Gut–kidney axis on chip for studying effects of antibiotics on risk of hemolytic uremic syndrome by shiga toxin-producing escherichia coli

Yugyeong Lee, Min Hyeok Kim, David Rodrigues Alves, Sejoong Kim, Luke P. Lee, Jong Hwan Sung, Sungsu Park

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Shiga toxin-producing Escherichia coli (STEC) infects humans by colonizing the large intestine, and causes kidney damage by secreting Shiga toxins (Stxs). The increased secretion of Shiga toxin 2 (Stx2) by some antibiotics, such as ciprofloxacin (CIP), increases the risk of hemolytic–uremic syndrome (HUS), which can be life-threatening. However, previous studies evaluating this relationship have been conflicting, owing to the low frequency of EHEC infection, very small number of patients, and lack of an appropriate animal model. In this study, we developed gut–kidney axis (GKA) on chip for co-culturing gut (Caco-2) and kidney (HKC-8) cells, and observed both STEC O157:H7 (O157) infection and Stx intoxication in the gut and kidney cells on the chip, respectively. Without any antibiotic treatment, O157 killed both gut and kidney cells in GKA on the chip. CIP treatment reduced O157 infection in the gut cells, but increased Stx2-induced damage in the kidney cells, whereas the gentamycin treatment reduced both O157 infection in the gut cells and Stx2-induced damage in the kidney cells. This is the first report to recapitulate a clinically relevant situation, i.e., that CIP treatment causes more damage than gentamicin treatment. These results suggest that GKA on chip is very useful for simultaneous observation of O157 infections and Stx2 poisoning in gut and kidney cells, making it suitable for studying the effects of antibiotics on the risk of HUS.

Original languageEnglish
Article number775
JournalToxins
Volume13
Issue number11
DOIs
StatePublished - Nov 2021

Bibliographical note

Funding Information:
Funding: This work is equally supported by both technology Innovation Program (Development of disease models based on 3D microenvironmental platform mimicking multiple organs and evaluation of drug efficacy) (20008413, 20008414) funded by the Ministry of Trade, Industry & Energy (MOTIE) in Korea and the ICT Creative Consilience program (IITP-2020-0-01821) supervised by the IITP (Institute for Information & communications Technology Planning & Evaluation) funded by MSIT (Ministry of Science and ICT) in Korea. This work was also supported by National Research Foundation of Korea, under Grant (Basic Research Lab, 2019R1A4A1025958).

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Antibiotics
  • Escherichia coli infection
  • Hemolytic–uremic syndrome (HUS)
  • Multi-organ-on-a-chip
  • Shiga toxin

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