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An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment
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Remote effects of kidney drug transporter OAT1 on gut microbiome composition and urate homeostasis

Vladimir S Ermakov1, Jeffry C Granados2, Sanjay K Nigam3,4

  • 1Department of Biology.

JCI Insight
|November 8, 2023
PubMed

Insights

The organic anion transporter OAT1 (SLC22A6) in the kidney regulates gut microbiome metabolism. Genetic deletion of OAT1 alters microbial pathways, suggesting a role in host-gut communication and chronic kidney disease (CKD).

Area of Science:

  • Nephrology
  • Microbiology
  • Systems Biology

Background:

  • The organic anion transporter 1 (OAT1, SLC22A6) eliminates small organic anions, including uremic toxins, from the kidney.
  • OAT1 functions as a hub in a homeostatic network regulating interorgan communication via small molecules.
  • The Remote Sensing and Signaling Theory predicts compensatory interorganismal communication upon deletion of key network hubs.

Purpose of the Study:

  • To investigate the impact of OAT1 genetic deletion on host-gut microbe dynamics.
  • To explore the role of OAT1 in mediating remote interorganismal communication.
  • To understand how OAT1 dysfunction in chronic kidney disease (CKD) affects gut microbiome metabolism.

Main Methods:

  • Metabolomic analysis of Oat1-knockout (KO) mice.
  • Functional metagenomic analysis of fecal 16S amplicon and whole-genome sequencing.
  • Analysis of bacterial tyrosine, tryptophan, purine, and fatty acid metabolism.

Main Results:

  • Genetic deletion of OAT1 significantly altered metabolites derived from bacterial tyrosine, tryptophan, purine, and fatty acid metabolism.
  • Loss of OAT1 was associated with microbial pathways regulating urate, p-cresol, tryptophan derivatives, and fatty acid production.
  • Alterations in gut microbiome urate metabolism suggested a compensatory response.

Conclusions:

  • OAT1 in the kidney mediates remote interorganismal communication by regulating gut microbiome composition and metabolic activity.
  • OAT1 dysfunction, prevalent in CKD, may contribute to altered gut-microbiome dynamics observed in kidney disease.
  • These findings highlight OAT1's crucial role in maintaining host-gut homeostasis.
Keywords:
Chronic kidney diseaseEpithelial transport of ions and waterHomeostasisNephrology

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