Microbiome modulation after severe acute kidney injury accelerates functional recovery and decreases kidney fibrosis

Sepideh Gharaie, Kyungho Lee, Andrea M. Newman-Rivera, Jiaojiao Xu, Shishir Kumar Patel, Mahta Gooya, Lois J. Arend, Dominic S. Raj, Jennifer Pluznick, Chirag Parikh, Sanjeev Noel, Hamid Rabb

Research output: Contribution to journalArticlepeer-review

Abstract

Targeting gut microbiota has shown promise to prevent experimental acute kidney injury (AKI). However, this has not been studied in relation to accelerating recovery and preventing fibrosis. Here, we found that modifying gut microbiota with an antibiotic administered after severe ischemic kidney injury in mice, particularly with amoxicillin, accelerated recovery. These indices of recovery included increased glomerular filtration rate, diminution of kidney fibrosis, and reduction of kidney profibrotic gene expression. Amoxicillin was found to increase stool Alistipes, Odoribacter and Stomatobaculum species while significantly depleting Holdemanella and Anaeroplasma. Specifically, amoxicillin treatment reduced kidney CD4+T cells, interleukin (IL)-17 +CD4+T cells, and tumor necrosis factor-α double negative T cells while it increased CD8+T cells and PD1+CD8+T cells. Amoxicillin also increased gut lamina propria CD4+T cells while decreasing CD8+T and IL-17+CD4+T cells. Amoxicillin did not accelerate repair in germ-free or CD8-deficient mice, demonstrating microbiome and CD8+T lymphocytes dependence for amoxicillin protective effects. However, amoxicillin remained effective in CD4-deficient mice. Fecal microbiota transplantation from amoxicillin-treated to germ-free mice reduced kidney fibrosis and increased Foxp3+CD8+T cells. Amoxicillin pre-treatment protected mice against kidney bilateral ischemia reperfusion injury but not cisplatin-induced AKI. Thus, modification of gut bacteria with amoxicillin after severe ischemic AKI is a promising novel therapeutic approach to accelerate recovery of kidney function and mitigate the progression of AKI to chronic kidney disease.

Original languageEnglish (US)
Pages (from-to)470-491
Number of pages22
JournalKidney international
Volume104
Issue number3
DOIs
StatePublished - Sep 2023

Keywords

  • acute kidney injury
  • amoxicillin
  • glomerular filtration rate
  • gut bacteria
  • kidney repair
  • microbiome

ASJC Scopus subject areas

  • Nephrology

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