites with structures; Group 3, 3 metabolites with structures; Group 4, 6 metabolites with structures). We were unable to find clearcut information for 2-amino–p-cresol sulfate, N2-acetyl, N6,N6-dimethyllysine, 4-allylcatechol sulfate, 4-ethylcatechol sulfate, 4-methoxyphenol sulfate, N-acetylhomocitrulline, succinoyltaurine, 3-methoxycatechol sulfate (2), or 1-methyl-5-imidazolelactate. (E) Thirteen of the 22 compounds in Group 2 (elevated by KO and decreased by microbiome depletion) were sulfated. Only 1 other compound in the other groups was sulfated. (F) Number of aromatic bonds was one of the features that most separates the 4 groups of compounds affected by Oat1 KO and microbiome depletion. Group 2 had higher numbers of aromatic bonds than the other 3 groups.