TY - JOUR
T1 - Gut–kidney axis on chip for studying effects of antibiotics on risk of hemolytic uremic syndrome by shiga toxin-producing escherichia coli
AU - Lee, Yugyeong
AU - Kim, Min Hyeok
AU - Alves, David Rodrigues
AU - Kim, Sejoong
AU - Lee, Luke P.
AU - Sung, Jong Hwan
AU - Park, Sungsu
N1 - 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.
PY - 2021/11
Y1 - 2021/11
N2 - 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.
AB - 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.
KW - Antibiotics
KW - Escherichia coli infection
KW - Hemolytic–uremic syndrome (HUS)
KW - Multi-organ-on-a-chip
KW - Shiga toxin
UR - http://www.scopus.com/inward/record.url?scp=85119114995&partnerID=8YFLogxK
U2 - 10.3390/toxins13110775
DO - 10.3390/toxins13110775
M3 - Article
C2 - 34822559
AN - SCOPUS:85119114995
SN - 2072-6651
VL - 13
JO - Toxins
JF - Toxins
IS - 11
M1 - 775
ER -